CADTH Reimbursement Review

Avacopan (Tavneos)

Sponsor: Otsuka Canada Pharmaceutical Inc.

Therapeutic area: Antineutrophil cytoplasmic autoantibody–associated vasculitis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; GPA = granulomatosis with polyangiitis; MPA = microscopic polyangiitis; NOC = Notice of Compliance.

Sources: Sponsor’s submission package for review of avacopan;¹ Tavneos product monograph.²

Introduction

Antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (ANCA-AV) is a group of inflammatory disorders affecting mostly small- to medium-sized blood vessels that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and other vasculitides.³ Patients often initially present with nonspecific symptoms that progress to involve the ears, nose, and throat; the respiratory system; the kidneys; the skin; or the nervous system.⁴ ANCA-AV can vary from non-life-threatening to severe disease —major organs are affected in the latter — and from limited disease (i.e., affecting a single organ) to systemic disease.⁵ As defined by the 2012 Chapel Hill Consensus Conference, GPA causes necrotizing granulomatous inflammation, often involving the lungs and kidneys, and more commonly leads to ear, nose, and throat manifestations than MPA does.^3,6,7 MPA also causes necrotizing inflammation, usually without immune deposits, often affecting the kidneys and lungs as well.^6,7 Limited information exists about the incidence and prevalence of GPA and MPA in Canada. According to the clinical expert consulted by CADTH, the total incidence of GPA and MPA in Canada is estimated to be 10 to 50 cases per million people per year and their prevalence is estimated to be between 75 and 300 cases per million people, or approximately 1,700 to 2,500 total patients living in Canada. Patients with ANCA-AV are at risk of increased morbidity and mortality, largely due to the disease causing irreversible inflammatory organ damage and the consequences of long-term and often high-dose immunosuppressant drugs and glucocorticoids.⁵ It is expected that at least 80% of untreated patients will die within 1 year of diagnosis. Even with treatment, patients are at increased risk of developing malignancies, serious infection, and end-stage kidney disease (ESKD), largely due to progressive disease and/or as a consequence of treatment.^5,8

GPA and MPA have been treated in the same manner, which consists of 2 main components: induction of remission and maintenance of remission to prevent relapse.⁵ According to the 2020 CanVasc consensus recommendations for the management of ANCA-AV, IV methylprednisolone pulses are recommended for patients with life-threatening ANCA-AV, followed by oral prednisone for those with severe disease.⁹ Patients with life-threatening disease are given cyclophosphamide or rituximab for a minimum of 3 to 6 months, with glucocorticoids, to induce remission.^7,9 Cyclophosphamide and rituximab have shown similar efficacy for inducing remission;^10-13 however, cyclophosphamide has been associated with fertility issues, alopecia, and malignancies, and rituximab may be preferred for specific patients (e.g., children, young adults concerned with infertility, and older adults).^5,14 Once patients begin induction therapy with cyclophosphamide or rituximab, tapering of glucocorticoids should begin within 2 weeks to reduce exposure to glucocorticoids and their associated risks.⁵ Once remission is achieved, patients should be transitioned to maintenance therapy, preferably rituximab (or azathioprine or methotrexate when rituximab cannot be used).^7,9 It has been emphasized in the literature and by the clinical expert consulted by CADTH that maintenance treatment should last for at least 2 years and that continued treatment should be considered for patients in high-risk groups (e.g., those with anti-PR3 ANCA, prior relapse, pulmonary involvement, or upper respiratory tract involvement).^5,9,15-18 The CanVasc recommendations state that the optimal duration for low-dose glucocorticoid use once remission is achieved is currently unknown.⁹

Avacopan (Tavneos) is a C5a receptor antagonist indicated for the adjunctive treatment of adult patients with severe active ANCA-AV (GPA and MPA) in combination with standard background therapy, including glucocorticoids.² Avacopan does not eliminate glucocorticoid use.² The recommended dosage is 30 mg (3 oral capsules of 10 mg each) taken twice daily.² The Health Canada product monograph did not specify the duration of treatment with avacopan.

The objective of this report is to perform a systematic review of the beneficial and harmful effects of avacopan 30 mg (3 oral capsules of 10 mg each) twice daily for the adjunctive treatment of adult patients with severe active ANCA-AV (GPA and MPA) in combination with standard background therapy, including glucocorticoids.

Stakeholder Perspectives

The information in this section is a summary of the input provided by 1 patient group that responded to CADTH’s call for patient input, 1 clinical expert consulted by CADTH, 1 clinical group that responded to CADTH’s call for clinician input, and the Canadian public drug programs.

Patient Input

CADTH received 1 patient group submission from Vasculitis Foundation Canada, an organization that aims to increase disease awareness and research support for all forms of vasculitis. Vasculitis Foundation Canada invited its mailing list subscribers to complete an online survey and received input from 46 patients (35 with GPA and 11 with MPA) living in Canada and the US who have experience using prednisone or avacopan. The patient group reported that GPA and MPA impact patients’ daily lives and that patients experience a host of physical manifestations that lead to chronic fatigue, mood swings, poor sleep, chronic infections, and stress due to fear of relapse. Patients treated with prednisone reported side effects that significantly affect quality of life, including body disfiguration, steroid-induced diabetes or hypertension, infections requiring medical care, anxiety, and depression. Vasculitis Foundation Canada reported that patients with GPA or MPA indicated a need for treatment that improves symptoms and quality of life that would also result in a reduction or elimination of the use of prednisone.

Clinician Input

Input From 1 Clinical Expert Consulted by CADTH

The clinical expert consulted by CADTH stated that patients need treatments that result in sustained remission, with limited organ damage (or better recovery from damage); limit the risk of severe infections; require less time on treatment (treatment shorter than 24 months has been associated with unacceptably high rates of relapse to date); and are safe for use in special populations (i.e., pediatric, pregnant, and older adult populations). The expert added that the disease and current ANCA-AV treatments have significant impact on patients’ health-related quality of life (HRQoL) and ability to work.

According to the clinical expert, avacopan would be used as a first-line treatment for adult patients with severe GPA or MPA in line with the patient population for the ADVOCATE trial. Although patients with the most severe forms of disease were excluded from the trial, the expert suggested that these patients may also be candidates for the drug after the disease is controlled with high-dose glucocorticoids. In practice, the expert stated that avacopan would be administered to induce remission alongside IV or oral cyclophosphamide or IV rituximab with glucocorticoids. Once remission is achieved, the clinical expert noted that patients should receive appropriate maintenance therapy, such as rituximab at month 6 and every 6 months thereafter for at least 24 months. There is currently a lack of clinical trial evidence for optimal patient management after 12 months of avacopan.

According to the expert, all adult patients with severe GPA or MPA could be treated with avacopan and it is not clear from the available evidence if any subpopulations would respond better to the drug than other patients.

The clinical expert noted that survival is the most important outcome. Other response measures include improvement of major organ disease (e.g., renal recovery, reduced use of mechanical ventilation), achievement of remission (typically assessed at month 3, then month 6), and sustained remission (at months 12, 18, and 24). The expert stated that it is also important to evaluate and limit the side effects caused by treatments. Although there are instruments to measure disease- and treatment-related changes in studies, the expert indicated that these instruments are not used in routine clinical practice.

The clinical expert stated that avacopan should be administered for 12 months, as was done in the ADVOCATE trial, and suggested that although the drug could be used for longer, there are limited data available for stopping the drug before 1 year or using it beyond that. According to the expert, discontinuing treatment should be considered if there are intolerable side effects, continual disease progression with clinical decline, or repeated relapses. In the expert’s opinion, another reason to discontinue avacopan is if it does not allow for reduced use of glucocorticoids.

Since GPA and MPA are rare diseases and require close monitoring, the clinical expert indicated that patients should be referred to a specialist with expertise in the disease area. In the clinical expert’s opinion, a rheumatologist, nephrologist, general internal medicine specialist, respirologist, or intensive care unit doctor should be able to prescribe avacopan in a hospital setting, and it was noted that restricting the prescription to only rheumatologists or nephrologists with expertise in vasculitis would likely delay treatment initiation by many weeks. However, in community clinics, the expert believed it would be reasonable to restrict access to rheumatologists or nephologists with experience treating vasculitis.

The clinical expert emphasized that treatment with avacopan should be associated with a mandate to stop or significantly decrease glucocorticoids within the first weeks of initiating avacopan; otherwise, the continued use of avacopan should be clinically justified. Given the lack of long-term data, the expert expressed uncertainty about patient management after 12 months of avacopan and about the long-term outcomes after stopping avacopan. Lastly, the clinical expert suggested that alongside the implementation of avacopan in Canada, it would be useful to set up a registry to track the drug’s use and patterns of use and to monitor safety and efficacy.

Clinician Group Input

CanVasc, a Canadian research network for vasculitis, provided input for this review. The clinician group expressed similar views to those of the clinical expert consulted by CADTH.

Drug Program Input

The drug programs described uncertainty around the following: how the ADVOCATE trial showed that avacopan could reduce the use of glucocorticoids, the possibility of aligning initiation and renewal criteria between avacopan and rituximab, and the possibility that avacopan could be used for other autoimmune diseases. The drug programs also asked questions about the patient population that could receive avacopan, the drug’s place in therapy, re-treatment after relapse, assessment of continued need for treatment, definition of refractory disease, duration of therapy, and definition of sustained remission. They also asked whether there are concerns with combining therapies for ANCA-AV.

The clinical expert consulted by CADTH agreed that many patients in the ADVOCATE trial received nonstudy glucocorticoids during the 52-week treatment period, which complicates interpretation of the results and of whether treatment with avacopan can reduce the use of glucocorticoids. According to the clinical expert, patients with active ANCA-AV, whether newly diagnosed or with relapsing disease, could be treated with avacopan as was done in the ADVOCATE trial. Regarding the place in therapy, the clinical expert stated that avacopan would be used as a first-line treatment and that standard of care treatment with immunosuppressants (i.e., IV rituximab or IV or oral cyclophosphamide) would remain the same, with the addition of glucocorticoids and/or avacopan. Based on clinical experience, the expert believed that most physicians and treating teams would be comfortable initially treating patients with standard of care immunosuppressants and glucocorticoids but that once a patient was referred to a specialist for ANCA-AV, avacopan could replace glucocorticoids. The clinical expert indicated that relapse is not common with rituximab maintenance and that if a patient relapsed, they would immediately be started on intensive treatment to reinduce remission. In most situations, the expert emphasized that patients should continue treatment for more than 1 year because — based on clinical experience — any less generally does not result in long-term sustained remission. After 1 year of avacopan treatment, the clinical expert expects that most patients would continue some form of maintenance therapy, such as rituximab or continuing with avacopan, but that it would be unlikely for a patient to receive no additional treatment after 1 year. The clinical expert indicated that it would be reasonable for a patient to continue receiving avacopan after their first relapse but that avacopan should be stopped after the second relapse and the patient should instead be treated with glucocorticoids. The expert stated that a patient may have refractory disease if no treatments work to induce remission and the disease continues to progress or that a patient may have clinical manifestations if most symptoms improve but remission is not achieved and there is still lingering disease activity despite having exhausted all standard of care treatments. The clinical expert expects avacopan to be used for 12 months, similar to the ADVOCATE trial, with the possibility of continuing the drug for longer. However, there is limited evidence for a treatment duration less than 12 months or more than 12 months, and there is uncertainty over how to manage patients after stopping avacopan. It is unclear how avacopan treatment compares to rituximab maintenance therapy, which is currently the standard. The expert typically assesses remission at 6 months and sustained remission at 12 months and every 6 months thereafter, then if the patient remains in remission at those subsequent 6 month time points, assesses if it is safe for the patient to stop maintenance therapy. The clinical expert had no concerns about interactions between the drug combinations typically used to treat ANCA-AV but noted a lack of data on the efficacy and safety of combining rituximab maintenance therapy with avacopan.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The ADVOCATE trial (N = 331) was a phase III, double-blind, randomized controlled trial designed to investigate the efficacy and safety of avacopan in patients with ANCA-AV with the aim to determine if avacopan could induce and sustain remission without chronic glucocorticoid use at levels currently used in standard of care regimens. The trial compared avacopan (30 mg twice daily, oral) to prednisone (60 mg/day tapered over 20 weeks, oral), with respective matching placebos, in addition to standard of care therapy (IV or oral cyclophosphamide followed by azathioprine, or IV rituximab without maintenance treatment), over 52 weeks with an 8-week follow-up. Patients were permitted to receive nonprotocol-specified, low-dosage oral glucocorticoids (10 mg/day or less) for the treatment of adrenal insufficiency or allergic reaction. Eligible patients included adults who had a clinical diagnosis of GPA or MPA, were ANCA positive for either anti-PR3 or antimyeloperoxidase (anti-MPO) antibodies, and had active disease at screening. Patients with limited disease or with the most severe disease (patients with alveolar hemorrhage requiring mechanical ventilation or with an estimated glomerular filtration rate [eGFR] less than 15 mL/min/1.73 m² at baseline) were not eligible. The primary outcomes were the proportions of patients who achieved disease remission at week 26 and sustained disease remission at week 52. Key secondary outcomes included glucocorticoid toxicity (Glucocorticoid Toxicity Index [GTI]), HRQoL (Short Form [36] Health Survey version 2 [SF-36v2], 5-Level EQ-5D [EQ-5D-5L], and EQ visual analogue scale [VAS]), kidney function (eGFR and urinary albumin–creatinine ratio [UACR]), systemic damage (Vasculitis Damage Index [VDI]), and the proportion of patients experiencing disease relapse. Harms and notable harms identified in the CADTH systematic review protocol were also assessed.

At baseline, the mean age of patients was 60.9 years (standard deviation [SD] = 14.5 years), more than half were male (56.5%), and most were white (84.3%). Most patients (69.4%) were newly diagnosed with ANCA-AV, and 30.6% had relapsing disease. More than half (54.8%) of patients had GPA, and 45.2% had MPA (45.2%). Less than half (43.0%) were positive for anti-PR3 antibodies, and 57.0% were positive for anti-MPO antibodies.

Efficacy Results

Efficacy results are summarized in Table 2 for the ADVOCATE trial. Survival was not assessed as an efficacy outcome in the trial but was captured as deaths in the assessment of harm outcomes. Hospitalizations were not assessed in the trial. Symptoms (e.g., fatigue) were not assessed as an efficacy outcome, but some symptoms may have been captured as harm outcomes. Only the primary outcomes of disease remission at week 26 and sustained disease remission at week 52 were controlled for multiple testing.

Disease Remission (Induction and Sustained Remission)

Based on the intention-to-treat (ITT) analyses, 72.3% (95% confidence interval [CI], 64.8% to 78.9%) of patients randomized to the avacopan group and 70.1% (95% CI, 62.5% to 77.0%) of patients randomized to the prednisone group achieved remission at week 26. The estimate of common difference in remission rates between groups was 3.4% (95% CI, –6.0% to 12.8%; noninferiority P < 0.0001; superiority P = 0.2387). Findings for the per-protocol (PP) population were similar.

At week 52, 65.7% (95% CI, 57.9% to 72.8%) of patients randomized to the avacopan group and 54.9% (95% CI, 46.9% to 62.6%) of patients randomized to the prednisone group achieved sustained remission. The estimate of common difference in sustained remission rates between groups was 12.5% (95% CI, 2.6% to 22.3%; noninferiority P < 0.0001; superiority P = 0.0066). Findings for the PP population were similar.

Renal Function (e.g., eGFR, Progression to ESKD)

For patients with renal disease at baseline (based on the Birmingham Vasculitis Activity Score [BVAS] renal component), the least squares mean (LSM) difference in change from baseline between treatment groups for eGFR was 2.9 mL/min/1.73 m² (95% CI, 0.1 mL/min/1.73 m² to 5.8 mL/min/1.73 m²) at week 26, 3.2 mL/min/1.73 m² (95% CI, 0.3 mL/min/1.73 m² to 6.1 mL/min/1.73 m²) at week 52, and ||| ||||||||||| || |||| || |||| || || ||||||||||| at week 60. Seven patients required dialysis during the trial: 3 patients (1.8%) in the avacopan group and 4 patients (2.4%) in the prednisone group.

For patients with renal disease (based on the BVAS renal component) and albuminuria (defined as a UACR of at least 10 mg/g creatinine) at baseline, the LSM difference in change from baseline between groups for UACR was 1.3 mg/g (95% CI, 1.0 mg/g to 1.6 mg/g) at week 26, 1.1 mg/g (95% CI, 0.9 mg/g to 1.5 mg/g) at week 52, and ||| |||| |||| || || || || ||||| at week 60.

Systemic Damage (Measured by VDI)

Based on the data assessed by the adjudication committee, the LSM difference in change from baseline between treatment groups for VDI score was 0.1 (95% CI, –0.1 to 0.3) at week 26, 0.0 (95% CI, –0.2 to 0.3) at week 52, and ||| |||| || |||| || |||| at week 60.

Disease Relapse (e.g., Time to Relapse or Duration of Remission, Minor Versus Major)

For patients who achieved remission at week 26 (n = 120 in the avacopan group; n = 115 in the prednisone group), 7.5% |||| || |||| || |||||| of patients in the avacopan group and 12.2% |||| || |||| || |||||| of patients in the prednisone group experienced disease relapse. The estimate of common difference in rates was –6.0% (95% CI, –14.4% to 2.4%). The hazard ratio was 0.46 (95% CI, 0.25 to 0.84) for avacopan versus prednisone. Due to the small number of patients who relapsed, the median time to relapse was not estimable and Kaplan-Meier (KM) estimates were not calculated. During the 8-week follow-up period, 3.8% of patients in the avacopan group and 4.5% of patients in the prednisone group experienced disease relapse.

Glucocorticoid Use and Related Toxicities and Safety

The LSM difference between treatment groups for the GTI Cumulative Worsening Score (GTI-CWS) was –11.0 (95% CI, –19.7 to –2.2) at week 13 and –16.8 (95% CI, –25.6 to –8.0) at week 26. The LSM difference between treatment groups for the GTI Aggregate Improvement Score (GTI-AIS) was –13.3 (95% CI, –22.2 to –4.4) at week 13 and –12.1 (95% CI, –21.1 to –3.2) at week 26.

Health-Related Quality of Life

The LSM difference in change from baseline between treatment groups for the SF-36v2 mental component summary was 1.6 (95% CI, –0.6 to 3.8) at week 26, 1.7 (95% CI, –0.5 to 3.9) at week 52, and ||| |||| || |||| || |||| at week 60. The LSM difference between treatment groups for the SF-36v2 physical component summary was 3.1 (95% CI, 1.2 to 5.0) at week 26, 2.4 (95% CI, 0.4 to 4.3) at week 52, and ||| |||| || |||| || |||| at week 60.

The LSM difference in change from baseline between treatment groups for the EQ VAS was 3.6 (95% CI, –0.1 to 7.2) at week 26, 5.9 (95% CI, 2.3 to 9.6) at week 52, and ||| |||| || |||| || |||| at week 60. The LSM difference between treatment groups for the EQ-5D-5L index score was 0.0 (95% CI, 0.0 to 0.1) at week 26, 0.1 (95% CI, 0.0 to 0.1) at week 52, and ||| |||| || || || |||| at week 60.

Harms Results

Harms results are summarized in Table 2 for the ADVOCATE trial.

Nearly all patients in the avacopan group (98.8%) and prednisone group (98.2%) experienced at least 1 treatment-emergent adverse event (TEAE). The 3 most common TEAEs in the avacopan group were nausea (23.5% avacopan versus 20.7% prednisone), peripheral edema (21.1% avacopan versus 24.4% prednisone), and headache (20.5% avacopan versus 14.0% prednisone). The 3 most common TEAEs in the prednisone group were peripheral edema, muscle spasms (22.6% prednisone versus 10.8% avacopan), and arthralgia (22.0% prednisone versus 18.7% avacopan).

Overall, 42.2% of patients in the avacopan group and 45.1% of patients in the prednisone group experienced a serious adverse event (SAE). The most common SAEs were ANCA-positive vasculitis (7.2% avacopan versus 12.2% prednisone) and pneumonia (5.4% avacopan versus 5.5% prednisone).

In total, 15.7% of patients in the avacopan group and 17.7% of patients in the prednisone group stopped treatment due to adverse events (AEs). The most common AE that led to withdrawal from treatment was ANCA-positive vasculitis (2.4% avacopan versus 4.9% prednisone); other AEs that led to withdrawal from treatment occurred at a frequency of less than 2% for either group.

Six patients died during the treatment period in the ADVOCATE trial (2 patients receiving avacopan and 4 patients receiving prednisone) and causes of death were reported by a single patient for each cause.

Notable Harms

Treatment-emergent infections were reported in 68.1% and 75.6% of patients in the avacopan and prednisone groups, respectively. Serious treatment-emergent infections were reported in 13.3% and 15.2% of patients in the avacopan and prednisone groups, respectively, of which pneumonia was the most common serious infection-related TEAE (experienced by 5.4% and 5.5% of patients in the avacopan and prednisone groups, respectively). Infections resulted in 9 patients withdrawing from the trial and 3 deaths.

Elevated alanine aminotransferase (ALT) was reported by 4% and 2% of patients in the avacopan and prednisone groups, respectively; elevated aspartate aminotransferase (AST) was reported in 2% of patients and no patients in the avacopan and prednisone groups, respectively; and elevated blood bilirubin was reported in 2% and 1% of patients in the avacopan and prednisone groups, respectively.

Acute myocardial infarction was reported by 0.6% of patients in the avacopan group and 1.2% of patients in the prednisone group; cardiac failure was reported by 1.2% of patients in the avacopan group and no patients in the prednisone group. Cardiac vasculitis was not reported in the trial.

In the avacopan and prednisone groups, respectively, nausea was reported by 23.5% and 20.7% of patients, diarrhea was reported by 15.1% and 14.6% of patients, vomiting was reported by 15.1% and 12.8% of patients, and dyspepsia was reported by 3.0% and 6.1% of patients.

Angioedema was reported by 1.2% of patients in the avacopan group and no patients in the prednisone group.

Table 2: Summary of Key Results From Pivotal Study

AE = adverse event; ALT = alanine aminotransferase; ANCA = antineutrophil cytoplasmic autoantibody; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; AST = aspartate aminotransferase; CI = confidence interval; eGFR = estimated glomerular filtration rate; EQ-5D-5L = 5-Level EQ-5D; GTI-AIS = Glucocorticoid Toxicity Index Aggregate Improvement Score; GTI-CWS = Glucocorticoid Toxicity Index Cumulative Worsening Score; ITT = intention to treat; LSM = least squares mean; MCS = mental component summary; MMRM = mixed model for repeated measures; MPO = myeloperoxidase; NR = not reported; PCS = physical component summary; SAE = serious adverse event; SEM = standard error of the mean; SF-36v2 = Short Form (36) Health Survey version 2; TEAE = treatment-emergent adverse event; UACR = urinary albumin–creatinine ratio; VAS = visual analogue scale; VDI = Vasculitis Damage Index; WDAE = withdrawal due to adverse event.

^aClopper and Pearson exact CI.

^bSummary score estimate of the common difference in remission rates using inverse-variance stratum weights.

^cMiettinen-Nurminen (score) confidence limits for the common difference in remission rates.

^dP value has been adjusted for multiple testing (i.e., the type I error rate has been controlled).

^eResults for the per-protocol analyses were similar to those of the ITT analyses (data included in table).

^fP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^gAnalysis used MMRMs, with treatment group, visit, and treatment-by-visit interaction as factors and baseline as a covariate. MMRM results by visit use the treatment-by-visit interaction term.

^hAnalysis used MMRMs, with treatment group, visit, and treatment-by-visit interaction as factors and baseline as a covariate. Logarithmic transformations were applied to the data before fitting the model. The 95% CI was transformed back to the original scale. MMRM results by visit use the treatment-by-visit interaction term.

ⁱAnalysis used MMRMs, with baseline VDI, treatment group, visit, treatment-by-visit interaction, and stratification factors (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) as covariates. MMRM results by visit use the treatment-by-visit interaction term.

^jPatients who achieved remission at week 26 is also the denominator for percentage calculations.

^kAnalysis used MMRMs, with treatment group, visit, treatment-by-visit interaction, and stratification factors (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) as covariates. MMRM results by visit use the treatment-by-visit interaction term.

^lAnalysis used MMRM models, with treatment group, visit, treatment-by-visit interaction, and randomization strata (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) as factors and baseline as a covariate. MMRM results by visit use the treatment-by-visit interaction term.

^mFrequency of greater than 2% in either treatment group.

Source: ADVOCATE Clinical Study Report.¹⁹

Critical Appraisal

The first notable limitations with the ADVOCATE trial were that rituximab was not used as maintenance therapy in the trial and that patients induced with rituximab did not receive any maintenance therapy, neither of which aligns with the current recommendation for using rituximab as first-line standard of care maintenance therapy for ANCA-AV.⁹ This was due to rituximab not being approved as a maintenance therapy when the protocol for the ADVOCATE trial was being developed. Further, it is unclear if the addition of avacopan to rituximab maintenance therapy would make a meaningful difference if these treatments were to be used in clinical practice today, and there is currently a lack of clinical data on such usage. The next major limitation was the use of nonstudy immunosuppressants (19.7% of patients) and glucocorticoids (89.1% of patients) during the trial. Nonstudy medication use is problematic for quantifying the effect of avacopan treatment alone on both efficacy and harms outcomes, and data for patients who did not use glucocorticoids were unavailable. The Health Canada indication has specified avacopan as an add-on or adjunctive therapy to standard treatment rather than as a glucocorticoid-sparing drug.^2,20 These deviations from current recommended standard of care maintenance therapy⁹ and from the protocol likely biased the results, although the magnitude and direction of the bias are unknown. Other issues included the relatively large number of discontinuations from treatment (more than 20% in each group), which resulted in missing data for nearly all outcomes, multiple outcome measures not being validated for ANCA-AV, and the absence of published minimal important differences (MIDs) for this population.

Patients with ANCA-AV who have only ever had negative antibody results, as well as those with very severe disease, were excluded from the ADVOCATE trial, and it is uncertain if the results of the trial can be generalized to patients with these characteristics. Also, the apparent difference in glucocorticoid use between treatment groups is more likely attributable to the trial design than to a change in disease activity such as avacopan effectively controlling ANCA-AV.²¹ The instruments used in the ADVOCATE trial are not used in clinical practice, secondary outcomes were not controlled for multiplicity, and between-group differences for multiple secondary outcomes (week 4 BVAS, UACR, VDI, patients experiencing disease relapse, SF-36v2, and EQ-5D-5L) were relatively small with wide CIs. Lastly, there was no rationale for the trial duration being 52 weeks or the follow-up being 8 weeks, and it is uncertain what long-term (beneficial or harmful) effects there are after discontinuing avacopan treatment. There was no indication from the trial about what posttreatment strategies should be used to manage patients with ANCA-AV, and there is a lack of data to inform such strategies or to indicate whether avacopan can be continued for longer than 12 months.

Conclusions

Avacopan 30 mg (3 capsules of 10 mg each) twice daily with nonprotocol-specified glucocorticoids was compared to oral prednisone tapered over 20 weeks in addition to nonprotocol-specified glucocorticoids over a 12-month treatment period. Treatments were combined with background therapy of IV or oral cyclophosphamide followed by azathioprine, or IV rituximab without maintenance therapy. Avacopan 30 mg twice daily was noninferior to oral prednisone in achieving disease remission at week 26 and was superior for sustained disease remission at week 52. Notably, 89% of patients received nonprotocol-specified glucocorticoids at some point during the ADVOCATE trial. Outcomes related to kidney function, systemic damage, disease relapse, glucocorticoid toxicity, and HRQoL provided limited support for the primary outcomes. Harms were generally balanced between groups in the trial, and no notable safety concerns were identified. The relevance of the findings to current standards of practice is unclear due to the lack of rituximab maintenance in both treatment groups, which is the current gold standard. It is unclear whether the findings would be generalizable to patients who are ANCA negative or who have very severe disease (e.g., patients who have alveolar hemorrhage requiring invasive pulmonary ventilation support or dialysis or patients who have an eGFR less than 15 mL/min/1.73 m²). Although the clinical expert suggested that avacopan could be used beyond 1 year, data to support long-term efficacy and safety beyond 12 months are not available at this time, and how patients should be managed after stopping avacopan is unknown. More evidence is needed to better understand the long-term efficacy and safety of avacopan and whether it can be used to effectively eliminate glucocorticoid use.

Introduction

Disease Background

ANCA-AV is a group of inflammatory disorders affecting mostly small- to medium-sized blood vessels that include GPA, MPA, and other vasculitides.³ With ANCA-AV, white blood cells attack and cause inflammation in the blood vessel walls, leading to loss of vessel integrity, bleeding, tissue ischemia, and necrosis.⁴ Patients often initially present with nonspecific symptoms such as fever, malaise, weight loss, myalgia, or arthralgia, which may last for weeks or months before there is clear evidence of organ involvement.⁴ As the disease progresses, there can be involvement of the ears, nose, and throat; respiratory system; kidneys; skin; and nervous system.⁴ ANCA-AV can vary from non-life-threatening to severe disease — major organs are affected in the latter — and from limited (i.e., affecting a single organ) to systemic disease.⁵ As defined by the 2012 Chapel Hill Consensus Conference, GPA causes necrotizing granulomatous inflammation, often involving the lungs and kidneys, and more commonly leads to ear, nose, and throat manifestations than MPA does.^3,6,7 MPA also causes necrotizing inflammation, usually without immune deposits, often affecting the kidneys and lungs as well.^6,7 There is evidence from the National Institutes of Health in the US that although less than one-fifth of patients with GPA or MPA may initially present with disease affecting the kidneys, more than 75% of patients will show evidence of glomerulonephritis within the first 2 years of disease onset.^3,8,22 Less common clinical manifestations include involvement of the gastrointestinal tract, heart, and other major organs.³

Limited information exists about the incidence and prevalence of GPA and MPA in Canada. The clinical expert consulted by CADTH estimated that the total incidence of GPA and MPA in Canada is 10 to 50 cases per million people per year and that their prevalence is between 75 and 300 cases per million people, or approximately 1,700 to 2,500 total patients living in Canada. Although cases of GPA and MPA vary with geography, GPA appears to be more common in populations with European ancestry, whereas MPA is more common in populations with East Asian ancestry.³ The 2 forms of ANCA-AV affect males and females equally and tend to occur more frequently in adults (typical age of onset is 45 years to 65 years for GPA and 55 years to 75 years for MPA).²³ Patients with ANCA-AV are at risk of increased morbidity and mortality, largely due to the disease causing irreversible inflammatory damage to organs and the consequences of long-term and often high-dose immunosuppressant drugs and glucocorticoids.⁵ It is expected that at least 80% of untreated patients will die within 1 year of diagnosis. Even with treatment, patients are at increased risk of developing malignancies, serious infections, and ESKD, largely due to progressive disease and/or as a consequence of treatment. Based on pooled data from an international cohort of 535 patients with GPA or MPA who had participated in 4 randomized controlled trials, cumulative survival at 1, 2, and 5 years was estimated to be 88%, 85%, and 78%, respectively,²⁴ which aligns with the clinical expert’s experience of 75% survival at 5 years in Canada. The clinical expert also indicated that, in their experience, around 30% of patients relapse within 5 years and that rates are reported to be higher among those with GPA than among those with MPA.²³ Key indicators of poor prognosis at presentation include renal failure, older age, and a high BVAS.^23,24

According to the literature and the clinical expert, ANCA-AV may be misdiagnosed, albeit rarely, or there can be delays in getting a proper diagnosis.³ ANCA-AV is suspected in patients who display the initial symptoms discussed in the first paragraph in this section and show evidence of kidney, respiratory, or nervous system involvement.³ Patients can be tested for the presence of anti-PR3 or anti-MPO ANCA, and other assessments of the affected organ(s) can be conducted to confirm a diagnosis.³ Also according to the literature and the clinical expert, approximately 65% to 75% of GPA cases are positive for PR3 ANCA and 55% to 85% of MPA cases are positive for MPO ANCA; however, some patients (20% to 30%) are positive for the other type of ANCA and a small proportion (around 10%) are ANCA negative.²³ There is increasing recognition that the type of ANCA positivity (PR3 or MPO) has greater prognostic and clinical meaning than the disease type (GPA or MPA).⁴ Other assessments can include biopsy of the affected organ, blood or urine tests, and imaging studies.⁴ Specialists such as rheumatologists, nephrologists, or pulmonologists may be involved in the diagnosis and are often involved in the management of the disease.⁴

Standards of Therapy

The clinical expert described the main goals of treatment to be achieving sustained remission and preventing relapse, reducing treatment-related side effects, and reducing glucocorticoid use, all of which are challenges with current treatments. Lasting organ damage, reduced HRQoL, the inability to continue working, and insufficient access to expertise and treatments for vasculitis are other issues patients face. The input submitted by patient and clinician groups and by the clinical expert noted the side effects associated with extended and/or high-dose glucocorticoid use and the need for treatments that reduce glucocorticoid use in managing ANCA-AV.

GPA and MPA are treated in the same manner, which consists of 2 main components: induction of disease remission and maintenance of remission to prevent relapse.⁵ Approaches to treatment and management largely depend on the severity of disease and on which organs are involved.⁵ According to the 2020 CanVasc consensus recommendations for the management of ANCA-AV, IV methylprednisolone pulses of 500 mg/day to 1,000 mg/day for 1 to 3 days is recommended for patients with life-threatening ANCA-AV.⁹ This treatment is usually followed by an oral prednisone equivalent dosage of 1 mg/kg/day (not exceeding 80 mg/day) for those with severe disease.⁹ Patients with life-threatening disease and organ involvement are given cyclophosphamide or rituximab for a minimum of 3 to 6 months, with glucocorticoids to induce remission.^7,9 Either oral cyclophosphamide is given at a dosage of 2 mg/kg/day (to a maximum of 200 mg/day) or IV cyclophosphamide is given at a dosage of 15 mg/kg (to a maximum of 1,200 mg) every 2 weeks for the first 3 doses, then every 3 weeks for the next 3 to 6 doses.⁷ IV rituximab for the induction of remission is given at a dosage of 375 mg/m² weekly for 4 doses or 1,000 mg at days 1 and 15.⁷ Cyclophosphamide and rituximab have shown similar efficacy for inducing remission;^10-13 however, cyclophosphamide has been associated with fertility issues, alopecia, and malignancies, and rituximab may be preferred for specific patients (e.g., children, young adults concerned with infertility, and older adults).^5,14 Once patients begin induction with cyclophosphamide or rituximab, glucocorticoid tapering should begin within 2 weeks to reduce the exposure to glucocorticoids and their associated risks.⁵ The clinical expert stated that, in their experience, the glucocorticoid dose can gradually be tapered to a final daily dose of 10 mg to 20 mg by month 3 and from 5 mg to 10 mg by month 6. The latest addendum (2022) to the CanVasc recommendations states that with avacopan, clinicians can consider tapering glucocorticoids using a faster protocol, with the aim of discontinuation by the end of week 4, and that this tapering should be done “in conjunction with best clinical judgement” and “close clinical monitoring for disease worsening.”²⁵

Once remission is achieved, patients should be transitioned to maintenance therapy, such as rituximab infusions of 500 mg to 1,000 mg every 4 to 6 months (often 500 mg every 6 months is used) for at least 24 months (4 doses).^7,9 Azathioprine (2 mg/kg/day oral to a maximum of 200 mg/day) or methotrexate (0.3 mg/kg/week oral or subcutaneous to a maximum of 25 mg/week) can be used instead of rituximab for maintenance therapy for patients who cannot receive or access the latter.^7,9 Mycophenolate mofetil or leflunomide have also been listed as options for maintenance therapy if contraindications, poor tolerance, or poor response occur with other drugs.^7,9 It has been stated in the literature and by the clinical expert that maintenance treatment should last for at least 2 years and that continued treatment should be considered for patients in high-risk groups (e.g., those with PR3 ANCA, prior relapse, pulmonary involvement, or upper respiratory tract involvement).^5,9,15-18 The CanVasc recommendations state that the optimal duration for low-dose glucocorticoid use once remission is achieved is currently unknown.⁹

Patients experiencing nonsevere (non-life-threatening or non-organ-threatening) relapse should receive an increased dose of glucocorticoids, and their current immunosuppressive treatment should be optimized.⁹ For those with severe relapse, reinduction of remission is necessary, and patients who were previously treated with cyclophosphamide should subsequently receive rituximab.⁹ The 2020 CanVasc recommendations also advise that patients with refractory disease and those with contraindications or poor tolerance to medications should be referred to and managed at a referral centre for vasculitis.⁹ Patients should also be followed for life, with regularly scheduled full clinical assessments to track disease activity and damage related to the disease or treatments.^5,9

Drug

The key characteristics of avacopan, prednisone, rituximab, and cyclophosphamide are summarized in Table 3. Rituximab and cyclophosphamide are included in the standard of care treatment for ANCA-AV and are to be used alongside avacopan.

Avacopan (Tavneos) is indicated for the adjunctive treatment of adult patients with severe active ANCA-AV (GPA and MPA) in combination with standard background therapy, including glucocorticoids.² Avacopan does not eliminate glucocorticoid use.² The drug is available in 10 mg capsules to be taken orally at a dosage of 30 mg twice per day.² The specific and selective blockade of C5aR1 by avacopan reduces the proinflammatory effects of C5a, which include neutrophil activation and migration, and decreases adherence to sites of small blood vessel inflammation, and vascular endothelial cell retraction and increased permeability.² The Health Canada product monograph did not specify the duration of treatment with avacopan.

Avacopan underwent a standard review at Health Canada and was issued a Notice of Compliance on April 14, 2022.¹ The sponsor has requested reimbursement as per the approved Health Canada indication.¹ Avacopan has not been previously reviewed by CADTH.

Table 3: Key Characteristics of Avacopan, Prednisone, Rituximab, and Cyclophosphamide

ALT = alanine aminotransferase; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; AST = aspartate aminotransferase; GPA = granulomatosis with polyangiitis; HBV = hepatitis B virus; INR = international normalized ratio; MPA = microscopic polyangiitis; RNA = ribonucleic acid; ULN = upper limit of normal.

^aHealth Canada–approved indication.

^bThe thresholds are leukopenia (white blood cell count less than 2 × 10⁹/L), neutropenia (neutrophils less than 1 × 10⁹/L), or lymphopenia (lymphocytes less than 0.2 × 10⁹/L).

^cA treatment regimen based on the combination with cyclophosphamide followed by azathioprine may carry an increased risk for cardiac disorders compared to a regimen based on the combination with rituximab.

Sources: Product monographs for Tavneos,² Apo-Prednisone,²⁶ Riximyo,²⁷ cyclophosphamide for injection,²⁸ and Procytox.²⁹

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by 1 patient group. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.

CADTH received 1 patient group submission from Vasculitis Foundation Canada. The organization aims to increase disease awareness and research support for all forms of vasculitis through collaborations with the medical community, patients, and the general public. Vasculitis Foundation Canada invited subscribers on its mailing list to complete an online survey and received input from 46 patients (35 with GPA and 11 with MPA) living in Canada and the US who have experience using prednisone or avacopan.

The patient group reported that GPA and MPA are uncommon but life-threatening diseases that impact patients’ daily lives and quality of life. Patients commonly reported kidney damage leading to chronic kidney disease, kidney failure, dialysis, and transplant. Many patients described experiencing a host of physical manifestations (e.g., breathing difficulties, weight gain, joint or nerve pain, loss of hearing, cataracts, disfigurements) that negatively impacted their well-being and led to chronic fatigue, mood swings, poor sleep, chronic infections, and stress due to fear of relapse. The group reported that patients experienced deteriorations in their quality of life, such as experiencing “anxiety and depression for the past 13 years,” job loss or unplanned early retirement, and/or overall reduced quality of life, highlighted by 1 patient in the following words: “Vasculitis eats away at you, your family, your quality of life and relationships.” For some patients, the devastating toll of the disease takes away their desire to live.

Vasculitis Foundation Canada stated that individuals with GPA or MPA require treatment with powerful immune suppressive medications to induce and maintain disease remission. All the patients surveyed had experience with oral glucocorticoids (i.e., prednisone) and 25 patients (53%) had required IV steroids at some point during the disease course. Patients who require steroids are commonly on high dosages (e.g., 1 g/day IV for 3 days or 60 mg/day for weeks), which may be slowly tapered, ranging from 6 months to 27 years. Patients treated with prednisone reported side effects that significantly affect quality of life, including body disfiguration, steroid-induced diabetes or hypertension, infections requiring medical care, anxiety, and depression. The conflict experienced by patients who rely on prednisone is highlighted in the following quote: “Prednisone saved my life (the benefit), but destroyed my body (the side effect!).” Only 1 patient surveyed had experience with avacopan in a clinical trial. Given the choice, 30 out of 46 respondents (63.8%) stated they would opt for avacopan, despite their limited experience and knowledge of the new drug, given the side effects of prednisone.

Vasculitis Foundation Canada reported that patients with GPA or MPA indicated a need for treatment that improves symptoms and quality of life and that would reduce or eliminate the use of prednisone.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition under review, in this case, adult patients with severe ANCA-AV. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of adult patients with severe ANCA-AV (GPA and MPA).

Unmet Needs

The clinical expert consulted by CADTH noted that the main goals of treatment include achieving sustained remission, preventing relapse, reducing treatment side effects, and reducing glucocorticoid use, all of which are challenges with current treatments. According to the clinical expert, approximately 10% of patients with severe GPA or MPA have very severe, acute disease resulting in death within the first weeks after diagnosis. Even with treatment, approximately 30% of patients experience disease relapse within 5 years. Other challenges include patient access to expert centres and treatments as well as considerable side effects from treatments, particularly glucocorticoids. The clinical expert stated that patients need treatments that result in sustained remission, limit organ damage (or allow for better recovery from damage), limit the risk of severe infections, require less time on treatment (currently, patients are treated for at least 24 months, and treatment shorter than that has been associated with unacceptable rates of relapse), and are safe for use in special populations (i.e., pediatric, pregnant, and older adult populations). It was also noted that both ANCA-AV and current treatments have significant impacts on patients’ HRQoL and ability to work.

Place in Therapy

According to the clinical expert, avacopan would be used as a first-line treatment for adults with severe GPA or MPA, similar to its use in the ADVOCATE trial, but the expert noted that the trial did not enrol patients with very severe disease or who were ANCA negative. The clinical expert suggested that patients with very severe disease may also be candidates for avacopan after the disease is controlled with high-dose glucocorticoids. The expert indicated that avacopan may allow for a reduction in glucocorticoids, which is particularly important for patients who are receiving glucocorticoid in high doses as well as for those who are at elevated risk of the side effects associated with glucocorticoids. The expert stated that, in practice, avacopan would be administered as it was in the ADVOCATE trial: to induce remission alongside IV or oral cyclophosphamide or IV rituximab with glucocorticoids. The clinical expert noted that, in general and following current guidelines, after remission is achieved with standard treatments patients should receive appropriate maintenance therapy, such as rituximab at month 6 and every 6 months thereafter for at least 24 months of total treatment. The clinical expert noted a current lack of clinical trial evidence on optimal patient management after 12 months of avacopan.

Patient Population

While GPA and MPA are rarely misdiagnosed, there are often delays in the diagnosis. The clinical expert indicated that all adult patients with severe active GPA or MPA need new treatment options and would be treated with avacopan. Given the available evidence, the clinical expert indicated that it is unclear if any subpopulations would respond better to avacopan than other patients. The expert described how avoiding glucocorticoids is ideal in all patients and more so in those who have a medical history of significant side effects as well as those who have concurrent infections because the infections can be exacerbated by glucocorticoids. It is in these patients that avacopan may be particularly useful for treating ANCA-AV according to the expert.

Assessing Response to Treatment

The clinical expert stated that survival is the most important outcome, particularly in the first weeks after diagnosis. Other response measures include improvement of major organ disease (e.g., renal recovery, reduced use of mechanical ventilation), achievement of remission (typically assessed at month 3, then at month 6), and sustained remission (assessed at months 12, 18, and 24). The expert also indicated that it would be important to evaluate and limit the side effects from treatments. The expert also noted that disease- and treatment-related instruments are available, such as the BVAS to assess remission and residual disease activity, the VDI to measure cumulative damage burden as of month 3, and the GTI to evaluate glucocorticoid-related toxicities, as well as other symptom and HRQoL scales, although these have been developed for clinical studies and are not used in routine clinical practice.

Discontinuing Treatment

The clinical expert stated that avacopan should be administered for 12 months, as was done in the ADVOCATE trial, with the possibility of continuing the drug for longer, but noted that there are limited data on stopping the drug before 1 year or using it beyond that. According to the expert, discontinuing treatment should be considered if there are intolerable side effects, continual disease progression with clinical decline, or repeated relapses. With disease progression or relapse, the expert would recommend that the patient be treated with glucocorticoids for a few weeks (either starting glucocorticoids or increasing the dose) while maintaining the same avacopan dose. If the patient relapsed a second time, the expert indicated that avacopan would likely be stopped. Further, disease progression and relapse would also indicate a need to reassess the treatment regimen; for example, a patient on cyclophosphamide induction therapy could be switched to rituximab, or rituximab could be added after 6 months of avacopan for maintenance therapy. In the expert’s opinion, another reason to discontinue avacopan would be if its use did not allow for reduced use of glucocorticoids.

Prescribing Conditions

Since GPA and MPA are rare diseases and require close monitoring, the clinical expert indicated that patients should be referred to a specialist with expertise in the disease area. The expert noted that once a patient is diagnosed, most physicians are able to begin treatment with glucocorticoids but suggested that many are not familiar with, or may not be comfortable, initiating and/or prescribing cyclophosphamide or rituximab before a specialist (e.g., rheumatologist) is involved. In the clinical expert’s opinion, a rheumatologist, nephrologist, general internal medicine specialist, respirologist, or intensive care unit doctor should be able to prescribe avacopan in a hospital setting, and the expert noted that restricting the prescription to only rheumatologists or nephrologists with expertise in vasculitis would likely delay treatment initiation by weeks. However, in community clinics, it would be reasonable to restrict access to only rheumatologists or nephologists with experience treating vasculitis. Additionally, the expert indicated that a patient should begin avacopan treatment as soon as possible after receiving the diagnosis to stop or rapidly reduce glucocorticoid use and limit the risk of glucocorticoid-associated side effects.

Additional Considerations

The clinical expert emphasized that treatment with avacopan should be associated with a mandate to stop or significantly decrease glucocorticoid use within the first weeks of initiating avacopan; otherwise, the continued use of avacopan should be clinically justified. Given the lack of long-term data, the expert expressed uncertainty about patient management after 12 months of avacopan use and about the long-term outcomes after stopping the drug. Lastly, the clinical expert suggested that alongside the implementation of avacopan in Canada, it would be useful to set up a registry to track the drug’s use and patterns of use and to monitor safety and efficacy.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by 1 clinician group. The full original clinician group input received by CADTH has been included in the stakeholder section at the end of this report.

CanVasc, a Canadian research network for vasculitis, provided input for this review. The clinician group expressed similar views to those of the clinical expert consulted by CADTH. The group highlighted the main unmet needs of patients with severe GPA or MPA as better survival, improved renal and neurologic recovery, induced remission (e.g., at 6 months) followed by sustained remission, reduced reliance on high-dose and prolonged glucocorticoid use due to associated toxicities, and access plus coverage for new treatments other than conventional therapies. CanVasc also advocated for a treatment regimen that is convenient and practical for patients and specialists (oral administration preferred over infusion, and without a complex tapering regimen). The clinician group anticipated that avacopan would be used in clinical practice initially as a combined treatment with rituximab, with or without steroids, for 12 months (benefits and harms beyond this time point are unknown). Discontinuation may be considered if relapse is observed at 6 months followed by a subsequent relapse, or earlier if AEs are detected. The respondents for the clinician group did not indicate having direct experience with the drug under review.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact the programs’ ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; CDEC = CADTH Canadian Drug Expert Committee; GPA = granulomatosis with polyangiitis; MPA = microscopic polyangiitis; MPO = myeloperoxidase.

Clinical Evidence

The clinical evidence included in the review of avacopan is presented in the systematic review, which includes the pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as studies selected according to an a priori protocol. No indirect evidence, long-term extension studies, or additional relevant studies were identified in the literature.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of avacopan 30 mg (3 oral capsules of 10 mg each) twice daily, for the adjunctive treatment of adult patients with severe active ANCA-AV (GPA and MPA) in combination with standard background therapy, including glucocorticoids. Avacopan does not eliminate glucocorticoid use.

Methods

The studies selected for inclusion in the systematic review included the pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as studies meeting the selection criteria presented in Table 5. Outcomes included in the CADTH systematic review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; ALT = alanine aminotransferase; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; GPA = granulomatosis with polyangiitis; HRQoL = health-related quality of life; MPA = microscopic polyangiitis; MPO = myeloperoxidase; RCT = randomized controlled trial; SAE = serious adverse event; VDI = Vasculitis Damage Index; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.³⁰

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was avacopan. The following clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on November 9, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on March 22, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.³¹ Included in this search were the websites of regulatory agencies (FDA and the European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished evidence.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

Two reports^19,32 of a single study were identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Study

AE = adverse event; ALT = alanine aminotransferase; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; AST = aspartate aminotransferase; BVAS = Birmingham Vasculitis Activity Score; DB = double blind; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EGPA = eosinophilic granulomatosis with polyangiitis; EQ-5D-5L = 5-level EQ-5D; GPA = granulomatosis with polyangiitis; GTI = Glucocorticoid Toxicity Index; HRQoL = health-related quality of life; MDRD = modification of diet in renal disease; MPA = microscopic polyangiitis; MPO = myeloperoxidase; RCT = randomized controlled trial; SAE = serious adverse event; SF-36v2 = Short Form (36) Health Survey version 2; TNF = tumour necrosis factor; UACR = urinary albumin–creatinine ratio; ULN = upper limit of normal; VDI = Vasculitis Damage Index; WDAE = withdrawal due to adverse event.

Note: Three additional reports were included (FDA, European Medicines Agency, and Health Canada reports).^19,21,33

^aPatients received either IV cyclophosphamide (15 mg/kg, up to 1.2 g maximum, at each of the day 1 and week 2, 4, 7, 10, and 13 study visits) or oral cyclophosphamide (2 mg/kg/day, up to 200 mg/day maximum, from day 1 to week 15). The cyclophosphamide dose was adjusted for age, eGFR, and white blood cell count. After week 15, patients received 1 mg/kg/day oral azathioprine up to 2 mg/kg/day at 2 weeks. If azathioprine was not tolerated, 2 g/day mycophenolate mofetil may have been given. If mycophenolate mofetil was not tolerated or not available, 1,440 mg/day enteric coated mycophenolate sodium may have been given.

^bPatients received IV rituximab (375 mg/m² weekly for 4 weeks) where glucocorticoid premedication for rituximab infusions was permitted.

^cGlucocorticoid use referred to both the prednisone study medication and other glucocorticoids that were not part of the prednisone study medication given for ANCA-AV for the 4 weeks before the BVAS assessment at weeks 26 and 52. Patients were permitted to receive low-dosage oral glucocorticoids (10 mg/day or less) outside of the trial protocol for treatment of adrenal insufficiency or to receive glucocorticoid treatment for other conditions (e.g., allergic reaction). These patients were to be considered responders if all other requirements for the end points were met.

^dRelapse was defined as disease worsening after having previously achieved remission that involved 1 or more major item in the BVAS, or 3 or more minor items in the BVAS, or 1 or 2 minor items in the BVAS recorded at 2 consecutive study visits.

Source: ADVOCATE Clinical Study Report.¹⁹

Description of the Study

The ADVOCATE trial (N = 331) was a phase III, double-blind, randomized controlled trial investigating the efficacy and safety of avacopan in patients with ANCA-AV with the intent to determine if avacopan could induce and sustain remission without chronic glucocorticoid use at the levels currently used in standard of care regimens. The trial took place at 143 centres in 20 countries, with 9 sites in Canada enrolling 13 patients.³⁴ The ADVOCATE trial consisted of a 2-week screening period to determine patient eligibility, a 52-week double-blind treatment period, and an 8-week follow-up period. Patients had visits scheduled every week for the first month, then nearly every third week until the end of the trial. Randomization was conducted centrally using an interactive response technology system, and patients were stratified by standard of care immunosuppressant treatment (IV rituximab, IV cyclophosphamide, or oral cyclophosphamide), ANCA positivity (PR3 or MPO) at diagnosis, and disease status (newly diagnosed or relapsed ANCA-AV). Overall, 331 patients were randomized 1:1 to receive either oral avacopan with oral prednisone-matching placebo (N = 166) or oral prednisone with oral avacopan-matching placebo (N = 165) along with, in both groups, background therapy of IV rituximab or oral or IV cyclophosphamide. Patients, investigators, the sponsor, and personnel involved with data monitoring and analysis were blinded to treatment assignment, and a double-dummy design (avacopan- and prednisone-matched placebos) was used.

Patients were withdrawn from the trial if they withdrew their consent or were lost to follow-up. Patients were discontinued from the study drug treatment if they withdrew their consent or if the investigator or sponsor determined that the patient should discontinue the treatment based on clinical judgment or for safety reasons.

Populations

Inclusion Criteria

To be included in the ADVOCATE trial, patients had to be adults (18 years and older, although allowance was made for patients aged 12 years to 17 years at approved trial centres) with newly diagnosed or relapsing ANCA-AV and a clinical diagnosis of GPA or MPA that was consistent with the Chapel Hill Consensus Conference definitions and had to have tested positive (based on historical medical data or at the time of screening) for either anti-PR3 or anti-MPO antibodies.⁶ At screening, patients had to have at least 1 major item, at least 3 minor items, or at least the 2 renal items of proteinuria and hematuria on the BVAS and an eGFR of at least 15 mL/min/1.73 m².

Exclusion Criteria

Individuals were excluded if they had severe disease, such as alveolar hemorrhage, requiring invasive pulmonary ventilation support, dialysis, or plasma exchange or if they had another multisystem autoimmune disease (e.g., eosinophilic GPA, systemic lupus erythematosus, immunoglobulin A vasculitis). Other exclusion criteria were administration of cyclophosphamide in the 12 weeks before screening; IV glucocorticoids greater than 3,000 mg methylprednisolone equivalent in the 4 weeks before screening; oral daily glucocorticoids of more than 10 mg prednisone equivalent for more than 6 weeks before screening; or rituximab or other B-cell antibody in the 52 weeks before screening (or 26 weeks, provided B-cell reconstitution had occurred). Evidence of recent cardiovascular symptoms, cancer, tuberculosis, hepatic disease, low white blood cell counts, or hypersensitivity to any of the study drugs were also reasons for exclusion.

Baseline Characteristics

Baseline characteristics are summarized in Table 7.

The mean age of patients in the ADVOCATE trial was 60.9 years (SD = 14.5 years). More than half the patients were male (56.5%), and most were white (84.3%). There was an aim to enrol 10 adolescent patients, but only 3 entered the trial. The mean age at diagnosis was 59.6 years (SD = 15.4 years). Most patients were from Europe (70.1%), and 18.1% were from North America. The proportions of patients by geographic location were imbalanced between treatment groups.

The baseline disease characteristics were generally balanced between treatment groups. Most patients were newly diagnosed with ANCA-AV (69.4%), and 30.6% had relapsing disease. A little more than half the patients had GPA (54.8%), and 45.2% had MPA. Less than half were positive for anti-PR3 antibodies (43.0%), and 57.0% were positive for anti-MPO antibodies. The mean baseline BVAS was 16.2 (SD = 5.8), with the most commonly reported BVAS components being renal (81.2%) and general symptoms (68.2%). Prior immunosuppressant use was generally balanced between treatment groups, with the most common drug being azathioprine (10.3%).

Table 7: Summary of Baseline Characteristics — ADVOCATE

ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; BVAS = Birmingham Vasculitis Activity Score; GPA = granulomatosis with polyangiitis; ITT = intention to treat; MPA = microscopic polyangiitis; MPO = myeloperoxidase; RBC = red blood cell; SD = standard deviation; VDI = Vasculitis Damage Index.

^aPatients can appear in more than 1 category.

^bPrior medications were defined as those taken in the year before the first dose of the study drug. Medications could be considered both prior and concomitant if started before the first dose of the study drug and continued into the treatment period.

Source: ADVOCATE Clinical Study Report.¹⁹

Interventions

Patients in the avacopan group received 30 mg oral avacopan twice daily with prednisone-matched oral placebo; those in the prednisone group received oral prednisone with 30 mg avacopan-matched oral placebo twice daily for 52 weeks. Over the first 20 weeks, prednisone (or matching placebo) was tapered down from a starting dosage of 60 mg/day for patients with a body mass of at least 55 kg or of 45 mg/day for patients with a body mass less than 55 kg. For adolescent patients who received avacopan, the dose was initially dependent on body mass but was further refined based on avacopan plasma exposure; adolescents weighing 37 kg or less received prednisone at 30 mg/day. Patients in both the avacopan and prednisone groups received background immunosuppressant therapy of IV cyclophosphamide for 13 weeks followed by oral azathioprine from week 15 onward, or of oral cyclophosphamide for 14 weeks followed by oral azathioprine from week 15 onwards, or of IV rituximab once weekly for 4 weeks without any subsequent maintenance therapy. Mycophenolate was given if azathioprine was contraindicated. Premedication with glucocorticoids was permitted for rituximab infusions. The choice of background therapy was at the discretion of the trial investigator. Based on previous phase I and II studies of avacopan, a twice daily 30 mg avacopan dose was deemed appropriate.^35-37 Dose regimens were consistent with standard clinical practice at the time of protocol development.

Patients who received glucocorticoids during the screening period had to have reduced their dose to 20 mg or less prednisone equivalent by day 1 of the trial, and the dose was to be further tapered to 0 mg within the first 4 weeks of the trial. Glucocorticoid treatments that were outside of the study protocol were to be avoided as much as possible. However, patients who experienced disease relapse or worsening disease involving a major item on the BVAS may have received IV glucocorticoids (0.5 g to 1 g methylprednisolone per day for 3 days) and/or oral glucocorticoids that were tapered according to the patient’s condition. Patients who experienced worsening disease not involving a major item on the BVAS may have received a short burst (2 weeks or less) of oral glucocorticoids to a maximum dose of 20 mg prednisone equivalent. Patients who had at least 1 major item on the BVAS before entering the trial that did not improve or stabilize during the first 4 weeks may have received additional IV or oral glucocorticoids that were tapered according to the patient’s condition. Furthermore, patients who relapsed may have received additional immunosuppressive therapy (e.g., additional rituximab or cyclophosphamide), as discussed with the medical monitor. Despite the use of glucocorticoids outside of the protocol, these patients were to continue in the trial.

Outcomes

A list of efficacy end points identified in the CADTH systematic review protocol and assessed in the clinical trial is provided in Table 8. These end points are further summarized in this section of the report. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Survival

Survival was not assessed in the ADVOCATE trial (aside from deaths, which were included in the assessment of harm outcomes).

Table 8: Summary of Efficacy Outcomes of Interest Identified in the CADTH Systematic Review Protocol

eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HRQoL = health-related quality of life; VDI = Vasculitis Damage Index.

^aNot reported as an efficacy outcome; mortality information was reported as deaths in the assessment of harm outcomes.

Disease Remission (Induction and Sustained Remission)

Disease remission was assessed using the BVAS version 3, a comprehensive multisystem clinical assessment of a patient’s current disease activity using a standardized list of 57 clinical items organized into 9 organ systems, with an “other” category.³⁸ Each item is assigned a numerical value based on its perceived clinical relevance according to expert consensus, and only symptoms attributable to active ANCA-AV are reported.¹⁹ The BVAS can range from 0 to 63, with 0 indicating no disease activity and any score greater than 0 indicating that active disease is present.³⁹ Face validity and convergent validity were acceptable, and convergent validity was correlated with the physician’s global assessment, treatment decision, and VDI.³⁸ Interobserver and intra-observer reliability were also acceptable, and responsiveness was examined in a cohort of 39 patients with ANCA-AV.³⁸ No MID was identified from the literature for patients with ANCA-AV.

In the ADVOCATE trial, the week 4 BVAS assessment was modified to include disease activity from the past 7 days, rather than 28 days, to exclude the trial’s baseline measurement. Early remission was assessed as a BVAS of 0 at week 4, regardless of glucocorticoid use. All other BVAS assessments considered the previous 28 days. Additionally, the “persistent” disease portion was not evaluated as only the presence or absence of disease was assessed in the trial. BVAS assessments were made at screening and at weeks 4, 10, 16, 26, 39, 52, and 60, and data were confirmed by a blinded adjudication committee.

Disease remission was defined by the adjudication committee as achieving a BVAS of 0, with no glucocorticoids for ANCA-AV in the 4 weeks before week 26 and no BVAS greater than 0 during the 4 weeks before week 26 (if collected for an unscheduled assessment). Sustained disease remission was defined by the adjudication committee as disease remission at week 26 and disease remission at week 52, which was a BVAS of 0 with no glucocorticoids for ANCA-AV in the 4 weeks before week 52 and no disease relapse between week 26 and week 52. Glucocorticoid use referred to both prednisone study medication and other nonstudy glucocorticoids for ANCA-AV during the 4 weeks before the BVAS assessments at week 26 and week 52. Patients were permitted to receive low dosages of oral glucocorticoids (10 mg/day or less) to treat adrenal insufficiency or allergic reaction. Patients were considered responders if all other requirements for the end points were met.

Renal Function (e.g., eGFR, Progression to ESKD)

Renal disease at baseline was defined as having at least 1 renal item on the BVAS at screening (i.e., hypertension, proteinuria greater than 1+ or greater than 0.2 g/g creatinine, hematuria of at least 10 red blood cells per high-power field, elevated serum creatinine [at least 125 μmol/L], or rise in serum creatinine [greater than 30%] or fall in creatinine clearance [greater than 25%] since previous assessment).

The eGFR was calculated for patients with renal disease at baseline from serum creatinine measurements using the modification of diet in renal disease equation for adults and the modified Schwartz equation for adolescents. A different calculation was used for adults identifying as Japanese, although the reason for this was not clear and no reference to literature was available. Serum creatinine measurements for eGFR were taken at screening, at day 1, and at weeks 1, 2, 3, 4, 7, 10, 13, 16, 20, 26, 32, 39, 45, 52, and 60. The number of patients who required dialysis during the trial was reported.

The UACR was calculated for patients with renal disease and albuminuria at baseline through quantitative albumin and creatinine measurements taken from urine samples, which were centrally assessed. Measurements were taken at screening, at day 1, and at weeks 1, 2, 4, 13, 26, 39, 52, and 60.

Systemic Damage (e.g., Measured by VDI)

The VDI is a standardized clinical assessment of damage in systemic vasculitis aimed at distinguishing damage or scarring (which are unlikely to respond to immunosuppression) from disease activity to aid in the selection of therapy.⁴⁰ The instrument is composed of 64 items, organized into 11 organ-based systems, where damage is defined as disease manifestations that have been present for at least 3 months (to be considered damage as opposed to ongoing activity).⁴⁰ Comorbidities developed before vasculitis are not scored.⁴⁰ Each item is scored as being present (1 point) or absent (0 points), and the items are summed.^19,40 A VDI score is cumulative and can remain the same or increase over time because previously scored items are carried forward to subsequent assessments (i.e., damage is considered irreversible).⁴⁰ Content, face, and criterion validity were assessed in patients with a range of systemic vasculitides.⁴⁰ Convergent and divergent validity were examined for the VDI compared with the Systemic Necrotizing Vasculitis Damage Index and the Systemic Lupus International Cooperating Clinics/American College of Rheumatology Damage Index. Low to moderate correlation was found between the instruments, but the VDI was more sensitive to detecting damage.⁴⁰ Inter-rater reliability of the VDI was fair to moderate when compared between different assessors, and responsiveness was examined in a group of 100 patients.⁴⁰ No MID was identified from the literature for patients with ANCA-AV.

VDI assessments were made at screening and at weeks 26, 52, and 60, and data were confirmed by an adjudication committee.

Disease Relapse (e.g., Time to Relapse or Duration of Remission, Minor Versus Major)

Disease relapse was defined as the occurrence of at least 1 major item, 3 or more minor items, or 1 or 2 minor items on the BVAS recorded at 2 consecutive visits, after having achieved remission at week 26 (BVAS of 0 and no glucocorticoids for ANCA-AV within 4 weeks) or after having achieved a BVAS of 0 at any time during the treatment period.

Glucocorticoid Use and Related Toxicities and Safety

The GTI version 2 quantifies and assesses changes in toxicity associated with glucocorticoid use.^41,42 It consists of 2 scores: the GTI-CWS and GTI-AIS.^41,42 The GTI-CWS measures cumulative toxicity, regardless of whether the toxicity has transient or lasting effects.^41,42 New toxicities are added without removing those that have resolved; therefore, the score can remain the same or increase over time.^41,42 In contrast, toxicities that improve can be removed from the GTI-AIS, and when overall glucocorticoid toxicity improves, the score can have a negative value.^41,42 The GTI-AIS is intended to capture changes in glucocorticoid toxicities over time and whether a treatment is effective at diminishing baseline toxicities.^41,42 No evidence of validation of the GTI was identified for patients with ANCA-AV, and Health Canada correspondingly considered it to be unvalidated and too general to be clinically meaningful for ANCA-AV.²⁰ The instrument has been validated in patients with asthma, although it is unclear if it has been validated in other populations.⁴³ A MID of 10 points was identified from the literature, which was based on a mixed population of patients with various inflammatory conditions, including ANCA-AV.⁴³

GTI assessments were made on day 1 and at weeks 13 and 26, the period during which prednisone was given to patients in the prednisone group. The sponsor stated that this was done to focus the assessment on the relevant study period. Data for the GTI did not appear to be confirmed by an adjudication committee.

Health-Related Quality of Life

HRQoL was assessed using the SF-36v2 and the EQ-5D-5L. The SF-36v2 is a generic health survey consisting of 36 questions yielding scores for 8 subscales of functional health and well-being that can be summarized in a physical component summary and a mental component summary.^44,45 Scores range from 0 to 100, where a higher score indicates better health status.⁴⁴ The EQ-5D-5L is a generic health instrument consisting of a descriptive system profile with 5 dimensions measured on a 5-point scale and a VAS measured on a 100-point scale.⁴⁶ The descriptive system profile can be linked to a “value set” (values or weights for each health state description according to the preferences of the general population or of a country or region) to derive an index score, where 0 represents death and 1.0 represents perfect health.⁴⁶ The VAS records a respondent’s self-rated health that day on a vertical line, with 0 labelled “worst imaginable health state” and 100 labelled “best imaginable health state.”⁴⁶ Translations for the instruments were used in the trial, where available. Although some articles indicate that evidence of validity and reliability have been identified for the SF-36v2 for patients with ANCA-AV, CADTH reviewers could not validate such claims. In addition, validity, reliability, and responsiveness were not assessed for the EQ-5D-5L in this population. No MID for either instrument was identified from the literature for patients with ANCA-AV.

The SF-36v2 and the EQ-5D-5L were completed on day 1 and at weeks 4, 10, 16, 26, 39, 52, and 60.

Hospitalizations

Hospitalizations were not assessed in the ADVOCATE trial.

Symptoms (e.g., Fatigue)

Symptoms (aside from those collected under harms) were not assessed in the ADVOCATE trial.

Harms

The incidence and seriousness of AEs, withdrawal due to AEs, and deaths were reported for the safety population during the trial. AEs, SAEs, and protocol-defined notable harms were described based on preferred term and associated system organ class. Notable harms from the CADTH systematic review protocol included serious infection, hepatic injury (e.g., elevated ALT or AST, total bilirubin), cardiovascular AEs (e.g., myocardial infarction, cardiac failure, cardiac vasculitis), gastrointestinal AEs (e.g., dyspepsia, vomiting, nausea, diarrhea), and immune-related AEs (e.g., angioedema).

Statistical Analysis

The statistical analysis of efficacy end points is summarized in Table 9.

Table 9: Statistical Analysis of Efficacy End Points

ANCA = antineutrophil cytoplasmic autoantibody; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; BVAS = Birmingham Vasculitis Activity Score; eGFR = estimated glomerular filtration rate; EQ-5D-5L = 5-Level EQ-5D; GTI = Glucocorticoid Toxicity Index; HRQoL = health-related quality of life; KM = Kaplan-Meier; MMRM = mixed effects model for repeated measures; MPO = myeloperoxidase; SF-36v2 = Short Form (36) Health Survey version 2; UACR = urinary albumin–creatinine ratio; VDI = Vasculitis Damage Index.

Source: ADVOCATE Clinical Study Report.¹⁹

Primary Outcome

The ADVOCATE trial had 2 primary efficacy end points. The first was the proportion of patients who achieved disease remission at week 26, and the second was the proportion of patients who achieved sustained disease remission at week 52. The number of patients adjudicated as having achieved remission at week 26 and week 52 was divided by the total number of patients in the treatment groups for the ITT and PP populations at the respective time points. The primary analysis compared remission rates for the 2 primary efficacy end points using the ITT population based on the stratification variables used for randomization. Data were summarized descriptively by treatment group. Continuous variables were presented as numbers, means, medians, ranges, SDs, and standard errors of the mean, and categorical variables were presented as frequency counts and percentages.

Statistical Testing

The proportion of patients who achieved disease remission at week 26 and sustained disease remission at week 52, and the 2-sided 95% CIs for the difference in proportions (avacopan minus prednisone), were calculated. For both noninferiority and superiority tests, 1-sided P values were presented, and statistical significance was claimed based on the 1-sided type I error of 0.025.

For the stratified analyses of the primary end point of remission, summary score estimates of the common difference in remission rates were calculated using the inverse-variance stratum weights along with their Miettinen-Nurminen (score) confidence limits. The summary score test was used for both noninferiority and superiority tests at week 26 and week 52. For the unstratified sensitivity analyses, Wald confidence limits were calculated for both noninferiority and superiority tests at week 26 and week 52. The Clopper and Pearson exact interval method was used for single proportion data.

A gatekeeping procedure was used to control the overall type I error rate at the 5% level, and the primary outcomes were tested in the following order:

1. Noninferiority test of the avacopan group compared to the prednisone group for disease remission at week 26. Testing continued if the P value for noninferiority for the 1-sided test was less than 0.025.

2. Noninferiority test of the avacopan group compared to the prednisone group for sustained disease remission at week 52. Testing continued if the P value for noninferiority for the 1-sided test was less than 0.025.

3. Superiority test of the avacopan group compared to the prednisone group for sustained disease remission at week 52. Testing continued if the P value for superiority for the 1-sided test was less than 0.025.

4. Superiority test of the avacopan group compared to the prednisone group for disease remission at week 26.

For noninferiority testing of the first primary end point, avacopan was considered noninferior to prednisone if the lower bound of the 2-sided 95% CI was greater than the noninferiority margin of –0.20 and the prednisone group’s disease remission rate was at least 40% at week 26 (if the observed rate of avacopan was lower than that of the prednisone group). For superiority testing, if the lower bound of the 2-sided 95% CI was greater than 0.0, avacopan was considered superior to prednisone in achieving disease remission at week 26. Similar testing was performed for the second primary end point at week 52.

Noninferiority Margin

A meta-analysis of 20 published studies investigating either rituximab with glucocorticoids or cyclophosphamide with glucocorticoids informed the noninferiority margin used for the first primary end point (–0.20). The lower bound of the 95% CI for remission rate across the studies was approximately 60%. Therefore, the selected noninferiority margin would demonstrate that avacopan retained at least 50% of the effect of the comparator (prednisone).

Sample Size and Power Calculation

Based on remission rates from a previous ANCA-AV study of 64% and 53% for rituximab and for cyclophosphamide with azathioprine, respectively, it was estimated that 60% of patients in the ADVOCATE trial’s prednisone group would experience remission at week 26.¹³ It was estimated that a sample size of 300 patients (150 per treatment group) would provide more than 90% power for the noninferiority test and 90% power to detect approximately 18% superiority for remission at week 26 if the rate of remission was 60% in the prednisone group. Based on a previous study comparing rituximab to cyclophosphamide with azathioprine, it was estimated that approximately 45% of patients in the prednisone group would achieve sustained remission at 52 weeks.¹² A sample size of 300 was expected to provide 85% power to detect approximately 18% superiority if the rate of sustained remission was 45% at week 52 in the prednisone group.

Data Imputation

Missing data for the primary end points were imputed as not achieving remission (week 26) or sustained remission (week 52) for the ITT population and were excluded from the PP population. No imputation was performed for other time points. For the first and second primary end points, patients who withdrew from the trial before week 26 and week 52, respectively, were considered as not achieving remission for the primary end point ITT analyses. Patients who discontinued treatment before the key time points but remained in the trial were adjudicated as achieving remission or not for the primary end point ITT analyses. These patients were imputed as not achieving remission for the PP analyses if they had a less than 75% adherence during the first 26 weeks or 52 weeks of the trial, for the respective primary end points.

Sensitivity Analyses

Sensitivity analyses were performed on the primary end point using unstratified analyses, as well as stratified analyses assessing the impact of nonstudy glucocorticoid use. The analyses assessing the impact of glucocorticoids defined high nonstudy glucocorticoid users as nonremitters or excluded patients with high nonstudy glucocorticoid use. Sensitivity analyses for remission were also performed using investigator-assessed (nonadjudicated) results and excluding results from Japan because patients in this region were only enrolled toward the end of the trial. Finally, analyses using alternative definitions of the primary end points were conducted. In these analyses, remission was defined as a BVAS of 0 at relevant time points, irrespective of glucocorticoid use.

Subgroup Analyses

Prespecified subgroup analyses were performed on the primary end points using 6 stratification factors: IV rituximab, IV or oral cyclophosphamide, PR3 ANCA positive, MPO ANCA positive, newly diagnosed ANCA-AV, and relapsed ANCA-AV.

Subgroups based on ANCA-AV type (GPA versus MPA), ANCA positivity (PR3 versus MPO), disease state (newly diagnosed versus relapsing versus refractory), background therapy (cyclophosphamide versus rituximab), and concomitant use of glucocorticoids (yes versus no) were identified as being relevant to the CADTH systematic review.

Secondary Outcomes

Summary statistics, point estimates for treatment differences and corresponding 95% CIs and P values were provided for secondary efficacy end point measures, although these were tested in parallel and none were controlled for multiplicity. BVAS and VDI data were assessed by a blinded, independent adjudication committee, and analysis of relevant outcomes (e.g., remission, relapse, BVAS at week 4, VDI) used adjudicated data. Glucocorticoid use, an input in remission evaluations, was also adjudicated by the committee.

The proportion of patients who achieved the end point of a BVAS of 0 at week 4 was analyzed similarly to the primary end point.

The change from baseline in eGFR for patients with renal disease at baseline was analyzed for the ITT population using a mixed effects model for repeated measures. Model covariates included treatment group, visit, treatment-by-visit interaction, and randomization stratification factors. Missing data were not imputed, and it was assumed that data were missing at random. The percent change from baseline in UACR for patients with renal disease and albuminuria (defined as UACR of at least 10 mg/g creatinine) at baseline was analyzed similarly to the eGFR outcome. These data were not normally distributed and were log_e-transformed before the mixed effects model for repeated measures analysis. LSM differences between treatment groups were back-transformed to calculate the estimate for baseline-adjusted percent reduction from control.

The change from baseline in VDI at week 26 and week 52 was analyzed similarly to the eGFR outcome and included the baseline VDI score in the model. It was found that after the database lock, some VDI scores had decreased (scores can only remain the same or increase). The sponsor concluded that the errors were minor and did not change the conclusions for the outcome.

The proportion of patients who experienced a relapse was determined by the number of patients who relapsed after remission divided by the number of patients who achieved remission at week 26. It was planned that the time to relapse would be analyzed using KM methods and log-rank testing of the treatment group differences; however, due to the small number of patients who relapsed, the median time to relapse was not estimable and KM estimates were not calculated. For patients who did not relapse during the 52 weeks, time to relapse was the time from the week 26 BVAS assessment to the last BVAS assessment during the treatment period, and patients were censored.

The GTI scores at week 13 and week 26 were analyzed for the ITT population similarly to the eGFR and VDI outcomes. The treatment differences at week 13 and week 26 were analyzed using linear contrast from the model. A compound symmetric covariance matrix was used to model the within-patient variance-covariance structure for the model errors.

HRQoL data during the 52-week treatment period were analyzed for the ITT population similarly to the eGFR, VDI, and GTI outcomes, with the same factors and including baseline values as a covariate. A Toeplitz covariance matrix was used to model the within-patient variance-covariance structure for the model errors. If the model did not converge, an autoregressive order 1 covariance matrix was used, and if convergence was not met again, a compound symmetric matrix was used.

Descriptive statistics (proportions) were provided for harms outcomes, and no statistical testing was performed.

Analysis Populations

The randomized population included all patients who provided written informed consent and were randomized in the trial. The ITT population included all patients who were randomized in the trial and who received at least 1 dose of blinded study drug; this was the main population for efficacy analyses. The safety population included all patients who were randomized and had received at least 1 dose of the study drug; this was the main population for safety analyses. The PP population consisted of all patients in the ITT population who were adherent with taking avacopan or placebo and who did not have major protocol deviations that could have significantly affected the interpretation of the results.

Results

Patient Disposition

Patient disposition is summarized in Table 10.

In total, 386 individuals were screened, of whom 55 (14.2%) failed screening, mostly due to not meeting the eligibility criteria. The remaining 331 patients were randomized 1:1 to avacopan (N = 166) or prednisone (N = 165), and all but 1 patient received at least 1 dose of the study drug. The single patient was randomized to the prednisone group but was withdrawn due to their renal biopsy not clearly indicating vasculitis.

Approximately 90% of patients completed all 60 weeks of the trial, and completion rates were balanced between groups. Overall, 22.3% of patients randomized to avacopan and 21.2% of patients randomized to prednisone discontinued early from treatment, with the most common reason being due to AEs (15.7% and 17.6%, respectively). Less than 10% of patients withdrew early from the trial (9.0% and 9.1% in the avacopan and prednisone groups, respectively), with the most common reasons being the patient choosing to withdraw (3.6%) in the avacopan group and AEs (3.6%) in the prednisone group. Reasons for early discontinuation of medication or early discontinuation from the trial were generally balanced between treatment groups.

Table 10: Patient Disposition

ITT = intention to treat; PP = per protocol.

Source: ADVOCATE Clinical Study Report.¹⁹

Exposure to Study Treatments

Exposure to study treatments is summarized in Table 11 and Table 12.

The mean adherence to the study drugs was 86.4% for avacopan (91.5% for matching placebo) and 98.4% for prednisone (89.5% for matching placebo). The mean exposure to avacopan was 305.1 days ||| |||||| ||||| in the avacopan group compared to ||||| |||| || ||||| ||||| || |||||||||||||||| ||||||| || || |||||||||| |||||. Likewise, the mean exposure to prednisone-matched placebo was ||||| |||| || ||||| ||||| in the avacopan group compared to the mean exposure to prednisone of 129.2 days ||| ||||| ||||| in the prednisone group. Median exposures were balanced for active and placebo drugs for both groups and were consistent with the expected durations in the trial (364 days for avacopan or matched placebo and 140 days for prednisone or matched placebo). Mean and median daily doses were similar to the expected doses for avacopan (i.e., 60 mg/day), and doses for avacopan and prednisone were similar between treatment arms. Overall adherence to nonbackground medications was lower in the avacopan group (86.4% and 89.5% for avacopan and prednisone-matched placebo, respectively) than in the prednisone group (91.5% and 98.4% for avacopan-matched placebo and prednisone, respectively). The mean overall glucocorticoid use (including both study-supplied and nonstudy-supplied glucocorticoids) was 1,348.9 mg (SD = 2,040.3 mg) and 3,654.5 mg (SD = 1,709.8 mg) in the avacopan and prednisone groups, respectively.

For background immunosuppressant therapy, 102 patients (30.9%) received IV cyclophosphamide, 14 patients (4.2%) received oral cyclophosphamide, and 214 patients (64.8%) received IV rituximab. Mean and median doses tended to be higher in the prednisone group than in the avacopan group for either form of cyclophosphamide, and doses were mostly balanced for IV rituximab.

Prior and concomitant medication use for ANCA-AV is summarized in Table 13.

Most patients were using glucocorticoids during screening: 75.3% and 82.3% for the avacopan and prednisone groups, respectively. Nearly all patients had some exposure to nonstudy glucocorticoids during the treatment period: 87.3% and 90.9% for the avacopan and prednisone groups, respectively, most of whom used them in the first 29 days of the trial (83.1% and 86.0%, respectively). During follow-up, 29.5% and 34.8% of patients in the avacopan and prednisone groups, respectively, received nonstudy glucocorticoids. Doses were reported for the specified period, rather than per day, and for most specified time periods the mean and median doses in the avacopan group were greater than in the prednisone group. Approximately one-fifth of patients had exposure to other nonprotocol-specified immunosuppressants or other treatments for ANCA-AV: 17.5% and 22.0% for the avacopan and prednisone groups, respectively. Overall, 21 patients (12.7%) in the avacopan group and 15 patients (9.1%) in the prednisone group did not receive nonstudy glucocorticoids.

Table 11: Treatment Exposure (ITT Population)

ITT = intention to treat; SD = standard deviation.

^aAvacopan and avacopan-matched placebo adherence was calculated as number of capsules taken divided by 6 times the number of days in the randomized treatment period times 100. Number of days in the randomized treatment period was the week 52 visit date (or the early termination visit date) minus the date of the first dose plus 1. For adolescents, the formula was altered, with the number of capsules taken daily based on the placebo starting dose and dose adjustments based on avacopan plasma exposure in adolescents. Prednisone and prednisone-matched placebo adherence was calculated as number of capsules taken divided by the number of expected doses in the randomized treatment period times 100. The number of expected doses during the treatment period was based on the prednisone and matching placebo schedule in the protocol.

Source: ADVOCATE Clinical Study Report.¹⁹

Table 12: Background Treatment Exposure (ITT Population)

ITT = intention to treat; SD = standard deviation.

^aEnd of treatment is day 365 or early termination visit.

^bThe n (the denominator for proportions) is the number of patients who used any glucocorticoids during the period (not all patients in period).

Source: ADVOCATE Clinical Study Report.¹⁹

Table 13: Prior and Concomitant Medication Use for ANCA-AV (ITT Population)

ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; ITT = intention to treat; SD = standard deviation.

^aConcomitant IV or oral glucocorticoids other than the prednisone study medication. Dose is the total dose for the specified period.

^bThe n (the denominator for proportions) is the number of patients who used any glucocorticoids during the period (not all patients in the period).

^cEnd of treatment is day 365 or early termination visit.

^dIncludes nonprotocol-specified rituximab, azathioprine, cyclophosphamide, mycophenolate, methotrexate, methotrexate sodium, cyclosporine, tacrolimus, alemtuzumab, belimumab, abatacept, or other immunosuppressants.

^ePatients who did not receive any glucocorticoids during the ADVOCATE trial, including tapered prednisone according to the trial protocol and nonstudy glucocorticoids (e.g., for adrenal insufficiency or allergic reaction).

^fPatients who did not receive nonstudy glucocorticoids but may have received tapered prednisone according to the trial protocol.

Source: ADVOCATE Clinical Study Report.¹⁹

Protocol Deviations

Protocol deviations are summarized in Table 14.

|||||||||| || ||||| |||||||||| || ||||||||| |||||||| ||||||||||| |||| || |||| |||||| ||||||| || |||||||| ||||||||||| || ||||||| ||||||| ||||| |||||||| |||||||||| || || ||||| |||| ||||||||||| |||||||||| || ||||||| |||||||| ||||| |||| |||||||||| || |||||||||| ||||| || |||||||||| || |||||| || ||||||||| |||| || || ||||||||| ||||| |||||||| |||| |||||||| |||| || || ||||||||||| ||||||||| ||| |||||||| ||||| || ||||||||| || || |||||||||| ||||| || ||||||| ||||| || |||| |||||||||||| ||||| |||||||||| ||||||||||| || || |||||||||||| || ||||| |||| || ||||||| ||||| || |||| ||||||||||| || ||||||| |||||| |||| || ||||| ||||||| || |||||||| |||||||||| |||||| || || |||||||||| ||||||||||||||||| |||||||||| || ||||||||| || ||||| |||||||||| ||||| |||| |||| |||| |||| ||||||||| |||||||||| || |||||||| |||| |||||||||| || |||||| || | ||||| ||||||| |||||||| ||||| ||||||||||| |||||||||| |||||| |||| ||||||||| ||||| |||||||| |||| || || ||||||||||| |||||||||||||| |||||||||||| |||||||| || |||| || ||||| |||||||| |||| ||||||| || ||||||||||||| || ||||| || || || |||||||| ||||| || ||||| || |||||||| || || |||||||| || |||||||||| ||||||| ||||||||||||| || |||||||| |||||||||| |||| |||||||| || ||||| ||||||| ||||| ||||||| || ||||||||||||| || |||| || ||||| ||||| || ||||| || |||||||| || || |||||||||| |||||| |||| ||||||| || ||||||||||||| || |||| |||

Table 14: Redacted

|||| ||||||||||||||| ||||||||||| ||||||||||||| |||| ||||||||||| |||||||||| |||||||| |||||| || |||||||||||||| || |||||||| ||||||| |||||||| |||||||||||| |||||||||| |||||||| |||||||||| ||||||||||||||||| ||||||||||||| |||||||||||||| || |||||||||||| || ||||||||| || ||||||||||| |||| |||| || |||||||| |||| |||||| ||||| |||||||||| ||||| || |||||||| ||||||| ||||||||| |||||||| || |||| |||| |||||||||||| |||||||||| || ||||||||| || |||||||| || || |||| |||| |||| || |||||||| |||| |||||| ||||| ||||||||||||||||||| |||||||| |||||||| ||||| |||||||¹⁹

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in this section. Refer to Appendix 3 for detailed efficacy data.

Survival

Survival was not assessed as an efficacy outcome in the ADVOCATE trial but was captured as deaths in the assessment of harm outcomes.

Disease Remission (Induction and Sustained Remission)

Based on the ITT analyses, 72.3% (95% CI, 64.8% to 78.9%) of patients randomized to avacopan and 70.1% (95% CI, 62.5% to 77.0%) of patients randomized to prednisone achieved remission at week 26 (Table 15). The estimate of common difference in remission rates between groups was 3.4% (95% CI, –6.0% to 12.8%; noninferiority P < 0.0001; superiority P = 0.2387). The PP analyses had findings that were consistent with the ITT analyses. The sensitivity analyses results for week 26 were generally consistent with those of the primary outcome. Analyses by randomization stratification factor and subgroup for the primary outcome are summarized in Table 27. Treatment estimates for subgroups were consistent with the primary analysis.

At week 52, 65.7% (95% CI, 57.9% to 72.8%) of patients randomized to avacopan and 54.9% (95% CI, 46.9% to 62.6%) of patients randomized to prednisone achieved sustained remission according to the ITT analyses (Table 15). The estimate of common difference in sustained remission rates between groups was 12.5% (95% CI, 2.6% to 22.3%; noninferiority P < 0.0001; superiority P = 0.0066). The PP analyses had findings that were consistent with the ITT analyses. The week 52 sensitivity analyses and subgroup analyses (Table 28) were generally consistent with those of the week 52 primary outcome.

Table 15: Stratified Analyses of the Proportion of Patients With Disease Remission and Sustained Disease Remission — Primary Outcomes

CI = confidence interval; ITT = intention to treat; PP = per-protocol; SD = standard deviation.

^aClopper and Pearson exact CI.

^bSummary score estimate of the common difference in remission rates using inverse-variance stratum weights.

^cMiettinen-Nurminen (score) confidence limits for the common difference in remission rates.

^dP value has been adjusted for multiple testing (i.e., the type I error rate has been controlled).

Source: ADVOCATE Clinical Study Report.¹⁹

At week 4, 62.7% (95% CI, 54.8% to 70.0%) and 68.9% (95% CI, 61.2% to 75.9%) of patients in the avacopan and prednisone groups, respectively, had a BVAS of 0 (use of glucocorticoids during this period was not considered) (Table 16). The estimate of common difference between groups was –5.6% (95% CI, –15.4% to 4.2%).

Renal Function (e.g., eGFR, Progression to ESKD)

For patients with renal disease at baseline (based on the BVAS renal component), the LSM difference in change from baseline between treatment groups for eGFR was 2.9 mL/min/1.73 m² (95% CI, 0.1 mL/min/1.73 m² to 5.8 mL/min/1.73 m²) at week 26, 3.2 mL/min/1.73 m² (95% CI, 0.3 mL/min/1.73 m² to 6.1 mL/min/1.73 m²) at week 52, and ||| ||||||||||| || |||| || |||| || || ||||||||||| at week 60 (Table 17). Data organized by eGFR category are summarized in Table 29. Seven patients required dialysis during the trial: 3 patients in the avacopan group (1.8%) and 4 patients in the prednisone group (2.4%).

Table 16: Patients Who Achieved BVAS of 0 at Week 4 — Secondary Outcome (ITT Population)

ANCA = antineutrophil cytoplasmic autoantibody; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; BVAS = Birmingham Vasculitis Activity Score; CI = confidence interval; ITT = intention to treat; MPO = myeloperoxidase.

^aThis is a modified version of the BVAS in which the week 4 measurement considered the last 7 days (as opposed to the last 28 days, which is the usual range).

^bCIs for treatment proportions were calculated using the Clopper and Pearson Method.

^cThe 2-sided 95% CI is calculated for the difference in proportions (avacopan minus prednisone), adjusted for randomization strata (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) using the stratified summary score test and the estimate for the common difference in proportions.

^dSuperiority P value is 1-sided.

^eP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: ADVOCATE Clinical Study Report.¹⁹

Table 17: Change From Baseline in eGFR in Patients With Renal Disease at Baseline — Secondary Outcome (ITT Population)

CI = confidence interval; eGFR = estimated glomerular filtration rate; ITT = intention to treat; LSM = least squares mean; MMRM = mixed effects model for repeated measures; SD = standard deviation; SEM = standard error of the mean.

^aAnalysis used MMRMs, with treatment group, visit, and treatment-by-visit interaction as factors and baseline as a covariate. MMRM results by visit use the treatment-by-visit interaction term.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

| |||| || || || |||||||| || || ||||||| |||||| |||| || |||| || |||| |||||| |||||| |||| ||||||||| ||||| || ||||||| || |||||||| || ||||||||||

Source: ADVOCATE Clinical Study Report.¹⁹

For patients with renal disease (based on the BVAS renal component) and albuminuria (defined as UACR of at least 10 mg/g creatinine) at baseline, the LSM ratio for change from baseline in UACR was 1.3 mg/g (95% CI, 1.0 mg/g to 1.6 mg/g) at week 26, 1.1 mg/g (95% CI, 0.9 mg/g to 1.5 mg/g) at week 52, and ||| |||| |||| || | || || ||||| at week 60 (Table 18).

Table 18: Change From Baseline in UACR in Patients With Renal Disease and Albuminuria at Baseline — Secondary Outcome (ITT Population)

CI = confidence interval; ITT = intention to treat; LSM = least squares mean; MMRM = mixed effects model for repeated measures; SEM = standard error of the mean; UACR = urinary albumin–creatinine ratio.

^aAnalysis for LSM, SEM, CI, and P value used MMRMs, with treatment group, visit, and treatment-by-visit interaction as factors and baseline as a covariate. Logarithmic transformations were applied to the data before fitting the model. The 95% CI was transformed back to the original scale. MMRM results by visit use the treatment-by-visit interaction term.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

| |||| || || || |||||||| || || ||||||| |||||| |||| || |||| || |||| |||||| |||||| |||| ||||||||| ||||| || |||||| || |||||||| || ||||||||||

Source: ADVOCATE Clinical Study Report.¹⁹

Systemic Damage (e.g., Measured by VDI)

Based on the data assessed by the adjudication committee, the LSM difference in change of the VDI from baseline between treatment groups was 0.1 (95% CI, –0.1 to 0.3) at week 26, 0.0 (95% CI, –0.2 to 0.3) at week 52, and ||| |||| || |||| || |||| at week 60 (Table 19).

Table 19: Change From Baseline in VDI Score — Secondary Outcome (ITT Population)

ANCA = antineutrophil cytoplasmic autoantibody; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; CI = confidence interval; ITT = intention to treat; LSM = least squares mean; MMRM = mixed effects model for repeated measures; MPO = myeloperoxidase; SD = standard deviation; SEM = standard error of the mean; VDI = Vasculitis Damage Index.

^aAnalysis used MMRMs, with baseline VDI, treatment group, visit, treatment-by-visit interaction, and stratification factors (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) as covariates. MMRM results by visit use the treatment-by-visit interaction term.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^c|||| || || || |||||||| || || ||||||| |||||| |||| || |||| || |||| |||||| |||||| |||| ||||||||| ||||| || ||||||||||||| |||||| |||||| ||||||||| || |||||||| |||||||| |||||||| || |||||||| ||||| | || ||||||||| || |||||||||||||||| || || ||||| |||||||| || |||| |||||||||| || ||||||| || |||||||| || ||||||||||

Source: ADVOCATE Clinical Study Report.¹⁹

Disease Relapse (e.g., Time to Relapse or Duration of Remission, Minor Versus Major)

Of the patients who achieved remission at week 26, 7.5% (95% CI, 3.5% to 13.8%) in the avacopan group and 12.2% (95% CI, 6.8% to 19.6%) in the prednisone group experienced disease relapse (Table 20). The estimate of common difference in rates was –6.0% (95% CI, –14.4% to 2.4%).

An exploratory analysis was conducted on the rate of relapse among patients who achieved a BVAS of 0 at any time during the 52-week treatment period (Table 30). Overall, 95.2% of patients in the avacopan group and 95.7% of patients in the prednisone group had a BVAS of 0 at any time point, and 10.1% and 21.0% of these patients in the respective treatment groups experienced disease relapse. The hazard ratio was 0.46 (95% CI, 0.25 to 0.84) for avacopan versus prednisone. Due to the small number of patients who relapsed, the median time to relapse was not estimable and KM estimates were not calculated.

During the follow-up period, from week 52 to week 60, 3.8% of patients in the avacopan group and 4.5% of patients in the prednisone group experienced disease relapse (Table 31). Also, during the 8-week follow-up, 5.7% of patients in the avacopan group and 7.6% of patients in the prednisone group experienced a worsening BVAS.

Table 20: Proportion of Patients With Disease Relapse After Previously Achieving Disease Remission at Week 26 — Secondary Outcome (ITT Population)

CI = confidence interval; ITT = intention to treat.

^aPatients who achieved remission at week 26, also the denominator for percentage calculations.

^bClopper and Pearson exact CI.

^cSummary score estimate of the common difference in remission rates using inverse-variance stratum weights.

^dMiettinen-Nurminen (score) confidence limits for the common difference in remission rates.

^eP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: ADVOCATE Clinical Study Report.¹⁹

Glucocorticoid Use and Related Toxicities and Safety

The LSM difference between treatment groups for the GTI-CWS was –11.0 (95% CI, –19.7 to –2.2) at week 13 and–16.8 (95% CI, –25.6 to –8.0) at week 26 (Table 21). The LSM difference between treatment groups for the GTI-AIS was –13.3 (95% CI, –22.2 to –4.4) at week 13 and –12.1 (95% CI, –21.1 to –3.2) at week 26. This end point was not assessed at later time points.

Table 21: Glucocorticoid-Induced Toxicity by GTI Score — Secondary Outcome (ITT Population)

ANCA = antineutrophil cytoplasmic autoantibody; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; CI = confidence interval; GTI = Glucocorticoid Toxicity Index; GTI-AIS = Glucocorticoid Toxicity Index Aggregate Improvement Score; GTI-CWS = Glucocorticoid Toxicity Index Cumulative Worsening Score; ITT = intention to treat; LSM = least squares mean; MMRM = mixed effects model for repeated measures; MPO = myeloperoxidase; SEM = standard error of the mean.

^aAnalysis used MMRMs, with treatment group, visit, treatment-by-visit interaction, and stratification factors (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) as covariates.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: ADVOCATE Clinical Study Report.¹⁹

Health-Related Quality of Life

The LSM difference in change from baseline between treatment groups for the SF-36v2 mental component summary was 1.6 (95% CI, –0.6 to 3.8) at week 26, 1.7 (95% CI, –0.5 to 3.9) at week 52, and ||| |||| || |||| || |||| at week 60 (Table 22). The LSM difference in change from baseline between treatment groups for the SF-36v2 physical component summary was 3.1 (95% CI, 1.2 to 5.0) at week 26, 2.4 (95% CI, 0.4 to 4.3) at week 52, and ||| |||| || |||| || |||| at week 60.

The LSM difference in change from baseline between treatment groups for the EQ VAS was 3.6 (95% CI, –0.1 to 7.2) at week 26, 5.9 (95% CI, 2.3 to 9.6) at week 52, and ||| |||| || |||| || |||| at week 60 (Table 23). The LSM difference in change from baseline between treatment groups for the EQ-5D-5L index score was 0.0 (95% CI, 0.0 to 0.1) at week 26, 0.1 (95% CI, 0.0 to 0.1) at week 52, and ||| |||| || || || |||| at week 60.

Hospitalizations

Hospitalizations were not assessed in the ADVOCATE trial.

Symptoms

Symptoms (e.g., fatigue) were not assessed as an efficacy outcome in the ADVOCATE trial, but some may have been captured as harm outcomes.

Table 22: SF-36v2 Mental Component Summary and Physical Component Summary — Secondary Outcome (ITT Population)

ANCA = antineutrophil cytoplasmic autoantibody; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; CI = confidence interval; ITT = intention to treat; LSM = least squares mean; MMRM = mixed effects model for repeated measures; MPO = myeloperoxidase; SD = standard deviation; SEM = standard error of the mean; SF-36v2 = Short Form (36) Health Survey version 2.

^aAnalysis used MMRMs, with treatment group, visit, treatment-by-visit interaction, and randomization strata (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) as factors and baseline as a covariate. MMRM results by visit use the treatment-by-visit interaction term.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

| |||| || |||| |||| |||| |||||| |||||| |||| ||||||||| ||||| || ||||||||||||| |||||| |||||| ||||||||| || |||||||| |||||||| |||||||| || |||||||| ||||| | || ||||||||| || |||||||||||||||| || || ||||| |||||||| || |||| |||||||||| || ||||||| || |||||||| || |||||||||.

Source: ADVOCATE Clinical Study Report.¹⁹

Table 23: EQ Visual Analogue Scale and EQ-5D-5L Index Scores — Secondary Outcome (ITT Population)

ANCA = antineutrophil cytoplasmic autoantibody; ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; CI = confidence interval; EQ-5D-5L = 5-Level EQ-5D; ITT = intention to treat; LSM = least squares mean; MMRM = mixed effects model for repeated measures; MPO = myeloperoxidase; SD = standard deviation; SEM = standard error of the mean.

^aAnalysis used MMRMs, with treatment group, visit, treatment-by-visit interaction, and randomization strata (newly diagnosed or relapsed ANCA-AV, anti-PR3 or anti-MPO ANCA, and IV rituximab or IV or oral cyclophosphamide standard of care treatment) as factors and baseline as a covariate. MMRM results by visit use the treatment-by-visit interaction term.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

| |||| || || || |||||||| || || ||||||| |||||| |||| || |||| |||||| |||||| |||| ||||||||| ||||| || ||||||||||||| |||||| |||||| ||||||||| || |||||||| |||| |||||||| || |||||||| ||||| || || ||||||||| || |||||||||||||||| || || ||||| |||||||| || |||| |||||||||| || ||||||| | |||||||| || ||||||||||.

Source: ADVOCATE Clinical Study Report.¹⁹

Harms

Only those harms identified in the review protocol are reported in this section; they are also summarized in Table 24.

Adverse Events

Nearly all patients in the avacopan group (98.8%) and prednisone group (98.2%) experienced at least 1 TEAE. The 3 most common AEs in the avacopan group were nausea (23.5% avacopan versus 20.7% prednisone), peripheral edema (21.1% avacopan versus 24.4% prednisone), and headache (20.5% avacopan versus 14.0% prednisone). Other AEs occurred at a frequency of less than 20% in the avacopan group. Headache was the only AE that appeared to be notably more common in the avacopan group than in the prednisone group. The most common AEs in the prednisone group were peripheral edema, muscle spasms (22.6% prednisone versus 10.8% avacopan), arthralgia (22.0% prednisone versus 18.7% avacopan), nausea, and ANCA-positive vasculitis (20.7% prednisone versus 15.7% avacopan), with other AEs occurring at a frequency of less than 20% in the prednisone group. Muscle spasms, ANCA-positive vasculitis, insomnia (15.2% prednisone versus 7.8% avacopan), urinary tract infection (14.0% prednisone versus 7.2% avacopan), hypercholesterolemia (12.2% prednisone versus 7.2% avacopan), lymphopenia (11.0% prednisone versus 3.6% avacopan), and increased weight (10.4% prednisone versus 0.6% avacopan) appeared to be notably more common in the prednisone group than in the avacopan group. Harms categorized by system organ class that had a greater than 10% difference in proportion between treatment groups included eye disorders and endocrine disorders (greater in the prednisone group), as well as gastrointestinal disorders (greater in the avacopan group).

Serious AEs

Overall, 42.2% of patients in the avacopan group and 45.1% of patients in the prednisone group experienced at least 1 SAE. The most common SAEs were ANCA-positive vasculitis (7.2% avacopan versus 12.2% prednisone) and pneumonia (5.4% avacopan versus 5.5% prednisone). ANCA-positive vasculitis had the greatest difference in frequency between treatment groups; other SAEs were generally similar.

Withdrawal Due to AEs

In total, 15.7% of patients in the avacopan group and 17.7% of patients in the prednisone group stopped treatment due to AEs. The most common AE that led to withdrawal from treatment was ANCA-positive vasculitis (2.4% avacopan versus 4.9% prednisone), and other such AEs occurred at a frequency of less than 2% in either group. The frequencies of AEs that led to withdrawal from treatment were generally similar between treatment groups.

Mortality

Six patients died during or after the treatment period in the ADVOCATE trial (2 patients receiving avacopan and 4 patients receiving prednisone), and causes of death were reported by a single patient for each cause.

Notable Harms

Serious Infection

Treatment-emergent infections were reported in 68.1% and 75.6% of patients in the avacopan and prednisone groups, respectively. Serious treatment-emergent infections were reported in 13.3% and 15.2% of patients in the avacopan and prednisone groups, respectively, of which pneumonia was the most common serious infection-related TEAE (5.4% and 5.5%, respectively). Infections resulted in 9 patients (4 in the avacopan group and 5 in the prednisone group) withdrawing from the trial and 3 deaths (1 in the avacopan group and 2 in the prednisone group).

Hepatic Injury (e.g., Increased ALT or AST, Total Bilirubin)

Elevated ALT was reported by 4% and 2% of patients in the avacopan and prednisone groups, respectively; elevated AST was reported in 2% of patients in the avacopan group and no patients in the prednisone group; and elevated blood bilirubin was reported in 2% and 1% of patients in the avacopan and prednisone groups, respectively.

Cardiovascular AEs (e.g., Myocardial Infarction, Cardiac Failure, Cardiac Vasculitis)

Acute myocardial infarction was reported by 1.2% of patients in the prednisone group and 0.6% of patients in the avacopan group, and cardiac failure was reported by 1.2% of patients in the avacopan group and no patients in the prednisone group. Cardiac vasculitis was not reported in the trial.

Gastrointestinal AEs (e.g., Dyspepsia, Vomiting, Nausea, Diarrhea)

Nausea was reported by 23.5% and 20.7% of patients in the avacopan and prednisone groups, respectively; diarrhea was reported by 15.1% and 14.6% of patients, respectively; vomiting was reported by 15.1% and 12.8% of patients, respectively; and dyspepsia was reported by 3.0% and 6.1% of patients, respectively.

Immune-Related AEs (e.g., Angioedema)

Angioedema was reported by 1.2% of patients in the avacopan group and no patients in the prednisone group.

Table 24: Summary of Harms (Safety Population)

AE = adverse event; ALT = alanine aminotransferase; ANCA = antineutrophil cytoplasmic autoantibody; AST = aspartate aminotransferase; GPA = granulomatosis with polyangiitis; NR = not reported; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aFrequency of greater than 10% in either treatment group.

^bWorsening of vasculitis is reported as the preferred term of “antineutrophil cytoplasmic antibody-positive vasculitis.”

^cFrequency of greater than 2% in either treatment group.

^dFrequency of greater than 1% in either treatment group.

^eNo autopsy was performed.

Source: ADVOCATE Clinical Study Report.¹⁹

Critical Appraisal

Internal Validity

In the ADVOCATE trial, the risk of bias arising from the randomization process is low. Stratified randomization was performed centrally, and a few baseline imbalances were noted, which may have been due to chance given the relatively small sample size. The sample size and power calculations were informed by previous studies on the treatment of patients with ANCA-AV and were adequate for noninferiority and superiority testing of the primary outcome.

There are concerns about bias due to deviations from the intended intervention. Patients received active treatment with matching placebos for both prednisone and avacopan, and patients appeared to be adequately blinded to treatments. Discontinuations from treatment were similar between groups, mostly due to AEs; more than 20% of patients in each group discontinued treatment, which is not an insignificant proportion of the total population. Additionally, the use of nonstudy immunosuppressants and glucocorticoids was an issue that likely biased results. The direction and magnitude of the bias are not fully clear. During the 52-week treatment period, 19.7% of patients in the trial used nonstudy immunosuppressants or other ANCA-AV treatments. Nonstudy glucocorticoid use was not considered a protocol violation, and patients could continue in the trial despite receiving glucocorticoids for reasons related to ANCA-AV (e.g., rescue therapy to treat disease relapse or worsening disease involving a major item on the BVAS) or for other reasons (e.g., adrenal insufficiency, allergic reaction). During the 52-week treatment period, 89.1% of patients in the trial used nonstudy glucocorticoids. The intent of the trial was to determine whether avacopan could induce and sustain remission without chronic glucocorticoid use at the levels currently used in standard of care regimens. However, the CADTH review team was unable to determine whether avacopan alone could accomplish this because most patients used nonstudy glucocorticoids and data for those who did not use glucocorticoids were unavailable. Nonstudy medication use is problematic for quantifying the effect of avacopan treatment alone for both efficacy and harm outcomes. Consequently, the Health Canada indication has specified avacopan as an add-on or adjunctive therapy to standard treatment rather than as a glucocorticoid-sparing drug.^2,20 Similarly, the FDA stated that the week 26 noninferiority assessment “is not the intended comparison of avacopan versus prednisone, but instead a comparison of avacopan plus lower dose glucocorticoids versus higher dose glucocorticoids.”²¹

The noninferiority margin was chosen based on a meta-analysis of 20 published studies, but the FDA reported that the noninferiority margin was not informed by a placebo-controlled trial for glucocorticoids as add-on to standard therapy and that, instead, single-arm results from studies were used.²¹ Further, the FDA noted that it is uncertain how similar or dissimilar the studies used to inform the margin were to the ADVOCATE trial and that there may have been heterogeneity between eligible study populations, patient characteristics, the definition of outcomes, and time points for assessments.²¹ The results of the ADVOCATE trial’s ITT and PP analyses were generally consistent because the populations were very similar. Patients who used nonstudy immunosuppressants or glucocorticoids could still be included in the PP analyses; the use of nonstudy immunosuppressants was a protocol violation, and patients were imputed as nonremission, whereas the use of glucocorticoids was not considered a protocol violation.

The risk of bias related to missing outcome data are low for the primary outcome. Analyses were based on the ITT population, which is appropriate for assessing the effect of assignment to the intervention. Findings for the PP population were provided for the primary outcomes, which is relevant given that this is likely to provide a more conservative estimate for noninferiority testing. While 9% of patients withdrew early from the study, data imputation methods were conservative for the PP analyses, with a similar amount of imputation between groups for patients who did not achieve remission at week 26 or sustained remission at week 52. For other outcomes, there was no imputation of missing data, which may have introduced bias to varying extents. The potential for bias is most apparent at later time points, due to both early withdrawal from the trial and other reasons, which resulted in data for about 10% of participants being missing (e.g., for HRQoL). Missing data tended to be relatively balanced across groups, resulting in an unclear direction of the potential bias.

Most of the outcome measures are affected by at least some degree of subjectivity, but they were centrally adjudicated, eliminating concerns for bias in the measurement of the outcome. However, there is some potential for bias related to the subjectivity of the patient-reported outcomes, especially if treatment became unblinded (e.g., due to known adverse effects of treatment). According to the literature, only the BVAS and the VDI appear to be adequately validated for ANCA-AV, although this does not apply to the BVAS at week 4, which had a shortened recall period in the ADVOCATE trial; additionally, no published MIDs were identified for a population with ANCA-AV. Additionally, Health Canada found no evidence of validation of the GTI in patients with ANCA-AV, although there is literature supporting validation in patients with asthma;⁴³ Health Canada considered the GTI to be unvalidated and too general to be clinically meaningful for ANCA-AV.²⁰ Additionally, secondary outcomes were not controlled for multiplicity, and between-group differences for several secondary outcomes (e.g., week 4 BVAS, UACR, VDI, patients experiencing disease relapse, SF-36v2, and EQ-5D-5L and EQ VAS) were relatively small with wide CIs.

All analyses were based on a prespecified statistical analysis plan; therefore, there is no concern for bias in the selection of the reported result.

External Validity

The clinical expert confirmed that the baseline demographics and disease characteristics of patients in the trial were similar to those of patients seen in clinical practice. The expert indicated that the proportion of patients with kidney involvement and with MPA in the ADVOCATE trial were higher than global cohorts of patients with ANCA-AV. It was explained that the specialist at a particular clinic will tend to dictate what type of patient attends the site; for instance, nephrologists manage mostly patients with kidney disease and MPA, and rheumatologists manage a mix of patients with GPA or MPA. The clinical expert stated that patients are generally treated in the same manner, regardless of whether they have GPA or MPA, and did not expect the differences to impact generalizability to practice. Overall, 18% of patients enrolled in the trial were from North America, and 13 patients (3.9%) were from Canada. Although this is a relatively small proportion of the total trial population, it helps to support the generalizability to patients with ANCA-AV in Canada. The clinical expert confirmed that the proportions of patients receiving cyclophosphamide or rituximab as induction therapy in the ADVOCATE trial were similar to the estimated proportions in Canada: 35% received cyclophosphamide (oral or IV) and 65% received rituximab in the trial compared to approximately 40% receive cyclophosphamide (oral or IV) and 60% receive rituximab in Canada.

Of the 386 individuals screened in the ADVOCATE trial, 14.2% failed screening, with the most common reason being not meeting eligibility criteria. According to the clinical expert, patients who met the trial’s eligibility criteria were generally similar to those seen in Canadian practice, but there were a few criteria that would prevent generalization to a broader population with ANCA-AV, who might also be treated with avacopan. For instance, the trial included only patients who had tested positive for anti-PR3 or anti-MPO antibodies at screening or historically, essentially ruling out patients who have only had negative antibody results. It has been noted, both in the literature and by the clinical expert, that a small proportion of patients are ANCA negative.²³ These patients can have an ANCA-AV status confirmed by other tests, and the clinical expert suggested that they would be treated similarly if the diagnosis was certain (e.g., with renal biopsy). Patients with very severe disease (e.g., patients who have alveolar hemorrhage requiring invasive pulmonary ventilation support or dialysis or patients who have an eGFR less than 15 mL/min/1.73 m²) were also excluded from the ADVOCATE trial. It is possible that these patients could be treated with avacopan, but it is uncertain if they would have comparable outcomes to patients in the trial. Lastly, although the Health Canada indication for avacopan is for adults, there is limited evidence of its use in the pediatric population.

The medications and doses used in the ADVOCATE trial were mostly consistent with those outlined in the CanVasc recommendations and used in clinical practice according to the clinical expert, with an important exception: rituximab was not used as maintenance therapy in the trial.^9,47 Understandably, at the time of protocol development, rituximab was not approved as a maintenance therapy for ANCA-AV and therefore was not used. Nevertheless, this is an issue because not only did no patients receive rituximab maintenance therapy (regardless of induction therapy), but patients who received rituximab for induction of remission did not receive any standard of care maintenance therapy in the trial. Furthermore, it was unclear to the CADTH review team and the clinical expert whether the addition of avacopan to rituximab maintenance therapy would make a meaningful difference if these treatments were to be used in clinical practice today, and there is currently a lack of clinical data on this usage. The FDA pointed out that prednisone was tapered at a protocol-defined fixed rate instead of the tapering being determined by disease activity.²¹ However, the latest addendum (2022) to the CanVasc recommendations states that with avacopan, clinicians can consider tapering glucocorticoids using a faster protocol with the aim of discontinuation by the end of week 4, and this is done “in conjunction with best clinical judgement” and “close clinical monitoring for disease worsening.”²⁵ The FDA also noted that the use of glucocorticoids was similar between treatment groups in the second half of the trial; the notable difference between groups occurred in the first half of the trial, specifically during the first 20 weeks, when prednisone was tapered.²¹ Therefore, the apparent difference in glucocorticoid use between groups is more likely attributable to the trial design (i.e., the tapering schedule) than to a change in disease activity such as avacopan effectively controlling ANCA-AV.²¹

The patient group highlighted outcomes relating to quality of life, organ involvement, vasculitis symptoms, and glucocorticoid use as being important, and these mostly aligned with the trial outcomes. The clinical expert also confirmed that the trial outcomes of remission, kidney function, systemic disease, disease relapse, glucocorticoid toxicity, and HRQoL were clinically relevant to ANCA-AV. Nevertheless, some limitations make it challenging to interpret the meaningfulness of the results. For example, the clinical expert confirmed that the instruments used in the ADVOCATE trial are not used in clinical practice (although they may be useful for informing clinicians of treatment effects) and that only the BVAS and the VDI were specific to ANCA-AV (refer to Appendix 4). Hospitalizations and ANCA-AV symptoms were identified as being important to patients but were not specifically assessed in the trial through, for example, hospitalization events or symptom scales.

There was no rationale for the trial duration being 52 weeks or the follow-up being 8 weeks. These are major limitations, and there is a lack of data on the efficacy and safety of avacopan for less than or more than 52 weeks. Also, due to the relatively short follow-up period, it is uncertain what the long-term effects after discontinuing avacopan treatment could be. Moreover, there was no discussion or indication from the trial about what posttreatment strategies should be used to manage patients with ANCA-AV (e.g., continue avacopan beyond 12 months, provide maintenance therapy without avacopan after the 12 months of initial treatment).

Discussion

Summary of Available Evidence

One double-blind, phase III, placebo-controlled randomized controlled trial (ADVOCATE) was included in the CADTH systematic review. The ADVOCATE trial (N = 331) was designed to investigate the efficacy and safety of avacopan in patients with ANCA-AV, with the aim to determine if avacopan could induce and sustain remission without chronic glucocorticoid use at the levels currently used in standard of care regimens. The trial compared avacopan to prednisone tapered over 20 weeks, with respective matching placebos, in addition to standard of care therapy (IV or oral cyclophosphamide followed by azathioprine, or IV rituximab without maintenance therapy) over 52 weeks with an 8-week follow-up. Patients in either group could receive nonstudy-specified glucocorticoids for reasons related to ANCA-AV (e.g., rescue therapy to treat disease relapse or worsening disease involving a major item on the BVAS) or for other reasons (e.g., adrenal insufficiency, allergic reaction). Eligible patients included adults who had a clinical diagnosis of GPA or MPA, were ANCA positive for either anti-PR3 or anti-MPO antibodies, and had active disease at screening. The mean age of patients was 60.9 years (SD = 14.5 years), more than half were male (56.5%), and most were white (84.3%). The primary outcomes were the proportions of patients who achieved disease remission at week 26 and sustained disease remission at week 52. Key secondary outcomes included glucocorticoid toxicity, HRQoL, kidney function, systemic damage, and the proportion of patients experiencing disease relapse. Harms and notable harms identified in the CADTH systematic review protocol were also assessed.

Interpretation of Results

Efficacy

Based on the ADVOCATE trial, avacopan — when provided with nonprotocol glucocorticoids — was noninferior to prednisone for disease remission at week 26 (but not superior at week 26) and was superior to prednisone for sustained disease remission at week 52. Subgroup analyses were aligned with the main analyses. The findings need to be interpreted with consideration of the main limitations of the trial, which include the use of nonstudy immunosuppressants, the use of nonstudy glucocorticoids, and the inclusion of a comparator arm that no longer aligns with present day standards of practice (although was aligned at the time that the protocol was developed). As a result, conclusions about the comparison of avacopan alone to prednisone (as specified in the ADVOCATE protocol) cannot be established because the true comparison described in the study results was avacopan with glucocorticoids versus prednisone, both in the presence of background immunosuppressant treatment. In addition, the relevance of the comparison to clinical practice needs to be interpreted with consideration of changes in practice that have occurred since the development of the study protocol. The clinical expert consulted by CADTH noted that rituximab maintenance (which is the current recommended first-line standard of care maintenance therapy but which was not used in the trial) reduces the rate of relapse to about 5% at 2 years.⁹ The ADVOCATE trial does not provide information that can be used to determine whether avacopan, with or without glucocorticoids, would be noninferior to the current recommended standard of care maintenance therapy. Finally, there is a lack of long-term data to inform understanding of the efficacy and safety of avacopan beyond 52 weeks.

Overall, only 21 patients (12.7%) in the avacopan group and 15 patients (9.1%) in the prednisone group did not receive nonstudy glucocorticoids in the trial, and data were not available for this subset of patients. The mean doses for any glucocorticoids used in the trial were 1,348.9 mg (SD = 2,040.3 mg) and 3,654.5 mg (SD = 1,709.8 mg) for the avacopan and prednisone groups, respectively, during the treatment period. Removing the protocol-tapered prednisone, the mean doses for just nonstudy glucocorticoids were 1,348.9 mg (SD = 2,040.3 mg) and 1,265.3 mg (SD = 1,650.6 mg) for the avacopan and prednisone groups, respectively, during the treatment period. Although the mean dose for any glucocorticoids is lower in the avacopan group, the difference may be inflated due to the use of protocol-specified prednisone during the first 20 weeks, and the mean dose appears to be greater in the avacopan group when looking at only nonstudy glucocorticoids. It is also unclear if these doses are high enough to effectively treat ANCA-AV or cause additional adverse effects.

The clinical expert indicated that the rates of remission in the trial were lower than what would be expected in practice but explained that it was likely because the trial’s definition of remission specified no glucocorticoids within 4 weeks of assessment, whereas in practice, patients may achieve remission with or without glucocorticoids. Further, the expert clarified that, in practice, remission is determined based on clinical judgment of no disease activity rather than using the BVAS as a formal tool as was done in the trial. According to the expert, the result of the BVAS is dichotomous rather than longitudinal or continuous in nature, such that a patient either has active disease (score greater than 0) or not (score of 0), and as such changes in the score are less meaningful. Although the trial outcomes were related to those considered important to patients according to the stakeholder input CADTH received, there were limitations that make it challenging to be certain of how meaningful the results are. Examples of these limitations are as follows: the clinical expert confirmed that none of the instruments used in the trial (e.g., BVAS, GTI, VDI, SF-36v2, EQ-5D-5L, EQ VAS) are used in routine clinical practice (although they may still inform clinicians of treatment effects), only the BVAS and the VDI were adequately validated for ANCA-AV, none of the trial end points had published MIDs for a population with ANCA-AV, and none of the secondary outcomes were controlled for multiplicity (i.e., there is some risk of a false-positive finding).

The eGFR and UACR results appeared to support avacopan treatment, but changes were small throughout the trial, and without published MIDs from the literature for this population, interpretation relies on clinical expert opinion. The clinical expert suggested that a 5 mL/min/1.73 m² change in eGFR could be interpreted as meaningful based on the MID for patients with diabetes but confirmed that there is no MID for patients with ANCA-AV and cautioned that the suggested estimate was based on a different patient population. VDI scores showed little to no difference between groups. the clinical expert explained that, as with the BVAS, items on the VDI carry the same weight in score but are not necessarily of equal clinical significance. Therefore, the change in magnitude of the total VDI score is less meaningful than assessing what clinical changes occurred, thus making it challenging to draw meaningful conclusions for this outcome.

The trial did not differentiate between major and minor relapses, which the clinical expert stated was a shortcoming because the reasons for relapse can vary from nasal symptoms to more serious respiratory or kidney failures. The CI was too wide to draw a conclusion about the proportion of relapses in the avacopan group versus in the prednisone group. The GTI scores indicated fewer glucocorticoid-related toxicities for the avacopan group, which the clinical expert felt was reasonable because this group received placebo prednisone instead of active prednisone tapered during the first 20 weeks. Based on evidence from the literature, a MID of 10 was estimated in a mixed population, including patients with ANCA-AV, which the LSM differences between treatment groups met for both GTI-CWS and GTI-AIS at week 26.⁴³ There is evidence of validity of the GTI for patients with asthma, although this validity is unclear for other patient populations.⁴³ Health Canada stated that the GTI was not validated for ANCA-AV and that “the end point was not specific enough to be discriminatory between treatment” groups.²⁰ HRQoL measures showed similarity between treatment groups, with wide CIs. Lastly, the results from the 8-week follow-up for eGFR, VDI, SF-36v2, EQ-5D-5L, and EQ VAS showed that the small differences between groups during the trial may not have been sustained after stopping avacopan and that the treatment differences during follow-up also had wide CIs. Hospitalizations and ANCA-AV symptoms were identified as being important to patients but were not specifically captured in the trial, for example as hospitalization events or through specific symptom scales.

The main limitations were the deviations from both current recommended standard of care treatment (rituximab maintenance) and the trial’s intended comparison (avacopan versus prednisone). The clinical expert indicated that the trial’s tapering regimen (20 weeks, or 5 months) was on the shorter end of what is considered standard (average 6 to 7 months in practice) but confirmed that it was acceptable, which is consistent with the 2022 addendum to the CanVasc recommendations for a faster glucocorticoid taper with clinical judgment and close clinical monitoring.²⁵ The FDA pointed out that the tapering of glucocorticoids was performed at a fixed rate and dictated by the protocol rather than being based on disease activity, the latter of which is used in practice.²¹ The clinical expert noted that protocolized tapering would be necessary to reduce subjectivity and increase uniformity of treatment for the purposes of a clinical trial. Due to the lack of rituximab maintenance therapy, patients may have been undertreated, putting them at a higher risk of relapse and making them less likely to achieve sustained remission.⁴⁸ Thus, it is possible that the rates of relapse in the ADVOCATE trial do not accurately reflect expected outcomes with current clinical practice.⁴⁸ The use of nonstudy glucocorticoids for 89% of the trial’s population and the lack of data for the remaining 11% make it difficult to assess avacopan versus prednisone without additional glucocorticoids. The clinical expert indicated that avacopan along with standard of care immunosuppressant therapy (i.e., rituximab or cyclophosphamide) should be used only if there is a meaningful reduction of glucocorticoids. Although there is no standard definition for what a meaningful reduction would be, the expert stated that it would be ideal if patients were on no glucocorticoids. Another major issue was that treatment duration stopped at 12 months, with only 8 weeks of posttreatment follow-up, and there was no rationale for these time frames. The clinical expert indicated that most patients should receive least 2 years of maintenance therapy to better ensure long-term sustained remission, which could include using avacopan longer than 12 months, although it must be taken into consideration that the limited data for long-term treatment and follow-up with avacopan result in uncertainty about how long avacopan can be used as well as how patients should be managed after discontinuing the drug. More evidence is needed to understand avacopan’s efficacy and safety in addition to rituximab maintenance therapy, long-term patient management with or without avacopan, and whether the drug can eliminate glucocorticoid use.

Harms

Nearly all patients in the trial experienced at least 1 TEAE, with the most common being nausea, peripheral edema, and headache for the avacopan group and peripheral edema, muscle spasms, and arthralgia for the prednisone group. Most events were balanced between treatment groups, and the clinical expert indicated that there was no clear reason for those that appeared imbalanced (e.g., headache, muscle spasms, insomnia). More than 42% of patients in each group experienced at least 1 SAE, and more than 15% of patients in each group stopped treatment due to an AE. There were 6 deaths during the trial (2 patients in the avacopan group and 4 patients in the prednisone group).

Notable harms were generally balanced between treatments, aside from treatment-emergent infections, and there did not appear to be any clear safety signal in the avacopan group. Serious infections were a significant concern raised in the inputs provided by the patient group, the clinician group, and the clinical expert consulted by CADTH. Treatment-emergent infections were higher in the prednisone group than in the avacopan group (75.6% and 68.1%, respectively), although the difference was not as large as would be expected in the ADVOCATE trial, where the aim was to eliminate glucocorticoids and the associated increased risk of infection. The clinical expert noted that rates were lower but still frequent in the avacopan group possibly due to patients in both groups being on immunosuppressants and/or receiving nonstudy glucocorticoids throughout the trial. This was also confirmed by a report from Health Canada.²⁰ Although there did not appear to be a difference in hepatic injury (for events identified as notable harms in the CADTH systematic review), Health Canada noted that hepatic AEs were more frequent in the avacopan group than in the prednisone group, and hepatic AEs have been identified under the warnings and precautions of the product monograph.^2,20

Similar to the efficacy results, the major limitations with the safety results re the lack of evidence for avacopan in addition to rituximab maintenance therapy as well as the lack of data for the long-term use of avacopan with or without other treatments for ANCA-AV. Health Canada has noted that the sponsor plans to gather long-term data for up to 36 months through a postauthorization safety study, which will include AEs of special interest such as liver injury, serious infections, malignancies, and cardiovascular events.²⁰ The input provided by the patient group raised concerns over glucocorticoid-related harms as well as symptoms related to kidney damage, fatigue, trouble breathing, infections, and pain. Given the mostly balanced harms results, the use of nonstudy glucocorticoids for the majority of patients, and the challenges with interpreting the GTI scores, it is unclear whether avacopan provides an advantage that would be acceptable to patients. More safety evidence, particularly for avacopan without glucocorticoids, is needed to know if avacopan provides a meaningful benefit over other treatments.

Overall, no clear safety concerns were raised by the clinical expert, and aside from the lower rates of treatment-emergent infections in the avacopan group, harms were generally balanced between the groups. However, this is applicable for only 12 months of treatment of the eligible population under specific trial conditions. More information is needed for patients who may be treated with avacopan but were excluded from the trial as well as for long-term treatment with the drug.

Conclusions

Avacopan 30 mg (3 capsules of 10 mg each) twice daily with nonprotocol-specified glucocorticoids was compared to oral prednisone tapered over 20 weeks in addition to nonprotocol-specified glucocorticoids over a 12-month treatment period. Treatments were combined with background therapy of IV or oral cyclophosphamide followed by azathioprine, or IV rituximab without maintenance therapy. Avacopan 30 mg twice daily was noninferior to oral prednisone in achieving disease remission at week 26 and was superior for sustained disease remission at week 52. Notably, 89% of patients received nonprotocol-specified glucocorticoids at some point during the ADVOCATE trial. Outcomes related to kidney function, systemic damage, disease relapse, glucocorticoid toxicity, and HRQoL provided limited support for the primary outcomes. Harms were generally balanced between groups in the trial, and no notable safety concerns were identified. The relevance of the findings to current standards of practice is unclear due to the lack of rituximab maintenance in both treatment groups, which is the current gold standard. It is unclear whether the findings would be generalizable to patients who are ANCA negative or who have very severe disease (e.g., patients who have alveolar hemorrhage requiring invasive pulmonary ventilation support or dialysis or patients who have an eGFR less than 15 mL/min/1.73 m²). Although the clinical expert suggested that avacopan could be used beyond 1 year, data to support long-term efficacy and safety beyond 12 months are not available at this time, and how patients should be managed after stopping avacopan is unknown. More evidence is needed to better understand the long-term efficacy and safety of avacopan and whether it can be used to effectively eliminate glucocorticoid use.

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Appendix 1: Literature Search Strategy

Note this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: November 9, 2022

Alerts: Biweekly search updates until project completion

Search filters applied: None

Limits:

• Conference abstracts: excluded

Table 25: Syntax Guide

Multidatabase Strategy

1. (Tavneos* or avacopan* or CCX168 or CCX 168 or vynpenta*).ti,ab,kf,rn,nm,hw,ot.

2. O880NM097T.rn,nm.

3. or/1-2

4. 3 use medall

5. *Avacopan/

6. (Tavneos* or avacopan* or CCX168 or CCX 168 or vynpenta*).ti,ab,kf,dq.

7. or/5-6

8. 7 use oemezd

9. conference abstract.pt.

10. 8 not 9

11. or/4,10

12. remove duplicates from 11

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search -- Studies with results | avacopan]

WHO ICTRP

International Clinical Trials Registry Platform, produced by the WHO. Targeted search used to capture registered clinical trials.

[Search terms -- avacopan]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms -- avacopan]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms -- avacopan]

Grey Literature

Search dates: September 23, 2020 – October 4, 2020

Keywords: Tavneos, avacopan, vasculitis, C5aR

Limits: None

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

• Open Access Journals.

Appendix 2: Excluded Studies

Note this appendix has not been copy-edited.

Table 26: Excluded Studies

Appendix 3: Detailed Outcome Data

Note this appendix has not been copy-edited.

Table 27: Proportion of Patients With Disease Remission at Week 26 Analyzed by Stratification Factor and by Subgroup (ITT Population)

ANCA-AV = antineutrophil cytoplasmic autoantibody–associated vasculitis; CI = confidence interval; GPA = granulomatosis with polyangiitis; ITT = intention to treat; MPA = microscopic polyangiitis; MPO = myeloperoxidase.

^a95% CIs for treatment proportions are calculated using the Clopper and Pearson Method.

^bTwo-sided 95% CIs are calculated for the difference in proportions (avacopan minus prednisone) using the Wald Method.

Source: ADVOCATE Clinical Study Report.¹⁹

Table 28: Proportion of Patients With Sustained Disease Remission at Week 52 Analyzed by Stratification Factor and by Subgroup (ITT Population)