CADTH Reimbursement Review

Upadacitinib (Rinvoq)

Sponsor: AbbVie

Therapeutic area: Ulcerative colitis

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

NOC = Notice of Compliance.

Introduction

Ulcerative colitis (UC) is the most common form of inflammatory bowel disease (IBD). Depending on the extent and severity of the disease, patients with UC may present with diarrhea with or without blood and mucus, urgency or tenesmus, incontinence, constipation, colicky abdominal pain, fever, malaise, and weight loss.^1,2 Regardless of severity, UC is also associated with high rates of fatigue and sleep difficulties.³ The disease has negative physical, emotional, and social impacts on patients. Aggressive disease course is experienced in 10% to 15% of patients. It was estimated that more than 120,000 people in Canada lived with UC in 2018.⁴

The selection of treatment regimens for UC is guided by disease severity and extent.⁵ While different drug classes are available for the long-term management of moderately to severely active UC, biologic therapies are the mainstay of treatment for patients with moderate to severe UC and are used for induction and maintenance when other treatments have been unsuccessful, or in those who cannot tolerate other treatments. At present, biologics include tumour necrosis factor (TNF) alpha antagonists (adalimumab, infliximab, and golimumab), anti-integrin drugs (vedolizumab), and interleukin 12 (IL-12) and interleukin 23 (IL-23) antagonists (ustekinumab). Small-molecule drugs, which include Janus kinase (JAK) inhibitors (tofacitinib) and the sphingosine 1-phosphate (S1P) receptor agonist ozanimod, are also used in patients with moderate to severe UC. Despite access to a variety of treatment options, not all patients respond to the available treatments and their condition may become refractory to the current treatment regimens.

Upadacitinib is a selective JAK1 inhibitor approved by Health Canada for the treatment of adult patients with moderately to severely active UC who have demonstrated treatment failure, i.e., an inadequate response, loss of response, or intolerance to at least 1 conventional and/or biologic therapy. Upadacitinib is available as 15 mg, 30 mg, and 45 mg oral extended-release tablets. The recommended oral induction dose of upadacitinib is 45 mg once daily for 8 weeks. The recommended oral dose of upadacitinib for maintenance treatment is 15 mg once daily; 30 mg once daily may be appropriate for some patients, such as those with refractory, severe, or extensive disease. For patients 65 years and older, the only recommended maintenance dose is 15 mg once daily.

The objective of this report is to perform a systematic review of the beneficial and harmful effects of upadacitinib (15 mg, 30 mg, and 45 mg) for the treatment of adult patients with moderately to severely active UC who have demonstrated treatment failure, i.e., an inadequate response, loss of response, or intolerance to at least 1 conventional and/or biologic therapy.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from the clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups submitted input: the Gastrointestinal (GI) Society and Crohn and Colitis Canada. The GI Society is a national charity committed to research, advocacy, and educational activities for people with gastrointestinal and liver conditions that works closely with health care professionals and governments at all levels to improve care and treatment. Crohn and Colitis Canada is a national, volunteer-based health charity committed to finding cures for IBD and improving the lives of children and adults affected by these diseases through research, patient programs, fundraising, spreading information, advocacy, and awareness activities. The information provided in the GI Society submission was gathered through various questionnaires distributed among patients with IBD in 2015 (n = 423), 2018 (n = 432), 2020 (n = 724), and 2022 (ongoing), as well as one-to-one conversations with patients; a patient roundtable; recent phone, email, and social media interactions; and stories submitted by patients over time. Crohn and Colitis Canada compiled data from 2 online surveys (respondents included 354 patients with moderate to severe UC and 2 participants in the Rinvoq clinical trial) conducted earlier this year and 1 phone interview with a patient who participated in the Rinvoq clinical trial.

Patients with UC commonly experience symptoms such as diarrhea (fecal urgency and poor control of bowel function), rectal bleeding, and abdominal pain. Patients commonly described flares, which occur at unpredictable times, as causing extreme pain and fatigue with a need to always be near a bathroom. Symptoms may be present even during periods of remission. UC has a profound effect on patients’ physical, emotional, and social lives at their home, school, or workplace, and is particularly difficult for children and young adults, since it affects their sense of self. Based on the Crohn and Colitis Canada survey, the most frequently reported UC-related complications among patients were mental stress (65%), joint inflammation and arthritis (51%), fissure and hemorrhoids (40%), anemia (33%), skin condition (approximately 30%), and malnutrition and weight loss (approximately 30%); other complications include bowel obstruction, intestinal fistulas, abscesses, stricture, liver conditions, and cancer. Patients said their social lives (including romantic relationships with partners) had been negatively affected by their UC diagnosis and that they felt isolated due to others’ misunderstanding of their condition. About 72% of respondents said they had to constantly adjust their lifestyle and expectations due to UC; 2 in 5 patients said they changed their travel plans and 1 in 5 patients said they changed their career aspirations.

According to the GI Society submission, patients consider sustained remission and treatment response more important than relieving any 1 symptom. Despite the available treatment options, patients have difficulty obtaining remission or symptom relief and there is a need for more diversity in effective treatments that achieve mucosal healing, reduce symptoms, and allow patients to live full and productive lives. Patients want adequate access to medications that work to reduce preventable suffering, unnecessary use of health care resources, and financial burden on the government and taxpayers. Finally, the GI Society stated that having a treatment with oral administration rather than infusion or injection would be helpful for many patients.

Clinician Input

Input From Clinical Experts Consulted by CADTH

According to the clinical expert, even though various treatment options are available for patients with moderately to severely active UC, not all patients respond to them, and they may become refractory to current treatments. In addition, some of the current treatments are associated with many safety concerns. Some treatments have lower patient adherence due to the inconvenient route of administration.

The expert indicated that patients with moderately to severely active UC, either biologic-naive or biologic-exposed, are suitable for treatment with upadacitinib. The expert also stated that if patients could access upadacitinib without the need for their disease to have previously failed to respond to conventional therapies, immunomodulators, or previously available biologics, then access to upadacitinib would potentially cause a shift in the current treatment paradigm.

The expert noted that in clinical practice, clinical response and remission are assessed using the partial Mayo score or components of the Mayo score, along with certain biomarkers. Clinicians usually schedule a colonoscopy 6 to 9 months after starting treatment with biologics or small-molecule drugs to examine endoscopic healing.

The expert also stated that treatment with upadacitinib should be discontinued if there is a lack of clinical response to induction therapy or if there is disease progression.

Clinician Group Input

Two clinician groups submitted input on upadacitinib: 3 clinicians on behalf of the IBD Centre of BC, and 12 gastroenterologists and a nurse practitioner on behalf of the Atlantic Specialist Group, who submitted jointly with members from the University of Calgary IBD Unit.

The clinician group input was consistent with that of the clinical expert consulted by CADTH in terms of unmet needs, place in therapy, patient population, assessing response to treatment, discontinuing treatment, and prescribing conditions. The clinician groups emphasized that upadacitinib use should be restricted among patients with a history of thrombosis or coronary artery disease. In terms of the place in therapy of upadacitinib in clinical practice, both clinician groups agreed that upadacitinib would be used in various circumstances for patients, including as first-line therapy.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for upadacitinib:

• considerations for discontinuation of therapy

• care provision issues

• system and economic issues.

The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

Three phase III randomized controlled trials (RCTs) submitted by the sponsor (U-ACHIEVE Induction, N = 474; U-ACCOMPLISH, N = 522; U-ACHIEVE Maintenance, N = 1,046) were included in this systematic review. The objective of all 3 studies was to evaluate the efficacy and safety of upadacitinib in patients with moderately to severely active UC. The studies enrolled adult patients with a diagnosis of moderate to severe UC who had an inadequate response, loss of response, or were intolerant to either conventional therapy or biologic drugs. In the induction trials (U-ACHIEVE Induction and U-ACCOMPLISH), eligible patients were randomized to receive oral upadacitinib 45 mg once daily or matching placebo for 8 weeks in a double-blind manner. At the end of the 8 weeks, those who were deemed clinical responders were eligible to enter the maintenance study (U-ACHIEVE Maintenance), while nonresponders were given open-label upadacitinib for an additional 8 weeks. Clinical response was defined as a decrease from baseline in the adapted Mayo score of 2 points or greater and a decrease of 30% or greater from baseline, plus a decrease in rectal bleeding subscore (RBS) of 1 point or greater or an absolute RBS score of 1 or less. Patients who entered the maintenance study were re-randomized and treated with oral upadacitinib 15 mg or 30 mg once daily or matching placebo for up to 52 weeks. The primary efficacy outcome of these 3 studies was the proportion of patients achieving or maintaining clinical remission according to the adapted Mayo score (defined as a stool frequency subscore [SFS] of ≤ 1, RBS of 0, and endoscopic subscore of ≤ 1).

In the 2 induction trials, about 60% of patients were male and 65% to 71% were White. The mean age of patients enrolled in the induction trials was 42 to 44 years. At baseline, 50% to 53% of patients had an inadequate response, loss of response, or intolerance to biologic therapy, and 47% to 50% of the patients had an inadequate response, loss of response, or intolerance to conventional therapy. The majority of the patients had a mean adapted Mayo score of 7 or less. Corticosteroids were the most commonly prescribed prior UC medications. During the maintenance therapy, patients’ baseline characteristics were generally comparable to those in the induction period.

Efficacy Results

During the induction period of U-ACHIEVE, clinical remission based on the adapted Mayo score at week 8 was achieved in 26.1% of patients in the upadacitinib group and 4.8% of patients in the placebo group; the between-group difference was 21.6% (95% confidence interval [CI], 15.8% to 27.4%). In U-ACCOMPLISH, clinical remission per adapted Mayo score was achieved in 33.5% of patients in the upadacitinib group and 4.1% of patients in the placebo group; the between-group difference was 29.0% (95% CI, 23.2% to 34.7%). At the end of the maintenance period of U-ACHIEVE at week 52, clinical remission was maintained in 42.3% of patients in the upadacitinib 15 mg group, 51.7% of patients in the upadacitinib 30 mg group, and 12.1% of patients in the placebo group; the between-group differences were 30.7% (95% CI, 21.7% to 39.8%) for upadacitinib 15 mg versus placebo and 39.0% (95% CI, 29.7% to 48.2%) for upadacitinib 30 mg versus placebo (Table 2). The proportion of patients achieving clinical remission at week 8 or maintaining clinical remission at week 52 was the primary efficacy outcome in all 3 studies.

Similarly, the results for the proportion of patients achieving clinical response, endoscopic improvement or remission, histologic improvement, and mucosal healing favoured patients who were treated with upadacitinib compared with those treated with placebo for both the induction and maintenance periods. For maintenance therapy, the treatment effect for upadacitinib 15 mg versus placebo was smaller than for upadacitinib 30 mg versus placebo. The clinical expert consulted by CADTH indicated that all of the between-group differences were clinically meaningful. The results of the subgroup analyses based on patients’ baseline characteristics were consistent with those in the overall population. The results for other efficacy outcomes suggested that treatment with upadacitinib was associated with better symptom relief and improved health-related quality of life (HRQoL) compared with placebo during both the induction and maintenance periods. The changes in HRQoL measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) and Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) favoured the upadacitinib therapy. The impact of UC on work was evaluated between the upadacitinib group and the placebo group; however, this outcome was not adjusted for multiplicity and the results should be interpreted with caution. Treatment with upadacitinib may be associated with lower rates of hospitalization due to UC for both induction and maintenance periods.

Harms Results

The proportion of patients experiencing at least 1 adverse event (AE) during induction was different between the 2 induction trials. In U-ACHIEVE Induction, at least 1 AE was reported by 56.4% and 61.9% of patients in the upadacitinib group and placebo group, respectively. In U-ACCOMPLISH, at least 1 AE was reported by 52.9% and 39.5% of patients in the upadacitinib group and placebo group, respectively. UC was more often reported in the placebo groups and was a major driver when the risk of AEs, serious adverse events (SAEs), or withdrawal due to adverse events (WDAEs) was high in the placebo group compared with the upadacitinib group. This may be explained by the fact that the AE “ulcerative colitis” was used to classify the exacerbation of a patient’s existing UC. Patients who were treated with placebo may be more likely to experience this exacerbation due to the lack of efficacy from the treatment of placebo. During the maintenance period, AEs were reported in 75.2%, 75.3%, and 73.5% of the patients in the upadacitinib 15 mg, upadacitinib 30 mg, and placebo groups, respectively.

In the induction period, there were no AEs of active tuberculosis, malignancy, adjudicated venous thromboembolic events (VTEs), or gastrointestinal perforation reported in the upadacitinib groups. The incidence of opportunistic infection, excluding tuberculosis and herpes zoster, herpes zoster, lymphopenia, and neutropenia, was higher in the upadacitinib groups. At the end of the maintenance period, patients treated with up to 1 year of upadacitinib reported cases of herpes zoster, neutropenia, malignancy, hepatic disorder, lymphopenia, and VTEs. The numbers of events were low for malignancy and VTE at this time point. Longer-term data are needed to fully understand the long-term safety profile of upadacitinib in patients with UC.

Table 2: Summary of Key Efficacy Results From Pivotal and Protocol Selected Studies

bio-IR = inadequate response to biologic therapy; CI = confidence interval; ITT = intention to treat; ITT1 = intention-to-treat population in part 1; non-bio-IR = inadequate response to conventional therapy; UPA = upadacitinib;.

Note: The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

For clinical remission, clinical response, endoscopic remission, histologic improvement, and mucosal healing, the following statistical model was used: 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation if there were no missing data due to COVID-19.

Sources: Clinical Study Reports for U-ACHIEVE Induction,⁶ U-ACCOMPLISH,⁷ and U-ACHIEVE Maintenance.⁸

Table 3: Summary of Key Safety Results From Pivotal and Protocol Selected Studies

AE = adverse event; GI = gastrointestinal; NMSC = nonmelanoma skin cancer; SA1 = safety population for part 1; SAE = serious adverse event; UPA = upadacitinib; VTE = venous thrombosis event; WDAE = withdrawal due to adverse event.

The SA1 population included all randomized patients who received at least 1 dose of the study drug in part 1 of U-ACHIEVE Induction and U-ACCOMPLISH. The SA_C population included all upadacitinib 45 mg once daily 8-week induction responders who were enrolled under the protocol for the 44- or 52-week maintenance treatment period in cohort 1.

Sources: Clinical Study Reports for U-ACHIEVE Induction,⁶ U-ACCOMPLISH,⁷ and U-ACHIEVE Maintenance.⁸

Critical Appraisal

Internal Validity

In the maintenance period, the discontinuation rates were high and imbalanced across treatment arms. In cohort 1, 30.4%, 18.8%, and 63.8% of patients in the upadacitinib 15 mg, upadacitinib 30 mg, and placebo arms, respectively, discontinued the study. “Other” was the main reason for study discontinuation, and the majority of patients in this category were labelled “lack of efficacy” or “loss of response.” These patients would have been considered nonresponders in the efficacy analyses; a bias is less likely to be introduced in that circumstance.

Prespecified subgroup analyses were performed to examine the consistency of the treatment effect observed for the primary efficacy end points. However, proper interpretation of all subgroups was not possible due to the lack of sample size considerations for these subgroups. The subgroups were underpowered to detect significant effect modification by subgroups of interest, such as inadequate response to previous biologics.

External Validity

According to the clinical expert consulted by CADTH, the population included in the pivotal studies was generally consistent with clinical practice. Based on the patient’s baseline characteristics, the study populations reflect a typical population in Canada that would receive upadacitinib in practice.

U-ACHIEVE Induction and U-ACCOMPLISH were 8 weeks of induction therapy. The clinical expert consulted for this review indicated this was a sufficient time frame to determine short-term treatment effects with upadacitinib. U-ACHIEVE Maintenance was a 52-week study. The expert noted that 52 weeks would not be considered sufficient to observe the long-term safety of this drug for rare events, such as malignancy.

The patient population in the maintenance period was likely enriched due to the study design. Approximately 72% of patients responded to the treatment after 8 weeks of induction therapy and, it should be noted that the interpretation of the maintenance period results differs between a re-randomized (RR) study design and a treat-through (TT) design.

Indirect Comparisons

The sponsor-submitted indirect treatment comparison (ITC) provided indirect evidence on the efficacy and safety of upadacitinib relative to other active treatments for moderately to severely active UC. The active comparators for upadacitinib included other JAK inhibitors (tofacitinib and filgotinib), TNF alpha antagonists (adalimumab, golimumab, and infliximab), anti-integrin drugs (vedolizumab), IL-12 and IL-23 antagonists (ustekinumab), and an S1P receptor agonist (ozanimod). Relevant RCTs were identified through a systematic literature search. Twenty-three RCTs were included in the network meta-analysis (NMA). Outcomes of clinical remission, clinical response, and endoscopic improvement were evaluated in both bio-naive and bio-exposed patients. Harm outcomes were evaluated in the overall population. A Bayesian NMA approach was taken for data synthesis.

In addition, 3 published ITCs were identified from the CADTH literature search. Limitations in these studies included: concerns of substantial heterogeneity from different sources and insufficient description on the methods used to address and adjust these heterogeneities, the underlying transitivity assumption of the NMA not being upheld, and wide CIs or credible intervals (CrIs) of the effect estimates, meaning that the magnitude of the effects is uncertain. The authors’ conclusions are provided in this report; however, due to the aforementioned limitations, the results of these ITCs are not described in detail.

Efficacy Results

Based on the results of the sponsor-submitted ITC, for the induction phase, treatment with upadacitinib 45 mg may be associated with higher rates of clinical remission, clinical response, and endoscopic improvement compared with some of the active comparators. The estimates are associated with considerable uncertainty due to the lack of direct evidence, the sparsity of the network, and the potential for the transitivity assumption to have been violated. The analysis of the findings for the maintenance phase required adjustment for differences in study designs and there were fundamental differences in the placebo arms across the studies. The statistical techniques adopted in the sponsor’s ITC are possible strategies to address cross-study heterogeneity, lessen the impact of potential clinical heterogeneity on the estimated treatment effect of upadacitinib, and make NMAs feasible; however, they cannot adequately remove uncertainty. Therefore, firm conclusions could not be established for the efficacy of upadacitinib compared with other relevant active treatments in achieving clinical response, clinical remission, and endoscopic improvement.

Harms Results

Due to the limitations in the sponsor-submitted ITC, a conclusion regarding the relative safety of upadacitinib versus other active treatments cannot be drawn.

Critical Appraisal

In the sponsor-submitted ITC, sources of heterogeneities and potential treatment effect modifiers (such as study design, e.g., inclusion and exclusion criteria, outcome definitions, and notable heterogeneity in a number of patients’ baseline characteristics, e.g., previous UC medications or differences across the placebo arms) in the included studies were identified and some of them were addressed in data analyses. However, in several studies, data for potential effect modifiers were unavailable. The maintenance phase in particular is problematic. Some of the placebo arms were considered fundamentally different from 1 another. Given all these concerns, the transitivity assumption in an NMA may not be upheld. Despite various statistical techniques being employed to lessen the impact of potential clinical heterogeneity, such as baseline risks on the estimated treatment effect of upadacitinib, there is still uncertainty in the ITC results. The approaches used to adjust the differences in study design (TT versus RR) are potential solutions to adjust the cross-study heterogeneity in UC trials; however, it is uncertain whether the adjustment is adequate. In addition, the network is sparse. Coherence could not be assessed due to the lack of relevant closed loops when comparing with other active treatments. All evidence is indirect, which reduces our certainty in the study findings. Wide CrIs are observed for many efficacy and safety outcomes, especially in the maintenance phase. This implies considerable uncertainty in the magnitude of the treatment effects of upadacitinib.

Safety data were sparse and only available in the overall population. These data are likely confounded by efficacy, since UC is commonly reported as an AE, SAE, and WDAE in clinical trials of UC.

Other Relevant Evidence

Data from a long-term clinical trial were not available at the time of this review. No other relevant evidence was identified for this review.

Conclusions

Based on the 2 induction trials and 1 maintenance trial, oral upadacitinib 15 mg, 30 mg, and 45 mg once daily was superior to placebo in achieving induction and maintenance of clinical remission, clinical response, endoscopic improvement, and mucosal healing in patients with moderately to severely active UC. Moreover, upadacitinib was also found to be effective in alleviating UC-related symptoms and improving HRQoL. Long-term data are needed to fully evaluate the safety profile of upadacitinib. Serious limitations in the available ITCs mean that it remains uncertain how upadacitinib compares with other active treatments in the efficacy and safety for moderately to severely active UC.

Introduction

Disease Background

UC is the most common form of IBD. It is characterized by recurring episodes of inflammation to the mucosal layer of the colon. Usually, the disease affects the rectum and may spread to other parts of the colon.^1,2,5 Depending on the extent and severity of the disease, patients with UC may present with diarrhea with or without blood and mucus, urgency or tenesmus, incontinence, constipation, colicky abdominal pain, fever, malaise, and weight loss^.1,2 Regardless of severity, UC is also associated with high rates of fatigue and sleep difficulties.³ Approximately half of all patients require UC-related hospitalization at some point during the disease course. Patients with UC are at increased risk of developing colon cancer. Previous research found that the risk of colon cancer was 2% in the first 10 years of UC, 8% during the first 20 years, and 18% during the first 30 years.⁹ Moreover, approximately 1.5% of patients with UC are diagnosed with colorectal cancer, typically after prolonged active inflammation. While UC is not associated with increased risk of all-cause mortality after the first year after diagnosis,¹⁰ gastrointestinal-specific mortality may be increased.^3,10 Poor prognostic factors for UC include young age of disease onset, extensive colitis, and deep ulcerations.⁵ The disease has negative physical, emotional, and social impacts on patients.

The diagnosis of UC is based on a combination of symptoms, endoscopic findings, histology, and the absence of an alternative diagnosis. Typical endoscopic findings in UC include erythema, loss of normal vascular pattern, granularity, erosions, friability, bleeding, and ulcerations. While endoscopy with biopsies is the only way to confirm the diagnosis, other laboratory tests of blood and stool are also required to eliminate the possibility that symptoms are being caused by enteric infections from bacteria, a virus or parasite, or by other forms of IBD, such as Crohn disease. The levels of markers of inflammation, such as C-reactive protein (CRP), can assist in determining the severity of disease.⁵

The majority of patients living with UC have a mild to moderate disease course, generally with active disease at diagnosis followed by alternating exacerbations and longer periods of remission.³ However, aggressive disease course is experienced in 10% to 15% of patients, with a cumulative risk of relapse between 70% to 80% at 10 years postdiagnosis.³ Determining the severity and extent of UC is essential for selecting appropriate treatment and predicting long-term outcomes.¹ In general, multiple factors are taken into account when assessing the disease severity: disease effect on patient symptoms (e.g., frequency and severity of diarrhea), HRQoL, and disability; measurable inflammatory burden using objective markers of disease activity (e.g., CRP) and extent; and disease course, including structural damage, number of flares, and extraintestinal manifestations.^1,5 In clinical practice, patients with moderate UC may have frequent (4 to 6 per day) loose bloody stools, mild anemia not requiring blood transfusions, and abdominal pain, while patients with severe UC typically have frequent loose bloody stools (more than 6 per day) with severe cramps and evidence of systemic toxicity such as fever, tachycardia, anemia, and weight loss.^11,12

UC has a worldwide annual incidence rate of 1.2 to 20.3 cases per 100,000 people and a prevalence of 7.6 to 246.0 cases per 100,000 people.² Canada has among the highest reported incidence and prevalence of UC in the world. Estimated annual incidence rates for UC in Canada ranged from a low of 8.4 per 100,000 people in Alberta to a high of 21.4 per 100,000 people in Nova Scotia.⁴ It was estimated that more than 120,000 people in Canada were living with UC in 2018.⁴

Standards of Therapy

The selection of treatment regimens for UC is guided by disease severity and extent.⁵ Treatment goals in UC are stepwise. According to the clinical expert consulted by CADTH, the short-term goals of UC treatment are to improve patient symptoms (cessation of rectal bleeding and reduction in stool frequency), prevent disease progression that requires hospitalization, prevent the need for colectomy, and improve the patient’s HRQoL. The intermediate goals are to achieve steroid-free remission and endoscopic improvement and healing. The long-term goals in this patient population include maintaining steroid-free clinical remission, endoscopic healing, and mucosal remission. These goals are consistent with the published clinical practice guidelines.¹¹ When selecting induction therapy for patients with moderate to severe UC, patient preferences, patient characteristics, risk of AEs, other medication use, prior therapy for UC, accessibility to an infusion centre, patient compliance, and coverage of medication costs by payers need to be considered.¹²

For mild to moderate disease, the first-line therapy is 5-aminosalicylic acid (5-ASA) drugs, or corticosteroids if the patients do not respond to or achieve remission on 5-ASA drugs. Due to their associated side effects, corticosteroids should be reserved for induction therapy and not considered for long-term maintenance therapy.^5,11

Different drug classes are available for long-term management of moderately to severely active UC; many are immunomodulators (e.g., azathioprine, 6-mercaptopurine, or methotrexate) or biologics. Biologic therapies are the mainstay of treatment for patients with moderate to severe UC and are used for induction and maintenance when other treatments have been unsuccessful, or in those who cannot tolerate other treatments. At present, biologics include TNF alpha antagonists (adalimumab, infliximab, and golimumab), anti-integrin drugs (vedolizumab), and IL-12 and IL-23 antagonists (ustekinumab). Small-molecule drugs, which include JAK inhibitors (tofacitinib) and S1P receptors (ozanimod), are also used in patients with moderate to severe UC. The clinical practice guidelines developed by the American Gastroenterological Association suggest early use of biologics with or without immunomodulator therapy rather than gradual step-up after failure of 5-ASA.¹¹ Systemic oral glucocorticoids can be used for inducing remission in patients with moderately to severely active UC, or given to provide more immediate symptom relief for patients who are started on a biologic drug for induction therapy. After clinical remission has been achieved, corticosteroids need to be tapered to avoid the adverse effects related to long-term use.¹²

Surgery is indicated in uncontrolled hemorrhage, perforation, and colorectal carcinoma or dysplastic lesions that are not amenable to endoscopic removal. In addition, surgery is indicated in refractory acute severe UC or medically refractory disease. Approximately 20% to 35% of patients with UC may require surgery.¹³ Risks associated with surgery may include anastomotic leak, pelvic sepsis, pouchitis, and bowel obstructions and strictures.⁵

Despite access to a variety of treatment options, not all patients respond to the available treatments and their disease may become refractory to the current treatment regimens. The results of previous studies showed that in patients with IBD who were treated with biologics, primary nonresponse was observed in 20% to 30% of these patients and another 30% became refractory due to secondary loss of response.¹⁴

Drug

JAKs are intracellular enzymes that transduce signals from cell-surface receptors for cytokines or growth factors involved in a broad range of cellular processes, including inflammatory responses, hematopoiesis, and immune surveillance. JAK inhibitors are a family of small molecules that block 1 or more of the intracellular tyrosine kinases: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Upadacitinib is a selective JAK1 inhibitor. It modulates the signalling pathway at the point of JAKs and has greater inhibitory potency at JAK1 and JAK1/JAK3 than at JAK2/JAK2.^15,16

Upadacitinib is approved by Health Canada for the treatment of adult patients with moderately to severely active UC who have demonstrated treatment failure, i.e., an inadequate response, loss of response, or intolerance to at least 1 conventional and/or biologic therapy. The reimbursement criteria for upadacitinib requested by the sponsor are the same as the indication approved by Health Canada. Upadacitinib has been previously approved by Health Canada for the treatment of patients with rheumatoid arthritis, psoriatic arthritis, and atopic dermatitis.

Upadacitinib is available as 15 mg, 30 mg, and 45 mg oral extended-release tablets. The recommended oral induction dose of upadacitinib is 45 mg once daily for 8 weeks. The recommended oral dose of upadacitinib for maintenance treatment is a dose of 15 mg once daily; 30 mg once daily may be appropriate for some patients, such as those with refractory, severe, or extensive disease. For patients 65 years and older, the only recommended maintenance dose is 15 mg once daily. In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Key characteristics of commonly used medical treatments for UC are presented in Table 4.

Table 4: Key Characteristics of Upadacitinib and Other Drugs for Moderate to Severe Ulcerative Colitis

6-MP = 6-mercaptopurine; CNS = central nervous system; DVT = deep venous thrombosis; IgG1 = immunoglobulin G1; IL = interleukin; JAK = Janus kinase; SC = subcutaneous; TNF = tumour necrosis factor; UC = ulcerative colitis.

^aHealth Canada–approved indication.

Source: Product monographs for upadacitinib (Rinvoq),¹⁵ adalimumab (Humira),¹⁷ golimumab (Simponi),¹⁸ infliximab (Remicade),¹⁹ tofacitinib (Xeljanz),²⁰ ustekinumab (Stelara),²¹ and vedolizumab (Entyvio).²²

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Two patient groups submitted input: the Gastrointestinal (GI) Society and Crohn and Colitis Canada. The GI Society is a national charity committed to research, advocacy, and educational activities for people with gastrointestinal and liver conditions that works closely with health care professionals and governments at all levels to improve care and treatment. Crohn and Colitis Canada is a national, volunteer-based health charity committed to finding cures for IBD and improving the lives of children and adults affected by these diseases through research, patient programs, fundraising, spreading information, advocacy, and awareness activities. The information provided in the GI Society submission was gathered through various questionnaires distributed among patients with IBD in 2015 (n = 423), 2018 (n = 432), 2020 (n = 724), and 2022 (ongoing) as well as one-to-one conversations with patients; a patient roundtable; recent phone, email, and social media interactions; and stories submitted by patients over time. Crohn and Colitis Canada compiled data from 2 online surveys (respondents included 354 patients with moderate to severe UC and 2 participants in the Rinvoq clinical trial) conducted earlier this year and 1 phone interview with a patient who participated in the Rinvoq clinical trial.

Patients with UC commonly experience symptoms such as diarrhea (fecal urgency and poor control of bowel function), rectal bleeding, and abdominal pain. Patients commonly described flares, which occur at unpredictable times, as causing extreme pain and fatigue with a need to always be near a bathroom. Symptoms may be present even during periods of remission. UC has a profound effect on patients’ physical, emotional, and social lives at their home, school, or workplace, and is particularly difficult for children and young adults, since it affects their sense of self. Based on the Crohn and Colitis Canada survey, the most frequently reported UC-related complications among patients were mental stress (65%), joint inflammation and arthritis (51%), fissure and hemorrhoids (40%), anemia (33%), skin condition (approximately 30%), and malnutrition and weight loss (approximately 30%); other complications include bowel obstruction, intestinal fistulas, abscesses, stricture, liver conditions, and cancer. Patients said their social lives (including romantic relationships with partners) had been negatively affected by their UC diagnosis and that they felt isolated due to others’ misunderstanding of their condition. About 72% of respondents said they had to constantly adjust their lifestyle and expectations due to UC; 2 in 5 patients said they changed their travel plans and 1 in 5 patients said they changed their career aspirations.

According to the GI Society submission, patients consider sustained remission and treatment response more important than relieving any 1 symptom. Despite the available treatment options, patients have difficulty obtaining remission or symptom relief and there is a need for more diversity in effective treatments that achieve mucosal healing and reduce symptoms and allow patients to live full and productive lives. Patients want adequate access to medications that work to reduce preventable suffering, unnecessary use of health care resources, and financial burden on the government and taxpayers. Finally, the GI Society stated that having a treatment with oral administration rather than infusion or injection would be helpful for many patients.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. 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 UC.

Unmet Needs

The expert noted several unmet needs related to the treatment of UC. Even though various treatment options are available for patients with moderately to severely active UC, not all patients respond to them, and they may become refractory to current treatments. Currently, there is no medication available to reverse the structural damage of the colon. However, if UC is treated and controlled early in the disease course, the progression of disease may be stopped or delayed, and the risk of dysplasia or colon cancer could be reduced. In addition, some of the current treatments are associated with many safety concerns; for example, patients treated with tofacitinib have an increased risk of herpes zoster and thrombosis. Treatments that are better tolerated and have safe profiles are needed. Some treatments have lower patient adherence due to the inconvenient route of administration. There is also a lack of evidence regarding the efficacy and safety of various medications among special populations, such as pregnant patients, older adults, patients with cardiovascular risk factors, or patients with previous or current malignancies.

Place in Therapy

The expert indicated that upadacitinib is a selective JAK1 inhibitor and would occupy a place in therapy similar to biologics and other targeted small-molecule drugs. Upadacitinib can be given after 5-ASA and used instead of immunomodulators. Due to its mechanism of action, it is thought that the safety profile of upadacitinib may be favourable compared with tofacitinib, which is a less selective JAK inhibitor.

The expert suggested that upadacitinib be offered to biologic-naive patients with UC as well as biologic-exposed patients. The expert stated that it may not be appropriate to have the patients try and fail prednisone and immunomodulators before initiating upadacitinib, considering the side effects and risks associated with treatment with prednisone and immunomodulators. For patients whose condition has already failed to respond to biologics or targeted small-molecule drugs, the expert was of the opinion that upadacitinib would likely be recommended before other medications that have known side effects, such as tofacitinib.

The expert also stated that if patients gain access to upadacitinib without the need for their disease to fail to respond to immunomodulators, access to upadacitinib would potentially cause a shift in the current treatment paradigm based on the current funding criteria; otherwise, upadacitinib would be at a level similar to biologics and the other JAK inhibitors.

Patient Population

The expert indicated that patients with moderately to severely active UC, either biologic-naive or biologic-exposed, are suitable for treatment with upadacitinib. These patients can be identified by clinician examination and judgment based on disease severity, age, sex, family planning stage, comorbidities, certain laboratory tests, and colonoscopy. The expert noted that misdiagnosis is less likely to occur in clinical practice. The expert indicated it is not possible to identify those patients whose condition is most likely to exhibit a response to treatment with upadacitinib. According to the expert, patients who are pregnant, or have active infections, active malignancy, or severe hepatic impairment would not be suitable for treatment with upadacitinib.

Assessing Response to Treatment

The expert noted that in clinical practice, clinical response and remission are assessed using the partial Mayo score or components of the Mayo score. Biomarkers such as CRP and fecal calprotectin are also measured. In terms of endoscopic response, clinicians usually schedule a colonoscopy 6 to 9 months after starting treatment to examine endoscopic healing. If a follow-up colonoscopy 8 weeks after treatment initiation is not feasible, postinduction response can be evaluated using the level of fecal calprotectin or a flexible sigmoidoscopy.

By the end of the induction period, patients who report no further rectal bleeding, no rectal incontinence, more solid stools, or whose symptoms have reduced to no more rectal urgency, a normal frequency of bowel movements, or no more abdominal pain, are considered to have had a clinically meaningful response to treatment. In general, clinical improvement may occur within 4 weeks of treatment, and clinical remission is expected within 8 weeks of treatment. However, depending on the severity of disease at the beginning of treatment and previous medication use, patients may experience a slower response or delay to remission; therefore, an additional 8 weeks of treatment may be required for induction therapy.

Discontinuing Treatment

Treatment with upadacitinib should be discontinued if there is a lack of clinical response to induction therapy, or disease progression occurs. Treatment should also be stopped if the patient is experiencing significant adverse effects, such as hematologic abnormalities, new-onset malignancy, or recurrent infections. Patients who are trying to conceive or are pregnant or breastfeeding should discontinue the treatment, as well.

Prescribing Conditions

Upadacitinib can be prescribed by a gastroenterologist who can perform colonoscopies and diagnose UC. This oral drug can be administered at home.

Clinician Group Input

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

Two clinician groups submitted input on upadacitinib: 3 clinicians on behalf of the IBD Centre of BC, and a group of 12 gastroenterologists and a nurse practitioner on behalf of the Atlantic Specialist Group, who submitted jointly with members from the University of Calgary IBD Unit.

The clinician group input was consistent with that from the clinical expert consulted by CADTH in terms of unmet needs, place in therapy, patient population, assessing response to treatment, discontinuing treatment, and prescribing conditions. The clinician groups emphasized that upadacitinib should be restricted from patients with a history of thrombosis or coronary artery disease. In terms of the place in therapy of upadacitinib in clinical practice, both clinician groups agreed that upadacitinib would be used in various circumstances for these patients, including as first-line therapy.

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 their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

b.i.d. = twice daily; CDEC = CADTH Canadian Drug Expert Committee; JAK = Janus kinase; p.o. = oral; q.d. = once daily; TNF = tumour necrosis factor; UC = ulcerative colitis.

Clinical Evidence

The clinical evidence included in the review of upadacitinib is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review. No studies were included in this section.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of oral upadacitinib 15 mg, 30 mg, and 45 mg per day for the treatment of adult patients with moderately to severely active UC who have had an inadequate response to, loss of response to, or were intolerant to either conventional therapy or a biologic drug (i.e., TNF alpha antagonists, integrin receptor antagonists, or IL-12 or IL-23 inhibitors).

Methods

The studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans. Of note, the systematic review protocol presented in Table 6 was established before the granting of a Notice of Compliance from Health Canada.

Table 6: Inclusion Criteria for the Systematic Review

AE = adverse event; RCT = randomized controlled trial; SAE = serious adverse event; TNF = tumour necrosis factor; 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.²³

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) through Ovid and Embase (1974–) through 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 concepts were Rinvoq, upadacitinib, and ulcerative colitis. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO’s International Clinical Trials Registry Platform (ICTRP) 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 May 16, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on September 28, 2022.

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.²⁴ Included in this search were the websites of regulatory agencies (the FDA and 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 by reviewing bibliographies of key papers. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

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

A total of 46 studies were identified from the literature for inclusion in the systematic review (Figure 1). A total of 5 reports were included that presented data from 3 unique studies. The included studies are summarized in Table 7.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 7: Details of Included Studies

ADA = adalimumab; CD = Crohn disease; CER = certolizumab; DB = double blind; GI = gastrointestinal; GOL = golimumab; HBV = hepatitis B virus; HCV = hepatitis C virus; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; INF = infliximab; JAK = Janus kinase; NAT = natalizumab; NR = not reported; NSAID = nonsteroidal anti-inflammatory drug; OL = open label; RBS = rectal bleeding subscore; RCT = randomized controlled trial; SFS = stool frequency subscore; TB = tuberculosis; TPN = total parenteral nutrition; UC = ulcerative colitis; UCEIS = Ulcerative Colitis Endoscopic Index of Severity; UST = ustekinumab; VED = vedolizumab.

Note: 1 additional report was included (submission²⁶).

Source: Clinical Study Reports for U-ACHIEVE Induction,⁶ U-ACCOMPLISH,⁷ and U-ACHIEVE Maintenance.⁸

Description of Studies

Studies U-ACHIEVE (substudies 2 and 3) and U-ACCOMPLISH are pivotal trials submitted by the sponsor.

U-ACHIEVE comprises 3 substudies that included patients with moderately to severely active UC. Substudy 1 is a phase IIb dose-ranging induction trial and is not included in the CADTH systematic review. Substudies 2 and 3 are phase III trials evaluating the efficacy and safety of upadacitinib in the induction and maintenance phases, respectively. The results of substudies 2 (U-ACHIEVE Induction) and 3 (U-ACHIEVE Maintenance) are included in the current report. U-ACCOMPLISH is a phase III induction trial in the study population.

Induction

The primary objective of U-ACHIEVE Induction and U-ACCOMPLISH was to evaluate the efficacy and safety of upadacitinib 45 mg once daily compared with placebo in inducing clinical remission in patients with moderately to severely active UC who have had an inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids, or biologic therapies.

U-ACHIEVE Induction (N = 474) included 2 parts: part 1 was a randomized, double-blind placebo-controlled 8-week induction period; part 2 was an open-label 8-week extended-treatment period for clinical nonresponders from part 1 of this study (Figure 2). Clinical response was defined as a decrease from baseline in the adapted Mayo score of 2 points or greater and a reduction of 30% or greater from baseline, plus a decrease in RBS of 1 or greater or an absolute RBS of 1 or less. In part 1, eligible patients were randomized in a 2:1 ratio to upadacitinib 45 mg or matching placebo for 8 weeks. The randomization was stratified by response to previous treatment (insufficient response to biologic therapy [bio-IR] or insufficient response to conventional therapy [non-bio-IR]), corticosteroid use (yes or no), and adapted Mayo score (≤ 7 or > 7) at baseline. Within the bio-IR group, the randomization was further stratified by the number of prior biologic therapies (≤ 1 or > 1). Within the non-bio-IR group, the randomization was further stratified by previous biologic use (yes or no). In part 2, patients who did not achieve clinical response based on adapted Mayo score at week 8 in part 1 (regardless of initial randomized treatment) continued the treatment with oral upadacitinib 45 mg once daily. Clinical responders in part 1 and part 2 could enter substudy 3 of U-ACHIEVE (U-ACHIEVE Maintenance), while clinical nonresponders discontinued.

Similar to U-ACHIEVE Induction, U-ACCOMPLISH (N = 522) included 2 parts (Figure 3). Part 1 was a randomized, double-blind placebo-controlled 8-week induction period, and part 2 was an open-label 8-week extended-treatment period for clinical nonresponders from part 1. Eligible patients were randomized in a 2:1 ratio to 1 of the 2 treatment groups (oral upadacitinib 45 mg once daily or matching placebo) for 8 weeks. The randomization was stratified using the same categories as for U-ACHIEVE Induction. Clinical responders in part 1 and part 2 could enter substudy 3 of U-ACHIEVE (U-ACHIEVE Maintenance).

Maintenance

The primary objective of U-ACHIEVE Maintenance was to evaluate the efficacy and safety of oral upadacitinib 15 mg or 30 mg once daily compared with placebo in achieving clinical remission in patients with moderately to severely active UC who achieved clinical response after completion of induction treatment or the extended-treatment period from substudy 1 and substudy 2 of U-ACHIEVE Induction or U-ACCOMPLISH. This study included 4 cohorts (Figure 4). Treatment allocation in this maintenance study depended on the treatment received in U-ACHIEVE substudies 1 and 2 or U-ACCOMPLISH.

During this study, patients who met the criteria for loss of response after at least 4 weeks of follow-up had the option to enrol into an ongoing extension study (M14 to 533) and receive open-label upadacitinib. Loss of response was defined as follows: patient presents with both an SFS and an RBS that is at least 1 point greater than their value at the end of induction (week 8 of substudies 1 or 2 and U-ACCOMPLISH) on 2 consecutive visits at least 14 days apart.

The primary outcome of the 3 studies was the proportion of patients achieving clinical remission at week 8 or maintaining clinical remission at week 52; clinical remission was measured using the adapted Mayo score. The full Mayo score is composed of 4 components: rectal bleeding, stool frequency, Physician’s Global Assessment (PGA), and endoscopy findings, while the adapted Mayo score contains 3 components: rectal bleeding, stool frequency, and endoscopy findings.

Figure 2: Study Design of U-ACHIEVE Induction (Substudy 2)

DB = double blind; OL = open label; QD = once daily; UPA = upadacitinib; wk = week.

Source: Clinical Study Report for U-ACHIEVE Induction.⁶

Figure 3: Study Design of U-ACCOMPLISH

DB = double blind; OL = open label; QD = once daily; UPA = upadacitinib.

Source: Clinical Study Report for U-ACCOMPLISH.⁷

Figure 4: Study Design of U-ACHIEVE Maintenance (Substudy 3)

QD = once daily; RR = re-randomized; UPA = upadacitinib.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Populations

Inclusion and Exclusion Criteria

Induction

Patients eligible for U-ACHIEVE Induction and U-ACCOMPLISH were between 18 and 75 years old with an inadequate response, loss of response, or intolerance to oral aminosalicylates, immunosuppressants, corticosteroids, and/or biologic therapies. The patients enrolled had to have received a diagnosis of UC at least 90 days before baseline, confirmed by colonoscopy during the screening period; patients with a current infection, colonic dysplasia, and/or malignancy were excluded. Eligible patients had to have an adapted Mayo score of 5 to 9 points and an endoscopy subscore of 2 to 3. The study allowed for up to 30% of enrolled bio-IR patients to have disease that had failed to respond to 3 or more biologics. Among non-bio-IR patients, patients who used a biologic for up to 1 year and discontinued for reasons other than inadequate response, loss of response, or intolerance (e.g., change of insurance or reimbursement, well-controlled disease) could be enrolled if other criteria for inadequate response, loss of response, or intolerance to aminosalicylates, corticosteroids, or immunosuppressants, as defined in the protocol, were met. The study allowed for enrolment of up to 20% of the enrolled non-bio-IR patients who had previously used biologic therapy but discontinued based on reasons other than inadequate response, loss of response, or intolerance.

Maintenance

Patients who achieved clinical response after completion of induction treatment or an extended-treatment period in the U-ACHIEVE Induction or U-ACCOMPLISH studies were eligible to enter U-ACHIEVE Maintenance. Clinical response was defined as a decrease from baseline in the adapted Mayo score of 2 points or greater and a decrease of at least 30% from baseline, plus a decrease in RBS of 1 point or greater or an absolute RBS score of 1 or less at week 8 or 16 of the U-ACHIEVE Induction study or in U-ACCOMPLISH, and who had not met any study discontinuation criteria.

Baseline Characteristics

The baseline characteristics of the patients who were enrolled in the induction period and the characteristics of the patients who entered into the maintenance period of U-ACHIEVE are summarized in Table 8 and Table 9. Baseline characteristics in the intention-to-treat (ITT) population for part 1 (ITT1) (i.e., all randomized patients who received at least 1 dose of the double-blinded study drug) are presented for both induction trials.

Most (62% to 63%) patients were male. The mean age of patients enrolled in the induction trials was 42 to 44 years. The majority (65% to 71%) of the patients were White. At baseline, 50% to 53% of patients had an inadequate response, loss of response, or intolerance to biologic therapy; the remaining 47% to 50% of the patients had inadequate response, loss of response, or intolerance to conventional therapy. The majority of the patients had a mean adapted Mayo score of 7 or less. Finally, almost all patients were previously treated with UC medications, although prior UC treatment was 1 of the inclusion criteria in the 2 induction trials. Corticosteroids were the most common previously prescribed UC medications (84% to 87%), followed by ASA, immunomodulators, and biologics. Overall, patients’ baseline characteristics in the 2 induction trials were comparable between the upadacitinib group and the placebo group.

During the maintenance therapy, patients’ baseline characteristics were generally comparable with those in the induction period. ITT_A is a subset of patients in the ITT population in U-ACHIEVE Maintenance who:

• received at least 1 dose of the study drug in the maintenance phase

• comprised the first 451 responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment

• were enrolled under the protocol for the 52-week maintenance treatment period in cohort 1.

The characteristics of the ITT_A population are presented in Table 9. It is unclear if the ITT_A population was similar to the overall ITT population in this study, although this was the largest subset of the overall ITT population and was also the primary analysis set for efficacy outcome assessment.

Table 8: Summary of Baseline Characteristics — Induction Trials (ITT1 Population)

ADA = adalimumab; bio-IR = patients with inadequate response, loss of response, or intolerance to biologic therapy; CRP = C-reactive protein; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; GOL = golimumab; IBD = inflammatory bowel disease; IBDQ = Inflammatory Bowel Disease Questionnaire; INF = infliximab; nonbio-IR = patients with inadequate response, loss of response, or intolerance to conventional therapy; NR = not reported; SD = standard deviation; UC = ulcerative colitis; UPA = upadacitinib; VED = vedolizumab.

Note: ITT1 population was the ITT population in part 1 of the 2 induction trials.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

Table 9: Summary of Baseline Characteristics — Maintenance Trial (ITT_A Population)

ADA = adalimumab; bio-IR = patients with inadequate response, loss of response, or intolerance to biologic therapy; CRP = C-reactive protein; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; GOL = golimumab; IBD = inflammatory bowel disease; IBDQ = Inflammatory Bowel Disease Questionnaire; INF = infliximab; non-bio-IR = patients with inadequate response, loss of response, or intolerance to conventional therapy; NR = not reported; SD = standard deviation; UPA = upadacitinib; VED = vedolizumab.

Note: The ITT_A population was the subset of the ITT population comprising the first 451 responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1. The ITT_A population was the primary analysis population in cohort 1 for efficacy end points.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Interventions

Induction

In both induction trials, patients were randomized to oral upadacitinib 45 mg once daily or matching placebo in a 2:1 ratio for 8 weeks in a double-blind manner. At the end of the 8-week induction period, patients who did not achieve clinical response were offered open-label upadacitinib 45 mg once daily for an additional 8 weeks until week 16. This is also known as the extended-treatment period.

During the induction period, concomitant UC-related medications (i.e., oral corticosteroids, antibiotics, aminosalicylates, and/or methotrexate) were allowed, and oral ASA and/or methotrexate were required to remain at a stable dose for the entire study period. For oral corticosteroids, a change in the dose during the induction period was not allowed, while the use of inhaled or topical dermatologic corticosteroids was not restricted. Rescue therapy with any allowed UC medications could be provided in the form of initiation or increased dosage at the investigator’s discretion to treat new or worsening UC symptoms. The allowed UC-related medications are locally acting, oral, or IV corticosteroids; aminosalicylates; methotrexate; or UC-related antibiotics.

Maintenance

U-ACHIEVE Maintenance included 4 cohorts (Figure 4). Treatment during the maintenance period continued for up to 52 weeks, and corticosteroid therapy was tapered during this period according to a prespecified schedule. Patients taking corticosteroids who had worsening of disease after steroid tapering could have their corticosteroid dose increased at the investigator’s discretion.

The treatment assignment in U-ACHIEVE Maintenance depended on the treatment received in substudies 1 and 2 in U-ACHIEVE Induction and U-ACCOMPLISH, as follows:

• Placebo: Continue placebo

• Upadacitinib 7.5 mg once daily: Continue upadacitinib 7.5 mg once daily

• Upadacitinib 15 mg once daily: Randomized 1:1 to receive either upadacitinib 15 mg once daily or matching placebo

• Upadacitinib 30 mg or 45 mg once daily: Randomized 1:1:1 to receive either upadacitinib 15 mg once daily, upadacitinib 30 mg once daily, or matching placebo

The dose of upadacitinib 7.5 mg once daily was not relevant to our review; therefore, the results of this dose are not reported.

During the maintenance period, concomitant UC-related medications were allowed, and oral aminosalicylates and/or methotrexate were required to remain at a stable dose for the entire study period. Doses could be decreased or terminated in the event of moderate to severe treatment-related toxicities. In addition, all patients receiving UC-related antibiotics could discontinue treatment starting at week 0 of this study at the discretion of the investigator. Use of inhaled or topical dermatologic corticosteroids was not restricted.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 10. These end points are further summarized subsequently. A detailed discussion and critical appraisal of these outcome measures is provided in Appendix 2.

Table 10: Summary of Efficacy Outcomes of Interest Identified in the CADTH Review Protocol

EQ-5D-5L = 5-level EQ-5D; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; NR = not reported; SF-36 = Short Form (36) Health Survey; UC = ulcerative colitis; WPAI-UC = Work Productivity and Activity Impairment–Ulcerative Colitis.

Note: The Mayo score, Geboes score, IBDQ, FACIT-F, SF-36, EQ-5D-5L, and WPAI-UC for work productivity are discussed in detail in Appendix 2.

Source: Clinical Study Reports for U-ACHIEVE Induction,⁶ U-ACCOMPLISH,⁷ and U-ACHIEVE Maintenance.⁸

Clinical Remission

Clinical remission was the primary efficacy end point in all 3 pivotal trials. It was expressed as the proportion of patients who were in clinical remission. Clinical remission was defined according to the adapted, full, or partial Mayo score.

The Mayo score is a disease-specific, physician-measured instrument that assesses disease severity and response to treatment in patients with UC.^27,28 The Mayo scoring system is a combined endoscopic and clinical scale used to assess the severity of UC. In its complete form, the Mayo score is composed of 4 components: rectal bleeding, stool frequency, PGA (this was left out for the adapted Mayo score), and endoscopy findings. Each component is rated from 0 to 3 and may be summed to yield a total score of 0 to 12. A higher Mayo score indicates more severe disease: a higher SFS indicates more stools than normal and a higher RBS indicates more severe bleeding with stool or blood alone passed.

Clinical remission was measured at the conclusion of the induction period at week 8 or 16 and at the conclusion of the maintenance period at week 52. The definitions of clinical remission were as follows:

• Clinical remission based on the adapted Mayo score: Defined as an SFS of 1 or less, an RBS of 0, and an endoscopic subscore of 1 or less. The adapted Mayo score was used to define the primary efficacy outcome in the 3 studies.

• Clinical remission based on the full Mayo score: Defined as a total score of 2 or less, with no individual subscore greater than 1. The full Mayo score was used to define secondary efficacy outcomes in the 3 studies.

• Clinical remission based on the partial Mayo score: A partial Mayo score is an adapted Mayo score minus the endoscopic finding.

• Corticosteroid-free clinical remission: Patients who had been taking steroids at baseline in the induction trials but who discontinued corticosteroid use, remained corticosteroid-free for longer than 90 days immediately before week 52, and achieved clinical remission per adapted Mayo score.

Endoscopy recordings were centrally read by a gastroenterologist blinded to treatment assignment to determine the endoscopy subscore for the Mayo score.

Clinical Response

Clinical response was a key secondary efficacy end point of the 3 pivotal trials and was expressed as the proportion of patients who had clinical response. Clinical response was also defined according to the adapted or partial Mayo score. Clinical response was assessed at the conclusion of the induction period at week 8 and at the conclusion of the maintenance period at week 52. The definitions of clinical response were as follows:

• Clinical response based on the adapted Mayo score was defined as a decrease from baseline in the adapted Mayo score of 2 points or greater and a reduction of 30% or greater, an RBS of 1 point or greater, or an absolute RBS of 1 point or less.

• Clinical response based on the partial Mayo score was defined as a decrease from baseline of 1 point or greater and at least a 30% reduction, and a decrease in RBS of 1 point or greater or an absolute RBS of 1 or less.

Patients were considered nonresponders and were censored for efficacy assessments if they experienced worsening of disease during corticosteroid tapering (and may have had their corticosteroid dose increased up to or beyond the dose used at baseline or the maximum steroid dose exceeded the dose used at baseline). In addition, patients who were not taking UC-related conventional medications (oral aminosalicylates, systemic corticosteroids, and methotrexate) at baseline, but who initiated treatment with them during the study or who had their dosages of these medications increased to greater than the dosages they were taking at baseline, were also considered nonresponders.

Endoscopic Remission or Improvement

Endoscopic remission was a key secondary outcome in the 3 pivotal trials and was expressed as the proportion of patients with endoscopic remission. Endoscopic remission was defined as an endoscopic subscore of 0, while endoscopic improvement was defined as an endoscopic subscore of 1 or less.

Endoscopic improvement or remission was assessed at the conclusion of the induction period at week 8 and at the conclusion of the maintenance period at week 52.

Histologic Remission or Improvement

Histologic improvement was a key secondary efficacy end point in the induction trials. Histologic remission or improvement was assessed using the Geboes index score and was expressed as the proportion of patients with histologic remission or improvement.^29,30 The Geboes score is a 6-item instrument that classifies histological changes into 1 of 6 grades (grade 0 to grade 5). Each grade is assessed on a 4-point scale and given equal weight, as follows: “no abnormality,” “mild abnormality,” “mild/moderate diffuse or multifocal abnormalities,” and “severe diffuse or multifocal abnormalities.” The Geboes score may also be converted into a continuous scale with each subgrade being assigned an ordinal value, yielding values between 0 and 22. Higher scores correspond to greater inflammation.

Histologic remission was defined as a Geboes index score of less than 2, and histologic improvement was defined as a decrease from baseline in Geboes score.

Histologic remission or improvement was assessed at the conclusion of the induction period at week 8 and at the conclusion of the maintenance period at week 52.

Mucosal Healing

Mucosal healing was a key secondary outcome in the 3 pivotal trials and expressed as the proportion of patients with mucosal healing. Mucosal healing was assessed using the endoscopy subscore of the Mayo score and the Geboes index score.

Mucosal healing was defined as an endoscopy subscore of 0 and a Geboes index score of less than 2. Mucosal healing was assessed during the induction period at week 8 and the maintenance period at week 52.

Symptoms Relief

Relief of symptoms such as abdominal pain, rectal bleeding, and bowel urgency was a key secondary efficacy end point in the included studies. The proportions of patients with no symptoms of abdominal pain, rectal bleeding, and bowel urgency were measured. Symptom relief was assessed during the induction period at week 8 and the maintenance period at week 52.

Fatigue was measured using FACIT-F. This is a questionnaire completed by the patients to assess fatigue during the past 7 days. It consists of 13 statements, each rated on a 4-point Likert scale, with higher FACIT-F scores representing less fatigue. A cut-off score of 30 or less is used to define fatigue in patients with IBD.

Health-Related Quality of Life

HRQoL in the 3 pivotal trials was generally classified as an “other efficacy end point” and was assessed using generic or disease-specific instruments: the 36-item Short Form Health Survey (SF-36), the 5-level EQ-5D (EQ-5D-5L), and/or the IBDQ total score. HRQoL outcomes were expressed as the change from baseline to week 8, and from baseline to week 52.

Hospitalization

UC-related hospitalization was measured in all 3 studies.

Work Productivity

Work productivity was classified as an “other efficacy end point” in the included studies and was assessed using the Work Productivity and Activity Impairment–Ulcerative Colitis (WPAI-UC) questionnaire. Work productivity was measured at week 8 of the induction studies and week 52 of the maintenance study.

The WPAI-UC questionnaire, version 2, is an instrument used to measure the impact of a disease on work and daily activities during the previous 7 days. The WPAI-UC consists of 6 questions: employment status (employed or not employed), hours at work missed because of UC, hours at work missed because of other reasons, hours actually worked, overall impairment in productivity while working (a visual analogue scale [VAS] from 0 to 10), and overall impairment in regular activities (VAS from 0 to 10) due to UC. Patients who are employed answer all questions, while those who are not employed answer only the first and last. Four scores are derived from the questionnaire. Scores are expressed as a percentage of impairment or productivity loss and range from 0 to 100%, with higher scores indicating greater impairment, for 4 domains:

• absenteeism (work time missed)

• presenteeism (percent of impairment while working)

• percent of overall work impairment due to UC

• impairment of regular activities due to UC.

Safety

The safety outcomes assessed in the included studies were:

• treatment-emergent AEs, defined as any untoward medical occurrence in a patient administered a pharmaceutical product, that do not necessarily have a causal relationship with this treatment

• SAEs, defined as death, life-threatening events, hospitalization or prolongation of hospitalization, congenital anomaly, persistent or significant disability or incapacity, or important medical event requiring medical or surgical intervention to prevent a serious outcome

• AEs leading to discontinuation of the study drug or from the study

• AEs of special interest, including serious or opportunistic infection, malignancy, thrombosis, hypersensitivity, hepatotoxicity, anemia, lymphopenia, neutropenia, gastrointestinal perforation, and hyperlipidemia.

All AEs that were reported from the time of the administration of the study drug until 30 days after the discontinuation of the study drug were collected, whether solicited or spontaneously reported by the patient.

Statistical Analysis

Primary Outcomes of the Studies

The primary outcome of the included studies was the proportion of patients who achieved clinical remission per adapted Mayo score at week 8 in the induction trial and at week 52 in the maintenance trial. The primary analysis of the proportion of patients in clinical remission at week 8 and week 52 and the 95% CI was carried out in the ITT population (including all randomized patients who received at least 1 dose of the double-blinded study drug) using the Cochran-Mantel-Haenszel test. The ITT1 (ITT population in part 1) and ITT2 (ITT population in part 2) populations were used for the primary efficacy analyses in the 2 induction trials, and the ITT-A population (defined as the subset of ITT population comprising the first 451 [actual] responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1) was used for the primary efficacy analyses in the maintenance trial. In the induction trials, the stratification factors included bio-IR status, baseline corticosteroid use (yes versus no), and baseline adapted Mayo score (≤ 7 versus > 7) while, in the maintenance trial, the stratification factors were bio-IR status at the baseline of the induction study, clinical remission status at week 0 (yes or no), and corticosteroid use at week 0 (yes or no). The nonresponder imputation (NRI) method was used to handle missing data while incorporating multiple imputation to handle missing data related to COVID-19 (NRI-C). Patients with missing data at a scheduled assessment visit for any reason (except COVID-19) were considered “not achieved” for clinical remission, which was used for the primary analysis. At or after the occurrence of UC-related corticosteroid intercurrent events (i.e., events occurring after treatment initiation), patients were also considered to be nonresponders. In addition, sensitivity analyses using various imputation methods (e.g., a hybrid multiple imputation, NRI with no special handling of data missing due to COVID-19 [NRI-NC], multiple imputation, and as observed) were conducted to address issues related to missing data. An analysis of observed cases that excluded the patients with missing data was performed as well, to determine the impact from missing data. Furthermore, prespecified subgroup analyses based on various patient demographic and disease characteristics were conducted for the primary outcome to explore the treatment effect of the study drug in different subgroups: sex, age, race, bio-IR status, baseline corticosteroid use, baseline adapted Mayo score, baseline full Mayo score, prior exposure to anti-TNF drugs for non-bio-IR, baseline weight, presence of pancolitis at baseline, disease duration at baseline, baseline high-sensitivity CRP, and region.

Power Calculation

The sample size calculation in U-ACHIEVE Induction and U-ACCOMPLISH was based on the expected proportion of patients who would achieve clinical remission per adapted Mayo score at week 8. Based on the results from the phase IIb upadacitinib study, U-ACHIEVE (substudy 1), the proportions of patients achieving clinical remission per adapted Mayo score in the upadacitinib 45 mg once daily group and placebo group were 19.6% and 0%, respectively. Considering the small sample size in the phase IIb study and the more stringent definition of primary end point used for phase III studies, the clinical remission rate was assumed to be 5% in the placebo group and 18% in the upadacitinib 45 mg once daily treatment group. Based on these assumptions, a sample size of 154 patients in the placebo group and 308 patients in the upadacitinib group would have greater than 95% power to detect the 13% treatment difference in the primary end point between the upadacitinib 45 mg once daily group and placebo group using a 2-sided Fisher’s exact test at a 0.05 significance level.

Sample size calculation in the maintenance trial was based on the expected proportion of patients who would achieve clinical remission per adapted Mayo score at week 52. Assuming a clinical remission rate of 12% in the placebo arm and 40% in 1 of the upadacitinib treatment arms at week 52, a sample size of 150 patients in the placebo group and 150 patients in each of the upadacitinib 15 mg and 30 mg treatment groups would have 95% power to detect the 28% treatment difference in the primary end point between an upadacitinib dose and placebo using a 2-sided Fisher exact test at a 0.025 significance level with multiplicity adjustment. Under the assumption that the average response rate to upadacitinib doses at the end of substudies 1 and 2 was 50%, a total of approximately 450 patients would be re-randomized.

Secondary and Other Efficacy Analysis

Secondary efficacy variables were divided into 2 groups. The first group included ranked secondary end points, which were ranked by clinical importance. The primary and ranked key secondary efficacy end points were tested with a fixed-sequence multiple testing procedure as well as a Holm procedure, to control for overall type I error rate at an alpha significance level of 0.05 (2-sided). Statistical significance was assessed at the prespecified alpha level (2-sided) in ranked end point order until the significance level exceeded the prespecified alpha level. No additional statistically significant treatment differences could be declared if the preceding ranked end point failed to achieve the prespecified alpha level. In the maintenance trial, multiplicity adjustment for the multiple-dose comparison (upadacitinib 15 mg versus placebo and upadacitinib 30 mg versus placebo) in the primary efficacy analysis was conducted using a 2-sided Fisher exact test at a significant level of 0.025. The second group included all other additional secondary variables. All analyses of secondary end points were performed using the ITT analysis set of each study: ITT1 and ITT2 for the induction trials, and the ITT-A population for the maintenance trial. In general, continuous secondary variables with repeated measurements were analyzed using a mixed-model for repeated measures at all visits, except that measurements at or after the occurrence of UC-related corticosteroid intercurrent events were excluded. The mixed model included the categorical fixed effects of treatment, visit and treatment-by-visit interaction, randomization stratification factors (bio-IR status [bio-IR versus non-bio-IR], baseline corticosteroid use [yes versus no], and baseline adapted Mayo score [≤ 7 versus > 7]), and the continuous fixed covariates of baseline measurements. An unstructured variance covariance matrix was used. If the model could not converge, an autoregressive covariance structure matrix was used. The parameter estimations were based on the method of restrictive maximum likelihood. The fixed effects were used to report model-based means at corresponding visits. These variables were also analyzed using an analysis of covariance model that included factors for treatment group and stratification variables. Both last observation carried forward (LOCF) and observed-case analyses were used for continuous end points. Binary secondary efficacy variables were analyzed using the Cochran-Mantel-Haenszel test, controlling for stratification variables. The handling of missing data for secondary efficacy end points was the same as for the primary end point: the NRI-C was the primary approach in the analyses of binary secondary efficacy end points. Sensitivity analyses for the secondary end points were performed using NRI-NC, hybrid multiple imputation, and as observed.

The ranked secondary efficacy variables for phase III induction and maintenance trials were as follows.

Induction Period (U-ACHIEVE Induction)

• Proportion of patients with endoscopic improvement at week 8.

• Proportion of patients with endoscopic remission at week 8.

• Proportion of patients achieving clinical response per adapted Mayo score at week 8.

• Proportion of patients achieving clinical response per Partial adapted Mayo score at week 2.

• Proportion of patients achieving histologic-endoscopic mucosal improvement at week 8.

• Proportion of patients who reported no bowel urgency at week 8.

• Proportion of patients who reported no abdominal pain at week 8.

• Proportion of patients who achieved histologic improvement at week 8.

• Change from baseline in IBDQ total score at week 8.

• Proportion of patients with mucosal healing at week 8.

• Change from baseline in FACIT-F score at week 8.

Induction Period (U-ACCOMPLISH)

• Proportion of patients with endoscopic improvement (defined as an endoscopic subscore ≤ 1) at week 8.

• Proportion of patients with endoscopic remission (defined as an endoscopic subscore of 0) at week 8.

• Proportion of patients achieving clinical response per adapted Mayo score (defined as a decrease from baseline in the adapted Mayo score ≥ 2 points and ≥ 30% from baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1) at week 8.

• Proportion of patients achieving clinical response per adapted Mayo score (defined as a decrease from baseline ≥ 1 point and ≥ 30% from baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1) at week 2.

• Proportion of patients achieving histologic-endoscopic mucosal improvement (endoscopic subscore ≤ 1 and Geboes score ≤ 3.1) at week 8.

• Proportion of patients who reported no bowel urgency at week 8.

• Proportion of patients who reported no abdominal pain at week 8.

• Proportion of patients who achieved histologic improvement at week 8.

• Change from baseline in IBDQ total score at week 8.

• Proportion of patients with mucosal healing (endoscopic subscore = 0 and Geboes score < 2) at week 8.

• Change from baseline in FACIT-F score at week 8.

Maintenance Period (U-ACHIEVE Maintenance)

• Proportion of patients with endoscopic improvement.

• Proportion of patients who maintain clinical remission per adapted Mayo score among patients who achieved clinical remission per adapted Mayo score in U-ACHIEVE Induction (substudy 1 or 2) or U-ACCOMPLISH.

• Proportion of patients who achieved clinical remission at week 52 per adapted Mayo score and were corticosteroid-free for at least 90 days among patients in clinical remission in the end of the induction treatment in U-ACHIEVE Induction (substudies 1 or 2) or U-ACCOMPLISH.

• Proportion of patients with endoscopic improvement among patients with endoscopic improvement in U-ACHIEVE Induction (substudy 1 or 2) or U-ACCOMPLISH.

• Proportion of patients with endoscopic remission.

• Proportion of patients who maintain clinical response per adapted Mayo score.

• Proportion of patients with histologic-endoscopic mucosal improvement.

• Change from baseline in the maintenance period in IBDQ total score.

• Proportion of patients with mucosal healing.

• Proportion of patients who reported no bowel urgency.

• Proportion of patients who reported no abdominal pain.

• Change from baseline in FACIT-F score.

Safety Analysis

The safety analysis in U-ACHIEVE Induction, U-ACCOMPLISH, and U-ACHIEVE Maintenance were carried out using the corresponding safety analysis set. Please refer to the following analysis populations section for descriptions of the safety analysis sets used in safety analyses.

In general, in the induction trials, all safety comparisons were to be performed between the treatment groups and placebo group using the ITT_A and safety analysis sets. The safety variables were summarized by treatment according to the treatment a patient actually received. The differences in safety parameters between treatment groups and placebo were evaluated using 2-sided tests at a significance level of 0.05. The treatment group differences in continuous safety variables were assessed using an analysis of variance model with the term of treatment; the treatment group differences in categorical safety variables were evaluated using a Fisher exact test. Missing safety data were not imputed.

In the maintenance trial, the standard safety analyses included reporting of AEs, AEs of special interest, and laboratory and vital sign measurements.

Analysis Populations

Induction

In U-ACHIEVE Induction (substudy 2) and U-ACCOMPLISH, the ITT population for the 8-week double-blind induction period (part 1) was denoted as ITT1 and included all randomized patients who received at least 1 dose of the double-blinded study drug in part 1. The ITT1 population was used for all efficacy and baseline analyses for part 1. These populations are similar to a true ITT population.

The ITT population for the 8-week open-label extended-treatment period (part 2) (ITT2) included all patients who received at least 1 dose of upadacitinib 45 mg in part 2.

The safety population for part 1 included all randomized patients who received at least 1 dose of upadacitinib 45 mg or placebo in part 1.

The safety population for part 2 included all patients who received at least 1 dose of upadacitinib 45 mg in part 2.

Maintenance

In U-ACHIEVE Maintenance, the ITT population included all patients who received at least 1 dose of the study drug in the maintenance study, and the patients were included in the analysis according to the treatment groups that they were randomized to. The following populations were subsets of this ITT population:

• ITT_A population: This was the subset of the ITT population comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1. The planned number of patients in the ITT_A population was 450; however, the actual number of patients was 451 because patients 450 and 451 had the same enrolment date. The ITT_A population was the primary analysis population in cohort 1 for efficacy end points.

• ITT_B population: This was the subset of the ITT population in cohort 3 who were responders to the upadacitinib 45 mg once daily 16-week induction.

• In this maintenance study, the safety population included all patients who received at least 1 dose of the study drug in the maintenance study. The following safety populations were subsets of this safety population (note that the primary population for safety data presentations was the SA_C population, which included the SA_A population):

• SA_C population, N = 746: A subset of the safety population comprising patients who were responders to upadacitinib 45 mg once daily 8-week induction and who were enrolled under the protocol for the 44- or 52-week maintenance treatment period in cohort 1 (i.e., all patients who responded to 8-week induction treatment with upadacitinib 45 mg and received maintenance therapy with upadacitinib 15 mg, 30 mg, or placebo).

• SA_A population, N = 451: The planned subset of the safety population was to comprise the first 450 responders to upadacitinib 45 mg once daily 8-week induction treatment who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1.

Results

Patient Disposition

Induction

In U-ACHIEVE Induction, 474 patients were randomized, with 319 randomized to the upadacitinib group and 155 randomized to the placebo group. In part 1 of this study, 13 patients (4.1%) in the upadacitinib group and 20 patients (12.9%) in the placebo group withdrew prematurely from the study. Patients treated with placebo (5.8%) were more likely to discontinue the study because of AEs compared with those treated with upadacitinib (1.9%).

In U-ACCOMPLISH, 522 patients were randomized, with 345 randomized to the upadacitinib group and 177 randomized to the placebo group. In part 1 of this study, 11 patients (3.2%) in the upadacitinib group and 13 patients (7.5%) in the placebo group withdrew prematurely from the study. Patients treated with placebo (7.5%) were more likely to discontinue the study because of AEs compared with those treated with upadacitinib (3.2%).

In both studies, UC symptoms were considered AEs.

Details of patient disposition in the induction trials are presented in Table 11.

Table 11: Patient Disposition — Induction Trials

ITT1 = intention-to-treat population in part 1; ITT2 = intention-to-treat population in part 2; NR = not reported; SA1 = safety population in part 1; SA2 = safety population in part 2.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

Maintenance

A total of 1,046 patients who achieved clinical response per adapted Mayo score after completion of induction treatment or an extended-treatment period in U-ACHIEVE substudy 1, substudy 2, or U-ACCOMPLISH entered U-ACHIEVE Maintenance, and 1,044 were treated with a blinded treatment assignment for up to 52 weeks. This study included 4 cohorts. In cohort 1, 847 patients who had achieved clinical response in U-ACHIEVE substudies 1 and 2 and U-ACCOMPLISH at either week 8 or week 16 were re-randomized in a 1:1:1 ratio to upadacitinib 15 mg once daily, upadacitinib 30 mg once daily, or placebo daily. At week 52 in cohort 1, 87 patients (30.4%) in the upadacitinib 15 mg group, 52 patients (18.8%) in the upadacitinib 30 mg group, and 178 patients (63.8%) in the placebo group withdrew prematurely from the study. The main reasons for early withdrawal were AEs and “other.”

According to the additional information provided by the sponsor, the majority of patients with reasons labelled as “other” withdrew due to lack of response or loss of efficacy. The ITT_A population was a subset of patients from cohort 1 who were the first 451 responders randomized to upadacitinib 45 mg induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1. The ITT_A population was the primary analysis population in cohort 1 for efficacy end points. The SA_C population was a subset of the patients in the safety population who had responded to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for a 44- or 52-week maintenance treatment period in cohort 1. The safety results of this population are presented in this review.

Cohort 2 included patients who received double-blind placebo daily for 8 weeks during U-ACHIEVE Induction substudy 1, substudy 2 part 1, or U-ACCOMPLISH, and achieved a clinical response at week 8; these patients continued to receive blinded placebo daily in substudy 3. Treatment for this cohort was not randomly assigned to the patients.

Cohort 3 included 75 patients who received upadacitinib 45 mg once daily in the induction phase and did not achieve clinical response and received upadacitinib 45 mg as extended treatment in U-ACHIEVE Induction substudy 2 part 2, or U-ACCOMPLISH part 2, and achieved clinical response at week 16; these patients were re-randomized 1:1 and received blinded upadacitinib 30 mg once daily or upadacitinib 15 mg once daily in U-ACHIEVE Maintenance (substudy 3).

Details of patient disposition in the maintenance trials are presented in Table 12.

Table 12: Patient Disposition — Maintenance Trial

ITT = intention to treat; NR = not reported; PP = per protocol; UPA = upadacitinib.

Note: Cohort 4 received UPA 7.5 mg. As this is not a recommended dosage for the study population, the results for this cohort are not included in the current report.

The ITT population included all patients who received at least 1 dose of the study drug. The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

The SA_C population comprised responders to UPA 45 mg 8-week induction who were enrolled for 44- or 52-week maintenance.

^aThe majority of “other” results were labelled as lack of response or loss of efficacy, as per the additional information provided by the sponsor.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Exposure to Study Treatments

In the induction period, the mean duration of exposure to upadacitinib 45 mg and placebo in U-ACHIEVE Induction was 56 days and 53 days, respectively, for part 1, and 54 days and 54 days, respectively, for part 2. In U-ACCOMPLISH, the mean duration of exposure to upadacitinib 45 mg and placebo was 56 days and 54 days, respectively, for part 1, and 56 days and 55 days, respectively, for part 2.

In the maintenance period, the mean duration of exposure to the study drug was 295 to 320 days in patients re-randomized to upadacitinib and 214 days to patients re-randomized to placebo.

Details of extent of exposure to the study drug in the induction and maintenance trials are presented in Table 13.

Table 13: Extent of Exposure — Induction and Maintenance Trials

SA = safety population; SA1 = safety population in part 1; SA2 = safety population in part 2; SD = standard deviation; UPA = upadacitinib.

Note: The SA_C population comprised responders to UPA 45 mg 8-week induction who were enrolled for 44- or 52-week maintenance.

Source: Clinical Study Reports for U-ACHIEVE Induction,⁶ U-ACCOMPLISH,⁷ and U-ACHIEVE Maintenance.⁸

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported subsequently.

Clinical Remission

In the double-blind treatment period of U-ACHIEVE Induction, clinical remission per adapted Mayo score was achieved in 26.1% of patients in the upadacitinib group and 4.8% of patients in the placebo group; the between-group difference was 21.6% (95% CI, 15.8% to 27.4%; P < 0.001). In U-ACCOMPLISH, clinical remission per adapted Mayo score was achieved in 33.5% of patients in the upadacitinib group and 4.1% of patients in the placebo group; the between-group difference was 29.0% (95% CI, 23.2% to 34.7%; P < 0.001) (Table 14).

The results of the sensitivity analyses were consistent with those in the primary analysis for clinical remission.

The results of clinical remission based on the full Mayo score were consistent with those based on the adapted Mayo score. The proportion of patients who achieved clinical remission in the induction phase was higher in the upadacitinib-treated group compared with the placebo-treated group in both the bio-IR and non-bio-IR subgroups. The efficacy results for the primary end point across all other subgroups were also consistent with the overall population (data not shown). Note that these subgroup analyses are not controlled for multiplicity.

In U-ACHIEVE Induction, among 59 patients who received upadacitinib 45 mg treatment in part 1 and did not respond, 2 (3.4%) achieved clinical remission per adapted Mayo score at week 16 with additional 8-week treatment with upadacitinib 45 mg once daily. In U-ACCOMPLISH, among 66 patients who received upadacitinib 45 mg treatment in part 1 and did not respond, 5 (7.6%) achieved clinical remission per adapted Mayo score at week 16 with additional 8-week treatment with upadacitinib 45 mg once daily.

Table 14: Efficacy Outcomes, Clinical Remission — Induction Trials, ITT1 Population

bio-IR = patients with inadequate response, loss of response, or intolerance to biologic therapy; CI = confidence interval; ITT1 = intention-to-treat population in part 1; non-bio-IR = patients with inadequate response, loss of response, or intolerance to conventional therapy; UPA = upadacitinib.

Note: Adapted Mayo score = stool frequency subscore + rectal bleeding subscore + endoscopic subscore. Clinical remission per adapted Mayo score is defined as an adapted Mayo score ≤ 2, with a stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1.

The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation if there were no missing data due to COVID-19.

^aP value not controlled for multiplicity.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

In the maintenance trial (U-ACHIEVE Maintenance), the primary and multiplicity-controlled secondary efficacy end points were analyzed based on the ITT_A population, which was defined as the subset of the ITT population comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1.

At week 52, clinical remission per adapted Mayo score was maintained in 42.3% of patients in the upadacitinib 15 mg group, 51.7% of patients in the upadacitinib 30 mg group, and 12.1% of patients in the placebo group in the ITT_A population. The between-group differences were as follows: upadacitinib 15 mg versus placebo, 30.7% (95% CI. 21.7% to 39.8%; P < 0.0001), upadacitinib 30 mg versus placebo, 39.0% (95% CI, 29.7% to 48.2%; P < 0.0001). In the ITT_B population (the subset of the ITT population in cohort 3 who were responders to upadacitinib 45 mg once daily 16-week induction treatment), clinical remission was maintained in 24 patients (33.3%) treated with upadacitinib 30 mg and 21 patients (19.0%) treated with upadacitinib 15 mg at week 52.

At week 52, in patients who were corticosteroid-free for more than 3 months, clinical remission was maintained in 57.1% of patients in the upadacitinib 15 mg group, 68.0% of patients in the upadacitinib 30 mg group, and 22.2% of patients in the placebo group. The between-group differences were as follows: upadacitinib 15 mg versus placebo, 35.4% (95% CI, 18.2% to 52.7%), upadacitinib 30 mg versus placebo, 45.1% (95% CI, 28.7% to 61.6%) (Table 15).

The results of the sensitivity analyses were consistent with those in the primary analysis for clinical remission.

The efficacy results for the primary end point across all subgroups were consistent with the overall population (data not shown aside from the bio-IR and non-bio-IR subgroups in Table 15).

Table 15: Efficacy Outcomes, Clinical Remission — Maintenance Trial, ITT_A Population

bio-IR = inadequate response to treatment with biologics; CI = confidence interval; ITT = intention to treat; non-bio-IR = inadequate response to conventional therapy; UPA = upadacitinib.

Note: Adapted Mayo score = stool frequency subscore + rectal bleeding subscore + endoscopic subscore. Clinical remission per adapted Mayo score is defined as an adapted Mayo score ≤ 2, with stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1.

The ITT_A population is defined as the first 450 randomized patients administered 8 weeks of upadacitinib 45 mg once daily induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1.

The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Clinical Response

Details of the results for clinical response in the induction period are shown in Table 16. In the double-blind treatment period of U-ACHIEVE Induction, clinical response per adapted Mayo score was achieved in 72.6% of patients in the upadacitinib group and 27.3% of patients in the placebo group; the between-group difference was 46.3% (95% CI, 38.4% to 54.2%; P < 0.001). In U-ACCOMPLISH, clinical response per adapted Mayo score was achieved in 74.5% of patients in the upadacitinib group and 25.4% of patients in the placebo group; the between-group difference was 49.4% (95% CI, 41.7% to 57.1%; P < 0.001).

The results of clinical response based on the partial Mayo score were consistent with that based on the adapted Mayo score.

In U-ACHIEVE Induction, among 59 patients who received upadacitinib 45 mg treatment in part 1 and did not respond, 30 (50.8%) achieved clinical response per adapted Mayo score at week 16 with additional 8-week treatment with upadacitinib 45 mg once daily. In U-ACCOMPLISH, among 66 patients who received upadacitinib 45 mg treatment in part 1 and did not respond, 30 (45.5%) achieved clinical response per adapted Mayo score at week 16 with additional 8-week treatment with upadacitinib 45 mg once daily.

Table 16: Efficacy Outcomes, Clinical Response — Induction Trials, ITT1 Population

CI = confidence interval; ITT1 = intention-to-treat population in part 1; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

Sources: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

At week 52 of U-ACHIEVE Maintenance, clinical response per adapted Mayo score was maintained in 63.0% of patients in the upadacitinib 15 mg group, 76.6% of patients in the upadacitinib 30 mg group, and 18.8% of patients in the placebo group. The between-group differences were as follows: upadacitinib 15 mg versus placebo, 44.6% (95% CI, 34.5% to 54.7%; P < 0.001), upadacitinib 30 mg versus placebo, 56.6% (95% CI, 47.2% to 66.0%; P < 0.001) (Table 17).

Table 17: Efficacy Outcomes, Clinical Response — Maintenance Trial, ITT_A Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; ITT = intention to treat; non-bio-IR = inadequate response to conventional therapy; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Endoscopic Improvement and Remission

In the double-blind treatment period of U-ACHIEVE Induction, endoscopic improvement (defined as an endoscopic subscore of 0 or 1) was achieved in 36.3% of patients in the upadacitinib group and 7.4% of patients in the placebo group; the between-group difference was 29.3% (95% CI, 22.6% to 35.9%; P < 0.001). In U-ACCOMPLISH, endoscopic improvement was achieved in 44.0% of patients in the upadacitinib group and 8.3% of patients in the placebo group; the between-group difference was 35.1% (95% CI, 28.6% to 41.6%; P < 0.001).

In U-ACHIEVE Induction, endoscopic remission (defined as an endoscopic subscore of 0) was achieved in 13.7% of patients in the upadacitinib group and 1.3% of patients in the placebo group; the between-group difference was 12.7% (95% CI, 8.4% to 17.0%; P < 0.001). In U-ACCOMPLISH, endoscopic remission was achieved in 18.2% of patients in the upadacitinib group and 1.7% of patients in the placebo group; the between-group difference was 15.9% (95% CI, 11.4% to 20.3%; P < 0.001) (Table 18).

Table 18: Efficacy Outcomes, Endoscopic Remission — Induction Trials, ITT1 Population

CI = confidence interval; ITT1 = intention-to-treat population in part 1; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

At week 52 of U-ACHIEVE Maintenance, endoscopic improvement was achieved in 48.7% of patients in the upadacitinib 15 mg group, 61.6% of patients in the upadacitinib 30 mg group, and 14.5% of patients in the placebo group; the between-group differences were as follows: upadacitinib 15 mg versus placebo, 34.4% (95% CI, 25.1% to 43.7%; P < 0.001), upadacitinib 30 mg versus placebo, 46.3% (95% CI, 36.7% to 55.8%; P < 0.001).

At week 52, endoscopic remission was achieved in 24.2% of patients in the upadacitinib 15 mg group, 25.9% of patients in the upadacitinib 30 mg group, and 5.6% of patients in the placebo group; the between-group differences were as follows: upadacitinib 15 mg versus placebo, 18.7% (95% CI, 11.0% to 26.4%; P < 0.001), upadacitinib 30 mg versus placebo, 19.4% (95% CI, 11.7% to 27.2%; P < 0.001) (Table 19).

Table 19: Efficacy Outcomes, Endoscopic Improvement, and Remission — Maintenance Trial, ITT_A Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; ITT = intention to treat; non-bio-IR = inadequate response to conventional therapy; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Histologic Remission or Improvement

In the double-blind treatment period of U-ACHIEVE Induction, histologic improvement (defined as a decrease from baseline in Geboes score) was achieved in 55.0% of patients in the upadacitinib group and 22.5% of patients in the placebo group; the between-group difference was 32.2% (95% CI, 23.8% to 40.7%; P < 0.001). In U-ACCOMPLISH, histologic improvement was achieved in 62.2% of patients in the upadacitinib group and 24.5% of patients in the placebo group; the between-group difference was 37.9% (95% CI, 29.8% to 46.1%; P < 0.001) (Table 20).

Table 20: Efficacy Outcomes, Histologic Improvement — Induction Trials, ITT1 Population

CI = confidence interval; ITT1 = intention-to-treat population in part 1; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

At week 52 of U-ACHIEVE Maintenance, histologic improvement was achieved in 42.8% of patients in the upadacitinib 15 mg group, 56.9% of patients in the upadacitinib 30 mg group, and 20.6% of patients in the placebo group; the between-group differences were as follows: upadacitinib 15 mg versus placebo, 23.0% (95% CI, 12.9% to 33.1%), upadacitinib 30 mg versus placebo, 36.0% (95% CI, 25.8% to 46.2%) (Table 21).

Table 21: Efficacy Outcomes, Histologic Improvement — Maintenance Trial, ITT_A Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; ITT = intention-to-treat; non-bio-IR = inadequate response to conventional therapy; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

This outcome was outside of the statistical hierarchy for multiplicity adjustment.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Mucosal Healing

In U-ACHIEVE Induction, mucosal healing (defined as an endoscopic subscore of 0 and Geboes score < 2) was achieved in 10.7% of patients in the upadacitinib group and 1.3% of patients in the placebo group; the between-group difference was 9.7% (95% CI, 5.7% to 13.7%). In U-ACCOMPLISH, mucosal healing was achieved in 13.5% of patients in the upadacitinib group and 1.7% of patients in the placebo group; the between-group difference was 11.3% (95% CI, 7.2% to 15.3%; P < 0.001) (Table 22).

At week 52, mucosal healing was achieved in 17.6% of patients in the upadacitinib 15 mg group, 19.0% of patients in the upadacitinib 30 mg group, and 4.7% of patients in the placebo group; the between-group differences were as follows: upadacitinib 15 mg versus placebo, 13.0% (95% CI, 6.0% to 20.0%; P < 0.001), upadacitinib 30 mg versus placebo, 13.6% (95% CI, 6.6% to 20.6%; P < 0.001) (Table 23).

Symptoms Relief

At the end of the induction period of U-ACHIEVE, the proportion of patients who reported no bowel urgency was higher in the upadacitinib group (48.4%) compared with those in the placebo group (21.4%); the between-group difference was 27.4% (95% CI, 19.2% to 35.6%; P < 0.001). In U-ACCOMPLISH, the proportion of patients who reported no bowel urgency was higher in the upadacitinib group (53.7%) compared with those in the placebo group (25.9%); the between-group difference was 27.1% (95% CI, 19.0 to 35.3%; P < 0.001).

Table 22: Efficacy Outcomes, Mucosal Healing — Induction Trials, ITT1 Population

CI = confidence interval; ITT1 = intention-to-treat population in part 1; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

^aMucosal healing was defined as endoscopic subscore of 0 and Geboes score < 2.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

Table 23: Efficacy Outcomes, Mucosal Healing — Maintenance Trial, ITT_A Population

CI = confidence interval; ITT = intention to treat; UPA = upadacitinib.

Note: The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

At the end of the induction period of U-ACHIEVE, the proportion of patients who reported no abdominal pain was higher in the upadacitinib group (46.6%) compared with those in the placebo group (23.4%); the between-group difference was 23.6% (95% CI, 15.1% to 32.1%; P < 0.001). In U-ACCOMPLISH, the proportion of patients who reported no abdominal pain was higher in the upadacitinib group (53.7%) compared with those in the placebo group (24.1%); the between-group difference was 29.1% (95% CI, 20.9% to 37.4%; P < 0.001).

In the 2 induction trials, patients treated with upadacitinib 45 mg reported fewer stools per day than those treated with placebo at week 8 compared with baseline. More patients in the upadacitinib 45 mg group reported no rectal bleeding at week 8 compared with those in the placebo group. Patients in the upadacitinib group reported higher FACIT-F scores than those in the placebo group, which indicate less fatigue (Table 24).

At week 52 of U-ACHIEVE Maintenance, the proportion of patients who reported no bowel urgency was 56.1% in the upadacitinib 15 mg group, 63.6% in the upadacitinib 30 mg group, and 17.4% in the placebo group; the between-group differences were as follows: upadacitinib 15 mg versus placebo, 38.7% (95% CI, 28.9% to 48.5%; P < 0.001), upadacitinib 30 mg versus placebo, 45.1% (95% CI, 35.5% to 54.8%; P < 0.001).

At week 52, the proportion of patients who reported no abdominal pain was 45.9% in the upadacitinib 15 mg group, 55.3% in the upadacitinib 30 mg group, and 20.8% in the placebo group; the between-group differences were as follows: upadacitinib 15 mg versus placebo, 24.3% (95% CI, 14.2 to 34.5%; P < 0.001), upadacitinib 30 mg versus placebo, 33.7% (95% CI, 23.6% to 43.9%; P < 0.001).

In the maintenance trial, patients treated with upadacitinib 15 mg or 30 mg reported fewer stools per day than those treated with placebo at week 52 compared with baseline. More patients in the upadacitinib groups reported no rectal bleeding at week 52 compared with those in the placebo group. Patients in the upadacitinib groups reported higher FACIT-F scores than those in the placebo group at week 52, which indicate less fatigue (Table 25).

Table 24: Efficacy Outcomes, Symptom Relief — Induction Trials, ITT1 Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; ITT = intention to treat; ITT1 = intention-to-treat population in part 1; LS = least squares; MMRM = mixed-model for repeated measures; non-bio-IR = inadequate response to conventional therapy; RBS = rectal bleeding subscore; UPA = upadacitinib.

Note: For bowel urgency, abdominal pain, and rectal bleeding, the 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19. Note that “rectal bleeding” was outside of the statistical hierarchy for multiplicity adjustment.

Change in stool frequency and FACIT-F score: MMRM was the mixed-effect model repeat measurement with baseline, treatment, visit, treatment-by-visit interaction, and strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) in the model. Baseline was defined as the last nonmissing value before the first dose of study drug. Patients with only nonmissing change from baseline values were included in analysis. This outcome was outside of the statistical hierarchy for multiplicity adjustment. Note that this outcome was outside of the statistical hierarchy for multiplicity adjustment.

Sources: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

Table 25: Efficacy Outcomes, Symptom Relief — Maintenance Trial, ITT_A Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; ITT = intention to treat; LS = least squares; non-bio-IR = inadequate response to conventional therapy; RBS = rectal bleeding subscore; UC = ulcerative colitis; UPA = upadacitinib.

Note: For bowel urgency, abdominal pain, and rectal bleeding, the 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero. Within each stratum, the 95% CI for difference was calculated based on the normal approximation to the binomial distribution and P value was calculated using a Chi-square test. The calculations were based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, or nonresponder imputation if there were no missing data due to COVID-19.

The LS mean, 95% CI, and standard error were the synthetic result based on mixed-model for repeated measures or analysis of covariance with baseline, week 0, treatment, and strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or nonbio-IR]), and visit and treatment-by-visit interaction in the model from PROC MIANALYZE procedure. Baseline was defined as the last nonmissing value before the first dose in the phase IIb induction or in the induction studies. Patients with only nonmissing change from baseline values were included in the analysis.

The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Health-Related Quality of Life

At week 8, the between-group findings for change from baseline for the IBDQ total score favoured upadacitinib in both U-ACHIEVE Induction and U-ACCOMPLISH. In U-ACHIEVE Induction, the IBDQ total score was 33.7 points higher in the upadacitinib 45 mg group compared with the placebo group. In U-ACCOMPLISH, this score was 31.2 points higher in the upadacitinib group compared with placebo.

Results of the EQ-5D-5L index score, SF-36 Physical Component Summary and Mental Component Summary scores, and the Ulcerative Colitis Symptoms Questionnaire (UC-SQ) score showed more changes from baseline in the upadacitinib group compared with the placebo group at week 8 in the 2 induction trials. However, the outcomes of the EQ-5D-5L index score, SF-36 Physical Component Summary and Mental Component Summary scores, and the UC-SQ score were unadjusted for multiple comparisons.

Details of the results for each HRQoL instrument are provided in Table 26.

Table 26: Efficacy Outcomes, HRQoL — Induction Trials, ITT1 Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; EQ-5D-5L = 5-level EQ-5D; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; ITT1 = intention-to-treat population for part 1; LS = least squares; MCS = Mental Component Summary; MMRM = mixed-model for repeated measures; non-bio-IR = inadequate response to conventional therapy; PCS = Physical Component Summary; SF-36 = Short Form (36) Health Survey; UC-SQ = Ulcerative Colitis Symptoms Questionnaire; UPA = upadacitinib; WPAI = Work Performance and Activity Impairment.

Note: IBDQ total score, EQ-5D index score, SF-36 PCS and MCS scores, WPAI scores, and UC-SQ score — MMRM is the mixed-effect model repeat measurement with baseline, treatment, visit, treatment-by-visit interaction, and strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) in the model. Baseline was defined as the last nonmissing value before the first dose of the study drug. Patients with only nonmissing change from baseline values were included in the analysis.

^aThese outcomes were unadjusted for multiple comparisons.

Sources: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

HRQoL analyses were performed in the ITT_A population in the maintenance trial. At week 52, the between-group findings for change from baseline for the IBDQ total score favoured upadacitinib (Table 27).

The results of the UC-SQ score showed more changes from baseline in the upadacitinib groups compared with the placebo group at week 52; however, the UC-SQ score was unadjusted for multiple comparisons.

Table 27: Efficacy Outcomes, HRQoL — Maintenance Trial, ITT_A Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; LS = least squares; non-bio-IR = inadequate response to conventional therapy; SE = standard error; UC-SQ = Ulcerative Colitis Symptoms Questionnaire; UPA = upadacitinib; WPAI = Work Performance and Activity Impairment.

Note: IBDQ total score, WPAI score, and UC-SQ score The LS mean, 95% CI, and SE were the synthetic result based on analysis of covariance with baseline, week 0, treatment, and strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]) in the model from PROC MIANALYZE procedure. Baseline was defined as the last nonmissing value before the first dose in phase IIb Induction or Induction Studies. Patients with only nonmissing change from baseline values were included in the analysis.

The ITT_A population is defined as the first 450 patients randomized and administered 8-week upadacitinib 45 mg once daily induction treatment who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1.

^aThese outcomes were unadjusted for multiple comparisons.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Need for Colectomy

Not assessed in the included studies.

Extraintestinal Manifestations

Not assessed in the included studies.

Emergency Department Visits or Hospitalization

At the end of the induction period of U-ACHIEVE, the proportion of patients with UC-related hospitalization was lower in the upadacitinib group (0.6%) compared with those in the placebo group (3.9%); the between-group difference was −3.5% (95% CI, −6.8% to −0.2%; P = 0.037). In U-ACCOMPLISH, the proportion of patients with UC-related hospitalization was similar in the upadacitinib group (2.1%) compared with those in the placebo group (2.3%); the between-group difference was −0.3% (95% CI, −3.2% to 2.6%, P > 0.05) (Table 28).

Table 28: Efficacy Outcomes, UC-Related Hospitalization — Induction Trials, ITT1 Population

bio-IR = inadequate response to biologic therapy; CI = confidence interval; ITT1 = intention-to-treat population in part 1; non-bio-IR = inadequate response to conventional therapy; UC = ulcerative colitis; UPA = upadacitinib.

Note: This outcome was not adjusted for multiplicity. The 95% CI for response rate was based on the normal approximation to the binomial distribution. The 95% CI for adjusted difference and P value were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline corticosteroid use [yes or no], baseline adapted Mayo score [≤ 7 or > 7], bio-IR status [bio-IR or non-bio-IR]) for the comparison of 2 treatment groups. If zero frequency occurred, the zero count was replaced by 0.1 to prevent dividing by zero.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

At week 52 of U-ACHIEVE Maintenance, the incidence rate of UC-related hospitalization was 0.76 in the upadacitinib 15 mg group, 1.36 in the upadacitinib 30 mg group, and 7.13 in the placebo group; the between-group differences were as follows: upadacitinib 15 mg versus placebo, 38.7% (95% CI, 28.9% to 48.5%; P < 0.001), upadacitinib 30 mg versus placebo, 45.1% (95% CI, 35.5% to 54.8%; P < 0.001) (Table 29).

The outcome of UC-related hospitalization was not included in the statistical hierarchy for multiplicity adjustment in these 3 studies.

Table 29: Efficacy Outcomes, UC-Related Hospitalization — Maintenance Trial, ITT_A Population

CI = confidence interval; ITT = intention to treat; UC = ulcerative colitis; UPA = upadacitinib.

Note: The 95% CI for incidence rate difference and P value were based on the normal approximation to poisson distribution.

The ITT_A population was a subset of the ITT population in U-ACHIEVE Maintenance comprising the first 451 (actual) responders who had been randomized to upadacitinib 45 mg once daily 8-week induction treatment and who were enrolled under the protocol for 52-week maintenance treatment period in cohort 1 of this maintenance study.

Source: Clinical Study Report for U-ACHIEVE Maintenance.⁸

Work Productivity

Work productivity was assessed using the WPAI-UC.

In U-ACHIEVE Induction, patients in the upadacitinib group showed a greater reduction in the overall work impairment score compared with the placebo group (upadacitinib = −26.7; placebo = −4.5) from baseline at week 8. In U-ACCOMPLISH, patients in the upadacitinib group showed a greater reduction in the overall work impairment score (upadacitinib = −27.3; placebo = −14.1) compared with the placebo group.

In U-ACHIEVE Maintenance, at week 52, patients in the 2 upadacitinib groups reported a greater reduction from baseline in the overall work impairment score compared with the placebo group (upadacitinib 15 mg = −25.3; upadacitinib 30 mg = −26.26; placebo = −12.63).

The WPAI overall work impairment score was unadjusted for multiple comparisons.

Results of change in work productivity are shown in Table 26 and Table 27.

Harms

Only those harms identified in the review protocol are reported subsequently. See Table 30 and Table 31 for detailed harms data.

Adverse Events

In U-ACHIEVE Induction, at least 1 treatment-emergent AE was reported by 56.4% and 61.9% of patients in the upadacitinib group and the placebo group, respectively. In U-ACCOMPLISH, at least 1 treatment-emergent AE was reported by 52.9% and 39.5% of patients in the upadacitinib group and the placebo group, respectively.

In these 2 studies, the most commonly reported AEs in the upadacitinib groups were blood creatine phosphokinase increased (4.7% to 5% in part 1; 10.2% to 10.3% in part 2), acne (4.7% to 7.0% in part 1; 3.4% to 8.8% in part 2), nasopharyngitis (3.8% to 4.7% in part 1; 2.9% to 8.5% in part 2), headache (2.3% to 4.1% in part 1; 5.1% to 5.9% in part 2), and anemia (2.5% to 4.1% in part 1; 5.1% to 13.2% in part 2). The most commonly reported AEs in the placebo groups were nasopharyngitis (2.3% to 3.9% in part 1), anemia (2.3% to 5.8% in part 1), and UC (4.5% to 13.5% in part 1).

During the maintenance period, AEs were reported in 75.2%, 75.3%, and 73.5% of the patients in the upadacitinib 15 mg, upadacitinib 30 mg, and placebo groups, respectively. Commonly reported AEs were nasopharyngitis (8.2% to 10.4%), blood creatine phosphokinase increased (2.0% to 7.6%), UC (7.2% to 29.8%), arthralgia (2.8% to 9.8%), and herpes zoster (0% to 4.0%).

Serious Adverse Events

In U-ACHIEVE Induction, at least 1 SAE was reported by 2.5% and 5.8% of patients in the upadacitinib group and the placebo group, respectively. In U-ACCOMPLISH, at least 1 SAE was reported by 3.2% and 4.5% of patients in the upadacitinib group and the placebo group, respectively. In the upadacitinib group, isolated cases of SAEs were reported. UC was the most commonly reported SAE in the placebo group (1.7% to 3.2% in part 1).

During the maintenance period, at least 1 SAE was reported in 8.0%, 8.0%, and 9.4% of the patients in the upadacitinib 15 mg group, upadacitinib 30 mg group, and placebo group, respectively. Isolated cases of SAEs were reported in this period. Most of the SAEs occurred in less than 1% of the study population.

Withdrawal Due to Adverse Events

In U-ACHIEVE Induction, WDAEs were reported by 1.9% and 9.0% of patients in the upadacitinib group and the placebo group, respectively. In U-ACCOMPLISH, WDAEs were reported by 1.7% and 5.1% of patients in the upadacitinib group and the placebo group, respectively. UC was the most commonly reported reason for a WDAE in the placebo group (2.8% to 7.1% in part 1; 0 in part 2).

During the maintenance period, WDAEs were reported in 4.0%, 4.8%, and 10.2% of the patients in the upadacitinib 15 mg group, upadacitinib 30 mg group, and placebo group, respectively.

Mortality

No deaths were reported during the induction and maintenance periods of the included studies.

Notable Harms

During the induction period in U-ACHIEVE Induction and U-ACCOMPLISH, there were no AEs of active tuberculosis, malignancy, malignancy excluding nonmelanoma skin cancer, nonmelanoma skin cancer, adjudicated VTE, and gastrointestinal perforation reported in the upadacitinib groups. The incidence of opportunistic infection, excluding tuberculosis and herpes zoster, herpes zoster, lymphopenia, and neutropenia, was higher in the upadacitinib groups.

During the maintenance period, patients treated with upadacitinib were more likely to report herpes zoster, neutropenia, malignancy, nonmelanoma skin cancer, hepatic disorder, lymphopenia, and VTE. Patients in the placebo group reported more cases of anemia.

In general, the number of patients who reported AEs of particular interest was low.

Table 30: Harm Outcomes — Induction Trials, Safety Population in Part 1 and Safety Population in Part 2

AE = adverse event; CPK = creatine phosphokinase; GI = gastrointestinal; NR = not reported; SAE = serious adverse event; TB = tuberculosis; UPA = upadacitinib; VTE = venous thromboembolic event; WDAE = withdrawal due to adverse event.

^aFrequency > 5%.

Source: Clinical Study Reports for U-ACHIEVE Induction⁶ and U-ACCOMPLISH.⁷

Table 31: Harm Outcomes — Maintenance Trial