Sponsor’s Summary of the Clinical Evidence

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Clinical and Economic Review Report: Vedolizumab (ENTYVIO SC): Takeda Canada Inc. Indication: Crohn disease [Internet] Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021 Apr.

Cover of Clinical and Economic Review Report: Vedolizumab (ENTYVIO SC)

Clinical and Economic Review Report: Vedolizumab (ENTYVIO SC): Takeda Canada Inc. Indication: Crohn disease [Internet]

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Sponsor’s Summary of the Clinical Evidence

The clinical evidence summarized in this section was prepared by the sponsor in accordance with the CADTH tailored review process.

Pivotal Studies

Table 5

Details of Included Studies.

Description of Studies

Study SC-3031 was a pivotal, phase III, multi-centre, multinational, randomized, double-blind, placebo-controlled study, designed to evaluate the efficacy and safety of maintenance treatment with vedolizumab SC injection in adult patients with moderately to severely active CD who achieved a clinical response at week 6 with open-label therapy with 300 mg vedolizumab IV infusion at weeks 0 and 2.

A total of 169 sites enrolled patients into the open-label induction phase, of which ▬ enrolled patients into the double-blind maintenance phase. Five of the sites were in Canada.

The primary objective was to assess the effect of vedolizumab SC maintenance treatment on clinical remission at week 52 in patients with moderately to severely active CD who achieved clinical response at week 6 following administration of vedolizumab IV at weeks 0 and 2. Secondary objectives were to determine the effect of vedolizumab SC maintenance treatment on enhanced clinical response at week 52, corticosteroid-free remission at week 52, and clinical remission at week 52 in patients who are naive to TNF alpha antagonist exposure.

Following a 4-week (28-day) screening period, 644 patients were enrolled and treated in a 6-week open-label induction phase with vedolizumab IV. These patients received open-label infusions of vedolizumab IV 300 mg at weeks 0 and 2, and were assessed for clinical response by CDAI at week 6 (defined as a ≥ 70-point decrease in CDAI score from baseline [week 0]). Of the patients who entered the induction phase, 412 (64%) achieved a clinical response at week 6 and were eligible for randomization into the double-blind maintenance phase of the study. A total of 410 patients were randomized in a 2:1 ratio to double-blind treatment with vedolizumab SC administered every 2 weeks or placebo SC every 2 weeks

Randomization was stratified by concomitant use of oral corticosteroids, clinical remission status at week 6, and previous treatment failure with or exposure to TNF alpha antagonists or concomitant immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate) use.

Figure 1

Study Design for SC-3031. CD = Crohn disease; CS = corticosteroid; IM = immunomodulators; Q2W = every 2 weeks; SC = subcutaneous; TNF = tumour necrosis factor.

Populations

Inclusion and Exclusion Criteria

Key Inclusion Criteria

Patient had a diagnosis of CD established at least 3 months before screening by clinical and endoscopic evidence and corroborated by a histopathology report.
Male or female and aged 18 to 80 years, inclusive.
Patient had moderately to severely active CD as determined by a CDAI score of 220 to 450 within 7 days prior to the first dose of the study drug and 1 of the following:
- CRP level greater than 2.87 mg/L during the screening period or
- ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic ulcerations (each > 0.5 cm in diameter) or 10 aphthous ulcerations (involving a minimum of 10 contiguous centimetres of intestine) consistent with CD, within 4 months before screening or
- fecal calprotectin > 250 mcg/g stool during the screening period in conjunction with computed tomography enterography, magnetic resonance enterography, contrast-enhanced small bowel radiography, or wireless capsule endoscopy revealing CD ulcerations (aphthae not sufficient), within 4 months before screening.
Patient had CD involvement of the ileum and/or colon, at a minimum.
Patients with extensive colitis or pancolitis of more than 8 years duration or left-sided colitis more than 12 years duration must have had documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit (if not performed in previous 12 months, must have been performed during screening).
Patients with a family history of colorectal cancer, personal history of increased colorectal cancer risk, older than 50 years, or other known risk factors must have been up-to-date on colorectal cancer surveillance (may have been performed during screening).
Patient had demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents:
- immunomodulators
- corticosteroids
- TNF alpha antagonists.

Key Exclusion Criteria

GI Exclusion Criteria

The patient had evidence of abdominal abscess at the initial screening visit.
The patient had extensive colonic resection, subtotal or total colectomy.
The patient had a history of more than 3 small bowel resections or diagnosis of short bowel syndrome.
The patient had received tube feeding, defined formula diets, or parenteral alimentation within 28 days before administration of the first dose of the study drug.
The patient had ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
The patient received any investigational or approved non-biologic therapies for the treatment of underlying disease within 30 days or 5 half-lives of screening (whichever was longer).
The patient had received any investigational or approved biologic or biosimilar agent within 60 days or 5 half-lives of screening (whichever was longer).
The patient had used topical (rectal) treatment with 5-aminosalicylic acid or corticosteroid enemas/suppositories within 2 weeks of administration of the first dose of the study drug.
The patient currently required or was anticipated to require surgical intervention for CD during the study.
The patient had a history or evidence of adenomatous colonic polyps that had not been removed.
The patient had a history or evidence of colonic mucosal dysplasia.
The patient had a suspected or confirmed diagnosis of UC, indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.

Infectious Disease Exclusion Criteria

The patient had evidence of an active infection during the screening period.
The patient had evidence of, or treatment for, Clostridium difficile infection or another intestinal pathogen within 28 days before the first dose of the study drug.
The patient had chronic hepatitis B virus infection or chronic hepatitis C virus infection.
The patient had active or latent tuberculosis.
The patient had any identified congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, HIV infection, organ transplantation).
The patient had received any live vaccinations within 30 days prior to screening.
The patient had clinically significant infection (e.g., pneumonia, pyelonephritis) within 30 days prior to screening, or ongoing chronic infection.

General Exclusion Criteria

The patient had previous exposure to approved or investigational anti-integrin antibodies (e.g., natalizumab, efalizumab, etrolizumab, abrilumab [AMG 181]), MAdCAM-1 antibodies, or rituximab.
The patient had previous exposure to vedolizumab.
The patient had hypersensitivity or allergies to any of the vedolizumab excipients.
The patient had any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise patient safety.
The patient had any surgical procedure requiring general anesthesia within 30 days prior to screening or was planning to undergo major surgery during the study period.
The patient had any history of malignancy, except for the following: (a) adequately treated nonmetastatic skin cancer; (b) squamous-cell skin cancer that had been adequately treated and that had not recurred for at least 1 year before screening; and (c) history of cervical carcinoma in situ that had been adequately treated and that had not recurred for at least 3 years before screening. Patients with remote history of malignancy (e.g., > 10 years since completion of curative therapy without recurrence) were to be considered based on the nature of the malignancy and the therapy received and must have been discussed with the sponsor on a case-by-case basis before screening.
The patient had a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumour, or neurodegenerative disease.
The patient had a positive progressive multifocal leukoencephalopathy subjective symptom checklist at screening (or before the administration of the first dose of the study drug at week 0).
The patient had any of the following laboratory abnormalities during the screening period:
- hemoglobin level less than 8 g/dL
- white blood cell count less than 3 × 10⁹/L
- lymphocyte count less than 0.5 × 10⁹/L
- platelet count less than 100 × 10⁹/L or > 1,200 × 10⁹/L
- alanine aminotransferase or aspartate aminotransferase greater than 3 × the upper limit of normal (ULN)
- alkaline phosphatase greater than 3 × ULN
- serum creatinine greater than 2 × ULN.

Baseline Characteristics

Overall, baseline demographics were similar for vedolizumab SC and placebo patients in the full analysis set (FAS) and safety analysis set (SAF). One randomized patient was not treated in the maintenance phase.

Among the patients who were randomized and received blinded treatment in the maintenance phase of the study (FAS), there was a higher proportion of male patients than female patients (54.5% and 45.5%, respectively). Most patients (91.4%) were White. The ▬▬▬▬▬ and few patients were 65 years of age or older (3.9%). The mean body weight was 69.8 kg in the placebo arm and 74.1 kg in the vedolizumab SC arm. With respect to geographic distribution, ▬ of patients in the placebo arm and vedolizumab SC arm, respectively, were enrolled at sites in North America.

Table 6

Summary of Baseline Characteristics.

Interventions

Vedolizumab, 108 mg, SC injection, every 2 weeks for 46 weeks.
Placebo, subcutaneous injection, every 2 weeks for 46 weeks.

A total of 139 patients (44 patients in the placebo group and 95 patients in the vedolizumab SC group) had concomitant oral corticosteroid (i.e., prednisone or equivalent and budesonide or equivalent) use at baseline. These patients continued on the same dose of corticosteroids until week 6, when they began a mandatory corticosteroid-tapering regimen. For patients who could not tolerate the corticosteroid taper without recurrence of clinical symptoms, corticosteroids may have been increased up to the original dose at the start of induction therapy (not to have exceeded the baseline dose). Patients who required consistently higher doses of corticosteroids were to be withdrawn from the study.

In this study, any new medication or any increase in the dose of a baseline medication required to treat new or unresolved CD symptoms (other than antidiarrheals for control of chronic diarrhea) was considered a rescue medication. An increase in corticosteroid dose back to baseline for patients undergoing corticosteroid tapering was not considered rescue medication. Administration of rescue medications, approved or investigational, constituted treatment failure. Rescue medications should not have been withheld if, in the opinion of the investigator, failure to prescribe them would have compromised patient safety.

Patients were trained by the health care provider (HCP), either an investigator or designee, on the proper SC injection technique and how to manage hypersensitivity reactions potentially associated with the injection. Patients or their caregivers injected vedolizumab SC or placebo SC under the supervision of the HCP during clinic visits to ensure proper injection technique and to allow the HCP to monitor AEs and potential hypersensitivity or injection-site reactions associated with SC injection.

Outcomes

Primary End Point

The proportion of patients with clinical remission, defined as a CDAI score of at least 150, at week 52.

Secondary End Points

The proportion of patients with enhanced clinical response, defined as a decrease of at least 100 points in CDAI score from baseline, at week 52.
The proportion of patients with corticosteroid-free remission, defined as patients using oral corticosteroids at baseline who have discontinued oral corticosteroids and are in clinical remission at week 52.
The proportion of TNF alpha antagonist–naive patients who achieved clinical remission, defined as a CDAI score of least 150, at week 52.

The CDAI consists of an 8-item list (soft or liquid stools, abdominal pain, general well-being, symptoms manifested, antidiarrheal use, abdominal mass, hematocrit, body weight), each with an individual score and weighting factor.ⁱⁱ The CDAI score is calculated as a weighted product of the scores of each item and their respective weighting factors. Index scores of 150 and below are associated with non-active disease (remission), while values above that indicate active disease; values above 450 indicated extremely severe disease.ⁱⁱⁱ

Statistical Analysis

All statistical testing was performed at a 2-sided 0.05 level of significance. To control the overall type I error rate for the comparison between vedolizumab SC and placebo groups for the primary and secondary end points, a hierarchical approach was applied to the statistical testing. The statistical inference for the first secondary end point of enhanced clinical response at week 52 was only performed if the primary end point, the proportion of patients with clinical remission at week 52, was statistically significant (P < 0.05). The second secondary end point of corticosteroid-free remission at week 52 was only tested if the first secondary end point was statistically significant (P < 0.05). The third secondary end point of clinical remission at week 52 among TNF alpha antagonist–naive patients was only tested if the second secondary end point was statistically significant (P < 0.05). Multiplicity was not adjusted across exploratory end points.

Data Imputation Methods

Missing data for dichotomous (i.e., proportion-based) end points were handled using the nonresponder imputation method in which any patient with missing information for determination of end-point status was considered a treatment failure/nonresponder in the analysis. A sensitivity analysis was conducted to assess the impact of dropouts for different missing mechanisms using a hybrid approach in which discontinuation due to an AE or lack of efficacy was imputed as nonresponder and other discontinuation/missing data were imputed using multiple imputation for primary and all secondary efficacy end points. Missing data for continuous end points were imputed using the last available post-baseline observation carried forward method. For patients with all post-baseline measurements missing, the missing data were imputed using the baseline observation carried forward method.

Primary Outcome(s) of the Studies

Power Calculation

Assuming a clinical remission rate of 38% for vedolizumab and 22% for placebo at week 52, a sample size of 258 patients in the vedolizumab group and 129 patients in the placebo group was needed to provide 90% power at a 2-sided 0.05 level of significance. To ensure a randomized sample size of 387 patients, and assuming 47% of the patients entering induction would achieve clinical response at week 6, approximately 824 patients were needed to be enrolled into the study.

Statistical Test or Model

The proportion of patients with clinical remission at week 52 was summarized descriptively by treatment group. Count, percentage, and associated 95% CI using the Clopper-Pearson method was provided for each treatment group. The primary end point was analyzed using Cochran-Mantel-Haenszel (CMH) test, stratified by randomization stratification factors reported in an interactive web response system (IWRS). Respondents were asked about concomitant use of oral corticosteroids (yes or no), clinical remission status at week 6 (yes or no), and previous TNF alpha antagonist failure/exposure or concomitant immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate) use (yes or no). The P value and the point estimate of the treatment difference based on the CMH method adjusted for stratification factors along with a 95% CI were presented. If the number of remitters or nonremitters in either treatment arm was too small (5 or fewer), Fisher exact method with exact unconditional confidence limits was to be used instead. All patients with missing data for determination of clinical remission status at week 52 were considered nonremitters in the analysis.

Secondary Outcomes of the Study

Enhanced clinical response at week 52 was analyzed in the FAS patients. Corticosteroid-free remission at week 52 was analyzed in a subset of the FAS patients with baseline concomitant oral corticosteroid use (based on data reported in the concomitant medications electronic case report form), where corticosteroid use was defined as prednisone or equivalent and/or budesonide or equivalent. The proportion of TNF alpha antagonist–naive patients who achieved clinical remission was analyzed in a subset of the FAS patients who were TNF alpha antagonist–naive (based on data reported in the prior therapy electronic case report form).

All secondary end points were analyzed in a manner similar to that of the primary efficacy end point, using CMH tests for treatment differences, stratified by randomization stratification factors reported in the IWRS (except for corticosteroid-free remission, for which concomitant use of the oral corticosteroid stratification factor was not considered). All patients with missing data for determination of the status of secondary efficacy end points at week 52 were considered nonresponders/nonremitters in the analysis. The exact method would be performed if the number of observations in either treatment arm was 5 or fewer.

Subgroup Analyses

Descriptive analyses were performed on the primary and all secondary end points to evaluate the treatment effect across subpopulations. The treatment effect in proportions in vedolizumab SC and placebo and associated 95% CI using the Clopper-Pearson method are provided for each subgroup. The point estimate of the absolute treatment difference between vedolizumab SC and placebo based on the crude estimate and associated 95% CI (using the normal approximation method) are presented. If the number of observations was too small (i.e., 5 or fewer) in either treatment arm, the exact method would be performed instead.

For subgroup analysis by prior use of TNF alpha antagonist only, nominal P values were obtained by the CMH test stratified by randomization stratification factors reported in the IWRS, or Fisher’s exact test in the event of small number of responders/remitters or nonresponders/nonremitters (i.e., 5 or fewer).

Subpopulations were defined by the following baseline characteristics:

age (< 35 years, ≥ 35 to < 65 years, ≥ 65 years)
gender
race (Asian, Black or African-American, White, other)
duration of CD (< 1 year, ≥ 1 year to < 3 years, ≥ 3 years to < 7 years, ≥ 7 years)
geographic region (North America, South America, Western/Northern Europe, Central Europe, Eastern Europe, East Asia, Africa/Australia)
baseline disease activity (moderate [CDAI ≤ 330], severe [CDAI > 330])
baseline fecal calprotectin (≤ 250 mcg/g, > 250 to ≤ 500 mcg/g, > 500 mcg/g)
baseline CRP (≤ 5 mg/L, > 5 mg/L to ≤ 10 mg/L, > 10 mg/L)
baseline fistula status (draining, all closed, none)
disease localization (ileum only, colon only, ileocolonic, other)
clinical remission status at week 6
prior TNF alpha antagonist therapy (naive, exposed but not failure, failure; failure was further categorized by type: inadequate response, loss of response, intolerance)
prior immunomodulator and TNF alpha antagonist failure (yes or no)
prior corticosteroids failure (yes or no)
prior immunomodulator failure (yes or no)
baseline concomitant therapies: corticosteroids and immunomodulators (concomitant corticosteroids only, concomitant immunomodulators only, concomitant corticosteroids and immunomodulators, no concomitant corticosteroids or immunomodulators)
worst prior treatment failure (patients with prior TNF alpha antagonist failure, patients with prior immunomodulator failure but not TNF alpha antagonist failure, patients with prior corticosteroid failure but not TNF alpha antagonist or immunomodulator failure).

If the value of the grouping variable could not be determined, the patient would be excluded from the corresponding subgroup analysis (e.g., if the age was missing for a particular patient, then that patient was not included in the age-related subgroup analysis). If the number of patients in any subgroup across the 2 treatment groups was fewer than 10, that subgroup would not be presented.

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Sensitivity Analyses

The following pre-specified sensitivity and additional analyses were performed for primary and all secondary end points:

The primary analysis was repeated for primary and secondary efficacy end points using the intention-to-treat (ITT) population for additional analysis.
The primary analysis was repeated for primary and secondary efficacy end points using the per-protocol set (PPS) for sensitivity analysis.
To assess the impact of dropouts for different missing mechanisms for primary and all secondary end points, a hybrid approach was performed as a sensitivity analysis, where discontinuations due to an AE or lack of efficacy were imputed using the nonresponder imputation and other discontinuation/missing data were imputed using multiple imputations. ▬▬▬▬▬
▬▬▬▬▬
If any clinical site had detected or reported significant noncompliance with regulatory requirements during the study, a sensitivity analysis was to be conducted for the primary efficacy end point in the FAS, excluding all patients from that particular site.

Analysis Populations

Full Analysis Set

The FAS included all randomized patients who received at least 1 dose of the study SC drug (placebo or vedolizumab). Patients who only received induction IV therapy and were not randomized into the maintenance phase were not included in the FAS. Patients in this set were analyzed according to the treatment they were randomized to receive.
The FAS was used for the efficacy analysis, except for: corticosteroid-free remission, clinical remission in TNF alpha antagonist–naive patients, ▬▬▬▬▬.

ITT Set

The ITT population included all randomized patients. Patients in this set were analyzed according to the treatment they were randomized to receive. Analyses of primary and secondary efficacy end points were performed in the ITT population as additional analyses.

Per-Protocol Set

The PPS is a subset of the FAS. The PPS consisted of all patients who did not violate the terms of the protocol in a way that would affect the study output significantly. All decisions to exclude patients from the PPS were made before study unblinding.
Analyses of primary and secondary efficacy end points were performed using the PPS as a sensitivity analysis.

Safety Analysis Set

The SAF included all patients who received at least 1 dose of the study SC drug. Patients in this set were analyzed according to the treatment they actually received. The SAF-induction included all patients who received at least 1 induction dose but were not dosed in the maintenance phase. The SAF-combined included all patients who received at least 1 dose of vedolizumab IV.

Pharmacokinetic Evaluable Set

The pharmacokinetic evaluable population was defined as all patients who received at least 1 dose of the study SC drug and had sufficient blood sampling to allow for pharmacokinetic evaluation.
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Sponsor’s Summary of the Results

Patient Disposition

A total of 1,072 patients were screened for enrolment in the study; of these, 428 patients failed screening ▬▬▬▬▬ ▬ ▬▬▬▬▬ and 644 patients were enrolled into the open-label induction phase. Patients who achieved a clinical response at week 6 following 2 doses of open-label vedolizumab IV infusions (at weeks 0 and 2), as assessed by CDAI score (defined as a ≥ 70-point decrease from baseline [week 0]) at week 6), were randomized into the double-blind maintenance phase. Patients who did not exhibit a clinical response at week 6 were not randomized into the maintenance phase and instead received a third IV dose of vedolizumab at week 6. Clinical response of these patients was assessed again at week 14 by CDAI score. Patients who achieved a clinical response at the week 14 assessment (defined as a ≥ 70-point decrease in CDAI score from baseline [week 0] at week 14) were eligible to participate in the OLE, Study SC-3030.

Of the 644 patients enrolled in the open-label vedolizumab IV induction period, 412 patients (64%) achieved a clinical response at week 6 based on a ≥ 70-point decrease from baseline in CDAI score. These 412 patients were eligible for randomization into the double-blind maintenance phase of the study. A total of 410 patients were randomized into the double-blind maintenance phase (ITT = 410 patients). One patient was randomized to the placebo group but did not receive any blinded treatment ▬ ▬ ▬ (FAS = 409 patients). A total of 107 patients (38.9%) in the vedolizumab SC group and 61 patients (45.2%) in the placebo group discontinued the study drug during the maintenance phase.

Table 7

Disposition of Patients – All Enrolled, Induction Phase.

Table 8

Disposition of Patients – Maintenance Phase.

Exposure to Study Treatments

Study Treatments

Exposure to study medication and study drug compliance for the SAF population are presented in Table 9. Exposure was ▬▬▬▬▬

Table 9

▬▬▬▬▬.

Concomitant Medications

Concomitant medication was defined as a medication that started on or was ongoing as of day 1 and no later than 126 days after the last dose of the study drug. Table 10 summarizes concomitant IBD medications taken by patients in the maintenance phase (SAF). Concomitant IBD medications used during the maintenance phase of this study were generally similar between the 2 arms.

Table 10

▬▬▬▬▬.

Efficacy

Clinical Remission at Week 52

Results of the primary end point analysis (FAS) showed a statistically significant treatment difference in favour of the vedolizumab SC arm (P = 0.008). A total of 132 of 275 vedolizumab SC–treated patients (48.0%) achieved clinical remission (defined as CDAI score ≤ 150) at week 52 compared with 46 of 134 patients who received placebo (34.3%). The adjusted treatment difference between treatment arms was 13.7% (95% CI, 3.8 to 23.7). ▬▬▬▬▬.

Table 11

Clinical Remission at Week 52 – FAS.

Enhanced Clinical Response at Week 52

Enhanced clinical response was defined as a decrease of at least 100 points in the CDAI score from baseline (week 0) at week 52. A greater proportion of patients (FAS) in the vedolizumab SC group (52.0%) compared with the placebo group (44.8%) achieved enhanced clinical response at week 52; however, the treatment difference of 7.3% was not statistically significant (95% CI, −3.0 to 17.5; P = 0.167).

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Table 12

Enhanced Clinical Response at Week 52 – FAS.

Corticosteroid-Free Remission at Week 52

A total of 139 patients (44 patients in placebo group, 95 patients in vedolizumab SC group) had concomitant oral corticosteroid (i.e., prednisone or equivalent and budesonide or equivalent) use at baseline and were included in this analysis. Among the patients (FAS) who were receiving corticosteroid or budesonide treatment at baseline, a greater proportion of patients treated with vedolizumab SC (43 of 95 patients; 45.3%) achieved corticosteroid-free remission at week 52 compared with patients who received placebo (8 of 44 patients; 18.2%). The treatment difference was 27.1% (95% CI, 11.9 to 42.3) with a nominal P value of 0.002. Results of the analyses with the ▬▬▬▬▬

Table 13

Corticosteroid-Free Remission at Week 52 – FAS.

Clinical Remission in Patients Who Were Naive to TNF Alpha Antagonists

In the FAS population, 170 patients (41.6%) did not have prior exposure to TNF alpha antagonist therapy. In TNF alpha antagonist–naive patients, a slightly higher proportion of patients treated with vedolizumab SC (48.6%) achieved clinical remission at week 52 compared with those treated with placebo (42.9%). The treatment difference was 4.3% (95% CI: −11.6 to 20.3; P = 0.591). ▬ ▬

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Table 14

Clinical Remission at Week 52 in Patients Naive to TNF Alpha Antagonists – FAS.

Health-Related Quality of Life

Assessment of HRQoL was conducted using the IBDQ and EQ-5D. Work productivity was assessed by the Work Productivity and Activity Impairment–Crohn’s disease (WPAI-CD) instrument.

IBDQ

A total score of 170 or higher is representative of clinical remission. A 16-point change in IBDQ total score is considered clinically meaningful.

The total IBDQ scores improved after the open-label induction phase and were similar at week 6 between the 2 treatment groups (mean [standard deviation]: 161.2 [▬] for placebo; 162.7 [▬] for vedolizumab SC). In the maintenance phase, patients who received vedolizumab SC showed further improvements in IBDQ total score and in all IBDQ domain scales compared with the placebo group. The greater improvements on the total IBDQ score and all domain scales for the vedolizumab SC treatment group at week 52 were clinically meaningful.

EuroQol 5-Dimensions Questionnaire

The EQ-5D index and VAS scores improved (increased values) after the open-label vedolizumab IV induction phase and were similar at week 6 in the 2 treatment groups (mean [standard deviation]: 0.8 [▬] for placebo, 0.8 [▬] for vedolizumab SC). In the maintenance phase, at week 52, patients in the vedolizumab SC treatment group had greater improvements in the EQ-5D index score and EQ-5D VAS score compared with the placebo group. Similarly, for all subscores of the EQ-5D assessment tool, vedolizumab SC treatment resulted in a greater improvement (change from baseline) at week 52 compared with placebo treatment.

WPAI-CD

WPAI-CD outcomes are expressed as impairment percentages, with higher values indicating greater impairment and less productivity.

Patients treated with vedolizumab SC had greater improvement in all subscores of the WPAI-CD (absenteeism, presenteeism, overall work productivity loss, activity impairment) compared with placebo at week 52.

Harms

Safety Evaluation Plan

All safety analyses were performed using the SAF. Data were summarized by treatment group. No statistical inference was made for safety analyses.

All AEs were coded using version 22.0 of the Medical Dictionary for Regulatory Activities. The number and percentage of patients with TEAEs, defined as an AE that started or worsened on or after study day 1, adverse events of special interest (AESIs), and SAEs that occur on or after the first dose date and up to 18 weeks after the last dose date of the study drug and the day before the first dose of the OLE study, SC-3030, were summarized by system organ class (SOC), high-level term and preferred term overall, by severity, and by relationship to study drug for each treatment group.

Overview of Safety

In the SAF population, the percentage of randomized patients who experienced at least 1 TEAE were comparable between the placebo (76.1%) and vedolizumab SC (73.5%) groups. ▬▬▬▬▬ The percentage of placebo patients who had AEs leading to study discontinuation was more than twice that of the vedolizumab SC group (8.2% and 4.0%). Within the placebo group, 10.4% of patients experienced an SAE compared with 8.4% in the vedolizumab SC group. Most of these SAEs were assessed by the investigator as not related to study medication. No deaths occurred during the study.

Table 15

Overview of TEAEs Including SAEs – SAF.

AEs

In the SAF population, the SOCs with the highest frequency of AEs were GI disorders (▬▬▬▬▬ ▬▬▬▬▬) and infections and infestations (34.3% and 31.3%, respectively). In the GI disorders SOC, most of the events were exacerbation or worsening of CD (19.4% and 15.3% for placebo and vedolizumab SC, respectively).

The most common AEs (occurring in at least 5% of patients in any treatment group) are summarized by frequency for the maintenance study SAF population in Table 16. The overall percentage of most-frequently reported (at least 5%) AEs was similar in the placebo and vedolizumab SC groups (41.8% and 39.3%, respectively). The condition under study was the most commonly reported AE in the SAF population, with CD reported in 19.4% and 15.3% of the placebo and vedolizumab SC groups, respectively. The next most common AEs were abdominal pain, nasopharyngitis, arthralgia, and upper respiratory tract infection. Nasopharyngitis, upper respiratory tract infection, and headache were more common in the vedolizumab SC treatment group than in the placebo group, while nausea, vomiting, and abdominal pain were more common in placebo group than in the vedolizumab SC group.

Table 16

Most Frequent (≥ 5%) TEAEs by SOC and PT – SAF.

SAEs

Overall, 9.0% of patients experienced at least 1 SAE (10.4% and 8.4% in placebo and vedolizumab SC groups, respectively). The incidence of SAEs was generally comparable between the treatment groups. The highest frequency of SAEs occurred in the GI disorders SOC and were more frequent in the placebo group (▬) than in the vedolizumab SC group (▬). The incidence of SAEs in the infections and infestations SOC was also greater in the placebo group (▬) than in the vedolizumab SC (▬) group. The overall incidences of SAEs in the other SOCs were less than 2%. Two events in the placebo-treated group, small intestinal obstruction and gastroenteritis, were considered by the investigator to be related to the study drug. Five events in the vedolizumab SC group were assessed as related to treatment with the study drug. These included ileal stenosis and abscess intestinal (both in 1 patient), and small intestinal obstruction, pneumonia, and exacerbation of CD (1 patient each). The SAEs in the SAF population are summarized in Table 17, in which SAEs in the GI and infections and infestations SOC are broken out by preferred term.

Table 17

Serious TEAEs by SOC and PT – SAF.

Withdrawals Due to Adverse Event

The overall incidence of AEs leading to study discontinuation was 22 of 409 patients (5.4%; 8.2% and 4.0% in the placebo and vedolizumab SC groups, respectively); of these 22 patients, ▬▬▬▬▬

Table 18

Adverse Events Leading to Study Discontinuation by SOC and PT – SAF.

Adverse Events of Special Interest

Infections

Overall, infections were reported in 132 of 409 patients (32.3%). A slightly higher number of infections was reported in the placebo-treated patients (34.3%) than in the vedolizumab SC–treated patients (31.3%).

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Hypersensitivity

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Injection-Site Reactions

Overall, 10 of 409 patients (2.4%) reported an injection-site reaction, and these reports were more frequent in the vedolizumab SC group (8 patients, 2.9%) than in the placebo group (2 patients, 1.5%). ▬▬▬▬▬

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Infusion Reactions

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Malignancies

Five malignancy TEAEs were reported (1.2%) overall. These included 3 in placebo-treated patients (2.2%) and 2 in vedolizumab SC–treated patients (0.7%).

▬▬▬▬▬

Liver Injury

There were 15 patients overall with liver injury AESIs (3.7%), which included a greater proportion of the placebo group (7 patients, 5.2%) than of the vedolizumab SC group (8 patients, 2.9%). ▬▬▬▬▬

Progressive Multifocal Leukoencephalopathy

▬▬▬▬▬

Bioequivalence

Study SC-101

This study was designed primarily to assess the absolute bioavailability and pharmacokinetics of vedolizumab (liquid formulation) following a single SC injection in healthy individuals. The study was a phase I, open-label, parallel-group design. A total of 48 individuals were randomized in a ratio of 1:1:1:1 to 1 of 4 treatment groups (12 per treatment). ▬▬▬▬▬ (Japanese and non-Japanese). All individuals received drug on day 1. The 4 treatment groups were:

vedolizumab (lyophilized) IV 300 mg by infusion over approximately 30 minutes
vedolizumab (liquid) SC 54 mg by SC injection (▬)
vedolizumab (liquid) SC 108 mg by SC injection (▬)
vedolizumab (liquid) SC 160 mg by SC injection (▬)

▬▬▬▬▬

Table 19

Summary of Pharmacokinetic Parameters Following a Single IV Infusion or a Single SC Injection of Vedolizumab.

CADTH Critical Appraisal

Internal Validity

VISIBLE 2 was the only pivotal study included in this review. The investigators adequately produced a randomization sequence, with a proper concealment of the random sequence using a central randomization scheme under the supervision of the sponsor, by means of an IWRS until participants were enrolled and assigned to the interventions. Differences were noted in the baseline characteristics of patients, such as prior anti–TNF alpha use, concomitant medications with immunomodulators only at week 0 and ileal disease. These differences were small and less likely to have a meaningful impact on the validity of the results; however, the higher proportion of patients with prior anti–TNF alpha use and ileal disease only, and the fewer patients who received concomitant immunomodulators only at baseline in the vedolizumab SC group compared to placebo may suggest that patients in the vedolizumab group would be more difficult to treat, which could result in a more conservative estimate of the treatment effect. The blinding of participants, clinicians, and researchers was achieved through identical placebo and vedolizumab presentations, which avoided important and unbalanced deviations from the intended interventions. There is no evidence that participants were aware of their assigned intervention on the double-dummy design of the trial. Patients who stopped or deviated from the interventions were properly accounted for and analyzed in an FAS, which was close to the ITT population in the study.

Multiplicity was properly considered, and adequate tests were conducted (i.e., a hierarchical approach was used) to control for an overall type I error rate.

During the maintenance phase, 41% of the participants prematurely discontinued the study drug, 45% in the placebo group and 39% in the vedolizumab SC group. The main reason for treatment discontinuation in the maintenance phase was lack of efficacy (with 71% and 73% on placebo and vedolizumab SC among those who discontinued, respectively), followed by voluntary withdrawal and AEs. This difference in missing data could bias the results. Sensitivity analyses were conducted to examine the robustness of study findings to missing data assumptions, ▬▬▬▬▬.

Outcomes were objectively obtained with validated tools (see Appendix 1) and the processes to carry out outcome measurements were well described and assessed in a blinded fashion. There is a low risk of bias due to selection of the reported results. A protocol was well described, and the presented results follow the pre-specified analysis plan. Amendments made during the study were well addressed and unlikely to affect the end results or imply bias due to selection of participants.

Subgroup analyses were performed to examine the consistency of the treatment effect observed for the primary and all secondary outcomes based on age, gender, race, duration of CD, geographic region, baseline disease activity, baseline fecal calprotectin, disease localization, clinical remission status at week 6, prior TNF alpha antagonist therapy, prior immunomodulator and TNF alpha antagonist failure, prior corticosteroid failure, prior immunomodulator failure, concomitant therapies, and worst prior treatment failure. However, conclusions in regard to these subgroups are uncertain due to the small sample sizes in the subgroups. In addition, subgroup analyses were exploratory in VISIBLE 2, and there was also a lack of adjustment for multiplicity. All of these increase the uncertainty in interpreting the results in the subgroups. Appendix 2 presents the efficacy outcomes by prior TNF alpha antagonist therapy (patients without prior exposure to TNF alpha antagonist therapy versus patients who had prior exposure to TNF alpha antagonist therapy but did not fail this treatment versus patients who had prior failure to TNF alpha antagonist therapy).

The VISIBLE 2 study was powered to assess the primary outcome of clinical remission after 52 weeks but was not sufficient to assess other secondary end points. This limitation contributed to the findings of numerically greater but not statistically significant differences between treatment arms for all secondary end points, such as enhanced clinical response and corticosteroid-free clinical remission.

External Validity

The populations included in VISIBLE 2 are, to an extent and within the limitations of a controlled setting of a clinical trial, similar to what it is encountered in clinical practice and relevant to the population of interest for this review, which focuses on SC administration and specific doses that are in accordance with what is approved by Health Canada and planned to be used in real-life practice. However, adherence could be overstated as it is usual in controlled randomized trials, and generalizability may be an issue when the medication is applied in real clinical settings.

The amount and type of co-interventions allowed during the study can be considered close to what happens in clinical practice, although more frequent clinical visits and assessments can be overestimated. Patients needed training to apply the SC vedolizumab doses and the study participants reportedly performed well in this sense. It is likely this training would be similar to real clinical practice.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

As there was no direct evidence comparing vedolizumab SC to other active treatments for moderately to severely active CD, a review of indirect evidence was undertaken. The aim of this section is to provide an overview and critical appraisal of the published and unpublished indirect evidence available for the assessment of the comparative efficacy and safety of vedolizumab SC to the currently available biologic treatments for adult patients with CD.

CADTH conducted a literature search to identify potentially relevant ITCs in patients with moderately to severely active CD, in addition to reviewing the sponsor’s CADTH Common Drug Review submission. No potentially relevant ITCs were identified in the literature search. One sponsor-submitted ITC was included in this review.⁸

Description of the Indirect Comparison

The sponsor-submitted ITC included a systematic review of the literature and an NMA that compared vedolizumab SC to the other biologic treatments available in Canada for patients with moderate to severe CD.

Methods of the Sponsor-Submitted NMA

Objectives

The objective of the sponsor-submitted report was to perform an ITC or NMA to obtain estimates of the comparative efficacy and safety of vedolizumab SC and competing interventions for the treatment of CD. The NMA was used to inform the health economic models for vedolizumab SC.

Study Selection Methods

The RCTs that were used to inform the ITC were identified through a systematic literature search conducted by the sponsor. Multiple databases were searched to identify RCTs that evaluated the efficacy of relevant biologic treatments for the treatment of CD. ▬▬▬▬▬

▬▬▬▬▬

The inclusion criteria for the sponsor submitted NMA are summarized in Table 20.

Table 20

Study Selection Criteria and Methods for the Sponsor-Submitted NMA.

ITC Analysis Methods

▬▬▬▬▬

Results of the Sponsor-Submitted NMA

Summary of Included Studies

▬▬▬▬▬

Figure 2

▬▬▬▬▬. Figure 2 contained confidential information and was removed at the request of the sponsor. ▬; PBO = placebo; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w = every 8 weeks; SC = subcutaneous; (more...)

Figure 3

▬▬▬▬▬. Figure 3 contained confidential information and was removed at the request of the sponsor. PBO = placebo; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w = every 8 weeks; SC = subcutaneous; VDZ = vedolizumab. (more...)

Figure 4

▬▬▬▬▬. Figure 4 contained confidential information and was removed at the request of the sponsor. ▬ PBO = placebo; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w = every 8 weeks; ▬▬▬▬▬ (more...)

Figure 5

▬▬▬▬▬. Figure 5 contained confidential information and was removed at the request of the sponsor. ▬ PBO = placebo; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w = every 8 weeks; SC = subcutaneous; (more...)

Figure 6

▬▬▬▬▬. Figure 6 contained confidential information and was removed at the request of the sponsor. ▬; PBO = placebo; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w = every 8 weeks; SC = subcutaneous; (more...)

Figure 7

▬▬▬▬▬. Figure 7 contained confidential information and was removed at the request of the sponsor. ▬; PBO = placebo; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w = every 8 weeks; SC = subcutaneous; (more...)

Figure 8

▬▬▬▬▬. Figure 8 contained confidential information and was removed at the request of the sponsor. ▬; PBO = placebo; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneous; ▬▬▬▬▬ (more...)

▬▬▬▬▬

Table 21

▬▬▬▬▬.

Table 22

▬▬▬▬▬.

Table 23

▬▬▬▬▬.

Results

▬▬▬▬▬

Results of the NMA on various efficacy and safety outcomes are summarized in Table 24.

Table 24

▬▬▬▬▬.

CADTH Critical Appraisal of the Sponsor-Submitted NMA

A number of RCTs were included in the sponsor-submitted NMA to evaluate the comparative effectiveness and safety of vedolizumab SC relative to other biologics. However, only a limited number of trials were relevant to the use of vedolizumab SC as maintenance treatment in patients with CD.

▬▬▬▬▬. However, due to limitations of the submitted NMA, the results comparing vedolizumab SC to other active treatments should be interpreted with caution. These limitations hinder the potential applicability of the comparative results. The major concerns with the submitted NMA are related to the limited size of the evidence base (for example, only 4 trials contributed to the analysis of ▬▬▬▬▬) and heterogeneity across trials in both design and patient baseline characteristics.

Even though quality of the included trials was examined using ▬▬▬▬▬.

A significant concern with the NMA presented is that studies included in the analyses were ▬▬▬▬▬

▬▬▬▬▬

Summary

Based on the results of the sponsor-submitted NMA, vedolizumab SC was not clearly favoured relative to other comparators of interest for either efficacy or safety. Little should be inferred regarding the comparative efficacy or safety to other products based solely on this submitted NMA. The applicability of sponsor’s NMA is undermined by the limited size of the evidence base (i.e., ▬ ▬ ▬▬▬▬▬), potential limitations in the submitted analysis, and heterogeneity in trial design and patient populations across trials. These limitations make it difficult to draw firm conclusions based on the results of this NMA.

Other Relevant Evidence

This section deals with submitted long-term extension studies and additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence found in the systematic review.

Long-Term Extension Studies

An OLE study to determine the long-term safety and efficacy of vedolizumab SC in patients with CD and UC was ongoing at the time of this review (SC-3030; NCT02620046; estimated completion date of February 2022).⁹ This study is intended to collect long-term safety data for vedolizumab SC dosing to complement the safety data gathered by VISIBLE 2 in CD patients. ▬▬▬▬▬.⁹

Methods

Patients are eligible to enter this OLE study if they participated in the SC-3027 (UC) or SC-3031 (CD) study, and are:

Patients with UC or CD who completed the maintenance phase (week 52) and received vedolizumab SC 108 mg every 2 weeks
Patients with UC or CD who withdrew early from the maintenance phase due to disease worsening or need for rescue medications received vedolizumab SC 108 mg weekly
Patients with UC or CD who did not achieve a clinical response at week 6, but after receiving a third vedolizumab IV infusion at week 6 achieved a clinical response at week 14 and received vedolizumab SC 108 mg every 2 weeks.

Patients entered in the extension study received open-label vedolizumab SC 108 mg either weekly or every 2 weeks. Participants continue the study drug for up to 5 years. Participants complete a final safety visit 18 weeks after the last dose of vedolizumab SC on the study, followed by a 6-month safety survey. The last dose of the study drug was defined as the last dose before study completion, or the last dose before an early withdrawal time point. An overview of the study design is depicted in Figure 9, and details of the study can be found in Table 25.⁹

Figure 9

Study Design of SC-3030.

Table 25

Details of the Long-Term Extension Study SC-3030.

Populations

The following 3 groups of patients were eligible for the VISIBLE 2 long-term extension study:

Randomized study completers: patients with CD who completed the maintenance phase of the VISIBLE 2 up to week 52
Randomized early terminators: patients with CD who withdrew early from the maintenance phase of the VISIBLE 2 due to disease worsening or need for rescue medications
Nonrandomized late responders: patients with CD who did not achieve a clinical response at week 6 in the induction phase of the VISIBLE 2 but achieved a clinical response at week 14 after receiving a third vedolizumab IV induction dose at week 6.

Patients who withdrew from VISIBLE 2 due to a drug-related AE were not eligible to enter the extension study. Additionally, patients who required surgical intervention for CD during or after participation in the VISIBLE 2 or were anticipated to require surgical intervention for CD during this study were not eligible to enter the extension study.⁹

Baseline and Demographic Characteristics

▬▬▬▬▬

Table 26

▬▬▬▬▬.

Interventions

All patients enrolled in the extension study were administered open-label vedolizumab SC 108 mg every 2 weeks, with the exception of the early terminators who were administered vedolizumab SC 108 mg weekly. Patients who experienced treatment failure (i.e., disease worsening or need for rescue medication) while receiving vedolizumab SC 108 mg every 2 weeks during the OLE study were permitted a dose escalation to vedolizumab SC 108 mg weekly. Patients who completed VISIBLE 2 or terminated VISIBLE 2 (i.e., early terminators) received their first dose of open-label vedolizumab SC 4 weeks after the last dose of the study drug or placebo in VISIBLE 2. For the late responders, patients received vedolizumab SC 108 mg every 2 weeks. Disease activity was assessed by Harvey-Bradshaw Index for CD patients.

Outcomes

The primary objective of the VISIBLE 2 OLE study was to obtain data on the long-term safety and tolerability of vedolizumab SC. The primary end point was patient-year-adjusted TEAEs. Secondary efficacy outcomes include patient-year-adjusted AESIs, clinical responses, and clinical remissions. Additional secondary end points include changes from baseline in IBDQ total and subscale scores, EQ-5D utility ▬▬▬▬▬

Statistical Analysis

▬▬▬▬▬

Analysis Sets

▬▬▬▬▬

Patient Disposition

▬▬▬▬▬

Table 27

Patient Disposition of SC-3030.

Exposure to Study Treatments

▬▬▬▬▬

Table 28

Extent of Exposure in SC-3030.

Efficacy

▬▬▬▬▬

Harms

▬▬▬▬▬

Table 29

▬▬▬▬▬.

Critical Appraisal

As with most long-term extension studies, the VISIBLE 2 long-term extension study was limited by the open-label administration of the study drug, the absence of an active or placebo comparator group, and the reporting of descriptive summary statistics. Additionally, given that the study is ongoing, results were limited to the interim analyses, ▬▬▬▬▬. Open-label administration can bias the reporting of end points, specifically subjective end points in the Harvey-Bradshaw Index and reporting of AEs. The lack of a comparator such as a placebo may result in an overestimate of the magnitude of clinical benefit reported to date. All efficacy and safety end points were descriptively summarized. Furthermore, ▬▬▬▬▬. Therefore, long-term benefit of vedolizumab on the treatment effect and harm remains uncertain. ▬▬▬▬▬; this allows for a comparison to the randomized study population, or to those in clinical practice. It is important to note, however, that patients enrolled in the OLE study had highly different ▬▬▬▬▬. Furthermore, the early terminators were dosed more frequently than the other 2 groups, and dose escalation to weekly was allowed in the randomized study completers for patients who experience treatment failure.

The ▬▬▬▬▬, which is representative of the Canadian population with CD. Additionally, administration of vedolizumab SC in the extension study is representative of how the drug would be used in clinical practice, i.e., self-administered by the patient.

▬▬▬▬▬. These factors may limit the applicability of the preliminary results.

Summary

A long-term extension study of the VISIBLE 2 study to assess the long-term safety and tolerability of vedolizumab SC in the treatment of CD is currently ongoing. The results of the second interim analysis ▬▬▬▬▬. The available efficacy results to date were limited by their descriptive nature and ▬ of evaluable patients. Results from this extension study to inform long-term durability of response of vedolizumab SC in responders on maintenance therapy should be interpreted with caution.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

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Clinical and Economic Review Report: Vedolizumab (ENTYVIO SC): Takeda Canada Inc. Indication: Crohn disease [Internet] Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021 Apr. Sponsor’s Summary of the Clinical Evidence.
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