| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| UC is a chronic disease of the large intestine, in which the lining of the colon becomes inflamed and develops tiny open sores, or ulcers |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the efficacy of induction therapy with etrolizumab-based combinations compared to etrolizumab monotherapy, assessed as corticosteroid-free endoscopic improvement at Week 14 |
|
| E.2.2 | Secondary objectives of the trial |
• Induction of corticosteroid-free: remission, clinical response, endoscopic remission, histologic remission, symptomatic remission, rectal bleeding score 0, remission at Week 14 in patients receiving corticosteroids at baseline
• Change in UC- Patient-Reported outcome (PRO) signs/symptoms and UC/PROs related to various aspects of QoL (quality of life) (induction and maintenance phase)
• Remission at Week 54 among patients with clinical response and remission at Week 14, respectively
• Endoscopic remission at Week 54 among patients in endoscopic remission and endoscopic improvement at Week 14, respectively
• Histologic remission at Week 54
• Corticosteroid-free remission at Week 54 in patients who were in corticosteroid-free remission at Week 14.
• Overall safety and tolerability of etrolizumab-based combinations compared to etrolizumab monotherapy
• The incidence and severity of immunosuppression-related adverse events and hypersensitivity reactions
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohort 1 only
• Age 18−80 years of age, inclusive, at time of signing Informed Consent Form
• Naïve to treatment with infliximab and ustekinumab
• Prior treatment with investigational JAK inhibitors for UC and other investigational treatments for UC (except for investigational anti-integrins) is allowed if discontinued at least 5 drug half-lives prior to randomization
Cohort 2 only
• Age 18−49 years of age, inclusive, at time of signing Informed Consent Form
• Naïve to treatment with tofacitinib
• Prior treatment with infliximab and ustekinumab is allowed if discontinued at least 5 drug half-lives prior to randomization (Day 1), or when serum drug levels of infliximab/ustekinumab are undetectable as measured using a commercial assay (if available), whichever is earlier
• Prior treatment with investigational treatments for UC is allowed if discontinued at least 5 drug half-lives prior to randomization (Day 1)
Cohort 1 and Cohort 2
• Ability to comply with the study protocol, in the investigator's judgment
• Diagnosis of UC established at least 3 months prior to randomization (Day 1) by clinical and endoscopic evidence. This diagnosis should be corroborated by histopathology conducted at any time prior to screening and documented by a histopathology report
• Moderate-to-severely active UC as determined by an mMCS of 4–9, with an endoscopic subscore ≥ 2 as determined by the central reading procedure, a rectal bleeding subscore ≥ 1, and a stool frequency subscore ≥ 1, during the screening period (prior to randomization [Day 1])
• Evidence of UC extending more than 15 cm from the anal verge as determined by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during screening, 4−16 days prior to randomization
• Naïve to treatment with etrolizumab or other anti-integrin agents
• Prior treatment with immunosuppressants (AZA, MTX, or 6-MP) is allowed if discontinued at least 5 drug half-lives (i.e. 5 days) prior to randomization (Day 1)
• Prior treatment with non-infliximab aTNF-α therapy (e.g., adalimumab, golimumab) is allowed if discontinued at least 4 weeks (for adalimumab) or 6 weeks (for golimumab) prior to randomization (Day 1), or when serum drug levels are undetectable as measured using a commercial assay (if available), whichever is earlier
• Patients must not have received more than two biological therapies intended to treat UC prior to Day 1
• Patients must have had an inadequate response, loss of response, or intolerance to prior immunosuppressant and/or corticosteroid treatment
• Any ongoing UC therapy must be at stable doses:
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 6 months after the final dose of study treatment
• For men who are not surgically sterile: agreement to remain abstinent or use contraception during the treatment period and for at least 6 months after the final dose of study treatment. Men must refrain from donating sperm during this same period.
• Patients must be up-to-date on their colorectal carcinoma (CRC) surveillance according to local standards and guidelines. If patients are not up-to-date, they must be willing to undergo a colonoscopy with appropriate CRC screening biopsies in lieu of a flexible sigmoidoscopy at screening
|
|
| E.4 | Principal exclusion criteria |
Inflammatory Bowel Disease
Cohort 1+2:
• Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC
• Past or present ileostomy or colostomy
• Diagnosis of indeterminate colitis
• Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
• Diagnosis of toxic megacolon within 12 months of initial screening visit
• Any diagnosis of Crohn’s disease
• Past or present fistula or abdominal abscess
• Current evidence of colonic mucosal dysplasia or history of colonic mucosal dysplasia within 5 years prior to inclusion
• Patients with any stricture (stenosis) of the colon
• Patients with history or evidence of adenomatous colonic polyps that have not been removed
Exclusion Criteria Related to Prior or Concomitant Therapy
Cohort 1 only
• Any prior treatment with infliximab or ustekinumab
Cohort 2 only
• Any prior treatment with tofacitinib
• Prior treatment with investigational JAK inhibitors for UC
• Receiving treatment with single or combined hormonal contraception therapy
• Current treatment with potent inhibitors of CYP3A4 or receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 that would increase serum availability of tofacitinib
Cohort 1+2
• Any prior treatment with etrolizumab or other anti-integrin agents
• Any prior treatment with anti-adhesion molecules
• Receiving treatment with immunosuppressants (AZA, 6-MP, or MTX) within the 5 drug half-lives(ie. 5 days) prior to Day 1
• Use of IV steroids within 30 days prior to screening with the exception of a single administration of IV steroid
• Use of agents that deplete B or T cells within 12 months prior to randomization, with the exception of AZA and 6-MP (which must be discontinued 5 half-lives (i.e. 5 days) prior to Day 1 )
• Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks prior to randomization
• Chronic nonsteroidal anti-inflammatory drug (NSAID) use
• Patients who are currently using anticoagulants
• Patients who have received treatment with corticosteroid enemas/suppositories and/or topical (rectal) 5-ASA preparations within 2 weeks prior to randomization
• Apheresis within 2 weeks prior to randomization
• Received any investigational treatment including investigational vaccines within 5 half-lives of the investigational product or 28 days after the last dose (whichever is greater) prior to randomization
• History of moderate or severe allergic or anaphylactic/anaphylactoid or hypersensitivity reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins
• Patients administered tube feeding, defined formula diets, or parenteral alimentation/nutrition who have not discontinued these treatments ≥ 3 weeks prior to randomization
Exclusion Criteria related to General Safety
Cohort 1 only
• History of moderate-to-severe heart failure New York Heart Association [NYHA] Class III/IV
Cohort 2 only
• History of heart failure
• Patients with inherited coagulation disorders
• History of venous thromboembolism, either deep venous thrombosis or pulmonary embolism
• Patients undergoing major surgery
Cohort 1+2
• Lack of peripheral venous access
• Significant uncontrolled comorbidity
• Neurological conditions or diseases that may interfere with monitoring for PML
• History of demyelinating disease
• Clinically significant abnormalities on screening neurologic examination
• Clinically significant abnormalities on the screening PML Subjective Checklist
• History of alcohol, drug, or chemical abuse ≤ 6 months prior to screening
• Use of marijuana ≤ 3 months prior to screening
• Conditions other than UC that could require treatment with > 10 mg/day of prednisone during the course of the study
• A history of primary sclerosing cholangitis
• Patients with a history of GI perforation
• History of cancer
Exclusion Criteria related to Infection Risk
Cohort 1+2
• Congenital or acquired immune deficiency
• Patients must undergo screening for HIV and test positive for preliminary and confirmatory tests
• Positive hepatitis C virus (HCV) antibody test result
• Patients must undergo screening for hepatitis B virus (HBV)
• Evidence of or treatment for Clostridium difficile within 60 days prior to randomization or other intestinal pathogens within 30 days prior to randomization
• Any diagnosis of cytomegalovirus (CMV) colitis in the past 60 days
• History of active or latent TB regardless of treatment history
• History of recurrent opportunistic infections and/or history of severe disseminated viral infections
• Any serious opportunistic infection within the last 6 months
• Any current or recent signs or symptoms of infection
• Any major episode of infection requiring treatment with IV antibiotics
• Received any live attenuated vaccine within 4 weeks prior to randomization
• History of organ transplant
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Corticosteroid-free endoscopic improvement at Week 14 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. To evaluate induction of corticosteroid-free remission at Week 14, as assessed by the mMCS
2. To evaluate corticosteroid-free clinical response at Week 14, as assessed by the mMCS
3. To evaluate corticosteroid-free endoscopic remission at Week 14
4. To evaluate corticosteroid-free histologic remission at Week 14
5. To evaluate corticosteroid-free symptomatic remission at Week 14
6. To evaluate onset of action, defined as time to rectal bleeding score of 0
7. To evaluate onset of action, defined as change from baseline (Day 1) in stool frequency subscore at Week 2, Week 4, and Week 6
8. To evaluate change in UC bowel movement signs and symptoms from baseline (Day 1) to Week 14, as assessed by the Ulcerative Colitis-Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) measure
9. To evaluate change in UC functional symptoms from baseline (Day 1) to Week 14, as assessed by the UC-PRO/SS measure
10. To evaluate change in UC systemic symptoms from baseline (Day 1) to Week 14, as assessed by the UC-PRO Systemic Symptoms measure
11. To evaluate change in UC daily coping strategies, daily life impact, and emotional impact from baseline (Day 1) to Week 14, as assessed by the UC-PRO Daily Coping (UC-PRO-DC), UC-PRO Daily Life Impact (UC-PRO-DLI), and UC-PRO Emotional Impact (UC-PRO-EI) measures
12. To evaluate change from baseline (Day 1) in patient-reported health-related quality of life at Week 14, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
13. To evaluate corticosteroid-free remission at Week 14 (off corticosteroid for at least 4 weeks prior to Week 14) in patients who were receiving corticosteroids at baseline (Day 1), as assesses by mMCS
14. To evaluate remission at Week 54 among patients with clinical response at Week 14
15. To evaluate remission at Week 54 among patients in remission at Week 14
16. To evaluate endoscopic remission at Week 54 among patients in endoscopic remission at Week 14
17. To evaluate endoscopic remission at Week 54 among patients with endoscopic improvement at Week 14
18. To evaluate histologic remission at Week 54
19. To evaluate corticosteroid-free remission at Week 54 in patients who were in corticosteroid-free remission at Week 14
20. To evaluate corticosteroid-free (at least 24 consecutive weeks during maintenance) remission at Week 54 among patients who were in corticosteroid-free remission at Week 14
21. To evaluate symptomatic remission at Week 54 among patients with clinical response at Week 14
22. To evaluate change in UC bowel movement signs and symptoms from baseline (Day 1) to Week 14 and Week 14 to Week 54, as assessed by the UC-PRO/SS measure
23. To evaluate change in UC functional symptoms from baseline (Day 1) to Week 14 and Week 14 to Week 54, as assessed by the UC-PRO/SS measure
24. To evaluate change in UC systemic symptoms from baseline (Day 1) to Week 14 and Week 14 to Week 54, as assessed by the UC-PRO Systemic Symptoms measure
25. To evaluate change in UC daily coping strategies, daily life impact, and emotional impact from baseline (Day 1) to Week 14 and Week 14 to Week 54, as assessed by the UC-PRO Daily Coping (UC-PRO-DC), UC-PRO Daily Life Impact (UC-PRO-DLI), and UC-PRO Emotional Impact (UC-PRO-EI) measures
26. To evaluate change in patient-reported health related quality of life from baseline (Day 1) to Week 14 and Week 14 to Week 54, as assessed by the IBDQ
27. To evaluate the overall safety and tolerability of etrolizumab-based combinations compared to etrolizumab monotherapy
28. To evaluate the incidence and severity of immunosuppression-related adverse events
29. To evaluate the incidence and severity of hypersensitivity reactions
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Week 14
6. Up to Week 54
7. Week 2, Week 4, and Week 6
8-13. Baseline (Day 1) to Week 14
14-21. Week 14, Week 54
22-26. Baseline to Week 14 and Week 14 to Week 54
27-29. Up to Week 66
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Latvia |
| Netherlands |
| Poland |
| Russian Federation |
| Serbia |
| Slovakia |
| Slovenia |
| Spain |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of this study is defined as the date when the last patient, last safety follow-up visit occurs. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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