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 |
A form of inflammatory bowel disease |
|
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 etrolizumab compared with infliximab for sustained remission at Weeks 10, 30, and 54 in patients with ulcerative colitis (MCS) |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate:
• Clinical remission at W10, W54
• Clinical remission achieved at both W10 and W54
• Clinical remission at W54 among patients with a clinical response at
W10
• Improvement in endoscopic appearance of the mucosa at W10, W54
• Improvement in endoscopic appearance of the mucosa achieved at
both W10 and W54
• Endoscopic remission at W54
• Clinical response at W10
• Clinical response achieved at both W10 and W54
• Corticosteroid-free clinical remission at W54 (off corticosteroids for at
least 24 weeks prior to W54) in patients who were receiving
corticosteroids at baseline
• Change from baseline in patient-reported health-related QOL at W10,
30, and 54
• The overall safety and tolerability of etrolizumab over a period of 54
weeks
• Incidence and the clinical significance of anti-therapeutic antibodies
to etrolizumab, or if necessary, infliximab
• Etrolizumab serum concentration at the timepoint w12 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- 18-80 years of age, inclusive.
- Diagnosis of UC established at least 3 months prior to Day 1 by clinical and endoscopic evidence
- Moderately to severely active UC as determined by the Mayo Clinic Score assessment (MCS)
- Evidence of UC extending a minimum of 20 cm from the anal verge as determined by baseline endoscopy
- Naive to treatment with any anti-TNF inhibitor therapy
- An inadequate response to, loss of response to, or intolerance to prior corticosteroid and/or immunosuppressant treatment
- Background regimen for UC may include oral 5-aminosalicylic acid (5-ASA), oral corticosteroids, budenoside, probiotics, azathioprine (AZA), 6-
mercaptopurine(6-MP), or methotrexate (MTX) if doses are stable, as defined by the protocol
- Use of highly effective contraception as defined by the protocol
- Received a colonoscopy within the past year or be willing to undergo a
colonoscopy in lieu of a flexible sigmoidoscopy at screening |
|
E.4 | Principal exclusion criteria |
-Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC
- A history of or current conditions and diseases affecting the digestive tract, such as ileostomy or colostomy indeterminate colitis, suspicion of
ischemic colitis, radiation colitis, or microscopic colitis, Crohn's disease, fistulas or abdominal abscesses, colonic mucosal dysplasia, intestinal
obstruction, toxic megacolon, or unremoved adenomatous colonic polyps
- Have received non-permitted inflammatory bowel disease (IBD)
therapies (including etrolizumab or other anti-integrin agents such as
natalizumab, vedolizumab, and efalizumab), as stated in the protocol
- Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)
- Any prior treatment with rituximab
- Any treatment with tofacitinib during screening
- History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins,
or murine proteins or hypersensitivity to etrolizumab or any of the excipients
- Neurologic conditions or diseases that may interfere with monitoring for PML
- History of demyelinating disease
- Clinically significant abnormalities on screening neurologic examination (PML Objective/Subjective Checklists)
- History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, within 5 years before screening, as defined by the protocol
- Congenital or acquired immune deficiency, chronic hepatitis B or C infection, HIV positive or history of tuberculosis (active or latent)
- Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) within 60 days prior to Day 1 or other intestinal
pathogens within 30 days prior to Day 1.
- Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis within 60 days prior to Day 1.
- History of recurrent opportunistic infections and/or history of severe disseminated viral infections, or organ transplant
- Any serious opportunistic infection within the last 6 months
- Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to screening or oral antibiotics within 4 weeks prior
to screening
- Received a live attenuated vaccine within 4 weeks prior to Day 1 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Both clinical response at W10 and clinical remission at W54 in patients with ulcerative colitis as determined by MCS |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1) Clinical remission at W10
2) Clinical remission at W54
3) Clinical remission achieved at both W10 and W54
4) Clinical remission at W54 among patients with a clinical response at
W10
5) Improvement in endoscopic appearance of the mucosa at W10
6) Improvement in endoscopic appearance of the mucosa at W54
7) Improvement in endoscopic appearance of the mucosa achieved at
both W10 and W54
8) Endoscopic remission at W54
9) Clinical response at W10
10) Clinical response achieved at both W10 and W54
11) Corticosteroid-free clinical remission at W54 in patients who were
receiving corticosteroids at baseline
12) Change from baseline in patient-reported health-related QOL at
W10, 30, and 54, as assessed by the Inflammatory Bowel Disease
Questionnaire
13) Incidence and severity of adverse events
14) Incidence of serious adverse events
15) Incidence and severity of infection-related adverse events
16) Incidence of serious infection-related adverse events
17) Incidence and severity of injection-site reactions
18) Incidence of adverse events leading to study drug discontinuation
19) Incidence of laboratory abnormalities
20) Incidence of malignancies
21) Incidence of Anti-Therapeutic Antibodies (ATAs) to etrolizumab, or if
necessary, infliximab
22) Incidence and severity of hypersensitivity reaction events
23) Serum concentration 2 weeks after the first dose and at steady
state during the dosing period from W12 to W54
24) Serum concentration at timepoints W10, 30 an 54 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) W10
2) W54
3) W10, and 54
4) W 54 among W10
5) W10
6) W54
7) W10, and 54
8) W54
9) W10
10) At W10, and 54
11) Baseline and W54
12) Baseline W10, 30, and 54
13-16) Baseline up to end of study (up to W66)
17, 18) W0 to W52
19) Baseline up to W54
20) Baseline up to end of study (up to W66)
21) Baseline, W10 and W54
22) Baseline up to end of study (up to W66)
23) W2, W12 to W54
24) W10, 30 and 54. |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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 |
Tolerability, exploratory biomarkers |
|
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
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 |
Austria |
Belgium |
Canada |
Czech Republic |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Norway |
Philippines |
Portugal |
Romania |
Singapore |
South Africa |
Spain |
Sweden |
Switzerland |
United Kingdom |
Vietnam |
|
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 the study is defined as the last patient last safety follow-up visit in this protocol, or last patient in this protocol enrolled in to the OLE-SM study (GA28951), whichever is later. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |