E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to severe Ulcerative Colitis |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045365 |
E.1.2 | Term | Ulcerative colitis |
E.1.2 | System Organ Class | 100000004856 |
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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 effect of AMG 181 on induction of remission in subjects with moderate to severe UC at week 8 as assessed by a total Mayo Score ≤ 2 points, with no individual subscore > 1 point |
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E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
- To evaluate the effects of AMG 181 on induction of response at week 8 as assessed by the total Mayo Score
- To evaluate the effects of AMG 181 on mucosal healing at week 8 as assessed by rectosigmoidoscopy
Other Secondary objective:
- To evaluate the effects of AMG 181 on sustained remission at both week 8 and week 24 as assessed by the total Mayo Score
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are 4 substudies for sites in Europe
- PK Substudy: Participation in the PK substudy is optional. Subjects will visit the clinic for additional pharmacokinetic samples
- Biomarker Development Blood and Stool Samples Substudy: A subgroup of subjects who provide additional informed consent will participate in the biomarker development substudy. Additional blood samples will be collected for assessment of transcript markers and plasma protein analytes. No additional stools samples will be collected other than those described for the main study
- Pharmacogenetic Substudy:A subgroup of subjects who provide additional informed consent will participate in the pharmacogenetic substudy. Participation in this substudy is optional. Subjects can only participate in the pharmacogenetic substudy if they have also provided consent for the biomarker substudy. No additional blood samples will be collected.
- Immunophenotyping and Absolute Counting (IPAC) PD Assay Substudy: A subgroup of subjects who provide additional informed consent will participate in the IPAC PD assay substudy for enumeration of, and assessment of α4β7 occupancy by AMG 181 on, naïve and memory CD4+ T cell subsets by flow cytometry. Participation in the IPAC substudy is limited to selected sites.
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E.3 | Principal inclusion criteria |
■ Age 18 to 65 at screening (inclusive)
■ Diagnosis of UC established ≥ 3 months before baseline by clinical and endoscopic evidence and corroborated by a histopathology report
■ Moderate to severe active UC as defined by a total Mayo score of 6 to 12 with a centrally read rectosigmoidoscopy score ≥ 2 prior to baseline
■ Demonstrated an inadequate response to, loss of response to, or intolerance to immunomodulators or anti-TNF agents or to corticosteroids (non-US sites only)
■ Subjects can be receiving the following treatments:
• Azathioprine or 6 mercaptopurine if treatment initiated at least 12 weeks prior to baseline and if stable dosage for ≥ 8 weeks prior to baseline
• Methotrexate up to 25 mg/week if stable dosage for ≥ 8 weeks prior to baseline
• 5 aminosalicylates and/or oral prednisone or equivalent up to 20 mg/day, if stable dosage for ≥ 2 weeks prior to baseline
■ Neurological exam free of clinically significant, unexplained signs or symptoms in the opinion of the investigator during screening and no clinically significant change prior to randomization
■ Subject has no known history of active tuberculosis
■ Subject has a negative test for tuberculosis during screening
■ Subject has provided informed consent
For full list of inclusion criteria, please refer to section 4.1 of the protocol |
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E.4 | Principal exclusion criteria |
Disease specific:
■ Disease limited to the rectum (ie, within 10 cm of the anal verge)
■ Toxic megacolon
■ Crohn’s Disease
■ History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for UC
■ Stool positive for C. Difficile toxin at screening
Excluded Medications:
■ Immunosuppressive therapy with either cyclosporine A, tacrolimus, or mycophenolate mofetil, within 1 month prior to baseline
■ Prior exposure to anti TNF agents, within 2 months, or 5 times the respective elimination half life (whichever is longer) prior to baseline
■ Any prior exposure to vedolizumab, rituximab, efalizumab, natalizumab
■ Use of topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to baseline
■ Use of intravenous or intramuscular corticosteroids within 2 weeks prior to screening and during screening
Laboratory Abnormalities:
■ Abnormal laboratory results at screening:
•Liver tests: either aspartate aminotransferase (AST), alanine transaminase (ALT) or alkaline phosphatase (ALP) > 2.0 Upper Limit of Normal (ULN) OR total bilirubin (TBL) > 1.5 ULN (except for subjects with Gilbert Syndrome)
• White blood cell count < 3,000 cells/mm³(< 3 x 10^9/L in SI units)
•Hemoglobin < 10 g/dL
General:
■ Female subject is not willing to prevent pregnancy from occurring
during treatment and for 7 months after the last dose of investigational
product (except if ≥ 2 years postmenopausal or surgically sterile).
Prevention of pregnancy involves a female subject not having
intercourse during treatment and for 7 months after the last dose of
investigational product, or the use of two methods of birth control. This
means the simultaneous use of: Two highly effective methods of birth
control, or one highly effective method of birth control and one effective
method of birth control.
Highly effective methods (≥ 99% effective when used correctly) of birth
control include: hormonal birth control methods (pills, shots, implants or
patches), intrauterine devices, sexual activity with a male partner who
has had a vasectomy, tubal sterilization (tie, clip, band, burn), or tubal
occlusion (insert placed in tube after confirmed occlusion).
Effective methods (< 99% effective) of birth control include: barrier
method of condom or occlusive cap (diaphragm or cervical/vault caps)
used with spermicide.
■ Subject is pregnant or breast feeding, or might become pregnant
within 7 months after the last dose of investigational product
For full list of exclusion criteria, please refer to section 4.2 of the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Remission at week 8 defined by a total Mayo Score ≤ 2 points, with no individual subscore > 1 point |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key Secondary Endpoints
- Response at week 8 as defined by a decrease from baseline in the total Mayo Score of ≥ 3 points and ≥ 30%, with an accompanying decrease in the subscore for rectal bleeding of ≥ 1 point or an absolute subscore for rectal bleeding of 0 or 1
- Mucosal healing at week 8 as defined by an absolute subscore for rectosigmoidoscopy of 0 or 1
Other Secondary Endpoints:
- Sustained remission at both week 8 and week 24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
key secondary endpoints: at week 8
Other secondary endpoint (i.e. sustained remission): week 8 and week 24 |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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 |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 |
placebo-controlled period followed by open label period (see Protocol section 3.1) |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 8 |
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 |
Australia |
Austria |
Belgium |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Latvia |
Netherlands |
Norway |
Poland |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |