E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to severe Crohn's Disease |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011402 |
E.1.2 | Term | Crohn's disease (colon) |
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 efficacy of AMG 181 as measured by the proportion of subjects achieving Crohn’s Disease Activity Index (CDAI) remission (CDAI < 150) at week 8 |
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E.2.2 | Secondary objectives of the trial |
Key Secondary:
- To evaluate the efficacy of AMG 181 as measured by the proportion of subjects achieving CDAI remission (CDAI < 150) at week 12
- To evaluate the efficacy of AMG 181 as measured by the proportion of subjects with a CDAI response (defined as either remission or a CDAI reduction from baseline of ≥ 100) at week 12
- To evaluate the efficacy of AMG 181 as measured by the proportion
of subjects with a CDAI response (defined as either remission or a CDAI reduction from baseline of ≥ 100) at week 8
Other Secondary:
- To evaluate the efficacy of AMG 181 as measured by the proportion of subjects achieving sustained remission at both week 12 and week 24
- To evaluate the efficacy of AMG 181 as measured by the proportion of subjects achieving sustained remission, defined as achieving the criteria for remission (CDAI < 150) at both week 8 and week 24
- To evaluate change from baseline in CDAI score at week 12
- To evaluate change from baseline in CDAI at week 8
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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 |
- Subject has provided informed consent
- Subject is ≥ 18 and ≤ 65 years of age at screening
- Subject has diagnosis of ileal, ileo-colonic, or colonic Crohn’s disease for a minimum of 6 months prior to baseline
- Subject has moderately to severely active Crohn’s disease, as defined by a CDAI score ≥ 220 and ≤ 450 at baseline
- Subject has evidence of active inflammation, as demonstrated by at least one of the following:
• Elevated C-Reactive Protein (CRP) at screening (≥ 5 mg/L)
• Elevated fecal calprotectin at screening (≥ 200 μg/g)
• Endoscopic evidence of inflammation within 12 weeks prior to baseline as demonstrated by 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 cm of intestine)
- Subject has demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following agents: Immunomodulators or Anti-TNF agents or to corticosteroids (non-US sites only)
- Subject can be receiving the following treatments:
• 5-aminosalicylates, oral prednisone or equivalent ≤ 20 mg/day, budesonide (≤ 9 mg/day), oral antibiotics for treatment of Crohn’s disease (ie, ciprofloxacin, metronidazole) if stable dosage for ≥ 2 weeks prior to baseline
• Methotrexate (≤ 25 mg/week), azathioprine, 6-mercaptopurine if stable dosage for ≥ 8 weeks prior to baseline
• Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the dose has been stable for the 2 weeks prior to baseline
• Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea
- Subject has 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
For a 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
- Subject has clinical manifestations of short bowel syndrome (defined as requiring oral or parenteral supplemental or total nutrition in order to maintain stable body weight)
- Subject had stricture with obstructive symptoms within 3 months prior to baseline
- Subject has ileostomy and/or colostomy, or gastric or intestinal pouch
- Subject has evidence of an infected abscess
- Subject had bowel perforation or evidence of noninflammatory obstruction during the 6 months prior to baseline
- Subject has stool positive for C. difficile toxin at screening
Excluded Medications
- Subject received an anti-TNF agent within 8 weeks or 5 times the respective elimination half-life, whichever is longer (eg, 8 weeks for infliximab, 10 weeks for adalimumab or certolizumab pegol), prior to baseline
- Subject received cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, or tacrolimus within 1 month prior to baseline
- Subject received topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to baseline
- Subject received intravenous or intramuscular corticosteroids within 2 weeks prior to screening and during screening
- Subject had any prior exposure to antagonists of integrins or integrin ligands (eg, natalizumab, efalizumab, or vedolizumab), rituximab, or TNF kinoid immunotherapies
- Subject had any prior exposure to AMG 181
Laboratory Abnormalities
- Subject has 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 109/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, breast feeding, or might become pregnant within 7 months after the last dose of investigational product
For a 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, as defined by a CDAI score of < 150 |
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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:
- Remission at week 12, as defined by a CDAI score of < 150
- Response at week 12, as defined by either remission or a CDAI reduction from baseline of ≥ 100
- Response at week 8, as defined by either remission or a CDAI reduction from baseline of ≥ 100
Other Secondary Endpoints:
- Sustained remission at both week 12 and week 24
- Sustained remission, defined as achieving the criteria for remission at both week 8 and week 24
- Change from baseline in CDAI score at week 12
- Change from baseline in CDAI score at week 8 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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 |
Belgium |
Canada |
Denmark |
France |
Austria |
Netherlands |
Czech Republic |
Germany |
Hungary |
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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |