E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that causes significant morbidity, impact on quality of life, and health care expenditures. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011401 |
E.1.2 | Term | Crohn's disease |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 | 10011398 |
E.1.2 | Term | Crohn's |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
• Objective: To assess the effect of BMS-986165 on clinical remission and endoscopic response at the end of the Induction Period (Week 12 [Day 85]) |
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E.2.2 | Secondary objectives of the trial |
• Objective: To assess the effect of BMS-986165 on clinical response at end of the Induction Period
• Objective: To assess the effect of BMS-986165 on PRO2 remission at the end of the Induction Period
• Objective: To assess the effect of BMS-986165 on gut mucosal disease activity by endoscopy at the end of the Induction Period |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) Willing to participate in the study and sign the ICF.
b) Willing and able to complete all study-specific procedures and visits.
2) Type of Subject and Target Disease Characteristics
a) to d) Not applicable per Global Revised Protocol v3.0
e) Documented diagnosis of CD for at least 3 months prior to screening, including ileal, colonic, or ileo-colonic disease distribution, confirmed by:
• Source: Medical records with report of a colonoscopy with ileal intubation (ileocolonoscopy), which shows features consistent with CD, as determined by the procedure performing physician, AND
• Source: Medical record documentation of a histopathology report showing features consistent with CD, as determined by the local pathologist.
Note: If a histopathology report is not available, histologic samples can be obtained at the screening endoscopy and sent to a local laboratory to confirm diagnosis of CD before proceeding to randomization. The screening endoscopy must show features consistent with CD.
f) Must have active moderate to severe CD, as defined by:
• CDAI score of 220 to 450 AND
• PRO2: Average daily score for abdominal pain ≥ 2 OR average daily number of very soft (loose) or liquid (watery) stools (BSS Type 6 or 7 only; see APPENDIX 18) ≥ 4, as collected in the 7 most recent daily diary entries in the previous 14 days, AND
• Evidence of active inflammation in at least 1 of the 5 ileocolonic segments (based on central reading) with total SES-CD ≥ 6 or SES-CD ≥ 4 if only isolated ileitis is present on baseline endoscopy
g) Must have had an inadequate response, LOR, or intolerance to a standard treatment course of 1 or more of the following medications as below:
• Oral 5-ASAs: (eg, mesalamine, sulfasalazine, olsalazine, balsalazine) at or above the approved label dose for induction therapy for at least 6 weeks
• Oral corticosteroids: Prednisone ≥ 40 mg/day or equivalent for 2 weeks, or 2 failed attempts to taper oral corticosteroids below prednisone or equivalent 10 mg daily, or a relapse within 3 months of discontinuing corticosteroids
• Intravenous (IV) corticosteroids: hydrocortisone ≥ 400 mg/day or equivalent for at least 1 week
• Immunomodulators: AZA ≥ 1.5 mg/kg/day, 6-MP ≥ 0.75 mg/kg/day, MTX ≥ 15 mg/week, or as per Institutional Practice/Country-approved label or guideline, for at least 12 weeks. At institutions that utilize thiopurine levels in clinical practice: AZA or 6-MP prescribed for at least 12 weeks with at least 1 demonstration of therapeutic thiopurine metabolite levels. Note: subjects with defined NUDT15 or TPMT mutations who experience intolerance to thiopurines at lower doses than those listed above may be eligible for this study. This should be discussed with the medical monitor on a case-by-case basis.
• Biologics: (eg, infliximab, adalimumab, certolizumab pegol, vedolizumab, natalizumab, ustekinumab) as defined in APPENDIX 4. Subjects can be included if treatment with a biologic was stopped due to primary or secondary nonresponse, or were intolerant to treatment, as defined in APPENDIX 4
3) Age and Reproductive Status
a) Men and women aged 18 to 75 years inclusive at the time of screening
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) to g) Not applicable per Global Revised Protocol v3.0
h) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section.
i) Not applicable per Global Revised Protocol v3.0
j) Not applicable per Global Revised Protocol v5.0
k) Investigators shall counsel WOCBP and men who are sexually active
with WOCBP, on the importance of pregnancy prevention and the
implications of an unexpected pregnancy. Investigators shall advise on
the use of methods of contraception (APPENDIX 5).
l) Male subjects should maintain their usual practice with regards to
contraception (if any). However, no specific additional contraceptive
measures are required.
m) WOCBP must agree to at least an acceptable, less than highly
effective means of contraception (see APPENDIX 5) for the duration of
treatment with study treatment(s) (BMS-986165 or placebo). |
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E.4 | Principal exclusion criteria |
1)Target Population
a)Severe or fulminant colitis that is likely to require surgery or hospitalization
b)Presence of a diagnosis of alternative forms of colitis (infectious, inflammatory including ulcerative colitis, malignant, toxic,
indeterminate, etc) other than CD
c)N/A per PAM v3.0
d)History of intra-abdominal abscess within the last 60 days
•Previous intra-abdominal abscess that has been drained and successfully treated with a local standard course of antimicrobial therapy is permitted (the course must be completed at least 60 days prior to Day 1)
e)History of diverticulitis within the last 60 days
•Previous diverticulitis that has been successfully treated with a local standard course of antimicrobial therapy is permitted. (the course must be completed at least 60 days prior to Day 1)
f)Receiving tube feeding, defined formula diets, or total parenteral alimentation
g)Current colonic dysplasia or past colonic dysplasia that has not been definitively treated
h)History of infectious (bacterial, viral, fungal, parasitic, etc.) colitis within past 30 days; must be fully treated to rescreen
i)Use of therapeutic enema or suppository, other than required for ileocolonoscopy, within 7 days prior to screening or during the Screening Period
j)N/A per PAM v3.0
k)N/A per PAM v3.0
l)Previous exposure to BMS-986165 in any study
m)N/A per PAM v5.0
n)N/A per PAM v3.0
o)N/A per PAM v5.0
p)Prior treatment with specific lymphocyte-depleting agents, such as alemtuzumab and rituximab, are prohibited within 12 months prior to the first dose of study treatment during the Induction Period.
q)Receipt of either lymphocyte apheresis or selective monocyte, granulocyte apheresis (eg, Cellsorba™) is prohibited within 12 months prior to the first dose of study treatment during the Induction Period
r)Previous treatment with investigational agents within 4 weeks or 5
half-lives (whichever is longer) prior to the first dose of study treatment
during the Induction Period. Subjects treated with investigational agents
4 to 12 weeks prior to the first dose of study treatment must be
discussed with the medical monitor.
s)Previous stem cell transplantation, (except local stem cell therapy to
treat perianal fistulae (eg, Alofisel® [darvadstrocel]). Please discuss on
a case by case basis with the medical monitor.
t)Presence of a stoma, gastric or ileoanal pouch, previous
proctocolectomy or total colectomy, or symptomatic, stenosing disease
that is likely to confound efficacy assessment (eg, symptomatic CDrelated
stricture), abscess or suspected abscess, pouchitis, short bowel
syndrome, or history of bowel perforation. In addition, subjects with
colonic or ileal strictures that are not passable via colonoscope that the
endoscopist normally uses in clinical practice, or strictures in the ileum
or ileocecal valve that are fibrotic in nature, will be excluded.
2)Other Medical Conditions and History
a)Women who are pregnant or breastfeeding
b)Any major illness/condition or evidence of an unstable clinical
condition (eg, renal, hepatic, hematologic, gastrointestinal, endocrine,
pulmonary, immunologic, psychiatric, or local active infection/infectious
illness) that, in the investigator's judgment, will substantially increase
the risk to the subject if he or she participates in the study
c)Any major surgery within the last 30 days before the first dose of
study treatment, or any surgery planned during the course of the study
d)N/A per PAM v3.0
e)Female subjects with a breast cancer screen suspicious for
malignancy, and in whom the possibility of malignancy cannot be
reasonably excluded after additional clinical, laboratory, or other
diagnostic evaluations
f)Significant blood loss (> 500 mL) or blood transfusion within 4
weeks of study treatment administration
g)Inability to tolerate oral medication
h)Inability to undergo venipuncture and/or tolerate venous access
i)N/A per PAM v3.0
j)Any other sound medical, psychiatric, and/or social reason as
determined by the investigator
k)Potential subjects with the following characteristics will be excluded
from the study:
• History of any kind of bowel resection within 6 months or any other
intra-abdominal surgery within 3 months prior to baseline
• History of any surgical procedure requiring general anesthesia, other
than required for ileocolonoscopy, within 30 days prior to the first dose
of study treatment, or is planning to undergo surgery during the study
period
• History of bleeding disorders or recent use of anti-platelet or antithrombotic
agents that in the investigator's judgment preclude safely
performing endoscopic procedures and biopsy within the timeframe
outlined in the study protocol
• Currently on any therapy for chronic infection (eg, pneumocystis,
cytomegalovirus, herpes simplex, herpes zoster, invasive bacterial or
fungal infections, or atypical mycobacteria)
Complete list of exclusion criteria provided in the Protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
•Co-primary endpoints:
o Proportion of subjects achieving clinical remission at week 12, and
o Proportion of subjects achieving endoscopic response at week 12, both at a population level.
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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) |
The exploratory and safety objectives and endpoints are summarized in Section 4. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | 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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 102 |
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 |
Brazil |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Taiwan |
United States |
Belgium |
Czechia |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Poland |
Portugal |
United Kingdom |
Netherlands |
Romania |
Spain |
Switzerland |
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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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |