| 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 |
Long-term condition that results in inflammation of the gastrointestinal
tract |
|
| 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 | PT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| 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 |
The coprimary objectives of this study are to evaluate the efficacy of ontamalimab in subjects with moderate to severe Crohn's Disease (CD) in:
Inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain severity and very soft stool/liquid stool frequency)
Inducing endoscopic response based on centrally read colonoscopy. |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives are as follows:
To evaluate the efficacy of ontamalimab in inducing clinical remission as measured by Crohn's Disease Activity Index (CDAI)
To evaluate the efficacy of ontamalimab in inducing enhanced endoscopic response based on centrally read colonoscopy
To evaluate the efficacy of ontamalimab in inducing clinical remission based on abdominal pain severity and very soft stool/liquid stool frequency (alternate thresholds)
To evaluate the efficacy of ontamalimab in inducing clinical response based on patient-reported clinical signs and symptoms (as measured by 2-item PRO)
To evaluate the efficacy of ontamalimab in inducing clinical remission based on patient-reported clinical signs and symptoms (as measured by 2-item PRO) as well as inducing endoscopic response based on centrally read colonoscopy in the same subject
To evaluate the efficacy of ontamalimab in inducing endoscopic healing based on centrally read colonoscopy.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Subjects and/or their parent or legally authorized representative must have an understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.Subjects must be able to voluntarily provide written, signed, and dated (personally or via a legally authorized representative) informed consent and/or assent as applicable to participate in the study.
3.Subjects must be between ≥16 and ≤80 years of age at the time of the signing of the informed consent/assent form. Note: Subjects <18 years of age must weigh ≥40 kg and must have body mass index ≥16.5 kg/m2.
4.Subjects must have active moderate to severe ileal (terminal ileum), ileocolic, or colonic CD at baseline (Visit 2) as defined by:
a.CDAI score between 220 and 450 (inclusive) AND
b.Meeting the following subscores in the 2-item PRO:
i.Abdominal pain subscore ≥5 (average worst daily pain on the 11-point NRS) AND abdominal pain subscore >2 (average daily pain on the 4-point abdominal pain variable of CDAI) over the 7 most recent days out of the 10 days before colonoscopy preparation (may or may not be contiguous) AND/OR
ii.Average of the daily stool frequency subscore ≥4 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days out of the 10 days before colonoscopy preparation (may or may not be contiguous).
AND
c. Presence of ulcerations that are characteristic to CD, as determined by
a colonoscopy performed during screening, and as defined by the SES-CD
>6 (SES-CD ≥4 for isolated ileitis)
Note that the subject must be confirmed as meeting the CDAI score and
PRO subscore requirements before a
colonoscopy is done.
5.Subjects must have a documented diagnosis (endoscopic with histology) of CD for ≥3 months before screening. Documented diagnosis is defined as:
A biopsy report in which the description of the histological findings is
consistent with the CD diagnosis AND
A report documenting disease duration based upon prior colonoscopy.
Note: If a biopsy report is not available in the source document at the time of screening, a biopsy must be performed during the screening colonoscopy and the histology report should be consistent with the CD diagnosis. If the histology description does not support the CD diagnosis at this time point, the subject should not be randomized
6.Subjects must be willing and able to undergo a colonoscopy during screening after all other inclusion criteria have been met.
7.Subjects must have had an inadequate response to, or lost response to, or had an intolerance to at least 1 conventional treatment such as sulfasalazine or mesalamine (5-ASA), glucocorticoids, immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF (see Appendix 4 of the protocol for guidance).
Subjects who have had an inadequate response to sulfasalazine or mesalamine should have also failed at least 1 other conventional treatment such as glucocorticoids.
8.Subjects receiving any treatment(s) for CD described in Section 5.2.1 of the protocol are eligible provided they have been, and are anticipated to be, on a stable dose for the designated period of time.
9. Subjects are males or nonpregnant, nonlactating females who, if sexually active, agree to comply with the contraceptive requirements of the protocol, or females of nonchildbearing potential. Males and females of reproductive potential who are sexually active must agree to use appropriate contraception (ie, highly
effective methods for female and medically appropriate methods for
male study subjects) (as described in Section 4.4 of the protocol) for the duration of the study. |
|
| E.4 | Principal exclusion criteria |
1.Subjects with indeterminate colitis, microscopic colitis, non-steroidal anti-inflammatory drug-induced colitis, ischemic colitis, infectious colitis, or clinical/histologic findings suggestive of ulcerative colitis.
2.Subjects with colonic dysplasia or neoplasia. (Subjects with prior history of adenomatous polyps will be eligible if the polyps have been completely removed.)
3.Subjects with past medical history or presence of toxic megacolon.
4.Subjects with presence of enterovesical (ie, between the bowel and urinary bladder) or enterovaginal fistulae.
5.Subjects with current symptomatic diverticulitis or diverticulosis.
6.Subjects with clinically significant obstructive colonic stricture, or
who have a history of bowel surgery within 6 months before screening, or who are likely to require surgery for CD during the treatment period. Subjects who have undergone previous colonic resection or ileocolectomy more than 6 months before screening must have at least
25 cm of colon remaining.
7.Subjects with past medical history of multiple small bowel resections resulting in clinically significant short bowel syndrome.
8.Subjects requiring total parenteral nutrition.
9.Subjects with past medical history of bowel surgery resulting in an existing or current stoma. Subjects who had a j-pouch are excluded as a j-pouch could result in a stoma.
10.Subjects have had prior treatment with ontamalimab (formerly PF-00547659; SHP647).
11.Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients.
12.Subjects have received any nonbiologic treatment with immunomodulatory properties (other than AZA, 6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment of CD within 30 days before baseline (Visit 2).
13.Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2).
14.Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 90 days before baseline (Visit 2).
15.Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, vedolizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule).
16.Subjects have received lymphocytes apheresis or selective monocyte granulocytes apheresis within 60 days before baseline (Visit 2).
17.Subjects have received enteral nutrition treatment within 30 days before baseline (Visit 2).
18.Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA within 14 days before screening colonoscopy.
19.Subjects have taken >20 mg/day of prednisone, >9 mg/day of
budesonide, or equivalent oral systemic corticosteroid dose within 14 days before baseline (Visit 2) or have taken ≥40 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 6 weeks before baseline (Visit 2).
20.Subjects have participated in other investigational studies within either 30 days or 5 half-lives of investigational product used in the study (whichever is longer) before screening (Visit 1).
21.Subjects have received a live (attenuated) vaccine within 30 days before baseline (Visit 2).
22.Subjects with active enteric infections (positive stool culture and sensitivity), Clostridium difficile infection or pseudomembranous colitis [subjects with C. difficile infection at screening may be allowed retest after treatment], evidence of active cytomegalovirus infection or Listeria monocytogenes, known active invasive fungal infections such as
histoplasmosis or parasitic infections, clinically significant underlying disease that could predispose the subjects to infections, or a history of serious infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks before baseline (Visit 2).
23. Subjects with abnormal chest x-ray or other imaging findings at screening (Visit 1), such as presence of active tuberculosis (TB), general infections, heart failure, or malignancy. (A chest x-ray, computed tomography scan, etc., performed up to 12 weeks before study entry [screening, Visit 1] may be used if available; documentation of the official reading
must be located and available in the source documentation). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The coprimary efficacy endpoints are:
Clinical remission at the Week 16 visit as defined by the following: 2-item PRO
subscores of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the
7 most recent days and average daily stool frequency ≤2 of type 6/7 (very soft
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent
days may or may not be contiguous during the 10 days of data collection before
colonoscopy preparation, depending on days to be excluded because of missing data.
If fewer than 7 days are available, the endpoint will be calculated on all available most
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as
missing.
Endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 25%
from baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints are as follows:
Clinical remission at the Week 16 visit as measured by a CDAI score of <150.
Enhanced endoscopic response at Week 16 as measured by a decrease in SES-CD of at
least 50% from baseline.
Clinical remission at the Week 16 visit as defined by the following: 2-item PRO
subscores of average daily abdominal pain ≤1 (based on the 4-point scale) over the
7 most recent days and average daily stool frequency ≤3 of type 6/7 (very soft
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent
days may or may not be contiguous during the 10 days of data collection before
colonoscopy preparation, depending on days to be excluded because of missing data.
If fewer than 7 days are available, the endpoint will be calculated on all available most
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as
missing.
Clinical response at the Week 16 visit as measured by the 2-item PRO and defined as
meeting at least 1 of the following 2 criteria:
o A decrease of ≥30% and at least 2 points from baseline in the average daily worst
abdominal pain over the 7 most recent days*, with the average daily stool frequency
of type 6/7 (very soft stools/liquid stools) either:
(a) Not worsening from baseline
and/or
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average
daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the
BSFS over the 7 most recent days*
o A decrease of ≥30% from baseline in the average daily stool frequency of type 6/7
(very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days*,
with the average daily worst abdominal pain either:
(a) Not worsening from baseline
and/or
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average
worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| 25 mg or 75 mg ontamalimab |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 107 |
| 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 |
| Israel |
| Japan |
| Russian Federation |
| Serbia |
| South Africa |
| United States |
| Austria |
| Croatia |
| Czechia |
| Germany |
| Italy |
| Lithuania |
| Netherlands |
| Poland |
| Romania |
| United Kingdom |
|
| 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 Study Completion Date is defined as the date the final subject, across all sites, completes their final protocol-defined assessment. This includes the follow-up visit or contact, whichever is later. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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