| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ulcerative colitis or Crohn's Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Long-term condition that results in inflammation and ulcers of the colon and rectum or 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| 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 primary objective of the study is to evaluate the safety and tolerability of long-term treatment with ontamalimab in subjects with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary - Subjects with Ulcerative Colitis:
To evaluate the effect of long-term ontamalimab treatment on clinical outcomes (including remission over time based on composite score of patient-reported symptoms using daily
diary and locally read endoscopy, Mayo-based remission over time, clinical remission over time, partial
Mayo score over time).
To evaluate the effect of long-term ontamalimab treatment on endpoints related to endoscopic healing.
Secondary - Subjects with Crohn's Disease:
To evaluate the effect of long-term ontamalimab treatment on clinical outcomes (including 2 -item patient-reported outcome [PRO ]-based clinical response over time, 2 item PRO-based and Crohn's Disease
Activity Index [CDAI]-based clinical remission over time)
To evaluate the effect of long-term ontamalimab treatment on endpoints related to endoscopic
outcomes
(enhanced endoscopic response as well as endoscopic healing). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects with UC Entering from an Induction or Maintenance Study:
1. Subjects must have been previously enrolled in study SHP647-301, SHP647 302, or SHP647-303, and reached 1 of the following clinical trial milestones:
- Completed the Week 12 visit in induction study SHP647-301 or SHP647 302, and did NOT achieve a clinical response. Clinical response is defined as: 1) a decrease from baseline in the composite score of
patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1, OR 2) a decrease from the induction study (SHP647-301 or SHP647-302) baseline total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.
- Completed the Week 52 visit in maintenance study SHP647-303.
- Withdrew early from maintenance study SHP647-303 due to treatment failure, defined by an endoscopic subscore that has increased by at least 1 point over baseline in the maintenance study or a value ≥2 plus an increase in clinical subscore (stool frequency + rectal bleeding score) of
at least 2 points. Centrally read endoscopic subscores will be used to determine treatment failure.
2. Subjects receiving any treatment(s) for UC described in Section 5.2.1 are eligible provided they have been, and are anticipated to be, on a stable dose for the designated period of time.
Subjects with UC Entering Directly:
1. 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.
2. Subjects must meet at least 1 of the 3 criteria below:
-Have previously received ontamalimab (SHP647) in a Shire or Pfizersponsored Phase 1 or Phase 2
clinical trial
-Have previously received vedolizumab
-Live in a country that has reached its enrollment cap for induction studies (SHP647-301 and/or
SHP647-302).
3. Subjects must have a documented diagnosis (radiologic or endoscopic with histology) of UC for 3
months before screening. The following must be available in each subject's source documentation:
-A biopsy report to confirm the histological diagnosis
-A report documenting disease duration based upon prior colonoscopy.
4. Subjects must be willing to undergo a flexible sigmoidoscopy or colonoscopy (if preferred or required per exclusion criterion #5), during screening after all other inclusion criteria have been met.
5. Subjects must have moderate to severe active UC, defined as a total Mayo score of ≥6, including a centrally read endoscopic subscore ≥2, rectal bleeding subscore ≥1, and stool frequency subscore ≥1 at baseline (Visit 1).
6. Subjects must have evidence of UC extending proximal to the rectum (ie, not limited to proctitis).
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 mesalamine (5-aminosalicylic acid
[5ASA]), glucocorticoids, immunosuppressants (azathioprine, 6-mercaptopurine [6-MP], or methotrexate), or anti-tumor necrosis factor (TNF).
8. Subjects receiving any treatment(s) for UC described in Section 5.2.2.1 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) for the duration of the study.
Subjects with Crohn's Disease
1. Subjects must have been previously enrolled in study SHP647-305, SHP647 306, or SHP647-307, and reached 1 of the following clinical trial milestones:
- Completed the Week 16 visit in induction study SHP647-305 or SHP647-306, and did NOT meet the efficacy criteria (clinical and/or endoscopic response/remission as appropriate) for entry into maintenance study SHP647-307.
- Completed the Week 52 visit in maintenance study SHP647-307.
- Withdrew early from maintenance study SHP647-307 due to treatment failure (or were considered to have failed treatment, at the time of the last visit in study SHP647-307), as defined in the SHP647-307 protocol.
2. Subjects receiving any treatment(s) for CD described in Section 5.3.1, are eligible provided they have been, and are anticipated to be, on a stable dose for the designated period of time. |
|
| E.4 | Principal exclusion criteria |
Subjects with UC Entering from an Induction or Maintenance
Study/Subjects with CD
1. Subjects who had major protocol deviation(s) (as determined by the sponsor) in previous studies.
2. Subjects who permanently discontinued investigational product because of an AE, regardless of relatedness to investigational product, in previous studies.
3. Subjects who are likely to require major surgery for UC/CD.
4. Subjects are females who became pregnant during the previous UC/CD studies, females who are lactating, females who are planning to become pregnant during the study period, or males or females of childbearing potential not agreeing to continue using appropriate contraception methods (ie, highly effective methods for female and medically appropriate methods for male study subjects) through the
conclusion of study participation.
5. Subjects who do not agree to postpone donation of any organ or tissue, including male subjects who are planning to bank or donate sperm and female subjects who are planning
to harvest or donate eggs, for the duration of the study and through 16 weeks after last dose of
investigational product.
6. Subjects who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with study procedures.
7. Subjects who have a newly-diagnosed malignancy or recurrence of malignancy
8. Subjects who have developed any major illness/condition or evidence of an unstable clinical condition (except disease under study) 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.
9. Subjects with any other severe acute or chronic medical or psychiatric condition or laboratory or electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study
results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
10. Subjects with known exposure to М.tuberculosis (TB) since testing at screening in previous UC/CD studies and who have been advised to require treatment for latent or active disease, but who are without agenerally accepted course of treatment.
Subjects with UC Entering directly
1. Subjects with indeterminate colitis, microscopic colitis, nonsteroidal anti-inflammatory drug-induced colitis, ischemic colitis, infectious colitis, or clinical/histologic findings suggestive of CD.
2. Subjects with colonic dysplasia or neoplasia.
3. Subjects with past medical history or presence of toxic megacolon.
4. Subjects with colonic stricture, past medical history of colonic resection, a history of bowel surgery within 6 months before screening, or who are likely to require surgery for UC during the treatment period.
5. Subjects at risk for colorectal cancer must have a colonoscopy (Eaden and Mayberry, 2002) performed during the screening period with results available within 10 days before the baseline visit (Visit 1), unless the subject has had a surveillance colonoscopy performed within 1 year prior to screening, and any adenomatous polyps found at that examination have been excised. 6. Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients.
7. Subjects have received anti-TNF treatment within 60 days or vedolizumab within 120 days before baseline
8. Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 90 days before baseline
9. Subjects have received any nonbiologic treatment with immunomodulatory properties within 30 days before baseline.
10. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule) with the exception of vedolizumab.
11. Subjects have received parenteral or rectal glucocorticoids, or rectal 5-ASA, within 14 days before screening endoscopic procedure.
12. Subjects have received leukocyte apheresis or selective lymphocyte, monocyte, or granulocyte apheresis or plasma exchange within 30 days before baseline
13. Subjects have participated in other investigational studies within either 30 days or 5 half-lives of investigational product used in the study before baseline
14. Subjects have received a live (attenuated) vaccine within 30 days before the baseline
15. Subjects with active enteric infections, Clostridium difficile infection or pseudomembranous colitis, evidence of active cytomegalovirus infection or Listeria monocytogenes, known active invasive fungal
infections, clinically significant underlying disease that could predispose the subjects to infections, or a history of serious infection within 4 weeks before the baseline |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is safety assessment as is assessment of safety as measured by: incidence and severity of AEs; incidence and nature of serious infections; actual values and change from baseline, as well as the incidence of abnormalities, in laboratory tests, ECGs, and vital signs; and antidrug antibodies. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section “Study Schedules” of the Protocol |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints – Subjects with Ulcerative Colitis:
The secondary efficacy endpoints are as follows:
• Remission based on composite score, assessed yearly and at end of study. Remission is defined as a composite score of patient-reported symptoms using daily diary and locally read endoscopy as follows: stool frequency subscore of 0 or 1 with at least a 1-point change from induction study (SHP647-301 or SHP647-302) baseline, or study SHP647-304 baseline for direct-entry subjects, AND rectal bleeding subscore of 0 AND locally-read endoscopic subscore of 0 or 1 (modified, excludes friability).
• Remission, based on total Mayo score, assessed yearly and at end of study. Remission is defined as a total Mayo score = 2 with no individual subscore (stool frequency, rectal bleeding, endoscopy [modified, excludes friability], and physician's global assessment) exceeding 1.
• Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point change from induction study (SHP647-301 or SHP647-302) baseline, or study SHP647-304 baseline for direct-entry subjects, in stool frequency subscore, and rectal bleeding subscore of 0, assessed yearly and at end of study.
• Partial Mayo score of =2 with no individual subscore >1 over time. The partial Mayo score does not include the endoscopy subscore.
• Endoscopic remission, as defined by locally read endoscopic subscore 0 or 1 (modified, excludes friability), assessed yearly and at end of study.
Secondary Efficacy Endpoints – Subjects with Crohn's Disease:
The secondary efficacy endpoints are as follows:
• Clinical remission over time. Clinical remission is defined by 2-item PRO CD daily e-diary subscore of average worst daily abdominal pain =3 (based on 11-point numeric rating scale [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.
• Enhanced endoscopic response, assessed yearly and at end of study, as measured by a decrease in Simple Endoscopic Score for Crohn's Disease [SES-CD) of at least 50% from induction study (SHP647-305 or SHP647-306) baseline.
• Clinical remission over time as measured by CDAI <150.
• Clinical remission over time as defined by the following: CD daily e diary subscores of average worst 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.
• Both clinical remission by 2-item PRO and enhanced endoscopic response over time (composite endpoint).
• Complete endoscopic healing at end of study, defined as SES-CD=0-2.
All efficacy analyses will be performed using the full-analysis set.
Secondary efficacy endpoints will be summarized by treatment group using descriptive statistics at each assessment visit. Summaries may be presented by the status at entry into the study (eg, induction non responder, maintenance ontamalimab completer, etc). Statistical summaries will include number of subjects and percentages, and 95% confidence
intervals. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| assessed every 24 weeks, yearly, at end of study, or a combination, as detailed in E.5.1 |
|
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 364 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Canada |
| Colombia |
| Croatia |
| Czech Republic |
| Estonia |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lebanon |
| Lithuania |
| Mexico |
| Netherlands |
| New Zealand |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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. Please note that 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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