Research study to determine whether an investigational drug, SHP647, is safe and effective in the treatment of moderate to severe Crohn’s Disease, compared with placebo (dummy treatment) – using a randomised and blinded study design (investigator and patients are not aware whether they receive study drug or placebo)(CARMEN CD 306).

• Register: EUCTR
• Last refreshed on: 23 November 2020
• Main ID: EUCTR2017-000576-29-ES
• Date of registration: 21/05/2018
• Prospective Registration: Yes
• Primary sponsor: Shire Human Genetic Therapies, Inc.
• Public title: Research study to determine whether an investigational drug, SHP647, is safe and effective in the treatment of moderate to severe Crohn’s Disease, compared with placebo (dummy treatment) – using a randomised and blinded study design (investigator and patients are not aware whether they receive study drug or placebo)(CARMEN CD 306).
• Scientific title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects With Moderate to Severe Crohn’s Disease (CARMEN CD 306) - CARMEN CD 306
• Date of first enrolment: 11/07/2018
• Target sample size: 1032
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000576-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: yes; Other specify the comparator: 25 mg or 75 mg SHP647; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Colombia, Estonia, France, Greece, Hungary, Ireland, Japan, Korea, Republic of, Mexico, Portugal, Slovakia, Spain, Switzerland, Ukraine, United States

Contacts

• Name: Melanie Ivarsson
• Affiliation: Shire Human Genetic Therapies, Inc.

• Name: Melanie Ivarsson
• Affiliation: Shire Human Genetic Therapies, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study.
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 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. 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) AND
c. Meeting the following subscores in the 2-item PRO:
i. Average of the abdominal pain subscores =5 (average worst daily pain on the 11-point numerical rating scale [NRS]) 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 Bristol Stool Form Scale (BSFS) over the 7 most recent days out of the 10 days before colonoscopy preparation (may or may not be contiguous).
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 to confirm the histological 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, the histology report of the biopsy performed mandatorily during the screening colonoscopy should be consistent with the CD diagnosis. If the histology diagnosis is not clear 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-aminosalicylic acid [5-ASA]), glucocorticoids, immunosuppressants (azathioprine [AZA], 6-mercaptopurine [6-MP], or
methotrexate [MTX]), or anti-TNF. 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 for the duration of the study.
Are the trial subjects under 18? yes
Number of subjects for this age range: 103
F.1.2 Adults (18-64 years) yes
F.1.2.1 Numbe
Exclusion criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met.
1. Subjects with indeterminate colitis, microscopic 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 obstructive 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 CD during the treatment period.
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 SHP647 (formerly PF-00547659).
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 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 the baseline visit (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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Crohn’s disease
MedDRA version: 20.0 Level: LLT Classification code 10011402 Term: Crohn's disease (colon) System Organ Class: 100000004856

Intervention(s)

Product Name: SHP647
Product Code: SHP647
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Anti-MAdCAM antibody
Current Sponsor code: SHP647
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 75-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Product Name: SHP647
Product Code: SHP647
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Anti-MAdCAM antibody
Current Sponsor code: SHP647
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

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.

Main Objective: The co-primary objectives of this study are:
- to evaluate the efficacy of SHP647 in inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain severity and
very soft stool/liquid stool frequency) in subjects with moderate to severe Crohn’s disease (CD).
- to evaluate the efficacy of SHP647 in inducing endoscopic response based on centrally read colonoscopy in subjects with moderate to severe Crohn’s disease (CD).

Secondary Objective: Key secondary objectives:
- To evaluate the efficacy of SHP647 in inducing clinical remission as measured by CD Activity Index CDAI
- To evaluate the efficacy of SHP647 in inducing enhanced endoscopic response based on centrally read colonoscopy.
- To evaluate the efficacy of SHP647 in inducing clinical remission based on abdominal pain severity and very soft stool/liquid stool frequency (alternate thresholds).
- To evaluate the efficacy of SHP647 in inducing clinical response based on patient-reported clinical signs and symptoms (as measured by 2-item PRO).
- To evaluate the efficacy of SHP647 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 SHP647 in inducing endoscopic healing based on centrally read colonoscopy.

Timepoint(s) of evaluation of this end point: Week 16 visit

Secondary Outcome(s)

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 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. 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*
*Note: 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 remission with endoscopic response, ie, both clinical remission by 2 item PRO and endoscopic response, as measured by a decrease in SES CD of at least 25% at Week 16 (composite endpoint)
-Complete endoscopic healing at Week 16 defined as SES-CD=0-2.

Timepoint(s) of evaluation of this end point: Week 16 visit

Secondary ID(s)

2017-000576-29-IE

SHP647-306

Source(s) of Monetary Support

Shire Human Genetic Therapies, Inc.

Ethics review

Status: Approved
Approval date: 21/06/2018
Contact: