Efficacy and Safety of Anti-MAP Therapy in Adult Crohn's Disease (MAPUS)

• ClinicalTrials.gov Identifier: NCT01951326
• Recruitment Status: Completed
• First Posted: September 26, 2013
• Results First Posted: May 1, 2020
• Last Update Posted: December 8, 2020
• Sponsor: RedHill Biopharma Limited
• Information provided by (Responsible Party): RedHill Biopharma Limited

Tracking Information

• First Submitted Date: September 19, 2013
• First Posted Date: September 26, 2013
• Results First Submitted Date: March 29, 2020
• Results First Posted Date: May 1, 2020
• Last Update Posted Date: December 8, 2020
• Study Start Date: September 2013
• Actual Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 21, 2020)

Remission at Week 26 [ Time Frame: Week 26 ]

Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.

Original Primary Outcome Measures (submitted: September 23, 2013)

Remission at week 26 [ Time Frame: Baseline to week 26 ]

Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150

Current Secondary Outcome Measures (submitted: April 21, 2020)

• Response at Week 26 [ Time Frame: Week 26 ]
  Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome.
• Remission at Week 52 [ Time Frame: Week 52 ]
  Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
• Durable Remission Week 26 Through Week 52 [ Time Frame: Week 26 through week 52 ]
  When a subject is in remission with a maximum CDAI score of 149 at every visit from Week 26 through and including Week 52
• Remission at Week 16 [ Time Frame: Week 16 ]
  Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
• Steroid Free Remission at Week 52 [ Time Frame: Week 52 ]
  Subjects who are maintained off steroids for a minimum of 3 weeks

Original Secondary Outcome Measures (submitted: September 23, 2013)

Response at week 26 [ Time Frame: Baseline to week 26 ]

Reduction of CDAI score by a minimum of 100 points

Current Other Pre-specified Outcome Measures (submitted: April 21, 2020)

• Duration of Remission [ Time Frame: Baseline through week 52 ]
  Number of weeks that a subject is in a state of remission. Subjects who experienced remission and continued to be in remission at the time of their last CDAI assessment are censored at the date of their last CDAI assessment.
• Duration of Response [ Time Frame: Baseline through week 52 ]
  Number of weeks a subject is in a state of response. Subjects who experienced response and continued to be in response at the time of their last CDAI assessment are censored at the date of their last CDAI assessment.
• Time to Remission [ Time Frame: Baseline through week 52 ]
  [Date of first observed remission (CDAI score < 150) - Date of first dose or date of randomization if not dosed + 1] / 7 Days. Subjects who never experienced remission during the study are censored at the date of their last CDAI assessment.
• Time to Response [ Time Frame: Baseline through week 52 ]
  [Date of first observed response (a reduction from baseline of ≥ 100 in CDAI score) - Date of first dose or date of randomization if not dosed + 1] / 7 Days. Subjects who never experienced response during the study are censored at the date of their last CDAI assessment.
• Durable Remission Week 16 Through Week 52 [ Time Frame: Week 16 through week 52 ]
  Remission in a subject from week 16 through week 52.
• Response at Week 16 [ Time Frame: Week 16 ]
  Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome.
• Cardiac Safety [ Time Frame: Week 26 ]
  Change-from-baseline to week 26 in QTcF (based on cardiac safety report)
• Cardiac Safety [ Time Frame: Baseline through week 52 ]
  Placebo-corrected change-from-baseline to week 52 in QTcF (based on cardiac safety report)

Original Other Pre-specified Outcome Measures (submitted: September 23, 2013)

• Time to remission and response [ Time Frame: Baseline through week 52 ]
  The time (weeks after randomization) that a subject first records a state of remission or response
• Duration of remission and response [ Time Frame: Baseline through week 26 ]
  The number of visits that a subject is in a state of remission or response
• Proportion of subjects in remission [ Time Frame: 52 Weeks ]
• Proportion of subjects who maintained remission [ Time Frame: Baseline to week 52 ]
• RHB-104 plasma concentration measurements at different time points [ Time Frame: Baseline through week 56 ]
• Changes in MAP blood status by polymerase chain reaction (PCR) [ Time Frame: Baseline through week 26 ]
• Change in Crohn's Disease Endoscopic Index of Severity (CDEIS) [ Time Frame: Baseline through week 26 ]
• Change in Inflammatory Bowel Disease Questionnaire (IBDQ) and Short Form 36 (SF-36) [ Time Frame: Baseline through Week 52 ]
• Change in inflammatory markers [ Time Frame: Baseline through Week 52 ]
• Proportion of subjects tapered off steroids [ Time Frame: Baseline through Week 52 ]
• Tissue levels of the active agents of RHB-104 in colon biopsy samples [ Time Frame: Baseline to Week 26 ]
• Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: Baseline through Week 56 ]

Descriptive Information

• Brief Title: Efficacy and Safety of Anti-MAP Therapy in Adult Crohn's Disease
• Official Title: A Randomized, Double Blind, Placebo-controlled, Multicenter, Parallel Group Study to Assess the Efficacy and Safety of Fixed-dose Combination RHB-104 in Subjects With Moderately to Severely Active Crohn's Disease
• Brief Summary: The investigators hypothesize that RHB-104 will have greater efficacy than placebo in Crohn's disease.
• Detailed Description: A Randomized, Double Blind, Placebo-controlled, Multicenter, Parallel Group Study to Assess the Efficacy and Safety of Fixed-dose Combination RHB-104 in Subjects with Moderately to Severely Active Crohn's Disease.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Crohn's Disease

Intervention

• Drug: RHB-104
  95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine
• Drug: Placebo
  5 placebo capsules administered orally BID

Study Arms

• Active Comparator: RHB-104
  5 RHB-104 capsules administered orally BID
  Intervention: Drug: RHB-104
• Placebo Comparator: Placebo
  5 placebo capsules administered orally BID
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 29, 2019): 331
• Original Estimated Enrollment (submitted: September 23, 2013): 240
• Actual Study Completion Date: August 2019
• Actual Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Signed fully informed consent provided as per this protocol.
2. Diagnosis of Crohn's Disease confirmed by endoscopy or radiography and/or histology at least 6 months prior to randomization into the study.
3. CD involving the ileum and/or colon
4. Moderately to severely active CD (Crohn's Disease Activity Index (CDAI) score of greater than or equal to 220 and less than or equal to 450) at baseline.

5. Current treatment with at least one of the following therapies:

   A. Oral 5-acetyl salicylic acid (5-ASA) compounds. Dose must be stable for at least 4 weeks before baseline.

   B. Corticosteroid therapy. Dose must be stable for at least 2 weeks before baseline.

   C. Azathioprine or 6-mercaptopurine (6-MP) or methotrexate. Dose must be stable for at least 8 weeks before baseline.

   D. Infliximab or adalimumab. Dose must be stable for at least 14 weeks before baseline.

6. White blood cell count greater than or equal to 3.5 x 109 at screening.
7. Active Crohn's disease, defined by at least one of the following: C-reactive protein greater than Upper Limit of Normal (ULN) at screening, fecal calprotectin greater than Upper Limit of Normal (ULN) at screening, OR radiographic (MRE or CTE) or endoscopic confirmation of the presence of active CD within 5 weeks of screening visit. .
8. Subject agrees to use barrier contraceptive methods (i.e. diaphragm, cervical cap, contraceptive sponge or condom) with spermicidal foam/gel/cream/suppository, IUD/IUS or progestogen injection (Depo-Provera®) throughout the study and for at least 6 weeks after last study drug administration, unless subject is post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy. In regions where local regulatory contraceptive requirements differ, the ICF will reflect local policies.

Exclusion Criteria

1. Crohn's Disease involvement isolated to the mouth, upper gastrointestinal tract, or anus.
2. History of total colectomy with ileorectal anastomosis or a proctocolectomy.
3. Presence of active fistulizing Crohn's Disease or healed fistula within 2 months prior to screening.
4. Subject has postoperative stoma, ostomy, or ileoanal pouch.
5. Subject has short bowel syndrome.
6. Subject is scheduled for surgical bowel resection.
7. Subject has known symptomatic obstructive strictures or bowel perforation in the 6 months prior to screening.
8. Change in dose or discontinuation of oral 5-acetyl salicylic acid (5-ASA) compounds less than 4 weeks prior to baseline.
9. Change in dose or discontinuation of corticosteroids less than 2 weeks prior to baseline.
10. Change in dose or discontinuation of azathioprine, 6-mercaptopurine (6-MP) or methotrexate less than 8 weeks prior to baseline.
11. Change in dose or discontinuation of infliximab or adalimumab less than 14 weeks prior to baseline.
12. Treatment with vedolizumab less than 120 days prior to baseline or biological therapies (apart from infliximab or adalimumab) less than 60 days prior to baseline.
13. Previous treatment with rifabutin and/or clofazimine.
14. Oral or parenteral antibiotics in the 4 weeks prior to baseline (topical antibiotics are permitted).
15. Treatment with probiotics (excluding yogurt and yogurt-derived products) in the 4 weeks prior to baseline.
16. Females who have a positive pregnancy test or are lactating.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Bulgaria, Canada, Czechia, Israel, New Zealand, Poland, Serbia, Slovakia, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01951326
• Other Study ID Numbers: RHB-104-01
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: RedHill Biopharma Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: RedHill Biopharma Limited
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Ira N Kalfus, MD; RedHill Biopharma
• Principal Investigator: David Y. Graham, MD; Department of Medicine/Gastroenterology, Baylor College of Medicine, Houston

• PRS Account: RedHill Biopharma Limited
• Verification Date: June 2020