Open Label Efficacy and Safety of Anti-MAP (Mycobacterium Avium Ssp. Paratuberculosis) Therapy in Adult Crohn's Disease (MAPUS2)

• ClinicalTrials.gov Identifier: NCT03009396
• Recruitment Status: Completed
• First Posted: January 4, 2017
• Results First Posted: February 24, 2021
• Last Update Posted: February 24, 2021
• Sponsor: RedHill Biopharma Limited
• Information provided by (Responsible Party): RedHill Biopharma Limited

Study Description

Brief Summary:

An open label extension to the RHB-104-01 Study.

Condition or disease	Intervention/treatment	Phase
Crohn Disease	Drug: RHB-104 (fixed-dose combination: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine)	Phase 3

Detailed Description:

An Open Label Phase III Study to Assess the Efficacy and Safety of Fixed-Dose Combination RHB-104 in Subjects with Active Crohn's Disease Despite 26 Weeks of Participation in the MAP US RHB-104-01 Study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 54 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Active
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Study to Assess the Efficacy and Safety of Fixed-Dose Combination RHB-104 in Subjects With Active Crohn's Disease Despite 26 Weeks of Participation in the MAP US RHB-104-01 Study
• Actual Study Start Date: March 18, 2017
• Actual Primary Completion Date: November 13, 2018
• Actual Study Completion Date: August 19, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: RHB-104 - patients on ACTIVE therapy in RHB-104-01 study; Subjects who were on the active therapy arm in the RHB-104-01 clinical study will continue to receive RHB-104 at 5 capsules twice a day in addition to the standard of care they received in the RHB-104-01 clinical study	Drug: RHB-104 (fixed-dose combination: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine); For patients on ACTIVE or PLACEBO in the parent study (RHB-104-01), who were not in remission after 26 weeks; Other Name: RHB-104
Experimental: RHB-104 - patients on PLACEBO therapy in RHB-104-01 study; Subjects who were on the active therapy arm in the RHB-104-01 clinical study will receive RHB-104 at 5 capsules twice a day in addition to the standard of care they received in the RHB-104-01 clinical study. The RHB-104 will be ramped up beginning at 1 capsule twice per day in week 1 increasing to 2 capsules twice per day in week 2, 3 capsules twice per day in week 3, 4 capsules per day in week 4 and achieving 5 capsules per day for the remainder of the study.	Drug: RHB-104 (fixed-dose combination: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine); For patients on ACTIVE or PLACEBO in the parent study (RHB-104-01), who were not in remission after 26 weeks; Other Name: RHB-104

Outcome Measures

Primary Outcome Measures :

1. Number of Patients in Remission at Week 16 [ Time Frame: Week 16 ]

   The number of patients who achieved a reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150 points.

   Lower CDAI scores indicate a better outcome.

Secondary Outcome Measures :

1. Response at Week 16 [ Time Frame: Week 16 ]
   Reduction of the total Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points Lower CDAI scores indicate a better outcome.
2. The Number of Weeks for Patients to Achieve Remission [ Time Frame: Baseline through week 52 ]
   [Date of first observed remission (CDAI less than 150) - date of first dose, or date of randomization if not dosed, plus 1] / 7 days. Subject who never experience remission during the study are censored at the time of their last CDAI assessment.
3. Number of Weeks the Patients Are in Remission [ Time Frame: Baseline through week 52 ]
   Duration of remission is defined as the number of weeks the subject is in remission (CDAI score < 150). It is calculated as the first date following remission at which CDAI is ≥150 minus the date of first remission, plus 1 day, divided by 7. 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.
4. Number of Weeks to Achieve 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.
5. Number of Weeks the Patients Are in Response. [ Time Frame: Baseline through week 52 ]
   Duration of response is defined as the number of weeks the subject is in a state of response (a reduction from baseline of ≥ 100 in CDAI score). It is calculated as the first date following response at which the reduction from baseline in CDAI is <100 minus the date of first response, plus 1 day, divided by 7. 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.
6. Durable Remission Week 16 Through Week 52 [ Time Frame: Week 16 through week 52 ]
   When a subject is in remission with a maximum CDAI score of 149 at every visit from week 16 through and including week 52.

Other Outcome Measures:

1. Increase in Milliseconds (ms) QT Wave [ Time Frame: week 52 ]
   The increase in the number of milliseconds change-from-baseline to week 52 in QTcF (Fridericia's Correction Formula of QT wave interval) (based on cardiac safety report).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 76 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed fully informed consent (ICF) provided as per this protocol.
• Participation in RHB-104-01 for 26 weeks, and a Crohn's Disease Activity Index (CDAI) score of ≥ 150 at Visit Week 26.

OR

• More than 26 weeks, with a CDAI ≥150 at Visit Week 26 and all subsequent visits, and subject is between Week 26 and 52 within 4 weeks (28 days) of site activation (e.g. Subject with CDAI = 249 at week 26 and who is at week 38 at the time of site's activation for RHB-104-04 has a 4-week window to be enrolled in the open label study via the Optional Screening Visit)

• Current treatment with at least one of the following therapies which may be discontinued by the investigator as clinically indicated after 8 weeks of open label RHB-104 treatment:

  • Oral 5-acetyl salicylic acid (5-ASA) compounds
  • Azathioprine or 6-mercaptopurine (6-MP) or methotrexate
  • Infliximab or adalimumab OR Current treatment with corticosteroid therapy which must begin tapering after 4 weeks of treatment with open label RHB-104 (Refer to Appendix 13)
• White blood cell count ≥ 3.5x109 at screening (RHB-104-01 Visit Week 26 visit or Optional Screening visit)

• Subject agrees to use the following effective contraceptive methods

  • diaphragm, cervical cap, contraceptive sponge or condom) with spermicidal foam/gel/cream/suppository
  • IUD (intrauterine device) /IUS (intrauterine system)
  • progestogen injection (Depo-Provera®) throughout the study and for at least 6 weeks after last study drug administration, unless subject or partner of subject is post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy. Post-menopausal is defined as having experienced 12 consecutive months without menstruation.

In regions where local regulatory contraceptive requirements differ, the ICF (Informed Consent Form) will reflect local policies.

Exclusion Criteria:

1. Positive stool results for C. difficile.
2. Currently diagnosed or history of uveitis confirmed by either an ophthalmologist or optometrist.
3. Treatment with any medication that causes QT prolongation or Torsades de Pointes, including but not limited to: amiodarone, amitriptyline, astemizole, cisapride, citalopram dose greater than 20 mg/day, dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, ibutilide, ondansetron or other 5-HT3 (5-hydroxytryptamine three) receptor antagonists, pimozide, procainamide, quinidine, quinine, quinolones, ranolazine, risperidone, sotalol, terfenadine and tolterodine. QT prolonging drugs may be referenced at the CredibleMeds® web site: https://crediblemeds.org/index.php/drugsearch/
4. Treatment with the following CYP3A4 interactive medications: alfentanyl, alprazolam, amlodipine, anti-retroviral agents, apixaban, aprepitant, aripiprazole, atorvastatin, boceprevir, buspirone, carbamazepine, carvedilol, colchicine, cyclosporine, digoxin, diltiazem, estrogens, felodipine, fluconazole, fluvoxamine, grapefruit juice, haloperidol, ketoconazole, lovastatin, lurasidone, metoprolol, nefazodone, nifedipine, nisoldipine, nitrendipine, propranol, roflumilast, simvastatin, St. John's wort, and voriconazole.
5. Any evidence of any newly diagnosed significant hematological, hepatic, renal, cardiac, pulmonary, metabolic, neurological, psychiatric or other disease (e.g. porphyria) that might interfere with subject's ability to safely enter and or complete the study requirements.
6. Females who have a positive pregnancy test or are lactating.
7. Refusal to sign the study informed consent form.
8. Inability to be able to adequately communicate with the investigator or their respective designee and/or comply with the requirements of the entire study.

9. Clinically significant abnormalities of hematology or biochemistry as confirmed by repeat testing based on investigator's discretion, including but not limited to, elevations greater than 2 times the upper limit of normal of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) or creatinine clearance less than 60 ml/min at screening via estimated Cockcroft-Gault formula:

   Creatinine Clearance = [140 - age in years] * weight (kg) / 72 * Serum Creatinine (mg/dl) [multiply estimated rate by 0.85 for women], using actual body weight.

10. QTcF (shortening of the QT interval in the heart rate) >450ms in males and QTcF>460ms in females, bundle branch block, or major ST or T wave abnormalities that make the assessment of the QT impossible.

Contacts and Locations

Locations

United States, California

Digestive Care Associates, Inc., 1000 Laurel Street

San Carlos, California, United States, 94070

United States, Georgia

Gastrointestinal Specialists of Georgia PC 711 Canton Rd. #300

Marietta, Georgia, United States, 30060

United States, Kansas

Cotton-O'Neil Clinical Research Center, 720 SW Lane St.

Topeka, Kansas, United States, 66606

United States, Maryland

Chevy Chase Clinical Research, 5550 Friendship Blvd.

Chevy Chase, Maryland, United States, 20815

United States, Massachusetts

Commonwealth Clinical Studies, 189 Quincy St.

Brockton, Massachusetts, United States, 02302-2926

United States, Tennessee

ClinSearch 6035 Shallowford Road Suite 109

Chattanooga, Tennessee, United States, 37421

Canada, British Columbia

Discovery Clinical Services Ltd., 601 A Discovery St.

Victoria, British Columbia, Canada, V8T 5G4

Czechia

Gastroenterologie s.r.o. Manesova 646

Hradec Kralove, Czechia, 500 02

Hepato-Gastroenterologie HK, s.r.o., Hradecka poliklinika III Trida Edvarda Benese 1549/34

Hradec Králové, Czechia, 500 12

Israel

Ha'Emek Medical Center, Institute of Gastroenterology and Liver diseases, 21 Yitshak Rabin Boulevard

Afula, Israel, 1834111

Gastroenterology Institute, Division of Medicine, Hadassah - Hebrew University Medical Center POB 12000

Jerusalem, Israel, 91120

Meir Medial Center, 59 Tchemacovsky St.

Kfar-Saba, Israel, 44281

New Zealand

Christchurch Hospital, 2 Riccarton Rd.

Christchurch, Canterbury, New Zealand, 80011

Waikato Hospital, Department of Gastroenterology, Level B1, Menzies Building, Pembroke Street

Hamilton, Waikato, New Zealand, 3240

Poland

NZOZ Specjalistyczne Centrum Gastrologii GASTROMED, Wiejska 81

Białystok, Poland, 15-351

Samodzielny Publiczny Zakład Opieki Zdrowotnej MSW W Gdańsku Oddział Gastroenterologiczny, Ul. Kartuska 4/6

Gdansk, Poland, 80-104

UNICARDIA Specjalistyczne Centrum Leczenia Chorob Serca i Naczyn & UNIMEDICA. Specjalistyczne Centrum Medyczne Sp. z o.o., Kluczborska 15

Kraków, Poland, 31-271

Wojewodzki Szpital Kliniczny w Olsztynie Oddzial Gastroenterologiczny, Zolnierska 18

Olsztyn, Poland, 10-561

EuroMedis sp. z.o.o., Al. Powstancow Wielkopolskich 33a

Szczecin, Poland, 70-111

Centralny Szpital Kliniczny MSW w Warszawie. Klinika Chorob Wewnetrznych i Gastroenterologii, Woloska 137,

Warsaw, Poland, 02-507

ARS MEDICA s.c., Powstancow Slaskich 56A/2

Wroclaw, Poland, 53-333

Serbia

Clinical Department of Gastroenterology and Hepatology Clinic for Internal Diseases Clinical Hospital Center Zvezdara Dimitrija Tucovica 161

Belgrade, Serbia, 11000

Department of Gastroenterology and Hepatology, Clinical Hospital Center Zemun, Vukova 9

Belgrade, Serbia, 11080

Center for Gastroenterohepatology, Clinic for Internal Medicine, Clinical Center Kragujevac, Zmaj Jovina 30

Kragujevac, Serbia, 34000

Sponsors and Collaborators

RedHill Biopharma Limited

Investigators

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

  Study Documents (Full-Text)

Documents provided by RedHill Biopharma Limited:

Statistical Analysis Plan  [PDF] December 23, 2019

Study Protocol  [PDF] December 16, 2016

More Information

Additional Information:

RedHill home page 

• Responsible Party: RedHill Biopharma Limited
• ClinicalTrials.gov Identifier: NCT03009396
• Other Study ID Numbers: RHB-104-04
• First Posted: January 4, 2017
• Results First Posted: February 24, 2021
• Last Update Posted: February 24, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by RedHill Biopharma Limited:

Crohn's Disease,; moderate to severe; remission; Mycobacterium avium paratuberculosis; antibiotic

Additional relevant MeSH terms:

Paratuberculosis; Crohn Disease; Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Mycobacterium Infections, Nontuberculous; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Clarithromycin; Rifabutin; Clofazimine; Anti-Bacterial Agents; Anti-Infective Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Inflammatory Agents; Leprostatic Agents