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

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

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

Study Overview

• Status: Completed
• Conditions: Crohn Disease
• Intervention / Treatment: Drug: RHB-104 (fixed-dose combination: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine)

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 Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Victoria, British Columbia, Canada, V8T 5G4
      • Discovery Clinical Services Ltd., 601 A Discovery St.
• Czechia
  • Hradec Kralove, Czechia, 500 02
    • Gastroenterologie s.r.o. Manesova 646
  • Hradec Králové, Czechia, 500 12
    • Hepato-Gastroenterologie HK, s.r.o., Hradecka poliklinika III Trida Edvarda Benese 1549/34
• Israel
  • Afula, Israel, 1834111
    • Ha'Emek Medical Center, Institute of Gastroenterology and Liver diseases, 21 Yitshak Rabin Boulevard
  • Jerusalem, Israel, 91120
    • Gastroenterology Institute, Division of Medicine, Hadassah - Hebrew University Medical Center POB 12000
  • Kfar-Saba, Israel, 44281
    • Meir Medial Center, 59 Tchemacovsky St.
• New Zealand
  • Canterbury
    • Christchurch, Canterbury, New Zealand, 80011
      • Christchurch Hospital, 2 Riccarton Rd.
  • Waikato
    • Hamilton, Waikato, New Zealand, 3240
      • Waikato Hospital, Department of Gastroenterology, Level B1, Menzies Building, Pembroke Street
• Poland
  • Białystok, Poland, 15-351
    • NZOZ Specjalistyczne Centrum Gastrologii GASTROMED, Wiejska 81
  • Gdansk, Poland, 80-104
    • Samodzielny Publiczny Zakład Opieki Zdrowotnej MSW W Gdańsku Oddział Gastroenterologiczny, Ul. Kartuska 4/6
  • Kraków, Poland, 31-271
    • UNICARDIA Specjalistyczne Centrum Leczenia Chorob Serca i Naczyn & UNIMEDICA. Specjalistyczne Centrum Medyczne Sp. z o.o., Kluczborska 15
  • Olsztyn, Poland, 10-561
    • Wojewodzki Szpital Kliniczny w Olsztynie Oddzial Gastroenterologiczny, Zolnierska 18
  • Szczecin, Poland, 70-111
    • EuroMedis sp. z.o.o., Al. Powstancow Wielkopolskich 33a
  • Warsaw, Poland, 02-507
    • Centralny Szpital Kliniczny MSW w Warszawie. Klinika Chorob Wewnetrznych i Gastroenterologii, Woloska 137,
  • Wroclaw, Poland, 53-333
    • ARS MEDICA s.c., Powstancow Slaskich 56A/2
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Department of Gastroenterology and Hepatology Clinic for Internal Diseases Clinical Hospital Center Zvezdara Dimitrija Tucovica 161
  • Belgrade, Serbia, 11080
    • Department of Gastroenterology and Hepatology, Clinical Hospital Center Zemun, Vukova 9
  • Kragujevac, Serbia, 34000
    • Center for Gastroenterohepatology, Clinic for Internal Medicine, Clinical Center Kragujevac, Zmaj Jovina 30
• United States
  • California
    • San Carlos, California, United States, 94070
      • Digestive Care Associates, Inc., 1000 Laurel Street
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia PC 711 Canton Rd. #300
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton-O'Neil Clinical Research Center, 720 SW Lane St.
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Chevy Chase Clinical Research, 5550 Friendship Blvd.
  • Massachusetts
    • Brockton, Massachusetts, United States, 02302-2926
      • Commonwealth Clinical Studies, 189 Quincy St.
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • ClinSearch 6035 Shallowford Road Suite 109

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: RHB-104

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients in Remission at 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.	Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response at 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.	Week 16
The Number of Weeks for Patients to Achieve Remission	[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.	Baseline through week 52
Number of Weeks the Patients Are in Remission	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.	Baseline through week 52
Number of Weeks to Achieve Response	[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.	Baseline through week 52
Number of Weeks the Patients Are in Response.	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.	Baseline through week 52
Durable Remission 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.	Week 16 through week 52

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase in Milliseconds (ms) QT Wave	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).	week 52

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

Helpful Links

• RedHill home page

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2017
• Primary Completion (Actual): November 13, 2018
• Study Completion (Actual): August 19, 2019

Study Registration Dates

• First Submitted: December 26, 2016
• First Submitted That Met QC Criteria: December 30, 2016
• First Posted (Estimate): January 4, 2017

Study Record Updates

• Last Update Posted (Actual): February 24, 2021
• Last Update Submitted That Met QC Criteria: February 7, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: antibiotic; remission; moderate to severe; Crohn's Disease,; Mycobacterium avium paratuberculosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Inflammatory Bowel Diseases; Mycobacterium Infections, Nontuberculous; Crohn Disease; Paratuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Rifabutin; Clarithromycin; Clofazimine
• Other Study ID Numbers: RHB-104-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No