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

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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:
Information provided by (Responsible Party):
RedHill Biopharma Limited

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.

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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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Crohn's Disease
Drug Information available for: Rifabutin

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




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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03009396


Locations
Show Show 24 study locations
Sponsors and Collaborators
RedHill Biopharma Limited
Investigators
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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

Additional Information:
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Responsible Party: RedHill Biopharma Limited
ClinicalTrials.gov Identifier: NCT03009396    
Other Study ID Numbers: RHB-104-04
First Posted: January 4, 2017    Key Record Dates
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

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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:
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Paratuberculosis
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial 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