Open Label Efficacy and Safety of Anti-MAP (Mycobacterium Avium Ssp. Paratuberculosis) Therapy in Adult Crohn's Disease
Condition: Crohn Disease
MeSH terms: Paratuberculosis; Crohn Disease
Intervention: RHB-104 (fixed-dose combination: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine)
Intervention description: For patients on ACTIVE or PLACEBO in the parent study (RHB-104-01), who were not in remission after 26 weeks
Intervention MeSH terms: Clarithromycin; Rifabutin; Clofazimine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Active
Masking: None (Open Label)
Enrollment: 54.0
Sex: All
Minimum age: 18 Years
Maximum age: 76 Years
Healthy volunteers: No
Keywords: Crohn's Disease,; moderate to severe; remission; Mycobacterium avium paratuberculosis; antibiotic

Summary:

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

Eligibility 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.