Proof of Concept Study of RHB-104 as Add-On Therapy to Interferon Beta-1a in Relapsing Remitting Multiple Sclerosis (RRMS) (CEASE-MS)

• ClinicalTrials.gov Identifier: NCT01717664
• Recruitment Status: Completed
• First Posted: October 30, 2012
• Last Update Posted: July 28, 2016
• Sponsor: RedHill Biopharma Limited
• Information provided by (Responsible Party): RedHill Biopharma Limited

Study Description

Brief Summary:

The investigators hypothesize that Mycobacterium avium paratuberculosis positive Relapsing Remitting MS subjects will have a greater response to Interferon beta-1a therapy plus RHB-104 than from Interferon beta-1a alone.

Condition or disease	Intervention/treatment	Phase
Relapsing Remitting Multiple Sclerosis	Drug: RHB-104	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IIa Proof of Concept Study to Assess the Efficacy and Safety of Fixed Dose Combination RHB-104 as Add-On Therapy to Interferon Beta-1a in Patients Treated for Relapsing Remitting Multiple Sclerosis
• Study Start Date: June 2013
• Actual Primary Completion Date: December 2015
• Actual Study Completion Date: July 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: RHB-104; 5 RHB-104 capsules administered orally BID	Drug: RHB-104; 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

Outcome Measures

Primary Outcome Measures :

1. Combined Unique Active lesions [ Time Frame: Baseline through Wk 24 ]

Other Outcome Measures:

1. Combined Unique Active lesions [ Time Frame: Week 24 to Week 48 ]
2. Change in cytokine panel [ Time Frame: Baseline to Week 24 ]
3. Change in cytokine panel [ Time Frame: Week 24 to Week 48 ]
4. MAP status as established by polymerase chain reaction (PCR) [ Time Frame: Baseline to Week 24 ]
5. MAP status as established by polymerase chain reaction (PCR) [ Time Frame: Week 24 to Week 48 ]
6. Relapses [ Time Frame: Baseline to Week 24 ]
7. Relapses [ Time Frame: Week 24 to Week 48 ]
8. Expanded Disability Status Scale (EDSS) [ Time Frame: Baseline to Week 24 ]
9. Expanded Disability Status Scale (EDSS) [ Time Frame: Week 24 to Week 48 ]
10. T2-hyperintense lesions [ Time Frame: Baseline to Week 24 ]
11. T2-hyperintense lesions [ Time Frame: Week 24 to Week 48 ]
12. T1 post-gadolinium lesions [ Time Frame: Baseline to Week 24 ]
13. T1 post-gadolinium lesions [ Time Frame: Week 24 to Week 48 ]
14. Burden of Disease [ Time Frame: Baseline to Week 24 ]
15. Burden of Disease [ Time Frame: Week 24 to Week 48 ]
16. Number of participants with adverse events [ Time Frame: Baseline through Week 24 ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Males and females aged ≥18 years
• Signed fully informed consent provided as per this protocol and willing to comply with the required scheduled assessments of the protocol.
• Diagnosis of relapsing-remitting multiple sclerosis (McDonald Criteria (2010)) with dissemination in time and space.
• Currently treated with a stable dose of Rebif®, or Avonex® for a minimum of 3 months duration prior to the screening visit.
• Active MS with history of at least one flare within the past 12 months or two flares in the past 24 months prior to screening.
• An Expanded Disability Status Scale (EDSS) of 6.0 or less at the screening visit.
• White blood cell count ≥ to 3.5x109.
• Subject agrees to use barrier contraceptive methods (i.e. diaphragm, cervical cap, contraceptive sponge or condom) with spermicidal foam/gel/cream/suppository, or IUD from study enrolment through 6 weeks after last dose of study medication, unless subject is post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy. Subject agrees to appropriate contraception method though completion of study.

Exclusion Criteria:

• Treatment with any other biological therapies including but not limited to Interferon beta-1b, natalizumab, anti-TNF biologic agents, or other agents intended to reduce TNF ≤ 8 weeks prior to screening or within 5 half-lives of agent prior to screening, whichever is longer.
• Previous treatment with rifabutin and/or clofazimine.
• Previous treatment with amiodarone.
• Oral or parenteral antibiotics in the 4 weeks prior to screening. (Topical antibiotics are permitted.)
• Use of Methylprednisolone sodium succinate, prednisone, or any other corticosteroid during the 30 days prior to screening.
• Relapse within the 30 days prior to screening, or between screening and baseline.
• Initiation or dose modification of 4-aminopyridine within 60 days of screening.
• Use of azathioprine, 6-mercaptopurine (6-MP), methotrexate, cyclosporine or mycophenolate (CellCept) within 8 weeks prior to screening.
• Use of glatiramer acetate, cyclophosphamide, or plasma exchange within 12 weeks prior to screening.
• Use of mitoxantrone within one year prior to screening.
• Any previous treatment with cladribine, T cell vaccine, or altered peptide ligand.
• Previous total body irradiation or total lymphoid irradiation.
• Treatment with any medication that causes QT prolongation or Torsades de Pointes within 7 days prior to initiation of study drug, including but not limited to: Cisapride, pimozide, astemizole, terfenadine, ergotamine, dihydroergotamine, quinidine, procainamide, disopyramide, sotalol, ibutilde, dofetilide, dronedarone, ondansetron or other 5-HT3 receptor agonists, citalopram dose greater than 20 mg/day, tolteridine and quinine.
• Treatment with the following medications within 7 days prior to initiation of study drug: colchicine, roflumilast, apixabin, latuda, nefazodone, buspirone, fluvoxamine, simvastatin, lovastatin, atorvastatin, amlodipine, diltiazem, felodipine, nifedipine, nitrendipine, nisoldipine, fluconazole, ketoconazole, voriconazole, St. Johns wort, grapefruit juice, antiretroviral agents, alprazolam, alfentanyl, aprepitant, aripiprazole, cyclosporine, boceprevir, carbamazepine, haloperidol, digoxin, propranolol, carvedilol, metoprolol, and estrogens.
• Adverse reaction or hypersensitivity to the study drug or any medications related to the study drug.
• Clinically significant abnormalities of hematology or chemistry at screening 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), or creatinine clearance less than 60 ml/min at screening.
• Serum potassium, magnesium or calcium outside the normal reference range considered clinically significant by the investigator.
• Positive stool results for C. difficile.
• A positive serology for Hepatitis B, Hepatitis C or HIV at screening except for the following:

If positive history of previously treated Hepatitis C, but HCV PCR is undetectable off medications for at least 6 months prior to screening, and treating hepatologist or infectious disease specialist believes the subject is cured - subject may be enrolled

• One of the following:

History of atypical mycobacterial infections (other than MAP). History of active tuberculosis (TB) requiring treatment in the past 3 years. Tuberculosis infection as determined by a positive diagnostic TB test result (defined as a positive or indeterminate (after two independent tests) quantiFERON TB Test Gold test).

• Currently diagnosed or history of uveitis confirmed by either an ophthalmologist or optometrist.
• Any evidence of any other significant hematological, hepatic, renal, cardiac, pulmonary, metabolic, thyroid, neurological or psychiatric disease that might interfere with the subject's ability to safely enter and or complete the study requirements.
• History of malignancy within the past five years except for basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been treated with no evidence of recurrence.
• Males who do not use barrier contraceptive methods (i.e. condom) with spermicidal foam/gel/cream/suppository or have not had a vasectomy.

• Females who:

  1. have a positive pregnancy test
  2. are lactating
• Refusal to sign the study informed consent form.
• Inability to adequately communicate with the investigator or their respective designee and/or comply with the requirements of the entire study.
• History of drug or alcohol abuse within the past 3 years.
• Participation in any experimental drug protocol within 12 weeks of date of screening.
• Cardiac pacemaker or any other type of metal implant or any other contraindication for MRI (including known allergy to gadolinium).
• QTc greater than 440ms, bundle branch block, or major ST or T wave abnormalities that make the assessment of the QT impossible.
• History of unstable cardiac syndromes including unstable angina, coronary artery bypass graft, myocardial infarction or coronary stenting within 2 months of screening; NYHA Class 3-4 CHF; history of ventricular tachycardia, ventricular fibrillation, personal or family history of sudden death, Long QT Syndrome, or Torsade de Pointes; HR<50BPM; having taken any Class 1 or Class 3 antiarrhythmic medications or medicines known to prolong the QT interval or be associated with Torsade de Pointes.
• Treatment with medical cannabis in the 4 weeks prior to screening.

Contacts and Locations

Locations

Israel

RedHill MS Clinical Trial Site 002

Tel Aviv, Israel

RedHill MS Clinical Trials Site 001

Zefat (Safed), Israel

Sponsors and Collaborators

RedHill Biopharma Limited

Investigators

• Study Director: Ira N Kalfus, MD; RedHill Biopharma
• Principal Investigator: Radi Shahien, MD; Ziv Medical Center

More Information

• Responsible Party: RedHill Biopharma Limited
• ClinicalTrials.gov Identifier: NCT01717664
• Other Study ID Numbers: RHB-104-02
• First Posted: October 30, 2012
• Last Update Posted: July 28, 2016
• Last Verified: July 2016

Keywords provided by RedHill Biopharma Limited:

Relapsing Remitting Multiple Sclerosis; MAP; antibiotic; Interferon beta 1-a; MS; MRI; EDSS; relapse rate

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases