<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01717664</url>
  </required_header>
  <id_info>
    <org_study_id>RHB-104-02</org_study_id>
    <nct_id>NCT01717664</nct_id>
  </id_info>
  <brief_title>Proof of Concept Study of RHB-104 as Add-On Therapy to Interferon Beta-1a in Relapsing Remitting Multiple Sclerosis (RRMS)</brief_title>
  <acronym>CEASE-MS</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>RedHill Biopharma Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>RedHill Biopharma Limited</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators hypothesize that Mycobacterium avium paratuberculosis positive Relapsing&#xD;
      Remitting MS subjects will have a greater response to Interferon beta-1a therapy plus RHB-104&#xD;
      than from Interferon beta-1a alone.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>June 2013</start_date>
  <completion_date type="Actual">July 2016</completion_date>
  <primary_completion_date type="Actual">December 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Combined Unique Active lesions</measure>
    <time_frame>Baseline through Wk 24</time_frame>
  </primary_outcome>
  <other_outcome>
    <measure>Combined Unique Active lesions</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in cytokine panel</measure>
    <time_frame>Baseline to Week 24</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in cytokine panel</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>MAP status as established by polymerase chain reaction (PCR)</measure>
    <time_frame>Baseline to Week 24</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>MAP status as established by polymerase chain reaction (PCR)</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Relapses</measure>
    <time_frame>Baseline to Week 24</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Relapses</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Expanded Disability Status Scale (EDSS)</measure>
    <time_frame>Baseline to Week 24</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Expanded Disability Status Scale (EDSS)</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>T2-hyperintense lesions</measure>
    <time_frame>Baseline to Week 24</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>T2-hyperintense lesions</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>T1 post-gadolinium lesions</measure>
    <time_frame>Baseline to Week 24</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>T1 post-gadolinium lesions</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Burden of Disease</measure>
    <time_frame>Baseline to Week 24</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Burden of Disease</measure>
    <time_frame>Week 24 to Week 48</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Number of participants with adverse events</measure>
    <time_frame>Baseline through Week 24</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Relapsing Remitting Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>RHB-104</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 RHB-104 capsules administered orally BID</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RHB-104</intervention_name>
    <description>95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine</description>
    <arm_group_label>RHB-104</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females aged ≥18 years&#xD;
&#xD;
          -  Signed fully informed consent provided as per this protocol and willing to comply with&#xD;
             the required scheduled assessments of the protocol.&#xD;
&#xD;
          -  Diagnosis of relapsing-remitting multiple sclerosis (McDonald Criteria (2010)) with&#xD;
             dissemination in time and space.&#xD;
&#xD;
          -  Currently treated with a stable dose of Rebif®, or Avonex® for a minimum of 3 months&#xD;
             duration prior to the screening visit.&#xD;
&#xD;
          -  Active MS with history of at least one flare within the past 12 months or two flares&#xD;
             in the past 24 months prior to screening.&#xD;
&#xD;
          -  An Expanded Disability Status Scale (EDSS) of 6.0 or less at the screening visit.&#xD;
&#xD;
          -  White blood cell count ≥ to 3.5x109.&#xD;
&#xD;
          -  Subject agrees to use barrier contraceptive methods (i.e. diaphragm, cervical cap,&#xD;
             contraceptive sponge or condom) with spermicidal foam/gel/cream/suppository, or IUD&#xD;
             from study enrolment through 6 weeks after last dose of study medication, unless&#xD;
             subject is post-menopausal or otherwise incapable of becoming pregnant by reason of&#xD;
             surgery or tubal ligation, or has had a vasectomy. Subject agrees to appropriate&#xD;
             contraception method though completion of study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Treatment with any other biological therapies including but not limited to Interferon&#xD;
             beta-1b, natalizumab, anti-TNF biologic agents, or other agents intended to reduce TNF&#xD;
             ≤ 8 weeks prior to screening or within 5 half-lives of agent prior to screening,&#xD;
             whichever is longer.&#xD;
&#xD;
          -  Previous treatment with rifabutin and/or clofazimine.&#xD;
&#xD;
          -  Previous treatment with amiodarone.&#xD;
&#xD;
          -  Oral or parenteral antibiotics in the 4 weeks prior to screening. (Topical antibiotics&#xD;
             are permitted.)&#xD;
&#xD;
          -  Use of Methylprednisolone sodium succinate, prednisone, or any other corticosteroid&#xD;
             during the 30 days prior to screening.&#xD;
&#xD;
          -  Relapse within the 30 days prior to screening, or between screening and baseline.&#xD;
&#xD;
          -  Initiation or dose modification of 4-aminopyridine within 60 days of screening.&#xD;
&#xD;
          -  Use of azathioprine, 6-mercaptopurine (6-MP), methotrexate, cyclosporine or&#xD;
             mycophenolate (CellCept) within 8 weeks prior to screening.&#xD;
&#xD;
          -  Use of glatiramer acetate, cyclophosphamide, or plasma exchange within 12 weeks prior&#xD;
             to screening.&#xD;
&#xD;
          -  Use of mitoxantrone within one year prior to screening.&#xD;
&#xD;
          -  Any previous treatment with cladribine, T cell vaccine, or altered peptide ligand.&#xD;
&#xD;
          -  Previous total body irradiation or total lymphoid irradiation.&#xD;
&#xD;
          -  Treatment with any medication that causes QT prolongation or Torsades de Pointes&#xD;
             within 7 days prior to initiation of study drug, including but not limited to:&#xD;
             Cisapride, pimozide, astemizole, terfenadine, ergotamine, dihydroergotamine,&#xD;
             quinidine, procainamide, disopyramide, sotalol, ibutilde, dofetilide, dronedarone,&#xD;
             ondansetron or other 5-HT3 receptor agonists, citalopram dose greater than 20 mg/day,&#xD;
             tolteridine and quinine.&#xD;
&#xD;
          -  Treatment with the following medications within 7 days prior to initiation of study&#xD;
             drug: colchicine, roflumilast, apixabin, latuda, nefazodone, buspirone, fluvoxamine,&#xD;
             simvastatin, lovastatin, atorvastatin, amlodipine, diltiazem, felodipine, nifedipine,&#xD;
             nitrendipine, nisoldipine, fluconazole, ketoconazole, voriconazole, St. Johns wort,&#xD;
             grapefruit juice, antiretroviral agents, alprazolam, alfentanyl, aprepitant,&#xD;
             aripiprazole, cyclosporine, boceprevir, carbamazepine, haloperidol, digoxin,&#xD;
             propranolol, carvedilol, metoprolol, and estrogens.&#xD;
&#xD;
          -  Adverse reaction or hypersensitivity to the study drug or any medications related to&#xD;
             the study drug.&#xD;
&#xD;
          -  Clinically significant abnormalities of hematology or chemistry at screening as&#xD;
             confirmed by repeat testing based on investigator's discretion, including but not&#xD;
             limited to, elevations greater than 2 times the upper limit of normal of Aspartate&#xD;
             Aminotransferase (AST), Alanine Aminotransferase (ALT), or creatinine clearance less&#xD;
             than 60 ml/min at screening.&#xD;
&#xD;
          -  Serum potassium, magnesium or calcium outside the normal reference range considered&#xD;
             clinically significant by the investigator.&#xD;
&#xD;
          -  Positive stool results for C. difficile.&#xD;
&#xD;
          -  A positive serology for Hepatitis B, Hepatitis C or HIV at screening except for the&#xD;
             following:&#xD;
&#xD;
        If positive history of previously treated Hepatitis C, but HCV PCR is undetectable off&#xD;
        medications for at least 6 months prior to screening, and treating hepatologist or&#xD;
        infectious disease specialist believes the subject is cured - subject may be enrolled&#xD;
&#xD;
          -  One of the following:&#xD;
&#xD;
        History of atypical mycobacterial infections (other than MAP). History of active&#xD;
        tuberculosis (TB) requiring treatment in the past 3 years. Tuberculosis infection as&#xD;
        determined by a positive diagnostic TB test result (defined as a positive or indeterminate&#xD;
        (after two independent tests) quantiFERON TB Test Gold test).&#xD;
&#xD;
          -  Currently diagnosed or history of uveitis confirmed by either an ophthalmologist or&#xD;
             optometrist.&#xD;
&#xD;
          -  Any evidence of any other significant hematological, hepatic, renal, cardiac,&#xD;
             pulmonary, metabolic, thyroid, neurological or psychiatric disease that might&#xD;
             interfere with the subject's ability to safely enter and or complete the study&#xD;
             requirements.&#xD;
&#xD;
          -  History of malignancy within the past five years except for basal cell carcinoma of&#xD;
             the skin or carcinoma in situ of the cervix that has been treated with no evidence of&#xD;
             recurrence.&#xD;
&#xD;
          -  Males who do not use barrier contraceptive methods (i.e. condom) with spermicidal&#xD;
             foam/gel/cream/suppository or have not had a vasectomy.&#xD;
&#xD;
          -  Females who:&#xD;
&#xD;
               1. have a positive pregnancy test&#xD;
&#xD;
               2. are lactating&#xD;
&#xD;
          -  Refusal to sign the study informed consent form.&#xD;
&#xD;
          -  Inability to adequately communicate with the investigator or their respective designee&#xD;
             and/or comply with the requirements of the entire study.&#xD;
&#xD;
          -  History of drug or alcohol abuse within the past 3 years.&#xD;
&#xD;
          -  Participation in any experimental drug protocol within 12 weeks of date of screening.&#xD;
&#xD;
          -  Cardiac pacemaker or any other type of metal implant or any other contraindication for&#xD;
             MRI (including known allergy to gadolinium).&#xD;
&#xD;
          -  QTc greater than 440ms, bundle branch block, or major ST or T wave abnormalities that&#xD;
             make the assessment of the QT impossible.&#xD;
&#xD;
          -  History of unstable cardiac syndromes including unstable angina, coronary artery&#xD;
             bypass graft, myocardial infarction or coronary stenting within 2 months of screening;&#xD;
             NYHA Class 3-4 CHF; history of ventricular tachycardia, ventricular fibrillation,&#xD;
             personal or family history of sudden death, Long QT Syndrome, or Torsade de Pointes;&#xD;
             HR&lt;50BPM; having taken any Class 1 or Class 3 antiarrhythmic medications or medicines&#xD;
             known to prolong the QT interval or be associated with Torsade de Pointes.&#xD;
&#xD;
          -  Treatment with medical cannabis in the 4 weeks prior to screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ira N Kalfus, MD</last_name>
    <role>Study Director</role>
    <affiliation>RedHill Biopharma</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Radi Shahien, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ziv Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>RedHill MS Clinical Trial Site 002</name>
      <address>
        <city>Tel Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>RedHill MS Clinical Trials Site 001</name>
      <address>
        <city>Zefat (Safed)</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>July 2016</verification_date>
  <study_first_submitted>October 24, 2012</study_first_submitted>
  <study_first_submitted_qc>October 26, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 30, 2012</study_first_posted>
  <last_update_submitted>July 27, 2016</last_update_submitted>
  <last_update_submitted_qc>July 27, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 28, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Relapsing Remitting Multiple Sclerosis</keyword>
  <keyword>MAP</keyword>
  <keyword>antibiotic</keyword>
  <keyword>Interferon beta 1-a</keyword>
  <keyword>MS</keyword>
  <keyword>MRI</keyword>
  <keyword>EDSS</keyword>
  <keyword>relapse rate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Multiple Sclerosis, Relapsing-Remitting</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01717664
org study id: RHB-104-02
nct id: NCT01717664
lead sponsor: 
has dmc: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Combined Unique Active lesions
time frame: Baseline through Wk 24
measure: Combined Unique Active lesions
time frame: Week 24 to Week 48
measure: Change in cytokine panel
time frame: Baseline to Week 24
measure: Change in cytokine panel
time frame: Week 24 to Week 48
measure: MAP status as established by polymerase chain reaction (PCR)
time frame: Baseline to Week 24
measure: MAP status as established by polymerase chain reaction (PCR)
time frame: Week 24 to Week 48
measure: Relapses
time frame: Baseline to Week 24
measure: Relapses
time frame: Week 24 to Week 48
measure: Expanded Disability Status Scale (EDSS)
time frame: Baseline to Week 24
measure: Expanded Disability Status Scale (EDSS)
time frame: Week 24 to Week 48
measure: T2-hyperintense lesions
time frame: Baseline to Week 24
measure: T2-hyperintense lesions
time frame: Week 24 to Week 48
measure: T1 post-gadolinium lesions
time frame: Baseline to Week 24
measure: T1 post-gadolinium lesions
time frame: Week 24 to Week 48
measure: Burden of Disease
time frame: Baseline to Week 24
measure: Burden of Disease
time frame: Week 24 to Week 48
measure: Number of participants with adverse events
time frame: Baseline through Week 24
arm group label: RHB-104
arm group type: Experimental
description: 5 RHB-104 capsules administered orally BID
intervention type: Drug
intervention name: RHB-104
description: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine
arm group label: RHB-104
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ira N Kalfus, MD
role: Study Director
affiliation: RedHill Biopharma
last name: Radi Shahien, MD
role: Principal Investigator
affiliation: Ziv Medical Center
facility: 
facility: 
country: Israel
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Relapsing-Remitting
mesh term: Sclerosis