<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/NCT03283397</url>
  </required_header>
  <id_info>
    <org_study_id>RAP-CS-01</org_study_id>
    <nct_id>NCT03283397</nct_id>
  </id_info>
  <brief_title>A Phase IIIb, Multicenter, International Study to Evaluate the Efficacy, Safety and Tolerability of EK-12 in Patients With RRMS</brief_title>
  <official_title>A Phase IIIb, Multi-center, International, Randomized, Assessor-blind, Active-controlled Parallel Arm Clinical Study to Evaluate the Efficacy, Safety and Tolerability of Neuropeptide Combination of Metenkefalin and Tridecactide (EK-12) in Comparison to Interferon Beta-1a (REBIF®) in Patients With Relapsing Remitting Multiple Sclerosis (RRMS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bosnalijek D.D</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>MonitorCRO</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Bosnalijek D.D</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Multiple sclerosis is a chronic autoimmune, inflammatory neurological disease of the central&#xD;
      nervous system. It is the most common disabling neurologic disease of young people. This&#xD;
      study is planned for the evaluation of efficacy, safety and tolerability of neuropeptide&#xD;
      combination of metenkefalin and tridecactide (EK-12) as compared to INF beta-1a (REBIF®) in&#xD;
      patients with RRMS. The primary objective of this study is to prove the superiority of&#xD;
      efficacy of neuropeptide combination of metenkefalin and tridecactide (EK-12) compared to INF&#xD;
      beta-1a (REBIF®) in patients with RRMS on the basis of annualized protocol defined relapse&#xD;
      rate by 144 weeks.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 26, 2019</start_date>
  <completion_date type="Anticipated">July 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Patients will be randomized to one of the two treatment arms and will be observed during the treatment period of 144 weeks</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>A blinded examining neurologist/assessor will conduct neurological examinations, relapse and EDSS evaluations at each site. Treating investigators will not be blinded to the study treatment. Additionally, blinded evaluation of MRI scans will be performed at a central reading facility in which, anonymized and standardized images of patient with RRMS will be read by a treatment blinded assessor and data will be implemented in a post-hoc analysis for selected time-points.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Superiority of efficacy of EK-12 to interferon beta-1a in patients with RRMS</measure>
    <time_frame>weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144</time_frame>
    <description>The primary objective of this study is to prove the superiority of efficacy of neuropeptide combination of metenkefalin and tridecactide (EK-12) compared to interferon beta-1a (INF beta-1a, 44 mcg, REBIF®) in patients with RRMS on the basis of annualized protocol defined relapse rate (ARR) by 144 weeks.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>EDSS score</measure>
    <time_frame>weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144</time_frame>
    <description>slowing the progression of disability, assessed by EDSS score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>clinical attacks</measure>
    <time_frame>weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144</time_frame>
    <description>reducing the rate of clinical attacks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T2 lesions</measure>
    <time_frame>weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144</time_frame>
    <description>reducing the total number of new and/or enlarging T2-hyperintense lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T1 lesions</measure>
    <time_frame>weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144</time_frame>
    <description>reducing the total number of Gd (+) T1 lesions on MRI scan</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">400</enrollment>
  <condition>Multiple Sclerosis, Relapsing-Remitting</condition>
  <arm_group>
    <arm_group_label>EK-12</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This arm will be treated with 12 mg EK-12 in 2 mL 0.9 % NaCl solution (SC, three times per week) for 144 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>INF Beta-1a</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will be treated with 44 mg INF Beta-1a in 0.5 mL solution (SC, three times per week) for 144 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EK-12</intervention_name>
    <description>10 mg metenkefalin acetate + 2 mg tridecactide acetate in 2 mL 0.9 % NaCl solution.</description>
    <arm_group_label>EK-12</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>INF beta-1a</intervention_name>
    <description>Active substance is INF beta-1a, 44 mcg in 0.5 mL solution</description>
    <arm_group_label>INF Beta-1a</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients from both genders with a confirmed and documented diagnosis of MS as defined&#xD;
             by the Revised McDonald criteria (2010), with relapse onset disease or a&#xD;
             relapsing-remitting disease course, between 18 and 55 years of age at screening&#xD;
             (inclusive).&#xD;
&#xD;
          2. Ambulatory patients with EDSS score of 0 to 4.5 at both screening and randomization&#xD;
             visits.&#xD;
&#xD;
          3. Patients who meet one of the following disease activity criteria:&#xD;
&#xD;
               -  At least 1 documented relapse within the last 12 months prior to screening or;&#xD;
&#xD;
               -  At least 1 documented relapse occurred within the last 24 months prior to&#xD;
                  screening and documented evidence of at least 1 Gadolinium Enhancing (GdE) lesion&#xD;
                  on brain MRI scan within the last 12 months prior to randomization.&#xD;
&#xD;
          4. Patients with a confirmed stable neurological condition, who are relapse-free and not&#xD;
             on a corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os&#xD;
             (PO)] or adrenocorticotrophic hormone (ACTH) treatment, at least 30 days prior to&#xD;
             randomization.&#xD;
&#xD;
          5. Women of child-bearing potential (e.g. women who are not postmenopausal or surgically&#xD;
             sterilized) must practice an acceptable method of birth control for 30 days before&#xD;
             taking the study drug and two acceptable methods of birth control during the duration&#xD;
             of the study and until 30 days after the last dose of study medication. Acceptable&#xD;
             methods of birth control include: intrauterine devices, barrier method (condom with&#xD;
             spermicide or diaphragm with spermicide) and hormonal methods of birth control (e.g.&#xD;
             oral contraceptive, contraceptive patch, and long-acting injectable contraceptive).&#xD;
&#xD;
          6. Patients must be able to sign and date a written Informed Consent Form (ICF) prior to&#xD;
             entering the study.&#xD;
&#xD;
          7. Patients must be willing and able to comply with the study protocol requirements for&#xD;
             the duration of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with progressive forms of MS.&#xD;
&#xD;
          2. Patients with disease duration of ≥10 years.&#xD;
&#xD;
          3. Inability to complete an MRI examination. Contraindications for MRI examination&#xD;
             include but are not restricted to overweight, pacemaker, cochlear implants, presence&#xD;
             of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks&#xD;
             of entry into the study, coronary stent implanted within 8 weeks prior to the time of&#xD;
             the intended MRI, etc.&#xD;
&#xD;
          4. Patients with neuromyelitis optica (NMO) or NMO spectrum disorders.&#xD;
&#xD;
          5. Use of experimental or investigational drugs and/or participation in drug clinical&#xD;
             studies within 6 months prior to randomization.&#xD;
&#xD;
          6. Use of immunosuppressive agents or cytotoxic agents, including cyclophosphamide within&#xD;
             6 months prior to randomization.&#xD;
&#xD;
          7. Use of either of the following agents within 2 years prior to randomization:&#xD;
             natalizumab, rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab.&#xD;
&#xD;
          8. Use of teriflunomide within 2 years prior to randomization, except if active washout&#xD;
             (with either cholestyramine or activated charcoal) was done 2 months or more prior to&#xD;
             randomization.&#xD;
&#xD;
          9. Previous treatment with glatiramer acetate, interferon-beta (either 1a or 1b),&#xD;
             fingolimod, dimethyl fumarate or intravenous immunoglobulin (IVIG) within 2 months&#xD;
             prior to randomization.&#xD;
&#xD;
         10. Chronic (more than 30 consecutive days) systemic (IV, IM or PO) corticosteroid&#xD;
             treatment within 30 days prior to randomization.&#xD;
&#xD;
         11. Previous use of mitoxantrone, cladribine, or alemtuzumab.&#xD;
&#xD;
         12. Previous use of EK-12.&#xD;
&#xD;
         13. Previous total body irradiation or total lymphoid irradiation.&#xD;
&#xD;
         14. Previous stem cell treatment, autologous bone marrow transplantation or allogeneic&#xD;
             bone marrow transplantation.&#xD;
&#xD;
         15. Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to randomization&#xD;
             (Appendix VII provides a list of such medications that are disallowed prior to and&#xD;
             during the study).&#xD;
&#xD;
         16. Use of inducers of CYP3A4 within 2 weeks prior to randomization (Appendix VII provides&#xD;
             a list of such medications that are disallowed prior to and during the study).&#xD;
&#xD;
         17. Pregnancy or breastfeeding.&#xD;
&#xD;
         18. Serum levels ≥3x upper limit of the normal range (ULN) of either alanine&#xD;
             aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.&#xD;
&#xD;
         19. Serum direct bilirubin ≥2x ULN at screening.&#xD;
&#xD;
         20. Patients with clinically significant or unstable medical or surgical condition or any&#xD;
             other condition that cannot be well controlled by the allowed medications permitted by&#xD;
             the study protocol that would preclude safe and complete study participation, as&#xD;
             determined by medical history, physical examinations, Electrocardiography (ECG),&#xD;
             laboratory tests, MRI scan or chest X-ray. Such conditions may include:&#xD;
&#xD;
               1. A major cardiovascular event (e.g. myocardial infarction, acute coronary&#xD;
                  syndrome, de-compensated congestive heart failure, pulmonary embolism, coronary&#xD;
                  revascularization) that occurred during the past 6 months prior to randomization.&#xD;
&#xD;
               2. Any acute pulmonary disorder&#xD;
&#xD;
               3. A Central Nervous System (CNS) disorder other than MS that may jeopardize the&#xD;
                  patient's participation in the study, including such disorders that are&#xD;
                  demonstrated at the baseline MRI scan.&#xD;
&#xD;
         21. Chronic renal insufficiency as Glomerular Filtration Rate (GFR) ≤60 mL/min at the&#xD;
             screening visit.&#xD;
&#xD;
         22. Patients who use haloperidol or dopamine antagonists.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Husnu Efendi, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kocaeli University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Medical Manager</last_name>
    <phone>902122341260</phone>
    <email>murato@monitorcroc.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Kocaeli University, Faculty of Medicine, Department of Neurology</name>
      <address>
        <city>Kocaeli</city>
        <country>Turkey</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Husnu Efendi, Prof</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Turkey</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>September 12, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>February 7, 2023</last_update_submitted>
  <last_update_submitted_qc>February 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03283397
org study id: RAP-CS-01
nct id: NCT03283397
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Multiple sclerosis is a chronic autoimmune, inflammatory neurological disease of the central
      nervous system. It is the most common disabling neurologic disease of young people. This
      study is planned for the evaluation of efficacy, safety and tolerability of neuropeptide
      combination of metenkefalin and tridecactide (EK-12) as compared to INF beta-1a (REBIF®) in
      patients with RRMS. The primary objective of this study is to prove the superiority of
      efficacy of neuropeptide combination of metenkefalin and tridecactide (EK-12) compared to INF
      beta-1a (REBIF®) in patients with RRMS on the basis of annualized protocol defined relapse
      rate by 144 weeks.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be randomized to one of the two treatment arms and will be observed during the treatment period of 144 weeks
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: A blinded examining neurologist/assessor will conduct neurological examinations, relapse and EDSS evaluations at each site. Treating investigators will not be blinded to the study treatment. Additionally, blinded evaluation of MRI scans will be performed at a central reading facility in which, anonymized and standardized images of patient with RRMS will be read by a treatment blinded assessor and data will be implemented in a post-hoc analysis for selected time-points.
measure: Superiority of efficacy of EK-12 to interferon beta-1a in patients with RRMS
time frame: weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144
description: The primary objective of this study is to prove the superiority of efficacy of neuropeptide combination of metenkefalin and tridecactide (EK-12) compared to interferon beta-1a (INF beta-1a, 44 mcg, REBIF®) in patients with RRMS on the basis of annualized protocol defined relapse rate (ARR) by 144 weeks.
measure: EDSS score
time frame: weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144
description: slowing the progression of disability, assessed by EDSS score
measure: clinical attacks
time frame: weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144
description: reducing the rate of clinical attacks
measure: T2 lesions
time frame: weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144
description: reducing the total number of new and/or enlarging T2-hyperintense lesions
measure: T1 lesions
time frame: weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144
description: reducing the total number of Gd (+) T1 lesions on MRI scan
arm group label: EK-12
arm group type: Experimental
description: This arm will be treated with 12 mg EK-12 in 2 mL 0.9 % NaCl solution (SC, three times per week) for 144 weeks
arm group label: INF Beta-1a
arm group type: Active Comparator
description: This arm will be treated with 44 mg INF Beta-1a in 0.5 mL solution (SC, three times per week) for 144 weeks
intervention type: Drug
intervention name: EK-12
description: 10 mg metenkefalin acetate + 2 mg tridecactide acetate in 2 mL 0.9 % NaCl solution.
arm group label: EK-12
intervention type: Drug
intervention name: INF beta-1a
description: Active substance is INF beta-1a, 44 mcg in 0.5 mL solution
arm group label: INF Beta-1a
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: No
last name: Husnu Efendi, Prof
role: Principal Investigator
affiliation: Kocaeli University
last name: Medical Manager
phone: 902122341260
email: murato@monitorcroc.com
facility: 
status: Recruiting
contact: 
country: Turkey
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Relapsing-Remitting
mesh term: Sclerosis
sharing ipd: No