Efficacy and Safety of Peginterferon Beta-1a (CinnaGen) in Participants With Relapsing Remitting Multiple Sclerosis
Condition: Relapsing Remitting Multiple Sclerosis (RRMS)
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to evaluate the efficacy and safety of peginterferon beta-1a
      produced by CinnaGen compared with CinnoVex® (CinnaGen) in subjects with relapsing remitting
      multiple sclerosis (RRMS). All the participants will receive one of the following regimens:
      pegylated interferon beta-1a (CinnaGen), autoinjector (Physioject™), 125mcg, subcutaneous,
      every 2 weeks for 24 months or CinnoVex® (CinnaGen), prefilled syringes, 30mcg,
      intramuscular, once a week for 24 months. The primary objective of this study is to verify
      the non-inferiority of peginterferon beta-1a (CinnaGen) versus CinnoVex® (CinnaGen) in
      reducing the annualized relapse rate (ARR) in participants with relapsing remitting multiple
      sclerosis (RRMS) at 2 years.

      The secondary objectives of this study are:

        -  Reducing the total number of new or newly enlarging T2 hyperintense lesions on brain
           magnetic resonance imaging (MRI) scans

        -  Slowing the progression of disability

        -  Comparing adverse events
    

Detailed description: 
      The purpose of this phase III, randomized, active control, parallel, non-inferiority,
      multicenter study is to verify the non-inferiority of peginterferon beta-1a produced by
      CinnaGen versus CinnoVex® (CinnaGen) in subjects with relapsing remitting multiple sclerosis
      (RRMS).

      All the participants will receive one of the following regimens:

      I. Pegylated interferon beta-1a (CinnaGen), autoinjector (Physioject™), 125mcg, subcutaneous,
      every 2 weeks for 24 months; II. Interferon beta-1a, CinnoVex® (CinnaGen), prefilled
      syringes, 30mcg, intramuscular, once a week for 24 months.

      With the aim of ensuring the compliance and safety, in the first two months of the study, in
      each monthly visit, a trained expert nurse will be responsible for drug injection for both
      intervention groups and will train all patients for self-injection. By the end of the first
      two months to the end of the study, patients will self-inject the medication in both groups.

      All other cares or medications will be allowed to continue by patients, except for disease
      modifying therapies (DMTs) and medicines which affect the immune system (e.g.
      immunosuppressants and immunomodulators). Any concomitant medication will be recorded for
      patients in their regular visits.

      The primary objective of this study is to verify the non-inferiority of peginterferon beta-1a
      (CinnaGen) versus CinnoVex® (CinnaGen) in reducing the annualized relapse rate (ARR) in
      participants with relapsing remitting multiple sclerosis (RRMS) at 2 years.

      The secondary objectives of this study are:

        -  Reducing the total number of new or newly enlarging T2 hyperintense lesions on brain
           magnetic resonance imaging (MRI) scans

        -  Slowing the progression of disability

        -  Comparing safety issues

      Sample size:

      Group sample sizes of 76 in the experimental group and 76 in the active comparator group will
      achieve almost 80% power to detect non-inferiority using a one-sided, two-sample t-test. The
      margin of non-inferiority is 0.17. The true ratio of the means at which the power is
      evaluated is 1.00. The significance level of the test is 0.05. The coefficients of variation
      of both groups are assumed to be 0.4. The dropout rate is assumed to be 10%; hence 168
      patients will be randomized.

      Sequence generation:

      The randomization plan of the patients will be carried out centrally using Cran-R version
      3.2.3. Using permuted block randomization, blocks (length of each block is 4 or 2) will be
      made, for a total of 168 patients with 1:1 allocation ratio. Once the randomization has been
      made, each patient is given a code with which he/she will be identified throughout the study.
      The assigned code will be made up of 3 numbers (corresponding to the randomization number)
      and by 4 initials (corresponding to the 2 first letter of the first name, the 2 first letter
      of the first surname) and 2 numbers (center code). The randomization number will be assigned
      in a consecutive way.

      Blinding:

      Because of the different routes of administration of drugs in the study groups, patient
      blinding is not possible.

      Data management:

      Principal investigator is responsible for safe keeping of all patients' records at all times.
      Original hard copies of case report forms (CRFs) will be sent to Clinical Trial Consultants
      (CTCs) upon request and at the end of the study for data management. A copy of the records
      will be kept at the center. Sending and receiving of all patients' documents will be made
      after taking into consideration safety and security issues.

      Principal investigator should set necessary schemes to control the quality of:

        -  Drug delivery, storage and handling

        -  All clinical examinations

        -  Laboratory tests and other paraclinical investigations

        -  Patient care

      Data monitoring:

      The objectives of the data quality control (QC) are:

        -  To ensure the existence of the patients and the respect of ethics, including signed
           patient informed consent forms (ICFs)

        -  To identify the issues, including systematic issues, as early as possible for
           appropriate setting of action plans and corrective actions

        -  To ensure the validity of the data To meet these objectives, the possibility of the
           sites' QC must be explained to the investigators at the time of the study initiation and
           agreed by them. QC will be performed on sites by the Local Study Teams.

      QC will be started after inclusion of 30% of patients and will be ended before 80% of
      inclusion.

      Two levels of QC will be performed:

      Quality of CRF completion: At the time of CRF reception, the Local Study Team will review the
      completed CRFs in order to assess the completeness and the quality of completion. The Local
      Study Team (monitor or designee) is responsible to set up an action plan in order to improve
      the quality at site level. In case of systematic issue, the Local Study Team will inform the
      Corporate Study Team.

      Central database checks: In addition to the standard data management activities, the
      following parameters will be systematically assessed as a part of the QC of the study, in
      country- and site-levels by the Study Central Team:

        -  Signed ICFs

        -  Rates of error and missing data for the key variables

        -  Completion of the patients' questionnaire

        -  Enough clarity of the forms During the QC visit, the monitor will have to complete a QC
           visit report.

      Principal investigators should set necessary schemes to control the quality of:

        -  Signed ICF

        -  Drug delivery, storage and handling

        -  All clinical examinations

        -  Laboratory tests and other paraclinical investigations

        -  Patient care

      Research ethics approval:

        -  Ethics committee approval is mandatory for this study to commence.

        -  No patient will be recruited to this study without an informed consent.

        -  It will be made clear to all patients that they can leave the study any time they desire
           with no need for any explanation.

        -  To keep confidentiality in case of a lost document, the name and surname of the patients
           will not appear on evaluation forms.

        -  Adverse effect report forms will be processed after each visit. Research team is
           responsible for dealing with immediate aftermath of any adverse event regardless of
           whether or not the event is directly related to the medication that is being studied.

        -  All serious adverse events should be reported to DSMB (Data and Safety Monitoring
           Board). The board is responsible for making necessary decisions to deal with the
           situation. These decisions may include determining the relationship between the drug and
           the observed adverse event.

        -  The protocol, CRF, information for patients and informed consent forms will be submitted
           to the ethics committees responsible for the investigators in TUMS, for review and
           approval according to the national regulatory guidelines.
    

Intervention name(s): Pegylated interferon beta-1a; Interferon Beta-1A Prefilled Syringe
Intervention type(s): Drug; Drug
Intervention description(s): Pegylated interferon beta-1a (CinnaGen) autoinjector (Physioject™),125 mcg, subcutaneous (SC) injection, every 2 weeks, for 24 months; Interferon Beta-1A Prefilled Syringe, CinnoVex® (CinnaGen), 30 mcg, intramuscular injection, once a week, for 24 months
Other intervention name(s): CinnoVex®
Intervention MeSH terms: Interferons; Interferon-beta; Interferon beta-1a
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment