Study to Demonstrate Non-Inferior Efficacy and Safety of CinnoRA® Versus Humira® for Treatment of Active RA
Condition: Active Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to compare the efficacy and safety of adalimumab produced by
      CinnaGen company and AbbVie adalimumab in subjects with active Rheumatoid Arthritis. Patients
      with the diagnosis of active Rheumatoid arthritis according to EULAR criteria (European
      League Against Rheumatism) aged between 18 to 75 years will be included. This study is a
      Phase III, randomized, two arms, double-blind (patient and assessor blinded), parallel
      active-controlled non-inferiority clinical trial. The eligible patients are randomized in a
      1:1 ratio to receive CinnoRA® or Humira®. Every two weeks, 40 mg of either of the drugs will
      be administered to each patient subcutaneously along with methotrexate (15 mg/week), folic
      acid (1 mg/day), and prednisolone (7.5 mg/day) over six months.

      The primary objective of the study is to compare the efficacy of test- adalimumab (CinnoRA®)
      and the reference adalimumab (Humira®) in patients with moderately to severely active
      rheumatoid arthritis regarding the evaluation of EULAR criteria based on Disease activity
      score (DAS).

      The secondary objectives of this study are:

        -  To further compare the efficacy of test- adalimumab to reference adalimumab

        -  To assess the safety of test- adalimumab compared to reference adalimumab
    

Detailed description: 
      The purpose of this study is to compare the efficacy and safety of Adalimumab produced by
      CinnaGen company and AbbVie adalimumab in subjects with active rheumatoid arthritis. Patients
      with the diagnosis of active rheumatoid arthritis according to EULAR criteria (European
      League Against Rheumatism) aged between 18 to 75 years will be included. This study is a
      Phase III, randomized, two arms, double-blind (patient and assessor blinded), parallel
      active-controlled non-inferiority clinical trial. The eligible patients will be randomized in
      a 1:1 ratio to receive CinnoRA® or Humira®. Every two weeks, 40 mg of either of the drugs
      will be administered to each patient subcutaneously along with methotrexate (15 mg/week),
      folic acid (1 mg/day), and prednisolone (7.5 mg/day) over six months.

      Physical examinations, vital signs, disease activity, and laboratory parameters will be
      evaluated for patients at baseline and 3 and 6-month visits. The incidence of adverse events
      at each visit will be recorded based on patients' reports, vital signs, physical
      examinations, and laboratory tests.

      The trial is reviewed by food and drug administration of Iran. The protocol, case report form
      (CRF), information for patients, and informed consent form are submitted to the ethics
      committees responsible for review and approval purposes, according to national regulatory
      guidelines.

      In this study, no patient will be recruited without an informed consent form. All the
      informed consent forms which will be signed by the patients will have two copies so that
      patients can receive a copy of it.

      Determination of sample size:

      The outcome measures of this study are changes in composite scores defined by the European
      League against Rheumatism (EULAR) and the American College of Rheumatology criterions. The
      CinnoRA® group proportion is assumed to be 0.7100 under the null hypothesis of inferiority.
      If the response rate of CinnoRA® is at most 18% worse than Humira® (δ = -0.18)
      (non-inferiority margin), it will be considered to be non-inferior. Sample size 64 in both
      Humira and CinnoRA® groups yields 90% power to detect non-inferiority margin. The
      significance level of the test is targeted at 0.0250 (The significance level actually
      achieved by this design is 0.0284).

      DATA QUALITY ASSURANCE:

      CinnaGen Company conducts clinical trials according to procedures that incorporate the
      ethical principles of good clinical practice (GCP). Accurate and reliable data collection is
      assured by verification and cross-check of the CRFs against the patient's records by clinical
      monitors, and the maintenance of a drug-dispensing log by the center.

      Principle and coordinating investigators, contract research organization (CRO) coordinators
      and sponsor personnel attend the investigator meetings, and at the end, they receive a GCP
      certificate.

      CRO coordinators and one sponsor attend the Site Initiation Visit (SIV) meetings. Protocol
      and GCP principles are reviewed by coordinating investigator of each site, and also the
      needed information for completing CRF and Trial Master File (TMF) forms are explained.

      Monitoring by CRO will be performed in 30% and 70% of study progress and at the end of the
      study. In the monitoring sessions, some sponsor personnel will audit the process. During the
      monitoring process, the CRO coordinator will check all CRFs and will confirm them to the
      source documents, and for required cases, the query form will be filled out.

      The temperature of the refrigerator which containing the medicines will be checked and
      recorded by a data logger which will be checked repeatedly by an auditor.

      TMF will be checked by CRO coordinator, and it will be rechecked by an auditor. Drug
      accountability data and information about the proper time for patients' injections will be
      checked by CRO coordinator and rechecked by sponsor personnel.

      After monitoring, problems will be reported by monitor and auditor to the trial centers.

      Blinding:

      The study will be double-blind. The Subjects and those who conduct the study will be unaware
      of the state of the patient with regard to the treatment assignments. For this purpose,
      subjects will be blinded by using a prefilled syringe of Adalimumab, which is quite similar
      to each other. The injection method, injection syringes, and cartridges are totally the same
      in both groups. To blind those who conduct the study, the person who delivers or checks the
      study drug will be different from those who examine the patients. All drugs packages will be
      identified by unique numbers (manufacture code). Finally, the randomization table will be
      concealed from research staff by using opaque sealed envelopes.

      It should be noted that CRO personnel who enter data into CRF and database and also the
      sponsor personnel who monitor data entry will be blinded. The study will be double-blind, and
      situations that might warrant breaking the code are defined in the protocol and include
      serious adverse events.

      Handling of Dropouts or Missing Data:

      Since the number of patients who will participate in this clinical trial is limited and
      small, the investigator can't perform missing imputation analysis and do statistical analysis
      on those patients who are completed the entire study. However, analyses of the adverse events
      will be performed on patients who entered the study.

      In this study, patients with at least one adverse event will be included in the report. For
      each adverse event, data will be summarized using frequencies and percentages and then
      classifies according to the body system. They will be reported in the form of incidence rate.
      In other words, patients with any number of Adverse Events will be counted only once in this
      calculation.
    

Intervention name(s): Adalimumab; Methotrexate; Folic Acid; Prednisolone
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 40 mg Adalimumab every other week is administered subcutaneously to all the patients.; 15 mg Methotrexate is weekly administered to all the patients.; At least 1 mg Folic acid is daily administered to all the patients.; 7.5 mg Prednisolone is daily administered to all the patients.
Intervention MeSH terms: Folic Acid; Prednisolone; Adalimumab; Methotrexate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment