Study to Demonstrate Non-Inferior Efficacy and Safety of CinnoRA® Versus Humira® for Treatment of Active RA

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase III, Randomized, Two-armed, Double-blind, Parallel, Active Controlled Clinical Trial to Determine the Non-inferior Efficacy and Safety of CinnoRA® (Adalimumab, CinnaGen Co.) Versus Humira® for Treatment of Active RA

Conditions
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Active Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Adalimumab
* Drug: Methotrexate
* Drug: Folic Acid
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18-75 years at the time of signing the informed consent form. Have been diagnosed as having active rheumatoid arthritis (RA) according to The European League Against Rheumatism criteria moderately to severely active RA for at least six months Patients who have an inadequate response to the treatment with the usual non-biological regimen for at least 12 weeks according to their investigator judgment. Ability to comprehend and willingness to sign the Informed Consent Form for this study. Exclusion Criteria: Tuberculosis patient or latent tuberculosis patient (PPD >5mm or abnormal Chest X-ray) Have been treated previously with any biological agents including any tumor necrosis factor inhibitors (including ORENCIA® (abatacept), KINERET® (anakinra), REMICADE® (infliximab), ENBREL® (etanercept), CIMZIA® (certolizumab pegol), SIMPONI® (golimumab), or Adalimumab). Have a known hypersensitivity to human immunoglobulin proteins or other components of Humira or test- Adalimumab Women who are pregnant, breastfeeding or planning to become pregnant during the study Have a positive serological test for hepatitis B or hepatitis C or have a known history of infection with human immunodeficiency virus (HIV) of the past three months. Physical incapacitation (ACR functional Class IV or wheelchair-/bed-bound) Have had a serious infection or have been treated with intravenous antibiotics for an infection within eight weeks or oral antibiotics within two weeks prior to screening Have a history of chronic or recurrent infection Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > two times upper limit of normal. Hemoglobin <8.5 g/dL. Platelets <125,000/µL. Leukocyte count <3500/µL. Serum Creatinine>2 mg/dl Concomitant use of Prednisolone > 10 mg/day and NSAIDs Treatment with intravenous, intramuscular, intra-articular and oral corticosteroids within four weeks prior to Day 1 (prednisolone, more than 7.5 mg/daily) Ever used RITUXAN® (rituximab), IMURAN® (azathioprine), or PURINETHOL® (mercaptopurine, 6-MP). Have any of the following conditions: History of congestive heart failure. History of acute myocardial infarction or unstable angina within the previous 12 months prior to Screening. History of demyelinating disorders (e.g., MS) History of multiple sclerosis History of any malignancy within the previous five years prior to Screening. Any other disease or disorder which, in the opinion of the Investigator, will put the subject at risk if they are enrolled.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CinnaGen adalimumab<br>CinnoRA® (adalimumab Prefilled Syringe produced by CinnaGen Company) 40 mg/0.8 ml Every other week 40 mg Adalimumab, will be subcutaneously administered to rheumatic patients during six months. Along with, 15 mg weekly methotrexate, at least 1 mg daily Folic acid and 7.5 mg daily Prednisolone over six months. | Drug: Adalimumab<br>* 40 mg Adalimumab every other week is administered subcutaneously to all the patients.<br>Drug: Methotrexate<br>* 15 mg Methotrexate is weekly administered to all the patients.<br>Drug: Folic Acid<br>* At least 1 mg Folic acid is daily administered to all the patients.<br>Drug: Prednisolone<br>* 7.5 mg Prednisolone is daily administered to all the patients.<br>|
| Active Comparator: AbbVie adalimumab<br>Humira® (adalimumab Prefilled Syringe produced by AbbVie Company) 40 mg/0.8 ml Every other week 40 mg Adalimumab, will be subcutaneously administered to rheumatic patients during six months. Along with, 15 mg weekly methotrexate, at least 1 mg daily Folic acid and 7.5 mg daily Prednisolone over six months. | Drug: Adalimumab<br>* 40 mg Adalimumab every other week is administered subcutaneously to all the patients.<br>Drug: Methotrexate<br>* 15 mg Methotrexate is weekly administered to all the patients.<br>Drug: Folic Acid<br>* At least 1 mg Folic acid is daily administered to all the patients.<br>Drug: Prednisolone<br>* 7.5 mg Prednisolone is daily administered to all the patients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With DAS28-EULAR Good and Moderate Responses at Week 24 | The primary variables are the percentage of patients with DAS28-EULAR Good and Moderate Responses at week 24 compared with Humira. Moderate response is defined as decrement of more than 1.2 in patient's DAS score while patient's DAS score is equal to or more than 3.2 or decrement of 0.6-1.2 while patient's DAS score is equal to or below 5.1. Good response is defined as decrement of more than 1.2 in patient's DAS score while patient's DAS score is below 3.2. We used the Disease Activity Score-28 for rheumatoid arthritis with erythrocyte sedimentation rate (DAS28-ESR) to assess disease activity in patients with rheumatoid arthritis. This score ranges from 2 to 10, and higher values indicate higher disease activity. DAS28-ESR is calculated with the following formula: DAS28-ESR= (0.56*√(Tender Joint Count)+0.28*√(Swollen Joint Count)+0.7*ln(ESR)+0.014*(global health)) | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Achieving ACR20, ACR50 and ACR70 Response Rates at Week 24 | ACR20, ACR50, and ACR70 Response Rates are considered as respectively an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score from Baseline at Week 24. | Week 24 | 
| Health Assessment Questionnaire (HAQ) Disability Index at Week 24. | Quality of life is assessed using the Health Assessment Questionnaire (HAQ). The HAQ is a self-reported scale used in studies of rheumatoid arthritis to assess areas such as dressing/grooming, arising, eating, walking, reach, grip, maintaining hygiene, and daily activities. There are 20 questions in the mentioned 8 sections. In each section, the highest score is considered as the main answer. Scores should be between 0 and 3 and the final answer is the average of scores relating to all sections. An increased score indicates a worsening of the disability. The disability index of Health Assessment Questionnaire (HAQ) at week 24 is reported. | Week 24 | 
| The Incidence of Adverse Events | The incidence of adverse events at each visit is recorded based on patients' reports, vital signs, physical examinations, and laboratory tests for systemic safety, including liver function, renal function, complete blood count and clinical chemistries, urinalysis, and hematologic testing. | From the time of first treatment up to the last dose of study treatment; 24 weeks. | 
| Immunogenicity: Number of Participants With Anti-Drug Antibodies (ADA) | Number of Participants with Anti-Drug Antibodies (ADA) at Week 24. The ELISA method was used for immunogenicity assessments of adalimumab. | Week 24 |