Active Rheumatoid ArthritisPhase 3NCT03172325
Study to Demonstrate Non-Inferior Efficacy and Safety of CinnoRA® Versus Humira® for Treatment of Active RA
A Phase 3 study testing Adalimumab, Methotrexate and Folic Acid in people with Active Rheumatoid Arthritis, run by Cinnagen at 10 sites in Iran.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Active Rheumatoid Arthritis
- What is being tested?
- Adalimumab, Methotrexate and Folic Acid
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 136 participants
- Where
- 10 sitesIran
- Study dates
- 18 Nov 2015to 4 Jan 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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)
Show all 23Show fewer
- 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.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
Iran10 sites
Alzahra Hospital
Isfahan
Besat 4 Clinic
Kerman
Ghaem Hospital
Mashhad
Razi Hospital
Rasht
Imam Ali Clinic
Shahr-e Kord
Hafez Hospital
Shiraz
Noor Medical Complex
Tabriz
Imam Reza Hospital (501 Artesh)
Tehran
Iran Rheumatism Center
Tehran
Loghman Hakim Hospital
Tehran
About this study
Official title: 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
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).
Read more
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
Read the 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.
- Conditions
- Active Rheumatoid Arthritis
- Being tested
- Adalimumab, Methotrexate, Folic Acid, Prednisolone
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AdalimumabDrug
40 mg Adalimumab every other week is administered subcutaneously to all the patients.
MethotrexateDrug
15 mg Methotrexate is weekly administered to all the patients.
Folic AcidDrug
At least 1 mg Folic acid is daily administered to all the patients.
PrednisoloneDrug
7.5 mg Prednisolone is daily administered to all the patients.
| Study group | Role | What they receive |
|---|---|---|
| CinnaGen adalimumab | Experimental | 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. Receives: Drug: Adalimumab; Drug: Methotrexate; Drug: Folic Acid; Drug: Prednisolone |
| AbbVie adalimumab | Active comparator | 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. Receives: Drug: Adalimumab; Drug: Methotrexate; Drug: Folic Acid; Drug: Prednisolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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))
Measured: Week 24
Secondary outcomes (4)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jun 2017
- Study start18 Nov 2015
- Primary completion17 Aug 2016
- Study completion4 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for Active Rheumatoid ArthritisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 136 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cinnagen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Ahmadreza Jamshidi, Professor, Principal investigator, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03172325
- Sponsor's protocol ID
- ADA.CIN.AJ94
- Other IDs
- IRCT2015030321315N1
- Status last verified
- Feb 2021
- First submitted
- 24 May 2017
- Last updated
- 2 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011 Dec 8;365(23):2205-19. doi: 10.1056/NEJMra1004965. No abstract available.
PubMed 22150039den Broeder A, van de Putte L, Rau R, Schattenkirchner M, Van Riel P, Sander O, Binder C, Fenner H, Bankmann Y, Velagapudi R, Kempeni J, Kupper H. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol. 2002 Nov;29(11):2288-98.
PubMed 12415583Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625-39. doi: 10.1002/acr.21641. No abstract available.
PubMed 22473917Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004 May;50(5):1400-11. doi: 10.1002/art.20217.
PubMed 15146409Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol. 2003 Dec;30(12):2563-71.
PubMed 14719195Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003 Jan;48(1):35-45. doi: 10.1002/art.10697.
PubMed 12528101Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R Jr, Paulus H, Strand V, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995 Jun;38(6):727-35. doi: 10.1002/art.1780380602.
PubMed 7779114Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002 May;301(2):418-26. doi: 10.1124/jpet.301.2.418.
PubMed 11961039Khan MOA, Mohiuddin E, Usmanghani K, Hannan A, Akram M, Shah SA, et al. Clinical evaluation of herbal medicines for the treatment of rheumatoid arthritis. Pak J Nutr. 2011;10(1):51-3.
Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine 18E Vol 2 EB: McGraw Hill Professional; 2012.
Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006 Dec;36(3):182-8. doi: 10.1016/j.semarthrit.2006.08.006. Epub 2006 Oct 11.
PubMed 17045630Yood RA, Guidelines ACoRSoRA. Guidelines for the management of rheumatoid arthritis: 2002 update. 2002.
Lee WY, Chen HY, Chen KC, Chen CY. Treatment of rheumatoid arthritis with traditional chinese medicine. Biomed Res Int. 2014;2014:528018. doi: 10.1155/2014/528018. Epub 2014 Jun 4.
PubMed 24991562Weinblatt ME, Schiff M, Valente R, van der Heijde D, Citera G, Zhao C, Maldonado M, Fleischmann R. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study. Arthritis Rheum. 2013 Jan;65(1):28-38. doi: 10.1002/art.37711.
PubMed 23169319Westhovens R, Kremer JM, Moreland LW, Emery P, Russell AS, Li T, Aranda R, Becker JC, Qi K, Dougados M. Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study. J Rheumatol. 2009 Apr;36(4):736-42. doi: 10.3899/jrheum.080813. Epub 2009 Feb 27.
PubMed 19273451
Study at a glance
From the registry record, last updated by the sponsor on 2 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03172325
- Acronym / sponsor ID
- ADA.CIN.AJ94
- Conditions
- Active Rheumatoid Arthritis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 136 participants (actual)
- Lead sponsor
- CinnagenIndustry (pharma, biotech, devices)
- Study start
- 18 Nov 2015 (actual)
- Primary completion
- 17 Aug 2016 (actual)
- Study completion
- 4 Jan 2017 (actual)
- First posted
- 1 Jun 2017 (actual)
- Results
- Posted 2 Feb 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| CinnaGen adalimumab | Experimental | Drug: Adalimumab, Drug: Methotrexate, Drug: Folic Acid, Drug: PrednisoloneCinnoRA® (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. |
| AbbVie adalimumab | Active comparator | Drug: Adalimumab, Drug: Methotrexate, Drug: Folic Acid, Drug: PrednisoloneHumira® (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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Adalimumab40 mg Adalimumab every other week is administered subcutaneously to all the patients. | Drug | AbbVie adalimumab, CinnaGen adalimumab |
| Methotrexate15 mg Methotrexate is weekly administered to all the patients. | Drug | AbbVie adalimumab, CinnaGen adalimumab |
| Folic AcidAt least 1 mg Folic acid is daily administered to all the patients. | Drug | AbbVie adalimumab, CinnaGen adalimumab |
| Prednisolone7.5 mg Prednisolone is daily administered to all the patients. | Drug | AbbVie adalimumab, CinnaGen adalimumab |
Primary outcome
Percentage of Patients With DAS28-EULAR Good and Moderate Responses at Week 24
Time frame: 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))
4 secondary outcomes
Percentage of Patients Achieving ACR20, ACR50 and ACR70 Response Rates at Week 24
Time frame: Week 24
Health Assessment Questionnaire (HAQ) Disability Index at Week 24.
Time frame: Week 24
The Incidence of Adverse Events
Time frame: 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)
Time frame: Week 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 22150039McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011 Dec 8;365(23):2205-19. doi: 10.1056/NEJMra1004965. No abstract available.
- Background: PubMed 12415583den Broeder A, van de Putte L, Rau R, Schattenkirchner M, Van Riel P, Sander O, Binder C, Fenner H, Bankmann Y, Velagapudi R, Kempeni J, Kupper H. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol. 2002 Nov;29(11):2288-98.
- Background: PubMed 22473917Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625-39. doi: 10.1002/acr.21641. No abstract available.
- Background: PubMed 15146409Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004 May;50(5):1400-11. doi: 10.1002/art.20217.
- Background: PubMed 14719195Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol. 2003 Dec;30(12):2563-71.
- Background: PubMed 12528101Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003 Jan;48(1):35-45. doi: 10.1002/art.10697.
- Background: PubMed 7779114Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R Jr, Paulus H, Strand V, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995 Jun;38(6):727-35. doi: 10.1002/art.1780380602.
- Background: PubMed 11961039Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002 May;301(2):418-26. doi: 10.1124/jpet.301.2.418.
- BackgroundKhan MOA, Mohiuddin E, Usmanghani K, Hannan A, Akram M, Shah SA, et al. Clinical evaluation of herbal medicines for the treatment of rheumatoid arthritis. Pak J Nutr. 2011;10(1):51-3.
- BackgroundLongo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine 18E Vol 2 EB: McGraw Hill Professional; 2012.
- Background: PubMed 17045630Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006 Dec;36(3):182-8. doi: 10.1016/j.semarthrit.2006.08.006. Epub 2006 Oct 11.
- BackgroundYood RA, Guidelines ACoRSoRA. Guidelines for the management of rheumatoid arthritis: 2002 update. 2002.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ahmadreza Jamshidi, Professor principal investigator
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Adalimumab, Methotrexate and Folic Acid in people with Active Rheumatoid Arthritis, run by Cinnagen at 10 sites in Iran.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Iran. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Patients With DAS28-EULAR Good and Moderate Responses at Week 24 (time frame: Week 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03172325, which also lists 19 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2021.