| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the efficacy of 4 and 6 mg of Revamilast compared to placebo in the treatment of patients with active rheumatoid arthritis (RA) who have had an inadequate response to Methotrexate (MTX). |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of revamilast at 2, 4 and 6 mg dose compared to placebo
• To determine a low precision estimate of the efficacy of 2mg of revamilast compared to placebo
• To investigate the pharmacokinetics of 2 mg,4 mg and 6 mg of revamilast and GRC 4037 in patients with RA (rich PK sampling in 48 subjects – 12 subjects in each arm, at selected sites with appropriate facility and population PK sampling in all patients including patients undergoing rich sampling).
• To investigate the effects of revamilast on pharmacodynamic parameters including:
serum IL-1,IL-6,TNF-α and Serum C Reactive Protein (CRP). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female ≥18 to ≤ 65 years of age at the time of Informed Consent.
• Documented history of RA diagnosed according to the revised (1987) American College of Rheumatology criteria (ACR) for at least 6 months prior to screening.
• Meets ACR functional class I, II or III.
• Active RA defined as patients with:
• 6 or more swollen joint counts both at screening (visit 1) and baseline(visit 4),
• 6 or more tender/painful joint counts both at screening(visit 1) and baseline
(visit 4), and
• At least two of the three following criteria:
i. Rheumatoid Factor positive or Anti CCP positive at screening visit as measured by the central laboratory,
ii.CRP ≥ 1.2 times upper limit of normal reference range of the central laboratory or ESR >28 mm/hr (by Westergren method) at local laboratory at screening (visit 1)
iii. Morning stiffness lasting > 45 min for at least 4 weeks prior to informed consent through screening visit 1
• DAS-28 CRP values greater or equal to 4.5 at screening (visit 1)
• Requirements for background RA therapies:
• Methotrexate (MTX):
•Patients must have been on stable or maximum tolerated dose of MTX for at least 12 weeks prior to screening visit (visit 1),
•On a weekly dose of at least 15 mg and not more than 25 mg or Maximum Tolerated Dose (with documented Adverse Drug Reaction at a higher dose) or Maximum approved dose.
• On a stable dose of folic acid supplementation of at least 5 mg per week for at least one week prior to screening (visit 1) and the same must be continued throughout the course of the trial unless dose escalation is required during the course of the study to treat MTX related Adverse Drug Reaction.
• Other DMARDs:
• A four week washout starting at visit 2 will be carried out for eligible patients on Hydroxychloroquine (HCQS) or Sulphasalazine (SSZ). Patients on HCQS should have been on a stable dose of 200-400 mg/day for at least 12 weeks prior to screening visit (visit 1). Patients on SSZ should have been on a stable dose of upto 2 g/day) for at least 4-8 weeks prior to screening visit (visit 1). These patients will complete their washout period while they are on single blind placebo (i.e. during run in period).
• Concomitant use of oral corticosteroids (equivalent to less than or equal to 10mg/day of prednisone) are permitted if doses have been stable (defined as at least 4 weeks prior to screening (visit 1)) and if patient and Investigator is willing to maintain the same dose throughout the run-in and treatment phase.
• A non-steroidal anti-inflammatory drug (NSAID) or selective COX inhibitor is allowed if patient is on stable dose for four weeks prior to randomisation and will be continued on same dose throughout the treatment period.
• Patients should not be treated with complementary/Alternative medicines anytime during the 3 months prior to screening visit. Diet (e.g. nutritional supplements like cod liver oil etc.), acupuncture, aromatherapy, chiropractic and massage are considered as non-pharmacological treatments and are allowed irrespective of the duration of use.
• The patient’s written informed consent to participate in the study.
• Female participants must have a negative serum pregnancy test at
screening visit. In addition, female of child bearing potential must agree to use at least TWO highly effective methods of contraception. Female patients must agree to have urine pregnancy test at every visit while on study medication and upto two weeks after taking the last dose of study medication (visit 9).
• Males (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in reproductive sexual activity with FCBP while on study medication and for 90 days after taking the last dose of study
medication.
• Must meet the following laboratory criteria:
o Hemoglobin greater or equal to 9 g/dL
o White blood cell (WBC) count; greater or equal to 3.0 X 109/L
o Platelet count greater or equal to 100,000 /μL (greater or equal to
100 X 10-9/L or greater or equal to 100 Gi/L)
o Serum creatinine less than 1.5 mg/dL (or 133mol/L)
o Total bilirubin less than 2.0 mg/dL
o Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) and alanine transaminase (ALT [serum glutamate pyruvic transaminase, SGPT]) less than 1.5 times upper limit of normal (ULN)
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| E.4 | Principal exclusion criteria |
• Diagnosis of RA prior to 16 years of age (Juvenile RA).
• Non-degenerative joint diseases or other joint diseases that could interfere with the evaluation of RA (i.e. Chikungunya arthritis, gout,
pseudogout, chondrocalcinosis, psoriatic arthritis, infectious arthritis, reactive arthritis or spondylitic arthritis).
• Patients with any other autoimmune rheumatic disorders with the exception of Sjogren’s syndrome.
• Patients with first degree relative with immune deficiency.
• Treatment with intraarticular/intravenous/intramuscular injection
with corticosteroids one month before screening.
• Patients who are on any DMARD other than MTX over the last 3 months (see criteria for HCQS and Sulphasalzine vide supra).
• Patients who have been on Anti TNF α agents or biological modifiers over the last 12 months prior to screening will not be eligible for participation in the study.
• Patients having history of active bacterial infection (or a bacterial infection requiring antibiotics) or active tuberculosis as deemed from medical history.
• History of infection with human immunodeficiency virus and/or active
hepatitis B or C.
• Severe disabling arthritis leaving the patient eligible for surgical intervention, or incapacitated and prostrated patients.
• Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to screening visit or planned during the study.
• Patients who exhibit abnormalities on physical examination or who have abnormal vital signs or clinical laboratory values, unless these abnormalities are judged by the Principal Investigator not to be clinically significant.
• Patients with a history of drug or alcohol abuse or chronic smoking.
• Uncontrolled diabetes mellitus as defined by a HbA1C value ≥ 7.0%.
• Concurrent diseases that might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient’s wellbeing e.g., evidence or history of malignancy other than excised basal cell carcinoma or indolent prostate cancer; any clinically significant hematologic, endocrine, cardiovascular (e.g. myocardial infarction within 3 months before visit 1), respiratory, renal, hepatic, or gastrointestinal disease. If there is a history of such disease but the condition has been stable for more than 1 year and is judged by the Investigator not to interfere with the patient’s participation in the study, the patient may be included, with the documented approval of the Investigator or Study Physician.
• QTcB interval of greater than 450 ms in ECG at visit 1, or other ECG abnormalities judged by the investigator to be clinically significant, a marked baseline prolongation of QT/QTc interval, a history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome), the use of concomitant medications that prolong the QT/QTc interval.
• History of using any other test drug, one month before the beginning of this trial.
• Women who are pregnant or breast-feeding.
• Patients who in the Investigator’s opinion might not be suitable for the study.
• Patients with a life expectancy of less than 1 year.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Primary Efficacy Assessment
Percentage of patients in 4 mg and 6 mg revamilast arms achieving ACR20 response at 12 weeks relative to placebo |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Percentage of patients in 4 mg and 6 mg revamilast arms achieving
ACR20 response at 4 and 8 weeks of treatment.
• Percentage of patients in 4 mg and 6 mg revamilast with ACR50 and
ACR70 response at 4, 8 and 12 weeks of treatment.
• Percentage of patients in 2 mg revamilast arm achieving ACR20,
ACR50 and ACR70 response at 4,8 and 12 weeks of treatment.
• Change in DAS-28 CRP (Disease activity scale) from baseline to week
12 in 2 mg, 4 mg and 6 mg revamilast.
• Change from baseline in serum CRP and ESR values in 2 mg, 4 mg and 6 mg revamilast
• To assess the pharmacodynamic effect of 2 mg, 4 mg and 6 mg of
revamilast
• Frequency and use of rescue medication (Paracetamol) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| India |
| Philippines |
| Poland |
| Sri Lanka |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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