治験総括報告書

1) Name of Sponsor/Company: Toyama Chemical Co., Ltd., Eisai Co., Ltd. 2) Brand Name: Kolbet tablet 25 mg,Careram tablet 25 mg 3) Name of Active Ingredient: iguratimod 4) Title of Study: A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Combination Therapy of T-614 and Methotrexate in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate. 5) Principal Investigators: 99 6) Medical Institutions: 99 7) Publication: Ishiguro N, Yamamoto K, Katayama K, Kondo M, Sumida T, Mimori T, Soen S, Nagai K, Yamaguchi T, Hara M; Iguratimod-Clinical Study Group.Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial. Mod Rheumatol. 2013;23:430-9. 8) The Period of Clinical Trial (year)：Two years and a month September, 2011 (Final Data Collection Date for Primary outcome measure) 10) Objectives: We investigated the efficacy and safety of T-614 with methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA) who had inadequate response to stable background MTX alone in the 28-week, randomized, double-blind period. T-614 was compared with placebo in the American College of Rheumatology 20% improvement criteria (ACR20) at week 24, the primary efficacy endpoint. More than we obtained safety and efficacy data on combination therapy of T-614 with MTX in a 52-week extension study contained double blind test for 28 week in patients with active RA. 11) Study Design: MTX at stable low doses of 6 or 8 mg/week and folic acid at a dose of 5 mg/week were administered to all patients for the entire treatment period (double-blind and extension periods). Eligible patients were separated into either the T-614 group, the treatment of T-614 with MTX, or the placebo group, the treatment of placebo with MTX, in 2:1 randomization. In double-blind period for 28 weeks, T-614 or placebo was orally administered at dosages of a tablet once daily for the first 4 weeks and a tablet twice daily for the subsequent 20 weeks. Patients who completed an initial 28-week, randomized, double-blind trial of adding placebo or T-614 to stable MTX therapy were allowed to enter an additional 24-week, open-label, extension study. Patients who initially were randomized to the T-614 group continued the treatment of T-614 with MTX. Patients who were initially randomized to the placebo group, the treatment of placebo with MTX, switched to the treatment of T-614 with MTX termed placebo/T-614 group. During the open-label 24-week extension period, patients in the T-614 group were administered 50 mg/day of T-614 (25 mg twice daily), and patients in the placebo/T-614 group were administered 25 mg /day of T-614 (25 mg once daily) for the first 4 weeks of the extension period and 50 mg/day (25 mg twice daily) for the subsequent 20-week extension period. 12) Number of Subjects (planned and analyzed): Planned: Total of 240 patients (160 patients in the T-614 group, 80 patients in the placebo group) Analyzed (a 24-week double-blind period): Number of patients treated: Total of 253 patients (165 patients in the T-614 group, 88 patients in the placebo group) Full analysis set (FAS); total of 252 patients (164 patients in the T-614 group, 88 patients in the placebo group) Per protocol set (PPS); total of 218 patients (144 patients in the T-614 group, 74 patients in the placebo group) Safety analysis set; total of 252 patients (164 patients in the T-614 group, 88 patients in the placebo group) Analyzed (a 52-week extension period): Number of patients treated: Total of 253 patients (165 patients in the T-614 group, 88 patients in the placebo/T-614 group) Efficacy analysis set; Total of 232 patients (164 patients in the T-614 group, 68 patients in the placebo/T-614 group) Safety analysis set; Total of 232 patients (164 patients in the T-614 group, 68 patients in the placebo/T-614 group) 13) Diagnosis and Main Criteria for Inclusion and Exclusion: The study population consisted of subjects with active RA. Key inclusion criteria were as follows: 1) Patients provided written informed consent and were aged greater or 20 years and less 2) Patients had a diagnosis of active RA for less than 10 years, based on American College 3) Patients had active RA despite MTX therapy (at least 6 mg/week) for more than 12 weeks, including stable dosages of MTX (6 or 8 mg/week) for at least 8 weeks before study enrollment 4) Patients also fulfilled the following criteria: At least six tender joints based on a 68-joint (except for distal interphalangeal joints) assessment and at least four swollen joints based on a 66-joint (except for distal interphalangeal joints) assessment. 5) Patients also fulfilled the following criteria: An erythrocyte sedimentation rate (ESR) of at least 28 mm/hr or a blood C-reactive protein (CRP) concentration of at least 1.0 mg/dL. 1) Body weight was less than 40 kg. 2) Steinbrocker’s class IV. 3) Hematopoietic disorder (leukocyte count <4000/μL, platelet count <100,000/μL, or 4) Positive results on serologic tests for hepatitis B or C. 5) Abnormal results on clinical laboratory tests [elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine, sialylated carbohydrate antigen (KL-6) or serum β-D-glucan] levels above the upper limit of normal. 6) Patients have the complication and anamnesis, different inflammatory joint disease from RA. Connective tissue disease (systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease etc expct for Sjogren's syndrome), seronegative spondyloarthropathy (psoriatic arthritis, Reiter's syndrome etc) etc. 7) Patients have the following complication and anamnesis. Hepatitis, critical liver damages (liver cirrhosis etc.), critical renal damages (renal insufficiency etc.), critical respiratory ailments (interstitial pneumonia, a chronic obstructive pulmonary disease, etc.), or a malignant tumor. 8) Patients have the following complication. Severe cardiac disease (heart failure, myocardial infarction shown within 90 days before the first administration, the poor control of angina pectoris etc.), severe infectious disease (sepsis, Pneumocystis pneumonia, tuberculosis etc), severe hematologic disorder (myelosuppression, aplastic anemia etc), active peptic ulcer disease or severe pancreatitis. 9) Patients have the positive results on serologic tests for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). 10) The patients that the following DMARDs (except for MTX) or immunosuppressive drugs for at least 28 days before test product administration start. Gold sodium thiomalate, auranofin, penicillamine, salazosulfapyridine, bucillamine, lobenzarit disodium, actarit, mizoribine, tacrolimus, tiopronin, azathioprine, cyclophosphamide or cyclosporine (except for instillation). 11) The patients that the following drugs were started or the patient whom a dose was changed to for at least 28 days before test product administration start. Corticosteroid (internal use and suppository), non-steroidal anti-inflammatory drug (NSAIDs) (expect for outside, the internal use agent of the potion and suppository), the Chinese medicine which have an effect of RA. 12) The patients who used corticosteroid (internal use) in prednisolone conversion more than 7.5 mg/day for at least 28 days before test product administration start. 13) The patients who received intravenous or intramuscular administration of corticosteroids within 28 days before test product administration. 14) The patients who received arthrocentesis or intraarticular administration of corticosteroids, sodium hyaluronate or local anesthetic for at least 28 days before test product administration start. 15) The patients who received biological antirheumatic agents, live vaccine or cytapheresis for at least 90 days before test product administration start. 16) The patients who received leflunomide, other RA clinical trial drugs, joint surgical therapy (synovectomy, surgical therapy for tendon rupture, joint replacement, arthrodesis, excision, osteotomy etc) for at least 180 days before test product administration start. 17) Patients enrolled in previous treatment with T-614. 18) Women of childbearing potential who are not practicing a successful method of contraception, or wish to become pregnant. 19) The patient of drug or alcohol abuse. 20) Subject who is considered by the investigator, for any reason, to be an unsuitable 14) Test product: T-614 (25 mg) tablet or placebo tablet 15) Dose and Mode of Administration: T-614 group (52 weeks): T-614 was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily after breakfast) and 50 mg/day for the subsequent 48 weeks (25 mg twice daily after breakfast or dinner). Placebo was orally administered at dosages of a tablet once daily after breakfast for 4 weeks and a tablet twice daily after breakfast and dinner for 24 weeks in double-blind period. T-614 was orally administered at dosages of 25 mg/day from 29 to 32 week (25 mg once daily after breakfast) and 50 mg/day from 33 to 52 week (25 mg twice daily after breakfast and dinner). 16) Duration of Study and Treatment: Treatment period: For 52 weeks (double-blind treatment period was for 28 weeks. Extension treatment period was for 24 weeks) 17) Control Product, Dose and Mode of Administration: none 18) Criteria for Evaluation: Efficacy (double-blind period; 24-week analysis)： Primary Outcome Measures: Number of patients who achieve American College of Rheumatology (ACR) response criterion of 20 Secondary Outcome Measures: Number of patients who ACR response criteria of 50, and 70, Disease Activity Score 28 (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI) Efficacy (extension period; 52-week analysis): ACR response criteria of 20, 50 and 70, DAS28, HAQ-DI Safety (24-week and 52-week analysis): Safety was evaluated by adverse event reports, laboratory assays for changes in hematologic characteristics, biochemical test, immunologic tests, urinalysis, and liver function, and vital sign. 19) Statistical analysis: In 24-week analysis (double-blind period), all efficacy analyses were primarily performed on the full analysis set. Efficacy variables were calculated using the last-observation-carried-forward (LOCF) method. The primary efficacy endpoint of ACR20 at week 24 (LOCF) was compared between the T-614 group and the placebo group using the Fisher’s exact test. ACR50 and 70 were analyzed in the same way. In 52-week analysis (extension period), efficacy variables were calculated using the LOCF method. Changes from baseline in individual ACR 20, 50 and 70 were analyzed by McNemar’s test. DAS28 and HAQ-DI presented as summary statistics for each group were made using the t test or the paired t test. All safety analyses were performed on the safety analysis set, defined as all randomized patients who received at least one dose of test product and from whom at least one assessment of safety under double-blind medication was available. The incidence of adverse events was calculated. At week 24, the two groups were compared using Fisher’s exact test. 20) Results: The ACR20 response rate, which was the primary efficacy endpoint in this clinical test, was significantly improved by 24-week (LOCF) treatment with T-614 group (69.5%, 114/164 patients) compared with placebo group (30.7%, 27/88 patients) in the FAS (p<0.001, Fisher’s exact test). When ACR20 was analyzed based on the PPS at 24-week (LOCF), ACR20 in the T-614 group (71.5 %, 103/144 patients) was significantly greater than that in the placebo group (35.1 %, 26/74 patients) (p<0.001, Fisher’s exact test). The ACR20 response rate in the T-614 group at week 52 (LOCF) is 71.3% (117/164 patients), which was similar to that at week 24 (LOCF). A total of 68 patients switched from placebo with MTX to the T-614 with MTX treatment (the placebo/T-614 group) at week 29. ACR20 in the placebo/T-614 group at week 52 (LOCF) were 72.1% (49/68 patients), which was similar to that at week 24 (LOCF) in the T-614 group. ACR50 response rate The ACR50 response rate was significantly improved by 24-week (LOCF) treatment with T-614 group (38.4%, 63/164 patients) compared with placebo group (15.9 %, 14/88 patients) in the FAS (p<0.001, Fisher’s exact test). The ACR50 at week 52 (LOCF) was 49.4% (81/164 patients) in the T-614 group, which was significantly greater than rates of 38.4% at week 24 (LOCF) (p=0.003, McNemar’s test). ACR50 response rate in the placebo/T-614 group at week 52 (LOCF) was 45.6% (31/68 patients). ACR70 response rate The ACR70 response rate was significantly improved by 24-week (LOCF) treatment with T-614 group (17.1%, 28/164 patients) compared with placebo group (5.7%, 5/88 patients) in the FAS (p=0.010, Fisher’s exact test). The ACR70 at week 52 (LOCF) was 23.8% (39/164 patients) in the T-614 group, which was significantly greater than rate of 17.1% in the T-614 group at week 24 (LOCF) (p=0.048, McNemar’s test).ACR70 response rate in the placebo/T-614 group at week 52 (LOCF) was 22.1% (15/68 patients). DAS28-CRP DAS28-CRP in the FAS at week 24 (LOCF) were 3.365±1.181 in the T-614 group and 4.311±1.306 in the placebo group (each volue is mean±SD). DAS28-CRP in the T-614 group was significantly lower than that in the placebo group (p<0.001, t test). Significantly more patients in the T-614 group showed remission (DAS28-CRP<2.6) at week 24 (LOCF) compared with the placebo group [27.4% (45/164 patients) versus 9.1 % (8/88 patients), respectively; p<0.001, Fisher’s exact test]. Significantly more patients in the T-614 group showed low disease activity (DAS28-CRP <3.2) compared with patients in the placebo group [47.6% (78/164 patients) versus 20.5% (18/88 patients), respectively; p<0.001, Fisher’s exact test]. DAS28-CRP in the FAS at week 52 (LOCF) were 3.146±1.240 in the T-614 group and 3.150 ± 1.188 in the placebo/T-614 group (each volue is mean±SD). At week 52 (LOCF), 55.9% (38/68 patients) of patients showed low disease activity (DAS28-CRP <3.2) in the placebo/T-614 group, which was similar to 53.7% (88/164 patients) in the T-614 group. Similarly at week 52, 33.8% (23/68 patients) of patients showed remission (DAS28-CRP <2.6) in the placebo/T-614 group, which was similar to 34.1% (56/164 patients) in theT-614 group. HAQ-DI Physical function as measured by HAQ-DI at week 24 (LOCF) significantly improved compared with baseline in the T-614 group (0.8178±0.5525 at baseline and 0.4634±0.4842 at week 24, each volue is mean±SD, p<0.001; paired t-test). The mean change in HAQ-DI of -0.3544±0.4492 (mean±SD) in the T-614 group at week 24 (LOCF) from baseline was significantly different from that of 0.0256±0.5490 (mean±SD) in the placebo group (p<0.001, HAQ-DI at week 52 (LOCF) significantly improved compared with baseline in the T-614 group (0.8178±0.5525 at baseline and 0.4085±0.4677 at week 52, each volue is mean±SD, p<0.001; paired t-test). In the placebo/T-614 group, HAQ-DI at week 52 (LOCF) was 0.4283±0.4955 (mean±SD). Adverse events (AEs) at week 24 were reported in 80.5% (132/164 patients) of patients in the T-614 group and 75.0% (66/88 patients) in the placebo group, with no significant differences between groups (p=0.336, Fisher’s exact test). Serious adverse events (SAEs) were reported by 5 patiants in the T-614 group (gastroduodenal, ulcer, tendon rupture, carbon monoxide poisoning, interstitial lung disease, and retinal hemorrhage) and 3 patients in the placebo group (synovial repture, fallopian tube cancer, and cardiac failure) at week 24. The serious adverse drug reactions were gastroduodenal ulcer and interstitial lung disease in the T-614 group, and tube cancer and cariac failure in the placebo group. No deaths were reported. The major AEs occurring in ≥5% in the T-614 group were nasopharyngitis [17.1% (28/164 patients)], upper respiratory tract inflammation [5.5 % (9/164 patients)], stomatitis [6.7 % (11/164 patients)], lymphocyte count decreased [14.0% (23/164 patients)], aspartate aminotransferase (AST) increased [9.8% (16/164 patients)], alanineamino- transferase (ALT) increased [5.5 % (9/164 patients)], β2-microglobulin increased [7.9% (13/164 patients)], β2-microglobulin urine increased [6.7% (11/164 patients)], and blood iron decreased [21.3% (35/164 patients)]. Those in the placebo group were nasopharyngitis [15.9% (14/88 patients)], pharyngitis [6.8% (6/88 patients)], lymphocyte count decreased [9.1% (8/88 patients)], AST increased [5.7% (5/88 patients)], ALT increased [8.0 % (7/68 patients)], and blood iron decreased [18.2% (16/88 patients)]. AEs occurred in 95.1% of patients in the T-614 group and 79.4% (54/68 patients) in the placebo/T-614 group at week 52. SAEs were observed in 2.4% of patients (4/164) in the T-614 group from week 25 to week 52. These events included pneumonia bacterial, breast cancer, anaphylactic shock (insect stings), and supraventricular tachycardia. In placebo/T-614 group, Meniere diseases were observed in two patients. Thses SAEs were judged not to be related to T-614 treatment. No deaths were reported. The major AEs occurring in ≥5% in the T-614 group were nasopharyngitis [31.7% (52/164 patients)], pharyngitis [6.1% (10/164 patients)], upper respiratory tract inflammation [12.2 % (20/164 patients)], diarrhea [6.7 % (11/164 patients)], stomatitis [11.0 % (18/164 patients)], rash [5.5 % (9/164 patients)], back pain [6.7 % (11/164 patients)], lymphocyte count decreased [17.7% (29/164 patients)], AST increased [16.5 % (27/164 patients)], ALT increased [14.6% (24/164 patients)], γ-glutamyl transpeptidase (γ-GTP) increase [9.1% (15/164 patients)], β2-microglobulin increased [9.1% (15/164 patients)], β2-microglobulin urine increased [9.1% (15/164 patients)], and blood iron decreased [26.2% (43/164 patients)]. Those in the placebo group were bronchitis [7.4% (5/68 patients)], nasopharyngitis [22.1% (15/68 patients)], upper respiratory tract inflammation [5.9% （ 4/68 patients)], abdominal discomfort [5.9%（4/68 patients)], stomatitis [5.9%（4/68 patients)], lymphocyte count decreased [10.3%（7/68 patients)], ALT increased [7.4%（5/68 patients)], β2-microglobulin increased [7.4%（ 5/68 patients)], β2-microglobulin urine increased [5.9% （ 4/68 patients)], and blood iron decreased [13.2%（9/68 patients)］

Source: http://www.toyama-chemical.co.jp/rd/clinical/pack/pdf/JapicCTI-R130364e.pdf