To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA).
To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA).
In this multicenter, double-blind trial, 489 patients randomly received either T-614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T-614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks.
After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T-614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T-614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T-614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T-614 therapy groups. Side effects in the T-614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T-614 groups.
Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.
Current treatments for rheumatoid arthritis (RA) emphasize the early use of disease-modifying antirheumatic drugs (DMARDs) to minimize or prevent joint damage (1). Although most of the data on new drugs such as biologic agents or leflunomide have been available, methotrexate (MTX) is considered to be the gold standard DMARD for the treatment of RA until now (2–5). However, no currently available medication is uniformly effective, and some of them may be significantly toxic or expensive. Therefore, there is still a need for more new reasonably cost-effective agents with a high ratio of efficacy to toxicity and to increase options for the treatment of RA.
T-614 (3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one) is a member of the family of methanesulfonanilide (6, 7). Although most of the members of this family act as cyclooxygenase 2 (COX-2) inhibitors, T-614 is considered to be a novel immunomodulator based on more and more evidence. Existing studies showed that T-614 reduced the production of some cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, IL-17, tumor necrosis factor α, and interferon-γ in vitro (synovial cells and some cell lines) and in vivo (mouse models) (8–14). T-614 has been shown to display a steroid-like improvement in several autoimmune animal models such as collagen-induced arthritis, MRL-lpr/lpr mice, and experimental autoimmune encephalomyelitis (9, 15). It could also reduce immunoglobulin production by acting directly on B lymphocytes in both mice and humans, despite having no notable action on B lymphocyte proliferation (14, 16). In addition, T-614 possessed anabolic effects on bone metabolism, as well as suppression of bone resorption, by increased expression of osterix (17). Recently, more direct evidence came from the findings of Du et al that T-614 dramatically suppressed disease progression and markedly protected affected joints against cartilage destruction and bone erosion in collagen-induced arthritis rats (14). Taken together, these data support the agent T-614 as a potential DMARD under development.
In several clinical trials, T-614 has been reported to be effective and safe in patients with active RA (18–20). This report presents the results of therapy in the 24-week utilization of T-614 in active RA patients, comparing 2 different initial doses of T-614 with MTX. This randomized, double-blind, parallel-group, phase III study was conducted in 12 centers in China. Clinical outcomes, individual responder rates, and adverse events associated with T-614 administration in this protocol are described.
Eligible patients had a diagnosis of active RA based on the criteria of the American College of Rheumatology (ACR; formerly the American Rheumatism Association) (21) and were of functional class II or III according to the ACR classification of global functional status in RA (22). Active disease was defined with 4 of the following 5 criteria: ≥5 tender joints, ≥3 swollen joints, morning stiffness lasting ≥60 minutes, Westergren erythrocyte sedimentation rate (ESR) ≥28 mm/hour, and assessment of pain at rest by the patient as moderate or severe. Previous use of DMARDs (including MTX) was allowed only if they were discontinued for at least 4 weeks. Use of nonsteroidal antiinflammatory drugs (NSAIDs) and corticosteroids in dosages of ≤10 mg of prednisone (or equivalent) daily was permitted, provided that the dose remained stable during the trial and for at least 4 weeks before enrollment. Intraarticular corticosteroid injections were not allowed within 6 weeks of an efficacy assessment. Notably, as a result of taking ethical responsibilities into account, patients were excluded if they had previously been found to have insufficient efficacy to MTX treatment in dosages of ≥15 mg/week for more than 20 weeks or had discontinued previous MTX therapy due to clinically important toxicity. Consenting patients, i.e., women and men ages 18–65 years, were required to use adequate methods of contraception, and women of childbearing potential had to have a urine test to exclude pregnancy before enrollment. Patients were enrolled in 12 study centers in China. This study was approved by the appropriate ethics review boards of all participating institutions and was conducted following the principles established by the Declaration of Helsinki.
Patients in this phase III protocol were assigned to 1 of 3 treatment groups in a 1:1:1 randomization: T-614 treatment group 1 (T-614 25 mg/day for the first 4 weeks with an oral dosage of 25 mg once daily, and 50 mg/day for the subsequent 20 weeks with an oral dosage of 25 mg twice daily), T-614 treatment group 2 (T-614 50 mg/day with an oral dosage of 25 mg twice daily), or the MTX treatment group (MTX 10 mg/week orally for the first 4 weeks and 15 mg/week orally for the subsequent 20 weeks). The daily dose of T-614 in each T-614 treatment group was decided based on the phase II efficacy and safety data (18, 19). All of these medications were administered in a double-dummy manner to preserve allocation concealment. Folate supplementation for the subjects was 5 mg/day orally for 24 weeks.
In patients who experienced an increase in the alanine aminotransferase (ALT) level to ≥3-fold the upper limit of normal, the study treatment was interrupted; if a second ALT elevation to ≥3-fold the upper limit of normal occurred when treatment recommenced, the study treatment was permanently discontinued. The study treatment was stopped in patients with an elevation in the ALT level of ≥5-fold the upper limit of normal, in those with indirect bilirubin levels ≥2-fold the upper limit of normal, and in patients whose absolute neutrophil count decreased to <500 cells/mm3.
Clinical assessments of RA activity were obtained at baseline and at weeks 4, 10, 17, and 24. The primary efficacy end point was the proportion of patients who had achieved a response according to the ACR criteria for 20% improvement (ACR20) (23) at week 24. To be considered an ACR20 responder, a subject had to have a 20% improvement in tender and swollen joint count and in at least 3 of the following 5 criteria: patient global assessment, physician global assessment, pain intensity, Health Assessment Questionnaire (HAQ), and C-reactive protein (CRP) level or ESR (23). Secondary end points included the proportion of patients with 50% improvement (ACR50) or 70% improvement (ACR70) at week 24.
The following secondary efficacy end points were assessed as well: rest pain intensity assessment, measured on a visual analog scale (VAS) ranging from 0 mm (no pain) to 100 mm (severe pain); duration of morning stiffness; tender joint count and swollen joint count based on a 28-joint count; tender joint score and swollen joint score, using 28 joints and a scale of 0 (none) to 3 (severe) to assess degrees of tenderness and/or swelling (24); physician and patient assessments of global RA disease activity based on a 100-mm VAS; and values of Westergren ESR, CRP level, and rheumatoid factor (RF). Functional disability was measured with a HAQ that rated a subject's ability to perform daily activities, ranging from 0 (without difficulty) to 3 (unable to perform tasks) (25). In addition, rates of withdrawal of NSAIDs were evaluated in patients receiving NSAIDs. Plain radiographs of both hands, including the wrists, were taken in the posteroanterior view at baseline.
The safety assessment included a complete medical history at baseline and a complete physical examination before the study and at 24-week intervals over the course of the study or as clinically indicated. Vital signs and weight were taken when patients were followed. Electrocardiogram and chest radiographs were taken at baseline, 10 weeks, 24 weeks, and if clinically indicated. Endoscopy at baseline and 24 weeks or early withdrawal was advocated to all subjects but was not mandatory, and was finally performed in 115 consenting volunteers. All documentation relating to potential ulcer complications was forwarded to a gastrointestinal (GI) events committee. The committee collectively reviewed each case in a treatment-blinded fashion and assigned it by unanimous consensus as either meeting or not meeting the definition of an upper GI ulcer complication. Pill counts were performed to assess compliance with medication protocols.
Standard hematologic and clinical chemistry studies and urinalyses were performed at each visit. All adverse events reported spontaneously by the subjects or observed or elicited by the investigator were recorded. The intensity of the adverse event and the possible relationship of the adverse event to the study medication were assessed by the investigator who recorded the event. An adverse event was classified as serious if it met any of the following criteria: fatal or life-threatening, permanently or significantly disabling, requiring hospitalization, involving cancer or a congenital anomaly, occurring with overdose, or suggestive of a significant hazard.
Randomization was centrally generated and site specific, and all patients, investigators, and data analysts remained blinded throughout the study. The formula by Chow et al (26) was used to calculate the sample sizes for the study on the basis of the hypothesis that the T-164 is noninferior to MTX. Based on the data from a 24-week phase II trial comparing leflunomide with MTX in China (27) and other trials involved with MTX (28, 29) in comparable treatment regimens and RA patient populations, we assumed that the ACR20 response rate for patients receiving MTX treatment was 55%. According to an ACR20 response rate of 61.3% for the T-614 group observed in a previous phase II study (18), sample sizes were calculated to ensure that 480 patients (160 per group, 40 per center) would satisfy the test power of 80% at a significance level of 0.05, the noninferiority test with a margin of 10%, an estimated 20% rate of loss to followup or protocol deviation, and would be evaluable for safety analysis. The margin for noninferiority was defined not to exceed 50% of known superiority between T-614 and placebo, based on published randomized controlled trials (18, 19).
All analyses were performed on the intent-to-treat population. The intent-to-treat population was defined as all randomized patients who received any dose of study medication with at least one study evaluation after randomization. Analyses used the last observation carried forward method. All tests were 2-tailed, and the 5% significance level was used.
Demographics and disease history were analyzed using Fisher's exact test for categorical data and the F test for age comparisons. Group comparisons were performed by the Kruskal-Wallis test. Comparisons of the mean changes of efficacy end points were performed by the Kruskal-Wallis test for group comparisons and Wilcoxon's signed rank test for results within the active treatment groups. Group comparisons of rates of withdrawal of NSAIDs were performed by Fisher's exact test. Overall assessments were compared by means of the Cochran-Mantel-Haenszel test and the noninferiority of T-614 to MTX was tested within a margin of 10%. A lower bound of 1-sided 95% confidence interval (95% CI) >10% indicated that the efficacy of T-614 was not inferior to MTX. Reports of adverse events, physical examination results, laboratory assessments, electrocardiogram results, and chest radiograph results were analyzed for safety, including mean changes in individual parameters over time. The randomization code was broken only after the database was locked.
A total of 492 patients were enrolled and randomly assigned to the different groups. Of these, 489 patients (the intent-to-treat population, 163 in each group) received at least 1 dose of a study drug and were evaluated for efficacy and safety. There were no statistically significant differences in age, sex, baseline disease characteristics, or concomitant use of NSAIDs or corticosteroids among the treatment groups (Table 1).
|MTX group (n = 163)||T-614 group 1 (n = 163)||T-614 group 2 (n = 163)||Group comparison|
|Age, years||47.2 ± 11.0||46.0 ± 10.6||45.9 ± 10.4||F = 0.83 P = 0.4386|
|Men/women||30/133||29/134||22/141||P = 0.4431|
|RA duration, median ± IQR months||48.0 ± 106.0||48.0 ± 96.0||36.0 ± 96.0||χ2 = 0.65 P = 0.7233|
|Functional status, no. (%)||χ2 = 1.92 P = 0.3825|
|Class I||0 (0.0)||0 (0.0)||0 (0.0)|
|Class II||117 (71.8)||106 (65.0)||108 (66.3)|
|Class III||46 (28.2)||57 (35.0)||55 (33.7)|
|Class IV||0 (0.0)||0 (0.0)||0 (0.0)|
|Functional status of joints||2.3 ± 0.5||2.34 ± 0.5||2.33 ± 0.5||χ2 = 0.58 P = 0.7488|
|Radiograph stage, no. (%)||χ2 = 0.61 P = 0.7354|
|I||62 (38.0)||62 (38.5)||59 (36.4)|
|II||53 (32.5)||63 (39.1)||63 (38.9)|
|III||45 (27.6)||33 (20.5)||35 (21.6)|
|IV||3 (1.8)||3 (1.9)||5 (3.1)|
|Rest pain intensity†||61.4 ± 18.7||62.1 ± 19.5||64.3 ± 18.0||χ2 = 2.04 P = 0.3613|
|Duration of morning stiffness, minutes||107.7 ± 98.6||117.2 ± 97.2||135.4 ± 193.4||χ2 = 1.55 P = 0.4618|
|Tender joint count||14.8 ± 7.3||15.0 ± 6.8||14.3 ± 6.9||χ2 = 1.01 P = 0.6049|
|Tender joint score||17.3 ± 9.9||18.0 ± 10.3||17.3 ± 11.2||χ2 = 1.05 P = 0.5917|
|Swollen joint count||9.1 ± 5.5||9.3 ± 5.3||9.6 ± 5.9||χ2 = 0.57 P = 0.7528|
|Swollen joint score||10.0 ± 6.3||10.2 ± 6.3||10.8 ± 7.8||χ2 = 0.33 P = 0.8465|
|HAQ score||1.0 ± 0.6||1.1 ± 0.7||1.0 ± 0.6||χ2 = 0.03 P = 0.9853|
|Patient global assessment†||64.9 ± 18.2||64.2 ± 19.4||66.6 ± 18.6||χ2 = 1.26 P = 0.5325|
|Physician global assessment†||63.4 ± 16.0||63.5 ± 16.6||63.7 ± 16.2||χ2 = 0.02 P = 0.9912|
|ESR, mm/hour||44.0 ± 31.4||45.8 ± 27.6||44.5 ± 27.6||χ2 = 1.44 P = 0.4869|
|CRP level, mg/ml||24.6 ± 31.1||22.7 ± 25.5||22.5 ± 27.7||χ2 = 0.42 P = 0.8110|
|Rheumatoid factor, IU/ml||287.8 ± 570.3||273.7 ± 504.8||269.1 ± 427.7||χ2 = 0.54 P = 0.7643|
|Previous DMARD treatment, no. (%)||24 (14.7)||21 (12.9)||23 (14.1)||P = 0.9195|
|Concomitant NSAIDs, no. (%)||89 (54.6)||71 (43.6)||83 (50.9)||P = 0.1257|
|Concomitant corticosteroids, no. (%)||34 (20.9)||40 (24.5)||45 (27.6)||P = 0.3725|
Fifty-six patients left the study before treatment was completed. Of these, 17 patients discontinued therapy due to adverse events, 27 due to lack of clinical benefit, and 12 due to other reasons (Table 2). A total of 433 (88.5%) patients completed protocol treatment. The group comparison about compliance in patients was not statistically significant.
|Adverse event||Lack of efficacy||Other|
|T-614 group 1||163||6||6||5||146|
|T-614 group 2||163||8||11||2||142|
After 24 weeks of treatment, the ACR20 response rates in T-614 group 2 and the MTX group (63.8% versus 62.0%) were not statistically significantly different from each other and within the range being tested for noninferiority as described below, but both were significantly higher than T-614 group 1 (50.9%; P = 0.0161 and 0.0414, respectively) (Table 3). ACR50 and ACR70 response rates for the patients at 24 weeks were also equivalent in T-614 group 2 and the MTX group (Table 3). ACR20, ACR50, and ACR70 response rates at all time points in T-614 group 2 were similar to those in the MTX group (Table 3). A dose response was observed, with clear superiority for T-614 group 2 compared with T-614 group 1, despite a lack of statistical differences in weeks 4, 10, and 17 (Table 3). In the noninferiority analysis, the 1-sided 95% CI for the ACR20 response rate difference ranged from −6.94% to +∞ between T-614 group 2 (63.8%) and the MTX group (62.0%). This indicates that the efficacy of T-614 (50 mg/day) is not lower than that of MTX by >10%. Herein, an actual power of 71.5% was calculated to demonstrate noninferiority at a significance level of 0.05.
|MTX group (n = 163)||T-614 group 1 (n = 163)||T-614 group 2 (n = 163)||P|
|ACR20||37 (22.7)||36 (22.1)||43 (26.4)||0.8801|
|ACR50||10 (6.1)||3 (1.8)||11 (6.8)||0.0659|
|ACR70||1 (0.6)||1 (0.6)||2 (1.2)||1.0000|
|ACR20||87 (53.4)||64 (39.3)||77 (47.2)||0.0072†|
|ACR50||27 (16.6)||21 (12.9)||30 (18.4)||0.3460|
|ACR70||11 (6.8)||8 (4.9)||14 (8.6)||0.4912|
|ACR20||97 (59.5)||76 (46.6)||91 (55.8)||0.0161‡|
|ACR50||52 (31.9)||44 (27.0)||47 (28.8)||0.3032|
|ACR70||22 (13.5)||15 (9.2)||23 (14.1)||0.2110|
|ACR20||101 (62.0)||83 (50.9)||104 (63.8)||0.0397§|
|ACR50||70 (42.9)||53 (32.5)||62 (38.0)||0.0457¶|
|ACR70||34 (20.9)||27 (16.6)||30 (18.4)||0.2779|
Mean changes in the individual efficacy end points in the subgroup of subjects treated with T-614 and MTX for 24 weeks are shown in Table 4. Statistical analysis of the efficacy end point parameters indicated that mean changes of all variables were not significantly different among the 3 groups. In addition, all secondary outcome measures, i.e., ESR, CRP level, and RF, demonstrated statistically significant improvement after 24 weeks of treatment in each of the 3 groups by means of Wilcoxon's signed rank test. The withdrawal rates of NSAIDs in 3 treatment groups (42.7% in the MTX group, 29.6% in T-614 group 1, and 38.5% in T-614 group 2; P = 0.2267) were not significantly different.
|MTX (n = 163)||T-614 group 1 (n = 163)||T-614 group 2 (n = 163)||Group comparison|
|Rest pain intensity†||28.7 ± 26.1||24.9 ± 28.4||27.4 ± 28.9||χ2 = 1.60 P = 0.4495|
|Duration of morning stiffness, minutes||81.5 ± 90.8||85.2 ± 115.3||85.9 ± 214.5||χ2 = 0.66 P = 0.7175|
|Tender joint count||7.4 ± 6.7||6.8 ± 8.3||6.9 ± 7.2||χ2 = 2.38 P = 0.3035|
|Tender joint score||10.0 ± 8.1||10.5 ± 10.6||10.2 ± 10.0||χ2 = 0.24 P = 0.8860|
|Swollen joint count||5.6 ± 5.3||4.9 ± 5.5||5.3 ± 5.9||χ2 = 2.06 P = 0.3566|
|Swollen joint score||7.0 ± 5.4||6.4 ± 6.0||7.0 ± 7.2||χ2 = 1.59 P = 0.4506|
|Patient global assessment†||28.3 ± 26.0||25.9 ± 27.1||26.9 ± 27.7||χ2 = 0.58 P = 0.7480|
|Physician global assessment†||29.3 ± 24.2||26.3 ± 25.3||26.0 ± 25.9||χ2 = 1.75 P = 0.4166|
|HAQ score||0.5 ± 0.6||0.6 ± 0.7||0.5 ± 0.6||χ2 = 0.16 P = 0.9237|
|ESR, mm/hour||11.4 ± 26.6||8.6 ± 25.5||9.0 ± 26.3||χ2 = 0.92 P = 0.6303|
|CRP level, mg/ml||8.8 ± 31.9||4.9 ± 24.3||6.6 ± 26.3||χ2 = 1.70 P = 0.4270|
|RF, IU/ml||149.2 ± 419.9||107.2 ± 294.6||145.9 ± 349.8||χ2 = 4.40 P = 0.1108|
During 24 weeks of treatment, the rates of adverse events in the treatment groups were 46.1% in the MTX group, 39.9% in T-614 group 1, and 48.5% in T-614 group 2 (P = 0.2696). In total, 220 primary adverse events were reported in 489 patients. Those reported adverse events judged to be related to study drug administration with an incidence of ≥1% are shown in Table 5. Serious adverse events that were considered to be treatment related were reported for 2 patients in T-614 group 2, 1 patient in the MTX group, and none in T-614 group 1. These included 2 cases of transaminase elevations (1 patient treated with T-614 with ALT 285 units/liter and 1 patient treated with MTX with ALT 1,742 units/liter) requiring hospitalization and 1 patient with thrombocytopenia (blood platelet count 31 × 109/liter), who was treated with T-614 50 mg/day. Patients with serious adverse events recovered after active treatment discontinuation. Seventeen patients were withdrawn from the study because of adverse events (3 from the MTX group, 6 from T-614 group 1, and 8 from T-614 group 2) (Table 2). No deaths occurred in the study.
|MTX (n = 163)||T-614 group 1 (n = 163)||T-614 group 2 (n = 163)|
|Nausea†||13 (8.0)||3 (1.8)||3 (1.8)|
|Heartburn||3 (1.8)||2 (1.2)||1 (0.6)|
|Upper abdominal discomfort||8 (4.9)||4 (2.5)||10 (6.1)|
|Stomachache||2 (1.2)||0 (0.0)||3 (1.8)|
|Abdominal distension||3 (1.8)||3 (1.8)||1 (0.6)|
|Anorexia‡||13 (8.0)||2 (1.2)||5 (3.1)|
|Diarrhea||2 (1.2)||0 (0.0)||1 (0.6)|
|Pruritus||0 (0.0)||0 (0.0)||3 (1.8)|
|Skin rash||1 (0.6)||3 (1.8)||4 (2.5)|
|Fatigue||4 (2.5)||0 (0.0)||1 (0.6)|
|Blurring||0 (0.0)||2 (1.2)||1 (0.6)|
|Dizziness§||5 (3.1)||0 (0.0)||0 (0.0)|
|Baldness||0 (0.0)||2 (1.2)||0 (0.0)|
|Elevated serum ALT¶||39 (23.9)||10 (6.1)||22 (13.5)|
|Leucopenia||4 (2.5)||4 (2.5)||5 (3.1)|
|Thrombocytopenia||3 (1.8)||1 (0.6)||3 (1.8)|
|Depressed ST segments in EKG||2 (1.2)||0 (0.0)||0 (0.0)|
|Premature ventricular contraction||0 (0.0)||2 (1.2)||0 (0.0)|
GI symptoms, specifically nausea and anorexia, were more commonly reported by patients receiving MTX treatment. The GI events committee identified 8 cases of new-onset or aggravating upper GI ulcer complications in 115 volunteers (including 34 in the MTX group, 39 in T-614 group 1, and 42 in T-614 group 2) by comparing the endoscopy results at 24 weeks or early withdrawal with those at baseline. Ulcers were more commonly found in the MTX treatment group (6 of 34) than in the T-614 treatment groups (1 of 39 in group 1 and 1 of 42 in group 2). Also, dizziness was more frequently reported by patients receiving MTX treatment. Skin rash and pruritus were more common in patients receiving T-614 treatment, in particular in group 2, than in patients receiving MTX treatment. As for infections, only 1 case each of upper respiratory infection was reported in the MTX treatment group and in T-614 group 2; 1 case of urinary tract infection was found in the MTX group and 1 case of varicella was reported in T-614 group 2. There were no prominent cardiovascular adverse effects in our trial.
Adverse effects on hematologic parameters were caused by both T-614 and MTX administration. These included 13 cases of leucopenia (4 in the MTX group, 4 in T-614 group 1, and 5 in T-614 group 2) and 7 cases of thrombocytopenia (3 in the MTX group, 1 in T-614 group 1, and 3 in T-614 group 2). Fortunately, these hematologic changes were reversible when treatment continued or after treatment discontinuation. The most common adverse events were elevations of plasma liver enzyme levels. Treatment with MTX resulted in elevated ALT levels that were >1.5 times the upper limits of normal in 23.9% of patients compared with 6.1% in T-614 group 1 and 13.5% in T-614 group 2 (P = 0.0001) (Table 5). All elevations for patients receiving active treatment reverted to <1.5 times the upper limits of normal while treatment continued or after treatment discontinuation.
Mean ± SD changes in immunoglobulins in the subgroup of subjects treated with T-614 and MTX for 24 weeks are shown in Table 6. Statistical analysis indicated that mean changes of these variables were not significantly different among the 3 groups except for IgA. However, IgA, IgG, and IgM demonstrated a statistically significant decrease after 24 weeks of treatment in each of the 3 groups by means of Wilcoxon's signed rank test.
|MTX||T-614 group 1||T-614 group 2|
|Baseline||3.2 ± 1.6||3.5 ± 2.0||3.3 ± 1.9|
|Change†||0.2 ± 1.2||0.5 ± 1.1||0.7 ± 1.4|
|Baseline||15.9 ± 4.7||16.2 ± 4.4||16.1 ± 4.3|
|Change||0.7 ± 3.3||1.1 ± 3.7||1.6 ± 3.9|
|Baseline||1.8 ± 0.9||2.0 ± 1.0||1.9 ± 0.9|
|Change||0.3 ± 0.6||0.4 ± 0.5||0.4 ± 0.5|
Recently, clinical trials of treatment of active RA with T-614 have been conducted in Japanese and Chinese patients (18–20). In Japan, Hara et al carried out a 28-week, randomized, double-blind, parallel-group study in 376 active RA patients to compare the efficacy and safety of T-614 with those of placebo and salazosulfapyridine (19). The results showed that an ACR20 response rate of T-614 was superior to placebo (53.8% versus 17.2%) and was not inferior to salazosulfapyridine (63.1% versus 57.7%; 95% CI for the rate difference −7.9%, 18.7%). Likewise, a statistically significant benefit in patients with active RA was also observed with the ACR20 efficacy end point in either 25 mg/day or 50 mg/day dosage groups of T-614 in our previous phase II trial when compared with placebo (39.13%, 61.29%, and 24.21%, respectively) (18). In the present study, the efficacy of T-614 in the treatment of active RA patients was further confirmed when compared with MTX. The ACR20 response rate of T-614 (50 mg/day) is comparable with that shown in other trials.
ACR20, ACR50, and ACR70 response rates at all followup time points in the T-614 50 mg/day group were similar to those in the MTX group (Table 3). Therefore, we can infer that the onset of effect that occurred for patients in the T-614 50 mg/day treatment group may be similar to those in the MTX treatment group. In our phase II study, improvement was evident at 6 weeks in the patients treated with T-614 when compared with patients with placebo (18). In the report from Japan, T-614 was shown to exhibit its therapeutic effect within 8 weeks after the initiation of treatment with an initial dosage of 25 mg/day for 4 weeks (19).
In addition, RF and IgA, IgG, and IgM demonstrated a statistically significant decrease after 24 weeks of treatment in all groups. Together with what had been observed in an in vitro study (14, 16), it seems that the immunomodulating effect on B lymphocytes may play a role in the mechanism of action of T-614.
The reported adverse effects suggest that T-614 may be different from MTX in several ways. GI symptoms, specifically nausea and anorexia, were less common, whereas mild allergic reactions (predominantly rash and pruritus) were more common in patients receiving T-614 treatment (particularly in the higher initial dose group).
The most notable difference in the adverse event profile of the 2 medications was the lower incidence of abnormal plasma liver enzyme levels found in patients receiving T-614 than in MTX. However, elevations of plasma liver enzyme levels were still the most common adverse events in the T-614 groups. Moreover, T-614 appeared to cause elevated liver function in a dose-dependent manner at the beginning of administration. The results from a 52-week clinical study to evaluate the long-term safety of T-614 showed that T-614 was safe to use for a long time, but patients should be monitored closely for hepatic enzymes (20). Up to now, there is no evidence to suggest that T-614 treatment is associated with the development of clinically significant liver disease.
Similar to methotrexate, leucopenia and thrombocytopenia also occurred with T-614 treatment, but these complications are reversible and usually not severe. The incidence of infections was low and similar in the T-614 and MTX treatment groups.
It has been reported that T-614, as a member of the family of methanesulfonanilide, can inhibit both the activity and induction of COX-2 (30, 31). Therefore, more attention was given to GI ulcers and cardiovascular adverse events in our study. Fortunately, the incidences of new-onset or aggravating upper GI ulcer complications in the T-614 treatment groups were far lower than those in the group receiving MTX treatment. Moreover, all of these incidences might be overestimated, since subjects willing to accept endoscopy at baseline were likely to have more GI diseases. Low incidence of GI ulcers may result from the weak potency against COX-1 in T-614. In addition, there were no prominent cardiovascular adverse effects found in the T-614 or MTX treatment groups.
It is worth mentioning that our exclusion criteria could bias the results. The criteria excluding a patient's insufficient response to MTX may select for subjects with a higher capacity to benefit from MTX treatment, resulting in overestimates of effect in the MTX group. Also, the criteria excluding patients who had discontinued previous MTX therapy due to clinically important toxicity may underrate adverse effects in the MTX group. To reduce the potential bias that might be associated with prior MTX therapy, prior to starting the study we defined patients in the MTX group to receive MTX at a dosage of 10 mg/week for 4 weeks, followed by 15 mg/week for 20 weeks; patients with insufficient efficacy to MTX treatment in dosages of ≥15 mg/week for more than 20 weeks were excluded. The reason lay in that multiple DMARDs, i.e., low-dose combination therapy as the preferred treatment regimen for RA, had been adopted by 12 centers participating in our trial and the majority of RA patients in these centers received MTX treatment at a dosage of <15 mg/week (commonly 10 mg/week). Therefore, very few patients would be excluded owing to the insufficient efficacy of MTX ≥15 mg/week according to our protocol. In addition, in fact, less than 15% of patients included in our trial had previous DMARD treatment (Table 1). Therefore, the bias resulting from prior MTX therapy was actually greatly limited. More importantly, these criteria could not actually exaggerate the efficacy and safety of T-614 itself, but instead raised the threshold to assess the noninferiority of T-614.
In summary, the results of this trial suggest that T-614 therapy 50 mg/day is as effective as MTX therapy in 24 weeks and represents a new option for the treatment of patients with active RA. However, attention should be paid to the potential adverse reactions of T-614 such as abnormal liver enzymes, hematologic disorder, skin reactions, and GI symptoms. Furthermore, to assess the effect of long-term T-614 treatment on the progression of articular destruction, a study evaluating radiograph progression in patients with early RA treated with T-614 for 2 years has been planned in China.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Bao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Bao, Jian-hua Li.
Acquisition of data. Lu, Bao, Dai, Teng, Fan, Du, Yang, Zhao, Chen, Xu, He, Wu, Tao, Zhang, Han, Xin-fu Li, Gu.
Analysis and interpretation of data. Lu, Bao, Yu.
Simcere Pharmaceuticals provided the study drugs (T-614 and methotrexate) and placebo tablets. The publication of this article was contingent on the approval of Simcere Pharmaceuticals.