Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study.

BACKGROUND: We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). METHODS: The study had two parts: a dose-response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). RESULTS: In the dose-response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. CONCLUSION: The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. CLINICAL TRIAL REGISTRATION: NCT02517320 (dose-response study) and NCT02676401 (extension study).

Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs: Final results of the GO-MONO trial through week 120.

OBJECTIVE: Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs. METHODS: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, n = 105), golimumab 50 mg (Group 2, n = 101), or golimumab 100 mg (Group 3, n = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120. RESULTS: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE. CONCLUSION: Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.

High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study.

BACKGROUND: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. METHODS: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: "low/low-C" (RF < 55 IU/ml, anti-CCP < 42 U/ml), "high/high-C" (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. RESULTS: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 µg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. CONCLUSIONS: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00691028 . Retrospectively registered on 3 June 2008.

A multicenter, open-label, long-term study of three-year infliximab administration in Japanese patients with ankylosing spondylitis.

OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of infliximab (IFX) in Japanese patients with active ankylosing spondylitis (AS). METHODS: In this multicenter open-label study, IFX was infused at 5 mg/kg to 33 Japanese patients with active AS using or intolerable to non-steroidal anti-inflammatory drugs (NSAIDs) at Weeks 0, 2, and 6, and then every six weeks for approximately three years (mean: 149.5 weeks). RESULTS: Assessment in Ankylosing Spondylitis (ASAS) 20 response at Week 24 (primary endpoint) was 97.0% (32/33) and was thereafter maintained at approximately 90% over the three-year study period. Improvements in range of motion, physical function, inflammatory parameters, and quality of life (QOL) were all maintained throughout the three-year study period. A serum IFX level of ≥5 µg/mL was maintained with six-week infusion intervals, and only two patients (6.1%) developed antibodies to IFX. Specific adverse events in AS patients were not observed. CONCLUSION: These findings suggest that a 5 mg/kg administration of IFX at six-week intervals to Japanese patients with active AS is safe, effective and provides long-term therapeutic benefits.

Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial.

OBJECTIVE: To evaluate the safety and efficacy of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). METHODS: Japanese patients with active RA despite MTX were randomized to placebo + MTX (Group 1, n = 88), golimumab 50 mg + MTX (Group 2, n = 86), or golimumab 100 mg + MTX (Group 3, n = 87). Patients with <20% improvement in swollen/tender joint counts entered early escape at week 16. At week 24, all remaining placebo patients crossed over to golimumab 50 mg. Efficacy assessments included ACR20, DAS28-ESR, and HAQ-DI. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. RESULTS: ACR20 response rates in Group 1, Group 2, and Group 3 were 67.9, 86.1, and 82.4%, respectively, at week 52 and were maintained through week 104 (87.1, 94.0, and 88.7%) and week 156 (97.1, 94.1, and 89.5%). Proportions of patients with good/moderate DAS28-ESR response or clinically meaningful improvement in HAQ-DI were also maintained through week 156. The majority of patients did not experience radiographic progression through week 156. Among 257 golimumab-treated patients, 251 (97.7%) had ≥1 AE; 54 (21.0%) had ≥1 serious AE through week 156. Infections were the most common type of AE. CONCLUSIONS: Response to golimumab + MTX was maintained over 3 years in Japanese patients with active RA despite MTX. Safety results were consistent with the known safety profile of golimumab.

Efficacy and safety of canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: A 52-week open-label study.

AIMS/INTRODUCTION: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor under development for the treatment of type 2 diabetes. Our aim was to examine its efficacy and safety as monotherapy or in combination with commonly used oral antihyperglycemic drugs in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: Patients on diet/exercise alone or diet/exercise plus an oral antihyperglycemic drug (sulfonylurea, glinide, α-glucosidase inhibitor, biguanide, thiazolidinedione or dipeptidyl peptidase-4 inhibitor) were randomized to either 100 or 200 mg canagliflozin while continuing prior therapy. Patients were treated for 52 weeks in an open-label manner. RESULTS: Canagliflozin significantly reduced hemoglobin A1c, fasting plasma glucose and bodyweight in all the study groups. Improvements were apparent by 4 weeks of treatment, and were maintained for 52 weeks. The reduction in hemoglobin A1c ranged from -0.80 to -1.06%, and from -0.93 to -1.26% in the 100 and 200 mg canagliflozin groups, respectively. Drug-related adverse events occurred in approximately one-third of patients, and included hypoglycemia/asymptomatic hypoglycemia and pollakiuria. Hypoglycemia/asymptomatic hypoglycemia was most common in patients treated with a sulfonylurea. Most adverse events were classified as mild or moderate in severity. CONCLUSIONS: The results of the present study confirmed that treatment with canagliflozin resulted in significant reductions in glycemic control and bodyweight that were maintained for 52 weeks of treatment irrespective of whether it was administered as monotherapy or in combination with another oral antihyperglycemic drug. Canagliflozin was well tolerated, with a low incidence of drug-related adverse events. This trial was registered with ClinicalTrials.gov (no. NCT01387737).

Prediction of clinical response after 1 year of infliximab therapy in rheumatoid arthritis based on disease activity at 3 months: posthoc analysis of the RISING study.

OBJECTIVE: To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). METHODS: Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. RESULTS: Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, > 50% of patients continuing 3 mg/kg therapy would not be able to achieve REM or LDA at W54. However, even in patients with high or moderate disease activity at W14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. CONCLUSION: Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy.

Pharmacokinetic and pharmacodynamic profiles of canagliflozin in Japanese patients with type 2 diabetes mellitus and moderate renal impairment.

BACKGROUND AND OBJECTIVES: This study examined the effects of moderate renal impairment on the pharmacokinetics and pharmacodynamics of canagliflozin in Japanese patients with type 2 diabetes mellitus. METHODS: Japanese patients with stable type 2 diabetes (12 with moderate renal impairment and 12 with normal renal function or mild renal impairment) were eligible. This was an open-label, randomized, two-way crossover, two-sequence, single-dose study performed at a single center in Japan. The subjects were hospitalized for the pharmacodynamic/pharmacokinetic evaluations. Twenty-four patients received a single dose each of canagliflozin 100 and 200 mg before breakfast in a crossover manner with a 14-day washout between doses. The main outcome measures were pharmacokinetics of canagliflozin and its main metabolites (M5 and M7) in plasma and urine, and change from baseline in 24-h urinary glucose excretion (ΔUGE24 h). RESULTS: There was no significant effect of moderate renal impairment on the maximum canagliflozin concentration. The ratios of least square means (90 % confidence intervals [CIs]) of moderate renal impairment relative to normal renal function or mild renal impairment were 0.982 (0.821-1.173) and 0.989 (0.827-1.182) for the 100 and 200 mg doses, respectively. The canagliflozin area under the plasma concentration-time curve was greater in those with moderate renal impairment than in those without, after both canagliflozin doses (ratio of least square means [90 % CI] 1.258 [1.061-1.490] and 1.216 [1.026-1.441]). ΔUGE24 h increased after administration of both doses, but in patients with moderate renal impairment, the increase was approximately 70 % of that in patients with normal renal function or mild renal impairment. The incidence of adverse events was low and no patient developed hypoglycemia. CONCLUSION: The pharmacokinetics of canagliflozin are affected by renal function, with slight decreases in renal clearance observed. No effect of renal impairment on the maximum concentration was observed. Renal impairment reduced the ability of canagliflozin to promote urinary glucose excretion.

Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study.

OBJECTIVE: To examine the efficacy and safety of canagliflozin monotherapy, a sodium/glucose co-transporter 2 inhibitor, in Japanese type 2 diabetes patients. METHODS: In this double-blind, multi-centre Phase III study, patients aged ≥ 20 years with hemoglobin A1c (HbA1c) 7.0-10.0% on diet/exercise therapy alone received placebo or canagliflozin (100 or 200 mg) once daily for 24 weeks. The main outcome measure was the change in HbA1c from baseline to Week 24. RESULTS: The changes in HbA1c (-0.74 and -0.76 vs + 0.29%), fasting plasma glucose (1 mg/dl = 0.0555 mmol/l; -31.6 and -31.9 vs + 3.7 mg/dl), 2-h plasma glucose after 75-g glucose load (-84.9 and -79.0 vs -0.5 mg/dl), body weight (percent change: -3.76 and -4.02 vs -0.76%) and systolic blood pressure (-7.88 and -6.24 vs -2.72 mmHg) were significantly greater with 100 and 200 mg canagliflozin than with placebo (all, p < 0.05). Genital infections in females (6.5, 6.3 and 0%) and asymptomatic hypoglycemia (4.4, 5.6 and 2.2%), but not symptomatic hypoglycemia (2.2, 1.1 and 1.1%), were more frequent in the 100- and 200-mg groups than in the placebo group. CONCLUSION: Canagliflozin significantly improved glycemic control and was well tolerated.

C-reactive protein is an indicator of serum infliximab level in predicting loss of response in patients with Crohn's disease.

BACKGROUND: The ability of serum infliximab level to predict clinical outcome in infliximab therapy in Crohn's disease is unclear. Here, we aimed to clarify the correlation between the timing of loss of response (LOR) to treatment and a decrease in serum infliximab level, and, in addition, to identify an indicator of infliximab level. METHODS: The study used data from a previous clinical study of infliximab for Crohn's disease, in which infliximab was initially given at 0, 2, 6 weeks at 5 mg/kg, and then at 8-week intervals to 62 week-10 responders. Of these 62, here we analysed data from 57 in whom Crohn's disease activity index and serum infliximab level were evaluated at week 14. RESULTS: Twelve patients showed a clinical response despite an infliximab level <1 µg/mL at week 14; of these, 8 (67 %) experienced LOR by week 54. A decrease in infliximab level preceded LOR in 6 (75 %). In receiver operating characteristic curve analysis, C-reactive protein (CRP) showed better performance in detecting an infliximab level <1 µg/mL. Infliximab level was <1 µg/mL in 60-80 % of patients with CRP >0.5 mg/dL. Time to LOR (median: 22.0 weeks) was significantly longer than that to a decrease in infliximab level to <1 µg/mL (14.0 weeks, p < 0.05) or to an increase in CRP to >0.5 mg/dL (14.0 weeks, p < 0.01). CONCLUSIONS: A decrease in serum infliximab level preceded LOR, and was easily detected by an increase in CRP. The CRP may be an indicator of serum infliximab level in predicting LOR.

Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicentre, randomised, double-blind, placebo-controlled GO-MONO study through 24 weeks.

OBJECTIVE: To evaluate the efficacy and safety of golimumab 50 and 100 mg monotherapy in Japanese patients with active rheumatoid arthritis (RA) despite treatment with disease-modifying antirheumatic drugs (DMARDs). METHODS: A total of 316 patients were randomised to receive subcutaneous injections every 4 weeks of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3); group 1 crossed over to golimumab 50 mg at week 16. The primary end point was the proportion of patients achieving ≥20% improvement in the American College of Rheumatology criteria (ACR20) at week 14. ACR50 and ACR70 response rates were also measured. Adverse events (AEs) were monitored throughout the study. RESULTS: Demographics were similar across groups; the mean age was 52 years and 81.8% of patients (252/308) were female. Week 14 ACR20 response rates were significantly greater in groups 2 (51/101 (50.5%)) and 3 (60/102 (58.8%)) than in group 1 (20/105 (19.0%); p<0.0001 for both), as were ACR50 and ACR70 response rates. After placebo crossover at week 16, week 24 ACR response rates were similar in groups 1 and 2. Through week 16, 63.8% of patients in group 1, 62.4% in group 2 and 60.8% in group 3 had AEs and 1.9%, 1.0% and 2.0% had serious AEs. After week 16, one malignancy was reported (breast cancer, group 3). Infections were the most common AEs. No deaths or cases of tuberculosis were reported through week 24. CONCLUSIONS: Golimumab monotherapy (50 and 100 mg) was effective in reducing the signs and symptoms of RA in Japanese patients with active disease despite DMARD treatment.

Dramatic impact of a Psoriasis Area and Severity Index 90 response on the quality of life in patients with psoriasis: an analysis of Japanese clinical trials of infliximab.

European S3 Guidelines on the systemic treatment of psoriasis in 2009 propose 75% or more improvement in the Psoriasis Area and Severity Index from baseline (PASI 75) and a Dermatology Life Quality Index (DLQI) of 0 or 1 as treatment goals. However, the relationship of these two parameters is yet to be clarified. Herein, we analyzed the data pooled from two Japanese phase III clinical trials on psoriasis with infliximab to clarify the PASI response necessary to achieve a DLQI of 0 or 1. Of the 90 patients, the mean percent improvement in PASI at week 50 or 66 was 74.5%, and the PASI 75 and PASI 90 response rates were 66.7% and 46.7%, respectively; no difference in the improvement was noted among the body areas. Significant improvements in nail psoriasis were also observed. A negative correlation was shown between the improvement in PASI and DLQI. Patients who achieved a PASI 90 response had a significantly higher percentage of achieving a DLQI of 0 or 1 than the patients who achieved a PASI 75 but not a PASI 90 response. The median serum trough level of infliximab was maintained at 2 µg/mL or more in the PASI 90 responders, whereas it was less than 1 µg/mL at week 30 and on in the others. The present results demonstrate that a PASI 90 response is necessary to achieve a DLQI of 0 or 1. Infliximab is considered a useful drug in meeting the treatment goal of achieving a DLQI of 0 or 1 through the attainment of a PASI 90 response.

Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study.

OBJECTIVE: To assess the efficacy and safety of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). METHODS: 269 Japanese patients with active RA despite treatment with MTX were randomised (1:1:1) to placebo + MTX (Group 1), golimumab 50 mg + MTX (Group 2) or golimumab 100 mg + MTX (Group 3). Subcutaneous golimumab/placebo was injected every 4 weeks; stable doses of oral MTX (6-8 mg/week) were continued. Patients were allowed to enter early escape (Group 1 added golimumab 50 mg, Group 2 increased golimumab to 100 mg, Group 3 continued golimumab 100 mg) based on swollen/tender joint counts at week 14. The primary study endpoint was achievement of at least 20% improvement in the American College of Rheumatology (ACR20) response criteria at week 14. To control for multiplicity of testing, treatment group comparisons were first made between combined Groups 2 and 3 versus Group 1, followed by comparisons of Group 2 and Group 3 versus Group 1. RESULTS: The proportion of patients with an ACR20 response at week 14 was significantly higher in combined Groups 2 and 3 (73.4%, 127/173) and in each of Group 2 (72.1%, 62/86) and Group 3 (74.7%, 65/87) compared with Group 1 (27.3%, 24/88; p<0.0001 for all comparisons). Golimumab + MTX also elicited a significantly better response than placebo + MTX in other efficacy parameters, including disease activity score (DAS28) response/remission and radiographic assessments. During the 16-week fixed treatment regimen study period, 72.7%, 75.6% and 78.2% of patients had adverse events and 1.1%, 1.2% and 2.3% had serious adverse events in Groups 1, 2 and 3, respectively. CONCLUSION: In Japanese patients with active RA despite MTX therapy, golimumab + MTX was significantly more effective than MTX monotherapy in reducing RA signs/symptoms and limiting radiographic progression with no unexpected safety concerns.

Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). METHODS: Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). RESULTS: In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 µg/ml) at 3 and 6 mg/kg but were greater than 2 µg/ml at 10 mg/kg, whereas the levels were approximately 1 µg/ml for each dosage group in TNF-low patients. CONCLUSION: In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab.