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In this study, researchers looked at the safety of tanezumab (a medication that blocks nerve growth factor) in Japanese people with chronic low back pain (CLBP). Researchers also looked at how well tanezumab improves the symptoms (pain and difficulty doing activities) of CLBP. People in the study were given oral (taken by mouth) celecoxib (a medication commonly used to treat CLBP) or injections of tanezumab (5 or 10 mg doses) under the skin of the belly or upper leg every 8 weeks for a total of 56 weeks. Side effects (something expected or unexpected that people experienced during the study that may or may not be due to the medication they received) occurred in 63.0% of people receiving tanezumab 5 mg, 54.8% of people receiving tanezumab 10 mg and 67.4% of patients receiving celecoxib. More people receiving tanezumab 5 mg (9.8% of people) had a side effect related to abnormal peripheral sensation (tingling, burning, numbness or sensitivity to heat or cold hands or feet) than people receiving tanezumab 10 mg (4.3% of people) or celecoxib (4.3% of people). More people receiving tanezumab (5 mg = 1.1% of people, 10 mg = 2.2% of people) had a problem with one of their joints (knees or hips) during the study than people receiving celecoxib (0% of people). All treatments improved pain and the ability to do activities. Overall, the researchers concluded that tanezumab was well tolerated in most people and may improve the symptoms of CLBP.

Background/Aims: PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAd CAM-1) that prevents the binding of α4β7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high af finity and selectivity, and is being developed for the treatment of Crohn’s disease (CD). Methods: OPERA is a randomized, mul ticenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 fol lowing subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein >3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn’s Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients. Results: In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) de fined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating β7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment. Conclusions: In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509) (Intest Res 2020;18:45-55)

Background: In the process of research and development of a new treatment, clinical trials are conducted to evaluate its safety and efficacy. Key to streamlining the process is to utilize appropriate historical information on an outcome of a control treatment when designing and analyzing a clinical trial. Methods: For the use of such historical control information, there exist a meta-analytic approach and power prior approach. In this article, we evaluate their performance with regard to the type I error (TIE) rate and power through a simulation study where we analyze the data on a binary outcome of an experimental treatment and a control treatment from a new small-scale trial, along with the corresponding data of the control treatment from multiple historical trials. The reason is that the difference in the performance between the 2 approaches has not been clear. Results: When historical trials were homogeneous, the power was higher in the power prior approach and the meta-analytic approach using a beta-binomial model with a less noninformative prior than the other approaches. However, when heterogeneous historical trials were mixed, the power was lower, or the TIE rates got inflated. Conclusions: To make use of historical control data, if importance is attached to control of the TIE rate, the meta-analytic approach using a normal-normal hierarchical model may be preferable to the power prior approach, whereas if attached to improvement of the power, this preference be reversed. Anyway, the best approach should be chosen by comparing the operational characteristics of the approaches.

Tanezumab is a monoclonal antibody against nerve growth factor that is under investigation for the treatment of osteoarthritis (OA) pain. We conducted subgroup analyses of two randomized phase 3 studies to summarize efficacy, general safety, and adjudicated joint safety of tanezumab in Japanese patients with moderate-to-severe OA.In Study 1 (NCT02528188), patients received subcutaneous tanezumab 2.5 mg or 5 mg every 8 weeks or daily oral nonsteroidal anti-inflammatory drugs (NSAID) for 56 weeks. The co-primary efficacy endpoints were change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale score and WOMAC Physical Function subscale score at Week 16 (overall study and Japan-specific endpoints) as well as Patient Global Assessment (PGA)-OA score at Week 16 (overall study endpoint only). In Study 2 (NCT02709486), patients received subcutaneous tanezumab 2.5 mg, 5 mg, or placebo every 8 weeks for 24 weeks. Safety monitoring included adjudicated composite joint safety endpoint (CJSE) including rapidly progressive osteoarthritis type 1 (RPOA1), RPOA2, primary osteonecrosis, pathological fracture, or subchondral insufficiency fracture.For Study 1, Japanese patients (n = 200) treated with tanezumab 2.5 mg and 5 mg showed numerically greater improvements in WOMAC Pain, WOMAC Physical Function, and PGA-OA scores versus NSAID at Week 16. Incidences of treatment-emergent adverse events were generally similar between tanezumab 2.5 mg, 5 mg, and NSAID groups. In the integrated safety analysis (Studies 1 + 2; n = 306), ten patients were adjudicated to have a component of CJSE: RPOA1 [tanezumab 2.5 mg (n = 2), tanezumab 5 mg (n = 5)], RPOA2 [tanezumab 2.5 mg (n = 1), tanezumab 5 mg (n = 1)], or primary osteonecrosis [tanezumab 2.5 mg (n = 1)]. Time-adjusted adjudicated rates of RPOA1 and RPOA2 were higher with tanezumab than NSAID or placebo and increased with dose of tanezumab.Observations from the Japanese subgroup were generally consistent with the overall study populations.

Inflammatory bowel disease (IBD), which encompasses both ulcerative colitis (UC) and Crohn's disease (CD), is a risk factor for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE).To investigate the incidence of, and risk factors for, VTE in patients with IBD in Japan.This was a retrospective, non-interventional study in patients with IBD from the Japan Medical Data Center claims database. Incidence rates (IRs; unique patients with events per 100 patient-years) were calculated for VTE, DVT, and PE among the IBD, UC, and CD cohorts. Odds ratios of potential risk factors were calculated by univariate and multivariate analyses in a nested case-control design.Overall, 16 273 patients with IBD were included: 13 585 with UC and 3443 with CD. VTE events occurred in 1.3%, 1.2%, and 1.9% of patients with IBD, UC, and CD, respectively. In patients with IBD, UC, and CD, IRs of VTE were 0.45, 0.40, and 0.64, respectively, IRs of DVT were 0.42, 0.38, and 0.61, respectively, and IRs of PE were 0.07, 0.07, and 0.11, respectively. In patients with IBD, treatment history (immunomodulators), cardiovascular risk (hypertension, high-density lipoprotein or diabetes mellitus, and history of coronary artery disease or heart failure), malignancy, and undergoing major surgery were identified as potential risk factors for VTE in the multivariate analysis, with similar risk factors reported for patients with UC and CD.This large study provides insight into the incidence and risk factors for VTE in patients with IBD from Japan.

[Abstract] Background: To evaluate if early improvements in pain and function with subcuta-neous tanezumab are meaningful and sustained over 24 weeks. Methods: Patients with moderate- to- severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within- patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT- OARSI) responders (within- patient) and Patient- reported Treatment Impact Assessment- Modified questionnaire. Results: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tan-ezumab group versus placebo from Week 2 through Week 12 (LS mean, unad-justed p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT- OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05). Conclusions: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The propor-tions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486. Significance: This exploratory analysis of data from a placebo- controlled, Phase 3 study of patients with moderate- to- severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24- week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis.

Background/Aims: Tofacitinib is an oral, small-molecule Janus kinase inhibitor being investigated for ulcerative colitis (UC). In OCTAVE Induction 1 and 2, patients with moderately to severely active UC received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Clinical responders in OCTAVE Induction were re-randomized to 52 weeks’ therapy with placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID. Methods: We conducted post-hoc efficacy and safety analyses of East Asian patients in OC TAVE Induction 1 and 2 and OCTAVE Sustain. Results: A total of 121 East Asian (Japan, Korea, and Taiwan) patients were ran domized in OCTAVE Induction 1 and 2 (placebo, n=26; tofacitinib 10 mg BID, n=95), and 63 in OCTAVE Sustain (placebo, n=20; tofacitinib 5 mg BID, n=22; tofacitinib 10 mg BID, n=21). At week 8 of OCTAVE Induction 1 and 2, 18.9% of patients (18/95) achieved remission with tofacitinib 10 mg BID versus 3.8% (1/26) with placebo. In OCTAVE Sustain, the week 52 remission rates were 45.5% (10/22), 47.6% (10/21), and 15.0% (3/20) with 5 mg BID, 10 mg BID, and placebo, respectively. Adverse event rates were similar between groups in OCTAVE Induction and numerically higher with tofacitinib in OCTAVE Sustain. Serious adverse event rates were similar across groups in all studies. Infections were numerically more frequent with tofacitinib than placebo. Increases in serum lipid levels were observed with tofacitinib. Conclusions: In East Asian patients with UC, tofacitinib demonstrated numerically greater efficacy versus placebo as induction and maintenance therapy, with a safety profile consistent with the global study population. ClinicalTrials.gov: NCT01465763; NCT01458951; NCT01458574. (Intest Res 2018;16:233-245)

A Bayesian confidence propagation neural network (BCPNN) is a signal detection method used by the World Health Organization Uppsala Monitoring Centre to analyze spontaneous reporting system databases. We modify the BCPNN to increase its sensitivity for detecting potential adverse drug reactions (ADRs). In a BCPNN, the information component (IC) is defined as an index of disproportionality between the observed and expected number of reported drugs and events. Our proposed method adjusts the IC value by borrowing information about events that have occurred in drugs defined as similar to the target drug. We compare the performance of our method with that of a traditional BCPNN through a simulation study. The false positive rate of the proposed method was lower than that of the traditional BCPNN method and close to the nominal value, 0.025, around the true difference in ICs between the target drug and similar drugs equal to 0. The sensitivity of the proposed method was much higher than that of the traditional BCPNN method in case in which the difference in ICs between the target drug and similar drugs ranges from 0 to 2. When applied to a database managed by Japanese regulatory authority, the proposed method could detect known ADRs earlier than the traditional method. The proposed method is a novel criterion for early detection of signals if similar drugs have the same tendencies. The proposed BCPNN tends to have higher sensitivity when the true difference is greater than 0.

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor approved in Japan for the treatment of ulcerative colitis (UC). Differences in the safety profile of tofacitinib in Japanese patients versus the global population, such as a higher risk of herpes zoster, have been reported. Objectives: We conducted post hoc analyses of tofacitinib treatment in Japanese patients with moderate-to-severe UC in two global phase III studies. Methods: In OCTAVE Induction 1 (NCT01465763), 62 patients were randomized to placebo or tofacitinib 10 mg twice daily (b.i.d.). In OCTAVE Sustain (NCT01458574), 39 patients with clinical response in OCTAVE Induction 1 were re-randomized to placebo, tofacitinib 5 mg, or 10 mg b.i.d. Efficacy endpoints included: remission (primary endpoint; total Mayo score ≤2; no individual subscore >1; rectal bleeding subscore 0); mucosal healing (Mayo endoscopic subscore ≤1); clinical response (≥30% and ≥3-point decrease from induction study baseline total Mayo score; decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1). Adverse events (AEs) and clinical laboratory parameters were recorded. Results: At week 8 of OCTAVE Induction 1, 22.4% of patients achieved remission with tofacitinib (placebo, 7.7%). At week 52 of OCTAVE Sustain, 31.3% and 66.7% of patients receiving tofacitinib 5 and 10 mg b.i.d., respectively, achieved remission (placebo, 9.1%). The occurrence of AEs or serious AEs in Japanese patients was generally similar to that in the global study population, with no new or unexpected safety risks observed. Conclusions: Although patient numbers were small, tofacitinib demonstrated numerically greater efficacy versus placebo among Japanese patients in OCTAVE Induction 1 and OCTAVE Sustain, with a safety profile consistent with that of the global study population.

In randomized clinical trials, many medical and biological measurements are not normally distributed and are often skewed. The Box–Cox transformation is a powerful procedure for comparing two treatment groups for skewed continuous variables in terms of a statistical test. However, it is difficult to directly estimate and interpret the location difference between the two groups on the original scale of the measurement. We propose a helpful method that infers the difference of the treatment effect on the original scale in a more easily interpretable form. We also provide statistical analysis packages that consistently include an estimate of the treatment effect, covariance adjustments, standard errors, and statistical hypothesis tests. The simulation study that focuses on randomized parallel group clinical trials with two treatment groups indicates that the performance of the proposed method is equivalent to or better than that of the existing non-parametric approaches in terms of the type-I error rate and power. We illustrate our method with cluster of differentiation 4 data in an acquired immune deficiency syndrome clinical trial. Copyright © 2015 John Wiley & Sons, Ltd.

Since April 2008, Ministry of Health, Labor and Welfare of Japan has carried out Health Checkups and Healthcare Advice with a particular focus on the Metabolic Syndrome which make it obiligatory for person aged 40 through 74 to reduce medical expenses and prevent lifestyle-related diseases. However, Kondo (2004) indicates a lack of foundation for health checkup. And we think that it is important to clarify foundation for effect of health checkups and healthcare advice. In this paper, through consistent statistical data analysis, we suggested a method which evaluate directed effect, attempting to figure the doctor's charactor, based on results of the health checkups carried out in April, 2004. As a result, we confirmed that the doctor classified subjects in the directed group from their body types such as weight and BMI, and in directed effect that it reduced weight and BMI, but it gave increase of TG and decrease of HDL which were likely to develop abnormal lipid metabolism. So, we found that adequate evaluation for effect of healthcare advice after careful consideration about the doctor's charactor leads to suggestion of scientific foundation for health checkups and healthcare advice.

To evaluate the efficacy and safety of intravitreal injections of pegaptanib sodium in subjects with diabetic macular edema (DME).There were 243 subjects with DME who were randomized to receive, every 6 weeks, either an intravitreal injection of pegaptanib sodium or a sham injection. The study was double-masked for the first 24 weeks, and then an open label phase continued to week 54. The primary efficacy endpoint was evaluated at week 24, and safety was assessed throughout the 54 weeks.The proportion of subjects who experienced more than 10 letters improvement of visual acuity in ETDRS chart from baseline to week 24 was statistically significantly greater (p-value = 0.0003) in the pegaptanib sodium group, 20.3%, than in the sham group, 5.0%. The incidence of treatment-related adverse events was similar between the treatment groups (pegaptanib sodium group: 10.6%, sham group: 10.0%). The reported adverse events were mainly mild or moderate ophthalmic events and related to the injection procedure. During open-label phase up to 54 weeks, no new safety concerns were identified compared with the double-masked phase. However, in light of the issue concerning proper maintenance of masking of the study treatments, the study was not considered as a well-controlled, double-masked study.