Immunogenicity of sarilumab and impact on safety and efficacy in Japanese patients with rheumatoid arthritis: analysis of two Phase 3 randomised clinical trials.

OBJECTIVES: To describe the immunogenicity profile of sarilumab in Japanese patients with rheumatoid arthritis (RA). METHODS: Patients enrolled in the KAKEHASI and HARUKA studies were included in our analysis. In these studies, patients received sarilumab 150 mg or 200 mg every 2 weeks for 52 or 28 weeks in combination with methotrexate (MTX) (KAKEHASI), or for 52 weeks as monotherapy or in combination with non-MTX conventional synthetic disease-modifying anti-rheumatic drugs (HARUKA). Anti-drug antibodies (ADAs) and neutralising antibodies (NAbs) were assessed in the pooled population. RESULTS: Positive ADA assay responses occurred in 10/149 (7.1%) patients treated with sarilumab 150 mg and 13/185 (7.0%) patients treated with sarilumab 200 mg, with persistent responses in 2 (1.4%) and 4 (2.2%) patients, respectively. Peak ADA titre was 30. No patients treated with the 150 mg dose and one patient (0.5%) treated with the 200 mg dose exhibited NAbs. There was no evidence of an association between ADA formation and hypersensitivity reactions or reduced efficacy. CONCLUSIONS: ADAs, which occurred at a low frequency and titre, did not affect the safety or efficacy of sarilumab 150 or 200 mg administered as monotherapy or combination therapy in Japanese patients with RA in the KAKEHASI or HARUKA studies.

Inference on the rate ratio of recurrent events for the matched pairs design.

As statistical methods for testing the null hypothesis of no difference between two groups for the matched pairs design, the paired-t test, Wilcoxon signed rank sum test and McNemar test are well known. However, there is no simple test for the comparison of incidence rate of recurrent events. This paper proposes a simple statistical method and a sample size formula for the comparison of counts of recurrent events over a specified period of observation under the matched pairs design, where the subject-specific incidence of recurrent events is assumed to follow a time-homogeneous Poisson process. As a special case, the proposed method is found to be virtually equivalent in form to Mantel-Haenszel method for a common rate ratio among the set of stratified tables based on person-time data. The proposed methods are illustrated with the within-arm comparison of data from a clinical trial of 59 epileptics with baseline count data.

Photoswitchable phospholipid FRET acceptor: Detergent free intermembrane transfer assay of fluorescent lipid analogs.

We have developed and characterized a novel photoswitchable phospholipid analog termed N-nitroBIPS-DPPG. The fluorescence can be switched on and off repeatedly with minimal photobleaching by UV or visible light exposure, respectively. The rather large photochromic head group is inserted deeply into the interfacial membrane region conferring a conical overall lipid shape, preference for a positive curvature and only minimal intermembrane transfer. Utilizing the switchable NBD fluorescence quenching ability of N-nitroBIPS-DPPG, a detergent free intermembrane transfer assay system for NBD modified lipids was demonstrated and validated. As NBD quenching can be turned off, total NBD associated sample fluorescence can be determined without the need of detergents. This not only reduces detergent associated systematic errors, but also simplifies assay handling and allows assay extension to detergent insoluble lipid species.

Sustained glycaemic control and less nocturnal hypoglycaemia with insulin glargine 300U/mL compared with glargine 100U/mL in Japanese adults with type 1 diabetes (EDITION JP 1 randomised 12-month trial including 6-month extension).

AIMS: To evaluate the efficacy and safety of insulin glargine 300U/mL (Gla-300) versus glargine 100U/mL (Gla-100) in adults with type 1 diabetes in Japan over 12months. METHODS: EDITION JP 1 was a multicentre, randomised, open-label phase 3 study. Following a 6-month on-treatment period, participants continued to receive Gla-300 or Gla-100 once daily, plus mealtime insulin, over a 6-month open-label extension phase. HbA1c, hypoglycaemia, body weight and adverse events were assessed. RESULTS: Overall, 114/122 (93%) and 114/121 (94%) of participants in the Gla-300 and Gla-100 group, respectively, completed the 6-month extension phase. Glycaemic control was sustained in both groups up to month 12 (mean HbA1c: Gla-300, 7.9% [62mmol/mol]; Gla-100, 7.8% [62mmol/mol]). Annualised rates of hypoglycaemia were lower with Gla-300 versus Gla-100; significantly for nocturnal confirmed (<3.0mmol/L [<54mg/dL]) or severe hypoglycaemia (2.39 and 3.85 events per participant-year; rate ratio: 0.62 [0.39-0.97]). No between-treatment differences in mean body weight change or adverse events were observed. CONCLUSION: Over 12months' treatment, participants with type 1 diabetes receiving Gla-300 achieved sustained glycaemic control and experienced less nocturnal hypoglycaemia that was confirmed (<3.0mmol/L [<54mg/dL]) or severe compared with Gla-100, supporting the 6-month results.

Protective effects of melatonin on gamma-ray induced intestinal damage.

PURPOSE: To examine the protective effects of melatonin on intestinal damage induced by gamma-rays. MATERIALS AND METHODS: Six-week-old Slc:ICR male mice were used. Mice were given whole-body irradiation at various exposure doses (7-21 Gy) with (137)Cs gamma-rays (0.98 Gy/min). The mice were orally administered 1 ml of either 1% carboxymethyl cellulose sodium salt (CMC) or melatonin (1, 5, 10 or 20 mg/ml) freshly prepared as a uniform suspension in CMC before or after irradiation. The concentrations of plasma melatonin were determined by the radioimmunoassay (RIA) method. The mice were killed at 3.5 days after the exposure. The jejunum was removed, fixed in formalin and then stained with hematoxylin and eosin. The numbers of crypts per transverse circumference were counted using a microscope for 10 histological sections of each mouse. RESULTS: The intestinal damage caused by gamma-ray irradiation was prevented by melatonin correlating to dosage. The D(0) (slope of the dose-survival curve) value significantly (p < 0.05) increased from 1.55 +/- 0.19 (mean +/- SD) Gy to 1.98 +/- 0.16 Gy by orally administering 20 mg melatonin 30 min before irradiation. The radioprotective effect of melatonin continued for 6 h after the administration. CONCLUSIONS: Melatonin is judged to be a potential protector against intestinal damage associated with radiotherapy. Further experimental and clinical studies on this subject are needed to allow its use for radiotherapy.