Comparison of the efficacy and safety of LBAL, a candidate adalimumab biosimilar, and adalimumab reference product in patients with active rheumatoid arthritis inadequately responding to methotrexate: a 52-week phase III randomised study.

OBJECTIVES: To evaluate the similarities between LBAL (adalimumab biosimilar candidate) and the adalimumab reference product (ADL) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 56-week study was conducted in Japan and Korea. During the first 24 weeks, patients subcutaneously received 40 mg of LBAL or ADL every two weeks (LBAL and ADL groups). During the subsequent 28 weeks, the LBAL group patients and half of the ADL group patients received LBAL (L-L and A-L arms). The remaining ADL group patients continued to receive ADL (A-A arm). The primary efficacy endpoint was the change from baseline in disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) at Week 24. American College of Rheumatology (ACR) response rates, adverse events (AEs), and anti-drug antibody (ADA) were also assessed. RESULTS: In total, 383 patients were randomised. The least squares (LS) mean changes from baseline in DAS28-ESR at Week 24 were -2.45 and -2.53 in the LBAL (n=191) and ADL (n=190) groups, respectively. The 95% confidence interval (CI; -0.139, 0.304) of the difference (0.08) was within the pre-specified equivalence margin (-0.6, 0.6). Up to Week 52, the decreases in DAS28-ESR were maintained in all three arms. No notable differences in ACR20/50/70 were observed. The AE and ADA incidences were comparable between the arms. CONCLUSIONS: LBAL was equivalent in efficacy and comparable in safety, including immunogenicity, to ADL. Switching from ADL to LBAL did not impact on efficacy and safety.

Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate.

OBJECTIVE: To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 54-week study was conducted in Japan and Korea. The primary efficacy endpoint was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24. American College of Rheumatology 20% (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated. RESULTS: In total, 374 patients were randomised to LBEC0101 (n=187) or ETN-RP (n=187). The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were -3.01 (95% CI -3.198 to -2.820) in the LBEC0101 group and -2.86 (95% CI -3.051 to -2.667) in the ETN-RP group. The estimated between-group difference was -0.15 and its 95% CI was -0.377 to 0.078, which was within the prespecified equivalence margin of -0.6 to 0.6. ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3% vs ETN-RP 86.7%). The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0% vs ETN-RP 92.5%), although fewer patients in the LBEC0101 group (1.6%) than the ETN-RP group (9.6%) developed ADAs. CONCLUSION: The clinical efficacy of LBEC0101 was equivalent to that of ETN-RP. LBEC0101 was well tolerated and had a comparable safety profile to ETN-RP. TRIAL REGISTRATION NUMBER: NCT02357069.

Comparative efficacy and safety of gemigliptin versus linagliptin in type 2 diabetes patients with renal impairment: A 40-week extension of the GUARD randomized study.

AIMS: The long-term safety and efficacy of gemigliptin was evaluated in the present extension study after a 12-week study during a 40-week follow-up period. METHODS: The main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7% to 11% and an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas patients in the placebo group were transitioned from placebo to linagliptin (N = 52). Each group received the indicated treatment over the subsequent 40-week period. A total of 102 patients consented to participate in the extension study, and 79 patients ultimately completed the study. RESULTS: The HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change ± standard error in HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00% ± 0.21% and 0.65% ± 0.22% lower at week 52 than at baseline (P < .001 and P = .003), respectively. No significant difference in the change in HbA1c level was found between the 2 groups (P = .148). Trends in fasting plasma glucose, fructosamine and glycated albumin levels in the 2 groups were similar to trends in HbA1c levels. The eGFR of both groups was also significantly lower at week 52 than at baseline, and no significant difference in change in eGFR was found between the 2 groups. In contrast, both drugs had little effect on urinary albumin excretion, although both drugs significantly reduced the urinary type IV collagen level. The overall rates of adverse events were similar between the 2 groups. CONCLUSIONS: Gemigliptin and linagliptin did not differ with respect to safety and efficacy in patients with T2DM and renal impairment. The 2 drugs had similar glucose-lowering effects, and the changes in eGFR and albuminuria were also similar. Additionally, the risk of side effects, including hypoglycaemia, was similar between the 2 groups.

Serum Urate-Lowering Efficacy and Safety of Tigulixostat in Gout Patients With Hyperuricemia: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Trial.

OBJECTIVE: To evaluate the safety and efficacy of the nonpurine xanthine oxidase inhibitor tigulixostat for lowering serum urate level in gout patients with hyperuricemia. METHODS: We conducted a multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding trial. After screening, gout patients with hyperuricemia were randomly assigned, after appropriate washout, to receive daily oral administration of 50 mg, 100 mg, or 200 mg of tigulixostat, or placebo for 12 weeks. Colchicine gout flare prophylaxis was administered to all patients. The primary end point was the proportion of patients with a serum urate level <5.0 mg/dl at week 12. RESULTS: A total of 143 patients were randomized to receive tigulixostat 50 mg (n = 34), 100 mg (n = 38), or 200 mg (n = 37), or placebo (n = 34). A significantly greater proportion of patients in the tigulixostat groups achieved the target serum urate level <5.0 mg/dl at week 12 (47.1% in the 50 mg group, 44.7% in the 100 mg group, and 62.2% in the 200 mg group) compared to the placebo group (2.9%) (P < 0.0001). The mean percentage change in serum urate level from baseline was also significantly greater in the tigulixostat groups (-38.8% to -61.8%) than in the placebo group at all time points (P < 0.0001). The rate of gout flares requiring rescue treatment ranged from 9.4% to 13.2% in the tigulixostat and placebo groups. The incidence of adverse events was 50.0% to 56.8% across all groups, and their severity was mild or moderate. CONCLUSION: Tigulixostat significantly lowered serum urate compared to placebo at all doses studied with an acceptable safety profile.

Two Randomized Controlled Trials of Hyaluronic Acid Fillers for the Correction of Nasolabial Folds.

YVOIRE Classic s (YC) and Restylane (RES) have similar rheological properties, which suit mid-dermis injection, while the rheological properties of YVOIRE Volume s (YV) are comparable to those of Perlane (PER), which suit deep dermis injection to treat deep wrinkles. Two similarly designed studies aimed to evaluate the performance and safety of YC and YV injected into the nasolabial folds (NLFs). METHODS: These were split-face designed, evaluator-blind, noninferiority studies. Fifty-eight subjects with moderate-to-severe NLFs were enrolled in the first study and treated with YC and RES, and 57 subjects were enrolled in the second study and treated with YV and PER. The Wrinkle Severity Rating Scale ranged from 1 (no visible fold) to 5 (extremely deep and long folds), and subject satisfaction was evaluated. RESULTS: The least squares mean Wrinkle Severity Rating Scale scores (standard error) at week 26 were 2.56 (0.09) for both YC- and RES-treated NLFs and 2.89 (0.08) and 2.91 (0.08) for YV- and PER-treated NLFs, respectively. The difference between the groups was 0 and 0.02, and the lower limit of its 95% confidence interval was -0.0725 and -0.0125, which was greater than the predefined margin (-0.29), proving the noninferiority of YC and YV to RES and PER, respectively. The safety profiles and subject satisfaction of YC and YV were similar to those of RES and PER, respectively. CONCLUSION: YC is comparable to RES and YV is comparable to PER in terms of performance and safety profiles, with NLF-correcting effects lasting for up to 26 weeks.

Long-term efficacy, safety and immunogenicity in patients with rheumatoid arthritis continuing on an etanercept biosimilar (LBEC0101) or switching from reference etanercept to LBEC0101: an open-label extension of a phase III multicentre, randomised, double-blind, parallel-group study.

BACKGROUND: To evaluate the long-term efficacy, safety and immunogenicity of continuing LBEC0101; the etanercept (ETN) biosimilar; or switching from the ETN reference product (RP) to LBEC0101 in patients with rheumatoid arthritis (RA). METHODS: This multicentre, single-arm, open-label extension study enrolled patients who had completed a 52-week randomised, double-blind, parallel phase III trial of LBEC0101 vs ETN-RP. Patients treated with ETN-RP during the randomised controlled trial switched to LBEC0101; those treated with LBEC0101 continued to receive LBEC0101 in this study. LBEC0101 (50 mg) was administered subcutaneously once per week for 48 weeks with a stable dose of methotrexate. Efficacy, safety and immunogenicity of LBEC0101 were assessed up to week 100. RESULTS: A total of 148 patients entered this extension study (70 in the maintenance group and 78 in the switch group). The 28-joint disease activity scores (DAS28)-erythrocyte sedimentation rate (ESR) were maintained in both groups from week 52 to week 100 (from 3.068 to 3.103 in the maintenance group vs. from 3.161 to 3.079 in the switch group). ACR response rates at week 100 for the maintenance vs. switch groups were 79.7% vs. 83.3% for ACR20, 65.2% vs. 66.7% for ACR50 and 44.9% vs. 42.3% for ACR70. The incidence of adverse events and the proportion of patients with newly developed antidrug antibodies were similar in the maintenance and switch groups (70.0% and 70.5%, 1.4% and 1.3%, respectively). CONCLUSIONS: Administration of LBEC0101 showed sustained efficacy and acceptable safety in patients with RA after continued therapy or after switching from ETN-RP to LBEC0101. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02715908 . Registered 22 March 2016.

A study of typhoid fever in five Asian countries: disease burden and implications for controls.

OBJECTIVE: To inform policy-makers about introduction of preventive interventions against typhoid, including vaccination. METHODS: A population-based prospective surveillance design was used. Study sites where typhoid was considered a problem by local authorities were established in China, India, Indonesia, Pakistan and Viet Nam. Standardized clinical, laboratory, and surveillance methods were used to investigate cases of fever of >or= 3 days' duration for a one-year period. A total of 441,435 persons were under surveillance, 159,856 of whom were aged 5-15 years. FINDINGS: A total of 21,874 episodes of fever were detected. Salmonella typhi was isolated from 475 (2%) blood cultures, 57% (273/475) of which were from 5-15 year-olds. The annual typhoid incidence (per 100,000 person years) among this age group varied from 24.2 and 29.3 in sites in Viet Nam and China, respectively, to 180.3 in the site in Indonesia; and to 412.9 and 493.5 in sites in Pakistan and India, respectively. Altogether, 23% (96/413) of isolates were multidrug resistant (chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole). CONCLUSION: The incidence of typhoid varied substantially between sites, being high in India and Pakistan, intermediate in Indonesia, and low in China and Viet Nam. These findings highlight the considerable, but geographically heterogeneous, burden of typhoid fever in endemic areas of Asia, and underscore the importance of evidence on disease burden in making policy decisions about interventions to control this disease.

Enteric fever burden in North Jakarta, Indonesia: a prospective, community-based study.

INTRODUCTION: We undertook a prospective community-based study in North Jakarta, Indonesia, to determine the incidence, clinical characteristics, seasonality, etiologic agent, and antimicrobial susceptibility pattern of enteric fever. METHODOLOGY: Following a census, treatment centre-based surveillance for febrile illness was conducted for two-years. Clinical data and a blood culture were obtained from each patient. RESULTS: In a population of 160,261, we detected 296 laboratory-confirmed enteric fever cases during the surveillance period, of which 221 (75%) were typhoid fever and 75 (25%)  were paratyphoid fever.  The overall incidence of typhoid and paratyphoid cases was 1.4, and 0.5 per thousand populations per year, respectively. Although the incidence of febrile episodes evaluated was highest among children under 5 years of age at 92.6 per thousand persons per year, we found that the burden of typhoid fever was greatest among children between 5 and 20 years of age. Paratyphoid fever occurred most commonly in children and was infrequent in adults. CONCLUSION: Enteric fever is a public health problem in North Jakarta with a substantial proportion due to paratyphoid fever. The results highlight the need for control strategies against enteric fever.