A Randomized, Placebo-Controlled Phase III Extension Trial of the Long-Term Safety and Tolerability of Anifrolumab in Active Systemic Lupus Erythematosus.

OBJECTIVE: To explore long-term safety and tolerability of anifrolumab 300 mg compared with placebo in patients with systemic lupus erythematosus (SLE) who completed a Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trial and enrolled in the placebo-controlled 3-year long-term extension (LTE) study (ClinicalTrials.gov identifier: NCT02794285). METHODS: In the blinded LTE study, patients continued anifrolumab 300 mg, switched from anifrolumab 150 mg to 300 mg, or were re-randomized from placebo to receive either anifrolumab 300 mg or to continue placebo, administered every 4 weeks. Primary comparisons in the LTE study were between patients who received anifrolumab 300 mg or placebo throughout the TULIP and LTE studies. For rare safety events, comparisons included patients who received any anifrolumab dose during TULIP or LTE. When exposure differed, exposure-adjusted incidence rates (EAIRs) per 100 patient-years were calculated. RESULTS: In the LTE study, EAIRs of serious adverse events (SAEs) were 8.5 with anifrolumab compared with 11.2 with placebo; likewise, EAIRs of AEs leading to treatment discontinuation were 2.5 versus 3.2, respectively. EAIRs of non-opportunistic serious infections were comparable between groups (3.7 with anifrolumab versus 3.6 with placebo). Exposure-adjusted event rates of COVID-related AEs, including asymptomatic infections, were 15.5 with anifrolumab compared with 9.8 with placebo. No COVID-related AEs occurred in fully vaccinated individuals. EAIRs of malignancy and major acute cardiovascular events were low and comparable between groups. Anifrolumab was associated with lower cumulative glucocorticoid use and greater mean improvement in the SLE Disease Activity Index 2000, compared with placebo. CONCLUSION: This LTE study represents the longest placebo-controlled clinical trial performed in SLE to date. No new safety findings were identified in the LTE study, supporting the favorable benefit-risk profile of anifrolumab for patients with moderate-to-severe SLE receiving standard therapy.

Efficacy and safety of three-times-daily versus twice-daily biphasic insulin aspart 30 in patients with type 2 diabetes mellitus inadequately controlled with basal insulin combined with oral antidiabetic drugs.

AIMS: To compare the efficacy and safety of biphasic insulin aspart 30 (BIAsp 30) administered three times daily (TID) vs. twice daily (BID), plus metformin, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on basal insulin ± 1 oral antidiabetic drug (OAD). METHODS: Randomised, multinational, open-label, treat-to-target trial. Subjects inadequately controlled (HbA1c 7.5-10.0%) on basal insulin and metformin ±â€¯1 OAD were randomised to BIAsp30 TID (n = 220) or BIAsp30 BID (n = 217). Primary endpoint was change from baseline in HbA1c after 24 weeks of treatment. RESULTS: Most (400/437, 91.5%) subjects completed the trial. The majority (276/400 [69.0%]) were from the China region. After 24 weeks, HbA1c decreased comparably in both BIAsp 30 groups (-1.7% vs. -1.6% [-19 vs. -18 mmol/mol], for TID and BID dosing, respectively; estimated treatment difference: -0.09% [-0.23; 0.06]95% CI, -1 mmol/mol [-3; 1], p = 0.26). Safety profiles, including number of subjects experiencing hypoglycaemia, were similar. CONCLUSIONS: BIAsp 30 administered either TID or BID with metformin was a safe and effective option when intensifying treatment after failure of basal insulin and OADs in patients with T2DM. Adding a third injection at lunchtime may be preferable if HbA1c remains above target, if the lunchtime meal is the largest meal of the day, or if persistent postprandial hyperglycaemia after lunch is observed. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT02582242.

A 32-Week Randomized Comparison of Stepwise Insulin Intensification of Biphasic Insulin Aspart (BIAsp 30) Versus Basal-Bolus Therapy in Insulin-Naïve Patients with Type 2 Diabetes.

INTRODUCTION: This 32-week, open-label, randomized, parallel-group, multinational trial aimed to compare the efficacy and safety of stepwise insulin intensification of biphasic insulin aspart 30 (BIAsp 30) relative to stepwise intensification of a basal-bolus regimen in insulin-naïve adults with type 2 diabetes (T2D) who continued pretrial treatment with metformin and sulfonylurea. METHODS: Adults with T2D were randomized into one of two treatment arms for 32 weeks: (1) BIAsp 30 once daily (OD), with the possibility of stepwise treatment intensification up to BIAsp 30 three times daily (TID); (2) insulin glargine OD, with the possibility of stepwise treatment intensification with insulin aspart up to TID. The primary endpoint was change from baseline in HbA1c after 32 weeks. RESULTS: After 32 weeks, the estimated mean change in HbA1c from baseline was statistically significantly lower in the BIAsp 30 arm (- 1.18%) versus basal-bolus (- 1.36%) [estimated treatment difference 0.18%; 95% confidence interval (95% CI) 0.01; 0.36; p < 0.05]. The proportion of patients with HbA1c below 7.0% was statistically significantly lower with BIAsp 30 (42.9%) compared with basal-bolus (56.9%) (odds ratio 0.58; 95% CI 0.37; 0.89; p = 0.01). The overall rate of severe or blood glucose (BG)-confirmed hypoglycemic events was numerically lower for BIAsp 30 compared with basal-bolus, and a statistically significantly lower rate in nocturnal severe or BG-confirmed hypoglycemia in the BIAsp 30 arm relative to basal-bolus was observed: estimated rate ratio 0.32 (95% CI 0.13; 0.79), p = 0.0131. The proportion of patients with adverse events was similar in both treatment arms. CONCLUSION: Insulin intensification with BIAsp 30 and basal-bolus showed an improvement in glycemic control; the change in HbA1c was statistically significantly lower for BIAsp 30 compared to basal-bolus. Basal-bolus treatment was accompanied by a numerically, and statistically significantly, higher rate of overall and nocturnal severe or BG-confirmed hypoglycemia, respectively, compared with BIAsp 30. FUNDING: Novo Nordisk A/S. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02453685.