Efficacy and safety of once-weekly efpeglenatide in people with suboptimally controlled type 2 diabetes: The AMPLITUDE-D, AMPLITUDE-L and AMPLITUDE-S randomized controlled trials.

AIM: To evaluate the efficacy and safety of once-weekly (QW) efpeglenatide in people with type 2 diabetes (T2D) suboptimally controlled with oral glucose-lowering drugs and/or basal insulin (BI). MATERIALS AND METHODS: Three phase 3, multicentre, randomized controlled trials compared the efficacy and safety of QW efpeglenatide versus dulaglutide when added to metformin (AMPLITUDE-D), efpeglenatide versus placebo when added to BI ± oral glucose-lowering drugs (AMPLITUDE-L) or metformin ± sulphonylurea (AMPLITUDE-S). All trials were terminated early by the sponsor because of funding rather than safety or efficacy concerns. RESULTS: In AMPLITUDE-D, non-inferiority of efpeglenatide to dulaglutide 1.5 mg was shown in HbA1c reduction from baseline to week 56, least squares mean treatment difference (95% CI): 4 mg, -0.03% (-0.20%, 0.14%)/-0.35 mmol/mol (-2.20, 1.49); 6 mg, -0.08% (-0.25%, 0.09%)/-0.90 mmol/mol (-2.76, 0.96). The reductions in body weight (approximately 3 kg) from baseline to week 56 were similar across all treatment groups. In AMPLITUDE-L and AMPLITUDE-S, numerically greater reduction in HbA1c and body weight were observed at all doses of efpeglenatide than placebo. American Diabetes Association level 2 hypoglycaemia (< 54 mg/dL [< 3.0 mmol/L]) was reported in few participants across all treatment groups (AMPLITUDE-D, ≤ 1%; AMPLITUDE-L, ≤ 10%; and AMPLITUDE-S, ≤ 4%). The adverse events profile was consistent with other glucagon-like peptide-1 receptor agonists (GLP-1 RAs); gastrointestinal adverse events were most frequent in all three studies. CONCLUSIONS: In people with T2D suboptimally controlled with oral glucose-lowering drugs and/or BI, QW efpeglenatide was non-inferior to dulaglutide in terms of HbA1c reduction and showed numerically greater improvements than placebo in glycaemic control and body weight, with safety consistent with the GLP-1 RA class.

Efficacy, Safety, and Immunogenicity of Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Compared with Originator Insulin Aspart Mix 70/30 in Adults with Diabetes (GEMELLI M): A Subgroup Analysis by Prior Type of Premix Insulin.

INTRODUCTION: We compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (70% intermediate SAR341402 protamine and 30% rapid SAR341402 solution) (SARAsp-Mix) with its originator NovoMix 30 insulin aspart mix (NN-Mix) in adults with type 1 or type 2 diabetes switching from different premix insulin analogs. METHODS: This phase 3, randomized, open-label, multinational, 26-week trial (GEMELLI M) enrolled 402 participants with type 1 or type 2 diabetes. At randomization, participants switched from their prestudy premix insulin NovoMix 30 (n = 341) or Humalog Mix 25/Liprolog Mix 25 (n = 61) to equivalent (1:1) doses of either SARAsp-Mix or NN-Mix at least twice daily (1:1 randomization). In this subgroup analysis, efficacy measures [change in hemoglobin A1c (HbA1c), daily insulin dose], and safety outcomes [hypoglycemia incidence, adverse events (including hypersensitivity and injection site reactions), anti-insulin aspart antibodies] of SARAsp-Mix were compared with those of NN-Mix separately according to the participants' prestudy premix insulin. RESULTS: At week 26, change from baseline in HbA1c (primary efficacy endpoint) was similar between SARAsp-Mix and NN-Mix in those participants pretreated with NovoMix 30 [least squares (LS) mean difference 0.05%, 95% confidence interval (CI) -0.195% to 0.289%] or Humalog Mix 25/Liprolog Mix 25 (LS mean difference 0.28%, 95% CI -0.279% to 0.830%) (P value for treatment-by-subgroup interaction = 0.46). In both subgroups, safety outcomes, including immunogenicity, and changes in daily insulin doses were similar between treatments over 26 weeks. CONCLUSIONS: Efficacy, safety, and immunogenicity profiles of SARAsp-Mix are similar to NN-Mix over 26 weeks in adults with diabetes irrespective of prior type of premix insulin. TRIAL REGISTRATION: EudraCT number 2017-000092-84.

Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Versus Originator Insulin Aspart Mix 70/30 (NovoMix 30) in People with Diabetes: A 26-Week, Randomized, Open-Label Trial (GEMELLI M).

INTRODUCTION: This study compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (SARAsp-Mix) with European-approved insulin aspart mix 70/30 - NovoMix® 30 (NN-Mix) in people with type 1 (T1D) or type 2 diabetes (T2D). METHODS: This 26-week, open-label, phase 3 trial enrolled 402 people with T1D (n = 105) or T2D (n = 297) previously treated with premix insulin, who were randomized (1:1) to SARAsp-Mix (n = 204) or NN-Mix (n = 198). RESULTS: After 26 weeks, the least squares (LS) mean [median] change in HbA1c from baseline was similar in both treatment groups (SARAsp-Mix - 0.55% [- 0.60%]; NN-Mix - 0.64% [- 0.60%]). The LS mean difference for SARAsp-Mix versus NN-Mix was 0.08%, with the upper bound of the two-sided 95% confidence interval (- 0.139 to 0.303) slightly above the prespecified noninferiority margin of 0.3%. Noninferiority of SARAsp-Mix over NN-Mix was not demonstrated in the primary intent-to-treat analysis, primarily because of one extreme outlying value impacted by the COVID-19 pandemic in the SARAsp-Mix group. Noninferiority was achieved in all secondary analyses, including prespecified per-protocol supportive and COVID-19 sensitivity analyses, as well as post hoc sensitivity analyses. Other efficacy endpoints, insulin dosages, anti-insulin aspart antibody response, hypoglycemia, and adverse events were similar between groups. CONCLUSIONS: The totality of evidence indicates that SARAsp-Mix provides effective glycemic control with a similar safety and immunogenicity profile to NN-Mix in people with diabetes treated for 26 weeks. TRIAL REGISTRATION: EudraCT number 2017-000092-84.

Real-world outcomes of treatment with insulin glargine 300 U/mL versus standard-of-care in people with uncontrolled type 2 diabetes mellitus.

Objective: To compare real-world outcomes with newer (insulin glargine 300 U/mL; Gla-300) versus standard of care (SoC) basal insulins (BIs) in the REACH (insulin-naïve; NCT02967224) and REGAIN (basal insulin-treated; NCT02967211) studies in participants with uncontrolled type 2 diabetes (T2DM) in Europe and Brazil.Methods: In these open-label, parallel-group, pragmatic studies, patients (HbA1c > 7.0%) were randomized to Gla-300 or SoC BI for a 6-month treatment period (to demonstrate non-inferiority of Gla-300 vs SoC BIs for HbA1c change [non-inferiority margin 0.3%]) and a 6-month extension period (continuing with their assigned treatment). Insulin titration/other medication changes were at investigator/patient discretion post-randomization.Results: Overall, 703 patients were randomized to treatment in REACH (Gla-300, n = 352; SoC, n = 351) and 609 (Gla-300, n = 305, SoC, n = 304) in REGAIN. The primary outcome, non-inferiority of Gla-300 versus SoC for HbA1c change from baseline to month 6, was met in REACH (least squares [LS] mean difference 0.12% [95% CI -0.046 to 0.281]) but not REGAIN (LS mean difference 0.17% [0.015-0.329]); no between-treatment difference in HbA1c change was shown after 12 months in either study. BI dose increased minimally from baseline to 12 months in REACH (Gla-300, +0.17 U/kg; SoC, +0.15 U/kg) and REGAIN (Gla-300, +0.11 U/kg; SoC, +0.07 U/kg). Hypoglycemia incidence was low and similar between treatment arms in both studies.Conclusions: In both REACH and REGAIN, no differences in glycemic control or hypoglycemia outcomes with Gla-300 versus SoC BIs were seen over 12 months. However, the suboptimal insulin titration in REACH and REGAIN limits comparisons of outcomes between treatment arms and suggests that more titration instruction/support may be required for patients to fully derive the benefits from newer basal insulin formulations.

Development and First Use of the Patient's Qualitative Assessment of Treatment (PQAT) Questionnaire in Type 2 Diabetes Mellitus to Explore Individualised Benefit-Harm of Drugs Received During Clinical Studies.

INTRODUCTION: Individualised benefit-harm assessments can help identify patient-perceived benefits and harms of a treatment, and associated trade-offs that may influence patients' willingness to use a treatment. This research presents the first use of a patient-reported outcome measure designed to assess patient-perceived benefits and disadvantages of drugs received during clinical studies. METHODS: The Patient's Qualitative Assessment of Treatment (PQAT) was developed in English and cognitively tested with US (n = 4) and Canadian (n = 3) patients with type 1 and type 2 diabetes mellitus (T2DM). The revised version of the PQAT comprises three qualitative open-ended questions focused on the benefits and disadvantages of treatment and reasons why patients would choose to continue/discontinue treatment. A final quantitative question asks patients to evaluate the balance between benefits and disadvantages using a 7-point scale. The revised version of the questionnaire was administered as an exploratory endpoint in a phase II clinical trial for a new injectable treatment for T2DM. Qualitative data were analysed using thematic analysis, and relationships between qualitative and quantitative data were identified. RESULTS: Patient-reported benefits of treatment administered during the clinical trial included clinical markers of efficacy and subjective markers. Disadvantages reported by patients were mainly related to drug adverse effects or to the mode of administration. Of the 57 patients completing the PQAT, 70.2% reported being willing to continue treatment, with 59.6% reporting that the benefits outweighed the disadvantages. The reported benefits of feeling better and improved energy levels were more likely to be associated with a more positive ratio (70% and 71.4%, respectively), while the disadvantages of fatigue, headaches, and stomach pain were associated with a negative ratio and patients not being willing to continue the treatment. CONCLUSIONS: The PQAT is a unique patient-reported outcome tool designed to aid understanding patients' real experience of benefits and disadvantages of a treatment. It combines the richness of qualitative data with quantitative data-information valuable for various stakeholders to make well-informed treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02973321.