Insulin glargine 300 U/mL versus first-generation basal insulin analogues in insulin-naïve adults with type 2 diabetes: 12-month outcomes of ACHIEVE Control, a prospective, randomized, pragmatic real-life clinical trial.

AIM: To report the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) versus standard-of-care basal insulin analogues (SOC-BI) at 12 months in the ACHIEVE Control trial, which is a prospective pragmatic randomized real-life study in insulin-naïve adults with type 2 diabetes (T2D). METHODS: A total of 3304 insulin-naïve adults with T2D and glycated haemoglobin (HbA1c) concentration of 64 to 97 mmol/mol (8.0% to 11.0%) after ≥1 year of treatment with two or more antihyperglycaemic agents were randomized to Gla-300 or SOC-BI. Key secondary endpoints included HbA1c target attainment without documented symptomatic (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia at 12 months. RESULTS: At 12 months, 26.1% (Gla-300) and 23.7% (SOC-BI) of adults achieved HbA1c targets without documented symptomatic (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia (odds ratio [OR] 1.14, 95% confidence interval [CI] 0.97-1.35); 33.0% and 29.5%, respectively, achieved HbA1c targets without documented symptomatic (<3.0 mmol/L [<54 mg/dL]) or severe hypoglycaemia (OR 1.19, 95% CI 1.02-1.38). The OR for HbA1c target achievement was 1.15 (95% CI 0.99-1.34), and favoured Gla-300 versus SOC-BI for absence of documented symptomatic or severe hypoglycaemia at 12 months for both ≤3.9 mmol/L (≤70 mg/dL; OR 1.21, 95% CI 1.05-1.40) and < 3.0 mmol/L (<54 mg/dL; OR 1.26, 95% CI 1.07-1.48). CONCLUSION: Gla-300 tended to be associated with lower hypoglycaemia risk than SOC-BI in real-world clinical practice during the 12-month follow-up.

A pragmatic randomized clinical trial of insulin glargine 300 U/mL vs first-generation basal insulin analogues in insulin-naïve adults with type 2 diabetes: 6-month outcomes of the ACHIEVE Control study.

AIMS: To compare the safety and efficacy of insulin glargine 300 U/mL (Gla-300) versus first-generation standard-of-care basal insulin analogues (SOC-BI; insulin glargine 100 U/mL or insulin detemir) at 6 months. METHODS: In the 12-month, open-label, multicentre, randomized, pragmatic ACHIEVE Control trial, insulin-naïve adults with type 2 diabetes (T2D) and glycated haemoglobin (HbA1c) 64 to 97 mmol/mol (8.0%-11.0%) after ≥1 year of treatment with ≥2 diabetes medications were randomized to Gla-300 or SOC-BI. The composite primary endpoint, evaluated at 6 months, was the proportion of participants achieving individualized HbA1c targets per Healthcare Effectiveness Data and Information Set (HEDIS) criteria without documented symptomatic (blood glucose ≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia at any time of the day at 6 months. RESULTS: Of 1651 and 1653 participants randomized to Gla-300 and SOC-BI, respectively, 31.3% and 27.9% achieved the composite primary endpoint at 6 months (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.01-1.39; P = 0.03 for superiority); 78.4% and 75.3% had no documented symptomatic or severe hypoglycaemia (OR 1.19, 95% CI 1.01-1.41). Changes from baseline to month 6 in HbA1c, fasting plasma glucose, weight, and BI analogue dose were similar between groups. CONCLUSIONS: Among insulin-naïve adults with poorly controlled T2D, Gla-300 was associated with a statistically significantly higher proportion of participants achieving individualized HEDIS HbA1c targets without documented symptomatic or severe hypoglycaemia (vs SOC-BI) in a real-life population managed in a usual-care setting. The ACHIEVE Control study results add value to treatment decisions and options for patients, healthcare providers, payers and decision makers.

Take Control: A randomized trial evaluating the efficacy and safety of self- versus physician-managed titration of insulin glargine 300 U/mL in patients with uncontrolled type 2 diabetes.

AIM: To compare the efficacy and safety of self- versus physician-managed titration of insulin glargine 300 U/mL (Gla-300) in people with inadequately controlled type 2 diabetes. METHODS: Take Control (EudraCT number: 2015-001626-42) was a 24-week, multi-national, open-label, controlled, two-arm, parallel-group study in insulin-naïve and pre-treated participants, randomized 1:1 to a self- or physician-managed titration of Gla-300. The fasting self-monitored plasma glucose (SMPG) target was 4.4 to 7.2 mmol/L. The primary outcome was non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 24. Secondary outcomes included SMPG target achievement without hypoglycaemia, hypoglycaemia incidence, adverse events and participant-reported outcomes (PROs). RESULTS: At week 24, the least squares (LS) mean HbA1c reduction was 0.97% (10.6 mmol/mol) and 0.84% (9.2 mmol/mol) in the self- and physician-managed groups, respectively, with an LS mean difference of -0.13% [95% confidence interval -0.2619 to -0.0004] (-1.4 mmol/mol [-2.863 to -0.004]), demonstrating non-inferiority (P < 0.0001) and superiority (P = 0.0247) of self- versus physician-managed titration. Significantly more of the self- than physician-managed group achieved SMPG target without hypoglycaemia (67% vs 58%; P = 0.0187). Overall, hypoglycaemia incidence was similar in each group. No safety concerns were reported. In both groups, similar PRO improvements were observed for distress related to diabetes disease burden and for confidence in diabetes self-management, with even more individuals achieving a clinically relevant reduction in emotional burden and fewer individuals with high emotional burden in the self-managed group. CONCLUSIONS: Self-managed titration of Gla-300 was superior to physician-managed titration in terms of HbA1c reduction, accompanied by similar total PRO scores, with a clinically relevant reduction in emotional burden, and similar hypoglycaemia frequency.

New Benchmarks on Protocol Amendment Practices, Trends and their Impact on Clinical Trial Performance.

The Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a follow-up study in 2022 to assess trends in protocol amendment experiences and the impact amendments have had on clinical trial performance, particularly during the COVID-19 pandemic. Sixteen pharmaceutical companies and contract research organizations provided data on 950 protocols and 2188 amendments. The results show that, since 2015, the prevalence of protocols with at least one amendment in phases I-IV has increased substantially (from 57 to 76%) and the mean number of amendments per protocol has increased 60% to 3.3, up from 2.1. Phase I and III protocols saw the highest increases in the mean number of amendments implemented per protocol. A much higher percentage of amendments-77%-were deemed unavoidable with regulatory agency requests and changes to the study strategy as the top reasons cited for amending a protocol. The total average duration to implement an amendment has nearly tripled during the past decade. The time from identifying the need-to-amend to last oversight approval now takes an average of 260 days and the mean duration during which investigative sites operate with different versions of the clinical trial protocol spans 215 days. Protocols that implemented at least one amendment were more effective at increasing patient screening volume and reducing the actual number of patients enrolled relative to plan. Lastly, the prevalence of protocols with at least one amendment and mean number of amendments was significantly higher for protocols conducted during the pandemic.

Reference intervals, intraindividual and interindividual variability, and reference change values for hematologic variables in laboratory beagles.

In research and development studies for human and veterinary medicine, relevant comparators for interpreting clinical pathology results are matched with concurrent control animals. However, reference intervals (RI) provide a comparator database and important aids for interpreting clinical pathology data, especially in laboratory beagle dogs. Furthermore, RI incorporate biologic variation, which includes analytical, intraindividual, and interindividual variation. No studies to date have established RI and studied the effect of biologic variation on hematologic variables in a large group of laboratory dogs. The purpose of this retrospective study was to establish hematologic RI for laboratory beagles according to international recommendations and estimate the effect of biologic variation in routinely measured hematologic analytes by using the databank at a pharmaceutical center. Blood specimens from 340 healthy beagles (age, 9 to 36 mo) were evaluated by using a flow-cytometry-based hematology analyzer. RI and their 90% confidence intervals were established by using a nonparametric method. Effects of sex, age, and weight were investigated. Weight had no effect on any analyte. RBC, Hgb, Hct, MCV, MCH, RBC distribution width, and platelet count increased with age, whereas WBC count decreased. The only clinically relevant effect of sex was observed for platelets, which were lower in male beagles than in female and warranted 2 different RI. The calculated index of individuality showed that population-based RI were appropriate for almost all hematologic analytes, as might be expected for a homogeneous group of laboratory beagles.