Dataset Information

Efficacy and safety of ultra-rapid lispro versus lispro in children and adolescents with type 1 diabetes: The PRONTO-Peds trial.

ABSTRACT:

Aims

To evaluate the efficacy and safety of ultra-rapid lispro (URLi) versus lispro in a paediatric population with type 1 diabetes (T1D) in a Phase 3, treat-to-target study.

Materials and methods

After a 4-week lead-in to optimize basal insulin, participants were randomized to double-blind URLi (n = 280) or lispro (n = 298) injected 0 to 2 minutes prior to meals (mealtime), or open-label URLi (n = 138) injected up to 20 minutes after start of meals (postmeal). Participants remained on pre-study basal insulin (degludec, detemir or glargine). The primary endpoint was glycated haemoglobin (HbA1c) change from baseline after 26 weeks (noninferiority margin 4.4 mmol/mol [0.4%]).

Results

Both mealtime and postmeal URLi demonstrated noninferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi -0.23 mmol/mol (95% confidence interval [CI] -1.84, 1.39) and postmeal URLi -0.17 mmol/mol (95% CI -2.15, 1.81). Mealtime URLi reduced 1-hour postprandial glucose (PPG) daily mean (P = 0.001) and premeal to 1 hour postmeal PPG excursion daily mean (P < 0.001) versus lispro. The rate and incidence of severe, nocturnal or documented hypoglycaemia (<3.0 mmol/L [54 mg/dL]) were similar for all treatments. With mealtime URLi versus lispro, the rate of postdose hypoglycaemia (<3.0 mmol/L) was higher at ≤2 hours (P = 0.034). The incidence of treatment-emergent adverse events was similar for all treatments. More participants reported an injection site reaction with mealtime URLi (7.9%) versus postmeal URLi (2.9%) and lispro (2.7%).

Conclusions

In children and adolescents with T1D, URLi demonstrated good glycaemic control, and noninferiority to lispro in HbA1c change for mealtime and postmeal URLi. When dosed at the beginning of meals, URLi reduced 1-hour PPG and PPG excursions versus lispro.

SUBMITTER: Wadwa RP

PROVIDER: S-EPMC10087819 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy and safety of ultra-rapid lispro versus lispro in children and adolescents with type 1 diabetes: The PRONTO-Peds trial.

Wadwa R Paul RP Laffel Lori M LM Franco Denise R DR Dellva Mary Anne MA Knights Alastair W AW Pollom Robyn K RK

Diabetes, obesity & metabolism 20220908 1

<h4>Aims</h4>To evaluate the efficacy and safety of ultra-rapid lispro (URLi) versus lispro in a paediatric population with type 1 diabetes (T1D) in a Phase 3, treat-to-target study.<h4>Materials and methods</h4>After a 4-week lead-in to optimize basal insulin, participants were randomized to double-blind URLi (n = 280) or lispro (n = 298) injected 0 to 2 minutes prior to meals (mealtime), or open-label URLi (n = 138) injected up to 20 minutes after start of meals (postmeal). Participants remain ...[more]

PMID: 36054737

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Project description:IntroductionThe PRONTO-T1D study, which evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes (T1D), met the primary endpoint of noninferiority of HbA1c change from baseline compared to lispro at 26 weeks. We present results of an additional 26-week treatment phase evaluating long-term efficacy and safety of URLi.MethodsIn this phase 3, treat-to-target study, subjects were randomized to double-blind mealtime URLi, lispro, or open-label postmeal URLi with insulin degludec or glargine for 26 weeks. Subjects in the double-blind URLi (n = 451) and lispro (n = 442) groups continued for another 26 weeks to assess long-term efficacy and safety.ResultsHbA1c increased marginally during the long-term maintenance period (week 26-52) in both groups to 7.47% (URLi) and 7.54% (lispro). At week 52, there were no statistically significant treatment differences in change from baseline HbA1c with a least-squares mean treatment difference (95% confidence interval) of - 0.06% (- 0.16, 0.03). Proportions of patients with HbA1c < 7% at week 52 were similar (URLi, 26.8%; lispro, 24.5%). Self-monitored blood glucose (SMBG) showed that 1-h (9.23 versus 10.14 mmol/L) and 2-h (8.40 versus 9.53 mmol/L) postmeal daily mean glucose was statistically significantly (p < 0.001) lower with URLi than lispro. The rate and incidence of severe, documented, and postprandial hypoglycemia (< 54 mg/dl [3.0 mmol/L]) were similar between treatments, but URLi demonstrated a 31% lower rate in the period more than 4 h after meals, (p = 0.023). Injection site reactions were reported by 3.3% of patients on URLi and 0.9% on lispro. The incidence of treatment-emergent adverse events was similar between treatments.ConclusionOverall glycemic control and improved postprandial glucose via SMBG were maintained after 52 weeks with URLi versus lispro, suggesting that the efficacy of URLi is preserved during long-term treatment in patients with T1D. No long-term safety issues were identified with URLi.Trial registrationClinicalTrials.gov, NCT03214367.

Project description:IntroductionThe aim of this study was to evaluate the efficacy and safety of ultra-rapid lispro (URLi) versus lispro in a subgroup analysis of Japanese adults with type 2 diabetes mellitus (T2DM) from the phase 3 PRONTO-T2D trial.MethodsAfter an 8-week lead-in period during which patients transitioned to insulin lispro 3 times a day before main meals in association with basal insulin (glargine or degludec), the patients were randomized to 26 weeks of double-blind URLi or lispro injected immediately prior to meals. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline to week 26 between URLi and lispro. The multiplicity-adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a test meal and change in HbA1c from baseline to week 26 in the URLi and lispro groups.ResultsResults were obtained from prespecified exploratory analyses of 26-week data in Japanese patients randomized to receive URLi (n = 47) or lispro (n = 46). Mean baseline HbA1c levels significantly improved during the lead-in period to a baseline value of 7.50% and 7.60% in patients subsequently randomized to the URLi and lispro treatment groups, respectively. At week 26, the least squares mean (LSM) difference in HbAc1 between the URLi and lispro groups was 0.13% (95% confidence interval [CI] - 0.12 to 0.39) (1.4 mmol/mol, 95% CI - 1.3 to 4.2). Although there were no significant differences in PPG excursions at any time-point, numerically smaller PPG excursions were consistently observed from 30 min to 3 h during the mixed-meal tolerance test in patients on URLi compared to those on lispro. LSM differences in PPG excursions at week 26 were - 10.5 mg/dL (95% CI - 32.7 to 11.7) (- 0.58 mmol/L, 95% CI - 1.82 to 0.65) at 1 h and - 14.9 mg/dL (95% CI - 40.3 to 10.5) (- 0.83 mmol/L, 95% CI - 2.24 to 0.58) at 2 h. There were no significant differences between treatments in rates of severe/overall hypoglycemia or incidence of treatment-emergent adverse events.ConclusionsURLi administered as prandial insulin in combination with basal insulin provides effective glycemic control when administered immediately before a meal in Japanese patients with T2DM. URLi was well tolerated in this population.Trial registrationClinicalTrials.gov, NCT03214380.

Project description:IntroductionUltra-rapid lispro (URLi) is a new prandial insulin lispro formulation. In the PRONTO-T2D study, URLi, in a basal-bolus regimen with glargine or degludec, was non-inferior to lispro (Humalog®) for HbA1c reduction and superior for postprandial glucose (PPG) control. We evaluated the efficacy and safety of URLi compared to lispro in younger versus older patients in PRONTO-T2D.MethodsPRONTO-T2D was a phase 3, 26-week, double-blind, treat-to-target study in people with type 2 diabetes. In this sub-group analysis, we compared URLi to lispro on the change from baseline in HbA1c and rate of level 2 hypoglycemia (< 54 mg/dl) in patients aged < 65 (N = 406) and ≥ 65 years (N = 267).ResultsAt baseline, patients < 65 versus ≥ 65 years had mean age of 54.9 versus 69.2 years and duration of diabetes 14.6 versus 19.4 years. Mean HbA1c at screening and randomization was 8.35 and 7.34%, respectively, in patients < 65 years, and 8.21 and 7.23%, respectively, in patients ≥ 65 years. At endpoint, mean HbA1c with URLi versus lispro was 6.92 versus 6.90%, respectively, in patients < 65 years and 6.89 versus 6.79%, respectively, in patients ≥ 65 years. URLi significantly reduced 1- and 2-h PPG excursions with a standardized meal test in both age groups: between-treatment differences at 1-h postmeal for younger and older patients was - 9.8 and - 15.1 mg/dl, respectively; and at 2-h postmeal, - 18.7 and - 15.1 mg/dl, respectively, all p < 0.05. Severe and nocturnal hypoglycemia were similar between groups. The relative rate (URLi/Humalog) of level 2 hypoglycemia was lower in older versus younger patients, with a significant treatment-by-age interaction observed. No differential treatment effects were noted for insulin dose, weight, and fasting and maximum glucose after the meal test.ConclusionsURLi, in a basal-bolus regimen, resulted in endpoint HbA1c < 7% and significantly lower PPG excursions compared to lispro in both age groups, with reduced level 2 hypoglycemia in older versus younger patients.Trial registrationClinicalTrials.gov, NCT03214380.

Project description:IntroductionWe evaluated the efficacy and safety of ultra-rapid lispro (URLi) in comparison to lispro in a subgroup analysis of Japanese adults with type 1 diabetes mellitus from the phase 3 PRONTO-T1D trial.MethodsAfter an 8-week lead-in to optimize basal insulin treatment, patients were randomized to 52-week double-blind mealtime URLi or lispro, or 26-week open-label postmeal URLi. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline (week 0) to week 26 between mealtime URLi and lispro. The multiplicity adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a meal test between mealtime URLi and lispro, and change in HbA1c from baseline to week 26 between postmeal URLi and mealtime lispro.ResultsThis manuscript presents pre-specified exploratory analyses of 26-week data from Japanese patients randomized to double-blind URLi (n = 62) or lispro (n = 59), or open-label URLi (n = 46). Mean baseline HbA1c levels were 7.52% for mealtime URLi, 7.44% for lispro, and 7.51% for postmeal URLi at randomization. At week 26, the least squares mean (LSM) difference compared to lispro was 0.04% (95% confidence interval [CI] - 0.14 to 0.22) for mealtime URLi, and 0.16% (95% CI - 0.04 to 0.35) for postmeal URLi. In comparison to lispro, mealtime URLi resulted in statistically significantly lower 1- and 2-h PPG excursions during the mixed-meal tolerance test. LSM differences were - 40.5 mg/dL, 95% CI - 59.5 to 21.4 (- 2.25 mmol/L, 95% CI - 3.3 to - 1.2) for 1-h PPG excursions and - 51.7 mg/dL, 95% CI - 81.7 to - 21.8 (- 2.87 mmol/L, 95% CI - 4.5 to - 1.2) for 2-h PPG excursions at week 26. There were no significant treatment differences in rates of severe/overall hypoglycemia, or incidence of treatment-emergent adverse events.ConclusionsMealtime and postmeal URLi provide effective and comparable glycemic control in Japanese patients. Mealtime URLi demonstrated more effective PPG control compared to lispro.Trial registrationClinicalTrials.gov, NCT03214367.

Project description:IntroductionThe PRONTO-T1D study evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes mellitus. After 26 weeks of treatment, mealtime and postmeal URLi provided effective and comparable glycemic control in a prespecified subpopulation analysis of Japanese patients from PRONTO-T1D. We present the results of a 52-week study which evaluated the long-term efficacy and safety of URLi in Japanese patients.MethodsAfter an 8-week lead-in period to optimize basal insulin treatment, Japanese patients were randomized to one of three treatment groups: the 52-week double-blind mealtime URLi (n = 62) or mealtime lispro (n = 59) group, respectively, or the 52-week open-label postmeal URLi (n = 46) group.ResultsAt week 52, there were no statistically significant differences in change from baseline in hemoglobin A1c (HbA1c) between Japanese patients on URLi and those on lispro; the least-squares mean (LSM) treatment difference was 0.04% (95% confidence interval [CI] - 0.18, 0.25) between mealtime URLi and lispro, and 0.04% (95% CI - 0.19, 0.28) between postmeal URLi and mealtime lispro. No significant between-group differences were observed in the number of patients achieving the HbA1c target of < 7.0% (20.0, 30.5 and 16.3% of those on mealtime URLi, mealtime lispro and postmeal URLi, respectively). Daily average blood glucose levels in the 10-point self-monitored blood glucose profiles at week 52 were similar between treatments. However, compared with lispro, lower blood glucose levels were observed for the mealtime URLi group at the morning 1- and 2-h postmeal time points with LSM differences of - 32.7 mg/dL (- 1.82 mmol/L) (p = 0.005) and - 23.2 mg/dL (- 1.29 mmol/L) (p = 0.029), respectively. There were no significant treatment differences in the incidences of treatment-emergent adverse events, documented hypoglycemia and severe hypoglycemia; however, the rate of documented hypoglycemia was lower in the mealtime URLi arm compared with the lispro arm.ConclusionsOverall glycemic control and improved postprandial glucose via self-monitoring was maintained in Japanese patients following 52 weeks of treatment with URLi versus lispro, including postmeal URLi administration.Trial registrationClinicalTrials.gov: NCT03214367.

Dataset Information

Efficacy and safety of ultra-rapid lispro versus lispro in children and adolescents with type 1 diabetes: The PRONTO-Peds trial.

Aims

Materials and methods

Results

Conclusions

Publications

Efficacy and safety of ultra-rapid lispro versus lispro in children and adolescents with type 1 diabetes: The PRONTO-Peds trial.

Similar Datasets

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