Dataset Information

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog^® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

ABSTRACT:

Background and objective

Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog^® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM).

Methods

This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured.

Results

Insulin lispro appeared in the serum 5 min faster (p < 0.0001) and exposure was 6.4-fold greater in the first 15 min (p < 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (p < 0.0001) and insulin action was 4.2-fold greater within the first 30 min (p < 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (p = 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated.

Conclusions

This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. CLINICALTRIALS.

Gov identifier

NCT03305822.

SUBMITTER: Leohr J

PROVIDER: S-EPMC7716902 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog<sup>®</sup> (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Leohr Jennifer J Dellva Mary Anne MA Coutant David E DE LaBell Elizabeth E Heise Tim T Andersen Grit G Zijlstra Eric E Hermanski Lidia L Nosek Leszek L Linnebjerg Helle H

Clinical pharmacokinetics 20201201 12

<h4>Background and objective</h4>Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog<sup>®</sup> after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM).<h4>Methods</h4>This was a phase I, randomised, two-period, two-treatment, double-bl ...[more]

PMID: 32468448

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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:Background: There are approximately 537 million adults with diabetes worldwide, and insulin still plays an important role in its treatment. However, the long-term use of insulin imposes a significant financial burden on patients. This study aims to explore the pharmacokinetic (PK)/ pharmacodynamic (PD) parameters of generic premixed insulin lispro 25 (25% insulin lispro and 75% protamine zinc lispro) and evaluate the bio-equivalence between generic and brand-name preparations to reduce medical costs while ensuring the effectiveness and safety of treatment. Research design and method: This is a single-center, randomized, open-label, two-period, crossover study. This study recruited 52 healthy volunteers and randomly divided them into two sequences to receive either the test (T) preparation or the reference (R) preparation in each period (Chinese Drug Trial Identifier: CTR20202288, URL: http://www.chinadrugtrials.org.cn). The C-peptide and plasma concentration of lispro 25 were analyzed using ELISA and high-performance liquid chromatography, respectively. A euglycemic clamp was used to measure the glucose infusion rate (GIR). The main PK parameters (AUC0-t and Cmax) and PD parameters (GIRmax and GIRAUC0-t) and the evaluation of bioequivalence were calculated using WinNonlin 8.3.1. Results: The quality of the clamp was approved by stable blood glucose and inhibited C-peptide levels. For PK parameters, the Cmax values of the T and R preparations were 1.40 ± 0.452 and 1.36 ± 0.418 ng·mL-1, respectively, and the AUC0-24h values were 497 ± 107 and 510 ± 86.2 ng h·mL-1, respectively. For PD parameters, GIRmax values were 4.47 ± 2.12 and 4.12 ± 1.81 mg kg·min-1, and AUCGIR0-24h values were 2,994 ± 1,232 and 2,994 ± 941 mg h·kg·min-1 for T and R, respectively. The 90% confidence intervals (CIs) for the geometric mean ratio (test/reference) of the main PK parameters (AUC0-t and Cmax) and PD parameters (GIRmax and GIRAUC0-t) in both cohorts were within the range of 80%-125%. Furthermore, there was no significant hypoglycemia and serious adverse events (SAEs) observed in this study. Conclusion: Bio-equivalence between insulin lispro (R) (Humalog®25) and insulin lispro (T) was demonstrated, with both showing good tolerance in healthy Chinese volunteers. The results provide evidence supporting the interchangeability of different drug formulations and offer more options for clinical drug use.

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:IntroductionTo assess time in range (TIR) (70-180 mg/dL) with postprandial glucose (PPG)-focused titration of ultra rapid lispro (URLi; Lyumjev®) in combination with insulin degludec in people with type 1 diabetes (T1D).MethodsThis phase 2, single-group, open-label, exploratory study was conducted in 31 participants with T1D on multiple daily injection therapy. Participants were treated with insulin degludec and Lispro for an 11-day lead-in and then URLi for a 46-day treatment period consisting of 35-day titration and 11-day endpoint maintenance period. Glucose targets for the titration period were PPG < 140 mg/dL or < 20% increase from premeal, fasting glucose 80-110 mg/dL, and overnight excursion ± 30 mg/dL or less. Participants used the InPen™ bolus calculator and Dexcom G6 continuous glucose monitoring (CGM).ResultsPrimary endpoint mean TIR (70-180 mg/dL) with URLi during the maintenance period was 70.2%. TIR (70-180 mg/dL) and times below/above range were not significantly different with URLi (maintenance) versus lispro (lead-in). HbA1c decreased from 7.1% at screening to 6.8% at endpoint (least squares mean [LSM] change from baseline, - 0.36%; P < 0.001). Fructosamine and 1,5-anhydroglucitol improved (P < 0.001). Mean hourly glucose using CGM was reduced from 8:00 AM to 4:00 PM with URLi. Overall highest PPG excursion across meals was significantly reduced at URLi endpoint compared with lispro lead-in (mean 56.5 vs 72.4 mg/dL; P < 0.001). Insulin-to-carbohydrate ratio (U/X g) was reduced (more insulin given) at breakfast at URLi endpoint vs lead-in (LSM 9.0 vs 9.7 g; P = 0.002) and numerically decreased at other meals. Total daily insulin dose (TDD) was higher at URLi endpoint compared with lispro lead-in (mean 50.2 vs 47.0 U; P = 0.046) with similar prandial/TDD ratio (mean 52.1% vs 51.2%). There were no severe hypoglycemia events during the study.ConclusionsURLi in a basal-bolus regimen focusing on PPG targets demonstrated improved overall glycemic control and reduced PPG excursions without increased hypoglycemia in participants with T1D.Trial registrationClinicalTrial.gov, NCT04585776.

Dataset Information

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog^® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Background and objective

Methods

Results

Conclusions

Gov identifier

Publications

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog<sup>®</sup> (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Background and objective

Methods

Results

Conclusions

Gov identifier

Publications

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog<sup>®</sup> (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog^® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.