Dataset Information

Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52-week, randomized, treat-to-target, phase III trial.

ABSTRACT:

Aims

To compare the safety and efficacy of fast-acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D).

Materials and methods

onset 1 was a randomized, multicentre, treat-to-target, phase III, 52-week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across 9 countries. Adults with T1D were randomly allocated to double-blind mealtime faster aspart or IAsp, each with once- or twice-daily insulin detemir. The primary endpoint, change in glycated haemoglobin (HbA1c) from baseline after the initial 26 weeks, has been reported previously. In the present paper, we report data from the full 52-week study period.

Results

Between August 2013 and June 2015, 381 participants were assigned to double-blind faster aspart and 380 participants to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were -0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference significantly favoured faster aspart (-0.10% [95% confidence interval {CI} -0.19;-0.00]; P = .0424). Changes from baseline in 1-hour postprandial plasma glucose (PPG) increment (meal test; faster aspart -1.05 mmol/L; IAsp -0.14 mmol/L) also significantly favoured faster aspart (estimated treatment difference -0.91 mmol/L [95% CI -1.40;-0.43]; -16.48 mg/dL [95% CI -25.17;-7.80]; P = .0002). There was no difference in overall severe or blood glucose-confirmed hypoglycaemic episodes or treatment-emergent adverse events between treatments.

Conclusions

At 52 weeks, overall glycaemic control had significantly improved with faster aspart vs IAsp, consistent with the 26-week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels compared with those achieved with IAsp in people with T1D.

SUBMITTER: Mathieu C

PROVIDER: S-EPMC5947306 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Publications

Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52-week, randomized, treat-to-target, phase III trial.

Mathieu Chantal C Bode Bruce W BW Franek Edward E Philis-Tsimikas Athena A Rose Ludger L Graungaard Tina T Birk Østerskov Anne A Russell-Jones David D

Diabetes, obesity & metabolism 20180204 5

<h4>Aims</h4>To compare the safety and efficacy of fast-acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D).<h4>Materials and methods</h4>onset 1 was a randomized, multicentre, treat-to-target, phase III, 52-week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across 9 countries. Adults with T1D were randomly allocated to double-blind mealtime faster aspart or IAsp, each with once- or twice-daily insulin detemir ...[more]

PMID: 29316130

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Project description:AimsTo investigate the pharmacokinetic/pharmacodynamic properties of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp) in people with type 2 diabetes (T2D).Materials and methodsIn a randomized, double-blind, crossover design, 61 people with T2D usually treated with insulin ± oral antidiabetic drug(s) received single-dose faster aspart and IAsp (0.3 U/kg) on separate visits. Blood samples for pharmacokinetic assessment were collected frequently until 12 hours post-dose. Glucose-lowering effect was determined in a euglycaemic clamp lasting up to 12 hours post-dose (target 5.0 mmol/L).ResultsThe serum IAsp pharmacokinetic profile and glucose-lowering effect profile were shifted to the left for faster aspart versus IAsp. Least squares mean (± SE) onset of appearance was 3.3 ± 0.3 minutes for faster aspart, which was 1.2 minutes earlier than for IAsp (95% confidence interval [CI] -1.8;-0.5; P = .001). Onset of action for faster aspart was 8.9 minutes earlier (95% CI -12.1;-5.7; P < .001) than for IAsp. During the first 30 minutes after dosing, 89% larger IAsp exposure (ratio faster aspart/IAsp 1.89 [95% CI 1.56;2.28]; P < .001) and 147% greater glucose-lowering effect (2.47 [95% CI 1.58;6.22]; P < .001) were observed for faster aspart compared with IAsp. Offset of exposure (time to 50% of maximum IAsp concentration in the late part of the pharmacokinetic profile) occurred earlier for faster aspart (difference faster aspart - IAsp -36.4 minutes [95% CI -55.3;-17.6]; P < .001). The treatment difference of faster aspart - IAsp in offset of glucose-lowering effect (time to 50% of maximum glucose infusion rate in the late part of the glucose infusion rate profile) was -14.4 minutes (95% CI -34.4;5.5; P = .152).ConclusionsIn people with T2D, faster aspart was associated with earlier onset and greater initial exposure and glucose-lowering effect compared with IAsp, as previously shown in people with type 1 diabetes.

Project description:AimsTo evaluate the pharmacokinetics and pharmacodynamics of faster-acting insulin aspart and insulin aspart in a randomized, single-centre, double-blind study.MethodsFifty-two patients with type 1 diabetes (mean age 40.3 years) received faster-acting insulin aspart, insulin aspart, or another faster aspart formulation (not selected for further development), each as a single 0.2 U/kg subcutaneous dose, under glucose-clamp conditions, in a three-way crossover design (3-12 days washout between dosing).ResultsFaster-acting insulin aspart had a faster onset of exposure compared with insulin aspart, shown by a 57% earlier onset of appearance [4.9 vs 11.2 min; ratio 0.43, 95% confidence interval (CI) 0.36; 0.51], a 35% earlier time to reach 50% maximum concentration (20.7 vs 31.6 min; ratio 0.65, 95% CI 0.59; 0.72) and a greater early exposure within 90 min after dosing. The greatest difference occurred during the first 15 min, when area under the serum insulin aspart curve was 4.5-fold greater with faster-acting insulin aspart than with insulin aspart. Both treatments had a similar time to maximum concentration, total exposure and maximum concentration. Faster-acting insulin aspart had a significantly greater glucose-lowering effect within 90 min after dosing [largest difference: area under the curve for the glucose infusion rate (AUC(GIR), 0-30 min) ratio 1.48, 95% CI 1.13; 2.02] and 17% earlier time to reach 50% maximum glucose infusion rate (38.3 vs 46.1 min; ratio 0.83, 95% CI 0.73; 0.94). The primary endpoint (AUC(GIR, 0-2 h)) was 10% greater for faster-acting insulin aspart, but did not reach statistical significance (ratio 1.10, 95% CI 1.00; 1.22). Both treatments had similar total and maximum glucose-lowering effects, indicating similar overall potency.ConclusionsFaster-acting insulin aspart was found to have earlier onset and higher early exposure than insulin aspart, and a greater early glucose-lowering effect, with similar potency.

Project description:BackgroundFast-acting insulin aspart (faster aspart) is an ultra-fast-acting formulation of insulin aspart (IAsp). This post hoc analysis investigated the pharmacokinetics of faster aspart versus IAsp, measured as free or total IAsp, and the relationship between anti-IAsp antibodies and the pharmacokinetics/pharmacodynamics of faster aspart and IAsp.MethodsFree and total IAsp concentrations and anti-IAsp antibodies were determined in adults with type 1 diabetes mellitus receiving subcutaneous faster aspart and/or IAsp in four single-dose clinical pharmacology trials (n = 175) and a 26-week phase IIIa trial (n = 1040). Pharmacodynamics were assessed by euglycaemic clamp or meal test, respectively.ResultsThe pharmacokinetic profile was left-shifted and early exposure was greater with faster aspart versus IAsp independent of free or total IAsp assay. The faster aspart-IAsp difference in the time to 50% of maximum IAsp concentration in the early part of the pharmacokinetic profile (tEarly 50 % Cmax) [95% confidence interval (CI)] was - 8.8 [- 10.0 to - 7.5] and - 7.6 [- 8.8 to - 6.4] min for free and total IAsp, respectively. The faster aspart/IAsp ratio for the area under the concentration-time curve (AUC) for IAsp from time zero to 30 min (AUCIAsp,0-30 min) [95% CI] was 1.88 [1.74-2.04] and 1.77 [1.64-1.90] for free and total IAsp. Higher anti-IAsp antibody levels were associated with a lower ratio of free/total IAsp for the total AUC for IAsp (AUCIAsp,0-t). Early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 60 min [AUCGIR,0-60 min]) was greater by 25-44% for faster aspart versus IAsp independent of anti-IAsp antibody levels. Total glucose-lowering effect (total AUC for GIR [AUCGIR,0-t]) in a clamp and 1-h postprandial glucose increment in a meal test appeared essentially unaffected by anti-IAsp antibodies.ConclusionsFaster aspart provides accelerated pharmacokinetics versus IAsp regardless if based on free or total IAsp assay. Higher anti-IAsp antibodies increase total IAsp concentrations but do not influence faster aspart nor IAsp pharmacodynamics. CLINICALTRIALS.Gov identifiersNCT01618188, NCT02003677, NCT01934712, NCT02568280, NCT01831765.

Dataset Information

Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52-week, randomized, treat-to-target, phase III trial.

Aims

Materials and methods

Results

Conclusions

Publications

Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52-week, randomized, treat-to-target, phase III trial.

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