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Faster‐acting insulin aspart provides faster onset and greater early exposure vs insulin aspart in children and adolescents with type 1 diabetes mellitus

Faster‐acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with additional excipients (L‐arginine and niacinamide). In adults, faster aspart provides faster onset and greater early exposure and action vs IAsp.

by the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD). [1][2][3] While premixed insulins and self-mixing of rapid-acting and intermediate-or long-acting insulin have received some attention in the younger age groups in order to reduce the number of daily injections, 4 nowadays intensified insulin therapy is the recommended treatment regimen to achieve glycemic targets in children and adolescents with T1DM. 2,3,5 In such a treatment regimen, rapid-acting insulin is an important tool to be able to closely match the varying prandial insulin needs during the often irregular daily life of children. 6 Current rapid-acting insulin analogs (insulin lispro, insulin aspart [IAsp], and insulin glulisine) represent a major improvement in pharmacokinetic properties compared with regular human insulin (RHI). In children and adolescents with T1DM, IAsp and insulin glulisine have shown earlier and greater peak concentration and shorter duration of exposure vs RHI. 7,8 However, the absorption of current rapid-acting insulins is still not fast enough to achieve sufficient postprandial glucose control. 9 Furthermore, delayed elimination of current rapidacting insulins, relative to the need for postmeal glucose reduction, increases the risk of late postmeal hypoglycemia, causing children and parents to compensate by introducing snacks. 10 Thus, there is a need for development of ultrafast insulins not only intended for adults but also for children and adolescents with T1DM.
This study is the first to investigate the pharmacokinetic and pharmacodynamic properties of faster-acting insulin aspart (faster aspart), an ultrafast-acting mealtime insulin, in children and adolescents with T1DM. Faster aspart is IAsp in a new formulation with 2 well-known additional excipients, L-arginine and niacinamide, providing a stable formulation with faster initial absorption after subcutaneous administration. Both excipients appear on the US Food and Drug Administration list of approved inactive ingredients in products for injection, 11 with a wealth of human/clinical data available to support safe systemic exposure. In adults with T1DM, faster aspart compared with IAsp demonstrated twice-as-fast onset of appearance, a 2-fold greater early insulin exposure and approximately 50% greater early glucose-lowering effect within the first 30 minutes of administration. 12 The objectives of this study were to assess the overall pharmacokinetic characteristics of faster aspart in children and adolescents compared with those in adults, and to compare the early pharmacokinetic and pharmacodynamic (using a meal test) properties of faster aspart vs IAsp in children and adolescents, using the same comparison in adults as a reference.

| Study design
This was a randomized, double-blind, single-dose, single-centre (Kinder-und Jugendkrankenhaus AUF DER BULT, Hannover, Germany), 2-period, crossover trial in children, adolescents, and adults with T1DM. Review and approval of the protocol were done by the appropriate health authority and ethics committee before initiation of the trial. The trial was performed in accordance with the Declaration of Helsinki, Good Clinical Practice as well as regulatory guidance on pediatric clinical trials. [13][14][15] Before initiation of any trial-related activities, adults and adolescents as well as parents or legally accepted representatives of the children and adolescents gave written informed consent. Children gave oral informed assent. The trial was registered at ClinicalTrials.gov (NCT02035371).

| Participants
Eligible subjects were males and females aged 6 to 11 years (children), 12 to 17 years (adolescents), or 18  Females who were pregnant or breast-feeding were also excluded from participation. In the morning of the dosing visit, the insulin and glucose infusion was terminated when 2 PG measurements done 30 minutes apart were both within the range of 100 to 160 mg/dL (5.6-8.9 mmol/L). Faster aspart or IAsp (0.2 U/kg single-dose) was then injected subcutaneously into a lifted skin fold of the lower abdominal wall above the inguinal area.

| Study procedures
Immediately after dosing (within 2 minutes), a standardized liquid meal (BOOST, Nestlé S.A., Vevey, Switzerland; containing 101 kcal per 100 mL, 68 energy percent [E%] carbohydrate, 17 E% protein, and 15 E% fat) was consumed as quickly as possible (within 8 minutes). Adjustment of the volume of the liquid meal was done according to the subject's body weight (Table S1, Supporting Information).
Blood samples for pharmacokinetic, PG and β-hydroxybutyrate assessment were drawn frequently up to 12 hours as shown in Table S2. In case PG fell below 56 mg/dL (3.1 mmol/L), or at a higher PG level at the discretion of the Investigator for safety reasons, the subject was treated to alleviate hypoglycemia. In case PG was consistently above 342 mg/dL (19 mmol/L) and/or β-hydroxybutyrate levels were above 1.8 mmol/L, RHI (Actrapid) was to be administered intravenously.
Subjects remained in a semi-supine position until 2 hours after dosing and in a supine or semi-supine position thereafter until 12 hours after dosing. Subjects avoided water consumption until 2 hours after dosing to the extent possible and refrained from eating until 6 hours after dosing. From 6 hours postdose, subjects were given meals and snacks. Use of short-acting insulin was limited to RHI from 6 to 12 hours postdose. Subjects remained at the hospital until 12 hours postdose.

| Assessments
A validated IAsp specific enzyme-linked immunosorbent assay was used to measure free serum IAsp concentrations (polyethylene glycol-precipitated). PG levels for pharmacodynamic and safety assessments and β-hydroxybutyrate levels for safety evaluation were measured by a combined blood glucose/β-ketone monitoring system (Precision Xceed Pro, Abbott Diabetes Care, Alameda, California).
Additional safety assessments included adverse events, local tolerability at the injection site, hypoglycemic episodes (defined as "confirmed" when they were either "severe" according to ADA criteria, that is, requiring third party assistance, 17 or verified by a PG level of <56 mg/dL [3.1 mmol/L]), laboratory safety parameters, physical examination, and vital signs.
Overall insulin exposure was assessed from total insulin exposure (AUC IAsp,0-t ; primary endpoint) and maximum insulin concentration (C max ).
Pharmacodynamic endpoints to evaluate early glucose-lowering effect during the standardized meal test included the mean PG excursion from 0 to 1 hour and 0 to 2 hours after trial product administration (ΔPG average,0-1h and ΔPG average,0-2h ) and the maximum PG excursion (ΔPG max ).
All endpoints were derived from the raw profiles. In the derivation of onset of appearance and AUC IAsp endpoints, IAsp concentration was imputed in the time period from dosing until the time of the first observed IAsp concentration above LLOQ, using compartmental modeling. AUC IAsp,0-t was derived by calculating the AUC until the time of last quantifiable IAsp concentration and then extrapolating until 12 hours (the last pharmacokinetic sampling time point) based on the terminal slope.
If the subject was treated to alleviate hypoglycemia, pharmacodynamic profiles and endpoints were derived by carrying forward the last observation before the intervention.

| Statistical analysis
The number of subjects needed to complete the trial was preset to 12 in each of the 3 age groups without any formal sample size calculation. This approach was based on relevant guidance on the conduct of clinical studies, and specifically pharmacokinetic studies, in the pediatric population. 13,15 Statistical analyses of pharmacokinetic and pharmacodynamic endpoints were conducted at a 5% significance level including all randomized subjects who received at least 1 dose of trial product. Pharmacokinetic endpoints were log-transformed (except for onset of appearance, t Early 50% Cmax, and t max ) and analyzed in a linear mixed model with period, age group, treatment, and interaction between age group and treatment as fixed effects, and subject as a random effect. The variance of the random subject effect and the residual variance depended on age group. Pharmacokinetic properties of faster aspart and IAsp were compared within each age group by deriving the treatment ratios and 95% confidence intervals (CIs) for all pharmacokinetic endpoints (treatment differences for onset of appearance, t Early 50% Cmax, and t max ). Treatment ratios and 95% CIs for onset of appearance, t Early 50% Cmax, and t max were calculated by Fieller's method. 18 To compare overall insulin exposure between age groups (children vs adults; adolescents vs adults; primary objective) for both faster aspart and IAsp, age group ratios and 95% CIs were calculated for AUC IAsp,0-t and C max .
Pharmacodynamic endpoints were analyzed on an additive scale using the same model as for pharmacokinetic endpoints and with predose PG included as a covariate. The pharmacodynamic properties of faster aspart and IAsp were compared within each age group by deriving the treatment differences and 95% CIs.

| Subjects and dosing information
Of the 55 screened individuals, 41 were randomized (13 children, 13 adolescents, and 15 adults) and 40 were exposed to trial product.
One randomized child was withdrawn before first dosing due to occurrence of hypoglycemia within 24 hours of planned dosing. A total of 38 subjects completed the trial (12 children, 13 adolescents, and 13 adults). Two adults were withdrawn after completing the first dosing visit (faster aspart dosing), due to difficulties in drawing predose blood samples at the second dosing visit and inability to attend the second dosing visit, respectively.
Baseline characteristics are presented in Table 1.
The mean absolute dose of faster aspart and IAsp administered at the dosing visits was 8.3 U in children, 12.8 U in adolescents, and 15.6 U in adults. Thus, the mean absolute dose in children and adolescents was 53% and 82%, respectively, of the dose in adults.

| Treatment differences in pharmacokinetic properties
The mean serum IAsp concentration-time profiles were shifted to the left for faster aspart vs IAsp in all 3 age groups (Figures 1 and S1).
For all 3 age groups, onset of appearance occurred approximately twice-as-fast (5-7 minutes earlier; P < .01), and t Early 50% Cmax was also shorter (by 6-11 minutes; P < .05), with faster aspart vs IAsp (Table 2). While t max occurred statistically significantly earlier for faster aspart than for IAsp in adults (P = .029), the earlier t max for faster aspart vs IAsp in children and adolescents did not reach statistical significance (P = .300 and P = .093, respectively). The effect of treatment on onset of exposure did not differ statistically significantly between age groups. P-values for treatment by age group interaction were .365, .326, and .395 for onset of appearance, t Early 50% Cmax, and t max , respectively.
AUC IAsp,0-t and C max were both similar for faster aspart and IAsp, irrespective of age group (Table S3).

| Treatment differences in early glucoselowering effect
Glucose intervention to alleviate hypoglycemia within the first 6 hours after dosing occurred in 8 subjects for both faster aspart   and Table S4). The effect of treatment did not differ statistically significantly between age groups. P-values for treatment by age group interaction were .149, .316, and .474 for ΔPG average,0-1h , ΔPG average,0-2h , and ΔPG max , respectively.

| Safety
Both faster aspart and IAsp were well-tolerated in all 3 age groups, and no safety issues were identified during the trial. There were no serious adverse events and the majority of adverse events were mild

| DISCUSSION
The key findings of this study were the faster onset of appearance and the greater early exposure observed for faster aspart compared with IAsp in children and adolescents. These results are in line with those observed in adults in this study as well as in a previous study. 12 The pharmacokinetic results translated into a statistically significant reduction in 2-hour postprandial PG excursion with faster aspart vs IAsp in children. Statistically non-significant trends in the same direction were seen in adolescents and adults. However, in a larger phase 3 study, mealtime faster aspart was shown to be superior vs mealtime IAsp in adult subjects with T1DM with respect to change from baseline in 2-hour postprandial glucose excursion in a meal test. 19 In younger age groups, where eating behavior is known to vary has not been tested in children or adolescents so far, but a clinical trial is currently being conducted to investigate this option. Abbreviations: CI, confidence interval; T1DM, type 1 diabetes mellitus; t Early 50% Cmax , time to 50% of maximum insulin aspart concentration in the early part of the pharmacokinetic profile; t max , time to maximum insulin aspart concentration.
a Data are least square means.
c Faster aspart − insulin aspart. An insulin with improved pharmacological properties vs current rapid-acting insulins may be useful in insulin pump therapy. 10 In a CSII setting in adults with T1DM, faster aspart provided earlier onset and greater early exposure and glucose-lowering effect vs IAsp. 22 In children and adolescents with T1DM, CSII has advantages over multiple daily injections in terms of improved glycemic control and reduced risk of hypoglycemia. 23,24 Over the last 2 decades, use of insulin pump therapy in youth with T1DM has increased substantially, although large geographical variation exists. 5,25,26 Using CSII, the faster absorption of faster aspart should shorten the lag time following adjustments of the insulin infusion rate. In closed-loop systems, the ultrafast properties of faster aspart may be even more relevant, as a faster insulin response to variations in measured blood glucose would be a very important step toward fully functional artificial pancreas systems. 10,27 These potential applications of faster aspart remain to be investigated in pediatric patients with T1DM.
Total exposure of faster aspart and IAsp was lower in children and adolescents than in adults in this study. For IAsp, this contradicts a study with the combination product insulin degludec/insulin aspart, where total exposure of the IAsp component was statistically significantly higher in children than in adults. 16 This discrepancy between studies may be due to the fact that we measured free IAsp in the current study, whereas total IAsp was measured in the previous study. 16 Higher levels of insulin antibodies in children, potentially interfering with the total IAsp assay, could provide an explanation for the previous observations. 16   despite the fact that the study was not powered to detect these differences. Another limitation was that a meal test rather than a glucose clamp was used to assess early pharmacodynamic properties.
While acknowledging its possible weaknesses, this approach was taken in order to reduce the invasive procedures and required blood volume and thereby the burden on the pediatric subjects in accordance with relevant guidance on the conduct of pediatric clinical trials. 13 The clinical interpretation of the results from the meal test may be difficult due to its experimental nature: a standardized liquid meal, with subjects staying in a supine position, and adjustment of the insulin dose and meal size relative to body weight rather than being individualized. The latter implies that between-subject comparison (ie comparison between age groups) of pharmacodynamic properties should be made with caution. Consequently, our focus with respect to early pharmacodynamic properties has been on the treatment comparison, taking advantage of the similar study conditions for faster aspart and IAsp dosing within each subject.
In conclusion, the current findings of a faster onset and greater early exposure for faster aspart vs IAsp in children and adolescents are in line with those in adults and suggest that the ultrafast insulin, faster aspart, may induce better mealtime glucose control relative to current rapid-acting insulins, also in pediatric patients with T1DM.