Pharmacology of Insulin Injected With Jet-injection in Diabetes

Study Overview
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Brief Summary
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A previous study showed that absorption and glucose-lowering action of rapid-acting insulin analogues occurred twice as fast when these analogues were administered by jet injection technology rather than by conventional insulin pen in healthy non-diabetic subjects. This study investigates if the rapid-acting insulin analogue aspart (Novorapid®) injected with jet-injection or a conventional insulin pen prior to a standardised meal in patients with diabetes shows the same difference in the pharmacokinetic and pharmacodynamic profile.

Detailed Description
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A previous study showed that absorption and glucose-lowering action of rapid-acting insulin analogues occurred twice as fast when these analogues were administered by jet injection technology rather than by conventional insulin pen in healthy non-diabetic subjects. This study investigates if the rapid-acting insulin analogue aspart (Novorapid®) injected with jet-injection or a conventional insulin pen prior to a standardised meal in patients with diabetes (type 1 and type 2) shows the same difference in the pharmacokinetic and pharmacodynamic profile.The pharmacokinetic and pharmacodynamic profile of insulin aspart will be derived from the time-action profiles of insulin and glucose, respectively, in response to insulin injected directly prior to a standardised meal. All patients will be investigated twice, where on one occasion the jet-injector device will be used to inject an individualised dose of insulin and a conventional insulin pen to inject a placebo solution, and on the other occasion insulin will be injected with the conventional pen and placebo with the jet-injector. The order of these occasions will be randomised and blinded to both the investigator and the participating patient. The primary endpoint is the hyperglycaemic burden as reflected by area under the baseline-subtracted plasma glucose concentration time-curve from time 0 to 2 h after insulin injection and meal ingestion (BG-AUC0-2h). Secondary study endpoints are the area under the baseline-subtracted plasma glucose concentration time-curve from time 0 to 6 h (BG-AUC0-6h), maximal glucose excursion (BGmax), time to maximal glucose excursion (T-BGmax), time until plasma glucose has returned to baseline (T-BGBL), maximal insulin concentration (C-INSmax), time to maximal insulin concentration (T-INSmax), area under the insulin concentration curve (INSAUC) and time until 50% of insulin absorption (T-INSAUC50%) after insulin injection and meal ingestion.

Official Title
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Pharmacology of Rapid-acting Insulin Injected by Needle-free Jet-injection in Patients With Diabetes

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Device: jet injection device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body-mass index 18-32 kg/m2 Stable glycaemic control with HbA1c 6.0-9.0% Duration of diabetes >1 year Insulin use at least once daily or with subcutaneous pump Blood pressure <160/90 mmHg Exclusion Criteria: Inability to provide informed consent Requirement of <8 units of rapid-acting insulin (analogue) before meals Chronic use of sulphonylurea derivatives, GLP-1 based treatments, acarbose or thiazolidinediones Treatment with prednisolone, non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressive agents, cytostatic drugs, hormone therapy except insulin, thyroid supplementation and oral anticonceptives Known allergy to aspart insulin Symptomatic diabetic neuropathy History of a major cardiovascular disease event (myocardial infarction, stroke, symptomatic peripheral artery disease, coronary bypass surgery, percutaneous coronary or peripheral artery angioplasty) in the past 6 months Pregnancy or the intention to become pregnant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: jet injector<br>Jet injectors deliver insulin at a high velocity (typically >100m/s) across the skin in the subcutaneous tissue, without the use of a needle | Device: jet injection device<br>* Rapid-acting insulin analogue aspart (Novorapid®) administration by means of a jet injector or a conventional insulin pen in the subcutaneous tissue. Dosage of insulin will be determined by the normal dosage of insulin used by the patient before breakfast.<br>* Other names: Insulin device: NovoPen® 3 from Novo Nordisk;|
| Active Comparator: conventional insulin pen<br> | Device: jet injection device<br>* Rapid-acting insulin analogue aspart (Novorapid®) administration by means of a jet injector or a conventional insulin pen in the subcutaneous tissue. Dosage of insulin will be determined by the normal dosage of insulin used by the patient before breakfast.<br>* Other names: Insulin device: NovoPen® 3 from Novo Nordisk;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BG-AUC0-2h (mmol•min-1•l-1): area under the baseline-subtracted plasma glucose concentration time-curve from time 0 to 2 h after insulin injection and meal ingestion. | based on plasma glucose levels during the first two hours of the 6-hour post-meal study duration | 2 days (2 hours per day) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BGmax (mmol/l): maximal glucose excursion after insulin injection and meal ingestion | Maximal plasma glucose value after the standardised meal | 2 days (6 hours each day) | 
| T-BGmax (min): time to maximal glucose excursion after insulin injection and meal ingestion | Time until maximal glucose value after the standardised meal and insulin injection | 2 days (6 hours per day) | 
| BG-AUC0-6h (mmol•min-1•l-1): area under the baseline-subtracted plasma glucose concentration time-curve from time 0 to 6 h after insulin injection and meal ingestion | Based on glucose concentration measurements for the total 6 hours of the study | 2 days (6 hours each day) | 
| T-BGBL (min): time until plasma glucose has returned to baseline values after insulin injection and meal ingestion | based on glucose level measurements during the total 6 hours of the study | 2 days (6 hours per day) | 
| T-INSmax (min): time to maximal insulin concentration (C-INSmax) | Maximal insulin concentration after insulin injection | 2 days (6 hours per day) | 
| INSAUC (pmol•min-1•l-1): area under the insulin concentration curve (from timepoint 0) | Based on insulin concentration measurements during the total 6 hours of the study | 2 days (6 hours per day) | 
| T-INSAUC50% (min): time until 50% of insulin absorption (mean residence time, MRT) | Based on insulin concentration measurements during the total 6 hours of the study | 2 days (6 hours each day) | 
| Number of patients requiring exogenous glucose infusion to prevent postprandial hypoglycaemia after insulin injection and meal ingestion | This will be assessed for the individual patient after every test. After completion of the experiments all cases of hypoglycemia will be assessed | 2 days | 
| Amount of exogenous glucose required to prevent postprandial hypoglycaemia after insulin injection and meal ingestion | This will be assessed for the individual patient after every test. After completion of the experiments the total amount of glucose infused will be calculate for each device | 2 days | 
| Duration of time that exogenous glucose is required to prevent postprandial hypoglycaemia after insulin injection and meal ingestion | This will be assessed for the individual patient after every test. After completion of the experiments the total amount of time will be calculate for each device | 2 days | 
| BG-AUC0-1h | the area under the baseline-subtracted plasma glucose concentration time-curve during the first hour | 2 days (6 hours per day) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin action, Jet injector, Diabetes Mellitus, Pharmacodynamics, Pharmacokinetics, Insulin analogs, Insulin aspart