Effect of NPH Insulin, Insulin Detemir and Insulin Glargine on GH-IGF-IGFBP Axis

Study Overview
=================
Brief Summary
-----------------
The objective is to describe the interaction of equal doses of NPH insulin (Neutral Protamine Hagedorn), insulin Detemir and insulin glargine on IGFBP-1 (Insulin-like Growth Factor Binding Protein-1) production as well as immunoreactive and bioactive IGF-I (Insulin-like Growth Factor-I) after once-daily injection on three separate visits in type 1 diabetic subjects.

Detailed Description
-----------------
Because of the importance of receptors activation and potential effects on the IGF system, a head-to-head comparison of the eventual differential impact of intermediate-acting human insulin (NPH), insulin detemir and insulin glargine on the growth hormone-insulin-like growth factor-insulin-like growth factor binding protein (GH-IGF-IGFBP) axis is relevant to be conducted for the safety assurance of insulin analogues. Therefore, this study aims to investigate whether the serum insulin profile obtained by once-daily injection of long-acting insulin analog, insulin detemir or insulin glargine, has a different impact on IGFBPs production and IGF-I concentrations (total IGF-I) bioactivity and tissue-availability as compared to that seen during treatment with intermediate-acting human insulin, NPH insulin.

Official Title
-----------------
Effect of NPH Insulin, Insulin Detemir and Insulin Glargine on IGFBP-1 Production and Serum IGF-I in Subjects With Type 1 Diabetes Mellitus: An Open-label, Randomised, Triple Cross-over Trial

Conditions
-----------------
Diabetes Mellitus, Type 1

Intervention / Treatment
-----------------
* Drug: NPH
* Drug: Detemir
* Drug: Glargine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent obtained before any trial-related activities. Diagnosis of diabetes mellitus according to WHO criteria; history and clinical course consistent with type 1 diabetes mellitus. Diagnosed with diabetes for more than 6 years and using continuous subcutaneous insulin infusion (CSII) at least 6 months at time of inclusion. Total daily insulin dose between 0.4 and 1.4 units/kg (both values included) HbA1c between 6% and 9% (both values included). Age ≥ 18 years. BMI between 18.5 and 28 kg /m2 (including both values). Exclusion Criteria: Known or suspected allergy to trial product(s) or related products. Recurrent major hypoglycaemic episodes. Heart: Unstable Angina Pectoris, AMI < 12 months or heart insufficiency classified according to NYHA III-IV Blood Pressure: Severe uncontrolled hypertension with BP > 180/110 mmHg, sitting Liver: Impaired hepatic function corresponding to serum-ALAT or basic phosphatase > 2 x upper reference limit of the local laboratory. Kidneys: Impaired renal function corresponding to serum-creatinin > 150 μmol/l according to the local laboratory. Any disease judged by the investigator to affect the trial. Pregnancy, breast-feeding or the intention of becoming pregnant or fertile women not using adequate contraceptive measures - adequate contraceptive method is sterilisation, hysterectomy or current use of contraceptive pills or intra uterine device.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NPH insulin injection<br>NPH insulin will be injected in random order in one of three seperated visit days. | Drug: NPH<br>* equal doses of NPH insulin, insulin Detemir and insulin glargine injection<br>* Other names: NPH insulin: Insulatard;|
| Experimental: detemir insulin injection<br>insulin detemir will be injected in random order in one of three seperated visit days. | Drug: Detemir<br>* equal doses of NPH insulin, insulin Detemir and insulin glargine injection<br>* Other names: insulin Detemir: Levemir;|
| Experimental: glargine insulin injection<br>insulin glargine will be injected in random order in one of three seperated visit days. | Drug: Glargine<br>* equal doses of NPH insulin, insulin Detemir and insulin glargine injection<br>* Other names: insulin glargine: Lamtus;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IGF-I(ng/ml) | Hourly samples will be taken from 18:00 to 10:00 next day. | 16 hours (from 18:00 to 10:00 next day) | 
| IGFBP-1(ng/ml) | Hourly samples will be taken from 18:00 to 10:00 next day. | 16 hours (from 18:00 to 10:00 next day) | 
| IGFBP-2(ng/ml) | Hourly samples will be taken from 18:00 to 10:00 next day. | 16 hours (from 18:00 to 10:00 next day) | 
| IGFBP-3(ng/ml) | Hourly samples will be taken from 18:00 to 10:00 next day. | 16 hours (from 18:00 to 10:00 next day) | 
| Growth Hormone(ng/ml) | Hourly samples will be taken from 18:00 to 10:00 next day. | 16 hours (from 18:00 to 10:00 next day) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma glucose concentration (mmol/L) after a single injection of either NPH insulin, insulin Detemir or insulin glargine | Hourly samples will be taken from 18:00 to 10:00 next day. | 16 hours (from 18:00 to 10:00 next day) | 
| insulin concentration (mmol/L) after a single injection of either NPH insulin, insulin Detemir or insulin glargine | Hourly samples will be taken from 18:00 to 10:00 next day. | 16 hours (from 18:00 to 10:00 next day) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes Mellitus, Type 1