A Trial to Assess Safety and Efficacy of ADO09 Versus Insulin Aspart in Subjects With Type 1 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, active-controlled, 2 period cross-over clinical trial in subjects with type 1 diabetes mellitus using a Multiple Daily Injection (MDI) regimen.

Detailed Description
-----------------
After a screening visit, eligible subjects will enter a run-in period. Subjects will receive a Continuous Glucose Monitoring (CGM) system for glucose monitoring and control at the beginning of the run-in and for the whole duration of the study. Each eligible subject will then be randomly allocated to a sequence of the 2 treatments, i.e. multiple daily injections of ADO09 and insulin aspart during 2 dosing periods. At Day 1 a mixed meal test (MMT) will be conducted at breakfast and subjects will remain at the clinical site until day 3. At Day 3 subjects will leave the clinical site and continue the treatment with IMP for the next 3 weeks. On Day 23 subjects will come back for a MMT on Day 24. This study is constituted of 2 parts. In the first part (Part A), only subjects with daily prandial insulin dose ≤ 40 U/day will be enrolled. Following the completion of the part A, an extension part (Part B) will be conducted to particularly assess the safety and tolerability of higher daily doses of ADO09 in patients with insulin requirements ≥ 40 U/day. The clinical conduct and procedures will not change for the Extension Part of the study.

Official Title
-----------------
A Randomized, Single-centre, Double-blind, 2-period Cross-over Trial to Assess Safety and Efficacy of ADO09 Versus Insulin Aspart in Subjects With Type 1 Diabetes Mellitus

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

Intervention / Treatment
-----------------
* Drug: ADO09 formulation
* Drug: NovoRapid®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed and dated informed consent obtained before any trial-related activities. Type 1 diabetes mellitus (as diagnosed clinically) ≥ 12 months. Treated with insulin ≥ 12 months. Using a multiple dosing insulin therapy (MDI) with basal and bolus insulin. HbA1c ≤ 9.0%. Fasting negative C-peptide (≤ 0.30 nmol/L). Total daily prandial dose: ≤ 40U in the Part A and ≥ 40 U in the Part B Exclusion Criteria: Known or suspected hypersensitivity to products used in the clinical trial Type 2 diabetes mellitus Previous participation in this trial. Participation is defined as randomized. Receipt of any medicinal product in clinical development within 3 months before randomization in this trial. Known slowing of gastric emptying, including gastroparesis, and or gastrointestinal surgery that in the opinion of the investigator might change gastrointestinal motility and food absorption. Presence of clinically significant acute gastrointestinal symptoms (e.g. nausea, vomiting, heartburn or diarrhoea), as judged by the Investigator. Intake of medication known to affect gastrointestinal motility, including but not limited to erythromycin, metoclopramide, cisapride, cholestyramine or colestipol within 4 weeks before screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Co-formulation of insulin analog and pramlintide (ADO09)<br>Subcutaneous injection of ADO09 formulation | Drug: ADO09 formulation<br>* Subcutaneous injection of ADO09 formulation<br>|
| Active Comparator: NovoRapid®<br>Subcutaneous injection of insulin aspart | Drug: NovoRapid®<br>* Subcutaneous injection of insulin aspart<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ΔAUCPG(0-4h) | Incremental area under the plasma glucose concentration-time curve from 0-4 hours after start of breakfast, assessed by Super GL at day 24. | From 0 to 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of pramlintide | Area under the pramlintide concentration-time curve | From 0 to 4 hours | 
| Pharmacokinetics of insulins | Area under the insulins concentration-time curve | From 0 to 4 hours | 
| Plasma glucose control as measured by CGM | Time and percentage of time in Range (TiR) [70-180] mg/dL | Over 24 hours | 
| Safety and tolerability (Adverse Events recording) | Number of Adverse Events | Up to 24 days |