A Trial Investigating the Dose Linearity and Safety of BC Combo THDB0207 in Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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This is a randomised, double-blind, four-period crossover euglycaemic clamp trial in subjects with type 2 diabetes. Each subject will be randomly allocated to one of four treatment sequences. Each sequence will comprise 3 different single doses of BC Combo THDB0207 (Low dose, Medium dose, and High dose) and one single dose of Humalog® Mix25. Subjects will come to the clinical trial centre in a fasted state in the morning of each dosing day and stay at the clinical trial centre until the 30-hour clamp procedures have been terminated.

Detailed Description
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Subjects will attend the study site in the morning in a fasted state and will be connected to an automated glucose clamp device. Prior to dose administration plasma glucose will be stabilised at a target level of 100 mg/dL by means of an intravenous infusion of glucose or insulin. IMP administration will be done by an unblinded person by means of subcutaneous injections in the abdominal wall. Following each dosing a euglycaemic glucose clamp procedure will be carried out for up to 30 hours. The pharmacodynamic assessment will be based on the time course of glucose infusion rate (GIR) and plasma glucose. Plasma insulin concentrations will be measured using a specific validated bioanalytical method differentiating concentrations of insulin glargine, of its main metabolites insulin-glargine-M1 and insulin-glargine-M2, and of insulin lispro. Pharmacokinetic assessments will be based on total insulin concentration (insulin glargine + insulin glargine-M1 + insulin glargine-M2 + insulin lispro), on insulin glargine concentration (insulin glargine + insulin glargine-M1 + insulin glargine-M2), or on insulin lispro concentration.

Official Title
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A Trial Investigating the Dose Linearity and Safety of BC Combo THDB0207 in Subjects With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Euglycemic clamp with BC Combo THDB0207
* Drug: Euglycemic clamp with Humalog® Mix25


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus (as diagnosed clinically) for ≥ 12 months HbA1c ≤9.0% Total insulin dose of < 1.2 U/kg/day Body mass index between 20.0 and 35.0 kg/m2 (both inclusive) Treated with a stable insulin regimen for ≥ 3 months prior to screening Exclusion Criteria: Known or suspected hypersensitivity to the IMPs or any of the excipients or to any component of the IMP formulation Receipt of any medicinal product in clinical development within 30 days or at least 5 half-lives of the related substances and their metabolites (whichever is longer) before randomisation in this trial Clinically significant abnormal screening laboratory tests, as judged by the Investigator considering the underlying disease Clinically relevant comorbidity, capable of constituting a risk for the subject when participating in the trial or of interfering with the interpretation of data Systolic blood pressure < 90 mmHg or >160 mmHg and/or diastolic blood pressure < 50 mmHg or > 95 mmHg (one repeat test will be acceptable in case of suspected white-coat hypertension) Heart rate at rest outside the range of 50-90 beats per minute Use of GLP-1 receptor agonists or oral antidiabetic drugs (OADs) other than stable intake of metformin within 4 weeks prior to screening Women of childbearing potential who are not using a highly effective contraceptive method

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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
Interventional Model Description: Four-period crossover
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BC Combo THDB0207 Low dose<br>Single administration of BC Combo THDB0207 (Low dose) | Drug: Euglycemic clamp with BC Combo THDB0207<br>* Administration of a single dose of BC Combo THDB0207 during an euglycemic clamp procedure.<br>|
| Experimental: BC Combo THDB0207 Medium dose<br>Single administration of BC Combo THDB0207 (Medium dose) | Drug: Euglycemic clamp with BC Combo THDB0207<br>* Administration of a single dose of BC Combo THDB0207 during an euglycemic clamp procedure.<br>|
| Experimental: BC Combo THDB0207 High dose<br>Single administration of BC Combo THDB0207 (High dose) | Drug: Euglycemic clamp with BC Combo THDB0207<br>* Administration of a single dose of BC Combo THDB0207 during an euglycemic clamp procedure.<br>|
| Active Comparator: Humalog® Mix25<br>Single administration of Humalog® Mix25 | Drug: Euglycemic clamp with Humalog® Mix25<br>* Administration of a single dose of Humalog® Mix25 during an euglycemic clamp procedure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCTOTAL0-last | Area under the total insulin concentration-time curve from t=0 to the last measured insulin concentration above LLOQ | From t=0 to t=30 hours after IMP administration | 
| CmaxTOTAL | Maximum total insulin concentration | From t=0 to t=30 hours after IMP administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCGIR 0-last | Area under the glucose infusion rate curve from 0 hours until the end of clamp | From t=0 to t=30 hours after IMP administration | 
| GIRmax | Maximum glucose infusion rate | From t=0 to t=30 hours after IMP administration | 
| tGIRmax | Time to maximum glucose infusion rate | From t=0 to t=30 hours after IMP administration | 
| Tonset of action | Time until Plasma Glucose (PG) has decreased by at least 5 mg/dL from the baseline PG value. | From t=0 to t=30 hours after IMP administration | 
| AUCGIR 0-6h | Area under the glucose infusion rate curve from t=0 hours to t=6 hours | From t=0 to t=6 hours | 
| AUCTOTALlast | Area under the insulin concentration-time curve from t=0 to the last measured insulin concentration above LLOQ | From t=0 to t=30 hours after IMP administration | 
| AUCTOTAL 0-1h | Area under the total insulin concentration-time curve from t=0 to t=1 hour | From t=0 to t=1 hour | 
| AUCTOTAL 0-2h | Area under the total insulin concentration-time curve from t=0 to t=2 hours | From t=0 to t=2 hours | 
| AUCTOTAL 0-6h | Area under the total insulin concentration-time curve from t=0 to t=6 hours | From t=0 to t=6 hours | 
| AUCTOTAL 2-6h | Area under the total insulin concentration-time curve from t=2 to t=6 hours | From t=2 to t=6 hours | 
| AUCTOTAL 6-12h | Area under the total insulin concentration-time curve from t=6 to t=12 hours | From t=6 to t=12 hours | 
| AUCTOTAL 6-24h | Area under the total insulin concentration-time curve from t=6 to t=24 hours | From t=6 to t=24 hours | 
| AUCTOTAL 12-24h | Area under the total insulin concentration-time curve from t=12 to t=24 hours | From t=12 to t=24 hours | 
| AUCTOTAL 12-30h | Area under the total insulin concentration-time curve from t=12 to t=30 hours | From t=12 to t=30 hours | 
| AUCTOTAL 0-30h | Area under the total insulin concentration-time curve from t=0 to t=30 hours | From t=0 to t=30 hours | 
| CTOTALmax | Maximum insulin concentration | From t=0 to t=30 hours after IMP administration | 
| tmaxTOTAL | Time to maximum total insulin concentration | From t=0 to t=30 hours after IMP administration | 
| AUCGLA 0-last | Area under the insulin glargine concentration-time curve from t=0 to the last measured insulin concentration above LLOQ | From t=0 to t=30 hours after IMP administration | 
| AUCGLA 0-1h | Area under the insulin glargine concentration-time curve from t=0 to t=1 hour | From t=0 to t=1 hour after IMP administration | 
| AUCGLA 0-2h | Area under the insulin glargine concentration-time curve from t=0 to t=2 hours | From t=0 to t=2 hours after IMP administration | 
| AUCGLA 0-6h | Area under the insulin glargine concentration-time curve from t=0 to t=6 hours | From t=0 to t=6 hours after IMP administration | 
| AUCGLA 2-6h | Area under the insulin glargine concentration-time curve from t=2 to t=6 hours | From t=2 to t=6 hours after IMP administration | 
| AUCGLA 6-12h | Area under the insulin glargine concentration-time curve from t=6 to t=12 hours | From t=6 to t=12 hours after IMP administration | 
| AUCGLA 12-24h | Area under the insulin glargine concentration-time curve from t=12 to t=24 hours | From t=12 to t=24 hours after IMP administration | 
| AUCGLA 12-30h | Area under the insulin glargine concentration-time curve from t=12 to t=30 hours | From t=12 to t=30 hours after IMP administration | 
| AUCGLA 0-30h | Area under the insulin glargine concentration-time curve from t=0 to t=30 hours | From t=0 to t=30 hours after IMP administration | 
| CmaxGLA | Maximum concentration of insulin glargine | From t=0 to t=30 hours after IMP administration | 
| tmaxGLA | Time to maximum insulin glargine concentration | From t=0 to t=30 hours after IMP administration | 
| AUCLIS0-last | Area under the insulin lispro concentration-time curve from t=0 to the last measured insulin concentration above LLOQ | From t=0 to t=30 hours after IMP administration | 
| AUCLIS 0-1h | Area under the insulin lispro concentration-time curve from t=0 to t=1 hour | From t=0 to t=1 hour after IMP administration | 
| AUCLIS 0-2h | Area under the insulin lispro concentration-time curve from t=0 to t=2 hours | From t=0 to t=2 hours after IMP administration | 
| AUCLIS 0-6h | Area under the insulin lispro concentration-time curve from t=0 to t=6 hours | From t=0 to t=6 hours after IMP administration | 
| AUCLIS 2-6h | Area under the insulin lispro concentration-time curve from t=2 to t=6 hours | From t=2 to t=6 hours after IMP administration | 
| AUCLIS 6-12h | Area under the insulin lispro concentration-time curve from t=6 to t=12 hours | From t=6 to t=12 hours after IMP administration | 
| AUCLIS 12-24h | Area under the insulin lispro concentration-time curve from t=12 to t=24 hours | From t=12 to t=24 hours after IMP administration | 
| AUCLIS 12-30h | Area under the insulin lispro concentration-time curve from t=12 to t=30 hours | From t=12 to t=30 hours after IMP administration | 
| AUCLIS 0-30h | Area under the insulin lispro concentration-time curve from t=0 to t=30 hours | From t=0 to t=30 hours after IMP administration | 
| CmaxLIS | Maximum concentration of insulin lispro | From t=0 to t=30 hours after IMP administration | 
| tmaxLIS | Time to maximum insulin lispro concentration | From t=0 to t=30 hours after IMP administration | 
| Adverse Events | Incidence of Adverse Events | From the first IMP administration to the follow-up visit (i.e. up to 14 weeks) | 
| Local tolerability | Incidence of Injection Site Reactions | From the first IMP administration to the follow-up visit (i.e. up to 14 weeks) |