A Trial Comparing the Pharmacodynamics and Pharmacokinetics of BC Combo THDB0207 and Lantus® and Humalog® in Subjects With Type 1 Diabetes

Study Overview
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Brief Summary
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This is a randomised, double-blind, three-period crossover euglycaemic clamp trial comparing pharmacokinetics and pharmacodynamics of BC Combo THDB0207 and Lantus® and Humalog® in subjects with type 1 diabetes. Each subject will be randomly allocated to one of the 6 treatment sequences and will be administered single subcutaneous doses of BC Combo THDB0207, Lantus®, and Humalog® at three separate dosing visits. Subjects will come in a fasted state to the clinical trial centre in the morning of each dosing day and stay at the clinical trial centre until the 24-hour clamp procedures have been terminated. Patients will return to the clinical trial centre for outpatient blood sampling visits for analysis of BC449 excipient until 144 hours after each dosing.

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 (ClampArt). 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 24 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 (INS) concentration (insulin glargine + insulin glargine-M1 + insulin glargine-M2 + insulin lispro). The investigation of PK properties of the BC449 excipient after dosing with BC Combo THDB0207 will be based on blood samples collected during the clamp procedure and at daily outpatient visits until 144 hours after dose administration.

Official Title
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A Trial Comparing the Pharmacodynamics and Pharmacokinetics of BC Combo THDB0207 and Lantus® and Humalog® in Subjects With Type 1 Diabetes

Conditions
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Type 1 Diabetes

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes mellitus (as diagnosed clinically) for ≥ 12 months HbA1c ≤8.5% Total insulin dose of < 1.2 U/kg/day BMI between 20.0 and 29.9 kg/m2 (both inclusive) Treated with insulin regimen for ≥ 12 months prior to screening Using multiple dosing insulin therapy (MDI) with basal and bolus insulin or insulin pump therapy (continuous subcutaneous insulin infusion, CSII) Fasting C-peptide <= 0.30 nmol/L Exclusion Criteria: Known or suspected hypersensitivity to the IMPs or any of the excipients or to any component of the IMP formulation. Type 2 diabetes mellitus Use of oral antidiabetic drugs (OADs) and/or GLP-1 receptor agonists (e.g. exenatide, liraglutide) 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 >139 mmHg and/or diastolic blood pressure < 50 mmHg or > 89 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. More than one episode of severe hypoglycaemia with seizure, coma or requiring assistance of another person during the past 6 months or hypoglycaemia unawareness as judged by the investigator 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: Three-period crossover
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCGIR 0-6h | Area under the glucose infusion rate curve until 6 hours after dosing of BC Combo THDB0207 and Lantus® | From t=0 to t=6 hours after IMP administration | 
| AUCGIR 6-24h | Area under the glucose infusion rate curve from 6 hours to 24 hours after dosing of BC Combo THDB0207 and Humalog® | From t=6 to t=24 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=24 hours after IMP administration | 
| AUCGIR 0-4h | Area under the glucose infusion rate curve from 0 hours until 4 hours | From t=0 to t=4 hours after IMP administration | 
| GIRmax | Maximum glucose infusion rate | From t=0 to t=24 hours | 
| tGIRmax | Time to maximum glucose infusion rate | From t=0 to t=24 hours | 
| 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=24 hours after IMP administration | 
| AUCINS 0-6h | Area under the insulin concentration-time curve from 0 hours until 6 hours | From t=0 to t=6 hours after IMP administration | 
| AUCINS 0-24h | Area under the insulin concentration-time curve from 0 hours until 24 hours | From t=0 to t=24 hours after IMP administration | 
| AUCINS 6-24h | Area under the insulin concentration-time curve from 6 hours until 24 hours | From t=6 to t=24 hours after IMP administration | 
| AUCINS 4-12h | Area under the insulin concentration-time curve from 4 hours until 12 hours | From t=4 to t=12 hours after IMP administration | 
| AUCINS 0-4h | Area under the insulin concentration-time curve from 0 hours until 4 hours | From t=0 to t=4 hours after IMP administration | 
| AUCINSlast | Area under the insulin concentration-time curve from t=0 to the last measured insulin concentration above LLOQ | From t=0 to t=24 hours | 
| Cmax INS | Maximum insulin concentration | From t=0 to t=24 hours after IMP administration | 
| RBA | Relative bioavailability of BC Combo THDB0207 vs Humalog® | From t=0 to t=24 hours after IMP administration | 
| AUCBC 0-12h | Area under the BC449 concentration-time curve from 0 hours until 12 hours | From t=0 to t=12 hours after IMP administration | 
| AUCBC 0-24h | Area under the BC449 concentration-time curve from 0 hours until 24 hours | From t=0 to t=24 hours after IMP administration | 
| AUCBC 0-last | Area under the BC449 concentration-time curve from t=0 to the last measured BC449 concentration above LLOQ | From t=0 to t=144 hours after IMP administration | 
| Adverse Events | Incidence of Adverse Events | From the first IMP administration to the follow-up visit (i.e. up to 11 weeks) | 
| Local tolerability | Incidence of injection site reactions | From the first IMP administration to the follow-up visit (i.e. up to 11 weeks) |