Effects of GABAA Receptor Modulation by AP-325 on Insulin Secretion in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The aim of this single-center, prospective, randomized, double-blind, placebo-controlled, 2-arm parallel-group interventional study is to investigate the effect of 4-week treatment with AP-325 on C-peptide release as measure of insulin secretion compared to placebo in type 2 diabetes (T2D) patients.

Official Title
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Effects of GABAA Receptor Modulation by AP-325 on Insulin

Conditions
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Type2 Diabetes

Intervention / Treatment
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* Drug: AP-325
* Drug: Placebo matching AP-325


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of T2D Age between 25 and 75 years HbA1c ≥6.5 and ≤9.5 % BMI ≤ 45 kg/m2 Treatment-naive or stable antihyperglycemic therapy with metformin, α-glucosidase-inhibitor and/or SGLT2 inhibitor Ability to give consent Exclusion Criteria: Acute infections (hsCRP > 5mg/dl, body temperature >37.5°C) Insulin therapy or treatment with sulfonylureas, glinides, GLP-1 receptor agonists, thiazolidinediones; current treatment with DPP-4 inhibitors or during the 4 weeks prior to baseline examination Uncontrolled hyperglycemia, e.g. fasting blood glucose >240 mg/dl Heart rate <50 or >100 beats per minute; systolic blood pressure <100 or >160 mmHg; diastolic blood pressure <50 or >100 mmHg; uncontrolled hypertension Creatinine clearance <60 ml/min (eGFR by MDRD formula) Severe chronic illnesses, such as congestive heart failure (NYHA III/IV), liver insufficiency (Child-Pugh Class B/C), history of acute coronary syndrome, stroke Anemia (Hb <12 g/l for men, Hb <11 g/l for women) Participation in another intervention study within 2 months before the examination Hypersensitivity against AP-325, placebo or other ingredients of IMP Immunocompromising diseases Immunomodulatory drugs (e.g. oral cortisone preparations, biologicals) Thyroid diseases with an unstable metabolic state (change in L-thyroxine dose within the past 6 weeks, TSH and fT4 outside the normal range) Planned pregnancy, pregnant or lactating women, positive pregnancy test, and woman of childbearing potential not using two adequate methods of contraception, including a barrier method and a highly efficacious non-barrier method Past (≤ 5 years) or current history of psychiatric disorders, including psychiatric depression HIV, hepatitis B or C disease Previous / current alcohol and / or drug abuse Malignant cancer BIA and MR-incompatible metal or magnetic implants, devices or objects inside of or on the body, claustrophobia Treatment with the following drug groups or agents: Anticoagulant drugs (exception: acetylsalicylic acid 100 mg/day), dihydropyridines (e.g. nifedipine, amlodipine), azilsartan, losartan and irbesartan, celecoxib; if applicable, other drugs that are predominantly metabolized by CYP2C9 Inhibitors or inducers of CYP2C9, CYP3A4, such as amiodarone, verapamil, rifampicin Poor CYP2C9 metabolizer

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 75 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AP-325 Treatment<br>AP-325, film-coated tablet, 50mg once daily | Drug: AP-325<br>* Measurement of the effect of AP-325 50mg/d compared to matching placebo after 4-week treatment.<br>|
| Placebo Comparator: Placebo Treatment<br>Placebo matching AP-325 film-coated tablet, once daily | Drug: Placebo matching AP-325<br>* Measurement of the effect of AP-325 50mg/d compared to matching placebo after 4-week treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating C-peptide by iAUC of C-peptide during an IVGTT | Change in circulating C-peptide levels from baseline to end of intervention measured by iAUC of C-peptide during an IVGTT until 60th minute (second phase) with AP-325 compared to placebo | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Basal insulin level | Change in basal insulin level from baseline to end of treatment | 4 weeks | 
| C-peptide level | Change in C-peptide level from baseline to end of treatment | 4 weeks | 
| Glucose level | Change in glucose level from baseline to end of treatment | 4 weeks | 
| iAUC of circulating insulin (overall) | Change in iAUC of circulating insulin during an IVGTT from baseline to end of treatment | 4 weeks | 
| iAUC of C-peptide level (overall) | Change in C-peptide level during an IVGTT from baseline to end of treatment | 4 weeks | 
| iAUC of glucose level (overall) | Change in iAUC of glucose level during an IVGTT from baseline to end of treatment | 4 weeks | 
| iAUC of circulating insulin (AIR) (first 10 min) | Change in iAUC of circulating insulin (AIR) during an IVGTT in the first 10 minutes from baseline to end of treatment | 4 weeks | 
| iAUC of C-peptide (first 10 min) | Change in iAUC of C-peptide during an IVGTT in the first 10 minutes from baseline to end of treatment | 4 weeks | 
| iAUC of glucose (first 10 min) | Change in iAUC of glucose during an IVGTT in the first 10 minutes from baseline to end of treatment | 4 weeks | 
| disposition index (DI) | Change in the disposition index (DI) through Minimal Model during an IVGTT from baseline to end of treatment | 4 weeks | 
| peak insulin response | Change in peak insulin response during an IVGTT from baseline to end of treatment | 4 weeks | 
| insulin secretion rate (ISR) | Change in insulin secretion rate (ISR) during an IVGTT from baseline to end of treatment | 4 weeks | 
| fructosamine levels | Change in 1.5-Anhydroglucitol glucose from baseline to end of treatment | 4 weeks | 
| fructosamine levels II | Change in fructosamine level from baseline to end of treatment | 4 weeks | 
| fructosamine levels III | Change in fasting blood glucose from baseline to end of treatment | 4 weeks | 
| Plasma concentrations of AP-325 | Change in Plasma concentrations of AP-325 at 1 hour post-dose on Days 1 and 28; pre-dose on Days 4 and 28. Accumulation of Ctrough from Day 4 to Day 28 | 4 weeks | 
| Ctrough-ss (Day 28) and the change from baseline to Day 28 | Change in relationship between Ctrough-ss (Day 28) and the change from baseline to Day 28 in primary and secondary endpoints | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Diabetes mellitus, GABAA receptor, β-cell function, glycemic control