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

Sponsor

The Deutsche Diabetes Forschungsgesellschaft e.V. (Other)

Overall Status

Recruiting

CT.gov ID

NCT05160272

Collaborator

komIT - Center of Competence for Innovative Diabetes Therapy (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

4.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type2 Diabetes	Drug: AP-325 Drug: Placebo matching AP-325	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

38 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Effects of GABAA Receptor Modulation by AP-325 on Insulin

Anticipated Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Sep 1, 2022

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: AP-325 Treatment

AP-325, film-coated tablet, 50mg once daily

Drug: AP-325

Measurement of the effect of AP-325 50mg/d compared to matching placebo after 4-week treatment.

Placebo Comparator: Placebo Treatment

Placebo matching AP-325 film-coated tablet, once daily

Drug: Placebo matching AP-325

Measurement of the effect of AP-325 50mg/d compared to matching placebo after 4-week treatment.

Outcome Measures

Primary Outcome Measures

Circulating C-peptide by iAUC of C-peptide during an IVGTT [4 weeks]
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

Secondary Outcome Measures

Basal insulin level [4 weeks]
Change in basal insulin level from baseline to end of treatment
C-peptide level [4 weeks]
Change in C-peptide level from baseline to end of treatment
Glucose level [4 weeks]
Change in glucose level from baseline to end of treatment
iAUC of circulating insulin (overall) [4 weeks]
Change in iAUC of circulating insulin during an IVGTT from baseline to end of treatment
iAUC of C-peptide level (overall) [4 weeks]
Change in C-peptide level during an IVGTT from baseline to end of treatment
iAUC of glucose level (overall) [4 weeks]
Change in iAUC of glucose level during an IVGTT from baseline to end of treatment
iAUC of circulating insulin (AIR) (first 10 min) [4 weeks]
Change in iAUC of circulating insulin (AIR) during an IVGTT in the first 10 minutes from baseline to end of treatment
iAUC of C-peptide (first 10 min) [4 weeks]
Change in iAUC of C-peptide during an IVGTT in the first 10 minutes from baseline to end of treatment
iAUC of glucose (first 10 min) [4 weeks]
Change in iAUC of glucose during an IVGTT in the first 10 minutes from baseline to end of treatment
disposition index (DI) [4 weeks]
Change in the disposition index (DI) through Minimal Model during an IVGTT from baseline to end of treatment
peak insulin response [4 weeks]
Change in peak insulin response during an IVGTT from baseline to end of treatment
insulin secretion rate (ISR) [4 weeks]
Change in insulin secretion rate (ISR) during an IVGTT from baseline to end of treatment
fructosamine levels [4 weeks]
Change in 1.5-Anhydroglucitol glucose from baseline to end of treatment
fructosamine levels II [4 weeks]
Change in fructosamine level from baseline to end of treatment
fructosamine levels III [4 weeks]
Change in fasting blood glucose from baseline to end of treatment
Plasma concentrations of AP-325 [4 weeks]
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
Ctrough-ss (Day 28) and the change from baseline to Day 28 [4 weeks]
Change in relationship between Ctrough-ss (Day 28) and the change from baseline to Day 28 in primary and secondary endpoints

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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