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

Effects of GABAA Receptor Modulation by AP-325 on Insulin

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.

Study Overview

• Status: Completed
• Conditions: Type2 Diabetes
• Intervention / Treatment: Drug: AP-325; Drug: Placebo matching AP-325

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • NRW
    • Duesseldorf, NRW, Germany, 40225
      • German Diabetes Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Deutsche Diabetes Forschungsgesellschaft e.V.
• Collaborators: Algiax Pharmaceuticals GmbH
• Investigators: Principal Investigator: Michael Roden, MD, Deutsches Diabetes-Zentrum

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2022
• Primary Completion (Actual): December 17, 2024
• Study Completion (Actual): December 17, 2024

Study Registration Dates

• First Submitted: November 17, 2021
• First Submitted That Met QC Criteria: December 3, 2021
• First Posted (Actual): December 16, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 9, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Type 2 Diabetes; Diabetes mellitus; glycemic control; β-cell function; GABAA receptor
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus
• Other Study ID Numbers: GAP-325

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No