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

Type2 Diabetes Clinical Trial

Official title:

Effects of GABAA Receptor Modulation by AP-325 on Insulin

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05160272
• Other study ID #: GAP-325
• Status: Recruiting
• Phase: Phase 2
• Start date: January 7, 2022
• Est. completion date: June 2025

Study information

• Verified date: September 2023
• Source: German Diabetes Center
• Contact: Sabine Kahl, MD
• Phone: +49 211 3382 0
• Email: sabine.kahl[@]ddz.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 38
• Est. completion date: June 2025
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 75 Years

Eligibility

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, a-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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type2 Diabetes

Intervention

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

Locations

Country	Name	City	State
Germany	German Diabetes Center	Duesseldorf	NRW

Sponsors (2)

Lead Sponsor	Collaborator
The Deutsche Diabetes Forschungsgesellschaft e.V.	Algiax Pharmaceuticals GmbH

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Basal insulin level	Change in basal insulin level from baseline to end of treatment	4 weeks
Secondary	C-peptide level	Change in C-peptide level from baseline to end of treatment	4 weeks
Secondary	Glucose level	Change in glucose level from baseline to end of treatment	4 weeks
Secondary	iAUC of circulating insulin (overall)	Change in iAUC of circulating insulin during an IVGTT from baseline to end of treatment	4 weeks
Secondary	iAUC of C-peptide level (overall)	Change in C-peptide level during an IVGTT from baseline to end of treatment	4 weeks
Secondary	iAUC of glucose level (overall)	Change in iAUC of glucose level during an IVGTT from baseline to end of treatment	4 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	disposition index (DI)	Change in the disposition index (DI) through Minimal Model during an IVGTT from baseline to end of treatment	4 weeks
Secondary	peak insulin response	Change in peak insulin response during an IVGTT from baseline to end of treatment	4 weeks
Secondary	insulin secretion rate (ISR)	Change in insulin secretion rate (ISR) during an IVGTT from baseline to end of treatment	4 weeks
Secondary	fructosamine levels	Change in 1.5-Anhydroglucitol glucose from baseline to end of treatment	4 weeks
Secondary	fructosamine levels II	Change in fructosamine level from baseline to end of treatment	4 weeks
Secondary	fructosamine levels III	Change in fasting blood glucose from baseline to end of treatment	4 weeks
Secondary	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
Secondary	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