Effects of GABAA Receptor Modulation by AP-325 on Insulin Secretion in Patients With Type 2 Diabetes
Primary Purpose
Type2 Diabetes
Status
Recruiting
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
AP-325
Placebo matching AP-325
Sponsored by
About this trial
This is an interventional treatment trial for Type2 Diabetes focused on measuring Type 2 Diabetes, Diabetes mellitus, GABAA receptor, β-cell function, glycemic control
Eligibility Criteria
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
Sites / Locations
- German Diabetes CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
AP-325 Treatment
Placebo Treatment
Arm Description
AP-325, film-coated tablet, 50mg once daily
Placebo matching AP-325 film-coated tablet, once daily
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
Basal insulin level
Change in basal insulin level from baseline to end of treatment
C-peptide level
Change in C-peptide level from baseline to end of treatment
Glucose level
Change in glucose level from baseline to end of treatment
iAUC of circulating insulin (overall)
Change in iAUC of circulating insulin during an IVGTT from baseline to end of treatment
iAUC of C-peptide level (overall)
Change in C-peptide level during an IVGTT from baseline to end of treatment
iAUC of glucose level (overall)
Change in iAUC of glucose level during an IVGTT from baseline to end of treatment
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
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
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
disposition index (DI)
Change in the disposition index (DI) through Minimal Model during an IVGTT from baseline to end of treatment
peak insulin response
Change in peak insulin response during an IVGTT from baseline to end of treatment
insulin secretion rate (ISR)
Change in insulin secretion rate (ISR) during an IVGTT from baseline to end of treatment
fructosamine levels
Change in 1.5-Anhydroglucitol glucose from baseline to end of treatment
fructosamine levels II
Change in fructosamine level from baseline to end of treatment
fructosamine levels III
Change in fasting blood glucose from baseline to end of treatment
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
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
Full Information
NCT ID
NCT05160272
First Posted
November 17, 2021
Last Updated
January 5, 2022
Sponsor
The Deutsche Diabetes Forschungsgesellschaft e.V.
Collaborators
komIT - Center of Competence for Innovative Diabetes Therapy
1. Study Identification
Unique Protocol Identification Number
NCT05160272
Brief Title
Effects of GABAA Receptor Modulation by AP-325 on Insulin Secretion in Patients With Type 2 Diabetes
Official Title
Effects of GABAA Receptor Modulation by AP-325 on Insulin
Study Type
Interventional
2. Study Status
Record Verification Date
January 2022
Overall Recruitment Status
Recruiting
Study Start Date
January 2022 (Anticipated)
Primary Completion Date
June 2022 (Anticipated)
Study Completion Date
September 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Deutsche Diabetes Forschungsgesellschaft e.V.
Collaborators
komIT - Center of Competence for Innovative Diabetes Therapy
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type2 Diabetes
Keywords
Type 2 Diabetes, Diabetes mellitus, GABAA receptor, β-cell function, glycemic control
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
38 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
AP-325 Treatment
Arm Type
Experimental
Arm Description
AP-325, film-coated tablet, 50mg once daily
Arm Title
Placebo Treatment
Arm Type
Placebo Comparator
Arm Description
Placebo matching AP-325 film-coated tablet, once daily
Intervention Type
Drug
Intervention Name(s)
AP-325
Intervention Description
Measurement of the effect of AP-325 50mg/d compared to matching placebo after 4-week treatment.
Intervention Type
Drug
Intervention Name(s)
Placebo matching AP-325
Intervention Description
Measurement of the effect of AP-325 50mg/d compared to matching placebo after 4-week treatment.
Primary Outcome Measure Information:
Title
Circulating C-peptide by iAUC of C-peptide during an IVGTT
Description
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
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Basal insulin level
Description
Change in basal insulin level from baseline to end of treatment
Time Frame
4 weeks
Title
C-peptide level
Description
Change in C-peptide level from baseline to end of treatment
Time Frame
4 weeks
Title
Glucose level
Description
Change in glucose level from baseline to end of treatment
Time Frame
4 weeks
Title
iAUC of circulating insulin (overall)
Description
Change in iAUC of circulating insulin during an IVGTT from baseline to end of treatment
Time Frame
4 weeks
Title
iAUC of C-peptide level (overall)
Description
Change in C-peptide level during an IVGTT from baseline to end of treatment
Time Frame
4 weeks
Title
iAUC of glucose level (overall)
Description
Change in iAUC of glucose level during an IVGTT from baseline to end of treatment
Time Frame
4 weeks
Title
iAUC of circulating insulin (AIR) (first 10 min)
Description
Change in iAUC of circulating insulin (AIR) during an IVGTT in the first 10 minutes from baseline to end of treatment
Time Frame
4 weeks
Title
iAUC of C-peptide (first 10 min)
Description
Change in iAUC of C-peptide during an IVGTT in the first 10 minutes from baseline to end of treatment
Time Frame
4 weeks
Title
iAUC of glucose (first 10 min)
Description
Change in iAUC of glucose during an IVGTT in the first 10 minutes from baseline to end of treatment
Time Frame
4 weeks
Title
disposition index (DI)
Description
Change in the disposition index (DI) through Minimal Model during an IVGTT from baseline to end of treatment
Time Frame
4 weeks
Title
peak insulin response
Description
Change in peak insulin response during an IVGTT from baseline to end of treatment
Time Frame
4 weeks
Title
insulin secretion rate (ISR)
Description
Change in insulin secretion rate (ISR) during an IVGTT from baseline to end of treatment
Time Frame
4 weeks
Title
fructosamine levels
Description
Change in 1.5-Anhydroglucitol glucose from baseline to end of treatment
Time Frame
4 weeks
Title
fructosamine levels II
Description
Change in fructosamine level from baseline to end of treatment
Time Frame
4 weeks
Title
fructosamine levels III
Description
Change in fasting blood glucose from baseline to end of treatment
Time Frame
4 weeks
Title
Plasma concentrations of AP-325
Description
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
Time Frame
4 weeks
Title
Ctrough-ss (Day 28) and the change from baseline to Day 28
Description
Change in relationship between Ctrough-ss (Day 28) and the change from baseline to Day 28 in primary and secondary endpoints
Time Frame
4 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sabine Kahl, MD
Phone
+49 211 3382 0
Email
sabine.kahl@ddz.de
First Name & Middle Initial & Last Name or Official Title & Degree
Jennifer Pützer, MD
Phone
+49 211 3382 0
Email
jennifer.puetzer-furmanczak@ddz.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Roden, MD
Organizational Affiliation
Deutsches Diabetes-Zentrum
Official's Role
Principal Investigator
Facility Information:
Facility Name
German Diabetes Center
City
Duesseldorf
State/Province
NRW
ZIP/Postal Code
40225
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sabine Kahl
Phone
+492113382 698
Email
sabine.kahl@ddz.de
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Effects of GABAA Receptor Modulation by AP-325 on Insulin Secretion in Patients With Type 2 Diabetes
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