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

Prior treatment

• 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
• Participation in another intervention study within 2 months before the examination
• Immunomodulatory drugs (e.g. oral cortisone preparations, biologicals)
• Previous / current alcohol and / or drug abuse
• 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

Other illness

• Acute infections (hsCRP \> 5mg/dl, body temperature \>37.5°C)
• Heart rate \<50 or \>100 beats per minute; systolic blood pressure \<100 or \>160 mmHg; diastolic blood pressure \<50 or \>100 mmHg; uncontrolled hypertension
• Severe chronic illnesses, such as congestive heart failure (NYHA III/IV), liver insufficiency (Child-Pugh Class B/C), history of acute coronary syndrome, stroke
• Hypersensitivity against AP-325, placebo or other ingredients of IMP
• Immunocompromising diseases
• Thyroid diseases with an unstable metabolic state (change in L-thyroxine dose within the past 6 weeks, TSH and fT4 outside the normal range)
• HIV, hepatitis B or C disease
• Malignant cancer

Lab values

• Uncontrolled hyperglycemia, e.g. fasting blood glucose \>240 mg/dl
• Creatinine clearance \<60 ml/min (eGFR by MDRD formula)
• Anemia (Hb \<12 g/l for men, Hb \<11 g/l for women)

Age

• Past (≤ 5 years) or current history of psychiatric disorders, including psychiatric depression

Other

• 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
• Poor CYP2C9 metabolizer

• 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