Diabetic Cardiomyopathy (DbCM) MedDRA version: 20.0 Level: PT Classification code 10012647 Term: Diabetic cardiomyopathy System Organ Class: 10007541 - Cardiac disorders
Conditions
Interventions
Product Code: IMB-1018972
Pharmaceutical Form: Tablet
INN or Proposed INN: Not assigned
Current Sponsor code: IMB-1018972
Other descriptive name: IMB-1018972 trihydrochloride monohydrate
Concentration
Sponsors
Imbria Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provision of written informed consent before any screening procedures; 2. Male or female aged =18 and =75 years at screening; 3. Must agree to adequate contraception requirements as follows: a. WOCBP must have a negative serum pregnancy test at screening and a negative pregnancy test (serum or urine) on the day of baseline pre-dose (Stage 1 and Stage 2), at Visit 5 pre dose (Stage 2 only), and at the end of study (EOS)/safety follow-up visit or early termination (Stage 1 and Stage 2); b. WOCBP must agree to use dual methods of contraception, including 1 highly effective and 1 effective method of contraception, from the day of first dosing until 3 months after the last administration of test product; and c. Male patients must use an effective barrier method of contraception if sexually active with a WOCBP, from the day of first dosing until 3 months after the last administration of test product; 4. Must agree not to donate sperm or ova from the day of first dosing until 3 months after last dosing; 5. Women not of childbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before screening) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years with follicle-stimulating hormone (FSH) in the postmenopausal range at screening; 6. Must be able and willing to comply with all study procedures and requirements. 7. Diagnosis of T2D; 8. Elevated HbA1c defined as =6.5% (=48 mmol/mol); 9. Elevated BMI defined as =30 kg/m2; 10. Preserved LVEF (defined as =50%); and 11. If on oral hypoglycaemic (anti-diabetic) therapy, no change in therapy over the past 3 months. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 21
Exclusion criteria
Exclusion criteria: 1. BMI >40 kg/m2; 2. Uncontrolled hypertension (defined as resting blood pressure >180/90 mmHg) at screening; 3. Standard contraindication(s) to magnetic resonance scanning; 4. More than mild to moderate valvular heart disease per Investigator’s judgement; 5. Persistent or permanent atrial fibrillation; 6. History of sustained ventricular tachycardia or cardiac arrest; 7. Exertional angina or intermittent claudication; 8. Known significant obstructive coronary artery disease per Investigator’s judgement; 9. Absolute or significant contraindication to dobutamine infusion, including: phaeochromocytoma, LV outflow tract obstruction, untreated hyperthyroidism, severe hypotension, aortic dissection, or large aneurysm; 10. History of stroke, transient ischaemic attack, acute coronary syndrome, myocardial infarction, peripheral vascular disease, diagnosis of NYHA functional class III or IV heart failure, hospitalization for heart failure, or any arterial revascularisation procedure (including coronary artery bypass grafting) within 6 months before screening; 11. Presence of indwelling cardiac device (pacemaker, cardiac resynchronisation therapy, and/or implantable cardioverter defibrillator); 12. Significant hepatic impairment defined as total bilirubin and/or alanine aminotransferase and/or aspartate aminotransferase >2 x upper limit of the normal; 13. Moderate or severe renal impairment defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 of body surface area; 14. History of Parkinson disease, Parkinsonian symptoms, restless leg syndrome, or other related movement disorders; 15. Known allergy, intolerance, or absolute contraindication to TMZ or nicotinic acid; 16. Concomitant use within the last 1 month of TMZ, nicotinic acid (at prescription/therapeutic dose), perhexiline, meldonium, or ranolazine; 17. Any use of insulin and/or SGLT2 inhibitors; 18. History of alcohol abuse or drug addiction within the previous 5 years; 19. Pregnant, or planning pregnancy or lactation; 20. Participation in another clinical study involving a test product or medical device within 28 days (or 5 half-lives of the test product, whichever is longer), prior to first dosing; 21. Any medical or surgical condition that may interfere with the patient’s participation in the clinical study, significantly interfere with the interpretation of the results, or put the patient at significant risk, according to the Investigator’s judgment, from study participation; or 22. For those in Cohort B, prior participation in Stage 1 of this study. 23. Known hypersensitivity to IMB-1018972, mannitol, hypromellose, magnesium stearate and pre-gelatinized corn starch (other ingredients of placebo and active).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to evaluate and characterise the dose-response relationship for short-term administration of IMB-1018972 on the myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio, a measure of cardiac energetic reserve, by 31P-magnetic resonance spectroscopy (MRS) at rest and during dobutamine stress.;Secondary Objective: -The secondary objectives are the following: • To assess the potential dose-response relationship of IMB-1018972 on cardiac systolic and diastolic function, measured by cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE); • To measure cardiac systolic augmentation to dobutamine stress by CMR; • To assess the potential dose-response relationship of IMB-1018972 on myocardial pyruvate dehydrogenase (PDH) flux inferred by the [13C]bicarbonate/[1 13C]pyruvate ratio measured by hyperpolarized [1-13C]pyruvate MRS (in all patients in Cohort A [Stage 1] and in up to 12 patients from Cohort B [Stage 2]); and • To evaluate the safety and tolerability of repeat oral doses of IMB-1018972 in patients with DbCM.;Primary end point(s): Primary efficacy endpoint: • Resting cardiac PCr/ATP ratio at rest measured by 31P-MRS at baseline and at each dose level of IMB-1018972; and • Change in cardiac PCr/ATP ratio with dobutamine stress (ie, dobutamine stress induced drop in PCr/ATP ratio from its resting value at the same time point) measured by 31P-MRS at baseline and at each dose level of IMB 1018972. ;Timepoint(s) of evaluation of this end point: Efficacy endpoints are planned for Stage 2 data. In addition, where appropriate, pooled efficacy data from Stage 1 (ie, reflecting data with 200 mg BID IMB-1018972 given for the same treatment duration) and Stage 2 will be examined. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Change in 31P-MRS-derived cardiac PCr/ATP ratio compared to baseline at each dose level at rest and during dobutamine stress; 2. CMR-derived cardiac functional measures: o Cardiac output and index augmentation to dobutamine stress; o Left ventricle ejection fraction (LVEF) augmentation to dobutamine stress; o LV end-systolic volume (LVESV) and LVESV index reduction with dobutamine stress; and o Cardiac diastolic function, specifically peak absolute LV diastolic filling rate and peak ventricular filling rate normalised to cavity size (ie, end-diastolic volume [EDV]), both derived from LV volume-time curves; •3. TTE-derived cardiac functional measures: o LV global longitudinal strain from LV strain analysis; o Cardiac diastolic function evaluated by E/e’ ratio from the medial, lateral, and mean values using mitral inflow Doppler and tissue Doppler imaging; and o LV untwist quantification including peak untwisting velocity by torsion analysis; and 4. In those undergoing hyperpolarized [1 13C]pyruvate MRS cardiac imaging, cardiac PDH flux defined as [13C]bicarbonate/[1-13C]pyruvate ratio after a standardised glucose load.;Timepoint(s) of evaluation of this end point: At baseline and at each dose level of IMB-1018972. | — |
Countries
United Kingdom
Contacts
Public ContactKaren Jauregi
Imbria Pharmaceuticals, Inc.
Outcome results
None listed