A Study of MSDC-0602K to Assess Glycemic Control and Cardiovascular Outcomes in Patients With Pre-T2D or T2D and NAFLD/NASH

Study Overview
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Brief Summary
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This is a randomized, double-blind study of MSDC-0602K or placebo in subjects with pre-T2D or T2D and evidence of NAFLD/NASH.

Detailed Description
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This is a randomized, double-blind study of MSDC-0602K or placebo given orally once daily to subjects with pre-T2D or T2D and evidence of NAFLD/NASH. Visits will include a Screening Period, a minimum Treatment of 26 weeks, and a Long-Term Follow-up Period during which subjects will continue taking assigned treatment. Safety will be assessed by periodic measurement of vital signs, physical examinations, blood laboratory analyses, and the occurrence of adverse events.

Official Title
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MMONARCh-1: Study of MSDC-0602K, a Modulator of the Mitochondrial Pyruvate Carrier for Outcomes in Patients With Pre Type 2 Diabetes (T2D) or T2D and NAFLD/NASH, Assessed for ImpRoved Glycemic Control and Cardiovascular Outcomes-1

Conditions
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Type2 Diabetes, NASH - Nonalcoholic Steatohepatitis, Nonalcoholic Steatohepatitis, Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: MSDC-0602K
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Written informed consent. Adult subjects with an age of > 18 years but < 80 years. Male or female subjects with reproductive potential must agree to comply with approved double barrier contraceptive method for the duration of the trial. Females of non-childbearing potential are considered: Post-menopausal Surgically sterile Diagnosis of NAFLD AST>27 U/L HgbA1c >6% Diagnosis of Pre-T2D or T2D History of macrovascular cardiovascular disease Key Exclusion Criteria: Prior liver transplantation or currently on transplant list. Other well-documented causes of active chronic liver disease Current cirrhosis Pregnant or nursing women AST or ALT > 5 times the upper limit of normal Total bilirubin > 1.3 mg/dL unless diagnosis of Gilbert's disease with direct bilirubin within normal reference range Serum albumin < 3.5 g/dL at Screening Alkaline phosphatase >2 times the upper limit of normal at Screening Estimated glomerular filtration rate (eGFR by MDRD) <30 ml/min/1.73 m2 but ≤75 ml/min/1.73 m2 In patients who are not anticoagulated, INR ≥ 1.3 times ULN at Screening or other evidence of impaired coagulation. Acute vascular events including ACS, stroke or TIA, worsening of peripheral vascular disease or any vascular/cardiac procedure Limb amputation for reason other than trauma. HbA1c >10% Any planned surgery or device implantation after screening Ejection fraction < 35% or Heart failure with NYHA class IV History of alcohol abuse or drug abuse within 6 months prior to Screening Diagnosis at any time of Type 1 diabetes. Current or history of recent (≤ 6 months) use of ursodeoxycholic acid. Current use of insulin. Current use of thiazolidinediones. Any history or current concomitant disorder such as haematological, pulmonary, metabolic, endocrine disorders that are severe or life-threatening. Use of concomitant medications with a known significant metabolism by CYP2C8 including paclitaxel or repaglinide for the duration of the study. History of diabetic ketoacidosis or hyperosmolar non-ketotic coma within the 6 months prior to Screening. Known or suspected intolerance or hypersensitivity to the study drugs, closely related compounds such as PPARγ agonists (pioglitazone or rosiglitazone), or any of their stated ingredients.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MSDC-0602K<br>MSDC-0602K one tablet per day taken orally | Drug: MSDC-0602K<br>* MSDC-0602K tablet<br>|
| Placebo Comparator: Placebo<br>Placebo one tablet per day taken orally | Drug: Placebo<br>* Matching tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glycosylated hemoglobin (HbA1c) from baseline to Week 26 |  | 26 weeks | 
| Change in the weighted average of standardized AST, CK-18, and HbA1c values (standard deviations) from baseline to Week 26 | This is a single composite outcome measure. This is derived by standardizing the values of AST, CK-18, and HbA1c by subtracting the respective study population means and dividing by respective study population standard deviations at each time point; averaging these standardized AST, CK-18,and HbA1c values (or z-scores) for a given patient at each time point; and then computing the difference from baseline to week 26 with respect to these averages. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first event of death, adjudicated nonfatal MI or USA hospitalization, adjudicated hospital admission for HF, or adjudicated nonfatal ischemic stroke. |  | through study completion, an expected average of 15 months | 
| Time to first event of death or adjudicated non-fatal MI or USA hospitalization, adjudicated hospital admission for HF, adjudicated nonfatal ischemic stroke, or liver event in all randomized subjects. | A liver event consists of ascites (confirmed by paracentesis or abdominal imaging), hepatic encephalopathy (defined clinically), variceal hemorrhage (confirmed by endoscopy), or liver transplant. | through study completion, an expected average of 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, NASH, NAFLD