Study of the Efficacy and Safety of NST-1024 Versus Placebo in Subjects With Hypertriglyceridemia

Study Overview
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Brief Summary
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This is a Phase IIa,multicentre proof of concept study consisting of 2 study periods to study Treatment with NST-1024 as an adjunct to diet to reduce triglyceride (TG) levels in subjects with TG levels of ≥500 mg/dL and ≤2000 mg/dL; determined by percentage change in TG from baseline after 28 days of treatment. The two periods consist of: A 3-week screening period that includes a TG qualifying period, and A 28-days, double-blind, randomized, parallel group, placebo-controlled treatment period. Subjects will return to the study site for a follow-up visit 2 weeks after the last dose. Approximately 50 subjects will be randomized at approximately 15-30 centres in USA.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled 28- Day Phase II Proof of Concept Study to Evaluate the Efficacy and Safety of NST-1024 400 mg BID Versus Placebo in Statin-Naïve or Statin-Stable Hypertriglyceridemic Subjects

Conditions
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High Triglycerides

Intervention / Treatment
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* Drug: NST-1024
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Understanding of the study procedures, willing to adhere to the study schedules, and agreement to participate in the study by giving written informed consent prior to screening (Visit 1 Week -3]) assessments; Men or women 18 to 79 years of age, inclusive; On statin or non-statin lipid-altering therapy, such as ezetimibe, niacin >200 mg/day, bempedoic acid, fibrates, prescription omega-3 products, other consumer products containing omega-3 fatty acids, or other herbal products or dietary supplements with potential lipid and glucose-altering effects. Subjects must be stable for ≥28 days prior to the first TG baseline qualifying measurement (i.e., Visit 1 [Week -3]), and should remain stable thereafter for the duration of study participation; Fasting TG levels ≥500 mg/dL and ≤2000 mg/dL (based on an average [arithmetic mean] of Visit 1 and Visit 2). Note: In cases in which a subject's average TG level from Visit 1 and Visit 2 falls outside the range for entry into the study, an additional visit (Visit 2a) can be arranged up to 7 days after Visit 2 for an additional measurement of fasting TG levels. If a third sample is collected, entry into the double-blind treatment period will be based on the average of the highest TG value from Visit 1 and 2 and the Visit 2a value. Neither one of the two values used for the arithmetic mean can be less than 400 mg/dL; If using oral or injectable weight loss drug, subjects must maintain stable dose of all oral and injectable weight loss drugs (e.g., GLP-1 receptor agonists) for at least 3 months prior to study period. Willingness to maintain stable diet and physical activity level throughout the study If a smoker, no plans to change smoking habits during the study period. Agree to use appropriate contraceptive methods based on biological sex and child-bearing potential as outlined in Section 12.5 of the protocol. Agree to abstain from sperm or egg donation through 90 or 30 days, respectively, after administration of the last dose of IP. Exclusion criteria Body mass index >50 kg/m2; Participation in another clinical study involving an investigational agent within 30 days prior to screening or 5 ½ half-lives whichever is longer(Visit 1 [Week -3]); Type 1 diabetes mellitus; HbA1c > 9.5% at screening (Visit 1 [Week -3]); History of stroke, myocardial infarction, life-threatening arrhythmia, or coronary revascularization within 6 months prior to screening; History of chronic pancreatitis or acute pancreatitis in the last year. Subjects at risk of developing pancreatitis (e.g., known cholelithiasis, known alcohol abuse or multiple incidences of acute pancreatitis) per the PI's assessment are excluded. Subjects with a history of acute pancreatitis due to gallstones who have been treated with cholecystectomy are allowed. History of symptomatic gallstone disease unless treated with cholecystectomy; History of nephrotic range (>3 g/day) proteinuria; Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 QTcF interval of >450ms for males or >470 for females A history of additional risk factors for torsades de pointes (TdP) (e.g., heart failure, hypokalaemia, family history of Long QT Syndrome) The use of concomitant medications that prolong the QT/QTc interval (Table 1); History or evidence of major and clinically significant hepatic, pulmonary, renal, hematologic, gastrointestinal (including clinically significant malabsorption), endocrine, immunologic, dermatologic, neurologic, psychiatric, oncologic, or allergic (including drug allergies, but excluding untreated or treated seasonal allergies at the time of dosing) disease that would interfere with the conduct of the study or interpretation of the data; Known lipoprotein lipase impairment or deficiency (Fredrickson Type I), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III); Requirement for peritoneal dialysis or haemodialysis for renal insufficiency; History of malignancy, except subjects who have been disease-free for >5 years, or whose only malignancy has been treated basal or squamous cell skin carcinoma; History of bariatric surgery less than 2 years prior to randomization. A history of bariatric surgery utilizing the gastric bypass technique (Roux-en-Y) or biliopancreatic diversion with duodenal switch is exclusionary; Uncontrolled hypertension; Known to be infected with human immunodeficiency virus (HIV); Positive test for HIV antibody, hepatitis B surface antigen, hepatitis B Core Total or hepatitis C antibody at screening (Visit 1 [Week -3]), except for those who have been successfully treated for hepatitis C infection and have achieved sustained virologic response for ≥1 year and who have a negative reflex HCV RNA test; Anticipation of major surgery during the screening or double-blind treatment periods of the study; Treatment with chronic prescription pharmacotherapy for metabolic or CV disease management or risk factor modification (e.g., antihypertensive and antidiabetic medications) that has not been stable for ≥28 days prior to screening (Visit 1 [Week -3]); Ongoing treatment with HIV-protease inhibitors, cyclophosphamide, or isotretinoin; Treatment with tamoxifen, estrogens, or progestins that has not been stable for ≥28 days prior to screening (Visit 1 [Week -3]); Routine or anticipated use of systemic corticosteroids at a dose >7.5mg daily prednisolone equivalent. Use of local injectable, inhaled, nasal administration, topical corticosteroids, or low dose glucocorticoids (≤7.5 mg prednisolone equivalent) is permitted. Low dose oral glucocorticoids should have been used for ≥ 3 months and stable for ≥ 28 days prior to baseline; Thyroid-stimulating hormone (TSH) > 2.0 x upper limit of normal (ULN), clinical evidence of hypothyroidism, or thyroid hormone therapy that has not been stable for ≥6 weeks prior to screening (Visit 1 [Week -3]); Alanine aminotransferase or AST >2.5 x ULN, unless exercise-related; Unexplained CK concentration >5 × ULN or CK elevation due to known muscle disease (e.g., polymyositis, mitochondrial dysfunction); Other recent or current serious disease that may interfere with the conduct of the study (renal, ophthalmic, pulmonary, hepatic, biliary, gastrointestinal, mental disorder, infectious disease, or cancer); Blood donation of ≥1 pint (0.5 L) within 30 days prior to screening (Visit 1 [Week -3]), or plasma donation within 7 days prior to screening (Visit 1 [Week -3]); History of illicit drug use or alcohol abuse within 1 year of screening. Alcohol abuse is defined as >21 standard drinks per week in men and >14 standard drinks per week in women, on average; Any condition or therapy, which, in the opinion of the investigator, might pose a risk to the subject or make participation in the study not in the subject's best interest; Poor mental function or any other reason to expect subject difficulty in complying with the requirements of the study; or in the investigator's opinion, not able to comply with study procedures. Pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Matched Placebo<br> | Other: Placebo<br>* matched placebo to active arm<br>|
| Active Comparator: NST-1024<br>NST-1024 400 mg BID | Drug: NST-1024<br>* 400 mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of NST-1024 by percentage change in TG | Evaluate the efficacy of NST-1024 400 mg BID by assessment of the percentage change in TG from baseline after 28 days of treatment | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lipoprotein associated phospholipase A2 | Percent change in lipoprotein associated phospholipase A2 from baseline to Week 4 | 4 weeks | 
| Change in hsCRP | Change in hsCRP from baseline to Week 4 | 4 weeks | 
| Safety Assessments | Incidence of Treatment-Emergent Adverse Events and abnormalities in clinical laboratory measurements (chemistry, haematology, and urinalysis), 12-lead ECGs, blood pressure, and physical examinations will be evaluated and monitored for any safety events through the study duration from screening through follow up. |   8 weeks | 
| Percent Change in Cholesterol Values | Percent changes in TC, HDL-C, LDL-C, calculated. non-HDL-C, and VLDL-C from baseline to Week 4 | 4 weeks | 
| Percent change in Apolipoprotein B and Apolipoprotein C3 | Percent changes in ApoB and ApoC3 from baseline to Week 4. | 4 weeks | 
| Percent Change in Lipoprotein a | Percent change in Lp(a) from baseline to Week 4. | 4 weeks | 
| Percent Change in remnant-like particle cholesterol (RLP-C) | Percent Change in RLP-C from baseline to Week 4. | 4 weeks | 
| Changes in fasting plasma glucose, fasting plasma insulin, and HbA1c | Changes in fasting plasma glucose (FPG), fasting plasma insulin (FPI) and HbA1c from baseline to Week 4 | 4 weeks | 
| Change in insulin resistance. | Change in insulin resistance, as assessed by the homeostasis model index insulin resistance, from baseline to Week 4 | 4 weeks |