Clinical trial NCT05889156: Study of the Efficacy and Safety of NST-1024 Versus Placebo in Subjects With Hypertriglyceridemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: High Triglycerides
Lead sponsor: NorthSea Therapeutics B.V.
Sponsor class: INDUSTRY
First posted: 2023-06-05
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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:

1. A 3-week screening period that includes a TG qualifying period, and
2. 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 15-35 centers in USA.


Eligibility criteria: Inclusion Criteria:

1. 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;
2. Men or women 18 to 79 years of age, inclusive;
3. If 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, subject's use 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;
4. 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;
5. 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 screening (i.e., Visit 1 \[Week -3\]), and during participation in the study.
6. Willingness to maintain stable diet and physical activity level throughout the study
7. If a smoker, no plans to change smoking habits during the study period.
8. Agree to use appropriate contraceptive methods based on biological sex and child-bearing potential as outlined in Section 12.5 of the protocol.
9. Agree to abstain from sperm or egg donation through 90 or 30 days, respectively, after administration of the last dose of IP.

Exclusion Criteria:

1. Body mass index \>50 kg/m2;
2. Participation in another clinical study involving an investigational agent within 30 days prior to screening or 5½ half-lives whichever is longer (Visit 1 \[Week -3\]);
3. Type 1 diabetes mellitus;
4. HbA1c \> 9.5% at screening (Visit 1 \[Week -3\]);
5. History of stroke, myocardial infarction, life-threatening arrhythmia, or coronary revascularization within 6 months prior to screening;
6. 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.
7. History of symptomatic gallstone disease unless treated with cholecystectomy;
8. History of nephrotic range (\>3 g/day) proteinuria;
9. Estimated glomerular filtration rate (eGFR) \< 45 mL/min/1.73 m2
10. QTcF interval of \>450ms for males or \>470ms for females
11. A history of additional risk factors for torsades de pointes (TdP) (e.g., heart failure, hypokalaemia, family history of Long QT Syndrome)
12. The use of concomitant medications that prolong the QT/QTc interval (Table 1);
13. 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;
14. Known lipoprotein lipase impairment or deficiency (Fredrickson Type I), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III);
15. Requirement for peritoneal dialysis or haemodialysis for renal insufficiency;
16. History of malignancy, unless:

    I. All treatment for the malignancy was completed ≥2 years prior to screening and there is no evidence of disease; II. Curatively resected squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix or uterus, ductal breast cancer in situ or low-grade prostate cancer III. Squamous cell or basal cell skin carcinomas that are not requiring tumour directed treatment during the subject's participation in the study
17. 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;
18. Uncontrolled hypertension;
19. Known to be infected with human immunodeficiency virus (HIV) AND who are not on stable antiretroviral therapy OR have a confirmed plasma HIV-1 RNA (Viral Load) \> lower limit of detection despite antiretroviral therapy OR have a CD4+ T-cell count \<350 cell/μL OR a history of acquired immunodeficiency syndrome(AIDS);
20. Hepatitis B or C:

    I. Acute or chronic Hepatitis B infection based on a positive hepatitis B surface antigen (HBsAg) test at screening (Visit 1 \[Week -3\]). Subjects with a past hepatitis B virus (HBV) infection or resolved HBV infection (defined by presence of hepatitis B core antibody (HBcAb) and absence of HbsAg are eligible if confirmed with negative HBV DNA test performed at screening; II. Positive test for 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;
21. Anticipation of major surgery during the screening or double-blind treatment periods of the study;
22. 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 \[Week -3\]);
23. Ongoing treatment with cyclophosphamide (unless chronic oral administration for inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease), or isotretinoin;
24. Treatment with tamoxifen, estrogens, or progestins that has not been stable for ≥28 days prior to screening (Visit 1 \[Week -3\]);
25. Use of systemic corticosteroids at a dose \>7.5mg daily prednisolone equivalent (per Appendix A) ≤28 days prior to screening or anticipated use during study. 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 (Visit 3);
26. 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 \[Week -3\]);
27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 x ULN, unless exercise-related;
28. Unexplained CK concentration \>5 × ULN or CK elevation due to known muscle disease (e.g., polymyositis, mitochondrial dysfunction);
29. 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);
30. Blood donation of ≥1 pint (0.5 L) within 8 weeks prior to screening (Visit 1 \[Week -3\]) or anticipated blood donation during study, or plasma donation within 7 days prior to screening (Visit 1 \[Week -3\]);
31. History of illicit drug use or alcohol abuse within 1 year of screening (Visit 1 \[Week -3\]). Alcohol abuse is defined as \>21 standard drinks per week in men and \>14 standard drinks per week in women, on average;
32. 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;
33. 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.
34. Pregnancy or breastfeeding.

Primary outcomes:
measure: Evaluate the efficacy of NST-1024 by percentage change in TG
timeFrame: 4 weeks
Secondary outcomes:
measure: Percent Change in Cholesterol Values
timeFrame: 4 weeks
measure: Percent change in Apolipoprotein B and Apolipoprotein C3
timeFrame: 4 weeks
measure: Percent Change in Lipoprotein a
timeFrame: 4 weeks
measure: Percent Change in remnant-like particle cholesterol (RLP-C)
timeFrame: 4 weeks
measure: Changes in fasting plasma glucose, fasting plasma insulin, and HbA1c
timeFrame: 4 weeks
measure: Change in insulin resistance.
timeFrame: 4 weeks
measure: Change in lipoprotein associated phospholipase A2
timeFrame: 4 weeks
measure: Change in hsCRP
timeFrame: 4 weeks
measure: Safety Assessments
timeFrame: ~ 8 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Heersink School of Medicine
state: Alabama
city: Daphne
country: United States
facility: Alliance for Multispecialty Research, LLC (AMR) - Daphne
state: Alabama
city: Tempe
country: United States
facility: Alliance for Multispecialty Research, LLC (AMR) - Phoenix
state: Arizona
city: La Mesa
country: United States
facility: Velocity Clinical Research, San Diego
state: California
city: North Hollywood
country: United States
facility: Velocity Clinical Research, North Hollywood
state: California
city: Santa Ana
country: United States
facility: Velocity Clinical Research - Costal Heart
state: California
city: Aurora
country: United States
facility: Lynn Institute of Denver
state: Colorado
city: Edgewater
country: United States
facility: Velocity Clinical Research, New Smyrna Beach
state: Florida
city: Largo
country: United States
facility: Clearwater Cardiovascular Consultants
state: Florida
city: Miami Lakes
country: United States
facility: Floridian Clinical Research
state: Florida
city: West Palm Beach
country: United States
facility: Metabolic Research Institute, Inc.
state: Florida
city: Lilburn
country: United States
facility: Lifeline Primary Care/ CCT Research
state: Georgia
city: Meridian
country: United States
facility: Velocity Clinical Research - Boise
state: Idaho
city: Evansville
country: United States
facility: Deaconess Clinic - Indiana
state: Indiana
city: Valparaiso
country: United States
facility: Velocity Clinical Research, Valparaiso
state: Indiana
city: Newton
country: United States
facility: Alliance for Multispecialty Research, LLC (AMR) - Newton
state: Kansas
city: Louisville
country: United States
facility: University of Louisville - UoL Physicians Outpatient Center
state: Kentucky
city: Troy
country: United States
facility: Troy Internal Medicine
state: Michigan
city: Kansas City
country: United States
facility: Clay Platte Family Medicine / CCT Research
state: Missouri
city: Lincoln
country: United States
facility: Velocity Clinical Research - Kearney
state: Nebraska
city: Berlin
country: United States
facility: Cenexel HRI
state: New Jersey
city: Cincinnati
country: United States
facility: Velocity Clinical Research - Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Velocity Clinical Research - Cleveland
state: Ohio
city: Hatboro
country: United States
facility: Hatboro Medical Associates/ CCT Research
state: Pennsylvania
city: Philadelphia
country: United States
facility: Mercado Medical Practice / CCT Research
state: Pennsylvania
city: Summerville
country: United States
facility: Palmetto Clinical Reserach
state: South Carolina
city: Union
country: United States
facility: Velocity Clinical Research - Union
state: South Carolina
city: Bellaire
country: United States
facility: Apex Mobile Clinical Research
state: Texas
city: San Antonio
country: United States
facility: Pinnacle Clinical Research - San Antonio
state: Texas
city: Pleasant View
country: United States
facility: Ogden Clinic, Mount View/CCT Research
state: Utah
city: Salt Lake City
country: United States
facility: Velocity Clinical Research - Salt Lake City
state: Utah
Study officials:
References: