Clinical trial NCT03385239: Study of ISIS 678354 (AKCEA-APOCIII-LRx) in Participants With Hypertriglyceridemia and Established Cardiovascular Disease (CVD)
Official title: A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 678354 Administered Subcutaneously to Patients With Hypertriglyceridemia and Established Cardiovascular Disease (CVD) or at a High Risk for CVD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertriglyceridemia
Cardiovascular Diseases
Keywords: AKCEA-APOCIII-LRx
IONIS-APOCIII-LRx
Dyslipidemia
Metabolic Disease
Hyperlipidemia
Cardiac Disease
Lipid Metabolism Disorders
Triglycerides High
Vascular Diseases
Lead sponsor: Akcea Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2017-12-28
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of different doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride (TG) levels in participants with hypertriglyceridemia and established CVD or at a high risk for CVD.


Eligibility criteria: Key Inclusion Criteria:

* Clinical diagnosis of CVD (defined as documented coronary artery disease, stroke, or peripheral artery disease).
* Fasting serum triglycerides (TG) greater than or equal to (≥) 200 milligrams per deciliter (mg/dL) (≥ 2.3 millimoles per liter (mmol/L)) and less than or equal to (≤) 500 mg/dL (≥ 5.7 mmol/L) at Screening.
* Fasting TG ≥ 200 mg/dL and ≤ 500 mg/dL at Qualification visit.
* Must be on standard-of-care preventative therapy for known CVD risk factors.

Key Exclusion Criteria:

* Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/transient ischemic attack (TIA).
* Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis.
* Heart failure New York Heart Association (NYHA) class IV.
* Type 1 diabetes mellitus.
* Type 2 diabetes mellitus with any of the following:

  * Newly diagnosed within 12 weeks of Screening.
  * Glycated hemoglobin (HbA1c) ≥ 9.0% at Screening.
  * Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new medication within 12 weeks of Screening \[with the exception of ± 10 units of insulin\].
* Body Mass Index (BMI) greater than (\>) 40 kilograms per square meter (kg/m\^2).

Primary outcomes:
measure: Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point
timeFrame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to the 13-week post-treatment follow-up period (Up to approximately 15 months)
Secondary outcomes:
measure: Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point
timeFrame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
measure: Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])
timeFrame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
measure: Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)
timeFrame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
measure: Maximum Plasma Concentration (Cmax) of ISIS 678354
timeFrame: Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354
timeFrame: Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
measure: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354
timeFrame: Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
Other outcomes:
Locations:
city: Cottonwood
country: United States
facility: Clinical Site
state: Arizona
city: Little Rock
country: United States
facility: Clinical Site
state: Arkansas
city: Carmichael
country: United States
facility: Clinical Site
state: California
city: Fresno
country: United States
facility: Clinical Site
state: California
city: La Jolla
country: United States
facility: Clinical Site
state: California
city: Long Beach
country: United States
facility: Clinical Site
state: California
city: Montclair
country: United States
facility: Clinical Site
state: California
city: Wilmington
country: United States
facility: Clinical Site
state: Delaware
city: Boca Raton
country: United States
facility: Clinical Site
state: Florida
city: Jacksonville
country: United States
facility: Clinical Site
state: Florida
city: New Port Richey
country: United States
facility: Clinical Site
state: Florida
city: Munster
country: United States
facility: Clinical Site
state: Indiana
city: Ames
country: United States
facility: Clinical Site
state: Iowa
city: Kansas City
country: United States
facility: Clinical Site
state: Kansas
city: Louisville
country: United States
facility: Clinical Site
state: Kentucky
city: Fall River
country: United States
facility: Clinical Site
state: Massachusetts
city: Cooperstown
country: United States
facility: Clinical Site
state: New York
city: High Point
country: United States
facility: Clinical Site
state: North Carolina
city: Portland
country: United States
facility: Clinical Site
state: Oregon
city: Lansdale
country: United States
facility: Clinical Site
state: Pennsylvania
city: Providence
country: United States
facility: Clinical Site
state: Rhode Island
city: Greer
country: United States
facility: Clinical Site
state: South Carolina
city: Houston
country: United States
facility: Clinical Site
state: Texas
city: Milwaukee
country: United States
facility: Clinical Site
state: Wisconsin
city: Cambridge
country: Canada
facility: Clinical Site
state: Ontario
city: Sudbury
country: Canada
facility: Clinical Site
state: Ontario
city: Brossard
country: Canada
facility: Clinical Site
state: Quebec
city: Chicoutimi
country: Canada
facility: Clinical Site
state: Quebec
city: Gatineau
country: Canada
facility: Clinical Site
state: Quebec
city: Montréal
country: Canada
facility: Clinical Site
state: Quebec
city: Québec
country: Canada
facility: Clinical Site
state: Quebec
Study officials:
References:
citation: Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Hurh E, Bartlett VJ, Kingsbury J, Figueroa AL, Alexander VJ, Tami J, Witztum JL, Geary RS, O'Dea LSL, Tsimikas S, Gaudet D. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820.