Study of ISIS 678354 (AKCEA-APOCIII-LRx) in Participants With Hypertriglyceridemia and Established Cardiovascular Disease (CVD)

NCT03385239 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: ISIS 678354-CS2
• Study Type: interventional
• Target: 114
• Locations: 2 countries
• Sites: 31

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.

Conditions

Hypertriglyceridemia; Cardiovascular Diseases

Keywords

AKCEA-APOCIII-LRx; IONIS-APOCIII-LRx; Dyslipidemia; Metabolic Disease; Hyperlipidemia; Cardiac Disease; Lipid Metabolism Disorders; Triglycerides High; Vascular Diseases

Outcome Measures

Primary Outcomes (2)

• Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point

  An analysis of covariance (ANCOVA) model was performed on the log ratio of TG value at the Primary Analysis Time Point to TG value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: (ratio of TG value at the Primary Analysis Time Point to TG value at Baseline - 1) × 100.

  Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

  An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered to be related to the investigational drug product. A TEAE was defined as any AE starting on or after the first dose of the study drug.

  Up to the 13-week post-treatment follow-up period (Up to approximately 15 months)

Secondary Outcomes (6)

• 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

  Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

• Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])

  Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

• Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)

  Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

• Maximum Plasma Concentration (Cmax) of ISIS 678354

  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)

• Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354

  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)

Study Arms (5)

Pooled Placebo

PLACEBO COMPARATOR

Participants in each cohort (A, B, C and D) were randomized to receive placebo at a dose-matched volume of study drug (ISIS 678354).

Drug: Placebo

Cohort A: ISIS 678354: 10 mg Q4W

EXPERIMENTAL

Cohort A participants received 10 milligrams (mg) ISIS 678354, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses.

Drug: ISIS 678354

Cohort C: ISIS 678354: 15 mg Q2W

EXPERIMENTAL

Cohort C participants received 15 mg ISIS 678354, SC injection, once every 2 weeks (Q2W) for up to 51 weeks and a maximum of 26 doses.

Drug: ISIS 678354

Cohort D: ISIS 678354: 10 mg QW

EXPERIMENTAL

Cohort D participants received 10 mg ISIS 678354, SC injection, once weekly (QW) for up to 52 weeks and a maximum of 52 doses.

Drug: ISIS 678354

Cohort B: ISIS 678354: 50 mg Q4W

PLACEBO COMPARATOR

Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses.

Drug: ISIS 678354

Interventions

ISIS 678354 DRUG

ISIS 678354 solution for SC injection.

Also known as: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx

Cohort A: ISIS 678354: 10 mg Q4W; Cohort B: ISIS 678354: 50 mg Q4W; Cohort C: ISIS 678354: 15 mg Q2W; Cohort D: ISIS 678354: 10 mg QW

Placebo DRUG

Sterile Normal Saline (0.9% NaCl).

Pooled Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Akcea Therapeutics: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (31)

Clinical Site

Cottonwood, Arizona, 86326, United States

Location

Clinical Site

Little Rock, Arkansas, 72205, United States

Location

Clinical Site

Carmichael, California, 95608, United States

Location

Clinical Site

Fresno, California, 93720, United States

Location

Clinical Site

La Jolla, California, 92037-7410, United States

Location

Clinical Site

Long Beach, California, 90807, United States

Location

Clinical Site

Montclair, California, 91763, United States

Location

Clinical Site

Wilmington, Delaware, 19803, United States

Location

Clinical Site

Boca Raton, Florida, 33434, United States

Location

Clinical Site

Jacksonville, Florida, 32216, United States

Location

Clinical Site

New Port Richey, Florida, 34652, United States

Location

Clinical Site

Munster, Indiana, 46321, United States

Location

Clinical Site

Ames, Iowa, 50010, United States

Location

Clinical Site

Kansas City, Kansas, 66160, United States

Location

Clinical Site

Louisville, Kentucky, 40213, United States

Location

Clinical Site

Fall River, Massachusetts, 02721, United States

Location

Clinical Site

Cooperstown, New York, 13326, United States

Location

Clinical Site

High Point, North Carolina, 27262, United States

Location

Clinical Site

Portland, Oregon, 97239, United States

Location

Clinical Site

Lansdale, Pennsylvania, 19446, United States

Location

Clinical Site

Providence, Rhode Island, 02906, United States

Location

Clinical Site

Greer, South Carolina, 29651, United States

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Clinical Site

Houston, Texas, 77030, United States

Location

Clinical Site

Milwaukee, Wisconsin, 53215, United States

Location

Clinical Site

Cambridge, Ontario, N1R 6V6, Canada

Location

Clinical Site

Greater Sudbury, Ontario, P3E 5M4, Canada

Location

Clinical Site

Brossard, Quebec, J4Z 2K9, Canada

Location

Clinical Site

Chicoutimi, Quebec, Canada

Location

Clinical Site

Gatineau, Quebec, J8Y 6S8, Canada

Location

Clinical Site

Montreal, Quebec, H1T 1C8, Canada

Location

Clinical Site

Québec, Quebec, G1V 4W2, Canada

Location

Related Publications (1)

• 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.

  PMID: 35025993 DERIVED

MeSH Terms

Conditions

Hypertriglyceridemia; Cardiovascular Diseases; Dyslipidemias; Metabolic Diseases; Hyperlipidemias; Heart Diseases; Lipid Metabolism Disorders; Vascular Diseases

Condition Hierarchy (Ancestors)

Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Akcea Therapeutics

clinicalstudies@akceatx.com

617-207-0289

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2017
• First Posted: December 28, 2017
• Study Start: January 30, 2018
• Primary Completion: November 25, 2019
• Study Completion: February 25, 2020
• Last Updated: January 11, 2023
• Results First Posted: January 11, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (24); CA (7)