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

• ClinicalTrials.gov Identifier: NCT03385239
• Recruitment Status: Completed
• First Posted: December 28, 2017
• Last Update Posted: November 20, 2020
• Sponsor: Akcea Therapeutics
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Akcea Therapeutics

Study Description

Brief Summary:

This is 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.

Condition or disease	Intervention/treatment	Phase
Hypertriglyceridemia; Cardiovascular Diseases	Drug: ISIS 678354; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 114 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 5, 2018
• Actual Primary Completion Date: November 25, 2019
• Actual Study Completion Date: February 25, 2020

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Pooled Placebo; 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; Sterile Normal Saline (0.9% NaCl).
Experimental: Cohort A: ISIS 678354: 10 mg Q4W; 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; ISIS 678354 solution for SC injection.; Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
Experimental: Cohort C: ISIS 678354: 15 mg Q2W; 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; ISIS 678354 solution for SC injection.; Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
Experimental: Cohort D: ISIS 678354: 10 mg QW; 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; ISIS 678354 solution for SC injection.; Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
Placebo Comparator: Cohort B: ISIS 678354: 50 mg Q4W; 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; ISIS 678354 solution for SC injection.; Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx

Outcome Measures

Primary Outcome Measures :

1. Efficacy of different doses and dosing regimens of ISIS 678354 on the reduction in serum triglyceride (TG) levels from baseline at the primary analysis time point. [ Time Frame: 6 months ]
   The comparison of percent change from baseline to primary analysis time point in fasting serum TG levels between ISIS 678354 treated groups and pooled placebo group.
2. The safety of ISIS 678354 by the incidence of treatment-emergent adverse events. [ Time Frame: 6 months and 12 months ]
   The safety of ISIS 678354 will be assessed by determining adverse effects by dose. Safety results in subjects dosed with ISIS 678354 will be compared with those from subjects dosed with placebo.

Secondary Outcome Measures :

1. Efficacy of different doses and dosing regimens of ISIS 678354 on serum triglyceride (TG) levels from baseline at the primary analysis time point. [ Time Frame: 6 months ]
   The comparison of the proportion of patients who achieve serum TG ≤ 150 mg/dL, and the proportion of patients achieving TG ≤ 100 mg/dL as compared to placebo at the primary analysis time point.
2. To evaluate the efficacy of ISIS 678354 on serum levels of apolipoprotein C-III (apoC-III). [ Time Frame: 6 months ]
   Percent change from baseline at the primary analysis time point in apoCIII will be compared between each ISIS 678354 treatment groups and pooled placebo group.
3. To evaluate the efficacy of ISIS 678354 on serum levels of cholesterol parameters. [ Time Frame: 6 months ]
   Percent change from baseline at the primary analysis time point in cholesterol parameters will be compared between each ISIS 678354 treatment groups and pooled placebo group.
4. To evaluate the efficacy of ISIS 678354 on serum levels of apolipoprotein B100 (apoB). [ Time Frame: 6 months ]
   Percent change from baseline at the primary analysis time point in apoB will be compared between each ISIS 678354 treatment groups and pooled placebo group.
5. To evaluate the efficacy of ISIS 678354 on serum levels of apolipoprotein A-1 (apoA-I). [ Time Frame: 6 months ]
   Percent change from baseline at the primary analysis time point in apoA-I will be compared between each ISIS 678354 treatment groups and pooled placebo group.
6. Plasma Cmax of ISIS 678354 across different doses and dose regimens. [ Time Frame: 6 months ]
   Cmax of ISIS 678354 in plasma will be calculated for the treatment groups.
7. Plasma Tmax of ISIS 678354 across different doses and dose regimens. [ Time Frame: 6 months ]
   Tmax of ISIS 678354 in plasma will be calculated for the treatment groups.
8. Plasma AUC values of ISIS 678354 across different doses and dose regimens. [ Time Frame: 6 months ]
   Plasma AUC values of ISIS 678354 will be calculated for the treatment groups.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, Arizona

Clinical Site

Cottonwood, Arizona, United States, 86326

United States, Arkansas

Clinical Site

Little Rock, Arkansas, United States, 72205

United States, California

Clinical Site

Carmichael, California, United States, 95608

Clinical Site

Fresno, California, United States, 93720

Clinical Site

La Jolla, California, United States, 92037-7410

Clinical Site

Long Beach, California, United States, 90807

Clinical Site

Montclair, California, United States, 91763

United States, Delaware

Clinical Site

Wilmington, Delaware, United States, 19803

United States, Florida

Clinical Site

Boca Raton, Florida, United States, 33434

Clinical Site

Jacksonville, Florida, United States, 32216

Clinical Site

New Port Richey, Florida, United States, 34652

United States, Indiana

Clinical Site

Munster, Indiana, United States, 46321

United States, Iowa

Clinical Site

Ames, Iowa, United States, 50010

United States, Kansas

Clinical Site

Kansas City, Kansas, United States, 66160

United States, Kentucky

Clinical Site

Louisville, Kentucky, United States, 40213

United States, Massachusetts

Clinical Site

Fall River, Massachusetts, United States, 02721

United States, New York

Clinical Site

Cooperstown, New York, United States, 13326

United States, North Carolina

Clinical Site

High Point, North Carolina, United States, 27262

United States, Oregon

Clinical Site

Portland, Oregon, United States, 97239

United States, Pennsylvania

Clinical Site

Lansdale, Pennsylvania, United States, 19446

United States, Rhode Island

Clinical Site

Providence, Rhode Island, United States, 02906

United States, South Carolina

Clinical Site

Greer, South Carolina, United States, 29651

United States, Texas

Clinical Site

Houston, Texas, United States, 77030

United States, Wisconsin

Clinical Site

Milwaukee, Wisconsin, United States, 53215

Canada, Ontario

Clinical Site

Cambridge, Ontario, Canada, N1R 6V6

Clinical Site

Sudbury, Ontario, Canada, P3E 5M4

Canada, Quebec

Clinical Site

Brossard, Quebec, Canada, J4Z 2K9

Clinical Site

Chicoutimi, Quebec, Canada

Clinical Site

Gatineau, Quebec, Canada, J8Y 6S8

Clinical Site

Montréal, Quebec, Canada, H1T 1C8

Clinical Site

Québec, Quebec, Canada, G1V 4W2

Sponsors and Collaborators

Akcea Therapeutics

Ionis Pharmaceuticals, Inc.

More Information

• Responsible Party: Akcea Therapeutics
• ClinicalTrials.gov Identifier: NCT03385239
• Other Study ID Numbers: ISIS 678354-CS2
• First Posted: December 28, 2017
• Last Update Posted: November 20, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Akcea Therapeutics:

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

Additional relevant MeSH terms:

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