CompletedNCT03385239Updated Jan 11, 2023Results posted

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

A Phase 2 interventional study of ISIS 678354 and Placebo in Hypertriglyceridemia and Cardiovascular Diseases, sponsored by Akcea Therapeutics. Completed at 31 sites in 2 countries. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2023-01-11.

Sponsored by Akcea Therapeutics (part of Ionis Pharmaceuticals, Inc.) · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 114
Allocation: Randomized
Ages: 18 Years to 80 Years
Sex: All

Study 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 studied

Hypertriglyceridemia
Cardiovascular Diseases

Browse trials for

Keywords

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

In context

Hypertriglyceridemia

324 studies on the registry are indexed under Hypertriglyceridemia; 38 are open to participants now.

This study's enrollment of 114 is above the median of 66 across 288 interventional studies indexed under Hypertriglyceridemia.

Browse Hypertriglyceridemia studies →

Lead sponsor

Akcea Therapeutics is the lead sponsor of 15 studies on the registry; 1 is open to participants now.

Of its 9 completed or terminated interventional studies of FDA-regulated products, 8 (89%) have results posted.

Browse Akcea Therapeutics studies →All Ionis Pharmaceuticals, Inc. studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 80 Years
Sexes eligible: All
Accepts healthy volunteers: No

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/ (TIA).
Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis.
Heart failure (NYHA) class IV.
Type 1 diabetes mellitus.
Type 2 diabetes mellitus with any of the following:
- Newly diagnosed within 12 weeks of Screening.
- (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].
(BMI) greater than (>) 40 kilograms per square meter (kg/m\^2).

Terms in these criteria, in plain language(4)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

TIA (transient ischaemic attack)

A “mini-stroke”: temporary stroke-like symptoms caused by reduced blood flow to part of the brain, spinal cord or eye, without signs of a new stroke on a scan.

Stroke symptoms need emergency care at once, even if they go away.

NYHA class (heart failure)

The New York Heart Association’s four classes of how much heart failure limits physical activity.

I: No limits: ordinary activity causes no undue tiredness or breathlessness.
II: Slight limits: comfortable at rest, ordinary activity causes symptoms.
III: Marked limits: comfortable at rest, less than ordinary activity causes symptoms.
IV: Symptoms even at rest; any activity makes them worse.

Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.

HbA1c

A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.

BMI (body mass index)

Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.

What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Triple (Participant, Investigator, Outcomes assessor)
Enrollment: 114 participants (actual)

Study arms

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
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
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
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
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

Interventions

DrugISIS 678354
ISIS 678354 solution for SC injection.
Also known as: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
DrugPlacebo
Sterile Normal Saline (0.9% NaCl).

What researchers measure

Primary outcomes

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

Secondary outcomes

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
An ANCOVA model was performed on the log ratio of Primary Analysis Time Point value to Baseline value for ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I. The estimate of the log ratio was converted back to the original scale and percent change for each lipid parameter was calculated using formula: (ratio of Primary Analysis Time Point value to Baseline value - 1) × 100.
Time frame: 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])
The percentage of participants who achieved \<= 150 mg/dL or \<= 1.7 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Time frame: 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)
The percentage of participants who achieved \<= 100 mg/dL or \<= 1.13 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Time frame: 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
Time frame: 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
Time frame: 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)
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354
Time frame: 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)

Results

Posted Jan 11, 2023

Participant flow

Participants with a clinical diagnosis of hypertriglyceridemia and established cardiovascular disease (CVD) or at high risk for CVD were enrolled in 32 study sites in United States and Canada between 30 January 2018 to 25 February 2020.

Participant flow — Overall Study
Milestone	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Started	24	22	23	23	22
Completed	22	19	20	19	22
Not completed	2	3	3	4	0
Withdrew: Voluntary withdrawal	2	3	2	3	0
Withdrew: Adverse event	0	0	1	0	0
Withdrew: Other	0	0	0	1	0

Outcome measures

PrimaryPercent 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.

Time frame:: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Reported as:: Mean · percent change

Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point
percent change	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point	6 (-9 to 23)	-23 (-34 to -10)	-56 (-62 to -49)	-60 (-66 to -54)	-60 (-65 to -53)

Statistical analysis

Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.0042 · Mean difference in % cfb: -27 · 95% CI -41 to -10Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -58 · 95% CI -66 to -48Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: -63 · 95% CI -70 to -54Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -62 · 95% CI -69 to -53Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

PrimaryNumber 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.

Time frame:: Up to the 13-week post-treatment follow-up period (Up to approximately 15 months)
Reported as:: Count of participants · Participants

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Participants	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	20	17	20	22	21

SecondaryPercent 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

An ANCOVA model was performed on the log ratio of Primary Analysis Time Point value to Baseline value for ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I. The estimate of the log ratio was converted back to the original scale and percent change for each lipid parameter was calculated using formula: (ratio of Primary Analysis Time Point value to Baseline value - 1) × 100.

Time frame:: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Reported as:: Mean · percent change

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
percent change	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Apo-C III	2 (-16 to 23)	-29 (-42 to -13)	-68 (-74 to -61)	-73 (-78 to -67)	-74 (-78 to -69)
TC	1 (-6 to 7)	-2 (-8 to 5)	-12 (-17 to -5)	-3 (-9 to 4)	-8 (-13 to -2)
LDL-C	-2 (-13 to 11)	5 (-7 to 19)	2 (-10 to 15)	27 (13 to 44)	10 (-2 to 23)
HDL-C	-1 (-8 to 6)	11 (3 to 19)	33 (24 to 43)	40 (30 to 51)	29 (20 to 39)
Non-HDL-C	1 (-8 to 10)	-6 (-15 to 3)	-24 (-31 to -17)	-15 (-23 to -7)	-19 (-26 to -12)
VLDL-C	-2 (-13 to 11)	-22 (-32 to -12)	-54 (-59 to -48)	-59 (-63 to -53)	-60 (-65 to -55)
ApoB	-2 (-8 to 5)	0 (-7 to 8)	-17 (-23 to -12)	-7 (-13 to 0)	-12 (-18 to -6)
ApoA-1	0 (-4 to 4)	5 (1 to 10)	14 (9 to 19)	18 (13 to 23)	14 (9 to 18)

Statistical analysis

Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.0123 · Mean difference in % cfb: -30 · 95% CI -47 to -8Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -68 · 95% CI -76 to -58Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: -74 · 95% CI -80 to -65Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -74 · 95% CI -80 to -66Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.568 · Mean difference in % cfb: -3 · 95% CI -11 to 7Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = 0.008 · Mean difference in % cfb: -12 · 95% CI -19 to -3Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = 0.4476 · Mean difference in % cfb: -3 · 95% CI -12 to 6Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = 0.0606 · Mean difference in % cfb: -8 · 95% CI -16 to 0Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.4509 · Mean difference in % cfb: 7 · 95% CI -10 to 26Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = 0.6746 · Mean difference in % cfb: 4 · 95% CI -12 to 23Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = 0.0032 · Mean difference in % cfb: 29 · 95% CI 9 to 53Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = 0.1996 · Mean difference in % cfb: 12 · 95% CI -6 to 32Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.0373 · Mean difference in % cfb: 12 · 95% CI 1 to 24Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = <0.0001 · Mean difference in % cfb: 34 · 95% CI 21 to 49Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: 42 · 95% CI 28 to 57Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: 30 · 95% CI 18 to 44Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.2826 · Mean difference in % cfb: -7 · 95% CI -18 to 6Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -24 · 95% CI -34 to -14Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = 0.0118 · Mean difference in % cfb: -15 · 95% CI -26 to -4Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = 0.0009 · Mean difference in % cfb: -20 · 95% CI -29 to -9Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.0086 · Mean difference in % cfb: -21 · 95% CI -34 to -6Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -53 · 95% CI -60 to -44Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: -58 · 95% CI -64 to -50Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -60 · 95% CI -66 to -52Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.6801 · Mean difference in % cfb: 2 · 95% CI -7 to 13Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = 0.0007 · Mean difference in % cfb: -16 · 95% CI -24 to -7Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = 0.3183 · Mean difference in % cfb: -5 · 95% CI -14 to 5Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = 0.024 · Mean difference in % cfb: -10 · 95% CI -19 to -1Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · ANCOVA · p = 0.0936 · Mean difference in % cfb: 5 · 95% CI -1 to 11Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · ANCOVA · p = <0.0001 · Mean difference in % cfb: 14 · 95% CI 8 to 21Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: 18 · 95% CI 11 to 25Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: 14 · 95% CI 7 to 20Mean difference in % CFB based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

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

The percentage of participants who achieved \<= 150 mg/dL or \<= 1.7 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.

Time frame:: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Reported as:: Number · percentage of participants

Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])
percentage of participants	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])	4.2	13.6	65.2	73.9	90.9

Statistical analysis

Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · Regression, Logistic · p = 0.2591 · Odds ratio (or): 3.34 · 95% CI 0.41 to 27.20
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · Regression, Logistic · p = <0.0001 · Odds ratio (or): 84.02 · 95% CI 9.54 to 740.02
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · Regression, Logistic · p = <0.0001 · Odds ratio (or): 322.79 · 95% CI 20.31 to 5130.99
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · Regression, Logistic · p = <0.0001 · Odds ratio (or): 342.13 · 95% CI 23.72 to 4933.89

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

The percentage of participants who achieved \<= 100 mg/dL or \<= 1.13 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.

Time frame:: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Reported as:: Number · percentage of participants

Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)
percentage of participants	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)	0	0	30.4	26.1	45.5

Statistical analysis

Pooled Placebo vs Cohort A: ISIS 678354: 10 mg Q4W · Regression, Logistic · p = 0.9119 · Odds ratio (or): 1.25 · 95% CI 0.02 to 69.88
Pooled Placebo vs Cohort C: ISIS 678354: 15 mg Q2W · Regression, Logistic · p = 0.0306 · Odds ratio (or): 27.18 · 95% CI 1.36 to 542.48
Pooled Placebo vs Cohort D: ISIS 678354: 10 mg QW · Regression, Logistic · p = 0.0344 · Odds ratio (or): 25.54 · 95% CI 1.27 to 514.20
Pooled Placebo vs Cohort B: ISIS 678354: 50 mg Q4W · Regression, Logistic · p = 0.0123 · Odds ratio (or): 44.47 · 95% CI 2.28 to 866.49

SecondaryMaximum Plasma Concentration (Cmax) of ISIS 678354

Time frame:: 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)
Reported as:: Geometric mean · nanograms per milliliter (ng/mL)

Maximum Plasma Concentration (Cmax) of ISIS 678354
nanograms per milliliter (ng/mL)	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Day 1	53.7 ± 181.2	45.9 ± 36.2	35.8 ± 71.1	48.8 ± 333.3
Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)	41.0 ± 324.1	48.0 ± 29.9	45.1 ± 47.4	127 ± 29.9

SecondaryTime to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354

Time frame:: 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)
Reported as:: Median · hours (h)

Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354
hours (h)	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Day 1	1.08 (1.00 to 2.00)	2.00 (1.98 to 4.00)	3.03 (2.00 to 4.00)	1.50 (1.05 to 1.95)
Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)	2.00 (0.917 to 8.00)	2.08 (1.00 to 4.00)	2.50 (1.00 to 4.00)	4.04 (4.02 to 4.07)

SecondaryArea Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354

Time frame:: 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)
Reported as:: Geometric mean · nanograms*hours per milliliter (ng*h/mL)

Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354
nanogramshours per milliliter (ngh/mL)	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Day 1	618 ± 115.6	499 ± 31.1	411 ± 59.0	563 ± 334.6
Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)	468 ± 258.4	499 ± 11.2	454 ± 26.3	1460 ± 13.6

Adverse events

Collected over Up to the 13-week post-treatment follow-up period (Up to approximately 15 months). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Pooled Placebo	0/24 (0%)	2/24 (8.3%)	16/24 (66.7%)
Cohort A: ISIS 678354: 10 mg Q4W	0/22 (0%)	3/22 (13.6%)	15/22 (68.2%)
Cohort C: ISIS 678354: 15 mg Q2W	1/23 (4.3%)	4/23 (17.4%)	19/23 (82.6%)
Cohort D: ISIS 678354: 10 mg QW	0/23 (0%)	1/23 (4.3%)	20/23 (87%)
Cohort B: ISIS 678354: 50 mg Q4W	0/22 (0%)	3/22 (13.6%)	22/22 (100%)

Most frequent serious events

Showing 10 of 13

Most frequent serious events
Event	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
Acute coronary syndromeCardiac disorders	0/24	1/22	0/23	0/23	0/22
Acute myocardial infarctionCardiac disorders	0/24	0/22	0/23	0/23	1/22
CardiomyopathyCardiac disorders	0/24	0/22	0/23	0/23	1/22
Supraventricular tachycardiaCardiac disorders	0/24	0/22	0/23	0/23	1/22
PneumoniaInfections and infestations	0/24	1/22	0/23	0/23	1/22
AstheniaGeneral disorders	0/24	1/22	0/23	0/23	0/22
Angina unstableCardiac disorders	0/24	0/22	1/23	0/23	0/22
Cardiac arrestCardiac disorders	0/24	0/22	1/23	0/23	0/22
InfluenzaInfections and infestations	0/24	0/22	1/23	0/23	0/22
CholelithiasisHepatobiliary disorders	0/24	0/22	1/23	0/23	0/22

Most frequent other events

Showing 10 of 45

Most frequent other events
Event	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W
NasopharyngitisInfections and infestations	3/24	3/22	4/23	5/23	4/22
Injection site erythemaGeneral disorders	0/24	2/22	3/23	5/23	4/22
Urinary tract infectionInfections and infestations	1/24	2/22	2/23	1/23	4/22
Pain in extremityMusculoskeletal and connective tissue disorders	1/24	1/22	0/23	2/23	4/22
NauseaGastrointestinal disorders	1/24	3/22	1/23	1/23	4/22
Upper respiratory tract infectionInfections and infestations	3/24	2/22	3/23	4/23	3/22
MyalgiaMusculoskeletal and connective tissue disorders	4/24	1/22	3/23	1/23	0/22
SinusitisInfections and infestations	1/24	0/22	2/23	0/23	3/22
ArthralgiaMusculoskeletal and connective tissue disorders	0/24	3/22	3/23	3/23	2/22
Back painMusculoskeletal and connective tissue disorders	1/24	3/22	1/23	3/23	3/22

Baseline characteristics

Full analysis set (FAS) included all participants who were randomized and received at least 1 dose of study drug (ISIS 678354 or placebo).

Age, Continuous
Age, Continuous(years)	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
Mean	64.6 ± 7.93	64.4 ± 9.13	68.9 ± 6.82	65.6 ± 8.48	62.9 ± 7.40	65.3 ± 8.10

Sex: Female, Male
Sex: Female, Male(Participants)	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
Female	4	8	4	5	7	28
Male	20	14	19	18	15	86

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
Hispanic or Latino	1	3	2	1	0	7
Not Hispanic or Latino	23	19	21	22	22	107
Unknown or Not Reported	0	0	0	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
American Indian or Alaska Native	0	0	0	0	0	0
Asian	1	0	0	0	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	1	1	0	0	2	4
White	22	20	23	23	18	106
More than one race	0	1	0	0	2	3
Unknown or Not Reported	0	0	0	0	0	0

Fasting Triglycerides (TG)
Fasting Triglycerides (TG)(milligrams per deciliter (mg/dL))	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
Mean	293.8 ± 86.68	281.6 ± 73.43	284.8 ± 94.54	292.3 ± 89.29	268.4 ± 85.08	284.4 ± 85.16

Apolipoprotein CIII (ApoC-III)
Apolipoprotein CIII (ApoC-III)(mg/dL)	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
Mean	16.618 ± 4.4720	16.030 ± 4.1482	15.849 ± 4.2456	16.810 ± 4.2021	15.669 ± 3.2484	16.205 ± 4.0466

Total Cholesterol (TC)
Total Cholesterol (TC)(mg/dL)	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
Mean	144.8 ± 26.00	149.2 ± 28.81	163.1 ± 35.09	160.0 ± 34.55	166.8 ± 35.30	156.7 ± 32.66

LDL Cholesterol (LDL-C)
LDL Cholesterol (LDL-C)(mg/dL)	Pooled Placebo	Cohort A: ISIS 678354: 10 mg Q4W	Cohort C: ISIS 678354: 15 mg Q2W	Cohort D: ISIS 678354: 10 mg QW	Cohort B: ISIS 678354: 50 mg Q4W	Total
Mean	55.9 ± 26.06	62.4 ± 22.57	73.1 ± 29.73	71.2 ± 30.24	74.8 ± 22.47	67.4 ± 27.02

5 further baseline measures are reported on the registry.

Study locations

31 sites

Clinical Site
Cottonwood, Arizona 86326, United States
Clinical Site
Little Rock, Arkansas 72205, United States
Clinical Site
Carmichael, California 95608, United States
Clinical Site
Fresno, California 93720, United States
Clinical Site
La Jolla, California 92037-7410, United States
Clinical Site
Long Beach, California 90807, United States
Clinical Site
Montclair, California 91763, United States
Clinical Site
Wilmington, Delaware 19803, United States
Clinical Site
Boca Raton, Florida 33434, United States
Clinical Site
Jacksonville, Florida 32216, United States
Clinical Site
New Port Richey, Florida 34652, United States
Clinical Site
Munster, Indiana 46321, United States
Clinical Site
Ames, Iowa 50010, United States
Clinical Site
Kansas City, Kansas 66160, United States
Clinical Site
Louisville, Kentucky 40213, United States
Clinical Site
Fall River, Massachusetts 02721, United States
Clinical Site
Cooperstown, New York 13326, United States
Clinical Site
High Point, North Carolina 27262, United States
Clinical Site
Portland, Oregon 97239, United States
Clinical Site
Lansdale, Pennsylvania 19446, United States
Clinical Site
Providence, Rhode Island 02906, United States
Clinical Site
Greer, South Carolina 29651, United States
Clinical Site
Houston, Texas 77030, United States
Clinical Site
Milwaukee, Wisconsin 53215, United States
Clinical Site
Cambridge, Ontario N1R 6V6, Canada
Clinical Site
Sudbury, Ontario P3E 5M4, Canada
Clinical Site
Brossard, Quebec J4Z 2K9, Canada
Clinical Site
Chicoutimi, Quebec, Canada
Clinical Site
Gatineau, Quebec J8Y 6S8, Canada
Clinical Site
Montréal, Quebec H1T 1C8, Canada
Clinical Site
Québec, Quebec G1V 4W2, Canada

References and documents

Publications

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. PubMed 35025993 ↗

Study documents

Protocol and statistical analysis plan ↗ · Dec 17, 2019

PDFs hosted by the registry, ClinicalTrials.gov.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jan 11, 2023, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03385239
Lead sponsor: Akcea Therapeutics
Collaborators: Ionis Pharmaceuticals, Inc.
Responsible party: Sponsor
First posted: Dec 28, 2017
Start date: Jan 30, 2018
Primary completion: Nov 25, 2019
Completion: Feb 25, 2020
Results posted: Jan 11, 2023
Last update: Jan 11, 2023

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Dec 2022. You cannot join it, but the record below documents what was studied.

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Studies of the drug tested here: Olezarsen

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