Trial Outcomes & Findings for The APPROACH Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Patients With Familial Chylomicronemia Syndrome (NCT NCT02211209)

NCT ID: NCT02211209

Last Updated: 2022-04-13

Results Overview

The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

67 participants

Primary outcome timeframe

Baseline to 3 months

Results posted on

2022-04-13

Participant Flow

67 participants were randomized at 40 study centers in the United States, Canada, Brazil, France, Germany, Israel, Italy, Netherlands, South Africa, Spain, and the United Kingdom.

67 participants were randomized, and 66 received study drug. The study included an 8-week screening period (including a diet-stabilization period), a 52-week treatment period, and a 13-week post-treatment evaluation period.

Participant milestones

Participant milestones
Measure	Placebo Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Overall Study STARTED	34	33
Overall Study Dosed	33	33
Overall Study COMPLETED	32	19
Overall Study NOT COMPLETED	2	14

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Overall Study Investigator judgment	0	1
Overall Study Voluntary withdrawal	1	4
Overall Study Adverse Event or Serious Adverse Event	0	9
Overall Study Reason Not Specified	1	0

Baseline Characteristics

The APPROACH Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Patients With Familial Chylomicronemia Syndrome

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=33 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.	Total n=66 Participants Total of all reporting groups
Age, Continuous	46 years STANDARD_DEVIATION 14 • n=5 Participants	47 years STANDARD_DEVIATION 13 • n=7 Participants	46 years STANDARD_DEVIATION 13 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	26 Participants n=5 Participants	26 Participants n=7 Participants	52 Participants n=5 Participants
Race/Ethnicity, Customized White	29 Participants n=5 Participants	24 Participants n=7 Participants	53 Participants n=5 Participants
Race/Ethnicity, Customized Asian	4 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Other Race	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Canada	8 participants n=5 Participants	6 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Netherlands	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment United States	6 participants n=5 Participants	5 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Brazil	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Italy	5 participants n=5 Participants	5 participants n=7 Participants	10 participants n=5 Participants
Region of Enrollment United Kingdom	3 participants n=5 Participants	5 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment South Africa	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Israel	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment France	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Germany	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Spain	6 participants n=5 Participants	1 participants n=7 Participants	7 participants n=5 Participants
Fasting Triglycerides	2152 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 1153 • n=5 Participants	2267 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 1259 • n=7 Participants	2209 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 1199 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline to 3 months

Population: The full analysis set included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.

The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments.

Outcome measures

Outcome measures
Measure	Placebo n=33 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3	17.6 percent change Interval -4.0 to 39.2	-76.5 percent change Interval -97.4 to -55.5

SECONDARY outcome

Timeframe: Baseline to an on-treatment assessment between Week 13 and Week 19

Population: The full analysis set included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment. Data were reported for evaluable participants.

Participants had 2 postprandial assessments - one at Baseline (completed at least 48 hours prior to first dose) and one at any time between Week 13 and 19, inclusive. Assessment timepoints include from 1-hr before to up to 9 hrs after ingestion of the meal at 1-hour interval. Postprandial AUC results were calculated using a linear trapezoidal rule for each postprandial measure in the subset of participants who had postprandial assessments 0-9 hour results at baseline and the postbaseline between Week 13 to 19.

Outcome measures

Outcome measures
Measure	Placebo n=11 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=10 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Change From Baseline in Postprandial TG Area Under the Curve (AUC)(0-9h)	36.92 millimole hours per liter (mmol*h/L) Standard Deviation 121.54	-234.77 millimole hours per liter (mmol*h/L) Standard Deviation 94.86

SECONDARY outcome

Timeframe: Baseline to 3 months

Population: The full analysis set included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.

The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments.

Outcome measures

Outcome measures
Measure	Placebo n=33 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Absolute Change From Baseline in Fasting TG at Month 3	92 mg/dL Interval -301.0 to 486.0	-1712 mg/dL Interval -2094.0 to -1330.0

SECONDARY outcome

Timeframe: Baseline to 3 months

The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments. mg/dL = milligrams per deciliter

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=30 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Treatment Response Rate Defined as Participants With Fasting Plasma TG < 750 mg/dL at Month 3	3 participants	23 participants

SECONDARY outcome

Timeframe: Baseline to 3 months

Population: The full analysis set included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.

The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments.

Outcome measures

Outcome measures
Measure	Placebo n=33 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3	3 participants	29 participants

SECONDARY outcome

Timeframe: Baseline to 12 months

Population: The full analysis set included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.

Abdominal pain was measured according to the Bracket electronic patient-reported outcomes (ePRO) assessment. Scores were categorized as follows: no pain (pain score: 0), mild (pain score: 1-3), moderate (pain score: 4-6), or severe (pain score: 7-10). The yearly frequency was calculated as the number of episodes during the on-treatment period / (last dose date - first dose date + 28) \* 365.25. Missing data were imputed by using next observation carried back (NOCB) if there was a subsequent score available.

Outcome measures

Outcome measures
Measure	Placebo n=33 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period Severe	8 participants	5 participants
Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period No pain	19 participants	18 participants
Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period Mild	1 participants	4 participants
Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period Moderate	5 participants	6 participants

SECONDARY outcome

Timeframe: 12 months

Population: The full analysis set included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.

Moderate/severe abdominal pain was defined as having a pain score of 4-10 on the Bracket electronic patient-reported outcomes (ePRO) assessment. Scores were categorized as follows: no pain (pain score: 0), mild (pain score: 1-3), moderate (pain score: 4-6), or severe (pain score: 7-10). The yearly frequency was calculated as the number of episodes during the on-treatment period / (last dose date - first dose date + 28) \* 365.25.

Outcome measures

Outcome measures
Measure	Placebo n=33 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Frequency of the Composite of Episodes of Acute Pancreatitis and Participant-reported Moderate/Severe Abdominal Pain During the Treatment Period	2.04 events per participant per year Standard Deviation 4.28	2.73 events per participant per year Standard Deviation 6.57

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: The full analysis set included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.

The Week 52 endpoint was defined as the average of Week 50 (Day 344)/Week 51 (Day 351) and Week 52 (Day 358) fasting assessments.

Outcome measures

Outcome measures
Measure	Placebo n=33 Participants Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 Participants Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Change From Baseline in Hepatosplenomegaly as Assessed by MRI at Week 52	-25 cubic centimeters (cm^3) Interval -150.0 to 100.0	113 cubic centimeters (cm^3) Interval -43.0 to 269.0

Adverse Events

Placebo

Serious events: 5 serious events

Other events: 27 other events

Deaths: 0 deaths

Volanesorsen

Serious events: 7 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=33 participants at risk Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks.	Volanesorsen n=33 participants at risk Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	6.1% 2/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal pain	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Colitis ischaemic	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Pancreatitis acute	6.1% 2/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
General disorders Cyst	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Hepatobiliary disorders Cholangitis	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Hepatobiliary disorders Drug-induced liver injury	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Dehydration	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.
Investigations Liver function test abnormal	3.0% 1/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/33 • Up to approximately 65 weeks. The safety set included all randomized participants who received at least one dose of study drug.

Other adverse events

Additional Information

Ionis Pharmaceuticals, Inc.

Phone: 800-679-4747

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place