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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of volanesorsen given for 52 weeks in participants with Familial Chylomicronemia Syndrome

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of ISIS 304801 Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS)

Conditions
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Familial Chylomicronemia Syndrome

Intervention / Treatment
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* Drug: Volanesorsen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of chylomicronemia A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) Fasting triglycerides (TG) ≥ 750 mg/dL (8.4 mmol/L) at Screening Exclusion Criteria: Diabetes mellitus if newly diagnosed or if HbA1c ≥ 9.0% Other types of severe hypertriglyceridemia Active pancreatitis within 4 weeks of screening Acute Coronary Syndrome within 6 months of screening Major surgery within 3 months of screening Treatment with Glybera therapy within 2 years of screening Previous treatment with IONIS-APOCIIIRx Have any other conditions in the opinion of the investigator which could interfere with the participant participating in or completing the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks. | Drug: Placebo<br> <br> |
| Experimental: Volanesorsen<br>Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks. | Drug: Volanesorsen<br> <br> * Other names: IONIS-APOCIIIRx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 | The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments. | Baseline to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Postprandial TG Area Under the Curve (AUC)(0-9h) | 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. | Baseline to an on-treatment assessment between Week 13 and Week 19 | 
| Absolute Change From Baseline in Fasting TG at Month 3 | The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments. | Baseline to 3 months | 
| Treatment Response Rate Defined as Participants With Fasting Plasma TG < 750 mg/dL at Month 3 | 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 | Baseline to 3 months | 
| Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3 | The Month 3 endpoint was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments. | Baseline to 3 months | 
| Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | 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. | Baseline to 12 months | 
| Frequency of the Composite of Episodes of Acute Pancreatitis and Participant-reported Moderate/Severe Abdominal Pain During the Treatment Period | 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. | 12 months | 
| Change From Baseline in Hepatosplenomegaly as Assessed by MRI at Week 52 | 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. | Baseline to Week 52 |