The Approach Open Label Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Chylomicronemia Syndrome

Study Overview
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Brief Summary
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An open-label study of volanesorsen (ISIS 304801) administered subcutaneously to participants with FCS.

Detailed Description
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This is a multi-center, open-label study for FCS participants rolling over from the ISIS 304801-CS6 (NCT02211209) index study, FCS participants rolling over from the ISIS 304801-CS16 (NCT02300233) index study and Treatment-naïve group. All participants were to receive volanesorsen 300 milligrams (mg) once per week for 52 weeks. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Participants had the option of continuing dosing for an additional 52 weeks (France: up to an additional 104 weeks for a total of 156 weeks) until an expanded access program was approved and available in their country. Participants who were not participating in an expanded access program were to enter a 13-week (France: 26-week) post-treatment evaluation period.

Official Title
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ISIS 304801-CS7 The APPROACH Open Label Study Volanesorsen (ISIS 304801) An Open-Label Study of Volanesorsen Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS)

Conditions
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Familial Chylomicronemia Syndrome, Lipoprotein Lipase Deficiency, Hyperlipoproteinemia Type 1

Intervention / Treatment
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* Drug: Volanesorsen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must give written informed consent to participate in the study (signed and dated) and any authorization required by law. Able and willing to participate in a 65-week study. Group 1 and 2: Satisfactory completion of ISIS 304801-CS6 (NCT02211209) or ISIS 304801-CS16 (NCT02300233) index studies with an acceptable safety profile, per Sponsor and Investigator judgment. Group 3: Participants who did not participate in the CS6 or CS16 index studies and meet additional inclusion criteria of FCS may enroll in the study. History of chylomicronemia. A diagnosis of FCS (Type 1 Hyperlipoproteinemia.) Fasting triglycerides greater than or equal to (≥)750 milligrams per deciliter [mg/dL] (8.4 millimoles per liter [mmol/L]) at Screening. Exclusion Criteria: Unwilling to comply with lifestyle requirements for the duration of the study. Group 1 and 2: Have any new condition or worsening of existing condition which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study. Group 3: Diabetes mellitus if newly diagnosed or if hemoglobin A1c (HbA1c)≥ 9.0%. 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. 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment-naïve Group<br>Treatment naïve group included combined group of ISIS 304801-CS7 (CS7-New) study participant and participant on placebo in index studies (ISIS 304801-CS6 [NCT02211209] and ISIS 304801-CS16 [NCT02300233]), were to receive 300 mg of volanesorsen as single SC once weekly for Weeks 1-52 of this study. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Following Week 52 visit, participants had option of participating in expanded access program or continuing treatment with 300 mg of volanesorsen as single SC once-weekly for up to additional 52 weeks (Weeks 53-104) and in France participants, up to additional 104 weeks for total of 156 weeks (Weeks 105 to Week 156) until expanded access program was approved and available in their country. Participants who were not participating in expanded access program were to enter 13-week post-treatment (PT) evaluation period and in France, participants not continuing treatment were to enter 26-week PT follow-up period. | Drug: Volanesorsen<br>* 300 mg volanesorsen administered via SC injection.<br>* Other names: ISIS 304801;|
| Experimental: CS6-Volanesorsen<br>Participants with FCS rolling over from the ISIS 304801-CS6 (NCT02211209) index study after receiving volanesorsen, were to receive 300 mg of volanesorsen as a single SC injection once weekly for Weeks 1-52 of this study. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Following the Week 52 visit, participants had the option of participating in an expanded access program or continuing treatment with 300 mg of volanesorsen as a single SC injection once-weekly for up to an additional 52 weeks (Weeks 53-104) and in France participants, up to an additional 104 weeks for total of 156 weeks of treatment (Weeks 105 to Week 156) of this study until an expanded access program was approved and available in their country. Participants who were not participating in an expanded access program were to enter a 13-week post-treatment evaluation period and in France, participants not continuing treatment were to enter a 26-week post-treatment follow-up period. | Drug: Volanesorsen<br>* 300 mg volanesorsen administered via SC injection.<br>* Other names: ISIS 304801;|
| Experimental: CS16-Volanesorsen<br>Participants with FCS rolling over from the ISIS 304801-CS16 (NCT02300233) index study after receiving volanesorsen, were to receive 300 mg of volanesorsen as a single SC injection once weekly for Weeks 1-52 of this study. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Following the Week 52 visit, participants had the option of participating in an expanded access program or continuing treatment with 300 mg of volanesorsen as a single SC injection once-weekly for up to an additional 52 weeks (Weeks 53-104) and in France participants, up to an additional 104 weeks for total of 156 weeks of treatment (Weeks 105 to Week 156) of this study until an expanded access program was approved and available in their country. Participants who were not participating in an expanded access program were to enter a 13-week post-treatment evaluation period and in France, participants not continuing treatment were to enter a 26-week post-treatment follow-up period. | Drug: Volanesorsen<br>* 300 mg volanesorsen administered via SC injection.<br>* Other names: ISIS 304801;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Baseline for treatment-naïve group was defined as the average of open-label Day 1 pre-dose assessment and the last measurement prior to open-label Day 1. Baseline for CS6-volanesorsen and CS16-volanesorsen arm groups was defined as the average of index study Day 1 pre-dose assessment and the last measurement prior index study Day 1. The values at the Month 3 analysis time point were defined as the average of the Week 12 (Day 78) and Week 13 (Day 85) fasting assessments. The Month 6 analysis time point was at the end of Month 6, and the values were defined as the average of the Week 25 (Day 169) and Week 26 (Day 176) fasting assessments. The values at the Month 12 analysis time point were defined as the average of the Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. | Baseline and Months 3, 6, and 12 | 
| 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), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. A TEAE was defined as any AE starting or getting worse on or after the first dose of the study drug. | From first dose of study drug to end of follow-up period [Up to Week 182] |