Familial Chylomicronemia Syndrome, Hyperlipoproteinemia Type 1, Lipoprotein Lipase Deficiency
Conditions
Brief summary
An open-label study of volanesorsen (ISIS 304801) administered subcutaneously to participants with FCS.
Detailed description
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.
Interventions
DRUGVolanesorsen
300 mg volanesorsen administered via SC injection.
Sponsors
Ionis Pharmaceuticals, Inc.
Akcea Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Baseline and Months 3, 6, and 12 | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From first dose of study drug to end of follow-up period [Up to Week 182] | 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. |
Countries
Brazil, Canada, France, Germany, Israel, Italy, Netherlands, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 19 study centers in Canada, France, Italy, Netherlands, South Africa, Spain, United Kingdom and the United States from 23 December 2015 to 15 January 2020.
Pre-assignment details
A total of 68 participants were enrolled into this study.
Participants by arm
| Arm | Count |
|---|---|
| Treatment-naïve Group Treatment naïve group included combined group of ISIS 304801-CS7 (CS7-New) study participant and participant on placebo in index studies (ISIS 304801-CS6- Placebo \[NCT02211209\] and ISIS 304801-CS16-Placebo \[NCT02300233\]), 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. | 51 |
| CS6-Volanesorsen 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. | 14 |
| CS16-Volanesorsen 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. | 3 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 1st Extended Treatment: Weeks 53 to 104 | Adverse Event or SAE | 7 | 0 | 0 |
| 1st Extended Treatment: Weeks 53 to 104 | Investigator Judgment | 1 | 0 | 0 |
| 1st Extended Treatment: Weeks 53 to 104 | Other | 1 | 0 | 1 |
| 1st Extended Treatment: Weeks 53 to 104 | Transferred to Early Access Programs | 8 | 2 | 0 |
| 1st Extended Treatment: Weeks 53 to 104 | Voluntary Withdrawal | 4 | 0 | 1 |
| 2nd Extended Treatment: Weeks 105 to156 | Adverse Event or SAE | 0 | 0 | 1 |
| 2nd Extended Treatment: Weeks 105 to156 | Transferred to Commercial Treatment | 1 | 0 | 0 |
| Treatment Period: Weeks 1 to 52 | Adverse Event or Serious Adverse Event (SAE) | 8 | 5 | 0 |
| Treatment Period: Weeks 1 to 52 | Investigator Judgment | 1 | 0 | 0 |
| Treatment Period: Weeks 1 to 52 | Voluntary Withdrawal | 6 | 2 | 0 |
Baseline characteristics
| Characteristic | Treatment-naïve Group | CS6-Volanesorsen | CS16-Volanesorsen | Total |
|---|---|---|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 14 | 48 years STANDARD_DEVIATION 14 | 48 years STANDARD_DEVIATION 11 | 47 years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 14 Participants | 3 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting Triglyceride (TG) | 2341 milligrams per decilitre (mg/dL) STANDARD_DEVIATION 1193 | 1523 milligrams per decilitre (mg/dL) STANDARD_DEVIATION 946 | 2081 milligrams per decilitre (mg/dL) STANDARD_DEVIATION 706 | 2161 milligrams per decilitre (mg/dL) STANDARD_DEVIATION 1166 |
| Race/Ethnicity, Customized Race Asian | 11 Participants | 3 Participants | 0 Participants | 14 Participants |
| Race/Ethnicity, Customized Race Other Race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 39 Participants | 11 Participants | 3 Participants | 53 Participants |
| Sex: Female, Male Female | 34 Participants | 7 Participants | 2 Participants | 43 Participants |
| Sex: Female, Male Male | 17 Participants | 7 Participants | 1 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 14 | 0 / 3 |
| other Total, other adverse events | 51 / 51 | 14 / 14 | 3 / 3 |
| serious Total, serious adverse events | 13 / 51 | 2 / 14 | 2 / 3 |
Outcome results
Primary
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.
Time frame: Baseline and Months 3, 6, and 12
Population: FAS included all participants who were enrolled and received at least one dose of study drug and who had an open-label study baseline TG assessment. Here, number analyzed signifies participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment-naïve Group | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 6 | -45.5 percent change | Standard Deviation 42.9 |
| Treatment-naïve Group | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 3 | -59.8 percent change | Standard Deviation 37 |
| Treatment-naïve Group | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 12 | -36.3 percent change | Standard Deviation 44.2 |
| CS6-Volanesorsen | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 6 | -54.8 percent change | Standard Deviation 23.8 |
| CS6-Volanesorsen | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 3 | -49.2 percent change | Standard Deviation 34.8 |
| CS6-Volanesorsen | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 12 | -35.1 percent change | Standard Deviation 45.6 |
| CS16-Volanesorsen | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 3 | -64.9 percent change | Standard Deviation 9.1 |
| CS16-Volanesorsen | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 12 | -41.6 percent change | Standard Deviation 36.3 |
| CS16-Volanesorsen | Mean Percent Change From Baseline in Fasting Triglyceride (TG) | Percent Change at Month 6 | -43.0 percent change | Standard Deviation 19.7 |
Primary
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.
Time frame: From first dose of study drug to end of follow-up period [Up to Week 182]
Population: Safety Set included all participants who were enrolled and received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment-naïve Group | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 51 Participants |
| CS6-Volanesorsen | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 14 Participants |
| CS16-Volanesorsen | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 3 Participants |