Familial Chylomicronemia Syndrome
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of volanesorsen given for 52 weeks in participants with Familial Chylomicronemia Syndrome
Interventions
DRUGVolanesorsen
DRUGPlacebo
Sponsors
Akcea Therapeutics
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Fasting TG at Month 3 | 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. |
| Treatment Response Rate Defined as Participants With Fasting Plasma TG < 750 mg/dL at Month 3 | 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 |
| Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3 | 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. |
| Change From Baseline in Postprandial TG Area Under the Curve (AUC)(0-9h) | Baseline to an on-treatment assessment between Week 13 and Week 19 | 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. |
| Frequency of the Composite of Episodes of Acute Pancreatitis and Participant-reported Moderate/Severe Abdominal Pain During the Treatment Period | 12 months | 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. |
| Change From Baseline in Hepatosplenomegaly as Assessed by MRI at Week 52 | Baseline to 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. |
| Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | Baseline to 12 months | 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. |
Countries
Brazil, Canada, France, Germany, Hungary, Israel, Italy, Netherlands, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Volanesorsen-matching placebo administered subcutaneously once-weekly for 52 weeks. | 33 |
| Volanesorsen Volanesorsen 300 mg administered subcutaneously once-weekly for 52 weeks. | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event or Serious Adverse Event | 0 | 9 |
| Overall Study | Investigator judgment | 0 | 1 |
| Overall Study | Reason Not Specified | 1 | 0 |
| Overall Study | Voluntary withdrawal | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo | Volanesorsen | Total |
|---|---|---|---|
| Age, Continuous | 46 years STANDARD_DEVIATION 14 | 47 years STANDARD_DEVIATION 13 | 46 years STANDARD_DEVIATION 13 |
| Fasting Triglycerides | 2152 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 1153 | 2267 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 1259 | 2209 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 1199 |
| Race/Ethnicity, Customized Asian | 4 Participants | 7 Participants | 11 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 7 Participants | 7 Participants | 14 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 26 Participants | 26 Participants | 52 Participants |
| Race/Ethnicity, Customized Other Race | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 29 Participants | 24 Participants | 53 Participants |
| Region of Enrollment Brazil | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Canada | 8 participants | 6 participants | 14 participants |
| Region of Enrollment France | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Germany | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Israel | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Netherlands | 1 participants | 3 participants | 4 participants |
| Region of Enrollment South Africa | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Spain | 6 participants | 1 participants | 7 participants |
| Region of Enrollment United Kingdom | 3 participants | 5 participants | 8 participants |
| Region of Enrollment United States | 6 participants | 5 participants | 11 participants |
| Sex: Female, Male Female | 19 Participants | 17 Participants | 36 Participants |
| Sex: Female, Male Male | 14 Participants | 16 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 33 |
| other Total, other adverse events | 27 / 33 | 32 / 33 |
| serious Total, serious adverse events | 5 / 33 | 7 / 33 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 | 17.6 percent change |
| Volanesorsen | Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 | -76.5 percent change |
p-value: <0.000195% CI: [-121.7, -66.6]ANCOVA
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Fasting TG at Month 3 | 92 mg/dL |
| Volanesorsen | Absolute Change From Baseline in Fasting TG at Month 3 | -1712 mg/dL |
p-value: <0.000195% CI: [-2306, -1302]ANCOVA
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Hepatosplenomegaly as Assessed by MRI at Week 52 | -25 cubic centimeters (cm^3) |
| Volanesorsen | Change From Baseline in Hepatosplenomegaly as Assessed by MRI at Week 52 | 113 cubic centimeters (cm^3) |
p-value: 0.120695% CI: [-36, 312]ANCOVA
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Volanesorsen | Change From Baseline in Postprandial TG Area Under the Curve (AUC)(0-9h) | -234.77 millimole hours per liter (mmol*h/L) | Standard Deviation 94.86 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | No pain | 19 participants |
| Placebo | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | Mild | 1 participants |
| Placebo | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | Moderate | 5 participants |
| Placebo | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | Severe | 8 participants |
| Volanesorsen | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | Severe | 5 participants |
| Volanesorsen | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | No pain | 18 participants |
| Volanesorsen | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | Moderate | 6 participants |
| Volanesorsen | Frequency and Severity of Participant-reported Abdominal Pain During the Treatment Period | Mild | 4 participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Volanesorsen | Frequency of the Composite of Episodes of Acute Pancreatitis and Participant-reported Moderate/Severe Abdominal Pain During the Treatment Period | 2.73 events per participant per year | Standard Deviation 6.57 |
p-value: 0.6131t-test, 2 sided
Secondary
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
Time frame: 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. Data were reported for evaluable participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Treatment Response Rate Defined as Participants With Fasting Plasma TG < 750 mg/dL at Month 3 | 3 participants |
| Volanesorsen | Treatment Response Rate Defined as Participants With Fasting Plasma TG < 750 mg/dL at Month 3 | 23 participants |
p-value: 0.0001Regression, Logistic
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3 | 3 participants |
| Volanesorsen | Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3 | 29 participants |
p-value: <0.000195% CI: [15.75, 631.06]Regression, Logistic