The BROADEN Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Partial Lipodystrophy

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 a randomized treatment (RT) period in participants with familial partial lipodystrophy (FPL). Following the randomized treatment period, participants who did not enter the open-label extension (OLE) period went straight to the 13-week post-treatment (PT) follow-up period and participants who were entered in the OLE period continued to receive volanesorsen for another 52 weeks (Weeks 53 to 104). Following the Week 104 visit of the OLE period, participants had an option of continued dosing for up to an additional 52 weeks (Week 105 to 156). Participants who did not enter the OLE period went straight to a 13-week post-treatment follow-up period. Following the Week 104 OLE period, participants were entered a 13-week post-treatment follow-up period, if they did not choose the option for continued dosing.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, With an Open Label Extension, Phase 2/3 Study of ISIS 304801 Administered Subcutaneously to Patients With Familial Partial Lipodystrophy

Conditions
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Familial Partial Lipodystrophy

Intervention / Treatment
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* Drug: volanesorsen
* Drug: Placebo


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 authorizations required by law. Clinical diagnosis of familial partial lipodystrophy (FPL) plus diagnosis of type 2 diabetes mellitus, hypertriglyceridemia, and fatty liver. Diagnosis of FPL is based on deficiency of subcutaneous body fat in a partial fashion assessed by physical examination and low skinfold thickness in anterior thigh by caliper measurement: men (less than or equal to [≤] 10 millimeters [mm]) and women (≤ 22 mm), and at least 1 of the following: Genetic diagnosis of FPL OR Family history of FPL or of similar abnormal fat distribution plus 1 Minor Criteria OR In the absence of FPL-associated genetic variant or family history, 2 Minor Criteria and body mass index (BMI) less than (<) 35 kilogram per meter square (kg/m^2). Diabetes not well controlled on antidiabetic therapy with glycated hemoglobin (Hb) HbA1c more than or equal to (≥) 7 percentage (%) to ≤ 12% at Screening. Hypertriglyceridemia with fasting triglycerides (TG) levels greater than or equal to (≥) 500 milligrams per deciliter (mg/dL) (≥ 5.7 millimoles per liter [mmol/L]) at Screening and Qualification visit, or Fasting TG levels ≥ 200 (≥ 2.26 mmol/L) at both Screening and Qualification Visits for participants who meet the genetic or family history criteria. Presence of hepatosteatosis (fatty liver), as evidenced by a screening magnetic resonance imaging (MRI) indicating a hepatic fat fraction (HFF) ≥ 6.4%. Exclusion Criteria: A diagnosis of generalized lipodystrophy. A diagnosis of acquired partial lipodystrophy. Acute pancreatitis within 4 weeks of Screening. History within 6 months of Screening of acute or unstable cardiac condition. Low-density lipoprotein cholesterol (LDL-C) more than (>) 130 mg/dL on maximal tolerated statin therapy. Platelet count < lower limit of normal (LLN). Treatment with metreleptin within the last 3 months prior to Screening.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo/Volanesorsen<br>Randomized Period: Volanesorsen-matching placebo as SC, QW for Weeks 1-52. Participants who received volanesorsen-matching placebo in RT period and not enter in OLE period went straight to 13-week PT follow-up period. Dose adjustment based on monitoring rules were allowed. OLE Period: Participants who received volanesorsen-matching placebo in RT period and completed RT period, were to receive 300 mg of volanesorsen as SC QW for 52 weeks (Weeks 53-104) in OLE period. Dose adjustment based on monitoring rules were allowed. After Week 104, participants had option of continuing treatment with 300 mg of volanesorsen as SC injection for up to additional 52 weeks (Weeks 105-156). Participants not entered in option for additional 52 weeks of dosing in OLE PT period went straight to 13-week PT follow-up period after completion of first 52 weeks (Weeks 53-104) of OLE. Participants entered in OLE PT period went straight to 13-week PT follow-up period after completion of Week 156 of OLE. | Drug: volanesorsen<br>* 300 mg of volanesorsen administered subcutaneous (SC) injection, once-weekly (QW).<br>* Other names: IONIS-APOCIIIRx;Drug: Placebo<br>* Volanesorsen-matching placebo administered SC injection.<br>|
| Experimental: Volanesorsen<br>Randomized Period: 300 mg of volanesorsen as SC, QW for Weeks 1-52. Participants who received 300 mg of volanesorsen in RT period and did not enter in OLE period went straight to 13-week PT follow-up period. Dose adjustment based on monitoring rules were allowed. OLE Period: Participants who received volanesorsen in RT period and completed RT period, were to receive 300 mg of volanesorsen as SC QW for 52 weeks (Weeks 53-104) in OLE period. Dose adjustment based on monitoring rules were allowed. After Week 104, participants had option of continuing treatment with 300 mg of volanesorsen as SC injection for up to additional 52 weeks (Week 105-156). Participants who were not entered in option for additional 52 weeks of dosing in OLE PT period went straight to 13-week PT follow-up period after completion of first 52 weeks (Weeks 53-104) of OLE. Participants entered in OLE PT period went straight to 13-week PT follow-up period after completion of Week 156 of OLE. | Drug: volanesorsen<br>* 300 mg of volanesorsen administered subcutaneous (SC) injection, once-weekly (QW).<br>* Other names: IONIS-APOCIIIRx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Randomized Treatment Period: Percent Change From Baseline to Month 3 in Fasting Triglycerides (TG) | Baseline was defined as the average of Day 1 predose fasting assessment and the last fasting measurement prior to Day 1 predose fasting assessment. Month 3 value was defined as the average of Week 12 and Week 13 fasting TG assessments of the randomized treatment period. The data was analyzed using an analysis of covariance (ANCOVA) model with the randomization stratification factor (diagnosis of disease with or without genetics and family history) and treatment group as factors and log-transformed baseline fasting TG as a covariate. | Baseline to Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Randomized Treatment Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using Magnetic Resonance Imaging (MRI) | Baseline was defined as the last non-missing assessment prior to the first dose of study drug in the randomized treatment period. Randomized treatment period: Month 6 value was defined as Week 25 or Week 26 for MRI assessment and Month 12 was defined as Week 50 or Week 52 for MRI assessment. Hepatic steatosis is a reversible condition in which large vacuoles of triglyceride fat accumulate in the liver cells, causing nonspecific inflammation. Hepatic Steatosis was assessed by hepatic fat fraction using MRI. | Baseline, Months 6 and 12 | 
| Open-Label Extension Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using MRI | Baseline was defined as the last non-missing assessment prior to the first dose of study drug in the randomized treatment period. Open-label extension period: Month 6 value was defined as Week 77 or Week 78 for MRI assessment and Month 12 value was defined as Week 102 or Week 104 for MRI assessment. Hepatic steatosis is a reversible condition in which large vacuoles of triglyceride fat accumulate in the liver cells, causing nonspecific inflammation. Hepatic Steatosis was assessed by hepatic fat fraction using MRI. | Baseline, Months 6 and 12 | 
| Randomized Treatment Period: Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline was defined as the last non-missing assessment prior to the first dose of study drug. Randomized treatment period: The Month 3 value was defined as Week 13, Month 6 value was defined as Week 26, Month 9 value was defined as Week 38 and Month 12 value was defined as Week 52. | Baseline, Months 3, 6, 9, and 12 | 
| Open Label Extension Period: Change From Baseline in HbA1c | Baseline was defined as the last non-missing assessment prior to the first dose of study drug. Open-label extension period: Month 3 value was defined as Week 65, Month 6 value was defined as Week 78, Month 9 value was defined as Week 90 and Month 12 value was defined as Week 104. | Baseline, Months 3, 6, 9, and 12 | 
| Randomized Treatment Period: Percentage of Participants Who Achieved Greater Than or Equal to (≥) 40% Reduction in Fasting Triglyceride and ≥ 30% Reduction of Hepatic Fat Fraction at Month 6 | The baseline of TG is defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment. The baseline of hepatic fat fraction is defined as the last non-missing assessment prior to the first dose of study drug. Randomized treatment period: Month 6 value was defined as average of Week 25 and Week 26 for fasting TG and Week 25 or Week 26 for hepatic fat fraction. | Month 6 | 
| Randomized Treatment Period: Change From Baseline in Disease Burden Score | The Disease Burden Score is a questionnaire that allows participants to self-report their chronic conditions and then assess the degree to which each condition interferes with daily activities. | From the first dose of study drug to Week 52 | 
| Open-Label Extension Period: Change From Baseline in Disease Burden Score | The Disease Burden Score is a questionnaire that allows participants to self-report their chronic conditions and then assess the degree to which each condition interferes with daily activities. | From the first dose of study drug in open label extension period to Week 117 | 
| Randomized Treatment Period: Patient-Reported Pain | Patient-reported pain was assessed by rating pain symptoms at its worst and least for the last 24 hours, on average, and at the moment, with 0 as the lowest score (no pain) and 10 as the highest score (worst pain as you can imagine). Patient-reported pain was also assessed by rating pain symptoms (rate pain on average, rate pain right now) that interfered with general activity, interfered with mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life, with 0 as the lowest score (did not interfered) and 10 as the highest score (completely interfered). The scores from each assessment time point were averaged for all of the below reported categories. | From the first dose of study drug up to Week 52 | 
| Open Label Extension Period: Patient-Reported Pain | Patient-reported pain was assessed by rating pain symptoms at its worst and least for the last 24 hours, on average, and at the moment, with 0 as the lowest score (no pain) and 10 as the highest score (worst pain as you can imagine). Patient-reported pain was also assessed by rating pain symptoms (rate pain on average, rate pain right now) that interfered with general activity, interfered with mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life, with 0 as the lowest score (did not interfered) and 10 as the highest score (completely interfered). The scores from each assessment time point were averaged for all of the below reported categories. | From the first dose of study drug in open label extension period up to Week 117 | 
| Randomized Treatment Period: Patient-Reported Hunger | Patient-reported hunger was assessed by participants who completed a questionnaire about: how hungry you feel, how satisfied you feel, how full you feel, how much you think you can eat, like to eat something sweet, like to eat something salty, like to eat something savory and like to eat something fatty. Participants also rated the palatability of meals that included visual appeal, smell, taste, and aftertaste. Scores of 1-39 were categorized as mild, 40-69 as moderate, and 70-100 as severe. The scores from each assessment time point were averaged for all of the below reported categories. | From the first dose of study drug up to Week 52 | 
| Open Label Extension Period: Patient-Reported Hunger | Patient-reported hunger was assessed by participants who completed a questionnaire about: how hungry you feel, how satisfied you feel, how full you feel, how much you think you can eat, like to eat something sweet, like to eat something salty, like to eat something savory and like to eat something fatty. Participants also rated the palatability of meals that included visual appeal, smell, taste, and aftertaste. Scores of 1-39 were categorized as mild, 40-69 as moderate, and 70-100 as severe. The scores from each assessment time point were averaged for all of the below reported categories. | From the first dose of study drug in open label extension period up to Week 117 | 
| Randomized Treatment Period: Change From Baseline in Mean Short Form-36 (SF-36) Weighted Sum of Scores | The SF-36 Health Survey is a 36-item, patient-reported survey of patient health. SF-36 consists of 8 health dimensions,which are weighted sums of the questions in each section. SF-36 included 36 questions related to 8 health dimensions:physical functioning, physical role functioning, bodily pain, general health perceptions, vitality, social role functioning,emotional role functioning, and mental health. Each dimension was scored on a scale of 0 to 100 where, higher score = better quality of life. A positive change from Baseline indicates improvement. | Baseline, Weeks 13, 26 and 52 | 
| Open-Label Extension Period: Change From Baseline in Mean SF-36 Weighted Sum of Scores | The SF-36 Health Survey is a 36-item, patient-reported survey of patient health. SF-36 consists of 8 health dimensions,which are weighted sums of the questions in each section. SF-36 included 36 questions related to 8 health dimensions:physical functioning, physical role functioning, bodily pain, general health perceptions, vitality, social role functioning,emotional role functioning, and mental health. Each dimension was scored on a scale of 0 to 100 where, higher score = better quality of life. A positive change from Baseline indicates improvement. | Baseline, Weeks 65, 78 and 104 | 
| Randomized Treatment Period: Change From Baseline in Mean EQ-5D: Index Scores and Visual Analog Scale (VAS) | EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of two components: a health state profile and VAS. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L- VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A negative change from baseline indicates worsening. A positive change from baseline indicates improvement. | Baseline, Weeks 13, 26 and 52 | 
| Open-Label Extension Period: Change From Baseline in Mean EQ-5D: Index and Visual Analog Scale (VAS) Scores | EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of two components: a health state profile and VAS. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L- VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A negative change from baseline indicates worsening. A positive change from baseline indicates improvement. | Baseline, Weeks 65, 78 and 104 |