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

NCT02527343 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: ISIS 304801-CS172015-000493-35
• Study Type: interventional
• Target: 40
• Locations: 7 countries
• Sites: 12

Brief Summary

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.

Conditions

Familial Partial Lipodystrophy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• Randomized Treatment Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using Magnetic Resonance Imaging (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, Months 6 and 12

• Randomized Treatment Period: Change From Baseline in Hemoglobin A1c (HbA1c)

  Baseline, Months 3, 6, 9, and 12

• Open Label Extension Period: Change From Baseline in HbA1c

  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

  Month 6

Study Arms (2)

Placebo/Volanesorsen

EXPERIMENTAL

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; Drug: Placebo

Volanesorsen

EXPERIMENTAL

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

Interventions

volanesorsen DRUG

300 mg of volanesorsen administered subcutaneous (SC) injection, once-weekly (QW).

Also known as: ISIS 304801, IONIS-APOCIIIRx

Placebo/Volanesorsen; Volanesorsen

Placebo DRUG

Volanesorsen-matching placebo administered SC injection.

Placebo/Volanesorsen

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Akcea Therapeutics: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (12)

IONIS Investigative Site

Ann Arbor, Michigan, 48105, United States

Location

IONIS Investigative Site

Rochester, Minnesota, 55905, United States

Location

IONIS Investigative Site

St Louis, Missouri, 63110, United States

Location

IONIS Investigative Site

Morehead City, North Carolina, 28557, United States

Location

IONIS Investigative Site

Philadelphia, Pennsylvania, 19104, United States

Location

IONIS Investigative Site

Dallas, Texas, 75390, United States

Location

IONIS Investigative Site

Leuven, 3000, Belgium

Location

IONIS Investigative Site

Rio de Janeiro, 20211-340, Brazil

Location

IONIS Investigative Site

Halifax, Nova Scotia, B3H 1C2, Canada

Location

IONIS Investigative Site

Münster, 48149, Germany

Location

IONIS Investigative Site

Amsterdam-Zuidoost, 1105 AZ, Netherlands

Location

IONIS Investigative Site

Moscow, 117036, Russia

Location

Related Publications (1)

• Prohaska TA, Alexander VJ, Karwatowska-Prokopczuk E, Tami J, Xia S, Witztum JL, Tsimikas S. APOC3 inhibition with volanesorsen reduces hepatic steatosis in patients with severe hypertriglyceridemia. J Clin Lipidol. 2023 May-Jun;17(3):406-411. doi: 10.1016/j.jacl.2023.04.007. Epub 2023 Apr 27.

  PMID: 37164837 DERIVED

MeSH Terms

Conditions

Lipodystrophy, Familial Partial

Interventions

ISIS 304801

Condition Hierarchy (Ancestors)

Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipodystrophy; Skin Diseases, Metabolic; Skin Diseases; Skin and Connective Tissue Diseases; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

The Sponsor decided to terminate the study early at a time point when sufficient data had been accumulated to inform a decision on further development of volanesorsen in participants with FPL.

Results Point of Contact

• Title: Study Director
• Organization: Akcea Therapeutics

clinicalstudies@akceatx.com

617-207-0289

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2015
• First Posted: August 19, 2015
• Study Start: December 28, 2015
• Primary Completion: June 30, 2018
• Study Completion: November 13, 2019
• Last Updated: October 18, 2021
• Results First Posted: October 18, 2021

Record last verified: 2021-09

Locations

BR (1); US (6); DE (1); BE (1); RU (1); CA (1); NL (1)