HELIOS-A: A Study of Vutrisiran (ALN-TTRSC02) in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis)

• ClinicalTrials.gov Identifier: NCT03759379
• Recruitment Status: Active, not recruiting
• First Posted: November 30, 2018
• Last Update Posted: March 19, 2021
• Sponsor: Alnylam Pharmaceuticals
• Information provided by (Responsible Party): Alnylam Pharmaceuticals

Tracking Information

• First Submitted Date: November 28, 2018
• First Posted Date: November 30, 2018
• Last Update Posted Date: March 19, 2021
• Actual Study Start Date: February 14, 2019
• Actual Primary Completion Date: November 10, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 2, 2020)

Change from Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 [ Time Frame: Baseline, Month 9 ]

The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome.

Original Primary Outcome Measures (submitted: November 28, 2018)

• Change from Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 [ Time Frame: Baseline, Month 9 ]
  The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome. The change in mNIS+7 will be evaluated for ALN-TTRSC02 and compared to the placebo arm of the APOLLO study (NCT01960348).
• Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 [ Time Frame: Baseline, Month 9 ]
  The Norfolk QoL-DN is a standardized 35-item patient-rated questionnaire used to assess 5 domains: physical function, large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome. The change in Norfolk QoL-DN will be evaluated for ALN-TTRSC02 and compared to the placebo arm of the APOLLO study (NCT01960348).

Current Secondary Outcome Measures (submitted: September 2, 2020)

• Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 [ Time Frame: Baseline, Month 9 ]
  The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.
• Change from Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 [ Time Frame: Baseline, Month 9 ]
• Change from Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 18 [ Time Frame: Baseline, Month 18 ]
  The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome.
• Change from Baseline in Norfolk QoL-DN Total Score at Month 18 [ Time Frame: Baseline, Month 18 ]
  The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.
• Change from Baseline in the 10-MWT at Month 18 [ Time Frame: Baseline, Month 18 ]
• Change from Baseline in the Modified Body Mass Index (mBMI) at Month 18 [ Time Frame: Baseline, Month 18 ]
• Change from Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 18 [ Time Frame: Baseline, Month 18 ]
  The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome.
• Percentage Reduction in Serum Transthyretin (TTR) Levels Through Month 18 [ Time Frame: Up to Month 18 ]

Original Secondary Outcome Measures (submitted: November 28, 2018)

• Change from Baseline in the Timed 10-Meter Walk Test (10-MWT) at Months 9 and 18 [ Time Frame: Baseline, Months 9 and 18 ]
  The 10-MWT is the time a participant takes to walk 10 meters (gait speed) without assistance from another person; ambulatory aids such as canes and walkers are permitted. The change in 10-MWT will be evaluated for ALN-TTRSC02 and compared to the placebo arm of the APOLLO study (NCT01960348).
• Change from Baseline in the Modified Body Mass Index (mBMI) at Months 9 and 18 [ Time Frame: Baseline, Months 9 and 18 ]
  The mBMI is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L). The change in mBMI will be evaluated for ALN-TTRSC02 and compared to the placebo arm of the APOLLO study (NCT01960348).
• Change from Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Months 9 and 18 [ Time Frame: Baseline, Months 9 and 18 ]
  The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in participants. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome. The change in R-ODS will be evaluated for ALN-TTRSC02 and compared to the placebo arm of the APOLLO study (NCT01960348).
• Percentage Reduction in Serum Transthyretin (TTR) Levels at Months 9 and 18 [ Time Frame: Baseline, Months 9 and 18 ]
  The percentage reduction in TTR levels will be evaluated for ALN-TTRSC02 and and compared to that in the patisiran-LNP arm.
• Frequency of All-Cause Deaths and/or All-Cause Hospitalizations Up to Month 18 [ Time Frame: Up to Month 18 ]
  The frequency of all-cause deaths and/or all-cause hospitalizations will be compared to the placebo arm of the APOLLO study (NCT01960348).
• Frequency of All-Cause Deaths and/or All-Cause Hospitalizations in Participants with Cardiac Involvement Up to Month 18 [ Time Frame: Up to Month 18 ]
  The frequency of all-cause deaths and/or all-cause hospitalizations in participants with cardiac involvement will be compared to the placebo arm of the APOLLO study (NCT01960348).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: HELIOS-A: A Study of Vutrisiran (ALN-TTRSC02) in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis)
• Official Title: HELIOS-A: A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy and Safety of ALN-TTRSC02 in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis)
• Brief Summary: The purpose of this study is to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in patients with hereditary transthyretin amyloidosis (hATTR amyloidosis). Participants will receive vutrisiran or the reference comparator patisiran during the Treatment Period. The Treatment Period is followed by a Treatment Extension Period during which all participants in the patisiran group will switch to vutrisiran. This study will use the placebo arm of the APOLLO study (NCT01960348) as an external comparator for the primary and most other efficacy endpoints.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Amyloidosis, Hereditary
• Transthyretin Amyloidosis

Intervention

• Drug: Patisiran
  Patisiran will be administered by intravenous (IV) infusion.
• Drug: Vutrisiran (ALN-TTRSC02)
  Vutrisiran will be administered by subcutaneous (SC) injection.

Study Arms

• Experimental: Vutrisiran (ALN-TTRSC02)
  Participants will receive vutrisiran during the Treatment and Treatment Extension Periods.
  Intervention: Drug: Vutrisiran (ALN-TTRSC02)
• Active Comparator: Patisiran
  Participants will receive patisiran during the Treatment Period and will switch to vutrisiran during the Treatment Extension Period.
  Interventions:

  • Drug: Patisiran
  • Drug: Vutrisiran (ALN-TTRSC02)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 16, 2020): 164
• Original Estimated Enrollment (submitted: November 28, 2018): 160
• Estimated Study Completion Date: May 2024
• Actual Primary Completion Date: November 10, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female of 18 to 85 years of age (inclusive);
• Has a diagnosis of hATTR amyloidosis with transthyretin (TTR) mutation;
• Has adequate neurologic impairment score (NIS);
• Has adequate polyneuropathy disability (PND) score;
• Has adequate Karnofsky Performance Status (KPS).

Exclusion Criteria:

• Had a prior liver transplant or is likely to undergo liver transplantation during the study;
• Has known other (non-hATTR) forms of amyloidosis or leptomeningeal amyloidosis;
• Has New York Heart Association heart failure classification >2;
• Clinically significant liver function test abnormalities;
• Has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) infection;
• Received an experimental drug within 30 days of dosing;
• Received prior TTR-lowering treatment;
• Has other known causes of neuropathy.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Cyprus, France, Germany, Greece, Italy, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, Portugal, Spain, Sweden, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03759379
• Other Study ID Numbers: ALN-TTRSC02-002; 2018-002098-23 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Alnylam Pharmaceuticals
• Study Sponsor: Alnylam Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Alnylam Pharmaceuticals

• PRS Account: Alnylam Pharmaceuticals
• Verification Date: March 2021