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

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)

The purpose of this study is to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in participants with hereditary transthyretin amyloidosis (hATTR amyloidosis). Participants will receive vutrisiran subcutaneous (SC) injection once every 3 months (q3M) or the reference comparator patisiran intravenous (IV) injection once every 3 weeks (q3w) during the 18 month Treatment Period. This study will use the placebo arm of the APOLLO study (NCT01960348) as an external comparator for the primary and most other efficacy endpoints during the 18 Month Treatment Period. Following the 18 Month Treatment Period, all participants will be randomized to receive vutrisiran SC injection once every 6 months (q6M) or q3M in the Randomized Treatment Extension (RTE) Period.

Study Overview

• Status: Active, not recruiting
• Conditions: Transthyretin Amyloidosis; Amyloidosis, Hereditary
• Intervention / Treatment: Drug: Vutrisiran; Drug: Patisiran

• Study Type: Interventional
• Enrollment (Actual): 164
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Clinical Trial Site
• Australia
  • Box Hill, Australia
    • Clinical Trial Site
  • Westmead, Australia
    • Clinical Trial Site
  • Woolloongabba, Australia
    • Clinical Trial Site
• Belgium
  • Bruxelles, Belgium
    • Clinical Trial Site
  • Leuven, Belgium
    • Clinical Trial Site
• Brazil
  • Rio De Janeiro, Brazil
    • Clinical Trial Site
• Bulgaria
  • Sofia, Bulgaria
    • Clinical Trial Site
• Canada
  • Montréal, Canada
    • Clinical Trial Site
  • Vancouver, Canada
    • Clinical Trial Site
• Cyprus
  • Nicosia, Cyprus
    • Clinical Trial Site
• France
  • Bordeaux, France
    • Clinical Trial Site
  • Créteil, France
    • Clinical Trial Site
  • Marseille, France
    • Clinical Trial Site
  • Paris, France
    • Clinical Trial Site
• Germany
  • Mainz, Germany
    • Clinical Trial Site
  • Münster, Germany
    • Clinical Trial Site
• Greece
  • Athens, Greece
    • Clinical Trial Site
• Italy
  • Messina, Italy
    • Clinical Trial Site
  • Pavia, Italy
    • Clinical Trial Site
  • Rome, Italy
    • Clinical Trial Site
• Japan
  • Kumamoto, Japan
    • Clinical Trial Site
  • Nagano, Japan
    • Clinical Trial Site
  • Nagoya, Japan
    • Clinical Trial Site
  • Osaka, Japan
    • Clinical Trial Site
• Korea, Republic of
  • Junggu, Korea, Republic of
    • Clinical Trial Site
• Malaysia
  • Kuala Lumpur, Malaysia
    • Clinical Trial Site
• Mexico
  • Mexico City, Mexico
    • Clinical Trial Site
• Netherlands
  • Groningen, Netherlands
    • Clinical Trial Site
• Portugal
  • Lisboa, Portugal
    • Clinical Trial Site
  • Porto, Portugal
    • Clinical Trial Site
• Spain
  • Barcelona, Spain
    • Clinical Trial Site
  • Huelva, Spain
    • Clinical Trial Site
  • Madrid, Spain
    • Clinical Trial Site
  • Valencia, Spain
    • Clinical Trial Site
• Sweden
  • Solna, Sweden
    • Clinical Trial Site
  • Umeå, Sweden
    • Clinical Trial Site
• Taiwan
  • Taipei, Taiwan
    • Clinical Trial Site
  • Taipei City, Taiwan
    • Clinical Trial Site
• United Kingdom
  • London, United Kingdom
    • Clinical Trial Site
• United States
  • California
    • San Diego, California, United States, 92120
      • Clinical Trial Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Clinical Trial Site
  • Illinois
    • Chicago, Illinois, United States, 97239
      • Clinical Trial Site
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Clinical Trial Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Clinical Trial Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Clinical Trial Site
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Clinical Trial Site
  • New York
    • New York, New York, United States, 10032
      • Clinical Trial Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Clinical Trial Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Clinical Trial Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Clinical Trial Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Clinical Trial Site
  • Texas
    • Fort Worth, Texas, United States, 75246
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vutrisiran + Vutrisiran (HELIOS-A); Participants will receive vutrisiran 25 mg subcutaneous (SC) injection once every 3 months (q3M) for 18 months during the Treatment Period followed by vutrisiran SC injection once every 6 months (q6M) or q3M during the Randomized Treatment Extension (RTE) Period.	Drug: Vutrisiran; Vutrisiran will be administered by SC injection.; Other Names: ALN-TTRSC02; AMVUTTRA
Active Comparator: Patisiran + Vutrisiran (HELIOS-A); Participants will receive patisiran 0.3 mg/kg intravenous (IV) infusion once every 3 weeks (q3w) for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.	Drug: Vutrisiran; Vutrisiran will be administered by SC injection.; Other Names: ALN-TTRSC02; AMVUTTRA; Drug: Patisiran; Patisiran will be administered by IV infusion.; Other Names: ONPATTRO; ALN-TTR02

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	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 mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.	Baseline, Month 9

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	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 total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.	Baseline, Month 9
Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.	Baseline, Month 9
Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.	Baseline, Month 18
Change From Baseline in Norfolk QoL-DN Total Score at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	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 total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.	Baseline, Month 18
Change From Baseline in the 10-MWT at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.	Baseline, Month 18
Change From Baseline in the Modified Body Mass Index (mBMI) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	The mBMI, which is a measure of nutritional status, 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) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome.	Baseline, Month 18
Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]	The R-ODS is a patient-reported measure of level of disability on a scale of 0-48, with 0 being the worst and 48 the best (no limitations); scores are based on activities of daily living and social participation. An increase in R-ODS from baseline suggests improvement in disability, and a decrease from baseline suggests worsening of disability.	Baseline, Month 18
Percent Reduction in Serum Transthyretin (TTR) Levels Through Month 18 Between the Vutrisiran Group (HELIOS-A) and the Patisiran Group (HELIOS-A)	Serum TTR was assessed at multiple timepoints up to Month 18.	Up to Month 18

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Adams D, Tournev IL, Taylor MS, Coelho T, Plante-Bordeneuve V, Berk JL, Gonzalez-Duarte A, Gillmore JD, Low SC, Sekijima Y, Obici L, Chen C, Badri P, Arum SM, Vest J, Polydefkis M; HELIOS-A Collaborators. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2023 Mar;30(1):1-9. doi: 10.1080/13506129.2022.2091985. Epub 2022 Jul 23.

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2019
• Primary Completion (Actual): November 10, 2020
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: November 28, 2018
• First Submitted That Met QC Criteria: November 28, 2018
• First Posted (Actual): November 30, 2018

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Amyloid Neuropathies; Amyloidosis; Amyloid Neuropathies, Familial; Amyloidosis, Familial
• Other Study ID Numbers: ALN-TTRSC02-002; 2018-002098-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No