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

Primary Purpose

Amyloidosis, Hereditary, Transthyretin Amyloidosis

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Patisiran
Vutrisiran
Sponsored by
Alnylam Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyloidosis, Hereditary

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Vutrisiran + Vutrisiran (HELIOS-A)

Patisiran + Vutrisiran (HELIOS-A)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
November 28, 2018
Last Updated
October 20, 2023
Sponsor
Alnylam Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT03759379
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)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 14, 2019 (Actual)
Primary Completion Date
November 10, 2020 (Actual)
Study Completion Date
October 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alnylam Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyloidosis, Hereditary, Transthyretin Amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
164 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vutrisiran + Vutrisiran (HELIOS-A)
Arm Type
Experimental
Arm Description
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.
Arm Title
Patisiran + Vutrisiran (HELIOS-A)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Patisiran
Other Intervention Name(s)
ONPATTRO, ALN-TTR02
Intervention Description
Patisiran will be administered by IV infusion.
Intervention Type
Drug
Intervention Name(s)
Vutrisiran
Other Intervention Name(s)
ALN-TTRSC02, AMVUTTRA
Intervention Description
Vutrisiran will be administered by SC injection.
Primary Outcome Measure Information:
Title
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)]
Description
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.
Time Frame
Baseline, Month 9
Secondary Outcome Measure Information:
Title
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)]
Description
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.
Time Frame
Baseline, Month 9
Title
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)]
Description
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.
Time Frame
Baseline, Month 9
Title
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)]
Description
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.
Time Frame
Baseline, Month 18
Title
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)]
Description
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.
Time Frame
Baseline, Month 18
Title
Change From Baseline in the 10-MWT at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
Description
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.
Time Frame
Baseline, Month 18
Title
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)]
Description
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.
Time Frame
Baseline, Month 18
Title
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)]
Description
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.
Time Frame
Baseline, Month 18
Title
Percent Reduction in Serum Transthyretin (TTR) Levels Through Month 18 Between the Vutrisiran Group (HELIOS-A) and the Patisiran Group (HELIOS-A)
Description
Serum TTR was assessed at multiple timepoints up to Month 18.
Time Frame
Up to Month 18

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Alnylam Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
San Diego
State/Province
California
ZIP/Postal Code
92120
Country
United States
Facility Name
Clinical Trial Site
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Clinical Trial Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
97239
Country
United States
Facility Name
Clinical Trial Site
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Clinical Trial Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Clinical Trial Site
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Clinical Trial Site
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63130
Country
United States
Facility Name
Clinical Trial Site
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Clinical Trial Site
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Clinical Trial Site
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Clinical Trial Site
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Clinical Trial Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
Clinical Trial Site
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
Clinical Trial Site
City
Buenos Aires
Country
Argentina
Facility Name
Clinical Trial Site
City
Box Hill
Country
Australia
Facility Name
Clinical Trial Site
City
Westmead
Country
Australia
Facility Name
Clinical Trial Site
City
Woolloongabba
Country
Australia
Facility Name
Clinical Trial Site
City
Bruxelles
Country
Belgium
Facility Name
Clinical Trial Site
City
Leuven
Country
Belgium
Facility Name
Clinical Trial Site
City
Rio De Janeiro
Country
Brazil
Facility Name
Clinical Trial Site
City
Sofia
Country
Bulgaria
Facility Name
Clinical Trial Site
City
Montréal
Country
Canada
Facility Name
Clinical Trial Site
City
Vancouver
Country
Canada
Facility Name
Clinical Trial Site
City
Nicosia
Country
Cyprus
Facility Name
Clinical Trial Site
City
Bordeaux
Country
France
Facility Name
Clinical Trial Site
City
Créteil
Country
France
Facility Name
Clinical Trial Site
City
Marseille
Country
France
Facility Name
Clinical Trial Site
City
Paris
Country
France
Facility Name
Clinical Trial Site
City
Mainz
Country
Germany
Facility Name
Clinical Trial Site
City
Münster
Country
Germany
Facility Name
Clinical Trial Site
City
Athens
Country
Greece
Facility Name
Clinical Trial Site
City
Messina
Country
Italy
Facility Name
Clinical Trial Site
City
Milano
Country
Italy
Facility Name
Clinical Trial Site
City
Pavia
Country
Italy
Facility Name
Clinical Trial Site
City
Rome
Country
Italy
Facility Name
Clinical Trial Site
City
Kumamoto
Country
Japan
Facility Name
Clinical Trial Site
City
Nagano
Country
Japan
Facility Name
Clinical Trial Site
City
Nagoya
Country
Japan
Facility Name
Clinical Trial Site
City
Osaka
Country
Japan
Facility Name
Clinical Trial Site
City
Junggu
Country
Korea, Republic of
Facility Name
Clinical Trial Site
City
Kuala Lumpur
Country
Malaysia
Facility Name
Clinical Trial Site
City
Mexico City
Country
Mexico
Facility Name
Clinical Trial Site
City
Groningen
Country
Netherlands
Facility Name
Clinical Trial Site
City
Lisboa
Country
Portugal
Facility Name
Clinical Trial Site
City
Porto
Country
Portugal
Facility Name
Clinical Trial Site
City
Barcelona
Country
Spain
Facility Name
Clinical Trial Site
City
Huelva
Country
Spain
Facility Name
Clinical Trial Site
City
Madrid
Country
Spain
Facility Name
Clinical Trial Site
City
Valencia
Country
Spain
Facility Name
Clinical Trial Site
City
Solna
Country
Sweden
Facility Name
Clinical Trial Site
City
Umeå
Country
Sweden
Facility Name
Clinical Trial Site
City
Taipei City
Country
Taiwan
Facility Name
Clinical Trial Site
City
Taipei
Country
Taiwan
Facility Name
Clinical Trial Site
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35875890
Citation
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.
Results Reference
derived

Learn more about this trial

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

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