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APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis

Primary Purpose

TTR-mediated Amyloidosis, Amyloidosis, Hereditary, Amyloid Neuropathies, Familial

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
patisiran (ALN-TTR02)
Sterile Normal Saline (0.9% NaCl)
Sponsored by
Alnylam Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for TTR-mediated Amyloidosis focused on measuring RNAi therapeutic, FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis

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);
  • Have a diagnosis of FAP
  • Neuropathy Impairment Score requirement of 5-130
  • Meet Karnofsky performance status requirements
  • Have adequate complete blood counts and liver function tests
  • Have adequate cardiac function
  • Have negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV)

Exclusion Criteria:

  • Had a prior liver transplant or is planned to undergo liver transplant during the study period;
  • Has untreated hypo- or hyperthyroidism;
  • Has known human immunodeficiency virus (HIV) infection;
  • Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated;
  • Recently received an investigational agent or device
  • Is currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

patisiran (ALN-TTR02)

Sterile Normal Saline (0.9% NaCl)

Arm Description

Outcomes

Primary Outcome Measures

Modified Neuropathy Impairment Score +7 (mNIS+7)
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mNIS+7 at 18 months. The mNIS+7 is a composite score that quantitates 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.

Secondary Outcome Measures

Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in Norfolk QoL-DN at 18 months. 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.
Neurological Impairment Score-Weakness (NIS-W) Score
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in NIS-W at 18 months. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome.
Rasch-built Overall Disability Scale (R-ODS) Score
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in R-ODS score at 18 months. The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in patients. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome.
Timed 10-meter Walk Test (10-MWT, Gait Speed)
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in 10-MWT at 18 months. Ability to ambulate (gait speed) was assessed through the 10-meter walk test (10-MWT). The walk had to be completed without assistance from another person; ambulatory aids such as canes and walkers were permitted.
Modified Body Mass Index (mBMI)
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mBMI at 18 months. The nutritional status of patients was evaluated using the mBMI; calculated as the product of BMI (weight in kilograms divided by the square of height in meters) and serum albumin (g/L).
Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31])
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in COMPASS 31 at 18 months. The COMPASS 31 is a measure of autonomic neuropathy symptoms. The questions evaluated 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome.

Full Information

First Posted
October 9, 2013
Last Updated
November 18, 2018
Sponsor
Alnylam Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01960348
Brief Title
APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis
Official Title
APOLLO: A Phase 3 Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Patisiran (ALN-TTR02) in Transthyretin (TTR)-Mediated Polyneuropathy (Familial Amyloidotic Polyneuropathy-FAP)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Completed
Study Start Date
November 2013 (undefined)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
August 2017 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety and efficacy of patisiran (ALN-TTR02) in patients with transthyretin (TTR) mediated amyloidosis. An open-label, single-arm, long-term follow-up extension study NCT02510261 (ALN-TTR02-006) was initiated to provide participants who completed this study with continued patisiran-LNP (lipid nanoparticle) treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
TTR-mediated Amyloidosis, Amyloidosis, Hereditary, Amyloid Neuropathies, Familial, Familial Amyloid Polyneuropathies, Amyloid Neuropathies, Amyloidosis, Hereditary, Transthyretin-Related
Keywords
RNAi therapeutic, FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
225 (Actual)

8. Arms, Groups, and Interventions

Arm Title
patisiran (ALN-TTR02)
Arm Type
Active Comparator
Arm Title
Sterile Normal Saline (0.9% NaCl)
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
patisiran (ALN-TTR02)
Intervention Description
administered by intravenous (IV) infusion
Intervention Type
Drug
Intervention Name(s)
Sterile Normal Saline (0.9% NaCl)
Intervention Description
administered by intravenous (IV) infusion
Primary Outcome Measure Information:
Title
Modified Neuropathy Impairment Score +7 (mNIS+7)
Description
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mNIS+7 at 18 months. The mNIS+7 is a composite score that quantitates 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.
Time Frame
18mo
Secondary Outcome Measure Information:
Title
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire
Description
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in Norfolk QoL-DN at 18 months. 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.
Time Frame
18mo
Title
Neurological Impairment Score-Weakness (NIS-W) Score
Description
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in NIS-W at 18 months. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome.
Time Frame
18mo
Title
Rasch-built Overall Disability Scale (R-ODS) Score
Description
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in R-ODS score at 18 months. The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in patients. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome.
Time Frame
18mo
Title
Timed 10-meter Walk Test (10-MWT, Gait Speed)
Description
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in 10-MWT at 18 months. Ability to ambulate (gait speed) was assessed through the 10-meter walk test (10-MWT). The walk had to be completed without assistance from another person; ambulatory aids such as canes and walkers were permitted.
Time Frame
18mo
Title
Modified Body Mass Index (mBMI)
Description
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mBMI at 18 months. The nutritional status of patients was evaluated using the mBMI; calculated as the product of BMI (weight in kilograms divided by the square of height in meters) and serum albumin (g/L).
Time Frame
18mo
Title
Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31])
Description
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in COMPASS 31 at 18 months. The COMPASS 31 is a measure of autonomic neuropathy symptoms. The questions evaluated 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome.
Time Frame
18mo

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); Have a diagnosis of FAP Neuropathy Impairment Score requirement of 5-130 Meet Karnofsky performance status requirements Have adequate complete blood counts and liver function tests Have adequate cardiac function Have negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV) Exclusion Criteria: Had a prior liver transplant or is planned to undergo liver transplant during the study period; Has untreated hypo- or hyperthyroidism; Has known human immunodeficiency virus (HIV) infection; Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated; Recently received an investigational agent or device Is currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jared Gollob
Organizational Affiliation
Alnylam Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
La Mesa
State/Province
California
Country
United States
Facility Name
Clinical Trial Site
City
Orange
State/Province
California
Country
United States
Facility Name
Clinical Trial Site
City
Denver
State/Province
Colorado
Country
United States
Facility Name
Clinical Trial Site
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Clinical Trial Site
City
Baltimore
State/Province
Maryland
Country
United States
Facility Name
Clinical Trial Site
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
Clinical Trial Site
City
Detroit
State/Province
Michigan
Country
United States
Facility Name
Clinical Trial Site
City
Rochester
State/Province
Minnesota
Country
United States
Facility Name
Clinical Trial Site
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
Clinical Trial Site
City
New York
State/Province
New York
ZIP/Postal Code
10029
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
Durham
State/Province
North Carolina
Country
United States
Facility Name
Clinical Trial Site
City
Portland
State/Province
Oregon
Country
United States
Facility Name
Clinical Trial Site
City
Buenos Aires
Country
Argentina
Facility Name
Clinical Trial Site
City
Westmead
Country
Australia
Facility Name
Clinical Trial Site
City
Ribeirao Preto
Country
Brazil
Facility Name
Clinical Trial Site
City
Rio de Janeiro
Country
Brazil
Facility Name
Clinical Trial Site
City
Sao Paulo
Country
Brazil
Facility Name
Clinical Trial Site
City
Sofia
Country
Bulgaria
Facility Name
Clinical Trial Site
City
Vancouver
State/Province
British Columbia
Country
Canada
Facility Name
Clinical Trial Site
City
Nicosia
Country
Cyprus
Facility Name
Clinical Trial Site
City
Bourdeaux
Country
France
Facility Name
Clinical Trial Site
City
Creteil
Country
France
Facility Name
Clinical Trial Site
City
Le Kremlin-bicetre
Country
France
Facility Name
Clinical Trial Site
City
Lille Cedex
Country
France
Facility Name
Clinical Trial Site
City
Marseille Cedex
Country
France
Facility Name
Clinical Trial Site
City
Heidelberg
Country
Germany
Facility Name
Clinical Trial Site
City
Muenster
Country
Germany
Facility Name
Clinical Trial Site
City
Regensburg
Country
Germany
Facility Name
Clinical Trial Site
City
Pavia
Country
Italy
Facility Name
Clinical Trial Site
City
Rome
Country
Italy
Facility Name
Clinical Trial Site
City
Sicily
Country
Italy
Facility Name
Clinical Trial Site
City
Matsumoto
State/Province
Nagano
Country
Japan
Facility Name
Clinical Trial Site
City
Aichi
Country
Japan
Facility Name
Clinical Trial Site
City
Kumamoto
Country
Japan
Facility Name
Clinical Trial Site
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
Clinical Trial Site
City
Seoul
ZIP/Postal Code
143-729
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
Lisbon
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
Palma De Mallorca
Country
Spain
Facility Name
Clinical Trial Site
City
Umeå
Country
Sweden
Facility Name
Clinical Trial Site
City
Taipai
ZIP/Postal Code
11217
Country
Taiwan
Facility Name
Clinical Trial Site
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
Clinical Trial Site
City
Istanbul
Country
Turkey
Facility Name
Clinical Trial Site
City
London
ZIP/Postal Code
NW32PF
Country
United Kingdom
Facility Name
Clinical Trial Site
City
London
ZIP/Postal Code
SW17 0RE
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
36120830
Citation
Quan D, Obici L, Berk JL, Ando Y, Aldinc E, White MT, Adams D. Impact of baseline polyneuropathy severity on patisiran treatment outcomes in the APOLLO trial. Amyloid. 2023 Mar;30(1):49-58. doi: 10.1080/13506129.2022.2118043. Epub 2022 Sep 18.
Results Reference
derived
PubMed Identifier
31322739
Citation
Zhang X, Goel V, Attarwala H, Sweetser MT, Clausen VA, Robbie GJ. Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis. J Clin Pharmacol. 2020 Jan;60(1):37-49. doi: 10.1002/jcph.1480. Epub 2019 Jul 19.
Results Reference
derived
PubMed Identifier
30878017
Citation
Minamisawa M, Claggett B, Adams D, Kristen AV, Merlini G, Slama MS, Dispenzieri A, Shah AM, Falk RH, Karsten V, Sweetser MT, Chen J, Riese R, Vest J, Solomon SD. Association of Patisiran, an RNA Interference Therapeutic, With Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis: The APOLLO Study. JAMA Cardiol. 2019 May 1;4(5):466-472. doi: 10.1001/jamacardio.2019.0849.
Results Reference
derived
PubMed Identifier
30586695
Citation
Solomon SD, Adams D, Kristen A, Grogan M, Gonzalez-Duarte A, Maurer MS, Merlini G, Damy T, Slama MS, Brannagan TH 3rd, Dispenzieri A, Berk JL, Shah AM, Garg P, Vaishnaw A, Karsten V, Chen J, Gollob J, Vest J, Suhr O. Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis. Circulation. 2019 Jan 22;139(4):431-443. doi: 10.1161/CIRCULATIONAHA.118.035831.
Results Reference
derived
PubMed Identifier
29972753
Citation
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP, Vita G, Attarian S, Plante-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH 3rd, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153.
Results Reference
derived
PubMed Identifier
28893208
Citation
Adams D, Suhr OB, Dyck PJ, Litchy WJ, Leahy RG, Chen J, Gollob J, Coelho T. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017 Sep 11;17(1):181. doi: 10.1186/s12883-017-0948-5.
Results Reference
derived

Learn more about this trial

APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis

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