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

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)

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.

Study Overview

• Status: Completed
• Conditions: Amyloid Neuropathies; Amyloid Neuropathies, Familial; TTR-mediated Amyloidosis; Amyloidosis, Hereditary; Amyloidosis, Hereditary, Transthyretin-Related; Familial Amyloid Polyneuropathies
• Intervention / Treatment: Drug: patisiran (ALN-TTR02); Drug: Sterile Normal Saline (0.9% NaCl)

• Study Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Clinical Trial Site
• Australia
  • Westmead, Australia
    • Clinical Trial Site
• Brazil
  • Ribeirao Preto, Brazil
    • Clinical Trial Site
  • Rio de Janeiro, Brazil
    • Clinical Trial Site
  • Sao Paulo, Brazil
    • Clinical Trial Site
• Bulgaria
  • Sofia, Bulgaria
    • Clinical Trial Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Clinical Trial Site
• Cyprus
  • Nicosia, Cyprus
    • Clinical Trial Site
• France
  • Bourdeaux, France
    • Clinical Trial Site
  • Creteil, France
    • Clinical Trial Site
  • Le Kremlin-bicetre, France
    • Clinical Trial Site
  • Lille Cedex, France
    • Clinical Trial Site
  • Marseille Cedex, France
    • Clinical Trial Site
• Germany
  • Heidelberg, Germany
    • Clinical Trial Site
  • Muenster, Germany
    • Clinical Trial Site
  • Regensburg, Germany
    • Clinical Trial Site
• Italy
  • Pavia, Italy
    • Clinical Trial Site
  • Rome, Italy
    • Clinical Trial Site
  • Sicily, Italy
    • Clinical Trial Site
• Japan
  • Aichi, Japan
    • Clinical Trial Site
  • Kumamoto, Japan
    • Clinical Trial Site
  • Nagano
    • Matsumoto, Nagano, Japan
      • Clinical Trial Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 135-710
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 143-729
    • Clinical Trial Site
• Malaysia
  • Kuala Lumpur, Malaysia
    • Clinical Trial Site
• Mexico
  • Mexico City, Mexico
    • Clinical Trial Site
• Netherlands
  • Groningen, Netherlands
    • Clinical Trial Site
• Portugal
  • Lisbon, 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
  • Palma De Mallorca, Spain
    • Clinical Trial Site
• Sweden
  • Umeå, Sweden
    • Clinical Trial Site
• Taiwan
  • Taipai, Taiwan, 11217
    • Clinical Trial Site
  • Taipei, Taiwan, 10002
    • Clinical Trial Site
• Turkey
  • Istanbul, Turkey
    • Clinical Trial Site
• United Kingdom
  • London, United Kingdom, NW32PF
    • Clinical Trial Site
  • London, United Kingdom, SW17 0RE
    • Clinical Trial Site
• United States
  • California
    • La Mesa, California, United States
      • Clinical Trial Site
    • Orange, California, United States
      • Clinical Trial Site
  • Colorado
    • Denver, Colorado, United States
      • Clinical Trial Site
  • Illinois
    • Chicago, Illinois, United States
      • Clinical Trial Site
  • Maryland
    • Baltimore, Maryland, United States
      • Clinical Trial Site
  • Massachusetts
    • Boston, Massachusetts, United States
      • Clinical Trial Site
  • Michigan
    • Detroit, Michigan, United States
      • Clinical Trial Site
  • Minnesota
    • Rochester, Minnesota, United States
      • Clinical Trial Site
  • Missouri
    • Saint Louis, Missouri, United States
      • Clinical Trial Site
  • New York
    • New York, New York, United States, 10032
      • Clinical Trial Site
    • New York, New York, United States, 10029
      • Clinical Trial Site
  • North Carolina
    • Durham, North Carolina, United States
      • Clinical Trial Site
  • Oregon
    • Portland, Oregon, United States
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sterile Normal Saline (0.9% NaCl)	Drug: Sterile Normal Saline (0.9% NaCl); administered by intravenous (IV) infusion
Active Comparator: patisiran (ALN-TTR02)	Drug: patisiran (ALN-TTR02); administered by intravenous (IV) infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	18mo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	18mo
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.	18mo
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.	18mo
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.	18mo
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).	18mo
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.	18mo

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Jared Gollob, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: October 9, 2013
• First Submitted That Met QC Criteria: October 9, 2013
• First Posted (Estimated): October 10, 2013

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: TTR; Amyloidosis; RNAi therapeutic; Transthyretin; FAP; Familial Amyloid Polyneuropathy
• 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; Amyloidosis; Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Amyloidosis, Familial
• Other Study ID Numbers: ALN-TTR02-004; 2013-002987-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.