Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Neurology
Published in: BMC Neurology 1/2017

Open Access 01-12-2017 | Study protocol

Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy

Authors: David Adams, Ole B. Suhr, Peter J. Dyck, William J. Litchy, Raina G. Leahy, Jihong Chen, Jared Gollob, Teresa Coelho

Published in: BMC Neurology | Issue 1/2017

Login to get access

Abstract

Background

Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality.

Methods

Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18–85 years old with hATTR amyloidosis, investigator-estimated survival of ≥2 years, Neuropathy Impairment Score (NIS) of 5–130, and polyneuropathy disability score ≤IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study.

Discussion

APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease.

Trial registration

This trial is registered at clinicaltrials.gov (NCT01960348); October 9, 2013.
Literature
1.
2.
Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625–38.CrossRefPubMedPubMedCentral
3.
Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63–76.
4.
Mohty D, Damy T, Cosnay P, Echahidi N, Casset-Senon D, Virot P, Jaccard A. Cardiac amyloidosis: updates in diagnosis and management. Arch Cardiovasc Dis. 2013;106(10):528–40.CrossRefPubMed
5.
Conceicao I, Gonzalez-Duarte A, Obici L, Schmidt HH, Simoneau D, Ong ML, Amass L. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5–9.CrossRefPubMedPubMedCentral
6.
7.
Coutinho P, DeSilva A, Lima J, Barbosa A. Forty years of experience with type I amyloid neuropathy: review of 483 cases. In: Glenner G, Costa P, de Freitas A, editors. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica; 1980. pp. 88–98.
8.
Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, Lewis WD, Obici L, Plante-Bordeneuve V, Rapezzi C, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.CrossRefPubMedPubMedCentral
9.
Koike H, Tanaka F, Hashimoto R, Tomita M, Kawagashira Y, Iijima M, Fujitake J, Kawanami T, Kato T, Yamamoto M, et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas. J Neurol Neurosurg Psychiatry. 2012;83(2):152–8.CrossRefPubMed
10.
Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10(12):1086–97.
11.
Benson MD, Teague SD, Kovacs R, Feigenbaum H, Jung J, Kincaid JC. Rate of progression of transthyretin amyloidosis. Am J Cardiol. 2011;108(2):285–9.CrossRefPubMed
12.
Mariani LL, Lozeron P, Theaudin M, Mincheva Z, Signate A, Ducot B, Algalarrondo V, Denier C, Adam C, Nicolas G, et al. Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol. 2015;78(6):901–16.CrossRefPubMedPubMedCentral
13.
Sattianayagam PT, Hahn AF, Whelan CJ, Gibbs SD, Pinney JH, Stangou AJ, Rowczenio D, Pflugfelder PW, Fox Z, Lachmann HJ, et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012;33(9):1120–7.CrossRefPubMed
14.
Rowczenio DM, Noor I, Gillmore JD, Lachmann HJ, Whelan C, Hawkins PN, Obici L, Westermark P, Grateau G, Wechalekar AD. Online registry for mutations in hereditary amyloidosis including nomenclature recommendations. Hum Mutat. 2014;35(9):E2403–12.CrossRefPubMed
15.
16.
Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, Judge DP, Lenihan DJ, Gottlieb SS, Shah SJ, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161–72.
17.
Suanprasert N, Berk JL, Benson MD, Dyck PJ, Klein CJ, Gollob JA, Bettencourt BR, Karsten V, Dyck PJ. Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. J Neurol Sci. 2014;344(1–2):121–8.CrossRefPubMed
18.
Andrade C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain. 1952;75(3):408–27.CrossRefPubMed
19.
Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Plante-Bordeneuve V, Lozeron P, Suhr OB, Campistol JM, Conceicao IM, Schmidt HH, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785–92.CrossRefPubMedPubMedCentral
20.
Vinik EJ, Vinik AI, Paulson JF, Merkies IS, Packman J, Grogan DR, Coelho T. Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2014;19(2):104–14.CrossRefPubMed
21.
Coelho T, Vinik A, Vinik EJ, Tripp T, Packman J, Grogan DR. Clinical measures in transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2017;55(3):323–32.CrossRefPubMed
22.
Inês M, Coelho T, Conceição I, Ferreira L, de Carvalho M, Costa J. Transthyretin familial amyloid polyneuropathy impact on health-related quality of life. Orphanet J Rare Dis. 2015;10(Supp. 1):O28.
23.
Wixner J, Mundayat R, Karayal ON, Anan I, Karling P, Suhr OB, THAOS investigators. THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease. Orphanet J Rare Dis. 2014;9:61.CrossRefPubMedPubMedCentral
24.
Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD, Litchy WJ, Wiesman JF, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658–67.CrossRefPubMedPubMedCentral
25.
Mita S, Maeda S, Shimada K, Araki S. Analyses of prealbumin mRNAs in individuals with familial amyloidotic polyneuropathy. J Biochem. 1986;100(5):1215–22.CrossRefPubMed
26.
Holmgren G, Steen L, Ekstedt J, Groth CG, Ericzon BG, Eriksson S, Andersen O, Karlberg I, Norden G, Nakazato M, et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet. 1991;40(3):242–6.CrossRefPubMed
27.
Adams D, Samuel D, Goulon-Goeau C, Nakazato M, Costa PM, Feray C, Plante V, Ducot B, Ichai P, Lacroix C, et al. The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. Brain. 2000;123(Pt 7):1495–504.CrossRefPubMed
28.
Ericzon BG, Wilczek HE, Larsson M, Wijayatunga P, Stangou A, Pena JR, Furtado E, Barroso E, Daniel J, Samuel D, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation. 2015;99(9):1847–54.CrossRefPubMed
29.
Suhr OB, Larsson M, Ericzon BG, Wilczek HE, on behalf of the FAPWTRʼs investigators. Survival after transplantation in patients with mutations other than Val30Met: extracts from the FAP World Transplant Registry. Transplantation. 2016;100(2):373–81.
30.
Carvalho A, Rocha A, Lobato L. Liver transplantation in transthyretin amyloidosis: issues and challenges. Liver Transpl. 2015;21(3):282–92.CrossRefPubMed
31.
Adams D, Buades J, Suhr O, Obici L, Coelho T. Preliminary assessment of neuropathy progression in patients with hereditary ATTR amyloidosis after orthotopic liver transplantation. Orphanet J Rare Dis. 2015;10(Suppl. 1):P19.CrossRefPubMedCentral
32.
33.
34.
35.
Coelho T, Maia LF, da Silva AM, Cruz MW, Plante-Bordeneuve V, Suhr OB, Conceicao I, Schmidt HH, Trigo P, Kelly JW, et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013;260(11):2802–14.CrossRefPubMedPubMedCentral
36.
Plante-Bordeneuve V, Gorram F, Salhi H, Nordine T, Ayache SS, Le Corvoisier P, Azoulay D, Feray C, Damy T, Lefaucheur JP. Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study. J Neurol. 2017;264(2):268–76.
37.
Cortese A, Vita G, Luigetti M, Russo M, Bisogni G, Sabatelli M, Manganelli F, Santoro L, Cavallaro T, Fabrizi GM, et al. Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area. J Neurol. 2016;263(5):916–24.CrossRefPubMed
38.
Lozeron P, Theaudin M, Mincheva Z, Ducot B, Lacroix C, Adams D, French Network for FAP (CORNAMYL). Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy. Eur J Neurol. 2013;20(12):1539–45.CrossRefPubMed
39.
Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, Perez J, Chiesa J, Warrington S, Tranter E, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819–29.CrossRefPubMed
40.
Okamoto S, Wixner J, Obayashi K, Ando Y, Ericzon BG, Friman S, Uchino M, Suhr OB. Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 2009;15(10):1229–35.CrossRefPubMed
41.
Tashima K, Ando Y, Terazaki H, Yoshimatsu S, Suhr OB, Obayashi K, Yamashita T, Ando E, Uchino M, Ando M. Outcome of liver transplantation for transthyretin amyloidosis: follow-up of Japanese familial amyloidotic polyneuropathy patients. J Neurol Sci. 1999;171(1):19–23.CrossRefPubMed
42.
Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid a protein. Lancet. 2001;358(9275):24–9.CrossRefPubMed
43.
Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR, Pepys MB, Hawkins PN. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol. 2003;122(1):78–84.CrossRefPubMed
44.
Gillmore JD, Stangou AJ, Tennent GA, Booth DR, O'Grady J, Rela M, Heaton ND, Wall CA, Keogh JA, Hawkins PN. Clinical and biochemical outcome of hepatorenal transplantation for hereditary systemic amyloidosis associated with apolipoprotein AI Gly26Arg. Transplantation. 2001;71(7):986–92.CrossRefPubMed
45.
Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, Schmidt H, Waddington-Cruz M, Campistol JM, Bettencourt BR, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.CrossRefPubMedPubMedCentral
46.
Suhr O, Adams D, Coelho T, Waddington Cruz M, Schmidt H, Buades J, Campistol J, Pouget J, Berk J, Polydefkis M, et al. Phase 2 open-label extension study of patisiran, an investigational RNAi therapeutic for the tereatment of hereditary ATTR amyloidosis with polyneuropathy. In: The XVth International Symposium on Amyloidosis (International Society of Amyloidosis) Uppsala: Abstract PA80; 2016.
47.
Adams D, Coelho T, Obici L, Merlini G, Mincheva Z, Suanprasert N, Bettencourt BR, Gollob JA, Gandhi PJ, Litchy WJ, et al. Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study. Neurology. 2015;85(8):675–82.CrossRefPubMedPubMedCentral
48.
Dyck PJ, Herrmann DN, Staff NP, Dyck PJ. Assessing decreased sensation and increased sensory phenomena in diabetic polyneuropathies. Diabetes. 2013;62(11):3677–86.CrossRefPubMedPubMedCentral
49.
Vinik EJ, Hayes RP, Oglesby A, Bastyr E, Barlow P, Ford-Molvik SL, Vinik AI. The development and validation of the Norfolk QOL-DN, a new measure of patients' perception of the effects of diabetes and diabetic neuropathy. Diabetes Technol Ther. 2005;7(3):497–508.CrossRefPubMed
50.
EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16:199–208.
51.
Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated composite autonomic symptom score. Mayo Clin Proc. 2012;87(12):1196–201.CrossRefPubMedPubMedCentral
52.
van Nes SI, Vanhoutte EK, van Doorn PA, Hermans M, Bakkers M, Kuitwaard K, Faber CG, Merkies IS. Rasch-built overall disability scale (R-ODS) for immune-mediated peripheral neuropathies. Neurology. 2011;76(4):337–45.CrossRefPubMed
53.
Suhr O, Danielsson A, Holmgren G, Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J Intern Med. 1994;235(5):479–85.CrossRefPubMed
54.
Backonja MM, Attal N, Baron R, Bouhassira D, Drangholt M, Dyck PJ, Edwards RR, Freeman R, Gracely R, Haanpaa MH, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain. 2013;154(9):1807–19.CrossRefPubMed
55.
Cruz-Almeida Y, Fillingim RB. Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Med. 2014;15(1):61–72.CrossRefPubMed
56.
Dyck PJ, Kincaid JC, Dyck PJB, Chaudhry V, Goyal NA, Alves C, Salhi H, Wiesman JF, Labeyrie C, Robinson-Papp J, et al. Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial. Muscle Nerve. 2017. doi:10.​1002/​mus.​25563. [Epub ahead of print].
57.
Lanier JB, Mote MB, Clay EC. Evaluation and management of orthostatic hypotension. Am Fam Physician. 2011;84(5):527–36.PubMed
58.
Dyck PJ, Overland CJ, Low PA, Litchy WJ, Davies JL, Dyck PJ, O'Brien PC, Cl vs. NPhys Trial Investigators, Albers JW, Andersen H, et al. Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial. Muscle Nerve. 2010;42(2):157–64.CrossRefPubMed
59.
Dyck PJ, Overland CJ, Low PA, Litchy WJ, Davies JL, Dyck PJ, Carter RE, Melton LJ, Andersen H, Albers JW, et al. “Unequivocally abnormal” vs “usual” signs and symptoms for proficient diagnosis of diabetic polyneuropathy: Cl vs N Phys trial. Arch Neurol. 2012;69(12):1609–14.
60.
Dyck PJ, Albers JW, Wolfe J, Bolton CF, Walsh N, Klein CJ, Zafft AJ, Russell JW, Thomas K, Davies JL, et al. A trial of proficiency of nerve conduction: greater standardization still needed. Muscle Nerve. 2013;48(3):369–74.CrossRefPubMedPubMedCentral
61.
Litchy WJ, Albers JW, Wolfe J, Bolton CF, Walsh N, Klein CJ, Zafft AJ, Russell JW, Zwirlein M, Overland CJ, et al. Proficiency of nerve conduction using standard methods and reference values (cl. NPhys trial 4). Muscle Nerve. 2014;50(6):900–8.CrossRefPubMedPubMedCentral
62.
Dyck PJ, Argyros B, Russell JW, Gahnstrom LE, Nalepa S, Albers JW, Lodermeier KA, Zafft AJ, Dyck PJ, Klein CJ, et al. Multicenter trial of the proficiency of smart quantitative sensation tests. Muscle Nerve. 2014;49(5):645–53.CrossRefPubMedPubMedCentral
63.
Li H, Schwartz J, Keohane D. Impact of baseline neurologic score on disease progression in transthyretin familial amyloid polyneuropathy. In: International Society of Amyloidosis (ISA). Uppsala: Poster PB2; 2016.
64.
Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054–60.CrossRefPubMedPubMedCentral
65.
Shy ME, Chen L, Swan ER, Taube R, Krajewski KM, Herrmann D, Lewis RA, McDermott MP. Neuropathy progression in Charcot-Marie-tooth disease type 1A. Neurology. 2008;70(5):378–83.CrossRefPubMed
66.
Coelho T, Suhr O, Conceicao I, Waddington Cruz M, Schmidt H, Buades J, Campistol J, Pouget J, Berk J, Ziyadeh N, et al. Relationship between TTR knockdown and change in mNIS+7: preliminary correlation findings from the Phase 2 open-label extension study of patisiran, an investigational RNAi therapeutic for hereditary ATTR amyloidosis with polyneuropathy. In: The XVth International Symposium on Amyloidosis (Internation Society of Amyloidosis). Uppsala: Poster PA83; 2016.
67.
68.
Amyloidosis Foundation: Understanding the patient voice in hereditary transthyretin-mediated amyloidosis. Chicago: Amyloidosis Foundation & Amyloidosis Support Groups Annual Meeting; 2015.
69.
Pruppers MH, Merkies IS, Faber CG, Da Silva AM, Costa V, Coelho T. The Val30Met familial amyloid polyneuropathy specific Rasch-built overall disability scale (FAP-RODS(c)). J Peripher Nerv Syst. 2015;20(3):319–27.
70.
Chao CC, Huang CM, Chiang HH, Luo KR, Kan HW, Yang NC, Chiang H, Lin WM, Lai SM, Lee MJ, et al. Sudomotor innervation in transthyretin amyloid neuropathy: pathology and functional correlates. Ann Neurol. 2015;78(2):272–83.CrossRefPubMedPubMedCentral
Metadata
Title
Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy
Authors
David Adams
Ole B. Suhr
Peter J. Dyck
William J. Litchy
Raina G. Leahy
Jihong Chen
Jared Gollob
Teresa Coelho
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2017
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-017-0948-5

Other articles of this Issue 1/2017

BMC Neurology 1/2017 Go to the issue

Research article

Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy

Research article

Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study

Research article

Comparison of neuropsychiatric symptoms and diffusion tensor imaging correlates among patients with subcortical ischemic vascular disease and Alzheimer’s disease

Research article

Atrial fibrillation is not uncommon among patients with ischemic stroke and transient ischemic stroke in China

Research article

Comparative assessment of clinical rating scales in Wilson’s disease

Research article

Relationship between Azathioprine metabolites and therapeutic efficacy in Chinese patients with neuromyelitis optica spectrum disorders