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Neurotherapeutics
Published in: Neurotherapeutics 2/2015

01-04-2015 | Review

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Authors: Katharine A. Nicholson, Merit E. Cudkowicz, James D. Berry

Published in: Neurotherapeutics | Issue 2/2015

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Abstract

The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.
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Literature
1.
Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435-442.PubMedCentralPubMedCrossRef
2.
3.
4.
Bensimon G, Lacomblez L, Delumeau JC, Bejuit R, Truffinet P, Meininger V. A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol 2002;249:609-615.PubMedCrossRef
5.
Paganoni S, Macklin EA, Lee A, Murphy A, Chang J, Zipf A, et al. Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Frontotemporal Degener 2014;15:453-456.PubMedCrossRef
6.
Miller TM, Smith RA, Kordasiewicz H, Kaspar BK. Gene-targeted therapies for the central nervous system. Arch Neurol 2008;65:447-451.PubMedCrossRef
7.
Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A 2013;110:E4530-E4539.PubMedCentralPubMedCrossRef
8.
Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, et al. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010;9:481-488.PubMedCentralPubMedCrossRef
9.
Miller RG, Moore DH, Forshew DA, Katz JS, Barohn RJ, Valan M, et al. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology 2011;77:973-979.PubMedCentralPubMedCrossRef
10.
van der Ploeg RJ, Oosterhuis HJ, Reuvekamp J. Measuring muscle strength. J Neurol 1984;231:200-203.PubMedCrossRef
11.
Hoagland RJ, Mendoza M, Armon C, Barohn RJ, Bryan WW, Goodpasture JC, et al. Reliability of maximal voluntary isometric contraction testing in a multicenter study of patients with amyotrophic lateral sclerosis. Syntex/Synergen Neuroscience Joint Venture rhCNTF ALS Study Group. Muscle Nerve 1997;20:691-695.PubMedCrossRef
12.
Visser J, Mans E, de Visser M, van den Berg-Vos RM, Franssen H, de Jong JM, et al. Comparison of maximal voluntary isometric contraction and hand-held dynamometry in measuring muscle strength of patients with progressive lower motor neuron syndrome. Neuromuscul Disord 2003;13:744-750.PubMedCrossRef
13.
Jette AM. Toward a common language for function, disability, and health. Phys Ther 2006;86:726-734.PubMedCrossRef
14.
Berry JD, Cudkowicz ME, Shefner JM. Predicting success: Optimizing phase II ALS trials for the transition to phase III. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:1-8.PubMedCrossRef
15.
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89-95.CrossRef
16.
17.
Sussmuth SD, Brettschneider J, Ludolph AC, Tumani H. Biochemical markers in CSF of ALS patients. Curr Med Chem 2008;15:1788-1801.PubMedCrossRef
18.
Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 2009;8:94-109.PubMedCrossRef
19.
Reijn TS, Abdo WF, Schelhaas HJ, Verbeek MM. CSF neurofilament protein analysis in the differential diagnosis of ALS. J Neurol 2009;256:615-619.PubMedCrossRef
20.
Brettschneider J, Petzold A, Sussmuth SD, Ludolph AC, Tumani H. Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology 2006;66:852-856.PubMedCrossRef
21.
Boylan K, Yang C, Crook J, Overstreet K, Heckman M, Wang Y, et al. Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker. J Neurochem 2009;111:1182-1191.PubMedCrossRef
22.
Boylan KB, Glass JD, Crook JE, Yang C, Thomas CS, Desaro P, et al. Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013;84:467-472.PubMedCrossRef
23.
Ganesalingam J, An J, Shaw CE, Shaw G, Lacomis D, Bowser R. Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem 2011;117:528-537.PubMedCentralPubMedCrossRef
24.
Levine TD, Bowser R, Hank NC, Gately S, Stephan D, Saperstein DS, et al. A pilot trial of pioglitazone HCl and tretinoin in ALS: Cerebrospinal fluid biomarkers to monitor drug efficacy and predict rate of disease progression. Neurol Res Int 2012;2012:582075.PubMedCentralPubMedCrossRef
25.
Lu CH, Petzold A, Topping J, Allen K, Macdonald-Wallis C, Clarke J, et al. Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: Insights from a longitudinal study. J Neurol Neurosurg Psychiatry 2014 Jul 9 [Epub ahead of print].
26.
Steinacker P, Fang L, Kuhle J, Petzold A, Tumani H, Ludolph AC, et al. Soluble beta-amyloid precursor protein is related to disease progression in amyotrophic lateral sclerosis. PLoS One 2011;6:e23600.PubMedCentralPubMedCrossRef
27.
Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 1996;67:2013-2018.PubMedCrossRef
28.
Zetterberg H, Pedersen M, Lind K, Svensson M, Rolstad S, Eckerström C, et al. Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years. J Alzheimers Dis 2007;12:255-260.PubMed
29.
Tortelli R, Ruggieri M, Cortese R, D'Errico E, Capozzo R, Leo A, et al. Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol 2012;19:1561-1567.PubMedCrossRef
30.
Gaiottino J, Norgren N, Dobson R, Topping J, Nissim A, Malaspina A, et al. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One 2013;8:e75091.PubMedCentralPubMedCrossRef
31.
Tortelli R, Copetti M, Ruggieri M, Cortese R, Capozzo R, Leo A, et al. Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis. Eur J Neurol 2015;22:215-218.PubMedCrossRef
32.
Zoccolella S, Simone IL, Capozzo R, Tortelli R, Leo A, D'Errico E, et al. An exploratory study of serum urate levels in patients with amyotrophic lateral sclerosis. J Neurol 2011;258:238-243.PubMedCrossRef
33.
Ikeda K, Hirayama T, Takazawa T, Kawabe K, Iwasaki Y. Relationships between disease progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with amyotrophic lateral sclerosis: A cross-sectional study. Intern Med 2012;51:1501-1508.PubMedCrossRef
34.
Paganoni S, Zhang M, Quiroz Zarate A, Jaffa M, Yu H, Cudkowicz ME, et al. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol 2012;259:1923-1928.PubMedCentralPubMedCrossRef
35.
Keizman D, Ish-Shalom M, Berliner S, Maimon N, Vered Y, Artamonov I, et al. Low uric acid levels in serum of patients with ALS: Further evidence for oxidative stress? J Neurol Sci 2009;285:95-99.PubMedCrossRef
36.
Abraham A, Drory VE. Influence of serum uric acid levels on prognosis and survival in amyotrophic lateral sclerosis: a meta-analysis. J Neurol 2014;261:1133-1138.PubMedCrossRef
37.
Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med 2013;5:64-79.PubMedCentralPubMedCrossRef
38.
Zhao W, Beers DR, Liao B, Henkel JS, Appel SH. Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis 2012;48:418-428.PubMedCentralPubMedCrossRef
39.
Koval ED, Shaner C, Zhang P, du Maine X, Fischer K, Tay J, et al. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet 2013;22:4127-4135.PubMedCentralPubMedCrossRef
40.
Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 2012;122:3063-3087.PubMedCentralPubMedCrossRef
41.
Parisi C, Arisi I, D'Ambrosi N, Storti AE, Brandi R, D'Onofrio M, et al. Dysregulated microRNAs in amyotrophic lateral sclerosis microglia modulate genes linked to neuroinflammation. Cell Death Dis 2013;4:e959.PubMedCentralPubMedCrossRef
42.
Miller TM, Kaspar BK, Kops GJ, Yamanaka K, Christian LJ, Gage FH, et al. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Ann Neurol 2005;57:773-776.PubMedCentralPubMedCrossRef
43.
Towne C, Raoul C, Schneider BL, Aebischer P. Systemic AAV6 delivery mediating RNA interference against SOD1: neuromuscular transduction does not alter disease progression in fALS mice. Mol Ther 2008;16:1018-1025.PubMedCrossRef
44.
Mann DM, Rollinson S, Robinson A, Bennion Callister J, Thompson JC, Snowden JS, et al. Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 2013;1:68.PubMedCentralPubMedCrossRef
45.
Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339:1335-1338.PubMedCrossRef
46.
Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 2014;83:1043-1050.PubMedCrossRef
47.
Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013;77:639-646.PubMedCentralPubMedCrossRef
48.
Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O'Neill MA, et al. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc Natl Acad Sci U S A 2014;111:3620-3625.PubMedCentralPubMedCrossRef
49.
Münch C, O'Brien J, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci U S A 2011;108:3548-3553.PubMedCentralPubMedCrossRef
50.
Winer L, Srinivasan D, Chun S, Lacomis D, Jaffa M, Fagan A, et al. SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol 2013;70:201-207.PubMedCrossRef
51.
Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008;321:1218-1221.PubMedCrossRef
52.
Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 2014;7:1-11.PubMedCentralPubMedCrossRef
53.
Andres PL, Skerry LM, Munsat TL, Thornell BJ, Szymonifka J, Schoenfeld DA, et al. Validation of a new strength measurement device for amyotrophic lateral sclerosis clinical trials. Muscle Nerve 2012;45:81-85.PubMedCrossRef
54.
Shefner JM, Cudkowicz ME, Zhang H, Schoenfeld D, Jillapalli D, Northeast ALSC. The use of statistical MUNE in a multicenter clinical trial. Muscle Nerve 2004;30:463-469.PubMedCrossRef
55.
Shefner JM, Cudkowicz ME, Zhang H, Schoenfeld D, Jillapalli D, Northeast ALSC. Revised statistical motor unit number estimation in the Celecoxib/ALS trial. Muscle Nerve 2007;35:228-234.PubMedCrossRef
56.
Shefner JM, Watson ML, Simionescu L, Caress JB, Burns TM, Maragakis NJ, et al. Multipoint incremental motor unit number estimation as an outcome measure in ALS. Neurology 2011;77:235-241.PubMedCentralPubMedCrossRef
57.
58.
Rutkove SB, Caress JB, Cartwright MS, Burns TM, Warder J, David WS, et al. Electrical impedance myography as a biomarker to assess ALS progression. Amyotroph Lateral Scler 2012;13:439-445.PubMedCentralPubMedCrossRef
59.
Cosottini M, Giannelli M, Siciliano G, Lazzarotti G, Michelassi MC, Del Corona A, et al. Diffusion-tensor MR imaging of corticospinal tract in amyotrophic lateral sclerosis and progressive muscular atrophy. Radiology 2005;237:258-264.PubMedCrossRef
60.
Ellis CM, Simmons A, Jones DK, Bland J, Dawson JM, Horsfield MA, et al. Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology 1999;53:1051-1058.PubMedCrossRef
61.
Pioro EP, Antel JP, Cashman NR, Arnold DL. Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology 1994;44:1933-1938.PubMedCrossRef
62.
Pioro EP, Majors AW, Mitsumoto H, Nelson DR, Ng TC. 1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology 1999;53:71-79.PubMedCrossRef
63.
Agosta F, Chio A, Cosottini M, De Stefano N, Falini A, Mascalchi M, et al. The present and the future of neuroimaging in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol 2010;31:1769-1777.PubMedCrossRef
64.
Pagani M, Chiò A, Valentini MC, Oberg J, Nobili F, Calvo A, et al. Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis. Neurology 2014;83:1067-1074.PubMedCrossRef
65.
Cistaro A, Pagani M, Montuschi A, Calvo A, Moglia C, Canosa A, et al. The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. Eur J Nucl Med Mol Imaging 2014;41:844-852.PubMedCrossRef
66.
Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown RH, Jr., Johnson H, Qureshi M, et al. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 2003;61:456-464.PubMedCrossRef
67.
Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007;6:1045-1053.PubMedCrossRef
68.
Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, et al. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med 2011;17:1652-1656.PubMedCrossRef
69.
Macaluso M, Krams M, Preskorn SH. Phase I trials: From traditional to newer approaches. Part I. J Psychiatr Pract 2011;17:200-203.PubMedCrossRef
70.
Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: A report from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res 2010;16:1726-1736.PubMedCrossRef
71.
Penel N, Isambert N, Leblond P, Ferte C, Duhamel A, Bonneterre J. "Classical 3 + 3 design" versus "accelerated titration designs": Analysis of 270 phase 1 trials investigating anti-cancer agents. Invest New Drugs 2009;27:552-556.PubMedCrossRef
72.
Macaluso M, Krams M, Preskorn SH. Phase I trials: from traditional to newer approaches part II. J Psychiatr Pract 2011;17:277-284.PubMedCrossRef
73.
Sulmasy DP, Astrow AB, He MK, Seils DM, Meropol NJ, Micco E, et al. The culture of faith and hope: patients' justifications for their high estimations of expected therapeutic benefit when enrolling in early phase oncology trials. Cancer 2010;116:3702-3711.PubMedCentralPubMedCrossRef
74.
Iasonos A, Wilton AS, Riedel ER, Seshan VE, Spriggs DR. A comprehensive comparison of the continual reassessment method to the standard 3 + 3 dose escalation scheme in Phase I dose-finding studies. Clin Trials 2008;5:465-477.PubMedCentralPubMedCrossRef
75.
Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the continual reassessment method for phase I studies. Stat Med 1995;14:1149-1161.PubMedCrossRef
76.
O'Quigley J, Shen LZ. Continual reassessment method: a likelihood approach. Biometrics 1996;52:673-684.PubMedCrossRef
77.
Jiang F, Jack Lee J, Muller P. A Bayesian decision-theoretic sequential response-adaptive randomization design. Stat Med 2013;32:1975-1994.PubMedCrossRef
78.
Kaufmann P, Thompson JL, Levy G, Buchsbaum R, Shefner J, Krivickas LS, et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009;66:235-244.PubMedCentralPubMedCrossRef
79.
Gordon PH, Cheung YK, Levin B, Andrews H, Doorish C, Macarthur RB, et al. A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotroph Lateral Scler 2008;9:212-222.PubMedCentralPubMedCrossRef
80.
Berry JD, Cudkowicz ME. New considerations in the design of clinical trials for amyotrophic lateral sclerosis. Clin Investig (Lond) 2011;1:1375-1389.CrossRef
81.
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med 1999;18:1341-1354.PubMedCrossRef
82.
Berry JD, Miller R, Moore DH, Cudkowicz ME, van den Berg LH, Kerr DA, et al. The Combined Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:162-168.PubMedCrossRef
Metadata
Title
Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?
Authors
Katharine A. Nicholson
Merit E. Cudkowicz
James D. Berry
Publication date
01-04-2015
Publisher
Springer US
Published in
Neurotherapeutics / Issue 2/2015
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-015-0341-2

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