The design of clinical trials is a key aspect to maximizing the possibility to detect a treatment effect. This fact is particularly challenging in progressive multiple sclerosis (PMS) studies due to the uncertainty about the right target and/or outcome in phase-2 studies. The aim of this review is to evaluate the current challenges facing the design of clinical trials for PMS. The selection of patients, the instrumental and clinical outcomes that can be used in PMS trials, and issues in their design will be covered in this report.
MontalbanXHauserSLKapposL. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med2017; 376(3): 209–220.
2.
OntanedaDFoxRJChatawayJ.Clinical trials in progressive multiple sclerosis: Lessons learned and future perspectives. Lancet Neurol2015; 14(2): 208–223.
3.
BeckerREGreigNH.Why so few drugs for Alzheimer’s disease? Are methods failing drugs?Curr Alzheimer Res2010; 7(7): 642–651.
4.
Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet1998; 352(9139): 1491–1497.
5.
Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon- beta-1a in secondary progressive MS: Clinical results. Neurology2001; 56(1): 1496–1504.
6.
KapposLWeinshenkerBPozzilliC. Interferon beta-1b in secondary progressive MS: A combined analysis of the two trials. Neurology2004; 63(10): 1779–1787.
7.
HawkerKO’ConnorPFreedmanMS. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol2009; 66(4): 460–471.
8.
ChatawayJSchuererNAlsanousiA. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): A randomised, placebo-controlled, phase 2 trial. Lancet2014; 383(9936): 2213–2221.
9.
WolinskyJSNarayanaPAO’ConnorP. Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol2007; 61(1): 14–24.
10.
WolinskyJSShochatTWeissS. Glatiramer acetate treatment in PPMS: Why males appear to respond favorably. J Neurol Sci2009; 286(1–2): 92–98.
11.
SimonJH.Brain atrophy in multiple sclerosis: What we know and would like to know. Mult Scler2006; 12(6): 679–687.
12.
De StefanoNAirasLGrigoriadisN. Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs2014; 28(2): 147–156.
13.
MillerDHBarkhofFFrankJA. Measurement of atrophy in multiple sclerosis: Pathological basis, methodological aspects and clinical relevance. Brain2002; 125(Pt 8): 1676–1695.
14.
GiovannoniGCutterGPia-SormaniM. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord2017; 12: 70–78.
15.
MontalbanXSastre-GarrigaJTintoreM. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Mult Scler2009; 15(10): 1195–1205.
16.
TurCMontalbanXTintoreM. Interferon (-1b for the treatment of primary progressive multiple sclerosis: Five-year clinical trial follow-up. Arch Neurol2011; 68(11): 1421–1427.
17.
AndersonVMBartlettJWFoxNC. Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: Sample size estimates. J Neurol2007; 254: 1588–1594.
18.
CawleyNTurCPradosF. Spinal cord atrophy as a primary outcome measure in phase II trials of progressive multiple sclerosis. Mult Scler. Epub ahead of print 1 May 2017. DOI: 10.1177/1352458517709954.
19.
IngleseMPetraccaMMorminaE. Cerebellar volume as imaging outcome in progressive multiple sclerosis. PLoS ONE2017; 12(4): e0176519.
20.
LiuZYaldizliOPardiniM. Cervical cord area measurement using volumetric brain magnetic resonance imaging in multiple sclerosis. Mult Scler Relat Disord2015; 4(1): 52–57.
21.
KosaPGhazaliDTanigawaM. Development of a sensitive outcome for economical drug screening for progressive multiple sclerosis treatment. Front Neurol2016; 7: 131.
22.
YaldizliOPardiniMSethiV. Characteristics of lesional and extra-lesional cortical grey matter in relapsing-remitting and secondary progressive multiple sclerosis: A magnetisation transfer and diffusion tensor imaging study. Mult Scler2016; 22(2): 150–159.
23.
HarrisonDMCaffoBSShieeN. Longitudinal changes in diffusion tensor-based quantitative MRI in multiple sclerosis. Neurology2011; 76: 179–186.
24.
PardiniMBotzkowskiDMullerS. The association between retinal nerve fibre layer thickness and N-acetyl aspartate levels in multiple sclerosis brain normal-appearing white matter: A longitudinal study using magnetic resonance spectroscopy and optical coherence tomography. Eur J Neurol2016; 23(12): 1769–1774.
25.
PetzoldAde BoerJFSchipplingS. Optical coherence tomography in multiple sclerosis: A systematic review and meta-analysis. Lancet Neurol2010; 9(9): 921–932.
26.
VrenkenHJenkinsonMHorsfieldMA. Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis. J Neurol2013; 260: 2458–2471.
27.
GoodkinDERudickRAVanderBrug MedendorpS. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol1995; 37(1): 30–40.
28.
RudickRAntelJConfavreuxC. Recommendations from the national multiple sclerosis society clinical outcomes assessment task force. Ann Neurol1997; 42(3): 379–382.
29.
CohenJACutterGRFischerJS. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology2002; 59(5): 679–687.
30.
FoxRJLeeJCRudickRA.Optimal reference population for the multiple sclerosis functional composite. Mult Scler2007; 13(7): 909–914.
31.
BenedictRHWaltonMK.Evaluating cognitive outcome measures for MS clinical trials: What is a clinically meaningful change?Mult Scler2012; 18(12): 1673–1679.
PardiniMYaldizliOSethiV. Motor network efficiency and disability in multiple sclerosis. Neurology2015; 85(13): 1115–1122.
34.
HaytonTFurbyJSmithKJ. Clinical and imaging correlates of the multiple sclerosis impact scale in secondary progressive multiple sclerosis. J Neurol2012; 259(2): 237–245.
35.
JamesNDSydesMRClarkeNW. Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): A multi-arm, multistage randomized controlled trial. BJU Int2009; 103(4): 464–469.
LenzRAPritchettYLBerrySM. Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease. Alzheimer Dis Assoc Disord2015; 29(3): 192–199.
38.
AntoniouMJorgensenALKolamunnage-DonaR.Biomarker-guided adaptive trial designs in phase II and phase III: A methodological review. PLoS ONE2016; 11(2): e0149803.
39.
BerryDA.Bayesian clinical trials. Nat Rev Drug Discov2006; 5: 27–36.
