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. 2015 Sep 22;10(9):e0138243.
doi: 10.1371/journal.pone.0138243. eCollection 2015.

Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review

T Ziemssen  1 , S Rauer  2 , C Stadelmann  3 , T Henze  4 , J Koehler  5 , I-K Penner  6 , M Lang  7 , D Poehlau  8 , M Baier-Ebert  9 , H Schieb  9 , S Meuth  10
Affiliations

Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review

T Ziemssen et al. PLoS One. .

Abstract

Background: So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population.

Objective: The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator.

Methods: A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared.

Results: Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately.

Conclusion: Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

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Conflict of interest statement

Competing Interests: TZ has received compensation for consulting services from Almirall, Biogen Idec, Bayer, Genzyme, GSK, MSD, Merck Serono, Novartis, Sanofi, Teva and Synthon, and has received research support from Bayer, Biogen Idec, Hertie Foundation, Roland Ernst Foundation, German Diabetes Foundation, Merck Serono, Novartis, Teva and Sanofi Aventis. SR has received compensation for serving as speaker, consultant or member of advisory boards from Bayer, Baxter, Biogen, Merck-Serono, Novartis, RG, Sanofi Aventis,Genzyme, Teva. He received research support from Bayer, BMBF, Biogen, Hertie-Stiftung, Merck-Serono, Novartis, Teva. He is co-founder and co-owner of Ravo-Diagnostika GmbH. CS received honoraria for speaking and travel reimbursement from Novartis Pharma GmbH, Teva Pharmaceutical Industries Ltd., Biogen, and Bayer Health Care. She served on scientific advisory boards of Novartis and Teva. She received research support from Teva. She is a member of the editorial board of the Multiple Sclerosis Journal and Neurology: Neuroimmunology & Neuroinflammation. TH has received financial support as compensation for serving as a member of advisory boards or as a consultant or speaker from the following companies: Almirall Hermal, BiogenIdec, Merck Serono and Novartis. JK has received honoraria for lecturing, travel expenses for attending meetings from Allmiral, Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Pfizer and TEVA. Consultant for Allmiral, Genzyme and Novartis. IP received honoraria, research or travel support from Bayer Pharma AG, Biogen, Genzyme, Merck Serono, Novartis, and Teva. ML has received travel grants, speaker's honoraria, financial research support, consultancy fees from Teva, Merck Serono, Genzyme -Sanofi, Novartis, Bayer, Biogen Idec. DP has received speaker’s honoraria from Biogen, Sanofi-Aventis, Teva, Bayer-Schering, Serono, Genzyme, Novartis and Boehringer. He received research support from Teva, Biogen, Schering, and Novartis. MB and HS are associates of Novartis Pharma GmbH (funder of the study) and receive salaries. Both authors were taking their decisions independently from their employers and the study funder’s commercial interests. SM has received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MSD, Novartis, Novo Nordisk, Sanofi-Aventis and Teva. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. PRISMA Flow-chart
(From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097).
Fig 2
Fig 2. Proportion of patients with clinical disability progression; N = number of patients in the respective group; Definition of clinical disability progression: sustained EDSS increase of ≥1.0 point in patients with an EDSS score at baseline of 3.0 to 5.0, or a sustained EDSS increase of ≥0.5 in patients with a baseline EDSS score of 5.5 to 6.5 (PROMiSe); sustained EDSS increase of ≥1.0 point in patients with an EDSS score at baseline of 2.0 to 5.5 points (inclusive), or an EDSS increase of ≥0.5 point in patients with a baseline EDSS score of >5.5 points (OLYMPUS); sustained EDSS increase of ≥1.0 point in patients with an EDSS score at baseline of ≤5.0, or a sustained EDSS increase by ≥0.5 points, in patients with an EDSS score of >5.0 at baseline (Poehlau et al.).
Fig 3
Fig 3. Median change from baseline in T25W in the OLYMPUS study (reported by Hawker et al. as z-score; the Z-score is calculated by subtracting the baseline mean from each individual test result and then dividing by the standard deviation of the baseline values to obtain a standardized score for each individual); * p<0.05 compared to placebo.
Fig 4
Fig 4. Results from the timed 10-meter walk in the study by Leary et al. (median time in seconds).
See this image and copyright information in PMC

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