Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2012;7(11):e50347.
doi: 10.1371/journal.pone.0050347. Epub 2012 Nov 29.

Placebo cohorts in phase-3 MS treatment trials - predictors for on-trial disease activity 1990-2010 based on a meta-analysis and individual case data

Jan-Patrick Stellmann  1 , Anneke Neuhaus, Lena Herich, Sven Schippling, Matthias Roeckel, Martin Daumer, Roland Martin, Christoph Heesen
Affiliations
Meta-Analysis

Placebo cohorts in phase-3 MS treatment trials - predictors for on-trial disease activity 1990-2010 based on a meta-analysis and individual case data

Jan-Patrick Stellmann et al. PLoS One. 2012.

Abstract

Background: Annualized relapse rates (ARR) in the placebo cohorts of phase-3 randomized controlled trials (RCT) of new treatments for relapsing remitting multiple sclerosis (RRMS) have decreased substantially during the last two decades. The causes of these changes are not clear. We consider a better understanding of this phenomenon essential for valuing the effects of new drugs and by designing new trials.

Objectives: To identify predictive factors of on-study ARR in early and recent MS trials.

Methods: ARR, rate of relapse-free patients, trial start dates, baseline demographics, relapse definitions and the use of McDonald criteria were retrieved by literature research of the placebo cohorts from RRMS phase-3 trials. Predictors were estimated by univariate and multivariate regression analyses and random-effects meta-regression. In addition, regression models were calculated by the Sylvia Lawry Centre's (SLC), including individual case data from clinical trials performed until 2000. The most reliable meta-analytic results can be gained from pooled individual case data. In lack of this, random-effects meta-analyses are recommended.

Results: Data from 12 published and one unpublished trial show a decrease of ARR from 1988 to 2012 (adjR(2) = 0.807, p<0.0001). Regression models identified McDonald criteria followed by baseline mean age and the pre-study relapse rate as predictors of the ARR. The pooled individual case data (n = 505) confirmed a decrease of ARR over time. The pre-study relapse rate was the best predictor for on-study relapses. Lacking individual case data after implementation of the McDonald criteria excludes a direct comparison concerning McDonald criteria.

Conclusion: Pre-study relapse rate was the best predictor for on-study relapse rate but failed to explain the decrease of the ARR over time alone. Higher age at baseline and the implementation of McDonald criteria were associated as well with a lowered relapse rate in the random-effects meta-regression. These findings need further clarification based on individual case data.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: J-PS, Christoph Heesen, SS and RM have received payment for lectures including service on speakers bureaus as well as travel/accomodation/meeting expenses (unrelated to the activities listed) from GlaxoSmithKline, Merck, Novartis, Biogen Idec, Teva. MD, Scientific Director of the Sylvia Lawry Centre for Multiple Sclerosis Research e.V. (SLC) and one of the two Managing Directors of Trium Analysis Online GmbH, serves on the Editorial Board of MedNous and holds Patent 10 2007 044 705.3–35, German patent and trademark office 307 19 449.3/09. The Sylvia Lawry Centre received honoraria for interviews of MD with Propagate Pharma Limited and Deerfield Research LLC; is Medical Advisor of the German Multiple Sclerosis Society; received honoraria for consultancy, statistical analysis and use of actibeltH technology from the following entities: Bayer Schering, Biopartners, Biogen Idec, Biogenerix, Böhringer-Ingelheim, EISAI Limited, Heron Evidence Development Ltd, Hoffmann-La Roche, Johnson & Johnson Pharmaceutical Research & Development LLC, Sanofi-Aventis U.S. INC., Novartis Pharma GmbH, University of Oxford, Imperial College London, University of Southampton, Charite Berlin, University of Vienna, Greencoat Ltd, University Medical Center Hamburg-Eppendorf; serves on the advisory board for EPOSA study and received research grants from the following governmental entities: Federal Ministry of Education and Research Grant No 01GI0904, 01GI0920, Mayo Clinic Rochester, European Union (for SLC and Trium) Grant No 215820, European Union (for SLC) Grant No 223865, Federal Ministry of Economics and Technology Grant No KF0564001KF7, University of Oxford, Technical University of Munich, Hertie Foundation Grant No 1.01.1/07/015, Bavarian Research Foundation, National Multiple Sclerosis Society (NMSS), Porticus Foundation Grant No 900.50578, European Union Grant No LSHM-CT-2006–03759, University of Rochester, European Union Grant No LSHM-CT-2004–503485. AN is employee of the Sylvia Lawry Centre for Multiple Sclerosis Research. MR is employee of Teva Pharma. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Flow chart: Study selection for meta-analyses.
According to the PRISMA guidelines. .
Figure 2
Figure 2. Change of annualized relapse rates of MS phase-3 placebo cohorts over time.
n = 13. Circle size corresponds to weighting by patient numbers of each cohort. R2 is the proportion of variability in the data that is accounted for by the weighted univariate regression model.
Figure 3
Figure 3. Change of the relapse free patients rate of MS phase-3 placebo cohorts over time.
N = 13. Circle size corresponds to weighting by patient numbers of each cohort. R2 is the proportion of variability in the data that is accounted for by the weighted univariate regression model.
Figure 4
Figure 4. Change of mean age and pre-study relapse rates of MS phase-3 placebo cohorts over time.
N = 13. Circle size corresponds to weighting by patient numbers of each cohort. R2 is the proportion of variability in the data that is accounted for by the weighted univariate regression model.
See this image and copyright information in PMC

References

    1. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, et al... (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine: 387–401. - PubMed
    1. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, et al. (2010) A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. The New England journal of medicine 362: 416–426 doi:10.1056/NEJMoa0902533. - DOI - PubMed
    1. Jacobs LD, Cookfair DL, Rudick R a, Herndon RM, Richert JR, et al. (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Annals of neurology 39: 285–294 doi:10.1002/ana.410390304. - DOI - PubMed
    1. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352: 1498–1504 doi:10.1016/S0140-6736(98)03334–0. - DOI - PubMed
    1. Held U, Heigenhauser L, Shang C, Kappos L, Polman C (2005) Predictors of relapse rate in MS clinical trials. Neurology 65: 1769–1773 doi:10.1212/01.wnl.0000187122.71735.1f. - DOI - PubMed

Publication types