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
Review
. 2015 Feb 6;10(2):e0116559.
doi: 10.1371/journal.pone.0116559. eCollection 2015.

Regression to the mean and predictors of MRI disease activity in RRMS placebo cohorts--is there a place for baseline-to-treatment studies in MS?

Jan-Patrick Stellmann  1 , Klarissa Hanja Stürner  1 , Kim Lea Young  1 , Susanne Siemonsen  2 , Tim Friede  3 , Christoph Heesen  1
Affiliations
Review

Regression to the mean and predictors of MRI disease activity in RRMS placebo cohorts--is there a place for baseline-to-treatment studies in MS?

Jan-Patrick Stellmann et al. PLoS One. .

Abstract

Background: Gadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials.

Objectives: To quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts.

Methods: 21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression.

Results: The mean number of GD+-lesions per scan was similar after 6 months (1.19, 95%CI: 0.87-1.51) and 2 years (1.19, 95%CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95%CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months.

Conclusion: Baseline GD-enhancing lesions predict evolution of Gd- and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+lesions per scan within 6 months.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. PRISMA 2009 Flow chart—Study selection for meta-analyses.
According to the PRISMA guidelines [15].
Figure 2
Figure 2. New MRI-lesions in RRMS placebo cohorts.
A: GD+-lesions at of phase 2 and 3 studies at baseline, after 6 months and 2 years. B: New T2 lesions of phase 2 and 3 studies after 6 months and 2 years. Estimates are based on random-effects meta-analyses. RRMS = GD+-lesions at of phase 2 and 3 studies at baseline, after 6 months and 2 years. Estimates are based on random-effects meta-analyses. Relapsing-remitting MS, Bold Line = predicted mean, area = 95% confidence interval, dot size reflects weighting by number of patients.
Figure 3
Figure 3. Forest plots for Mean number of Gd-lesions and new T2 lesions after 6 months and 2 years.
Random-effects meta-analysis with estimated outcome and 95%-confidence interval (brackets) without outliers.
Figure 4
Figure 4. Predicted number and rate of GD+-enhancing lesions and new T2 lesion after 6 months in placebo cohorts of RRMS.
Predicted models based on mixed-effects meta-regression with at least 4 studies. X-axis ranges from 0.5 to 3 mean GD+-lesions per baseline scan, Line = predicted mean outcome after 6 months, area = 95% confidence interval.
See this image and copyright information in PMC

References

    1. European Medicines Agency (2012) Guideline on clinical investigation of medicinal products for the treatment of Multiple Sclerosis.
    1. Sormani MP, Bruzzi P, Rovaris M, Barkhof F, Comi G, et al. (2001) Modelling new enhancing MRI lesion counts in multiple sclerosis. Mult Scler 7: 298–304. 10.1177/135245850100700505 - DOI - PubMed
    1. Sormani MP, Bonzano L, Roccatagliata L, Cutter GR, Mancardi GL, et al. (2009) Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol 65: 268–275. 10.1002/ana.21606 - DOI - PubMed
    1. Miller D (1996) Guidelines for MRI monitoring of the treatment of multiple sclerosis: recommendations of the US Multiple Sclerosis Society’s task force. Mult Scler. - PubMed
    1. Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, et al. (2006) Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 13: 604–610. 10.1111/j.1468-1331.2006.01292.x - DOI - PubMed