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Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: Sample size estimates

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Abstract

Brain atrophy, thought to reflect neuroaxonal degeneration, may be considered an objective marker of disease progression in multiple sclerosis (MS). Our objective was to estimate sample sizes required for parallel group placebo-controlled trials of disease-modifying treatments in relapsing remitting MS (RRMS), using brain atrophy on MRI as the outcome measure. In addition, we investigated how brain atrophy measurement method and trial duration affect sample sizes. Thirtythree patients with RRMS and 16 controls had T1-weighted volumetric MR imaging acquired at baseline and up to six repeat timepoints (six monthly intervals). Brain atrophy was quantified between baseline and each repeat image using four methods: segmented brain volume difference, BBSI, SIENA and ventricular enlargement. Linear mixed models were fitted to data from each subject group and method. Sample size calculations were performed using mean and variance estimates from these models. For a 2 year trial, a treatment slowing atrophy rate by 30% required 123 subjects in each treatment arm if using SIENA to measure atrophy, 157 for the BBSI, 140 for ventricular enlargement and 763 for segmented brain volume difference. For a given effect size and method, sample sizes were statistically significantly reduced the longer the trial duration. Our estimations suggest that brain atrophy could provide an additional outcome measure to clinical assessment for monitoring treatment effects in RRMS although the relationship between atrophy and subsequent disability, and potential confounding factors to atrophy measurement must be further investigated.

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References

  1. Anderson VM, Fernando KT, Davies GR, Rashid W, Frost C, Fox NC, Miller DH (2007) Cerebral atrophy measurement in clinically isolated syndromes and relapsing remitting multiple sclerosis: a comparison of registrationbased methods. J Neuroimaging 17:61–68

    Article  PubMed  Google Scholar 

  2. Dalton CM, Miszkiel KA, O'Connor PW, Plant GT, Rice GP, Miller DH (2006) Ventricular enlargement in MS: one-year change at various stages of disease. Neurology 66:693–698

    Article  CAS  PubMed  Google Scholar 

  3. Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman RI, Scotti G, Comi G, Falini A (2003) Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 126:433–437

    Article  CAS  PubMed  Google Scholar 

  4. Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, Comi G (2004) Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 364:1489–1496

    Article  CAS  PubMed  Google Scholar 

  5. Fisher E, Rudick RA, Simon JH, Cutter G, Baier M, Lee JC, Miller D, Weinstock-Guttman B, Mass MK, Dougherty DS, Simonian NA (2002) Eight-year follow-up study of brain atrophy in patients with MS. Neurology 59:1412–1420

    CAS  PubMed  Google Scholar 

  6. Fox NC, Freeborough PA (1997) Brain atrophy progression measured from registered serial MRI: validation and application to Alzheimer's disease. J Magn Reson Imaging 7:1069–1075

    Article  CAS  PubMed  Google Scholar 

  7. Fox NC, Jenkins R, Leary SM, Stevenson VL, Losseff NA, Crum WR, Harvey RJ, Rossor MN, Miller DH, Thompson AJ (2000) Progressive cerebral atrophy in MS: a serial study using registered, volumetric MRI. Neurology 54:807–812

    CAS  PubMed  Google Scholar 

  8. Freeborough PA, Fox NC (1997) The boundary shift integral: an accurate and robust measure of cerebral volume changes from registered repeat MRI. IEEE Trans. Med Imaging 16:623–629

    Article  CAS  Google Scholar 

  9. Freeborough PA, Fox NC, Kitney RI (1997) Interactive algorithms for the segmentation and quantitation of 3-D MRI brain scans. Comput. Methods Programs Biomed 53:15–25

    Article  CAS  Google Scholar 

  10. Frost C, Kenward MG, Fox NC (2004) The analysis of repeated 'direct' measures of change illustrated with an application in longitudinal imaging. Stat.Med 23:3275–3286

    Article  PubMed  Google Scholar 

  11. Hardmeier M, Wagenpfeil S, Freitag P, Fisher E, Rudick RA, Kooijmans M, Clanet M, Radue EW, Kappos L (2005) Rate of brain atrophy in relapsing MS decreases during treatment with IFNbeta-1a. Neurology 64:236–240

    CAS  PubMed  Google Scholar 

  12. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE, Priore RL, Pullicino PM, Scherokman BJ, Weinstock-Guttman B, Whitman RH, Baird WC, Fillmore M, Bona LM, Colon Ruiz ME, Nadine BS, Donovan A, Bennett S, Kieffer YM, Umhauer MA, Miller CE, Kilic AK, Sargent EL, Schachter M, Shucard DW, Weider V, Catalano BA, Cervi JM, Czekay C, Farrell JL, Filippini JS, Matyas RC, Michienzi KE, Ito M, OMalley JA, Zielezny MA, Brun JM, Davidson AL, Green LA, OReilly KM, Shelton JA, Wende KE, Barilla DY, Boyle SL, Perkins KK, Perryman JE, Stiebeling BG, Konecsni JF, Ross JS, Choi KS, Gustafson CJ, Quandt BJ, Scherzinger AL, Griffith DA, Harris JM, Lezak MD, Mimica I, Saunders JA, Coit WE, Force CR, Gilmore FJ, Harris LB, Jones MM, Kauffman JA, Marberger KE, McBride JW, Miller LL, Wright GK, Brooks JA, Brown HR, Graves ME, Schmidt JA, Mothena JW, Grafman JH, Kenworthy MK, Morton MM, Brown DM, Brown DC, Levy LM, Borden EC, Ransohoff RM, Vilcek JT, McCarthy Kirby K, Campion M (1996) Intramuscular interferon beta-1 alpha for disease progression in relapsing multiple sclerosis. Annals of Neurology 39:285–294

    Article  CAS  PubMed  Google Scholar 

  13. Johnson KP, Brooks BR, Cohen JA, Ford CC,Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45:1268–1276

    CAS  PubMed  Google Scholar 

  14. Kalkers NF, Ameziane N, Bot JC, Minneboo A, Polman CH, Barkhof F (2002) Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype. Arch Neurol 59:1572–1576

    Article  PubMed  Google Scholar 

  15. Molyneux PD, Miller DH, Filippi M, Yousry T, Kappos L, Gasperini C, Ader HJ, Barkhof F (2000) The use of magnetic resonance imaging in multiple sclerosis treatment trials: power calculations for annual lesion load measurement. J Neurol 247:34–40

    Article  CAS  PubMed  Google Scholar 

  16. Paolillo A, Pozzilli C, Giugni E, Tomassini V, Gasperini C, Fiorelli M, Mainero C, Horsfield M, Galgani S, Bastianello S, Buttinelli C (2002) A 6-year clinical and MRI follow-up study of patients with relapsing-remitting multiple sclerosis treated with Interferon-beta. Eur J Neurol 9:645–655

    Article  CAS  PubMed  Google Scholar 

  17. Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400

    Article  CAS  PubMed  Google Scholar 

  18. Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910

    Article  CAS  PubMed  Google Scholar 

  19. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231

    Article  CAS  PubMed  Google Scholar 

  20. Rovaris M, Agosta F, Sormani MP, Inglese M, Martinelli V, Comi G, Filippi M (2003) Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study. Brain 126:2323–2332

    Article  PubMed  Google Scholar 

  21. Rudick RA, Fisher E, Lee JC, Duda JT, Simon J (2000) Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon beta-1a. Mult Scler 6:365–372

    CAS  PubMed  Google Scholar 

  22. Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsingremitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53:1698–1704

    CAS  PubMed  Google Scholar 

  23. Simon JH, Jacobs LD, Campion M, Wende K, Simonian N, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Alam JJ, Fischer JS, Goodkin DE, Granger CV, Lajaunie M, Martens-Davidson AL, Meyer M, Sheeder J, Choi K, Scherzinger AL, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE, Priore RL, Pullicino PM, Scherokman BJ, Weinstock-Guttman B, Whitham RH (1998) Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol 43:79–87

    Article  CAS  PubMed  Google Scholar 

  24. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23 (Suppl 1):S208–S219

    Article  PubMed  Google Scholar 

  25. Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, De Stefano N (2002) Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17:479–489

    Article  PubMed  Google Scholar 

  26. Sormani MP, Miller DH, Comi G, Barkhof F, Rovaris M, Bruzzi P, Filippi M (2001) Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets. J Neurol Neurosurg Psychiatry 70:494–499

    Article  CAS  PubMed  Google Scholar 

  27. The IFNB Multiple Sclerosis Study Group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, doubleblind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology 43:655–661

    Google Scholar 

  28. Tubridy N, Ader HJ, Barkhof F, Thompson AJ, Miller DH (1998) Exploratory treatment trials in multiple sclerosis using MRI: sample size calculations for relapsing-remitting and secondary progressive subgroups using placebo controlled parallel groups. J Neurol Neurosurg Psychiatry 64:50–55

    Article  CAS  PubMed  Google Scholar 

  29. van Waesberghe JH, Kamphorst W, De Groot CJ, van Walderveen MA, Castelijns JA, Ravid R, Nijeholt GJ, van d, V, Polman CH, Thompson AJ, Barkhof F (1999) Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 46:747–754

    Article  CAS  PubMed  Google Scholar 

  30. Wolinsky JS, Narayana PA, Johnson KP (2001) United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates. Multiple Sclerosis Study Group and the MRI Analysis Center. Mult Scler 7:33–41

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. MS NMR Research Unit, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    V. M. Anderson BSc, L. Fisniku MD, MRCP & D. H. Miller MD, FRCP

  2. Medical Statistics Unit, London School of Hygiene and Tropical Medicine University of London, London, UK

    J. W. Bartlett MSc

  3. Dementia Research Centre, University College London Institute of Neurology, Queen Square, London, UK

    V. M. Anderson BSc & N. C. Fox MD, FRCP

Authors
  1. V. M. Anderson BSc
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  2. J. W. Bartlett MSc
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  3. N. C. Fox MD, FRCP
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  4. L. Fisniku MD, MRCP
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  5. D. H. Miller MD, FRCP
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Correspondence to V. M. Anderson BSc.

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Anderson, V.M., Bartlett, J.W., Fox, N.C. et al. Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: Sample size estimates. J Neurol 254, 1588–1594 (2007). https://doi.org/10.1007/s00415-007-0599-3

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  • DOI: https://doi.org/10.1007/s00415-007-0599-3

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