Abstract
Duchenne muscular dystrophy (DMD) is a rare X-linked genetic pediatric disease characterized by a lack of functional dystrophin production in the body, resulting in muscle deterioration. Lower body muscle weakness progresses to non-ambulation typically by early teenage years, followed by upper body muscle deterioration and ultimately death by the late twenties. The objective of this study was to enhance the quantitative understanding of DMD disease progression through nonlinear mixed effects modeling of the population mean and variability of the 6-min walk test (6MWT) clinical endpoint. An indirect response model with a latent process was fit to digitized literature data using full Bayesian estimation. The modeling data set consisted of 22 healthy controls and 218 DMD patients from one interventional and four observational trials. The model reasonably described the central tendency and population variability of the 6MWT in healthy subjects and DMD patients. An exploratory categorical covariate analysis indicated that there was no apparent effect of corticosteroid administration on DMD disease progression. The population predicted 6MWT began to rise at 1.32 years of age, plateauing at 654 meters (m) at 17.2 years of age for the healthy population. The DMD trajectory reached a maximum of 411 m at 8.90 years before declining and falling below 1 m at age 18.0. The model has potential to be used as a Bayesian estimation and posterior simulation tool to make informed model-based drug development decisions that incorporate prior knowledge with new data.
Similar content being viewed by others
Notes
The elements in the \({\varvec{\theta }}_{prior}\) mean vector and diagonal vector of the variance-covariance matrix are, row-wise, as follows: \(\theta _1\), \(\theta _2\), \(\theta _3\), \(\theta _4\), \(\theta _5\), \(\theta _6\). The elements in the \({\varvec{\varOmega }}_{prior,DMD}\) matrix are, row-wise, as follows: \(\omega ^2_{K_{out,DMD}}\); \(\omega _{K_{out,DMD}-K_{in,DMD}}\); \(\omega ^2_{K_{in,DMD}}\); \(\omega _{K_{\alpha }-K_{out,DMD}}\); \(\omega _{K_{\alpha }-K_{in,DMD}}\); \(\omega ^2_{K_{\alpha }}\)
References
Sharma P, Basu S, Mitchell RW, Stelmack GL, Anderson JE, Halayko AJ (2014) Role of dystrophin in airway smooth muscle phenotype, contraction and lung function. PLoS ONE 9(7):e102737
Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C, DMD Care Considerations Working Group (2010) Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 9(1):77–93
MCDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Atkinson L, Elfring GL, Reha A, Miller LL (2010) The 6-minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations. Muscle Nerve 42(6):966–974
Goemans N, van den Hauwe M, Wilson R, van Impe A, Klingels K, Buyse G (2013) Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids. Neuromuscul Disord 23(8):618–623
Mazzone E, Vasco G, Sormani MP, Torrente Y, Berardinelli A, Messina S, D’Amico A, Doglio L, Politano L, Cavallaro F, Frosini S, Bello L, Bonfiglio S, Zucchini E, De Sanctis R, Scutifero M, Bianco F, Rossi F, Motta MC, Sacco A, Donati MA, Mongini T, Pini A, Battini R, Pegoraro E, Pane M, Gasperini S, Previtali S, Napolitano S, Martinelli D, Bruno C, Vita G, Comi G, Bertini E, Mercuri E (2011) Functional changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study. Neurology 77(3):250–256
Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N, Campion G, De Kimpe SJ, Eagle M, Guglieri M, Hood S, Liefaard L, Lourbakos A, Morgan A, Nakielny J, Quarcoo N, Ricotti V, Rolfe K, Servais L, Wardell C, Wilson R, Wright P, Kraus JE (2014) Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 13(10):987–996
Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM, Eteplirsen Study Group (2013) Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 74(5):637–647
Muntoni F, Torelli S, Ferlini A (2003) Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol 2(12):731–740
Aartsma-Rus A, Ginjaar IB, Bushby K (2016) The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet 53(3):145–151
Pane M, Mazzone ES, Sormani MP, Messina S, Vita GL, Fanelli L, Berardinelli A, Torrente Y, D’Amico A, Lanzillotta V, Viggiano E, D’Ambrosio P, Cavallaro F, Frosini S, Bello L, Bonfiglio S, Scalise R, De Sanctis R, Rolle E, Bianco F, Van der Haawue M, Magri F, Palermo C, Rossi F, Donati MA, Alfonsi C, Sacchini M, Arnoldi MT, Baranello G, Mongini T, Pini A, Battini R, Pegoraro E, Previtali SC, Napolitano S, Bruno C, Politano L, Comi GP, Bertini E, Morandi L, Gualandi F, Ferlini A, Goemans N, Mercuri E (2014) 6 minute walk test in Duchenne MD patients with different mutations: 12 month changes. PLoS ONE 9(1):e83400
Wang RT, Barthelemy F, Martin AS, Douine ED, Eskin A, Lucas A, Lavigne J, Peay H, Khanlou N, Sweeney L, Cantor RM, Miceli MC, Nelson SF (2018) DMD genotype correlations from the Duchenne registry: endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype. Hum Mutat 39(9):1193–1202
van den Bergen JC, Ginjaar HB, Niks EH, Aartsma-Rus A, Verschuuren JJGM (2014) Prolonged ambulation in Duchenne patients with a mutation amenable to exon 44 skipping. J Neuromuscul Dis 1(1):91–94
Servais L, Montus M, Guiner CL, Ben Yaou R, Annoussamy M, Moraux A, Hogrel JY, Seferian AM, Zehrouni K, Le Moing AG, Gidaro T, Vanhulle C, Laugel V, Butoianu N, Cuisset JM, Sabouraud P, Cances C, Klein A, Leturcq F, Moullier P, Voit T (2015) Non-ambulant Duchenne patients theoretically treatable by exon 53 skipping have severe phenotype. J Neuromuscul Dis 2(3):269–279
Bello L, Morgenroth LP, Gordish-Dressman H, Hoffman EP, McDonald CM, Cirak S, CINRG Investigators (2016) DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study. Neurology 87(4):401–409
McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, Atkinson L, Reha A, Hirawat S, Miller LL (2010) The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve 41(4):500–510
Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP, Connolly AM, Day JW, Flanigan KM, Goemans N, Jones KJ, Mercuri E, Quinlivan R, Renfroe JB, Russman B, Ryan MM, Tulinius M, Voit T, Moore SA, Lee Sweeney H, Abresch RT, Coleman KL, Eagle M, Florence J, Gappmaier E, Glanzman AM, Henricson E, Barth J, Elfring GL, Reha A, Spiegel RJ, O’donnell MW, Peltz SW, Mcdonald CM, PTC124-GD-007-DMD STUDY GROUP (2014) Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 50(4):477–487
Brehm MA, Kempen JCE, van der Kooi AJ, de Groot IJM, van den Bergen JC, Verschuuren JJGM, Niks EH, Harlaar J (2014) Age-related longitudinal changes in metabolic energy expenditure during walking in boys with Duchenne muscular dystrophy. PLoS ONE 9(12):e115200
Goemans N, Klingels K, van den Hauwe M, Van Orshoven A, Vanpraet S, Feys H, Buyse G (2013) Test-retest reliability and developmental evolution of the 6-min walk test in caucasian boys aged 5–12 years. Neuromuscul Disord 23(1):19–24
Mcdonald CM, Henricson EK, Abresch RT, Florence JM, Eagle M, Gappmaier E, Glanzman AM, Spiegel R, Barth J, Elfring G, Others (2013) The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve 48(3):343–356
Pane M, Mazzone ES, Sivo S, Sormani MP, Messina S, Damico A, Carlesi A, Vita G, Fanelli L, Berardinelli A, Torrente Y, Lanzillotta V, Viggiano E, Dambrosio P, Cavallaro F, Frosini S, Barp A, Bonfiglio S, Scalise R, De Sanctis R, Rolle E, Graziano A, Magri F, Palermo C, Rossi F, Donati MA, Sacchini M, Arnoldi MT, Baranello G, Mongini T, Pini A, Battini R, Pegoraro E, Previtali S, Bruno C, Politano L, Comi GP, Bertini E, Mercuri E, (2014) Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes. PLoS ONE 9:e108205
Wang RT, Silverstein Fadlon CA, Ulm JW, Jankovic I, Eskin A, Lu A, Rangel Miller V, Cantor RM, Li N, Elashoff R, Martin AS, Peay HL, Halnon N, Nelson SF (2014) Online self-report data for Duchenne muscular dystrophy confirms natural history and can be used to assess for therapeutic benefits. PLoS Curr. https://doi.org/10.1371/currents.md.e1e8f2be7c949f9ffe81ec6fca1cce6a
Kameyama T, Ohuchi K, Funato M, Ando S, Inagaki S, Sato A, Seki J, Kawase C, Tsuruma K, Nishino I, Nakamura S, Shimazawa M, Saito T, Takeda S, Kaneko H, Hara H (2018) Efficacy of prednisolone in generated myotubes derived from fibroblasts of Duchenne muscular dystrophy patients. Front Pharmacol 9:1402
Angelini C, Peterle E (2012) Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy. Acta Myol 31(1):9–15
Chmp E (2014) Translarna. Assessment report for initial marketing authorisation application. https://www.ema.europa.eu/en/documents/assessment-report/translarna-epar-public-assessment-report_en.pdf
Food US, Administration D et al (2016) FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. FDA Med Bull. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm
Mendell JR, Sahenk Z, Rodino-Klapac LR (2017) Clinical trials of exon skipping in Duchenne muscular dystrophy. Expert Opin Orphan Drugs 5(9):683–690
McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, Goemans N, Heydemann P, Kaminska A, Kirschner J, Muntoni F, Osorio AN, Schara U, Sejersen T, Shieh PB, Sweeney HL, Topaloglu H, Tulinius M, Vilchez JJ, Voit T, Wong B, Elfring G, Kroger H, Luo X, McIntosh J, Ong T, Riebling P, Souza M, Spiegel RJ, Peltz SW, Mercuri E, Clinical Evaluator Training Group, ACT DMD Study Group (2017) Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390(10101):1489–1498
Echigoya Y, Lim KRQ, Nakamura A, Yokota T (2018) Multiple exon skipping in the Duchenne muscular dystrophy hot spots: prospects and challenges. J Pers Med 8(4):41
Brown KJ, Marathi R, Fiorillo AA, Ciccimaro EF, Sharma S, Rowlands DS, Rayavarapu S, Nagaraju K, Hoffman EP, Hathout Y (2012) Accurate quantitation of dystrophin protein in human skeletal muscle using mass spectrometry. J Bioanal Biomed Suppl 7:001
Guiraud S, Squire SE, Edwards B, Chen H, Burns DT, Shah N, Babbs A, Davies SG, Wynne GM, Russell AJ, Elsey D, Wilson FX, Tinsley JM, Davies KE (2015) Second-generation compound for the modulation of utrophin in the therapy of DMD. Hum Mol Genet 24(15):4212–4224
Center for Drug Evaluation, Research (2019a) Rare diseases: natural history studies for drug development. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-natural-history-studies-drug-development. Accessed: 1 Aug 2019
Center for Drug Evaluation, Research (2019b) Rare diseases: Common issues in drug development guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-common-issues-drug-development-guidance-industry. Accessed 1 Aug 2019
Austin CP, Carrillo N, Charnas L, Chen KS, Darras BT, Eichler F, Escolar ML, Furlong P, Gallin JI, Groft SC, Gunay-Aygun M, Haslett P, Introne WJ, Kaufmann P, Kaye EM, Kishnani PS, Krischer JP, McDonald CM, McKew J, Moscicki RA, Pariser A, Paulsen JS, Pearce D, Rao GR, Shapiro EG, Stemhagen A, Summar ML, Tandon P, Walton MK (2012) Workshop summary. In Presented at the workshop on natural history studies of rare diseases: meeting the needs of drug development and research, Bethesda, MD
Pariser A (2014) Rare disease and clinical trials. Presentation
Lapteva L, Vatsan R, Purohit-Sheth T (2018) Regenerative medicine therapies for rare diseases. Transl Sci Rare Dis 3(3–4):121–132
Davidian M, Giltinan DM (2003) Nonlinear models for repeated measurement data: an overview and update. J Agric Biol Environ Stat 8(4):387
Davidian M (2017) Nonlinear models for repeated measurement data. Routledge, Abingdon
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6(7):e1000100
Software A (2010) GraphClick—graph and movie digitizer for mac OS X—free download. http://www.arizona-software.ch/graphclick/. Accessed 27 Apr 2018
McElreath R (2016) Statistical rethinking: a Bayesian course with examples in R and Stan. CRC Press/Taylor & Francis Group, Boca Raton
Gelman A, Carlin JB, Stern HS, Dunson DB, Vehtari A, Rubin DB (2013) Bayesian data analysis, 3rd edn. CRC Press, Boca Raton
R Core Team (2018) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/
Mercuri E, Signorovitch JE, Swallow E, Song J, Ward SJ, DMD Italian Group, Trajectory Analysis Project (cTAP) (2016) Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy. Neuromuscul Disord 26(9):576–583
Liang WC, Nishino I (2013) Daily or alternative, that is the question: steroid therapy for Duchenne muscular dystrophy patients. J Neurol Neurosurg Psychiatry 84(6):591–591
Gelman A, Rubin DB (1992) Inference from iterative simulation using multiple sequences. Stat Sci 7(4):457–472
Brooks SP, Gelman A (1998) General methods for monitoring convergence of iterative simulations. J Comput Graph Stat 7(4):434–455. https://doi.org/10.1080/10618600.1998.10474787
Plummer M, Best N, Cowles K, Vines K (2006) CODA: convergence diagnosis and output analysis for MCMC. R News 6(1):7–11
Holford NH (2012) An introduction to visual predictive checks. http://holford.fmhs.auckland.ac.nz/docs/vpc-tutorial-and-datatop.pdf
Baron KT, Gastonguay MR (2015) Simulation from ODE-based population PK/PD and systems pharmacology models in R with mrgsolve. J Pharmacokinet Pharmacodyn 42:S84–S85
Hamuro L, Chan P, Tirucherai G, AbuTarif M (2017) Developing a natural history progression model for Duchenne muscular dystrophy using the six-minute walk test. CPT Pharmacomet Syst Pharmacol 6(9):596–603
Hajjar-Lennie JL, Fisher J, Gastonguay MR (2016) Modeling Duchenne muscular dystrophy disease progression as assessed by the 6-minute walk test. In: Presented at the annual meeting of the Population Approach Group in Europe
Lee JJ, Chu CT (2012) Bayesian clinical trials in action. Stat Med 31(25):2955–2972
Ruberg SJ, Harrell FE, Gamalo-Siebers M, LaVange L, Jack Lee J, Price K, Peck C (2019) Inference and decision making for 21st-century drug development and approval. Am Stat 73(sup1):319–327
Hampson LV, Whitehead J, Eleftheriou D, Brogan P (2014) Bayesian methods for the design and interpretation of clinical trials in very rare diseases. Stat Med 33(24):4186–4201
Amrhein V, Greenland S, McShane B (2019) Scientists rise up against statistical significance. Nature 567(7748):305–307
Thompson LA (n.d.) Bayesian methods for making inferences about rare diseases in pediatric populations. https://www.fda.gov/media/87358/download
Mutsvari T (n.d.) The value of Bayesian statistics for assessing comparability. In: Presented on behalf of European Federation of Statisticians in the Pharmaceutical Industry Working Group
Chakravarty A (2018) Promoting the use of complex innovative designs in clinical trials. https://www.fda.gov/drugs/news-events-human-drugs/promoting-use-complex-innovative-designs-clinical-trials
Berry DA (2004) Bayesian statistics and the efficiency and ethics of clinical trials. Stat Sci 19(1):175–187
Bittl JA, He Y (2017) Bayesian analysis: a practical approach to interpret clinical trials and create clinical practice guidelines. Circ Cardiovasc Qual Outcomes 10(8):e003563
Lewis RJ, Berry Consultants LLC (2012) An overview of Bayesian adaptive clinical trial design. Berry Consultants, Austin
Psioda MA, Ibrahim JG (2019) Bayesian clinical trial design using historical data that inform the treatment effect. Biostatistics 20(3):400–415
Holford NH, Kimko HC, Monteleone JP, Peck CC (2000) Simulation of clinical trials. Annu Rev Pharmacol Toxicol 40:209–234
Chen DT, Schell MJ, Fulp WJ, Pettersson F, Kim S, Gray JE, Haura EB (2019) Application of Bayesian predictive probability for interim futility analysis in single-arm phase II trial. Transl Cancer Res 8(Suppl 4):S404–S420
Quintana M, Shrader J, Slota C, Joe G, McKew JC, Fitzgerald M, Gahl WA, Berry S, Carrillo N (2019) Bayesian model of disease progression in GNE myopathy. Stat Med 38(8):1459–1474
Brard C, Hampson LV, Gaspar N, Le Deley MC, Le Teuff G (2019) Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study. BMC Med Res Methodol 19(1):85
Lim J, Walley R, Yuan J, Liu J, Dabral A, Best N, Grieve A, Hampson L, Wolfram J, Woodward P, Yong F, Zhang X, Bowen E (2018) Minimizing patient burden through the use of historical subject-level data in innovative confirmatory clinical trials: review of methods and opportunities. Ther Innov Regul Sci 52(5):546–559
Center for Devices, Radiological Health (2019) Guidance for the use of Bayesian statistics in medical device clinical. http://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-use-bayesian-statistics-medical-device-clinical-trials. Accessed 26 Nov 2019
Sarepta Therapeutics I (2016) Eteplirsen briefing document NDA 206488. Tech. rep., Sarepta Therapeutics, Inc., Cambridge
FDA (2018) Duchenne muscular dystrophy and related dystrophinopathies: developing drugs for treatment guidance for industry. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)
Mayhew A, Mazzone ES, Eagle M, Duong T, Ash M, Decostre V, Vandenhauwe M, Klingels K, Florence J, Main M, Bianco F, Henrikson E, Servais L, Campion G, Vroom E, Ricotti V, Goemans N, McDonald C, Mercuri E, Performance of the Upper Limb Working Group (2013) Development of the performance of the upper limb module for Duchenne muscular dystrophy. Dev Med Child Neurol 55(11):1038–1045
Klingels K, Mayhew AG, Mazzone ES, Duong T, Decostre V, Werlauff U, Vroom E, Mercuri E, Goemans NM, Upper Limb Clinical Outcome Group (2017) Development of a patient-reported outcome measure for upper limb function in Duchenne muscular dystrophy: DMD upper limb PROM. Dev Med Child Neurol 59(2):224–231
Acknowledgements
Thanks to the scientists at Metrum Research Group for support and advisement during this analysis. We acknowledge the researchers and patients from the included literature studies, and thank them for contributing to public data sharing in the rare disease therapeutic area.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lennie, J.L., Mondick, J.T. & Gastonguay, M.R. Latent process model of the 6-minute walk test in Duchenne muscular dystrophy. J Pharmacokinet Pharmacodyn 47, 91–104 (2020). https://doi.org/10.1007/s10928-020-09671-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-020-09671-7