TY - JOUR
T1 - Development of a model-based clinical trial simulation platform to optimize the design of clinical trials for Duchenne muscular dystrophy
AU - the Cooperative International Neuromuscular Research Group investigators and Duchenne Regulatory Science Consortium members
AU - Lingineni, Karthik
AU - Aggarwal, Varun
AU - Morales, Juan Francisco
AU - Conrado, Daniela J.
AU - Corey, Diane
AU - Vong, Camille
AU - Burton, Jackson
AU - Larkindale, Jane
AU - Romero, Klaus
AU - Schmidt, Stephan
AU - Kim, Sarah
AU - McDonald, C.
AU - Henricson, E.
AU - Cregan, M.
AU - Johnson, L.
AU - Han, J.
AU - Joyce, N.
AU - Nicorici, A.
AU - Reddy, D.
AU - Mah, J.
AU - Chiu, A.
AU - Haig, T.
AU - Harris, M.
AU - Kornelsen, M.
AU - Rincon, N.
AU - Sanchez, K.
AU - Walker, L.
AU - Tulinius, M.
AU - Alhander, A.
AU - Ekstrom, A.
AU - Gustafsson, A.
AU - Kroksmark, A.
AU - Sterky, U.
AU - Wahlgren, L.
AU - Leshner, R.
AU - Brody, N.
AU - Drogo, B.
AU - Leach, M.
AU - Tesi-Rocha, C.
AU - Birkmeier, M.
AU - Tadese, B.
AU - Toles,, A.
AU - Thangarajh, M.
AU - Kornberg, A.
AU - Carroll, K.
AU - DeValle, K.
AU - Kennedy, R.
AU - Rodriguez, V.
AU - Villano, D.
AU - Kuntz, N.
N1 - Funding Information:
The authors acknowledge the support of Parent Project Muscular Dystrophy and Duchenne Muscular Dystrophy Regulatory Science Consortium (D‐RSC) member companies. Critical Path Institute is supported by the US Food and Drug Administration (FDA) of the US Department of Health and Human Services (HHS) and is 69% funded by the FDA/HHS totaling $19,471,171 and 31% funded by nongovernment source(s) totaling $8,612,313. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, FDA/HHS or the US government. Imaging DMD data were supported by National Institutes of Health Grant R01AR056973. Work at the University of Florida was funded by the Critical Path Institute through Grant AWD05774‐P0116210 from the D‐RSC
Funding Information:
The authors thank the patients and their families for their participation in the study. The authors also thank the study team members at the participating Cooperative International Neuromuscular Research Group (CINRG) sites: University of California Davis: CMcDonald, EHenricson, MCregan, LJohnson, JHan, NJoyce, ANicorici, and DReddy; Sundaram Medical Foundation and Apollo Children’s Hospital, Alberta Children’s Hospital: JMah, AChiu, THaig, MHarris, MKornelsen, NRincon, KSanchez, and LWalker; Queen Silvia Children’s Hospital: MTulinius, AAlhander, AEkstrom, AGustafsson, AKroksmark, USterky, and LWahlgren; Children’s National Health System: RLeshner, NBrody, BDrogo, MLeach, CTesi‐Rocha, MBirkmeier, BTadese, AToles, and MThangarajh; Royal Children’s Hospital: AKornberg, KCarroll, KDeValle, RKennedy, VRodriguez, and DVillano; Hadassah Hebrew University Hospital: YNevo, RAdani, ABarLeve, LChen‐Joseph, MDaana, VPanteleyev‐Yitshak, ESimchovitz, and DYaffe; Instituto de Neurosciencias Fundacion Favaloro: LAndreone, FBonaudo, JCorderi, LLevi, LMesa, and PMarco; Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center and the University of Pittsburgh: PClemens, HAbdel‐Hamid, RBendixen, CBise, ACraig, KKarnavas, CMatthews, GNiizawa, ASmith, and JWeimer; Washington University: JAnger, TChristenson, JFlorence, RGadeken, PGolumbak, BMalkus, APestronk, RRenna, JSchierbecker, CSeiner, and CWulf; Children’s Hospital of Richmond at Virginia Commonwealth University: JTeasley, SBlair, BGrillo, and EMonasterio; University of Tennessee: TBertorini, MBarrett‐Adair, CBenzel, KCarter, JClift, BGatlin, RHenegar, JHolloway, MIgarashi, FKiphut, AParker, APhillips, and RYoung; Children’s Hospital of Westmead: KNorth, KCornett, NGabriel, MHarman, CMiller, KRose, and SWicks; University of Alberta: HKolski, LChen, and CKennedy; Centro Clinico Nemo: MBeneggi, LCapone, AMolteni, and VMorettini; Texas Children’s Hospital: TLotze, AGupta, AKnight, BLott, RMcNeil, GOrozco, and RSchlosser; University of Minnesota: GChambers, JDay, JDalton, AErickson, MMargolis, JMarsh, and CNaughton; Mayo Clinic: KColeman‐Wood, AHoffman, WKorn‐Petersen, and NKuntz; University of Puerto Rico: BDeliz, SEspada, PFuste, CLuciano, and JTorres; and the CINRG Coordinating Center: Lauren Morgenroth, MAhmed, AArrieta, NBartley, TBrown‐Caines, CCarty, TDuong, JFeng, FHu, LHunegs, ZSund, WTang, and AZimmerman. The Cooperative International Neuromuscular Research Group‐DMD Natural History Study was funded by the US Department of Education/National Institute on Disability and Rehabilitation Research (nos. H133B031118, H133B090001); US Department of Defense (no. W81XWH‐12‐1‐0417); National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; no. R01AR061875); and the Parent Project Muscular Dystrophy. The Duchenne Regulatory Science Consortium includes the following: Binghamton University, Children’s Hospital of Philadelphia, Children's National Health System, Children’s National Heart Institute, Cincinnati Children’s Hospital Medical Center, Hadassah Medical Center, Indiana University School of Medicine, Leiden University Medical Center, Stanford University, University of California Davis, UMass Memorial, University of Arizona, University of Florida, University of Leicester, Vanderbilt University Medical Center, Cincinnati Children’s Hospital, Parental Project for Muscular Dystrophy, CureDuchenne, Edgewise Therapeutics, Epirium Bio, Pfizer, Regenxbio, Sarepta Therapeutics Takeda Pharmaceuticals, Ultragenyx, Vertex Pharmaceuticals, NIH, Glen Nuckolls from the National Institute of Neurological Disorders and Stroke, and Emily Carifi from the NIAMS.
Publisher Copyright:
© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2022/3
Y1 - 2022/3
N2 - Early clinical trials of therapies to treat Duchenne muscular dystrophy (DMD), a fatal genetic X-linked pediatric disease, have been designed based on the limited understanding of natural disease progression and variability in clinical measures over different stages of the continuum of the disease. The objective was to inform the design of DMD clinical trials by developing a disease progression model-based clinical trial simulation (CTS) platform based on measures commonly used in DMD trials. Data were integrated from past studies through the Duchenne Regulatory Science Consortium founded by the Critical Path Institute (15 clinical trials and studies, 1505 subjects, 27,252 observations). Using a nonlinear mixed-effects modeling approach, longitudinal dynamics of five measures were modeled (NorthStar Ambulatory Assessment, forced vital capacity, and the velocities of the following three timed functional tests: time to stand from supine, time to climb 4 stairs, and 10 meter walk-run time). The models were validated on external data sets and captured longitudinal changes in the five measures well, including both early disease when function improves as a result of growth and development and the decline in function in later stages. The models can be used in the CTS platform to perform trial simulations to optimize the selection of inclusion/exclusion criteria, selection of measures, and other trial parameters. The data sets and models have been reviewed by the US Food and Drug Administration and the European Medicines Agency; have been accepted into the Fit-for-Purpose and Qualification for Novel Methodologies pathways, respectively; and will be submitted for potential endorsement by both agencies.
AB - Early clinical trials of therapies to treat Duchenne muscular dystrophy (DMD), a fatal genetic X-linked pediatric disease, have been designed based on the limited understanding of natural disease progression and variability in clinical measures over different stages of the continuum of the disease. The objective was to inform the design of DMD clinical trials by developing a disease progression model-based clinical trial simulation (CTS) platform based on measures commonly used in DMD trials. Data were integrated from past studies through the Duchenne Regulatory Science Consortium founded by the Critical Path Institute (15 clinical trials and studies, 1505 subjects, 27,252 observations). Using a nonlinear mixed-effects modeling approach, longitudinal dynamics of five measures were modeled (NorthStar Ambulatory Assessment, forced vital capacity, and the velocities of the following three timed functional tests: time to stand from supine, time to climb 4 stairs, and 10 meter walk-run time). The models were validated on external data sets and captured longitudinal changes in the five measures well, including both early disease when function improves as a result of growth and development and the decline in function in later stages. The models can be used in the CTS platform to perform trial simulations to optimize the selection of inclusion/exclusion criteria, selection of measures, and other trial parameters. The data sets and models have been reviewed by the US Food and Drug Administration and the European Medicines Agency; have been accepted into the Fit-for-Purpose and Qualification for Novel Methodologies pathways, respectively; and will be submitted for potential endorsement by both agencies.
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U2 - 10.1002/psp4.12753
DO - 10.1002/psp4.12753
M3 - Article
C2 - 34877803
AN - SCOPUS:85122155453
SN - 2163-8306
VL - 11
SP - 318
EP - 332
JO - CPT: Pharmacometrics and Systems Pharmacology
JF - CPT: Pharmacometrics and Systems Pharmacology
IS - 3
ER -