2-year Change in Revised Hammersmith Scale scores in a large cohort of untreated paediatric type 2 and 3 SMA participants.

Abstract

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function and baseline RHS score. We consider a new transitional group, spanning crawlers, standers and walkers-with-assistance, and analyse that alongside non-sitters, sitters and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. In the stronger participants (between 10 and 42 on the RHS) in the 5-7 age group, both the RHS and HFMSE can detect 1-year change. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

Competing Interest Statement

A.D. has received compensation as a consultant on advisory boards for Roche, Biogen and AveXis. A.M. has served on medical/scientific advisory boards for Biogen and Roche; has received fees for consulting and training services for Biogen, Roche, Novartis and Biohaven. A.M.G. receives fees for consulting services for Biogen, Roche, and Audentes and li-censing fees for co-development of the CHOP INTEND. A.P. has served on medical/scientific advisory boards for AveXis, Biogen and Roche; has received fees for consulting services for Biogen, Roche and Audentes. B.T.D. has served as an ad hoc scientific ad-visory board member for Audentes, AveXis/Novartis Gene Therapies, Biogen, Pfizer, Sarepta, Vertex and Roche/Genentech; Steering Committee Chair for Roche FIREFISH and MANATEE studies and DSMB member for Amicus Inc. and Lexeo Therapeutics; B.T.D. has no financial interests in these companies. B.T.D. has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund and has received grants from Ionis Pharmaceuticals, Inc., for the ENDEAR, CHERISH, CS2/CS12 studies; from Biogen for CS11; and from AveXis, Sarepta Pharmaceuticals, Novartis (AveXis), PTC Therapeutics, Roche, Scholar Rock, and Fibrogen. B.T.D. has also received royalties for books and online publications from Elsevier and UpToDate, Inc. C.B. has served as a consultant, speaker in sponsored symposiums and principal investigator for Roche, and has received personal fees for AveXis and Roche. C.M. has received consultancy honoraria from Biogen, Roche and Novartis for participation in educational activities/meetings. C.M. has also received research funding from Roche and Biogen to support Adult SMA REACH activity. D.C.D.V has served as an advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis, METAFORA, Roche, Sanofi, Sarepta, Scholar Rock, SMA Foundation, and Ultragenyx, with no financial interests in these companies; received grants from Cure SMA, Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, National Institutes of Health, and SMA Foundation; received research funding from Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, iSMAC initiative (Biogen), Na-tional Institutes of Health, Sanofi, and SMA Foundation; received clinical trial funding from Ionis, Mallinckrodt, PTC, Santhera, Sarepta, Scholar Rock, and Ultragenyx; serves as the Data Safety Monitoring Committee Chair for Aspa Therapeutics; and is an inventor on a patent for Glut1DS gene therapy. D.R. reports participation to teaching initiatives for Roche. E.A. has served as a consultant and as a speaker in sponsored symposiums for Biogen. E.B. reports participation to Scientific Advisory Boards for Roche, Biogen, PTC Therapeutics, Pfizer and Novartis. E.B. is involved in Clinical Trials with Roche, Biogen, Novartis, and PTC Therapeutics. E.Mercuri has participated in advisory boards for SMA studies for AveXis, Biogen, Ionis, Novartis, and Roche; has been a Principal Investigator for ongoing Biogen and Roche clinical trials; and received research grants from Famiglie SMA Italy, Italian Telethon, Novartis, Scholar Rock, and SMA Europe. E.S.M. reports conuultancy fees from Roche, Biogen, Scholar Rock and Novartis. F.M. reports participation to Scientific Advisory boards and teaching initiatives for AveXis, Biogen, Roche and Novar-tis. E.S.M. is a member of the Rare Disease Scientific Advisory Board for Pfizer. E.S.M. is involved as an investigator in clinical trials from AveXis, Biogen and Roche. E.S.M. is the principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and by SMA UK. G.B. is principle investigator of clinical trials Sponsored by Pfizer, NS Pharma, and Reveragen, and has received speaker and/or consulting fees from Sarepta, PTC Therapeutics, Biogen, Novartis Gene Therapies, Inc. (AveXis), and Roche and has worked as principal investigator of SMA studies sponsored by Novartis Gene Therapies, Inc., and Roche. G.C. reports participation to Scientific Advisory boards and teaching initiatives for AveXis, Biogen, Roche and Novartis. J.W.D. has received personal fees for AveXis, Biogen, Roche and Novartis. J.M. serves on advisory boards for Biogen, Roche, Genentech, and Sarepta and as a consultant for Scholar Rock and Biogen. She receives grant support from the Muscular Dystrophy Association, Cure SMA, Genentech, and No-vartis. M.P. has served as a consultant and as a speaker in sponsored symposiums for Bi-ogen, and has received personal fees for AveXis. M.S. reports participation to Scientific Advisory boards and teaching initiatives for AveXis, Biogen, Roche; M.S. is involved as an investigator in clinical trials from AveXis, Biogen and Roche. R.M.L. has served in advisory boards for Biogen, Roche and Novartis, has received consulting fees by Roche, Biogen and Novartis and research support by Roche and Biogen. R.S.F. has served on medical/scientific advisory boards on SMA-related topics for AveXis, Biogen, Capricor, Families of SMA, Genentech, Ionis Pharmaceuticals, Novartis, Roche, and ScholarRock; received research support from AveXis/Novartis, Biogen/Ionis, Capricor, Roche/Genentech, Scholar Rock, NIH, and receives license fees for co-development of the CHOP INTEND. S.D.Y. serves on advisory boards for Biogen, Roche, Scholar Rock and as a consultant for Biogen, Roche, and Cure SMA. S.D.Y. receives grant support from Cure SMA. S.M. has received honoraria from Biogen , Roche and Novartis for advisory boards and presentations. T.D. has served on scientific advisory boards for AveXis, Biogen, Roche, Scholar Rock, Novartis, CureSMA, Dyne and Actigraph; has received consulting fees Roche, Biogen, Biohaven, Dyne, Sarepta, Solid Bio, Tayjus, Astellas, ATOM, Trinds. V.S. has served as a consultant and as a speaker in sponsored symposiums for Biogen, and has received personal fees for AveXis. A.W., E.Milev, G.S., M.C., M.M. and Z.Z.C. has no conflicting interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Funding Statement

The support of Biogen and advocacy group SMA TRUST and Muscular Dystrophy UK to the Neuromuscular Centre at UCL and to the SMA REACH network is grate-fully acknowledged. The Pediatric Neuromuscular Clinical Research (PNCR) Network for SMA (Boston Children's Hospital, Children's Hospital of Philadelphia, Vagelos College of Physicians and Surgeons, Columbia University, New York; Nemours Children's Hospital, Orlando; and Stanford University, Palo Alto) gratefully acknowledges the support of the SMA Foundation and Cure SMA. The support of Famiglie SMA, Telethon (GSP 13002), and ASAMSI to the Nemo Center in Rome and to the Italian network is gratefully acknowledged.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was conducted in accordance with the Declaration of Helsinki. Each of the International SMA Consortium natural history studies had ethical approval in place per-mitting collection of RHS natural history data. SMA REACH UK: National Research Ethics Committee (REC) London Bromley, Health Research Authority REC reference 13/LO/1748. PNCR USA Institutional Review Boards (IRB) and Numbers: IRB Numbers-Columbia University Medical Center Human Research Protection Office IRB reference AAAE8252, The Children's Hospital of Philadelphia IRB reference 10-007816, Boston Children's Hospital Office of Clinical Investigations IRB reference 05-02-028, Stanford University Re-search Compliance Office IRB reference 31140, Nemours Children's Hospital reference number 1004092. Italian SMA Network is co-ordinated by Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS (IRB protocol number 2533/18) and includes: University of Messina; IRCCS Bambino Gesù Children's; University of Milan, Niguarda Hospital; IRCCS Istituto Giannina Gaslini.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produced in the present study may be made available upon reasonable request to the authors and approval from the iSMAC steering committee.

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