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Effect of Mexiletine on Muscle Stiffness In mexiletine201011 Mexiletine vs. placebo in NDMs Study title; Combining N-of-1 trials to estimate population clinical effectiveness of drugs using Bayesian hierarchical modeling; The case of Mexiletine for patients with Non-Dystrophic Myotonia. (June 2011, version 2) Downloaded From: https://jamanetwork.com/ on 10/02/2021 mexiletine201011 Mexiletine vs. placebo in NDMs Protocol ID mexiletine201011 Short title Mexiletine vs. placebo in NDMs Version 2 Date 03-06-2011 Coordinating investigator/project Dr. G. Drost leader (Neurologist/ Clinical neurophysiologist) tel: 024-3613450 E-mail: [email protected] Principal investigators Dr. G. Drost (Neurologist/ Clinical neurophysiologist) Prof. G.J. van der Wilt (Professor Department of Epidemiology, Biostatistics and HTA) Tel: 024-3610383 E-mail: [email protected] MSc. B.C. Stunnenberg (Medical Biologist/ PhD-student Neurology/ HTA) Tel: 024-3615285 E-mail: [email protected] Sponsor The Netherlands Organisation for Health Research and Development (ZonMw) Independent physician(s) Dr. F.E. de Leeuw (Neurologist/ Clinical epidemiologist) Tel:024-3668374 E-mail: [email protected] Pharmacy Department of Clinical Pharmacy Postbus 9101 6500 HB Nijmegen. Tel: 024-3617613/ Fax: 024-3668755 Downloaded From: https://jamanetwork.com/ on 10/02/2021 mexiletine201011 Mexiletine vs. placebo in NDMs PROTOCOL SIGNATURE SHEET Name Signature Date Head of Department: Prof. G.J. van der Wilt (Professor Department of Epidemiology, Biostatistics and HTA) Coordinating Investigator/Project leader/Principal Investigator: Dr. G. Drost (Neurologist/ Clinical neurophysiologist) Phd student: MSc. B.C. Stunnenberg (Medical Biologist) Downloaded From: https://jamanetwork.com/ on 10/02/2021 mexiletine201011 Mexiletine vs. placebo in NDMs TABLE OF CONTENTS 1. INTRODUCTION AND RATIONALE .............................................................................. 8 2. OBJECTIVES ................................................................................................................10 3. STUDY DESIGN ...........................................................................................................12 4. STUDY POPULATION ..................................................................................................18 4.1 Population (base) ..................................................................................................18 4.2 Inclusion criteria................................................................................................. ......17 4.3 Exclusion criteria ....................................................................................................18 4.4 Sample size calculation ..........................................................................................19 5. TREATMENT OF SUBJECTS .......................................................................................22 5.1 Investigational product/treatment ............................................................................22 5.2 Use of co-intervention (if applicable) ......................................................................22 5.3 Escape medication (if applicable) ...........................................................................22 6. INVESTIGATIONAL MEDICINAL PRODUCT ................................................................24 6.1 Name and description of investigational medicinal product(s) ................................24 6.2 Summary of findings from non-clinical studies ........................................................24 6.3 Summary of findings from clinical studies ...............................................................25 6.4 Summary of known and potential risks and benefits ...............................................28 6.5 Description and justification of route of administration and dosage .........................30 6.6 Dosages, dosage modifications and method of administration ...............................30 6.7 Preparation and labelling of Investigational Medicinal Product ...............................30 6.8 Drug accountability .................................................................................................30 7. METHODS ....................................................................................................................31 7.1 Study parameters/endpoints ...................................................................................31 7.1.1 Main study parameter/endpoint .......................................................................31 7.1.2 Secondary study parameters/endpoints (if applicable) ....................................31 7.1.3 Other study parameters (if applicable) .............................................................31 7.2 Randomisation, blinding and treatment allocation ..................................................31 7.3 Study procedures ...................................................................................................31 7.4 Withdrawal of individual subjects ..........................................................................35 7.4.1 Specific criteria for withdrawal (if applicable) .................................................35 7.5 Replacement of individual subjects after withdrawal .............................................35 7.6 Follow-up of subjects withdrawn from treatment ...................................................35 7.7 Premature termination of the study .........................................................................35 8. SAFETY REPORTING ..................................................................................................36 8.1 Section 10 WMO event ..........................................................................................36 Downloaded From: https://jamanetwork.com/ on 10/02/2021 mexiletine201011 Mexiletine vs. placebo in NDMs 8.2 Adverse and serious adverse events ......................................................................36 8.2.1 Suspected unexpected serious adverse reactions (SUSAR) ...........................37 8.2.2 Annual safety report ........................................................................................38 8.3 Follow-up of adverse events ...................................................................................38 8.4 Data Safety Monitoring Board (DSMB) ...................................................................38 9. STATISTICAL ANALYSIS ............................................................................................40 9.1 Multivariate analysis ...............................................................................................40 9.2 Interim analysis (if applicable) ................................................................................40 10. ETHICAL CONSIDERATIONS ......................................................................................43 10.1 Regulation statement .............................................................................................43 10.2 Recruitment and consent........................................................................................44 10.3 Objection by minors or incapacitated subjects (if applicable) ..................................47 10.4 Benefits and risks assessment, group relatedness .................................................47 10.5 Compensation for injury .........................................................................................48 10.6 Incentives (if applicable) .........................................................................................48 11. ADMINISTRATIVE ASPECTS AND PUBLICATION ..................................................49 11.1 Handling and storage of data and documents ........................................................49 11.2 Amendments ..........................................................................................................49 11.3 Annual progress report ...........................................................................................50 11.4 End of study report .................................................................................................50 11.5 Public disclosure and publication policy ..................................................................50 12. REFERENCES ..........................................................................................................51 Downloaded From: https://jamanetwork.com/ on 10/02/2021 mexiletine201011 Mexiletine vs. placebo in NDMs LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ABR ABR form, General Assessment and Registration form, is the application form that is required for submission to the accredited Ethics Committee (In Dutch, ABR = Algemene Beoordeling en Registratie) AE Adverse Event AR Adverse Reaction CA Competent Authority CCMO Central Committee on Research Involving Human Subjects; in Dutch: Centrale Commissie Mensgebonden Onderzoek CV Curriculum Vitae DSMB Data Safety Monitoring Board EU European Union EudraCT European drug regulatory affairs Clinical Trials GCP Good Clinical Practice IB Investigator’s Brochure IC Informed Consent IMP Investigational Medicinal Product IMPD Investigational Medicinal Product Dossier METC Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing commissie (METC) (S)AE (Serious) Adverse Event SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst) Sponsor The sponsor is the party that commissions the organisation or performance of the research, for example a pharmaceutical
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