Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety
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(2019) 1:33
CLINICAL TRIAL PROTOCOL
Neurological Research and Practice
Open Access
Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA) Kathrin Reetz1,2 , Ralf-Dieter Hilgers3, Susanne Isfort4, Marc Dohmen4, Claire Didszun1,2, Kathrin Fedosov1,2, Jennifer Kistermann4, Caterina Mariotti5, Alexandra Durr6, Sylvia Boesch7, Thomas Klopstock8,9,10, Francisco Javier Rodríguez de Rivera Garrido11, Ludger Schöls12,13, Thomas Klockgether14,15, Massimo Pandolfo16, Rudolf Korinthenberg17, Philip Lavin18, Geert Molenberghs19, Vincenzo Libri20, Paola Giunti21†, Richard Festenstein22†, Jörg B. Schulz1,2,4* and the EFACTS or NICOFA study group Abstract Introduction: Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown. Methods: The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1–4) to the individually highest tolerated dose of 2–4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5–104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician’s and patient’s global impression-change scales as well as the upregulation of the frataxin protein level, safety and survival/death. (Continued on next page)
* Correspondence: [email protected] † Paola Giunti and Richard Festenstein contributed equally to this work. 1 Department of Neurology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany 2 JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungsze
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