title: Treatment with L-citrulline and metformin in Duchenne muscular dystrophy: study protocol for a single-centre, randomised, placebo-controlled trial.
abstract: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1 in 3500-6000 male births. Despite broad research aiming to improve muscle function as well as heart and brain function, sufficient therapeutic efficacy has not yet been achieved and current therapeutic management is still supportive. In a recent pilot trial, oral treatment with L-arginine and metformin showed consistent changes of muscular metabolism both in vitro and in vivo by raising NO levels and expression of mitochondrial proteins in the skeletal muscle tissue of patients with DMD. This randomised, double-blind, placebo-controlled trial aims to demonstrate the superiority of L-citrulline and metformin therapy over placebo in DMD patients with regard to the Motor Function Measure (MFM) D1 subscore (primary endpoint) as well as additional clinical and subclinical tests.
  
  
  
  A total of 40-50 ambulant patients with DMD will be recruited at the outpatient department of the University of Basel Children's Hospital (Switzerland), as well as from the DMD patient registries of Switzerland, Germany and Austria. Patients will be randomly allocated to one of the two arms of the study and will receive either a combination of L-citrulline and metformin or placebo for 26 weeks. Co-medication with glucocorticoids is allowed. The primary endpoint is the change of the MFM D1 subscore from baseline to week 26 under L-citrulline and metformin therapy. Secondary endpoints will include the motor function measure (MFM) and its items and subscores, the 6-minute walking test, timed function tests and quantitative muscle testing. Furthermore, quantitative muscle MRI assessment to evaluate the muscle fat fraction as well as safety and biomarker laboratory analyses from blood will be included. For comparison, muscle metabolism and mitochondrial function will be analysed in 10-20 healthy age-matched male children.
  
  
  
  The aim of this study is to test if a 6-month treatment of a combination of L-citrulline and metformin is more effective than placebo in preventing loss of motor function and muscle degeneration in DMD. The MFM D1 subscore is used as a clinical outcome measure and a quantitative muscle MRI assessment as the surrogate outcome measure of fatty muscle degeneration.
  
  
  
  ClinicalTrials.gov: NCT01995032 . Registered on 20 November 2013.
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland. patricia.hafner@ukbb.ch.|Division of Neurology, Medical University Clinic, Kantonsspital Baselland, Bruderholz, Switzerland. patricia.hafner@ukbb.ch.|Division of Neuropaediatrics, University Children's Hospital, Spitalstrasse 33, Postfach, Basel, 4056, Switzerland. patricia.hafner@ukbb.ch.
authors.forename: Patricia
authors.identifier: 0000-0003-1381-0216
authors.initials: P
authors.lastname: Hafner
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bonati
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rubino
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Vanya
authors.initials: V
authors.lastname: Gocheva
authors.affiliation: Department of Clinical research, Clinical Trial Unit, University of Basel Hospital, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zumbrunn
authors.affiliation: Pharmacy, School of Medicine, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Nuri
authors.initials: N
authors.lastname: Gueven
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.|Division of Neurology, Medical University Clinic, Kantonsspital Baselland, Bruderholz, Switzerland.|Department of Neurology, University of Basel Hospital, Basel, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
mesh_terms: D015415:Biomarkers / Q000097:blood; D002648:Child; D002956:Citrulline / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005060:Europe; D017079:Exercise Tolerance / Q000187:drug effects; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D020127:Recovery of Function; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D000070857:Walk Test
chemical_list: D015415:Biomarkers; D002956:Citrulline; D008687:Metformin
keywords: Clinical trial; DMD; L-citrulline; Metformin; Mitochondrial function; Quantitative MRI