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1 Articles Efficacy of idebeoe o respiratory fuctio i patiets with Duchee muscular dystrophy ot usig glucocorticoids (DELOS): a double-blid radomised placebo-cotrolled phase trial Guar M Buyse, Thomas Voit, Ulrike Schara, Chiara S M Straathof, M Grazia D Agelo, Güther Berert, Jea-Marie Cuisset, Richard S Fikel, Nathalie Goemas, Craig M McDoald, Christia Rummey, Thomas Meier, for the DELOS Study Group Summary Backgroud Cardiorespiratory failure is the leadig cause of death i Duchee muscular dystrophy. Based o precliical ad phase evidece, we assessed the efficacy ad safety of idebeoe i youg patiets with Duchee muscular dystrophy who were ot takig cocomitat glucocorticoids. Methods I a multicetre phase trial i Belgium, Germay, the Netherlads, Switzerlad, Frace, Swede, Austria, Italy, Spai, ad the USA, patiets (age 8 years old) with Duchee muscular dystrophy were radomly assiged i a oe-to-oe ratio with a cetral iteractive web respose system with a permuted block desig with four patiets per block to receive idebeoe ( mg three times a day) or matchig placebo orally for 5 weeks. Study persoel ad patiets were masked to treatmet assigmet. The primary edpoit was chage i peak expiratory flow (PEF) as percetage predicted (PEF%p) from baselie to week 5, measured with spirometry. Aalysis was by itetio to treat (ITT) ad a modified ITT (mitt), which was prospectively defied to exclude patiets with at least % differece i the yearly chage i PEF%p, measured with hospital-based ad weekly home-based spirometry. This study is registered with CliicalTrials.gov, umber NCT788. Fidigs patiets i the idebeoe group ad i the placebo group comprised the ITT populatio, ad ad 7 comprised the mitt populatio. Idebeoe sigificatly atteuated the fall i PEF%p from baselie to week 5 i the mitt ( 5%p [95% CI 7 8 to 97], p=, vs placebo 9 %p [ 8 to 8], p= ; differece 5 96%p [ 6 to 76], p= ) ad ITT populatios ( 57%p [ 6 68 to 5], p= 5, vs 8 8%p [ 7 to 95], p< ; differece 6 7%p [ 6 to 9], p= ). Idebeoe also had a sigificat effect o PEF (L/mi), weekly home-based PEF, FVC, ad FEV. The effect of idebeoe o respiratory fuctio outcomes was similar betwee patiets with previous corticosteroid use ad steroid-aive patiets. Treatmet with idebeoe was safe ad well tolerated with adverse evet rates were similar i both groups. Nasopharygitis ad headache were the most commo adverse evets (idebeoe, eight [5%] ad six [9%] of patiets; placebo, ie [6%] ad seve [%] of patiets). Trasiet ad mild diarrhoea was more commo i the idebeoe group tha i the placebo group (eight [5%] vs four [%] patiets). Iterpretatio Idebeoe reduced the loss of respiratory fuctio ad represets a ew treatmet optio for patiets with Duchee muscular dystrophy. Fudig Sathera Pharmaceuticals. Itroductio Duchee muscular dystrophy is the most commo ad devastatig type of muscular dystrophy. Progressive weakess of respiratory muscles leads to restrictive pulmoary disease that evolves ito respiratory complicatios ad early morbidity ad mortality. 7 Glucocorticoids are the oly medicatios that ca slow the declie i muscle stregth ad fuctio ad delay the oset ad progressio of respiratory dysfuctio. 8 However, ot all patiets with Duchee muscular dystrophy respod to steroids to the same extet ad the well kow side-effects of steroids restrict their cliical use, particularly i o-ambulatory patiets i the later stage of the disease. I a atural history study, % of patiets with Duchee muscular dystrophy aged years ad older had ever used glucocorticoids or discotiued their use because of side-effects ad tolerability limitatios. 9 Cosequetly, for may patiets with Duchee muscular dystrophy there are o pharma cological treatmet optios at about the age whe patiets become o-ambulatory ad the declie i their respiratory fuctio becomes cliically relevat. The short-chai bezoquioe idebeoe is a potet atioxidat ad ihibitor of lipid peroxidatio that is capable of stimulatig mitochodrial electro flux ad cellular eergy productio., The results of a placebo-cotrolled study i the mdx mouse showed sigificat cardioprotective ad volutary exercise performace effects after idebeoe treatmet. The fidigs from a phase radomised placebo-cotrolled Published Olie April, 5 S-676(5)65- See Olie/Commet S-676(5) Uiversity Hospitals Leuve, Leuve, Belgium (Prof G M Buyse MD, N Goemas MD); Istitut de Myologie, Uiversité Pierre et Marie Curie INSERM UMR 97, CNRS FRE 67, Groupe Hospitalier de la Pitié Salpetrière, Paris, Frace (Prof T Voit MD); Uiversitätskliikum, Esse, Germay (Prof U Schara MD); Leide Uiversity Medical Ceter, Leide, Netherlads (C S M Straathof MD); Istituto di Ricovero e Cura a Carattere Scietifico Eugeio Medea, Lecco, Italy (M G D Agelo MD); Gottfried vo Preyer sches Kiderspital, Viea, Austria (G Berert MD); Cetre Hospitalier Régioal Uiversitaire de Lille, Lille, Frace (J-M Cuisset MD); Nemours Childre s Hospital, Orlado, FL, USA (Prof R S Fikel MD); Uiversity of Califoria Davis Medical Ceter, Sacrameto, CA, USA (Prof C M McDoald MD); Pharma, Liestal, Switzerlad (C Rummey PhD); ad Sathera Pharmaceuticals, Liestal, Switzerlad (T Meier PhD) Correspodece to: Prof Guar M Buyse, Child Neurology, Uiversity Hospitals Leuve, Herestraat 9, B Leuve, Belgium guar.buyse@uzleuve.be Published olie April, 5

2 Articles See Olie for appedix placebo (safety populatio) 7 mitt populatio trial (DELPHI) showed beeficial effects of idebeoe o early fuctioal cardiac ad respiratory markers. A importat fidig from the DELPHI study was that patiets treated with idebeoe had stabilised peak expiratory flow as percetage predicted (PEF%p), a marker of expiratory muscle stregth compared with a reductio i patiets give placebo. Additioal aalyses idicated that the effect of idebeoe o respiratory fuctio outcomes was larger i patiets ot takig cocomitat glucocorticoids. 5 We ivestigated the efficacy, tolerability, ad safety of idebeoe i a cofirmatory phase trial i patiets with Duchee muscular dystrophy ot takig cocomitat glucocorticoids. Methods Study desig ad patiets Patiets aged 8 years with a documeted diagosis of Duchee muscular dystrophy were eligible for iclusio i this phase trial. Recruitig cetres were 96 patiets screeed 65 radomly assiged o-radomly assiged 66 treated early discotiuatio adverse evets o-compliace protocol violatio 6 >% differece i yearly chage i PEP%p idebeoe (safety populatio) completed study 5 completed study ITT populatio ITT populatio mitt populatio 9 excluded PEF%p ot withi 5% 6 other reasos* ot treated (withdrew coset) 7 early discotiuatio adverse evet o-compliace withdrawal of coset lost to follow-up spial fixatio surgery >% differece i yearly chage i PEP%p Figure : Trial profile PEF%p=peak expiratory flow as percetage predicted. ITT=itetio to treat. mitt=modified itetio to treat. *Two patiets were uable to form a mouth seal, two had PEF %p greater tha 8% at baselie, two required assisted vetilatio, oe patiet was usig steroids, oe required spial fixatio surgery, two patiets were uable to comply with study procedures, oe patiet withdrew iformed coset, oe was a smoker, ad four patiets had oe or more other reasos for exclusio. i Belgium, Germay, the Netherlads, Switzerlad, Frace, Swede, Austria, Italy, Spai, ad the USA. A full list of iclusio, exclusio, ad withdrawal criteria is provided i the appedix. Patiets were erolled betwee July 7, 9 (study start date), ad Dec, ; the study ed date (last patiet completed the study) was Ja,. Radomisatio ad maskig We used a iteractive web respose system to radomly allocate patiets i a oe-to-oe ratio with a permuted block desig with four patiets per block to film-coated tablets of idebeoe (5 mg per tablet, Raxoe/Catea, Sathera Pharmaceuticals, Liestal, Switzerlad; mg three times a day, orally, durig meals) or matchig placebo for 5 weeks. Two sibligs of patiets who were already radomly allocated were assiged to the same group as their sibligs to avoid mix up of study medicatio. Radomisatio was balaced for PEF%p at baselie (two PEF%p strata: <%p ad 8%p). All study persoel ad patiets were masked to treatmet group assigmet. Compliace was moitored with etries i a patiet s diary ad pill couts. After erolmet, safety ad efficacy were assessed durig hospital visits at weeks, 6, 9, ad 5. Additioal safety assessmets were udertake weeks after radomisatio ad at the follow-up visit weeks after the week 5 visit or after early discotiuatio of study medicatio. Patiets were istructed ad educated to assess their weekly respiratory fuctio (peak expiratory flow [PEF] ad forced expiratory volume i s [FEV ]) usig the had-held ASMA- device (usb model, Vitalograph, Maids Moreto, UK) at home. The study had several protocol amedmets, which are listed i the appedix. The trial ad ay chages to the protocol were approved by relevat atioal authorities ad the istitutioal review boards or idepedet ethics committees i the coutries of the participatig cetres ad doe i accordace with good cliical practice ad the priciples of the Declaratio of Helsiki. We obtaied writte iformed coset from patiets. Outcomes The primary objective was to assess the efficacy of idebeoe, compared with placebo, i improvig or reducig loss of respiratory fuctio, measured by a qualified, traied, ad certified evaluator at each cetre i accordace with stadardised procedures ad iteratioal guidelies. Pulmoary fuctio tests were doe at each hospital visit with a Peumotrac Spirometer 68 (Vitalograph) ad maximal static airway pressures were assessed with a MicroRPM istrumet (Medical Supply Store, Chorley, UK). At each hospital visit, PEF ad FEV were also measured with the patiet s portable ASMA- device. The primary edpoit was the chage i spirometer-measured PEF%p from baselie to week 5. Secodary respiratory efficacy edpoits were chages Published olie April, 5

3 Articles i PEF, forced vital capacity (FVC), FEV, maximum ispiratory pressure (MIP), maximum expiratory pressure (MEP), ad peak cough flow assessed durig hospital visits at weeks, 6, 9, ad 5. PEF ad FEV were also measured weekly at home with the portable ASMA- device. The highest value from a miimum of three ad up to five cosecutive maoeuvres was used for each assessmet. Percetage predicted (%p) values were calculated with established equatios (appedix). 6 Safety assessmets were physical exam iatio, vital sigs, ad blood or urie samplig. Cardiac fuctio (trasthoracic echocardiography ad -lead electrocardiography [ECG]) was assessed for safety moitorig, but ot as efficacy edpoits. Blood ad urie aalyses were doe at BARC Europe NV (Get, Belgium). Adverse evets were graded for severity ad relatio to the study drug ad coded with the MedDRA dictioary (versio.). Statistical aalysis A statistical aalysis pla was prepared before the database was locked. The primary aalysis of the primary edpoit (chage i PEF%p from baselie to week 5) was to be made i a modified itetio-to-treat populatio (mitt; appedix), which excluded patiets with at least % differece i the yearly chage i PEF%p measured with hospital-based spirometry ad home-based ASMA- assessmets. Like all the other edpoits, the primary edpoit was also calculated i the full ITT populatio. Cotiuous variables were aalysed with a mixed model for repeated measuremets with treatmet group, visit, ad iteractio betwee treatmet group ad visit used as fixed factors i the model ad baselie assessmet used as a covariate. For respoder aalyses, respoders were defied as patiets who did ot have deterioratio i respiratory fuctio tests. Respoder rates were compared betwee treatmet groups with the Cochra-Matel- Haeszel test with missig data imputed with the last observatio carried forward method. All hypotheses tested ad 95% CIs preseted were two-sided ad p values of less tha 5% were sigificat without adjustmet for multiplicity ad regarded as exploratory except for the primary edpoit. The sample size for the study provided 8% power to detect a differece of % i PEF%p. A plaed futility aalysis was doe after all 6 patiets had bee radomly assiged ad 7 had completed the trial. This aalysis, doe by the data ad safety moitorig board, cofirmed o-futility of the trial. This study is registered with CliicalTrials.gov, umber NCT788. Role of the fudig source The study fuder was ivolved i the study desig, ad data gatherig ad aalysis. The ivestigators ad all authors had sole discretio i the data aalysis ad iterpretatio, writig of the report, ad the decisio to submit for publicatio. Results 96 patiets were screeed ad 9 were excluded from participatio because they did ot meet iclusio or exclusio criteria. 65 patiets were radomly assiged ad two patiets were allocated to the same treatmet as their radomly assiged sibligs (figure ). Oe patiet ever took study medicatio, resultig i 66 patiets who were treated ad icluded i the safety populatio ( i the placebo group ad i the idebeoe group). 55 patiets completed the trial ad withdrew or discotiued the drug durig the study. The ITT populatio ( patiets i the placebo group ad i the idebeoe group) excluded patiets who were allocated to the same treatmet as their sibligs ad the Idebeoe group (=) Placebo group (=) Age (years) 5 ( 7) 5 ( 5) Weight (kg) 55 (8 ) 6 9 (8 ) Height* (cm) 57 ( ) 6 ( ) Body-mass idex (kg/m²) (5 9) (5 6) Ethic origi White 9 (9%) (9%) Orietal (%) Hispaic (%) Other (%) (%) Previous glucocorticoid use Yes 7 (55%) 9 (58%) No (5%) (%) Time sice last glucocorticoid use 9 ( 8) ( ) (years) Patiet i wheelchair 8 (9%) (9%) Baselie PEF%p <%p 5 (6%) 7 (%) 8%p 6 (8%) 6 (79%) Baselie respiratory fuctio test PEF%p 5 5 ( ) 5 ( ) PEF (L/mi) 7 7 (8 6) 8 (59 6) FVC%p 55 (5 8) 5 ( ) FVC (L) 9 ( 5) 9 ( 5) FEV %p 5 (5 ) 9 7 (8 ) FEV (L) 5 ( ) 7 ( 57) MIP%p 5 ( ) 8 5 (6 9) MIP (cm H₂O) 7 ( ) 6 (6 9) MEP%p 8 ( ) 5 ( ) MEP (cm H₂O) 6 (5 6) 9 7 (6 6) PCF (L/mi) (7 7) 56 (5 5) Data are mea (SD) or umber (%). ITT=itetio-to-treat populatio. PEF%p=peak expiratory flow as percetage predicted. FVC%p=forced vital capacity as percetage predicted. FVC=forced vital capacity. FEV %p=forced expiratory volume i s as percetage predicted. FEV =forced expiratory volume i s. MIP%p=maximum ispiratory pressure as percetage predicted. MIP=maximum ispiratory pressure. MEP%p=maximum expiratory pressure as percetage predicted. MEP=maximum expiratory pressure. PCF=peak cough flow. *Derived from ular legth., Table : Demographic characteristics ad baselie pulmoary fuctio values i the ITT populatio Published olie April, 5

4 Articles mitt populatio prospectively excluded seve patiets (7 ad patiets; appedix). Patiets characteristics at baselie were balaced betwee the treatmet groups (table ), except for youger age i the idebeoe group. Time sice last steroid use before erolmet i the trial was well above the required -moth washout i both groups (table ). At baselie more tha 9% of patiets were A B PEF%p PEF (L/mi) ( 8 to 8 6) ( 5 to ) ( 8 to 7) 9 6 Differece (95% CI) p value Idebeoe Placebo ( 6 to 9) Differece (95% CI) ( 6 7 to 5 ) ( 6 to 5 5) (6 6 to 59 7) ( 69 to 5 5) p value 8 7 C D 5 FVC%p 5 FVC (L) Differece (95% CI) ( 5 to 6 ) ( 8 to 7 6) ( 86 to 9 9) ( to 6 97) p value 9 8 E Differece (95% CI) p value F 9 ( to 8) 6 ( 6 to 6) 6 ( 5 to 7) 5 ( to 7) 5 FEV %p 5 FEV (L) Differece (95% CI) p value 5 5 ( 8 to ) Week 8 6 ( 85 to 67) 5 77 ( to 5) ( 88 to 5 7) Differece (95% CI) p value 8 ( to ) Week 7 ( 6 to 8) ( to 7) 6 ( 7 to 58) Figure : Results of respiratory fuctio test outcomes i the ITT populatio (A) PEF%p. (B) PEF. (C) FVC%p. (D) FVC. (E) FEV %p. (F) FEV. Data are mea (SE), uless otherwise idicated; treatmet differeces ad p values are show for the betwee-group comparisos. ITT=itetio-to-treat populatio. PEF%p=peak expiratory flow as percetage predicted. PEF=peak expiratory flow. FVC%p=forced vital capacity as percetage predicted. FVC=forced vital capacity. FEV %p=forced expiratory volume i s as percetage predicted. FEV =forced expiratory volume i s. Published olie April, 5

5 Articles Idebeoe group (=) Placebo group (=) Group differece Mea (SD) Chage (95% CI) p value Mea (SD) Chage (95% CI) p value Differece (95% CI) p value PEF%p Baselie 5 5 ( ) 5 ( ) Chage from baselie (MMRM) Week 5 57 ( 6 68 to 5) ( 7 to 95) < 6 7 ( 6 to 9) Weeks 5 ( 59 to 9) 7 8 ( to 69) < 6 5 ( 98 to 6) 6 PEF (L/mi) Baselie mea (SD) 7 7 (8 6) 8 (59 6) Chage from baselie (MMRM) Week 5 7 ( 6 7 to ) ( 8 to 8 95) 8 9 ( 69 to 5 5) Weeks 5 8 ( 96 to 5 9) ( 9 6 to 67) 7 (6 97 to 7 9) 9 ITT=itetio to treat. MMRM=mixed model for repeated measuremets. PEF=peak expiratory flow. PEF%p=peak expiratory flow as percetage predicted. Table : Chage i PEF from baselie to week 5 ad across all post-baselie assessmet timepoits (weeks 5) i the ITT populatio o-ambulatory ad most patiets preseted with PEF%p of 8%p (table ). Compliace with study medicatio was good with similar exposures betwee treatmet groups (mea 7 days [SD 7 9] i the idebeoe group ad 8 days [65 ] i the placebo group). Patiets were well balaced betwee treatmet groups for baselie respiratory fuctio variables (table ). The primary efficacy variable (PEF%p), as measured with hospital-based spirometry or with the home-based ASMA- device, was similar betwee groups at baselie (appedix), cofirmig the reliability of the data obtaied. For the primary edpoit (mitt populatio), there was a sigificat fall i PEF%p by 9 %p (95% CI 8 to 8; p= ) from baselie to week 5 i the placebo group compared with a o-sigificat declie of 5%p ( 7 8 to 97; p= ) i the idebeoe group, resultig i a sigificat differece betwee treatmet groups of 5 96%p ( 6 to 76; p= ) at week 5 ad this represeted a 66% reductio i loss of PEF%p. The effect of idebeoe was sigificat at week 6 (p= 7) ad week 9 (p= ) ad at all post-baselie assessmet timepoits together (p= 8). Baselie PEF%p values i the mitt populatio were well balaced (idebeoe 5 %p [SD ] ad placebo 5 %p [ 5]). Similar results were obtaied for the full ITT populatio with a sigificat declie i PEF%p from baselie to week 5 i the placebo group by 8 8%p (95% CI 7 to 95; p< ) compared with a o-sigificat declie of 57%p ( 6 68 to 5; p= 5) i the idebeoe group, resultig i sigificat differeces betwee treatmet groups at week 5 (6 7%p [ 6 to 9]; p= ) ad at other study timepoits (figure A; table ). Results for the primary edpoit, assessed with stadard spirometry durig hospital visits, were cofirmed with the results for the secodary PEF edpoits, measured at home with the ASMA- device, through liear regressio aalysis for the yearly chage (p= 55) ad mea of data obtaied durig 6 weeks Assessmet methods (ITT populatio) Hospital based Home based, liear regressio Home based, widow approach Populatios ad imputatio methods mitt PP Completers LOCF, ITT Cook s D*, ITT 5 Effect size (95% CI) Effect size (95% CI) 6 7 ( 6 to 9) 6 8 ( 5 to 8) 7 ( 8 to 66) 5 96 ( 6 to 76) 6 8 ( 8 to ) 5 8 ( 8 to 7) 6 9 ( 99 to 79) 6 9 ( to 5) p value Figure : Comparative effect sizes i favour of idebeoe i PEF%p at week 5 with differet assessmet methods, populatios, ad methods of imputatio for missig data PEF%p=peak expiratory flow as percetage predicted. mitt=modified itetio to treat. PP=per protocol. LOCF=last observatio carried forward. ITT=itetio to treat. *Two patiets (oe i the placebo group ad oe i the idebeoe group) were idetified as affectig the result of the primary aalysis; these patiets were excluded i this post-hoc aalysis. Published olie April, 5

6 Articles Idebeoe group (=) Placebo group (=) p value* Patiets who did ot deteriorate from baselie to week 5 PEF%p (5%) 8 (%) 8 PEF 8 (58%) 9 (7%) FVC%p 7 (%) (9%) FVC 5 (8%) 6 (8%) FEV %p (5%) (%) FEV 8 (58%) (%) 9 Patiets who did ot deteriorate by % or more from baselie to week 5 PEF%p (7%) (%) PEF 6 (8%) 6 (8%) FVC%p (%) 8 (%) 5 FVC (77%) 7 (5%) FEV %p 8 (58%) (9%) 8 FEV (7%) 7 (5%) Data are umber (%), uless otherwise idicated. ITT=itetio-to-treat populatio. PEF%p=peak expiratory flow as percetage predicted. FVC%p=forced vital capacity as percetage predicted. FVC=forced vital capacity. FEV %p=forced expiratory volume i s as percetage predicted. FEV =forced expiratory volume i s. *Cochra-Matel-Haeszel test. Table : Respoder rates i the ITT populatio for respiratory fuctio test results aroud hospital visits (p= 8; figure ; appedix). Sesitivity aalyses were doe to assess the robustess of the results by applyig differet imputatio methods for missig data i the ITT populatio, aalysig a differet populatio, ad by excludig patiets likely to affect the results (figure ). The results show that the treatmet effect was ot altered by differet assumptios about missig data or by the exclusio of data for patiets defied as beig i differet populatios. Divergig trajectories betwee treatmet groups were also oted i PEF with sigificat differeces betwee treatmet groups at week 5 (8 L/mi [95% CI 69 to 5 5]; p= ) ad at other visit timepoits (figure B; table ; appedix). Other respiratory fuctio edpoits such as FVC%p, FVC, FEV %p, ad FEV showed a cosistet patter with treatmet differeces, ledig support to the efficacy of idebeoe over placebo i the preservatio of respiratory fuctio (figure C F; appedix). Chage from baselie to week 5 was well correlated betwee PEF%p ad FVC%p (r²= ; p< ; appedix). No sigificat differeces were oted i the chage from baselie to week 5 for MIP, MEP, ad peak cough flow (data ot show). Also, o treatmet effect was oted i upper limb stregth (measured with had-held myometry) ad fuctio (assessed with the Brooke s scale) ad patiet-reported outcomes assessed with Pediatric Quality of Life Ivetory (data ot show). Sice the study populatio was a mix of patiets who i the past had used glucocorticoids ad patiets who had ever used steroids (table ), it was of iterest to assess whether previous steroid use affected the outcome of respiratory fuctio tests. Post-hoc aalysis showed that respiratory fuctio test outcomes were similar betwee patiets with previous steroid use ad steroid-aive patiets (appedix). To ivestigate the effect of age, dichotomised age at baselie ( years or > years) ad the iteractio betwee age ad treatmet group were icluded as fixed factors i the model i a post-hoc aalysis. Both these factors were osigificat for PEF%p (p= 8 ad p= 89) ad FVC%p (p= ad p= 9), showig that age did ot affect the outcome for PEF%p ad FVC%p. Treatmet effects were also assessed for the ITT patiet subgroups separated by the media age ( years). A positive treatmet effect i favour of idebeoe was evidet from this post-hoc aalysis for patiets youger ad older tha years of age (appedix). Positive outcomes favourig idebeoe over placebo were further supported by the results of prespecified respoder aalyses, which showed a higher proportio of idebeoe-treated patiets who did ot deteriorate i respiratory fuctio tests betwee baselie ad week 5 (table ). Idebeoe s effects were also supported with cliical fidigs. I a prespecified aalysis, we couted the umber of patiets who at ay time durig the trial dropped below 6 L/mi i peak cough flow, a cliically meaigful threshold below which cough is o loger effective eough to provide adequate mucociliary clearace ad cosesus care recommeds mechaical cough assistace. 7,, I the ITT populatio there were six (8%) of patiets i the placebo group but oly oe (%) of 5 patiets i the idebeoe group above the threshold at baselie fallig below the 6 L/mi threshold. Moreover, the results of a post-hoc aalysis showed that there were five (6%) of patiets i the placebo group but oly oe (%) of patiets i the idebeoe group who fell below L i FVC, a cliically importat threshold ad predictor of early mortality. Also, the umber of patiets reportig upper respiratory tract ifectio-related adverse evets was lower i the idebeoe group tha i the placebo group (appedix). Similarly, there were more patiets i the placebo group reportig lower respiratory tract ifectio-related adverse evets (brochitis ad peumoia) tha i the idebeoe group, although the differece was ot sigificat (appedix). Treatmet with idebeoe was safe ad well tolerated. No deaths occurred durig the study. Of the 66 patiets icluded i the safety aalyses, 6 (9%) had at least oe adverse evet: (9%) i the idebeoe group ad (9%) i the placebo group. Nasopharygitis (6%) ad headache (%) were the most commo adverse evets without differeces i their icidece betwee the treatmet groups (appedix). Trasiet ad mild diarrhoea, a kow side-effect of idebeoe itake, was 6 Published olie April, 5

7 Articles more commo i idebeoe-treated patiets (5% vs %), whereas costipatio was more commo i the placebo group tha i the idebeoe group (8% vs 9%; appedix). Most adverse evets were of mild or moderate itesity. Serious adverse evets were reported i 6% ad severe adverse evets i % of idebeoe-treated patiets ad i 5% ad % of placebo-treated patiets, oe of which were classified as related to itake of study medicatio (appedix). The adverse evets that led to discotiuatio of treatmet were sleep apoea sydrome (=) ad diarrhoea (=) i the idebeoe group ad supravetricular arrhythmia ad respiratory failure with peumoia i the placebo group (all i same patiet). Noe of the adverse evets that led to premature discotiuatio from the study were judged by the ivestigator to be related to study treatmet. There was o evidece for a cliically relevat effect of idebeoe o ay haematological or cliical chemistry variable, vital sigs, physical examiatios, or results from ECG ad echocardiography assessmets. Discussio The DELOS trial met its primary objective ad the results showed that idebeoe sigificatly reduced the loss of respiratory fuctio i patiets with Duchee muscular dystrophy. Vetilatory support ad the chroic use of glucocorticoids have cotributed to icreased logevity i patiets with Duchee muscular dystrophy. Nevertheless, respiratory complicatios cotiue to be a mai cause of early morbidity ad mortality i steroidtreated patiets ad a subset of patiets with Duchee muscular dystrophy do ot respod to or do ot tolerate steroid treatmet. I a attempt to develop ovel treatmet optios, ad cotiuig from previous studies,, we have ow ivestigated the efficacy ad safety of idebeoe i patiets with Duchee muscular dystrophy i the first ever successful phase study of patiets with this disease (pael). Based o the results from a phase study, PEF was selected as the primary efficacy variable, which i the absece of brochial obstructio is a measure of expiratory muscle stregth. I patiets with Duchee muscular dystrophy, progressive weakess of chest wall muscles precedes weakess of the diaphragm (used maily for ispiratory fuctio) ad leads to restrictive lug volume chages (ie, reduced FVC).,5 8 Compared with other respiratory variables, FVC is less sesitive to mild muscle weakess i the early stages of the disease. 9,9 Loss of lug volume iitially results from the iability to pull up the respiratory system to total lug capacity ad to push it dow to residual volume. I the later stage of disease, additioal restrictio occurs as a result of progressive muscle fibrosis ad chages i lug ad chest wall recoil. Therefore, respiratory stregth might be more sesitive to treatmet itervetio tha is lug volume, because this is affected ot Pael: Research i cotext Systematic review We searched PubMed ad cliical trial registries for registratios ad reports of radomised double-blid placebo-cotrolled trials of idebeoe i the treatmet of patiets with Duchee muscular dystrophy. We idetified oly oe study (phase DELPHI trial; CliicalTrials.gov, umber NCT6578). The phase DELOS trial of idebeoe i patiets with dystrophi-deficiet muscular dystrophy was based o existig evidece: a observer-masked log-term placebo-cotrolled study i the mdx mouse model of Duchee muscular dystrophy ad the proof-of-cocept phase DELPHI trial i patiets with Duchee muscular dystrophy. The results of the aimal model study showed pheotypic correctio with substatial cardioprotectio ad volutary exercise performace improvemet. DELPHI s results showed a sigificat respiratory effect of idebeoe o peak expiratory flow (primary edpoit i DELOS). The desig of the DELOS trial was based o the DELPHI fidigs ad scietific advice cosultatio with regulatory authorities. The DELPHI ad DELOS trials had some differeces i drug dosig ad patiets characteristics. I DELPHI, idebeoe was dosed at 5 mg daily (because of few safety data available at the time); i DELOS we used 9 mg daily. Patiets i DELPHI were aged 8 6 years ad were a mix of idividuals ot usig cocomitat glucocorticoids ad those o steroids for Duchee muscular dystrophy. The DELOS study populatio cosisted of 8-year-old patiets ot takig cocomitat glucocorticoids. Iterpretatio To the best of our kowledge, we report for the first time a phase radomised cotrolled trial i patiets with Duchee muscular dystrophy with a positive outcome. Sigificat ad cliically relevat results for primary ad secodary edpoits showed that idebeoe reduced the loss of respiratory fuctio i 8-year-old patiets with Duchee muscular dystrophy who were ot usig cocomitat glucocorticoids. Also, idebeoe was safe ad well tolerated. The relevace of modifyig the atural course of respiratory disease i Duchee muscular dystrophy is emphasised i cliical practice where respiratory failure leads to vetilator-depedecy ad cotiues to be the predomiat cause of early death i patiets with Duchee muscular dystrophy. oly by respiratory muscle stregth but also by thoracic wall compliace ad deformities. Additioally, abormal respiratory mech aics i Duchee muscular dystrophy are ot restricted to the lugs ad chest wall ad might also ivolve the upper airways. Here, weakess of pharygeal dilator muscles decreases upper airway calibre, causig a icrease i upper airway resistace durig ispiratio, which imposes a icreased mechaical load o the diaphragm ad other ispiratory muscles. Therefore, PEF is a measure ot oly of expiratory stregth but also ispiratory effort ad upper airway resistace., I the DELOS trial, there was a sigificat fall i PEF%p from baselie to week 5 i the placebo group compared with a o-sigificat declie i the idebeoe group, resultig i a sigificat ad cliically relevat idebeoe treatmet effect. No treatmet effect was oted for MIP ad MEP, which at baselie were more severely affected tha were the expiratory flow ad lug volume variables. These low baselie values are i lie with previous data idicatig that maximum static airway pressures are regarded as early markers of respiratory dysfuctio i Duchee muscular dystrophy ad their Published olie April, 5

8 Articles much reduced values at study start could have precluded the detectio of ay treatmet effect. Morbidity ad mortality i patiets with Duchee muscular dystrophy are associated with progressive restrictive lug disease ad irreversible loss of lug fuctio, commoly measured as a reductio i FVC. Therefore, reducig the declie i FVC, as show i this trial, is of cliical relevace. I DELOS, the decrease i FVC i the placebo group is similar to recet atural history data i steroid-aive patiets with Duchee muscular dystrophy., Furthermore, the idebeoe effect size i DELOS is similar to outcomes reported for ivestigatioal treatmets of idiopathic pulmoary fibrosis, aother restrictive lug disease (appedix). 5,6 Results from a phase trial (DELPHI) showed a larger effect size of idebeoe o respiratory fuctio i patiets ot takig cocomitat glucocorticoids tha i patiets who took steroids. 5 To accout for this ifluece, oly patiets ot usig cocomitat steroids were erolled i DELOS. Subgroup aalyses showed that the effect sizes i favour of idebeoe for PEF, FVC, ad FEV were geerally similar betwee patiets who were steroid aive ad those who had used steroids i the past for Duchee muscular dystrophy. These results are i agreemet with previous fidigs that lug volume measuremets i past users of steroids are ot differet from steroid-aive patiets, 9 idicatig that the thera peutic effect of steroids o respiratory fuctio is dimiished after their discotiuatio. Although data from the curret trial were obtaied i patiets ot usig steroids, there is o reaso a priori why idebeoe could ot also be exertig a treatmet effect i patiets usig steroids cocomitatly. However, it might be challegig to covicigly show this additive effect of idebeoe o top of steroids. 5 The results of DELOS showed a somewhat larger effect size for PEF%p ad FVC%p i the subgroup of patiets aged years ad youger tha i the older patiets (appedix), idicatig that patiets may derive a larger beefit from idebeoe if treatmet is iitiated early. Idebeoe was safe ad well tolerated with frequecy ad severity of adverse evets that were similar betwee treatmet groups, i lie with previous reports.,7 Limitatios of this study are related to the sample size ad treatmet duratio. The study had several protocol amedmets (appedix), most otably a amedmet that defied the fial study populatio to the subgroup of patiets ot usig glucocorticoids. No patiets usig cocomitat glucocorticoids were erolled i the study. The robustess of the outcome was assessed with sesitivity aalyses by use of differet imputatio methods, by excludig patiets whose iclusio might affect the outcome, ad with differet assessmet methods ad itervals. Overall, the data set is robust, thereby alleviatig cocers that might result from the small sample size of the study. The duratio of a placebo-cotrolled trial i childre with Duchee muscular dystrophy with advaced disease ievitably has to be limited by ethical reasos. Although a study of moths caot provide data o hard outcome measures such as time to assisted vetilatio or death, this limitatio is mitigated by the cosistecy of the idebeoe effects o respiratory fuctio outcomes (PEF, FVC, ad FEV ) together with cliically relevat fidigs. Specifically, the proportio of patiets with reductios i FVC or peak cough flow below crucial thresholds,,8 kow to be predictive of immiet vetilatory failure, ad the reduced umber of upper airway tract ifectios i the idebeoe group, are strogly supportive for the cliical meaigfuless of the idebeoe effect. The overall umber of lower airway tract ifectios reported durig the -year follow-up was small ad, therefore, o coclusio ca be draw. However, the umerical differece i favour of idebeoe treatmet is ecouragig ad merits further ivestigatio durig loger follow-up. I the past, improved patiet care with best-practice recommedatios ad the itroductio of glucocorticoids has greatly icreased the survival time of patiets with Duchee muscular dystrophy. 7,8,9, Nevertheless, loss of respiratory fuctio cotiues to be a predomiat cause of early morbidity ad mortality i patiets with Duchee muscular dystrophy. Efficacy data from this trial show that idebeoe sigificatly reduced the loss of respiratory fuctio i patiets with Duchee muscular dystrophy who were ot takig cocomitat glucocorticoids. With its favourable safety ad tolerability profiles, idebeoe therefore is a suitable treatmet optio to ameliorate a life-threateig complicatio of Duchee muscular dystrophy. Cotributors GMB ad TM cotributed to the study cocept, desig, ad coduct, aalysis of data, ad writig of the mauscript. TV, US, CSMS, MGD A, GB, J-MC, NG, ad CMM participated i the study coduct ad reportig o behalf of the DELOS Study Group. RSF cotributed to the study cocept ad desig. CR coordiated the study aalysis ad prepared tables ad figures. All authors participated i the preparatio, review, ad crucial revisio of the report, which has bee approved by each author. DELOS Study Group Austria: G Berert, F Kipp (Viea); Belgium: G M Buyse, N Goemas, M va de Hauwe (Leuve); Frace: T Voit, V Doppler, T Gidaro (Paris); J-M Cuisset, S Coopma (Lille); Germay: U Schara, S Lutz (Esse); J Kirscher, S Borell, M Will (Freiburg); Italy: M G D Agelo, E Brighia, S Gadossii (Lecco); K Gori, E Falcier (Mila); L Politao, P D Ambrosio, A Taglia (Naples); Netherlads: J J G M Verschuure, C S M Straathof (Leide); Spai: J J Vílchez Padilla, N Muelas Gómez (Valecia); Swede: T Sejerse, M Hovmöller (Stockholm); Switzerlad: P-Y Jeaet, C Bloetzer (Lausae); ad USA: S Laaccoe, D Castro (Dallas, TX); G Teekoo, R Fikel, C Böema (Philadelphia, PA); C McDoald, E Hericso, N Joyce (Sacrameto, CA); S Apko, R C Richardso (Seattle, WA). Declaratio of iterests GMB was ivestigator for cliical trials i Duchee muscular dystrophy sposored by Sathera Pharmaceuticals, Prosesa Therapeutics, ad GlaxoSmithKlie. TV was a ivestigator for cliical trials of Duchee muscular dystrophy sposored by PTC Therapeutics, GlaxoSmithKlie, Prosesa, ad Sathera Pharmaceuticals; he serves as 8 Published olie April, 5

9 Articles a scietific advisory board member to Prosesa. US was a ivestigator for cliical trials sposored by PTC Therapeutics, Lilly Pharma, Sathera Pharmaceuticals, Prosesa, ad GlaxoSmithKlie. CSMS has participated i trials sposored by GlaxoSmithKlie, Prosesa, ad Sathera Pharmaceuticals. RSF has participated i studies of Duchee muscular dystrophy sposored by PTC Therapeutics, the US Natioal Istitutes of Health (UDP RNS6, Wellstoe 5U5AR566-, Imagig DMD R-AR5697, ad FOR-DMD U NS6799-A), Lilly, Muscular Dystrophy Associatio, Sarepta, served as a member of the data ad safety moitorig board for the Sarepta study, ad served as adviser to Catabasis. CMM has served as a cosultat for trials urelated to this scope of work for PTC Therapeutics, Prosesa, Sarepta, Eli Lilly, Pfizer, Halo Therapeutics, Cardero, ad Mitokye, ad serves o exteral advisory boards related to Duchee muscular dystrophy for PTC Therapeutics ad Eli Lilly. TM is a regular employee of Sathera Pharmaceuticals. GMB ad TM are coivetors of relevat patet applicatios. The other authors declare o competig iterests. Ackowledgmets The study was sposored by Sathera Pharmaceuticals. The DELOS Study Group is idebted to the participatig patiets ad their parets. We thak Frédérique Couttet ad Diaa Petraki for cliical study coordiatio ad Nicholas Coppard (Sathera Pharmaceuticals) for overall cliical trial oversight; Michelle Eagle (Newcastle, UK), Elisabeth Watso (Vitalograph, Buckigham, UK), Meredith James (Newcastle, UK), ad Julaie Florece (St Louis, MO, USA) for physiotherapist traiig ad writig of a physiotherapist traiig maual, ad Gary Jasso ad Mika Leioe (Pharma, Turku ad Helsiki, Filad, ad Stockholm, Swede) for statistical support; the study data ad safety moitorig board: Ludwig Kappos (chair, Basel, Switzerlad), Stephe Krähebühl (Basel, Switzerlad), George Wilmot (Atlata, GA, USA), Corrado Berascoi (statisticia, Vacallo, Switzerlad), ad Dirk Fischer (Basel, Switzerlad). GMB is Seior Cliical Ivestigator of the Research Foudatio Fladers (FWO Vlaadere, Belgium). Refereces Medell JR, Lloyd-Puryear M. Report of MDA muscle disease symposium o ewbor screeig for Duchee muscular dystrophy. Muscle Nerve ; 8: 6. Ikley SR, Oldeburg FC, Vigos PJ. Pulmoary fuctio i Duchee muscular dystrophy related to stage of disease. Am J Med 97; 56: Rideau RY, Jakowski LW, Grellet J. Respiratory fuctio i the muscular dystrophies. Muscle Nerve 98; : McDoald CM, Abresch RT, Carter GT, et al. Profiles of euromuscular diseases. Duchee muscular dystrophy. Am J Phys Med Rehabil 995; 7: S Tagsrud S, Peterse IL, Lødrup Carlse KC, Carlse KH. Lug fuctio i childre with Duchee s muscular dystrophy. Resp Med ; 95: Kohler M, Clarebach CF, Böi L, Brack T, Russi EW, Bloch KE. Quality of life, physical disability, ad respiratory impairmet i patiets with Duchee muscular dystrophy. Am J Respir Crit Care Med 5; 7: 6. 7 Bushby K, Fikel R, Birkrat D, et al, for the DMD Care Cosideratios Workig Group. Diagosis ad maagemet of Duchee muscular dystrophy, part : implemetatio of multidiscipliary care. Lacet Neurol ; 9: Bushby K, Fikel R, Birkrat D, et al, for the DMD Care Cosideratios Workig Group. Diagosis ad maagemet of Duchee muscular dystrophy, part : diagosis, pharmacological ad psychosocial maagemet. Lacet Neurol ; 9: Hericso EK, Abresch RT, Caa A, et al. The cooperative iteratioal euromuscular research group Duchee atural history study: glucocorticoid treatmet preserves cliically meaigful fuctioal milestoes ad reduces rate of disease progressio as measured by maual muscle testig ad other commoly used cliical trial outcome measures. Muscle Nerve ; 8: Ricotti V, Ridout DA, Scott E, et al. Log-term beefits ad adverse effects of itermittet versus daily glucocorticoids i boys with Duchee muscular dystrophy. J Neurol Neurosurg Psychiatry ; 8: Haefeli RH, Erb M, Gemperli AC, et al. NQO-depedet redox cyclig of idebeoe: effects o cellular redox potetial ad eergy levels. PLoS Oe ; 6: e796. Jaber S, Polster BM. Idebeoe ad europrotectio: atioxidat, pro-oxidat, or electro carrier? J Bioeerg Biomembr 5; 7: 8. Buyse GM, Va der Miere G, Erb M, et al. Log-term placebo-cotrolled study showig pheotypic correctio of dystrophi-deficiecy i the mdx mouse by SNT-MC7/idebeoe. Eur Heart J 9; : 6. Buyse GM, Goemas N, va de Hauwe M, et al. Idebeoe as a ovel, therapeutic approach for Duchee muscular dystrophy: results from a moth, double-blid, radomized placebo-cotrolled trial. Neuromusc Disord ; : Buyse GM, Goemas N, va de Hauwe M, Meier T. Effects of glucocorticoids ad idebeoe o respiratory fuctio i patiets with Duchee muscular dystrophy. Pediatr Pulmool ; 8: 9. 6 Godfrey S, Kamburoff PL, Nair JR. Spirometry, lug volumes ad airway resistace i ormal childre aged 5 to 8 years. Br J Dis Chest 97; 6: 5. 7 Quajer PH, Stocks J, Polgar G, Wise M, Karlberg J, Borsboom G. Compilatio of referece values for lug fuctio measuremets i childre. Eur Respir J Suppl 989; : 8s 6s. 8 Hakiso JL, Odecratz JR, Feda KB: Spirometric referece values from a sample of the geeral US populatio. Am J Respir Crit Care Med 999; 59: Domeech-Clar R, Lopez-Adreu JA, Compte-Torrero L, et al. Maximal static respiratory pressures i childre ad adolescets. Pediatr Pulmool ; 5: 6. Gauld LM, Kappers J, Carli JB, Robertso CF. Predictio of childhood pulmoary fuctio usig ula legth. Am J Respir Crit Care Med ; 68: 8 9. Gauld LM, Kappers J, Carli JB, Robertso CF. Height predictio from ula legth. Dev Med Child Neurol ; 6: Gauld LM, Boyto A. Relatioship betwee peak cough flow ad spirometry i Duchee muscular dystrophy. Pediatr Pulmool 5; 9: Bach JR, Ishikawa Y, Kim H. Prevetio of pulmoary morbidity for patiets with Duchee muscular dystrophy. Chest 997; : 8. Philipps MF, Quiliva RCM, Edwards RHT, Calverley PMA. Chages i spirometry over time as a progostic marker i patiets with Duchee muscular dystrophy. Am J Respir Crit Care Med ; 6: Quajer PH, Lebowitz MD, Gregg I, et al. Peak expiratory flow: coclusios ad recommedatios of a Workig Party of the Europea Respiratory Society. Eur Respir J Suppl 997; : S 8S. 6 Hah A, Bach JR, Delaubier A, Reardel-Irai A, Guillou C, Rideau Y. Cliical implicatios of maximal respiratory pressure determiatios for idividuals with Duchee muscular dystrophy. Arch Phys Med Rehabil 997; 78: 6. 7 Suarez AA, Pessolao FA, Moteiro SG, et al. Peak flow ad peak cough flow i the evaluatio of expiratory muscle weakess ad bulbar impairmet i patiets with euromuscular disease. Am J Phys Med Rehabil ; 8: Vicke WG, Elleker MG, Cosio MG. Flow-volume loop chages reflectig respiratory muscle weakess i chroic euromuscular disorders. Am J Med 987; 8: Griggs R. The use of pulmoary fuctio testig as a quatitative measuremet for therapeutic trials. Muscle Nerve 99; : S S. Kha Y, Heckmatt JZ. Obstructive apoeas i Duchee muscular dystrophy. Thorax 99; 9: Vicke W, Guillemiault C, Silvestri L, Cosio M, Grassio A. Ispiratory muscle activity as a trigger causig the airways to ope i obstructive sleep apea. Am Rev Respir Dis 987; 5: Pederse OF. The Peak Flow Workig Group: physiological determiats of peak expiratory flow. Eur Respir J 997; (suppl ): s 6s. Tzelepis GE, Zakythios S, Vassilakopoulos T, Geroulaos S, Roussos C. Ispiratory maeuver effects o peak expiratory flow. Role of lug elastic recoil ad expiratory pressure. Am J Respir Crit Care Med 997; 56: Published olie April, 5

10 Articles Humbertclaude V, Hamrou D, Bezzou K, et al. Motor ad respiratory heterogeeity i Duchee patiets: implicatios for cliical trials. Eur J Pediatr Neurol ; 6: Noble PW, Albera C, Bradford WZ, et al, for the CAPACITY Study Group. Pirfeidoe i patiets with idiopathic pulmoary fibrosis (CAPACITY): two radomised trials. Lacet ; 77: Richeldi L, du Bois RM, Raghu G, et al. Efficacy ad safety of itedaib i idiopathic pulmoary fibrosis. N Egl J Med ; 7: Di Prospero NA, Sumer CJ, Pezak SR, Ravia B, Fischbeck KH, Taylor JP. Safety, tolerability, ad pharmacokietics of high-dose idebeoe i patiets with Friedreich ataxia. Arch Neurol 7; 6: Tzeg AC, Bach JR. Prevetio of pulmoary morbidity for patiets with euromuscular disease. Chest ; 8: McDoald CM, Hericso EK, Abresch RT, et al. The cooperative iteratioal euromuscular research group Duchee atural history study-a logitudial ivestigatio i the era of glucocorticoid therapy: desig of protocol ad the methods used. Muscle Nerve ; 8: 5. Goemas N, Buyse GM. Curret treatmet ad maagemet of dystrophiopathies. Curr Treat Optios Neurol ; 6: Published olie April, 5

11 Supplemetary appedix This appedix formed part of the origial submissio ad has bee peer reviewed. We post it as supplied by the authors. Supplemet to: Buyse GM, Voit T, Schara U, et al, for the DELOS Study Group. Efficacy of idebeoe o respiratory fuctio i patiets with Duchee muscular dystrophy ot usig glucocorticoids (DELOS): a double-blid radomised placebo-cotrolled phase trial. Lacet 5; published olie April (5)65-.

12 Supplemet Material This appedix has bee provided by the authors to give readers additioal iformatio about their work.

13 Supplemet Table : Iclusio Criteria:. Patiets - 8 years of age at Baselie.. Siged ad dated iformed coset.. Documeted diagosis of DMD or severe dystrophiopathy ad cliical features cosistet of typical DMD at diagosis (i.e. documeted delayed motor skills ad muscle weakess by age 5 years). DMD should be cofirmed by mutatio aalysis i the dystrophi gee or by substatially reduced levels of dystrophi protei (i.e. abset or <5% of ormal) o Wester blot or immuostai.. Ability to provide reliable ad reproducible repeat PEF withi 5% of the first assessmet (i.e. Baselie vs. Screeig). 5. Patiets assessed by the ivestigator as willig ad able to comply with the requiremets of the study, possess the required cogitive abilities ad are able to swallow study medicatio. Exclusio Criteria:. Patiets depedet o assisted vetilatio at Screeig ad/or Baselie (defied as o-ivasive octural vetilatio, daytime o-ivasive vetilatio or cotiuous ivasive vetilatio).. Patiets with documeted DMD-related hypovetilatio for which assisted vetilatio is eeded accordig to curret stadard of care guidelies (e.g. FVC< %) or is required i the opiio of the Ivestigator.. Patiets with a percet predicted PEF > 8% at Baselie.. Patiets uable to form a mouth seal to allow precise respiratory flow measuremets ad mouth pressures. 5. Symptomatic heart failure (high probability of death withi oe year of Baselie) ad/or symptomatic vetricular arrhythmias. 6. Participatio i the previous Phase II or Phase II Extesio study (SNT-II- or SNT-II--E) for idebeoe. 7. Participatio i ay other therapeutic trial ad/or itake of ay ivestigatioal drug withi 9 days prior to Baselie. 8. Use of caritie, creatie, glutamie, oxatomide, or ay herbal medicies withi days prior to Baselie. 9. Use of coezyme Q or vitami E (if take at a dose of 5 times above the daily physiological requiremet) withi days prior to Baselie.. Ay previous use of idebeoe.. Ay cocomitat medicatio with a depressive or stimulatig effect o respiratio or the respiratory tract.

14 . Plaed or expected spial fixatio surgery durig the study period (as judged by the ivestigator).. Asthma, brochitis/copd, brochiectasis, emphysema, peumoia or the presece of ay other o-dmd respiratory illess that affects PEF.. Chroic use of beta- agoists or ay use of other brochodilatig medicatio (e.g. ihaled steroids, sympathomimetics, aticholiergics). 5. Moderate or severe hepatic impairmet or severe real impairmet. 6. Prior or ogoig medical coditio or laboratory abormality that i the Ivestigator's opiio could adversely affect the safety of the subject. Please ote: Patiets who suffer from a severe, ustable coditio icludig (but ot limited to) cacer, auto-immue diseases, haematological diseases, metabolic disorders or immuodeficiecies, ad who are at risk of a aggravatio urelated to the study coditio, ca oly be icluded i the study if accepted i writig by the Sposor's Medical Moitor. 7. Relevat history of or curret drug or alcohol abuse or use of ay tobacco/marijuaa products/smokig 8. Kow idividual hypersesitivity to idebeoe or to ay of the igrediets/excipiets of the study medicatio 9. Systemic glucocorticoid therapy a. Chroic use of systemic glucocorticoid therapy for DMD related coditios withi moths of Baselie (the " moth o-use period") b. More tha rouds of acute systemic glucocorticoid burst therapy (of week duratio) for o-dmd related coditios withi the moth o-use period c. Use of ay roud of systemic glucocorticoid burst therapy of loger tha weeks duratio withi the moth o-use period d. Use of systemic glucocorticoid burst therapy less tha 8 weeks prior to baselie Withdrawal Criteria (patiets were ot replaced):. Spial fixatio surgery. Iitiatio of assisted vetilatio. Acute hospitalizatio for treatmet of complicatios associated with DMD disease progressio. Itake of prohibited medicatio 5. No-compliace to study procedures 6. Itake of ay other ivestigatioal drug 7. Ay itercurret medical coditio affectig patiet s safety or compliace with trial procedures 8. Ay violatio of the steroid o-user rule defied above