2016 American Academy of Neurology Practice Guideline Update

© 2016 American Academy of Neurology

Practice Guideline Update Corticosteroid Treatment of Duchenne Muscular Dystrophy Report by: Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology © 2016 American Academy of Neurology

Guideline Endorsement and Funding This guideline was endorsed by the American Academy of Pediatrics, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the Child Neurology Society. This guideline was developed with financial support from the American Academy of Neurology. Authors who serve as AAN subcommittee members or methodologists (D. G. , S. A. , M. O. ) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed. © 2016 American Academy of Neurology Slide 2

Sharing This Information The American Academy of Neurology (AAN) develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan. com to learn about options for sharing this content beyond your personal use. © 2016 American Academy of Neurology Slide 3

Presentation Objectives To update the 2005 AAN guideline on corticosteroid treatment of Duchenne muscular dystrophy (DMD). The following questions were asked: • What is the efficacy of corticosteroids in DMD? • What are their side effects? • What is the optimal dosing regimen? • Are there useful interventions to maximize bone health in patients with DMD taking corticosteroids? © 2016 American Academy of Neurology Slide 4

Overview § Introduction § Clinical questions § AAN guideline process § Methods § Conclusions § Practice recommendations © 2016 American Academy of Neurology Slide 5

Introduction § DMD is the most common muscular dystrophy in childhood, affecting 1. 3– 1. 8: 10, 000 live male births. e 1 § The natural history of DMD without intervention leads to loss of independent ambulation typically before age 12, declining pulmonary function from increasing respiratory muscle weakness, scoliosis, and chest wall abnormalities, and progressive cardiac dysfunction, with cardiomyopathy universally present by adulthood. e 3, e 4 § Studies of long-term use have observed prolonged ambulation, improved cardiopulmonary function, reduced need for scoliosis surgery, and increased survival. e 12 © 2016 American Academy of Neurology Slide 6

Clinical Questions Clinical Question 1 • What is the efficacy of corticosteroids with regard to DMD progression, specifically their effect on survival, quality of life (Qo. L), motor function, scoliosis, pulmonary function, and cardiac function? Clinical Question 2 • What are the side effects of corticosteroid treatment in DMD? © 2016 American Academy of Neurology Slide 7

Clinical Questions Clinical Question 3 • How do prednisone and deflazacort compare in efficacy or side effect profile? Clinical Question 4 • What is the optimal dosing regimen for corticosteroids in DMD? © 2016 American Academy of Neurology Slide 8

Clinical Questions Clinical Question 5 • Are there any useful interventions for maximizing bone health in patients with DMD taking corticosteroids? © 2016 American Academy of Neurology Slide 9

AAN Guideline Process* • Clinical Question • Evidence • Conclusions • Recommendations *Guideline developed using the 2004 AAN Clinical Practice Guideline Process Manual. © 2016 American Academy of Neurology Slide 10

Literature Search/Review Rigorous, Comprehensive, Transparent 757 abstracts 63 rated articles © 2016 American Academy of Neurology Searched: MEDLINE databases from Jan. 2004 June 2012; updated search of MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Science Citation Index from July 2012 April 2013 and May 2013 July 2014 Inclusion criteria: Exclusion criteria: • Retrospective and prospective studies • All Class I–III trials from original guideline • <10 patients with DMD Slide 11

AAN Classification of Evidence (2004) Therapeutic Scheme Class I • Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) clearly defined b) exclusion/inclusion criteria clearly defined c) adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. © 2016 American Academy of Neurology Class II • Prospective matched group cohort study in a representative population with masked outcome assessment that meets a–d above OR an RCT in a representative population that lacks one criteria a–d. Slide 12

AAN Classification of Evidence (2004) Therapeutic Scheme Class III • All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement. * Class IV • Evidence from uncontrolled studies, case series, case reports, or expert opinion. *Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e. g. , blood tests, administrative outcome data). © 2016 American Academy of Neurology Slide 13

AAN Classification of Recommendations Level A • Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. • Requires at least two consistent Class I studies. Level B • Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. • Requires at least one Class I study or two consistent Class II studies. Level C • Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. • Requires at least one Class II study or two consistent Class III studies. Level U • Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. • Studies not meeting criteria for Class I–III. © 2016 American Academy of Neurology Slide 14

Clinical Question 1 What is the efficacy of corticosteroids with regard to DMD progression, specifically their effect on survival, Qo. L, motor function, scoliosis, pulmonary function, and cardiac function? © 2016 American Academy of Neurology Slide 15

Q 1 a. Do corticosteroids have an effect on survival? • In patients with DMD, deflazacort possibly increases survival over 5 to 15 years of treatment (3 Class III studies). • There is insufficient evidence to support or refute the benefit of prednisone on survival in patients with DMD (1 Class III study using both prednisone and deflazacort and 1 negative underpowered study). © 2016 American Academy of Neurology Slide 16

Q 1 b. Do corticosteroids have an effect on Qo. L? • There is insufficient evidence to support or refute the benefit of corticosteroids on Qo. L in patients with DMD (1 Class III study). © 2016 American Academy of Neurology Slide 17

Q 1 c. Is there an effect on motor function with corticosteroids compared with no treatment? • In patients with DMD, prednisone 0. 3 to 1. 5 mg/kg/day probably improves strength (2 Class II studies and several Class III studies) and possibly improves timed motor function (1 Class II study and several Class III studies). • In patients with DMD, deflazacort 0. 9 to 1 mg/kg/day possibly improves strength, age at loss of ambulation by 1. 4 to 2. 5 years, and timed motor function (several Class III studies). © 2016 American Academy of Neurology Slide 18

Q 1 d. Do corticosteroids decrease the need for scoliosis surgery? • Corticosteroids (prednisone and deflazacort) possibly slow the development of scoliosis and reduce the need for scoliosis surgery by 18 years of age (10 Class III studies). © 2016 American Academy of Neurology Slide 19

Q 1 e. Do corticosteroids have an effect on pulmonary function? • In patients with DMD, prednisone probably improves pulmonary function as measured by forced vital capacity (2 Class II studies, several Class III studies). • In patients with DMD, deflazacort possibly improves pulmonary function (several Class III studies). © 2016 American Academy of Neurology Slide 20

Q 1 f. Do corticosteroids have an effect on cardiac function? • In patients with DMD, corticosteroids (deflazacort 0. 9 mg/kg/day or prednisone 0. 75 mg/kg/day) possibly delay the onset of cardiomyopathy (defined as shortening fraction < 28% or left ventricular ejection fraction < 45%) by 18 years of age (several Class III studies with various endpoints). © 2016 American Academy of Neurology Slide 21

Clinical Question 2 What are the side effects of corticosteroid treatment in DMD? © 2016 American Academy of Neurology Slide 22

Q 2. What are the side effects of corticosteroid treatment in DMD? • In patients with DMD, corticosteroids probably have the AEs of • • short stature, behavioral changes, fractures, and cataracts (multiple Class II and Class III studies). Prednisone 0. 75 mg/kg/day is probably associated with significant risk of weight gain, hirsutism, and cushingoid appearance (2 Class II studies). Prednisone 0. 3 mg/kg/day possibly has a lower incidence of these AEs (1 Class II study). Deflazacort is inconsistently associated with weight gain, hirsutism, and cushingoid appearance (multiple Class III studies, not all consistent with each other). Deflazacort possibly increases the risk of cataracts (3 Class III studies). © 2016 American Academy of Neurology Slide 23

Clinical Question 3 How do prednisone and deflazacort compare in efficacy or side effect profile? © 2016 American Academy of Neurology Slide 24

Q 3 a. Is there a significant difference in efficacy between prednisone 0. 75 mg/kg/day and deflazacort 0. 9 mg/kg/day? • Prednisone and deflazacort are possibly equally effective for improving motor function in patients with DMD (2 Class III studies). • There is insufficient evidence to directly compare the effectiveness of prednisone versus deflazacort in cardiac function in patients with DMD (1 Class III study of a combined cohort). © 2016 American Academy of Neurology Slide 25

Q 3 b. Is there a significant difference in AEs between prednisone 0. 75 mg/kg/day and deflazacort 0. 9 mg/kg/day? • Prednisone is possibly associated with greater weight gain in the first 12 months of treatment, with no significant difference in weight gain with longer-term use compared with deflazacort (2 Class III studies). • Deflazacort is possibly associated with an increased risk of cataracts compared with prednisone, although most are not vision impairing (2 Class III studies). © 2016 American Academy of Neurology Slide 26

Clinical Question 4 What is the optimal dosing regimen for corticosteroids in DMD? © 2016 American Academy of Neurology Slide 27

Q 4 a. Is there a preferred dose of deflazacort (0. 6 mg/kg/day for the first 20 days of each month vs 0. 9 mg/kg/day) with regard to efficacy or AEs? • Evidence is insufficient to determine whethere is a significant difference in efficacy between 2 different deflazacort doses (0. 6 mg/kg/day for the first 20 days of each month vs 0. 9 mg/kg/day) (1 Class III study). • Evidence is insufficient to determine whethere is a significant difference in AEs between 2 different deflazacort doses (0. 6 mg/kg/day for the first 20 days vs 0. 9 mg/kg/day) (1 Class III study). © 2016 American Academy of Neurology Slide 28

Q 4 b. Is there a difference in efficacy or AEs between prednisone dosing regimens of 0. 75 mg/kg/day and 10 mg/kg/weekend? • Prednisone dosing regimens of 0. 75 mg/kg/day and 10 mg/kg/weekend probably provide equivalent benefit to patients with DMD at 12 months (1 Class I study). • Prednisone dosing regimens of 0. 75 mg/kg/day and 10 mg/kg/weekend probably have similar AE profiles over 12 months (1 Class I study). • There is insufficient evidence to compare the long-term efficacy or AE profile of these 2 regimens. © 2016 American Academy of Neurology Slide 29

Q 4 c. Is there a difference in efficacy or AEs between prednisone dosing regimens of 0. 75 mg/kg/day and 1. 5 mg/kg/day? • Prednisone dosing regimens of 0. 75 mg/kg/day and 1. 5 mg/kg/day possibly provide equivalent benefit to patients with DMD, although smaller differences cannot be excluded (1 Class II study). • Prednisone dosing regimens of 0. 75 mg/kg/day and 1. 5 mg/kg/day possibly have similar AE profiles (1 Class II study). © 2016 American Academy of Neurology Slide 30

Q 4 d. Is there a difference in efficacy or AEs between prednisone dosing regimens of 0. 3 mg/kg/day and 0. 75 mg/kg/day? • A prednisone dosing regimen of 0. 75 mg/kg/day is possibly more efficacious than a regimen of 0. 3 mg/kg/day (1 Class II study and 1 Class III study). • A prednisone dosing regimen of 0. 75 mg/kg/day possibly has a greater rate of AEs than a regimen of 0. 3 mg/kg/day (1 Class II study and 1 Class III study). © 2016 American Academy of Neurology Slide 31

Q 4 e. Is there a difference in efficacy or AEs between daily and alternate-day dosing of prednisone? • Evidence is insufficient to determine whethere is a significant difference in efficacy or AE rates between daily and alternate-day regimens for prednisone dosing (1 Class III study). © 2016 American Academy of Neurology Slide 32

Q 4 f. Is there a difference in efficacy or AEs between daily and intermittent dosing of prednisolone? • Evidence is insufficient to determine whethere is a significant difference in efficacy or AE rates between daily and intermittent regimens for prednisolone dosing (1 Class III study). © 2016 American Academy of Neurology Slide 33

Clinical Question 5 Are there any useful interventions for maximizing bone health in patients with DMD taking corticosteroids? © 2016 American Academy of Neurology Slide 34

Q 5 a. Are there any useful interventions for maximizing bone health? • Evidence is insufficient to determine whether the addition of an active vitamin D metabolite (calcifediol) or a bisphonate (alendronate) improves bone health in patients with DMD who are taking prednisone (2 Class III studies). Clinical Context § Although data are insufficient to determine whether vitamin D supplementation or alendronate improves bone health, calcium and vitamin D supplementation with optimization of dietary calcium may be of benefit in patients with DMD taking corticosteroids. © 2016 American Academy of Neurology Slide 35

Q 5 b. Does treating bone health have an impact on survival? • It is unknown whether bisphonates improve survival in patients with DMD who are taking corticosteroids (1 Class III study). © 2016 American Academy of Neurology Slide 36

Clinical Context • Prednisone 0. 75 mg/kg/day has significant benefit in DMD management and should be considered the optimal prednisone dose at this point. • Prednisone 10 mg/kg/weekend is equally effective over a 12 -month period, although long-term outcomes of this alternate regimen remain to be seen. • The ideal time to start and stop therapy is not currently known. © 2016 American Academy of Neurology Slide 37

Clinical Context • The expectation of significant AEs (e. g. , short stature, behavioral changes, cataracts, cushingoid appearance, weight gain, hirsutism, fractures) and their nature should be discussed with patients and their families prior to therapy initiation and should be managed proactively. • Calcium and vitamin D intake are optimized and encouraged in clinical practice, as these children have several risk factors for low bone density and fractures, such as chronic corticosteroid use and decreased weight-bearing activities. © 2016 American Academy of Neurology Slide 38

Clinical Context • If a significant number of AEs develop, reducing the prednisone dose to 0. 3 mg/kg/day may reduce the AE burden, albeit with a lesser degree of efficacy. • Deflazacort and prednisone show slightly different AE profiles in studies where each drug was compared with no treatment or the drugs were compared with each other. • Weight gain and cushingoid appearance may occur more frequently with prednisone than deflazacort, but cataracts are more frequently reported with deflazacort. • Deflazacort and prednisone require proper informed consent from the patient’s family prior to initiation due to their AE risk. © 2016 American Academy of Neurology Slide 39

Recommendations: Efficacy, Dosing • Prednisone, offered as an intervention for patients with DMD, • should be used to improve strength • should be used to improve pulmonary function Level B © 2016 American Academy of Neurology • If patients with DMD are treated with prednisone, prednisone 0. 75 mg/kg/day should be the preferred dosing regimen. • Prednisone 10 mg/kg/weekend is equally effective over 12 months, but long-term outcome is not yet established. • Prednisone 0. 75 mg/kg/day is probably associated with significant risk of weight gain, hirsutism, and cushingoid appearance, with equal side effect profile seen over 12 months with the 10 mg/kg/weekend dosing. Slide 40

Recommendations: Efficacy • Prednisone, offered as an intervention for patients with DMD, • may be used to improve timed motor function • may be used to reduce the need for scoliosis surgery • may be used to delay the onset of cardiomyopathy by 18 years of age Level C © 2016 American Academy of Neurology • Deflazacort, offered as an intervention for patients with DMD, • may be used to improve strength and timed motor function and delay the age at loss of ambulation by 1. 4 to 2. 5 years • may be used to improve pulmonary function • may be used to reduce the need for scoliosis surgery • may be used to delay the onset of cardiomyopathy by 18 years of age Slide 41 • may be used to increase survival at 5 and 15 years of follow-up

Recommendations: Dosing • Prednisone Level C © 2016 American Academy of Neurology • 0. 3 mg/kg/day may be used as an alternative dosing regimen with lesser efficacy and fewer AEs. • 1. 5 mg/kg/day is another alternative regimen; it may be equivalent to 0. 75 mg/kg/day but may be associated with more AEs. Slide 42

Recommendations: Prednisone vs Deflazacort Level C © 2016 American Academy of Neurology • Deflazacort and prednisone may be equivalent in improving motor function. • Prednisone may be associated with increased weight gain in the first years of treatment compared with deflazacort. • Deflazacort may be associated with increased risk of cataracts compared with prednisone. Slide 43

Recommendations: Insufficient Evidence Level U © 2016 American Academy of Neurology • Data are insufficient to support or refute the following: • the addition of calcifediol and bisphonates (alendronate) as significant interventions for improving bone health in patients with DMD taking prednisone • a benefit of bisphonates for improving survival in patients with DMD taking corticosteroids • a benefit of prednisone for survival in patients with DMD • a significant difference in efficacy or AE rates between daily, alternate-day, and intermittent regimens for prednisone or prednisolone dosing • a preferred dose of deflazacort in DMD • an effect of corticosteroids on Qo. L in patients with DMD Slide 44 • There is insufficient evidence to establish a difference in effect on cardiac function.

Suggestions for Counseling Patients with DMD and their families should have a voice in the choice of the corticosteroid used, noting that the various corticosteroids differ in evidence supporting use, cost, availability, and AE profiles. When a corticosteroid has been agreed upon, a focused discussion of the risks particular to that corticosteroid should take place if they were not discussed when the choice was made. All patients with DMD taking corticosteroids and their families should be informed of the risks and benefits of adding a bisphonate until better evidence supporting efficacy and safety is made available. © 2016 American Academy of Neurology Slide 45

Recommendations for Future Research More high-quality data are needed on the long-term efficacy of prednisone and deflazacort. Suggestions from low-quality studies should be verified with well-designed long-term trials. e 61 Targeted treatment for optimization of bone health has suggested a survival benefit for patients with DMD on corticosteroids, but the evidence needs to be verified. Other treatments for complications of long-term corticosteroid use in patients with DMD on corticosteroids should be pursued. The effect of prednisone on survival has not been studied in trials with higher than Class IV evidence. The optimal deflazacort dose remains unclear, and further study using well-designed prospective RCTs would help to clarify this. © 2016 American Academy of Neurology Slide 46

References cited here can be found in the complete guideline, an online data supplement to the summary article. To locate these materials, please visit AAN. com/guidelines. © 2016 American Academy of Neurology Slide 47

Access Guideline and Summary Tools • To access the complete guideline and related summary tools, visit AAN. com/guidelines. • Summary guideline article • Complete guideline article (available as a data supplement to the published summary) • Summary for clinicians and summary for patients/families © 2016 American Academy of Neurology Slide 48

Questions? © 2016 American Academy of Neurology