Clinical trial NCT04054375: Weekly Steroids in Muscular Dystrophy
Official title: Open Label Safety and Efficacy of Once Weekly Steroid in Patients With LGMD and Becker Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Limb-girdle Muscular Dystrophy
Becker Muscular Dystrophy
Keywords: Steroids, Prednisone
Lead sponsor: Northwestern University
Sponsor class: OTHER
First posted: 2019-08-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and efficacy of oral weekly glucocorticoid steroids in patients with Becker Muscular Dystrophy (BMD), an inherited disorder in which patients experience weakness of the legs and pelvis, and Limb Girdle Muscular Dystrophy (LGMD), an inherited disorder in which patients experience progressive muscular weakness predominately in their hip and shoulders. The primary objective is safety which we the investigators will measure using laboratory testing and forced vital capacity (FVC), a breathing test that measures the strength of your lungs. The secondary objective is efficacy which will be measured by a change in MRI muscle mass, improved muscle performance, and quality of life.

The investigators hypothesize that patients who receive oral weekly glucocorticoid steroids will have improviements in strength and quality of life compared to their baseline. Furthermore, the investigators anticipate that oral weekly glucocorticoid steroids will not have significant adverse impact on patients.

Detailed description: Glucocorticoid (GC) steroids are a mainstay of therapy for Duchenne Muscular Dystrophy, where they have been shown to prolong ambulation in for DMD in random clinical trials (Gloss et al., 2016). Dosing regimen vary for DMD, but most trials utilized oral daily dosing at 0.75- 1 mg/kg of prednisone or deflazacort (Birnkrant et al., 2018). The age at which to begin oral glucocorticoids and the age at which to cease steroid use are not well established by clinical trial investigation. High dose weekend dosing of oral glucocorticoid steroids has also been suggested to be noninferior to daily dosing when evaluated in a year-long study in DMD, and this approach is preferred in some settings since related to a reduced side effect profile, particularly with respect to behavioral changes which can occur with daily GC steroid dosing in children (Escolar et al., 2011). The use of GC steroids for other forms of muscular dystrophy, including Becker Muscular Dystrophy (BMD) and the Limb Girdle Muscular Dystrophies (LGMDs) is not considered standard of care and has insufficiently been investigated by randomized clinical trials (RCT). An RCT of GC steroids in LGMD 2B (DYSF mutations) was associated with unfavorable outcomes in the steroid treated group (Walter et al., 2013).

Recently, weekly steroid dosing was investigated in preclinical mouse models of muscular dystrophy, including the mdx mouse model of DMD/BMD and two models of LGMD, including LGMD 2B (DYSF) and 2C (SGCG) (Quattrocelli et al., 2017a; Quattrocelli et al., 2017b). All three models showed improved strength and reduced fibrosis with weekly GC steroid dosing. Moreover, in unpublished data, long term studies (24-52 weeks duration) in mice, showed favorable results with improved muscle strength in the mdx and DYSF models.

The investigators propose to carry out an open label safety and efficacy trial of oral weekly GC steroids in patients with BMD and LGMD subtypes. Subjects will be recruited based on age, molecular diagnosis of BMD and LGMD subtypes, and willingness to participate. Both ambulatory and nonambulatory subjects will be included. Subjects will be excluded if they have diabetes mellitus, full time ventilator use, or severely compromised cardiac function, including symptoms referable to heart failure. Subjects must provide consent.

Subjects will be asked to take weekly GC oral prednisone dosed based on weight (1mg/kg for patients who weigh less than or equal to 70 kg and 0.75 mg/kg for patients who weigh more than 70 kg). Subjects will also be instructed to take their weekly prednisone on Mondays after their last meal between 7 and 9 PM. Prior to initiation, subjects will provide a blood sample for baseline screening including serum chemistries, HgbA1-C, creatine kinase, and lipid panel (HDL, LDL, triglycerides, and total cholesterol) and for exploratory biomarkers. Subjects will also provide a urine sample to analyze changes in metabolic biomarkers that are excreted. Subjects will have a physical exam and medical record review. Subjects will have strength testing and complete 10 meter timed run test in addition to a 6 min walk test (if ambulatory). Subjects will be asked to complete quality of life questionnaire. At 6 months, subjects will be evaluated with a physical exam, strength testing, spirometry, 10 meter timed run test and 6 min walk test (if ambulatory), blood draw for serum chemistry, HgbA1-C, creatine kinase, lipid panel and for exploratory biomarkers. Subjects will also provide a urine specimen to be analyzed for any changes in excretion of metabolic markers as an exploratory endpoint. Subjects will be asked to complete a quality of life questionnaire. An MRI/ MRS will be performed before starting GC oral prednisone and at 6 months.

Eligibility criteria: Inclusion Criteria:

1. Patients with Becker muscular dystrophy or LGMD2A (CAPN3), LGMD 2B (DYSF), LGMD 2C (SGCG), LGMD2E (SGCB), LGMD2F (SGCD), LGMD 2I (FKRP), LGMD (ANO5). Genetic mutation or muscle biopsy staining required to confirm genetic subtype
2. Ages 18-65 years
3. EKG without evidence of prior infarct or atrial fibrillation done within 2 months of study initiation.
4. Echocardiogram with LVEF \>25% done within 6 months of study initiation.
5. Stable medications (same medication and dose) for the previous 3 months
6. Stable pulmonary status for the previous 6 months (No change in FVC by more than 20% in the past 6-months)

Exclusion Criteria:

1. Diabetes
2. BMI\>35 kg/m2
3. Cardiac transplantation
4. Myocardia Infarct in the past 2-years from screening
5. Any history of tuberculosis
6. Untreated or uncontrolled (medication and/or dose change in previous month from screening) hypertension
7. A diagnosis of congestive heart failure
8. A diagnosis of chronic kidney disease
9. A diagnosis of untreated hypothyroidism
10. The patient is believed to be at high risk of osteoporosis by the primary investigator
11. Inability to provide consent
12. Full time ventilator dependency
13. Heart failure symptoms or LVEF \<25%
14. Orthopedic surgery within the prior year or upcoming elective orthopedic surgery within the 6-months from Day 0.
15. Inability to complete MRI (claustrophobia, metal implants)
16. Pregnant women at screening, women seeking to become pregnant, or men seeking to father a child within 6-months from Day 0 should not participate in this study.

Primary outcomes:
measure: Fasting Glucose
timeFrame: Baseline and 6 months (Final Visit)
measure: HbgA1c
timeFrame: Baseline and 6 months (Final Visit)
measure: Fasting Lipid Profile
timeFrame: Baseline and 6 months (Final Visit)
measure: Creatine Kinase
timeFrame: Baseline and 6 months (Final Visit)
measure: Respiratory Changes
timeFrame: Baseline, 6 months
Secondary outcomes:
measure: Functional Assessments - NSAD Change
timeFrame: Baseline, Month 6
measure: 6 Minute Walk Test
timeFrame: Baseline, Month 6
measure: 10 Meter Run Timed
timeFrame: Baseline, Month 6
measure: Brooke Scale Score
timeFrame: Baseline, Month 6
measure: Vignos Scale Score
timeFrame: Baseline, Month 6
measure: Muscle Imaging
timeFrame: Baseline, 6 months
measure: Bone Density
timeFrame: Baseline, 6 months
measure: Lean Mass %
timeFrame: Baseline, 6 months
measure: Functional Assessments - Upper Limb Strength
timeFrame: Baseline and 6 months
measure: Muscle Strength Test
timeFrame: baseline, 6 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
Study officials:
affiliation: Associate Professor of Neurology (Neuromuscular Disease)
name: Senda Ajroud-Driss, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, Case LE, Clemens PR, Hadjiyannakis S, Pandya S, Street N, Tomezsko J, Wagner KR, Ward LM, Weber DR; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3. Epub 2018 Feb 3.
citation: Escolar DM, Hache LP, Clemens PR, Cnaan A, McDonald CM, Viswanathan V, Kornberg AJ, Bertorini TE, Nevo Y, Lotze T, Pestronk A, Ryan MM, Monasterio E, Day JW, Zimmerman A, Arrieta A, Henricson E, Mayhew J, Florence J, Hu F, Connolly AM. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology. 2011 Aug 2;77(5):444-52. doi: 10.1212/WNL.0b013e318227b164. Epub 2011 Jul 13.
citation: Gloss D, Moxley RT 3rd, Ashwal S, Oskoui M. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy [RETIRED]: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016 Feb 2;86(5):465-72. doi: 10.1212/WNL.0000000000002337.
citation: Quattrocelli M, Barefield DY, Warner JL, Vo AH, Hadhazy M, Earley JU, Demonbreun AR, McNally EM. Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy. J Clin Invest. 2017 Jun 1;127(6):2418-2432. doi: 10.1172/JCI91445. Epub 2017 May 8.
citation: Quattrocelli M, Salamone IM, Page PG, Warner JL, Demonbreun AR, McNally EM. Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy. Am J Pathol. 2017 Nov;187(11):2520-2535. doi: 10.1016/j.ajpath.2017.07.017. Epub 2017 Aug 18.
citation: Walter MC, Reilich P, Thiele S, Schessl J, Schreiber H, Reiners K, Kress W, Muller-Reible C, Vorgerd M, Urban P, Schrank B, Deschauer M, Schlotter-Weigel B, Kohnen R, Lochmuller H. Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial. Orphanet J Rare Dis. 2013 Feb 14;8:26. doi: 10.1186/1750-1172-8-26.