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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Weekly Steroid | Experimental | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prednisone | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Fasting Glucose | mg/dL, 0-unlimited, higher score indicates worse outcome | Baseline and 6 months (Final Visit) |
| HbgA1c | % , 0-100, higher score indicates worse outcome | Baseline and 6 months (Final Visit) |
| Fasting Lipid Profile | cholesterol levels - mg/dL, higher levels indicate worse outcomes | Baseline and 6 months (Final Visit) |
| Creatine Kinase | units/L, 0-unlimited, higher scores indicate worse outcome | Baseline and 6 months (Final Visit) |
| Respiratory Changes | Force Vital Capacity (% of predicted value), decrease in FVC indicates declining respiratory function. | Baseline, 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Functional Assessments - NSAD Change | Northstar Assessment for Dysferlinopathy - score out of 58, range from 0 to 58, higher score indicates greater functional ability. | Baseline, Month 6 |
| 6 Minute Walk Test |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Senda Ajroud-Driss, MD | Associate Professor of Neurology (Neuromuscular Disease) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Northwestern University | Chicago | Illinois | 60611 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29395989 | Background | 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. | |
| 21753160 |
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Patient Diagnosis Subtype:
19 with Limb-Girdle Muscular Dystrophy
1 with Becker Muscular Dystrophy
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| ID | Title | Description |
|---|---|---|
| FG000 | Weekly Steroid | 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 Prednisone: 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
The analysis population is the same as the numbers in the participant flow.
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| ID | Title | Description |
|---|---|---|
| BG000 | Weekly Steroid | 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 Prednisone: 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Fasting Glucose | mg/dL, 0-unlimited, higher score indicates worse outcome | Posted | Mean | Standard Deviation | mg/dL | Baseline and 6 months (Final Visit) |
|
Participants were monitored for 24 weeks or 6 months while taking study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Weekly Steroid | 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 Prednisone: 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 |
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Some patients were not able to complete the study visits at end of the study due to COVID-19 and fearing safely coming to our site for visits. This is why many metrics do not have 20 data points. All patients completed the 24 weeks of steroid dosing and adverse event check-in. No participants left the study early.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Senda Ajroud-Driss | Northwestern University School of Medicine | (312) 944-0063 | s-ajroud@northwestern.edu |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Aug 12, 2019 | Jun 14, 2021 | Prot_001.pdf |
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| ID | Term |
|---|---|
| D049288 | Muscular Dystrophies, Limb-Girdle |
| D020388 | Muscular Dystrophy, Duchenne |
| ID | Term |
|---|---|
| D009136 | Muscular Dystrophies |
| D020966 | Muscular Disorders, Atrophic |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| D011241 | Prednisone |
| D011239 | Prednisolone |
| ID | Term |
|---|---|
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
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|
|
number of meters walked in 6 minute period. Higher values indicate more motor function.
| Baseline, Month 6 |
| 10 Meter Run Timed | time in seconds to walk/run 10 meters , less time to run indicates greater motor function | Baseline, Month 6 |
| Brooke Scale Score | upper extremity assessment, scoring between 1- 6, lower score indicates more upper extremity function | Baseline, Month 6 |
| Vignos Scale Score | Lower extremity assessment, score from 1-10, lower score indicates more function. | Baseline, Month 6 |
| Muscle Imaging | MRI of leg muscles to measure changes in muscle fat percentage. The data point was collected by taking fat percentage at 6 months minus fat percentage at baseline with the following equation: (([final fat percentage - initial fat percentage]/initial fat percentage) * 100%)). All participants were included, both ambulatory and nonambulatory, with all genetic subtypes included. Five participants didn't have an MRI scan at 6 months and therefore were not included. Muscles imaged were analyzed for muscle fat changes from baseline to 6 months. Data is limited in interpretation due to various muscle groups in both ambulatory and non-ambulatory patients. | Baseline, 6 months |
| Bone Density | whole dexa body scan to assess bone density with Z scores (more negative z score indicates increased risk for fractures). Z-score of 0 represents the population mean, and is the average bone density. Positive scores indicate greater bone density and negative scores indicate decreased bone density, which could be clinically correlated with osteoporosis. | Baseline, 6 months |
| Lean Mass % | whole body dexa scans to assess lean mass % (0- 100 %). Increase lean mass % is the desired outcome. | Baseline, 6 months |
| Functional Assessments - Upper Limb Strength | Grip strength of the total force (Newtons) in both hands. Participants attempted 3 trials in the right hand that was then averaged to create a right-hand average force score. Then, the participants attempted 3 trials in the left hand that was then averaged to create a left-hand average force score. The right-hand average force score was added to the left-hand average force score to create a total grip strength score. | Baseline and 6 months |
| Muscle Strength Test | Manual motor testing of the right knee flexion muscle group. | baseline, 6 months |
| Background |
| 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. |
| 26833937 | Background | 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. |
| 28481224 | Background | 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. |
| 28823869 | Background | 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. |
| 23406536 | Background | 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. |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Primary | HbgA1c | % , 0-100, higher score indicates worse outcome | Posted | Mean | Standard Deviation | % A1c | Baseline and 6 months (Final Visit) |
|
|
|
| Primary | Fasting Lipid Profile | cholesterol levels - mg/dL, higher levels indicate worse outcomes | Posted | Mean | Standard Deviation | mg/dL | Baseline and 6 months (Final Visit) |
|
|
|
| Primary | Creatine Kinase | units/L, 0-unlimited, higher scores indicate worse outcome | Posted | Mean | Standard Deviation | U/L | Baseline and 6 months (Final Visit) |
|
|
|
| Primary | Respiratory Changes | Force Vital Capacity (% of predicted value), decrease in FVC indicates declining respiratory function. | Posted | Mean | Standard Deviation | % Expected | Baseline, 6 months |
|
|
|
| Secondary | Functional Assessments - NSAD Change | Northstar Assessment for Dysferlinopathy - score out of 58, range from 0 to 58, higher score indicates greater functional ability. | Posted | Mean | Standard Deviation | score on a scale | Baseline, Month 6 |
|
|
|
| Secondary | 6 Minute Walk Test | number of meters walked in 6 minute period. Higher values indicate more motor function. | Posted | Mean | Standard Error | meters | Baseline, Month 6 |
|
|
|
| Secondary | 10 Meter Run Timed | time in seconds to walk/run 10 meters , less time to run indicates greater motor function | Posted | Mean | Standard Error | seconds | Baseline, Month 6 |
|
|
|
| Secondary | Brooke Scale Score | upper extremity assessment, scoring between 1- 6, lower score indicates more upper extremity function | Posted | Mean | Standard Error | scores on a scale | Baseline, Month 6 |
|
|
|
| Secondary | Vignos Scale Score | Lower extremity assessment, score from 1-10, lower score indicates more function. | Posted | Mean | Standard Error | scores on a scale | Baseline, Month 6 |
|
|
|
| Secondary | Muscle Imaging | MRI of leg muscles to measure changes in muscle fat percentage. The data point was collected by taking fat percentage at 6 months minus fat percentage at baseline with the following equation: (([final fat percentage - initial fat percentage]/initial fat percentage) * 100%)). All participants were included, both ambulatory and nonambulatory, with all genetic subtypes included. Five participants didn't have an MRI scan at 6 months and therefore were not included. Muscles imaged were analyzed for muscle fat changes from baseline to 6 months. Data is limited in interpretation due to various muscle groups in both ambulatory and non-ambulatory patients. | MRI of the muscles was collected on all baseline patients (20 participants). Due to clinical heterogeneity, different muscles had to be imaged for each patient. Five participants didn't get follow-up MRI scans due to COVID-19 pandemic. | Posted | Mean | Standard Deviation | percent of change from baseline | Baseline, 6 months |
|
|
|
| Secondary | Bone Density | whole dexa body scan to assess bone density with Z scores (more negative z score indicates increased risk for fractures). Z-score of 0 represents the population mean, and is the average bone density. Positive scores indicate greater bone density and negative scores indicate decreased bone density, which could be clinically correlated with osteoporosis. | Posted | Mean | Standard Error | z-score | Baseline, 6 months |
|
|
|
| Secondary | Lean Mass % | whole body dexa scans to assess lean mass % (0- 100 %). Increase lean mass % is the desired outcome. | Posted | Mean | Standard Error | percentage | Baseline, 6 months |
|
|
|
| Secondary | Functional Assessments - Upper Limb Strength | Grip strength of the total force (Newtons) in both hands. Participants attempted 3 trials in the right hand that was then averaged to create a right-hand average force score. Then, the participants attempted 3 trials in the left hand that was then averaged to create a left-hand average force score. The right-hand average force score was added to the left-hand average force score to create a total grip strength score. | Posted | Mean | Standard Deviation | Force (Newtons) | Baseline and 6 months |
|
|
|
| Secondary | Muscle Strength Test | Manual motor testing of the right knee flexion muscle group. | Manual muscle testing scores are from 0 to 5, with 5 being the strongest and 0 no muscle movement at all. | Posted | Mean | Full Range | Units on scale | baseline, 6 months |
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| 0 |
| 20 |
| 0 |
| 20 |
| 0 |
| 20 |
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| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D040181 | Genetic Diseases, X-Linked |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D011246 | Pregnadienetriols |