A Phase 2 interventional study of Prednisone in Limb-girdle Muscular Dystrophy and Becker Muscular Dystrophy, sponsored by Northwestern University. Completed at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2023-09-21.
Sponsored by Northwestern University · Phase 2, Interventional, and Treatment
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.
548 studies on the registry are indexed under Muscular Dystrophies; 89 are open to participants now.
This study's enrollment of 20 is below the median of 24 across 344 interventional studies indexed under Muscular Dystrophies.
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Exclusion Criteria:
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
Drug: 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
Also known as: Prednisolone
Fasting Glucose
mg/dL, 0-unlimited, higher score indicates worse outcome
Time frame: Baseline and 6 months (Final Visit)
HbgA1c
% , 0-100, higher score indicates worse outcome
Time frame: Baseline and 6 months (Final Visit)
Fasting Lipid Profile
cholesterol levels - mg/dL, higher levels indicate worse outcomes
Time frame: Baseline and 6 months (Final Visit)
Creatine Kinase
units/L, 0-unlimited, higher scores indicate worse outcome
Time frame: Baseline and 6 months (Final Visit)
Respiratory Changes
Force Vital Capacity (% of predicted value), decrease in FVC indicates declining respiratory function.
Time frame: Baseline, 6 months
Functional Assessments - NSAD Change
Northstar Assessment for Dysferlinopathy - score out of 58, range from 0 to 58, higher score indicates greater functional ability.
Time frame: Baseline, Month 6
6 Minute Walk Test
number of meters walked in 6 minute period. Higher values indicate more motor function.
Time frame: Baseline, Month 6
10 Meter Run Timed
time in seconds to walk/run 10 meters , less time to run indicates greater motor function
Time frame: Baseline, Month 6
Brooke Scale Score
upper extremity assessment, scoring between 1- 6, lower score indicates more upper extremity function
Time frame: Baseline, Month 6
Vignos Scale Score
Lower extremity assessment, score from 1-10, lower score indicates more function.
Time frame: 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.
Time frame: 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.
Time frame: Baseline, 6 months
Lean Mass %
whole body dexa scans to assess lean mass % (0- 100 %). Increase lean mass % is the desired outcome.
Time frame: 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.
Time frame: Baseline and 6 months
Muscle Strength Test
Manual motor testing of the right knee flexion muscle group.
Time frame: baseline, 6 months
Patient Diagnosis Subtype: 19 with Limb-Girdle Muscular Dystrophy 1 with Becker Muscular Dystrophy
| Milestone | Weekly Steroid |
|---|---|
| Started | 20 |
| Completed | 20 |
| Not completed | 0 |
mg/dL, 0-unlimited, higher score indicates worse outcome
| mg/dL | Weekly Steroid |
|---|---|
| Baseline | 93 ± 2 |
| End | 102 ± 4 |
% , 0-100, higher score indicates worse outcome
| % A1c | Weekly Steroid |
|---|---|
| Baseline | 5.2 ± 0.08 |
| End | 5.3 ± 0.09 |
cholesterol levels - mg/dL, higher levels indicate worse outcomes
| mg/dL | Weekly Steroid |
|---|---|
| Baseline | 182 ± 10 |
| End | 185 ± 9 |
units/L, 0-unlimited, higher scores indicate worse outcome
| U/L | Weekly Steroid |
|---|---|
| Baseline | 1574 ± 269 |
| End | 1047 ± 171 |
Force Vital Capacity (% of predicted value), decrease in FVC indicates declining respiratory function.
| % Expected | Weekly Steroid |
|---|---|
| Baseline | 80 ± 8 |
| End | 79 ± 8 |
Northstar Assessment for Dysferlinopathy - score out of 58, range from 0 to 58, higher score indicates greater functional ability.
| score on a scale | Weekly Steroid |
|---|---|
| baseline | 18.4 ± 17 |
| 6 months | 18.6 ± 17 |
number of meters walked in 6 minute period. Higher values indicate more motor function.
| meters | Steroid Group |
|---|---|
| Baseline | 386 ± 37 |
| 6 months | 410 ± 40 |
time in seconds to walk/run 10 meters , less time to run indicates greater motor function
| seconds | Steroid Treatment |
|---|---|
| Baseline | 7.32 ± 0.92 |
| 6 months | 6.67 ± 0.77 |
upper extremity assessment, scoring between 1- 6, lower score indicates more upper extremity function
| scores on a scale | Weekly Steroid |
|---|---|
| baseline | 3 ± 1 |
| 6 months | 3 ± 1 |
Lower extremity assessment, score from 1-10, lower score indicates more function.
| scores on a scale | Steroid Treatment Group |
|---|---|
| baseline | 5 ± 1 |
| 6 months | 5 ± 1 |
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.
| percent of change from baseline | Weekly Steroid |
|---|---|
| Muscle Imaging | -14 ± 13 |
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.
| z-score | Weekly Steroid |
|---|---|
| baseline | -1.64 ± 0.33 |
| 6 months | -1.65 ± 0.34 |
whole body dexa scans to assess lean mass % (0- 100 %). Increase lean mass % is the desired outcome.
| percentage | Weekly Steroid |
|---|---|
| baseline | 37.5 ± 2.5 |
| 6 months | 38.1 ± 2.6 |
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.
| Force (Newtons) | Weekly Steroid |
|---|---|
| Baseline | 39 ± 25 |
| 6 months | 41 ± 27 |
Manual motor testing of the right knee flexion muscle group.
| Units on scale | Weekly Steroid |
|---|---|
| Baseline | 3 (1 to 5) |
| 6 months | 3 (1 to 5) |
Collected over Participants were monitored for 24 weeks or 6 months while taking study drug.. Non-serious events are listed at a 3% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Weekly Steroid | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) |
The analysis population is the same as the numbers in the participant flow.
| Age, Categorical(Participants) | Weekly Steroid |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 20 |
| >=65 years | 0 |
| Age, Continuous(years) | Weekly Steroid |
|---|---|
| Mean | 35 (18 to 60) |
| Sex: Female, Male(Participants) | Weekly Steroid |
|---|---|
| Female | 7 |
| Male | 13 |
| Race (NIH/OMB)(Participants) | Weekly Steroid |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 1 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 18 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Weekly Steroid |
|---|---|
| United States | 20 |
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