WSiMD: Weekly Steroids in Muscular Dystrophy
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: 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 |
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
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Fasting Glucose [Baseline and 6 months (Final Visit)]
mg/dL, 0-unlimited, higher score indicates worse outcome
- HbgA1c [Baseline and 6 months (Final Visit)]
% , 0-100, higher score indicates worse outcome
- Fasting Lipid Profile [Baseline and 6 months (Final Visit)]
cholesterol levels - mg/dL, higher levels indicate worse outcomes
- Creatine Kinase [Baseline and 6 months (Final Visit)]
units/L, 0-unlimited, higher scores indicate worse outcome
- Respiratory Changes [Baseline, 6 months]
Force Vital Capacity (% of predicted value), decrease in FVC indicates declining respiratory function.
Secondary Outcome Measures
- Functional Assessments - NSAD Change [Baseline, Month 6]
Northstar Assessment for Dysferlinopathy - score out of 58, range from 0 to 58, higher score indicates greater functional ability.
- 6 Minute Walk Test [Baseline, Month 6]
number of meters walked in 6 minute period. Higher values indicate more motor function.
- 10 Meter Run Timed [Baseline, Month 6]
time in seconds to walk/run 10 meters , less time to run indicates greater motor function
- Functional Assessments - Upper Limb Strength [Baseline, Month 6]
Performance of Modified Upper Limb Module - Yes or No questions, ability to raise 50 gram, 100 gram, 200 gram, 500 gm weights above the head and to the mouth.
- Brooke Scale Score [Baseline, Month 6]
upper extremity assessment, scoring between 1- 6, lower score indicates more upper extremity function
- Vignos Scale Score [Baseline, Month 6]
Lower extremity assessment, score from 1-10, lower score indicates more function.
- Muscle Strength Test [Baseline, 6 months]
Motor Muscle Testing: score of 1 - 5 , higher score indicates more muscle strength.
- Muscle Imaging [Baseline, 6 months]
MRI of leg muscles to measure changes in muscle
- Bone Density [Baseline, 6 months]
whole dexa body scan to assess bone density with Z scores (more negative z score indicates increased risk for fractures)
- Lean Mass % [Baseline, 6 months]
whole body dexa scans to assess lean mass % (0- 100 %). Increase lean mass % is the desired outcome.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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
-
Ages 18-65 years
-
EKG without evidence of prior infarct or atrial fibrillation done within 2 months of study initiation.
-
Echocardiogram with LVEF >25% done within 6 months of study initiation.
-
Stable medications (same medication and dose) for the previous 3 months
-
Stable pulmonary status for the previous 6 months (No change in FVC by more than 20% in the past 6-months)
Exclusion Criteria:
-
Diabetes
-
BMI>35 kg/m2
-
Cardiac transplantation
-
Myocardia Infarct in the past 2-years from screening
-
Any history of tuberculosis
-
Untreated or uncontrolled (medication and/or dose change in previous month from screening) hypertension
-
A diagnosis of congestive heart failure
-
A diagnosis of chronic kidney disease
-
A diagnosis of untreated hypothyroidism
-
The patient is believed to be at high risk of osteoporosis by the primary investigator
-
Inability to provide consent
-
Full time ventilator dependency
-
Heart failure symptoms or LVEF <25%
-
Orthopedic surgery within the prior year or upcoming elective orthopedic surgery within the 6-months from Day 0.
-
Inability to complete MRI (claustrophobia, metal implants)
-
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Northwestern University | Chicago | Illinois | United States | 60611 |
Sponsors and Collaborators
- Northwestern University
Investigators
- Principal Investigator: Senda Ajroud-Driss, MD, Associate Professor of Neurology (Neuromuscular Disease)
Study Documents (Full-Text)
More Information
Publications
- 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. Review. Erratum in: Lancet Neurol. 2018 Apr 4;:.
- 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.
- Gloss D, Moxley RT 3rd, Ashwal S, Oskoui M. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: 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. Review.
- 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.
- 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. Erratum in: Am J Pathol. 2021 Nov;191(11):2039.
- Walter MC, Reilich P, Thiele S, Schessl J, Schreiber H, Reiners K, Kress W, Müller-Reible C, Vorgerd M, Urban P, Schrank B, Deschauer M, Schlotter-Weigel B, Kohnen R, Lochmüller 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.
- STU00208443
Study Results
Participant Flow
Recruitment Details | Patient Diagnosis Subtype: 19 with Limb-Girdle Muscular Dystrophy 1 with Becker Muscular Dystrophy |
---|---|
Pre-assignment Detail |
Arm/Group Title | Weekly Steroid |
---|---|
Arm/Group Description | 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 |
Period Title: Overall Study | |
STARTED | 20 |
COMPLETED | 20 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | Weekly Steroid |
---|---|
Arm/Group Description | 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 |
Overall Participants | 20 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
20
100%
|
>=65 years |
0
0%
|
Age (years) [Mean (Full Range) ] | |
Mean (Full Range) [years] |
35
|
Sex: Female, Male (Count of Participants) | |
Female |
7
35%
|
Male |
13
65%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
1
5%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
1
5%
|
White |
18
90%
|
More than one race |
0
0%
|
Unknown or Not Reported |
0
0%
|
Region of Enrollment (participants) [Number] | |
United States |
20
100%
|
Outcome Measures
Title | Fasting Glucose |
---|---|
Description | mg/dL, 0-unlimited, higher score indicates worse outcome |
Time Frame | Baseline and 6 months (Final Visit) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Weekly Steroid |
---|---|
Arm/Group Description | 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 |
Measure Participants | 16 |
Baseline |
93
(2)
|
End |
102
(4)
|
Title | HbgA1c |
---|---|
Description | % , 0-100, higher score indicates worse outcome |
Time Frame | Baseline and 6 months (Final Visit) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Weekly Steroid |
---|---|
Arm/Group Description | 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 |
Measure Participants | 17 |
Baseline |
5.2
(0.08)
|
End |
5.3
(0.09)
|
Title | Fasting Lipid Profile |
---|---|
Description | cholesterol levels - mg/dL, higher levels indicate worse outcomes |
Time Frame | Baseline and 6 months (Final Visit) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Weekly Steroid |
---|---|
Arm/Group Description | 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 |
Measure Participants | 17 |
Baseline |
182
(10)
|
End |
185
(9)
|
Title | Creatine Kinase |
---|---|
Description | units/L, 0-unlimited, higher scores indicate worse outcome |
Time Frame | Baseline and 6 months (Final Visit) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Weekly Steroid |
---|---|
Arm/Group Description | 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 |
Measure Participants | 17 |
Baseline |
1574
(269)
|
End |
1047
(171)
|
Title | Respiratory Changes |
---|---|
Description | Force Vital Capacity (% of predicted value), decrease in FVC indicates declining respiratory function. |
Time Frame | Baseline, 6 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Weekly Steroid |
---|---|
Arm/Group Description | 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 |
Measure Participants | 11 |
Baseline |
80
(8)
|
End |
79
(8)
|
Title | Functional Assessments - NSAD Change |
---|---|
Description | Northstar Assessment for Dysferlinopathy - score out of 58, range from 0 to 58, higher score indicates greater functional ability. |
Time Frame | Baseline, Month 6 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | 6 Minute Walk Test |
---|---|
Description | number of meters walked in 6 minute period. Higher values indicate more motor function. |
Time Frame | Baseline, Month 6 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | 10 Meter Run Timed |
---|---|
Description | time in seconds to walk/run 10 meters , less time to run indicates greater motor function |
Time Frame | Baseline, Month 6 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Functional Assessments - Upper Limb Strength |
---|---|
Description | Performance of Modified Upper Limb Module - Yes or No questions, ability to raise 50 gram, 100 gram, 200 gram, 500 gm weights above the head and to the mouth. |
Time Frame | Baseline, Month 6 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Brooke Scale Score |
---|---|
Description | upper extremity assessment, scoring between 1- 6, lower score indicates more upper extremity function |
Time Frame | Baseline, Month 6 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Vignos Scale Score |
---|---|
Description | Lower extremity assessment, score from 1-10, lower score indicates more function. |
Time Frame | Baseline, Month 6 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Muscle Strength Test |
---|---|
Description | Motor Muscle Testing: score of 1 - 5 , higher score indicates more muscle strength. |
Time Frame | Baseline, 6 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Muscle Imaging |
---|---|
Description | MRI of leg muscles to measure changes in muscle |
Time Frame | Baseline, 6 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Bone Density |
---|---|
Description | whole dexa body scan to assess bone density with Z scores (more negative z score indicates increased risk for fractures) |
Time Frame | Baseline, 6 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Lean Mass % |
---|---|
Description | whole body dexa scans to assess lean mass % (0- 100 %). Increase lean mass % is the desired outcome. |
Time Frame | Baseline, 6 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Adverse Events
Time Frame | Participants were monitored for 24 weeks or 6 months while taking study drug. | |
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Weekly Steroid | |
Arm/Group Description | 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 | |
All Cause Mortality |
||
Weekly Steroid | ||
Affected / at Risk (%) | # Events | |
Total | 0/20 (0%) | |
Serious Adverse Events |
||
Weekly Steroid | ||
Affected / at Risk (%) | # Events | |
Total | 0/20 (0%) | |
Other (Not Including Serious) Adverse Events |
||
Weekly Steroid | ||
Affected / at Risk (%) | # Events | |
Total | 0/20 (0%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Dr. Senda Ajroud-Driss |
---|---|
Organization | Northwestern University School of Medicine |
Phone | (312) 944-0063 |
s-ajroud@northwestern.edu |
- STU00208443