Muscular Dystrophy, Duchenne
Conditions
Brief summary
This is a randomized, open-label, pilot clinical trial of spironolactone suspension versus oral prednisolone for use in Duchenne muscular dystrophy. The goals are to determine the safety of 6 months of treatment with spironolactone treatment int he steroid-naive DMD population as well as to determine if either spironolactone or a standard clinical dose of corticosteroids results in equivalent improvement in time to complete the 100 meter timed test (100M).
Detailed description
Until recently, the only treatment shown to improve strength and preserve ambulation in DMD patients was the use of glucocorticoids, which are accompanied by significant side effects including obesity, cushingoid features, osteoporosis, and behavioral disturbances. Spironolactone is an aldosterone antagonist primarily used as a potassium sparing diuretic that is widely used in the pediatric population, with limited side-effects including gynecomastia and hyperkalemia. Recent studies by Dr. Rafael-Fortney have evaluated the effect of spironolactone treatment in several different mouse models of DMD. Her results show that treatment of these mice demonstrates increased muscle membrane stabilization while reducing the negative side-effects typically associated with standard of care glucocorticoids. This pilot study is designed to determine whether this commonly used medication, spironolactone, may have similar beneficial effects with a lower side effect profile and be applicable to a wider population of DMD patients. The hypothesis for this controlled pilot trial is that spironolactone and prednisolone are of equal efficacy in improving skeletal muscle function over a 6-month period, and that spironolactone will be well tolerated in this patient population. One outcome is that both drugs demonstrate equal efficacy in motor function. This would then serve as pilot data for a longer term study.
Interventions
DRUGSpironolactone
Spironolactone will be prescribed for 6 months, after which the family and primary care physician will determine to either remain on spironolactone or transfer to prednisolone.
DRUGPrednisolone
Prednisolone will be prescribed for 6 months as the clinical standard of care.
Sponsors
Muscular Dystrophy Association
Kevin Flanigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subjects will be randomly assigned to either to the spironolactone treatment group or to the standard clinical dose of corticosteroids.
Eligibility
Sex/Gender
MALE
Age
4 Years to 7 Years
Healthy volunteers
No
Inclusion criteria
* Duchenne muscular dystrophy (DMD) patients ≥4 to ≤7 years of age * Clinical features of DMD that include proximal predominant weakness and/or gait disturbance * Presence of a truncating mutation of the DMD gene in the patient or an affected male relative OR a muscle biopsy that demonstrates \<5% dystrophin in the patient or an affected male relative * Normal left ventricular ejection fraction by screening echocardiogram * Ability to cooperate for testing * No prior treatment with glucocorticoids or vamorolone * No concomitant experimental therapies
Exclusion criteria
* Subject amenable to or currently being treated with eteplirsen, casimersen, or viltolarsen * Hyperkalemia at screening * History of or ongoing renal failure (elevated creatinine, oliguria, anuria) * Hypersensitivity to spironolactone (rash, respiratory distress, arrhythmia, numbness or tingling of extremities) * Current treatment with an ACEi * Severe peptic ulcer disease or recent gastrointestinal perforations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Change in Time to Complete a 100 Meter Timed Test. | 6 months | The determination of whether spironolactone has similar efficacy to glucocorticoids in improving muscle strength in steroid naïve DMD patients. This will be determined by measuring the time to complete a 100 meter timed test (100M). |
| Safety Will be Monitored Through Regular Review of Electrolytes. | 6 months | Electrolytes (Sodium, Potassium, Cloride and Carbon dioxide, mmol/L) will be measured on a monthly basis following initiation of either spironolactone or prednisolone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Dynamometry Score | 6 months | Secondary outcome measures will be Dynamometry score, which is a summation of maximum voluntary isometric contraction test values for knee flexion, knee extension, elbow flexion, and elbow extension |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Spironolactone Twelve subjects will be prescribed a standard clinical dose of spironolactone of 1 mg/kg/day. The spironolactone will be provided as suspension.
Spironolactone: Spironolactone will be prescribed for 6 months, after which the family and primary care physician will determine to either remain on spironolactone or transfer to prednisolone. | 1 |
| Prednisolone Twelve subjects will be prescribed a standard clinical dose of prednisolone of 0.75 mg/kg/day or weekend dosing per sites standard of care. The prednisolone will be provided will be provided as suspension.
Prednisolone: Prednisolone will be prescribed for 6 months as the clinical standard of care. | 1 |
| Total | 2 |
Baseline characteristics
| Characteristic | Prednisolone | Total | Spironolactone |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 1 participants | 2 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
Efficacy: Change in Time to Complete a 100 Meter Timed Test.
The determination of whether spironolactone has similar efficacy to glucocorticoids in improving muscle strength in steroid naïve DMD patients. This will be determined by measuring the time to complete a 100 meter timed test (100M).
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Spironolactone | Efficacy: Change in Time to Complete a 100 Meter Timed Test. | -0.6 sec |
| Prednisolone | Efficacy: Change in Time to Complete a 100 Meter Timed Test. | -5.3 sec |
Primary
Safety Will be Monitored Through Regular Review of Electrolytes.
Electrolytes (Sodium, Potassium, Cloride and Carbon dioxide, mmol/L) will be measured on a monthly basis following initiation of either spironolactone or prednisolone.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 4 | 4.5 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Baseline | 142 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 1 | 142 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 2 | 141 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 3 | 142 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 4 | 139 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 5 | 139 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 6 | 140 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Baseline | 4.5 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 1 | 4.7 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 2 | 4.2 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 3 | 4.1 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 5 | 4.5 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 6 | 4.3 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Baseline | 103 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 1 | 109 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 2 | 107 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 3 | 103 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 4 | 103 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 5 | 103 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 6 | 101 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Baseline | 29 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 1 | 22 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 2 | 25 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 3 | 27 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 4 | 28 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 5 | 28 mmol/L |
| Spironolactone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 6 | 26 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 3 | 24 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Baseline | 105 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Baseline | 140 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Baseline | 22 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 1 | 140 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 1 | 105 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 2 | 139 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 5 | 26 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 3 | 141 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 2 | 104 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 4 | 139 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 1 | 24 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 5 | 139 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 3 | 105 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Sodium-Month 6 | 143 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 4 | 25 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Baseline | 3.8 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 4 | 105 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 1 | 4 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 2 | 24 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 2 | 4.5 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 5 | 106 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 3 | 3.9 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 4 | 4.6 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | CO2-Month 6 | 26 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 5 | 4.2 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Chloride-Month 6 | 105 mmol/L |
| Prednisolone | Safety Will be Monitored Through Regular Review of Electrolytes. | Potassium-Month 6 | 3.9 mmol/L |
Secondary
Efficacy: Dynamometry Score
Secondary outcome measures will be Dynamometry score, which is a summation of maximum voluntary isometric contraction test values for knee flexion, knee extension, elbow flexion, and elbow extension
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Spironolactone | Efficacy: Dynamometry Score | Elbow Flexion (Right)-Baseline | 0 kg |
| Spironolactone | Efficacy: Dynamometry Score | Elbow Flexion (Left)-Baseline | 0 kg |
| Spironolactone | Efficacy: Dynamometry Score | Elbow Extension (Right)-Baseline | 0 kg |
| Spironolactone | Efficacy: Dynamometry Score | Elbow Extension (Left)-Baseline | 0 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Flexion (Right)-Baseline | 4.1 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Flexion (Left)-Baseline | 2.8 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Extension (Right)-Baseline | 3.8 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Extension (Left)-Baseline | 5.9 kg |
| Spironolactone | Efficacy: Dynamometry Score | Elbow Flexion (Right)-Month 6 | 3.1 kg |
| Spironolactone | Efficacy: Dynamometry Score | Elbow Flexion (Left)-Month 6 | 3.5 kg |
| Spironolactone | Efficacy: Dynamometry Score | Elbow Extension (Right)-Month 6 | 2.4 kg |
| Spironolactone | Efficacy: Dynamometry Score | Elbow Extension (Left)-Month 6 | 2.5 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Flexion (Right)-Month 6 | 4.3 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Flexion (Left)-Month 6 | 4.1 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Extension (Right)-Month 6 | 7.2 kg |
| Spironolactone | Efficacy: Dynamometry Score | Knee Extension (Left)-Month 6 | 8.3 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Extension (Left)-Month 6 | 5.1 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Flexion (Right)-Baseline | 3.6 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Flexion (Right)-Month 6 | 2.9 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Flexion (Left)-Baseline | 4.1 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Flexion (Right)-Month 6 | 4.1 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Extension (Right)-Baseline | 5.3 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Flexion (Left)-Month 6 | 3.4 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Extension (Left)-Baseline | 4.1 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Extension (Right)-Month 6 | 6 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Flexion (Right)-Baseline | 3.3 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Extension (Right)-Month 6 | 4.3 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Flexion (Left)-Baseline | 3.4 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Flexion (Left)-Month 6 | 3.9 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Extension (Right)-Baseline | 4.8 kg |
| Prednisolone | Efficacy: Dynamometry Score | Elbow Extension (Left)-Month 6 | 3.8 kg |
| Prednisolone | Efficacy: Dynamometry Score | Knee Extension (Left)-Baseline | 5.2 kg |