Duchenne Muscular Dystrophy
Conditions
Brief summary
The purpose of this study is to see whether PRO044 is safe and effective to use as medication for DMD patients with a mutation around location 44 in the DNA for the dystrophin protein.
Detailed description
To assess the effect of PRO044 at different dose levels in subjects with Duchenne muscular dystrophy To assess the safety and tolerability of PRO044 at different dose levels in subjects with Duchenne muscular dystrophy To determine the pharmacokinetics of PRO044 at different dose levels after subcutaneous and intravenous administration in subjects with Duchenne muscular dystrophy.
Interventions
DRUGPRO044 SC
Subcutaneous injection, once a week, for five weeks
DRUGPRO044 IV
Intravenous injection, once a week, for five weeks
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
5 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
1. Boys aged between 5 and 16 years inclusive. 2. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with PRO044. 3. Life expectancy of at least 6 months. 4. No previous treatment with investigational medicinal treatment within 6 months prior to the start of the (pre)-screening for the study. 5. No previous treatment with idebenone within 6 months prior to the start of the (pre)-screening for the study. 6. Willing and able to adhere to the study visit schedule and other protocol requirements. 7. Written informed consent signed (by parent(s)/legal guardian and/or the patient, according to the local regulations). 8. Glucocorticosteroids use which is stable for at least 2 months prior first drug administration.
Exclusion criteria
1. Aberrant RNA splicing and/or aberrant response to PRO044, detected by in vitro PRO044 assay during pre-screening. 2. Known presence of dystrophin in ≥ 5% of fibers in a pre-study diagnostic muscle biopsy. 3. Severe muscle abnormalities defined as increased signal intensity in \>50% of the tibialis anterior muscle at MRI. 4. FEV1 and/or FVC \< 60% of predicted. 5. Current or history of liver or renal disease. 6. Acute illness within 4 weeks prior to treatment (Day 1) which may interfere with the measurements. 7. Severe mental retardation which in the opinion of the investigator prohibits participation in this study. 8. Severe cardiac myopathy which in the opinion of the investigator prohibits participation in this study. 9. Need for mechanical ventilation. 10. Creatinine concentration above 1.5 times the upper limit of normal (age corrected). 11. Serum ASAT and/or ALAT concentration(s) which suggest hepatic impairment. 12. Use of anticoagulants, antithrombotics or antiplatelet agents. 13. Use of idebenone. 14. Use of any investigational product within 6 months prior to the start of the (pre)-screening for the study. 15. Subject has donated blood less than 90 days before the start of the (pre)-screening for the study. 16. Current or history of drug and/or alcohol abuse. 17. Participation in another trial with an investigational product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | Within 13 weeks after 5 weeks of treatment | — |
| Safety and Tolerability of PRO044 | During the 5 weeks of treatment and during the 13 weeks after treatment | number of subjects with 1 or more treatment emergent adverse events following SC or IV PRO044 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1, Week 5 | Pharmacokinetic population evaluated for maximum plasma concentration (Cmax) |
Countries
Belgium, Italy, Netherlands, Sweden
Participant flow
Recruitment details
3 Subjects were recruited to each of cohorts 1-6 (total n=18) for SC administration PRO044 9 of these 18 subjects were recruited to cohorts 7-9 (n=3 in each cohort) for IV adminstration PRO044
Pre-assignment details
3 Subjects were recruited to each of cohorts 1-6 (total n=18) for SC administration PRO044 9 of these 18 subjects were recruited to cohorts 7-9 (n=3 in each cohort) for IV adminstration PRO044
Participants by arm
| Arm | Count |
|---|---|
| PRO044, Cohort 1 Subcutaneous injection of 0.5 mg/kg on day 1, 8, 15, 22 and 29.
PRO044 SC: Subcutaneous injection, once a week, for five weeks | 3 |
| PRO044, Cohort 2 Subcutaneous injection of maximally 1.5 mg/kg on day 1, 8, 15, 22 and 29.
PRO044 SC: Subcutaneous injection, once a week, for five weeks | 3 |
| PRO044, Cohort 3 Subcutaneous injection of maximally 5 mg/kg on day 1, 8, 15, 22 and 29.
PRO044 SC: Subcutaneous injection, once a week, for five weeks | 3 |
| PRO044, Cohort 4 Subcutaneous injection of maximally 8 mg/kg on day 1, 8, 15, 22 and 29.
PRO044 SC: Subcutaneous injection, once a week, for five weeks | 3 |
| PRO044, Cohort 5 Subcutaneous injection of maximally 10 mg/kg on day 1, 8, 15, 22 and 29
PRO044 SC: Subcutaneous injection, once a week, for five weeks | 3 |
| PRO044, Cohort 6 Subcutaneous injection of maximally 12 mg/kg on day 1, 8, 15, 22 and 29
PRO044 SC: Subcutaneous injection, once a week, for five weeks | 3 |
| Total | 18 |
Baseline characteristics
| Characteristic | PRO044, Cohort 1 | PRO044, Cohort 2 | PRO044, Cohort 3 | PRO044, Cohort 4 | PRO044, Cohort 5 | PRO044, Cohort 6 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 18 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Belgium | 3 participants | 1 participants | 0 participants | 0 participants | 1 participants | 1 participants | 6 participants |
| Region of Enrollment Italy | 0 participants | 0 participants | 3 participants | 1 participants | 1 participants | 2 participants | 7 participants |
| Region of Enrollment Netherlands | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Sweden | 0 participants | 2 participants | 0 participants | 1 participants | 1 participants | 0 participants | 4 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 2 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts
Time frame: Within 13 weeks after 5 weeks of treatment
Population: For some participants it was not possible to determine dystrophin expression in muscle biopsy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PRO044, Cohort 1 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 1 Participants |
| PRO044, Cohort 2 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 1 Participants |
| PRO044, Cohort 3 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 0 Participants |
| PRO044, Cohort 4 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 1 Participants |
| PRO044, Cohort 5 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 1 Participants |
| PRO044, Cohort 6 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 2 Participants |
| PRO044, Cohort 7 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 2 Participants |
| PRO044, Cohort 8 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 3 Participants |
| PRO044, Cohort 9 | Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts | 1 Participants |
Primary
Safety and Tolerability of PRO044
number of subjects with 1 or more treatment emergent adverse events following SC or IV PRO044
Time frame: During the 5 weeks of treatment and during the 13 weeks after treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PRO044, Cohort 1 | Safety and Tolerability of PRO044 | 3 Participants |
| PRO044, Cohort 2 | Safety and Tolerability of PRO044 | 3 Participants |
| PRO044, Cohort 3 | Safety and Tolerability of PRO044 | 3 Participants |
| PRO044, Cohort 4 | Safety and Tolerability of PRO044 | 3 Participants |
| PRO044, Cohort 5 | Safety and Tolerability of PRO044 | 3 Participants |
| PRO044, Cohort 6 | Safety and Tolerability of PRO044 | 3 Participants |
| PRO044, Cohort 7 | Safety and Tolerability of PRO044 | 2 Participants |
| PRO044, Cohort 8 | Safety and Tolerability of PRO044 | 3 Participants |
| PRO044, Cohort 9 | Safety and Tolerability of PRO044 | 3 Participants |
Secondary
PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration
Pharmacokinetic population evaluated for maximum plasma concentration (Cmax)
Time frame: Week 1, Week 5
Population: Pharmacokinetic population evaluated
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| PRO044, Cohort 1 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 0.4 ug/mL | Geometric Coefficient of Variation 28.8 |
| PRO044, Cohort 1 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 0.4 ug/mL | Geometric Coefficient of Variation 42.5 |
| PRO044, Cohort 2 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 1.5 ug/mL | Geometric Coefficient of Variation 22.9 |
| PRO044, Cohort 2 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 1.6 ug/mL | Geometric Coefficient of Variation 21.7 |
| PRO044, Cohort 3 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 4.2 ug/mL | Geometric Coefficient of Variation 61.5 |
| PRO044, Cohort 3 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 3.4 ug/mL | Geometric Coefficient of Variation 31.4 |
| PRO044, Cohort 4 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 5.1 ug/mL | Geometric Coefficient of Variation 24.2 |
| PRO044, Cohort 4 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 6.2 ug/mL | Geometric Coefficient of Variation 53.8 |
| PRO044, Cohort 5 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 4.9 ug/mL | Geometric Coefficient of Variation 21.7 |
| PRO044, Cohort 5 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 4.4 ug/mL | Geometric Coefficient of Variation 7 |
| PRO044, Cohort 6 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 4.8 ug/mL | Geometric Coefficient of Variation 35.7 |
| PRO044, Cohort 6 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 5.2 ug/mL | Geometric Coefficient of Variation 16 |
| PRO044, Cohort 7 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 3.1 ug/mL | Geometric Coefficient of Variation 28.9 |
| PRO044, Cohort 7 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 2.2 ug/mL | Geometric Coefficient of Variation 20.6 |
| PRO044, Cohort 8 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 4.7 ug/mL | Geometric Coefficient of Variation 18.9 |
| PRO044, Cohort 8 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 3.5 ug/mL | Geometric Coefficient of Variation 69.5 |
| PRO044, Cohort 9 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 1 | 8.7 ug/mL | Geometric Coefficient of Variation 31.3 |
| PRO044, Cohort 9 | PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Week 5 | 8.7 ug/mL | Geometric Coefficient of Variation 33.6 |