Phase I/II Study of PRO044 in Duchenne Muscular Dystrophy (DMD)

A Phase I/IIa, Open Label, Escalating Dose, Pilot Study to Assess the Effect, Safety, Tolerability and Pharmacokinetics of Multiple Subcutaneous and Intravenous Doses of PRO044 in Patients With Duchenne Muscular Dystrophy

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.

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: PRO044 SC; Drug: PRO044 IV

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Italy
  • Ferrara, Italy
    • S.Anna Hospital
• Netherlands
  • Leiden, Netherlands, 2300
    • Leiden University Medical Center
• Sweden
  • Gothenburg, Sweden
    • The Queen Silvia Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PRO044, cohort 1; Subcutaneous injection of 0.5 mg/kg on day 1, 8, 15, 22 and 29.	Drug: PRO044 SC; Subcutaneous injection, once a week, for five weeks
Experimental: PRO044, cohort 2; Subcutaneous injection of maximally 1.5 mg/kg on day 1, 8, 15, 22 and 29.	Drug: PRO044 SC; Subcutaneous injection, once a week, for five weeks
Experimental: PRO044, cohort 3; Subcutaneous injection of maximally 5 mg/kg on day 1, 8, 15, 22 and 29.	Drug: PRO044 SC; Subcutaneous injection, once a week, for five weeks
Experimental: PRO044, cohort 4; Subcutaneous injection of maximally 8 mg/kg on day 1, 8, 15, 22 and 29.	Drug: PRO044 SC; Subcutaneous injection, once a week, for five weeks
Experimental: PRO044, cohort 5; Subcutaneous injection of maximally 10 mg/kg on day 1, 8, 15, 22 and 29	Drug: PRO044 SC; Subcutaneous injection, once a week, for five weeks
Experimental: PRO044, cohort 6; Subcutaneous injection of maximally 12 mg/kg on day 1, 8, 15, 22 and 29	Drug: PRO044 SC; Subcutaneous injection, once a week, for five weeks
Experimental: PRO044, cohort 7; Intravenous injection of maximally 1.5 mg/kg on day 1, 8, 15, 22 and 29	Drug: PRO044 IV; Intravenous injection, once a week, for five weeks
Experimental: PRO044, cohort 8; Intravenous injection of maximally 5 mg/kg on day 1, 8, 15, 22 and 29	Drug: PRO044 IV; Intravenous injection, once a week, for five weeks
Experimental: PRO044, cohort 9; Intravenous injection of maximally 8 mg/kg on day 1, 8, 15, 22 and 29	Drug: PRO044 IV; Intravenous injection, once a week, for five weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	number of subjects with 1 or more treatment emergent adverse events following SC or IV PRO044	During the 5 weeks of treatment and during the 13 weeks after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration	Pharmacokinetic population evaluated for maximum plasma concentration (Cmax)	Week 1, Week 5

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Principal Investigator: A. Ferlini, PhD, Università di Ferrara and S.Anna Hospital, Ferrara, Italy; Principal Investigator: J. J. Verschuuren, MD, Leiden University Medical Center, Leiden, The Netherlands; Principal Investigator: N. Goemans, MD, UZ Leuven, Leuven, Belgium; Principal Investigator: M. Tulinius, MD, The Queen Silvia Children's Hospital, Gothenburg, Sweden

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: December 21, 2009
• First Submitted That Met QC Criteria: December 21, 2009
• First Posted (Estimate): December 23, 2009

Study Record Updates

• Last Update Posted (Actual): October 16, 2018
• Last Update Submitted That Met QC Criteria: September 19, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: PRO044-CLIN-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No