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

• ClinicalTrials.gov Identifier: NCT01037309
• Recruitment Status: Completed
• First Posted: December 23, 2009
• Results First Posted: April 9, 2015
• Last Update Posted: October 16, 2018
• Sponsor: BioMarin Pharmaceutical
• Information provided by (Responsible Party): BioMarin Pharmaceutical

Tracking Information

• First Submitted Date: December 21, 2009
• First Posted Date: December 23, 2009
• Results First Submitted Date: September 1, 2014
• Results First Posted Date: April 9, 2015
• Last Update Posted Date: October 16, 2018
• Study Start Date: December 2009
• Actual Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 19, 2018)

• 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 ]
• Safety and Tolerability of PRO044 [ Time Frame: 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

Original Primary Outcome Measures (submitted: December 21, 2009)

• To assess the 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 ]
• Safety and Tolerability of PRO044 [ Time Frame: During the 5 weeks of treatment and during the 13 weeks after treatment ]
• Determine the Pharmacokinetics of PRO044 [ Time Frame: During the 5 weeks of treatment and during the 13 weeks after treatment ]

Current Secondary Outcome Measures (submitted: September 19, 2018)

PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration [ Time Frame: Week 1, Week 5 ]

Pharmacokinetic population evaluated for maximum plasma concentration (Cmax)

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase I/II Study of PRO044 in Duchenne Muscular Dystrophy (DMD)
• Official Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy

Intervention

• Drug: PRO044 SC
  Subcutaneous injection, once a week, for five weeks
• Drug: PRO044 IV
  Intravenous injection, once a week, for five weeks

Study Arms

• Experimental: PRO044, cohort 1
  Subcutaneous injection of 0.5 mg/kg on day 1, 8, 15, 22 and 29.
  Intervention: Drug: PRO044 SC
• Experimental: PRO044, cohort 2
  Subcutaneous injection of maximally 1.5 mg/kg on day 1, 8, 15, 22 and 29.
  Intervention: Drug: PRO044 SC
• Experimental: PRO044, cohort 3
  Subcutaneous injection of maximally 5 mg/kg on day 1, 8, 15, 22 and 29.
  Intervention: Drug: PRO044 SC
• Experimental: PRO044, cohort 4
  Subcutaneous injection of maximally 8 mg/kg on day 1, 8, 15, 22 and 29.
  Intervention: Drug: PRO044 SC
• Experimental: PRO044, cohort 5
  Subcutaneous injection of maximally 10 mg/kg on day 1, 8, 15, 22 and 29
  Intervention: Drug: PRO044 SC
• Experimental: PRO044, cohort 6
  Subcutaneous injection of maximally 12 mg/kg on day 1, 8, 15, 22 and 29
  Intervention: Drug: PRO044 SC
• Experimental: PRO044, cohort 7
  Intravenous injection of maximally 1.5 mg/kg on day 1, 8, 15, 22 and 29
  Intervention: Drug: PRO044 IV
• Experimental: PRO044, cohort 8
  Intravenous injection of maximally 5 mg/kg on day 1, 8, 15, 22 and 29
  Intervention: Drug: PRO044 IV
• Experimental: PRO044, cohort 9
  Intravenous injection of maximally 8 mg/kg on day 1, 8, 15, 22 and 29
  Intervention: Drug: PRO044 IV

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 14, 2011): 18
• Original Estimated Enrollment (submitted: December 21, 2009): 12
• Actual Study Completion Date: October 2013
• Actual Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 5 Years to 16 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands, Belgium, Italy, Sweden

Administrative Information

• NCT Number: NCT01037309
• Other Study ID Numbers: PRO044-CLIN-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: BioMarin Pharmaceutical
• Study Sponsor: BioMarin Pharmaceutical
• Collaborators: Not Provided

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

• PRS Account: BioMarin Pharmaceutical
• Verification Date: September 2018