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Use of Ravicti™ in Patients With MCAD Deficiency With the 985A>G (K304E) Mutation

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ClinicalTrials.gov Identifier: NCT01881984
Recruitment Status : Completed
First Posted : June 20, 2013
Results First Posted : July 11, 2017
Last Update Posted : September 25, 2017
Sponsor:
Collaborator:
Horizon Pharma Ireland, Ltd., Dublin Ireland
Information provided by (Responsible Party):
Gerard Vockley, MD, PhD, University of Pittsburgh

Study Description
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Brief Summary:
This is a medical research study to test a medication in adult patients with a disease called medium-chain acyl-CoA dehydrogenase (MCAD) deficiency caused by at least one copy of the 985A>G mutation. The medication is glycerol phenylbutyrate, called Ravicti, which is currently FDA approved for the treatment of urea cycle disorders. Previous research suggests that Ravicti may also be effective in the treatment MCAD deficiency. This study will investigate the safety and efficacy (how well it works) of Ravicti in patients with MCAD deficiency caused by having at least one copy of the 985A>G mutation.

Condition or disease Intervention/treatment Phase
Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency Drug: Ravicti Phase 1

Detailed Description:

Participation in the study will require one overnight admission and three outpatient visits at the Clinical and Translational Research Center at Children's Hospital of Pittsburgh of UPMC (also called the PCTRC). The total length of the study is 7 weeks.

Subjects will have blood work and an intravenous access line (IV) placed for several blood draws during the visit. Subjects will begin fasting at 8pm during the admission, which means they may consume only non-caloric fluids (water, unsweetened black coffee or tea, or sugar-free beverages). The next morning, fasting blood work will be obtained. The subject can then eat breakfast and will receive the study drug, Ravicti. The total time of fasting will be 12 hours.

Dosing for this study will begin at 2 grams/m2/day, which is about one-fifth (1/5) the dose used for other disorders. The reason for starting the dose lower in MCAD patients is that Ravicti is metabolized by the MCAD enzyme. Following the initial dose, blood will be drawn from the IV every two hours for 8 hours. These blood studies will check the levels of Ravicti in the subject's blood and monitor how the subject's body metabolizes them. The subject will be discharged 8 hours after drug administration. Following discharge, the subject will take Ravicti every day for two weeks.

Visit 2: After two weeks at a dose of 2 grams/m2/day, the subject will fast after 8 PM, and will come to the PCTRC the following morning to have an IV placed and blood draws. If the subject's blood work from the first visit shows that there is no concern, the subject's dose will be increased to 4 grams/m2/day. The subject will receive the first dose at this level in the PCTRC with breakfast, and blood samples will be collected from the IV every 2 hours for the next 8 hours. The subject will continue on this dose for two weeks.

Visit 3: After two weeks at a dose of 4 grams/m2/day, the subject will fast after 8 PM, and will come to the PCTRC the following morning to have an IV placed and blood draws. If the subject's blood work from the previous visit shows that there is no concern, the subject's dose will be increased to 6 grams/m2/day. The subject will receive the first dose at this level in the PCTRC with breakfast, and blood samples will be collected from the IV every 2 hours for the next 8 hours. The subject will continue on this dose for two weeks.

Visit 4 (final): After two weeks at a dose of 6 grams/m2/day, the subject will fast after 8 PM, and will come to the CTRC the following morning to have one blood draw. The subject will return any unused Ravicti, and their study participation will be completed.

All study procedures will be done at no cost to the subjects.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Use of Glycerol Phenylbutyrate (Ravicti™) as a Chaperone to Stabilize Enzyme in Patients With MCAD Deficiency Due to the Common MCAD 985A>G (K304E) Mutation
Study Start Date : June 2013
Actual Primary Completion Date : February 2016
Actual Study Completion Date : February 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Ravicti
Open Label Study
 Drug: Ravicti
Open-label design comparing Ravicti at doses of 2, 4, and 6 grams/m2/day
Other Name: glycerol phenylbutyrate


Outcome Measures
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Primary Outcome Measures :
  1. Metabolic Stress [ Time Frame: 7 weeks ]
    Changes in the assessments of metabolic stress pre- and post-dosing with Ravicti will be the main outcome variable.


Secondary Outcome Measures :
  1. Pharmacokinetic (pK)Analysis [ Time Frame: 7 weeks ]
    Results from the pharmacokinetic (pK)analysis (the rate of conversion of the phenylbutyrate to phenylacetate) will also be reviewed to assess for changes pre- and post-dosing with Ravicti as well as changes in these levels at the different doses of Ravicti.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • confirmation of a diagnosis of MCAD deficiency
  • at least one copy of 985A>G MCAD mutation
  • ability to follow protocol

Exclusion Criteria:

  • positive pregnancy test
  • currently breastfeeding
  • currently taking any medication for which there is a potential drug interaction with Ravicti, includes corticosteroids, valproic acid, haloperidol, and probenecid
  • liver or kidney insufficiency
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01881984


Locations
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United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
Sponsors and Collaborators
University of Pittsburgh
Horizon Pharma Ireland, Ltd., Dublin Ireland
Investigators
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Principal Investigator: Gerard Vockley, MD, PhD University of Pittsburgh/Children's Hospital of Pittsburgh of UPMC
More Information
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Additional Information:
U.S. National Library of Medicine Genetics Home Reference Information on MCAD Deficiency  This link exits the ClinicalTrials.gov site

Publications:

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Responsible Party: Gerard Vockley, MD, PhD, Professor of Pediatrics/Human Genetics, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01881984     History of Changes
Other Study ID Numbers: PRO13050530
First Posted: June 20, 2013    Key Record Dates
Results First Posted: July 11, 2017
Last Update Posted: September 25, 2017
Last Verified: September 2017

Keywords provided by Gerard Vockley, MD, PhD, University of Pittsburgh:
Medium-chain acyl-CoA dehydrogenase deficiency
MCAD deficiency
MCADD
ACADM deficiency
MCADH deficiency
 985A>G mutation
K304E mutation
Ravicti
glycerol phenylbutyrate

Additional relevant MeSH terms:
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Glycerol
4-phenylbutyric acid
Cryoprotective Agents
 Protective Agents
Physiological Effects of Drugs
Antineoplastic Agents