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

• 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: University of Pittsburgh
• Collaborator: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Information provided by (Responsible Party): Gerard Vockley, MD, PhD, University of Pittsburgh

Study Description

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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 4 participants
• Allocation: N/A
• 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

Arms and Interventions

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

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

• 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

Locations

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

• Principal Investigator: Gerard Vockley, MD, PhD; University of Pittsburgh/Children's Hospital of Pittsburgh of UPMC

More Information

Additional Information:

U.S. National Library of Medicine Genetics Home Reference Information on MCAD Deficiency 

Publications:

Kormanik K, Kang H, Cuebas D, Vockley J, Mohsen AW. Evidence for involvement of medium chain acyl-CoA dehydrogenase in the metabolism of phenylbutyrate. Mol Genet Metab. 2012 Dec;107(4):684-9. doi: 10.1016/j.ymgme.2012.10.009. Epub 2012 Oct 18.

• Responsible Party: Gerard Vockley, MD, PhD, Professor of Pediatrics/Human Genetics, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01881984
• Other Study ID Numbers: PRO13050530
• First Posted: June 20, 2013
• 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:

Glycerol; Cryoprotective Agents; Protective Agents; Physiological Effects of Drugs