Ignite Creation Date:
2024-05-06 @ 3:36 AM
Last Modification Date:
2024-10-26 @ 11:35 AM
Study NCT ID:
NCT02323100
Status:
TERMINATED
Last Update Posted:
2022-03-21
First Post:
2014-12-18
Brief Title:
Glycerol Phenylbutyrate Corrector Therapy For CF Cystic Fibrosis
Sponsor:
National Jewish Health
Organization:
National Jewish Health
Study Overview
Official Title:
A Double Blind Placebo Controlled Dose Escalation Trial of Glycerol Phenylbutyrate Corrector Therapy for Cystic Fibrosis
Status:
TERMINATED
Status Verified Date:
2022-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
funding ended
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GPBA
Brief Summary:
We propose to test the effectiveness of the combination of CF pancreatic enzyme replacement therapy PERT on absorption of Ravicti and subsequent restoration of nasal epithelial cystic fibrosis transmembrane conductance regulator CFTR-mediated chloride transport during the nasal potential difference NPD test Funding source FDA Office of Orphan Products Development
Detailed Description:
We were the first to test 4-phenylbutyrate Buphenyl as a systemic corrector of these defects in F508del under an investigator-initiated Investigational New Drug INDapplication held by P Zeitlin In a series of Phase 1 and 2 trials we established the maximum tolerated dose as 20 gm daily divided tid and the maximum induction of cyclic AMP cAMP-mediated nasal epithelial chloride transport with 30 gm daily as a median of -10 millivolt mV on days 4 and 7 of treatment12 Under those conditions there was no significant decrease in sweat chloride values or in amiloride-inhibited nasal potential difference NPD We interpreted these results as a proof of concept of corrector therapy but corrector therapy alone was likely an insufficient therapy for this mutation in CF and therefore closed the IND for 4-phenylbutyrate
In the ensuing years Vertex Pharmaceuticals Inc has had success with the development of ivacaftor334 VX-770 as a potentiator of G551D CFTR and has studied the drug alone and in combination with their corrector lumacaftor5 VX-809 and VX-661 We at Johns Hopkins University JHU University of Alabama at Birmingham UAB and Childrens Hospital of PhiladelphiaUniversity of Pennsylvania CHOPPenn have participated in many of the clinical trials and are pleased and encouraged by the success of VX-770 It is not yet certain that future combinations of correctors and potentiators will be safe and effective and it is prudent to explore alternative correctors and potentiators Furthermore recent structural investigations in a number of laboratories support the idea that more than one corrector may be necessary to fully restore F508del to the trafficking pathway 6 Precedent for combination of 4PBA with other CFTR modulators has been established in vitro 78 4-Phenylbutyrate tablets are formulated for oral delivery and we showed that the pharmacokinetics were similar in CF to that in patients with urea cycle disorders However the large number of tablets that had to be ingested at each meal were somewhat daunting at the 30 gm daily dose A new pro-drug of 4-phenylbutyrate glycerol phenylbutyrate or Ravictiowned by Hyperion Pharmaceuticals Inc was approved in February 2013 by the US FDA This new formulation is a significant advance for patients with urea cycle disorders because it is an oral odorless tasteless liquid that contains 3 molecules of 4-phenylbutyrate for every molecule of the triglyceride Simple arithmetic would suggest that one mole equivalent of the pro-drug provides three moles of active drug However pancreatic lipase enzymes are required to break the covalent bonds and release the active drug in the intestines Because most CF patients homozygous for F508del are pancreatic-insufficient and already on enzyme therapy we propose to test the effectiveness of the combination of CF pancreatic enzyme replacement therapy PERT on absorption of Ravicti and subsequent restoration of nasal epithelial CFTR-mediated chloride transport during the nasal potential difference NPD test
In the ensuing years Vertex Pharmaceuticals Inc has had success with the development of ivacaftor334 VX-770 as a potentiator of G551D CFTR and has studied the drug alone and in combination with their corrector lumacaftor5 VX-809 and VX-661 We at Johns Hopkins University JHU University of Alabama at Birmingham UAB and Childrens Hospital of PhiladelphiaUniversity of Pennsylvania CHOPPenn have participated in many of the clinical trials and are pleased and encouraged by the success of VX-770 It is not yet certain that future combinations of correctors and potentiators will be safe and effective and it is prudent to explore alternative correctors and potentiators Furthermore recent structural investigations in a number of laboratories support the idea that more than one corrector may be necessary to fully restore F508del to the trafficking pathway 6 Precedent for combination of 4PBA with other CFTR modulators has been established in vitro 78 4-Phenylbutyrate tablets are formulated for oral delivery and we showed that the pharmacokinetics were similar in CF to that in patients with urea cycle disorders However the large number of tablets that had to be ingested at each meal were somewhat daunting at the 30 gm daily dose A new pro-drug of 4-phenylbutyrate glycerol phenylbutyrate or Ravictiowned by Hyperion Pharmaceuticals Inc was approved in February 2013 by the US FDA This new formulation is a significant advance for patients with urea cycle disorders because it is an oral odorless tasteless liquid that contains 3 molecules of 4-phenylbutyrate for every molecule of the triglyceride Simple arithmetic would suggest that one mole equivalent of the pro-drug provides three moles of active drug However pancreatic lipase enzymes are required to break the covalent bonds and release the active drug in the intestines Because most CF patients homozygous for F508del are pancreatic-insufficient and already on enzyme therapy we propose to test the effectiveness of the combination of CF pancreatic enzyme replacement therapy PERT on absorption of Ravicti and subsequent restoration of nasal epithelial CFTR-mediated chloride transport during the nasal potential difference NPD test
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| FD-R-0005380 | OTHER_GRANT | FDA Office of Orphan Products Development | None |