Denver, Colorado 80206


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.

Study summary:

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 (IND)application held by P. Zeitlin. In a series of Phase 1 and 2 trials we established the maximum tolerated dose as 20 gm daily divided t.i.d. 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 treatment.1;2 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 ivacaftor3;3;4 (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 Philadelphia/University of Pennsylvania (CHOP/Penn) 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 corrector(s) and potentiator(s) 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 7;8 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 Ravicti®(owned 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.


Inclusion Criteria: 1. Male or female 18 years or older. 2. Confirmed diagnosis of CF based on the following criteria: any CFTR genotype combination EXCEPT two stop codons and one or more clinical features consistent with the CF phenotype 3. Taking pancreatic enzyme replacement therapy (PERT). 4. Ability to perform acceptable spirometry. 5. Ability to understand and sig a written informed consent and comply with the requirements of the study. 6 FEV1 greater than 30% predicted normal for age, gender, height (Hankinson standards) pre or post-bronchodilator at Screening. 7. Oxygen saturation by pulseoximetry 90% or greater breathing ambient air or regular oxygen regimen at screening and day 1. 8. Hematology and clinical chemistry of blood and urine results with no clinically significant abnormalities that would interfere with the study assessments (as judged by the principal investigator) at screening. If electrolyte abnormality at screening, values must be corrected prior to dosing. 9. Subjects on chronic inhaled antibiotic therapy are eligible if they can continue their usual antibiotic regimen, or remain on their off-cycle period, for the duration of study drug exposure. 10. Negative pregnancy test for women of child-bearing potential. 11. If of childbearing potential, agree to use one highly effective method of contraception from the time of consent through the Visit 4 study visit, per section 9.1.13 of the protocol. Exclusion Criteria: 1. Current use of ivacaftor (Kalydeco), lumacaftor/ivacaftor combination, or other corrector or potentiator (Symdeko) less than 30 days from Screening. 2 Any investigational drug or device within 30 days of Screening or within 6 half-lives of the investigational drug (whichever is longer). 3. History of any illness or condition that in the opinion of the investigator could confound the results of the study or pose additional risk to subjects. 4. Any change in chronic therapies for CF lung disease (e.g., Ibuprofen, Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 5. Pregnant, planned pregnancy or breast feeding 6. Clinically significant cardiac, liver or kidney disease 7. Seizure disorder 8. Acute upper respiratory infection within 2 weeks or acute pulmonary exacerbation requiring intravenous antibiotics within 4 weeks of Screening Visit 9. Sinus surgery within 6 weeks of Screening Visit 10. Abnormal renal function 11. Abnormal liver function, defined as ≥3x upper limit of normal (ULN) of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or known cirrhosis. 12. Screening laboratory results which in the judgment of the investigator would interfere with completion of the study 13. History of or listed for solid organ or hematological transplantation

Study is Available At:

Original ID:




Secondary ID:


Study Acronym:


Brief Title:

Glycerol Phenylbutyrate Corrector Therapy For CF (Cystic Fibrosis)

Official Title:

A Double Blind, Placebo Controlled, Dose Escalation Trial of Glycerol Phenylbutyrate Corrector Therapy for Cystic Fibrosis

Overall Status:


Study Phase:

Phase 1/Phase 2



Minimum Age:

18 Years

Maximum Age:


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

National Jewish Health

Oversight Authority:

  • United States: Food and Drug Administration
  • United States: Institutional Review Board
  • United States: Data and Safety Monitoring Board

Reasons Why Stopped:

Study Type:


Study Design:

Number of Arms:


Number of Groups:


Total Enrollment:


Enrollment Type:


Overall Contact Information

Official Name:Pamela L Zeitlin, MD, PhD
Principal Investigator
National Jewish Health
Primary Contact:Jennifer Brandorff
Backup Contact:Britany Zeglin, BS

Study Dates

Start Date:December 2, 2018
Completion Date:June 30, 2021
Completion Type:Anticipated
Primary Completion Date:June 30, 2021
Primary Completion Type:Anticipated
Verification Date:July 2019
Last Changed Date:July 12, 2019
First Received Date:December 18, 2014

Study Outcomes

Outcome Type:Primary Outcome
Measure:The primary biological endpoint will be the change in average measurement of nasal potential difference between day 7 and baseline.
Time Frame:7 days
Safety Issues:False
Description:chloride and sodium transport in nasal epithelium
Outcome Type:Secondary Outcome
Measure:Change in other NPD measures from baseline and Days 4, 7, and 14 to include baseline PD, change in amiloride, low chloride, and low chloride plus isoproterenol.
Time Frame:14 days
Safety Issues:False
Description:change between date and baseline in sodium and chloride transport
Outcome Type:Secondary Outcome
Measure:Change in average sweat chloride measurement between days 4, 7, 14 and baseline.
Time Frame:14 days
Safety Issues:False
Description:change between study time point and baseline in sweat chloride
Outcome Type:Secondary Outcome
Measure:Safety and tolerability.
Time Frame:14 days
Safety Issues:False
Description:standard safety and tolerability lab values
Outcome Type:Secondary Outcome
Measure:Efficacy of PERT on absorption of Ravicti®.
Time Frame:14 days
Safety Issues:False
Description:quantification of exogenous pancreatic enzyme effects on release of active drug from the pro-drug triglyceride form

Study Interventions

Intervention Type:Drug
Name:Ravicti low dose
Description:8 am, 4pm and midnight
Arm Name:Ravicti low dose
Other Name:Ravicti, glycerol phenylbutyrate
Intervention Type:Drug
Name:Ravicti high dose
Description:8 am, 4pm and midnight
Arm Name:Ravicti high dose
Other Name:Ravicti, glycerol phenylbutyrate
Intervention Type:Drug
Description:8 am, 4pm and midnight
Arm Name:Placebo

Study Arms

Study Arm Type:Active Comparator
Arm Name:Ravicti low dose
Description:Low dose Ravicti® oral liquid at 6ml (6.6 gm) by mouth or gastrostomy tube at 8 am, 5.5 ml (6.05gm) at 4pm and midnight for 7 days.
Study Arm Type:Active Comparator
Arm Name:Ravicti high dose
Description:Ravicti® oral liquid at 9ml (9.9 gm)at 8 am and 8.25ml (9.08 gm) at 4pm and midnight for 7 days.
Study Arm Type:Placebo Comparator
Arm Name:Placebo
Description:Matching placebo taken at 8am, 4pm and midnight for 7 days.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:National Jewish Health
Agency Class:Other
Agency Type:Collaborator
Agency Name:University of Alabama at Birmingham

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source:

Date Processed: January 21, 2020

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