Glycerol Phenylbutyrate Corrector Therapy For CF (Cystic Fibrosis) (GPBA)

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

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 Overview

• Status: Terminated
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Ravicti low dose; Drug: Placebo

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 (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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University School of Medicine
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female ≥ 18 years of age.

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), or have documented pancreatic sufficiency.
4. Ability to perform acceptable spirometry.
5. Ability to understand and sign a written informed consent and comply with the requirements of the study.
6. FEV1 ≥30% of predicted normal for age, gender, and height (Hankinson standards): pre or post-bronchodilator at Screening.
7. Oxygen saturation by pulse oximetry ≥90% breathing either 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. Administration of any investigational drug or device within 30 days of Screening or within 6 half-lives of the investigational drug (whichever is longer).
2. History of any illness or condition that in the opinion of the investigator could confound the results of the study or pose additional risk in administering study drug to subjects.
3. 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.
4. Pregnant, planned pregnancy or breast feeding at Screening.
5. Clinically significant cardiac, liver or kidney disease.
6. Seizure disorder.
7. Acute upper respiratory infection within 2 weeks or acute pulmonary exacerbation requiring intravenous antibiotics within 4 weeks of Screening Visit.
8. Sinus surgery within 6 weeks of Screening Visit.
9. Abnormal renal function.
10. Abnormal liver function, defined as ≥3x upper limit of normal (ULN), of serum aspartate transaminase (AST) or serum alanine transaminase (ALT), or known cirrhosis.
11. Screening laboratory results which in the judgment of the investigator would interfere with completion of the study.
12. History of or listed for solid organ or hematological transplantation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ravicti low dose; 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.	Drug: Ravicti low dose; 8 am, 4pm and midnight; Other Names: Ravicti, glycerol phenylbutyrate
Placebo Comparator: Placebo; Matching placebo taken at 8am, 4pm and midnight for 7 days.	Drug: Placebo; 8 am, 4pm and midnight

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Chloride and Sodium Transport in Nasal Epithelium	Change in average measurement of nasal potential difference in millivolts (mV) between baseline (Visit 0) and Day 4 (Visit 2) or Day 7 (Visit 3). Note: the outcome is assessed as change in mV at each visit, and then comparisons between visits are made.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Average Sweat Chloride	Change in average sweat chloride measurement between baseline Day 1 (Visit 1) and Day 7 (Visit 3).	7 days of treatment as measured on Day 1 (Visit 1) and Day 7 (Visit 3)
Change in Baseline Nasal Potential Difference (NPD)	Change in baseline nasal potential difference (NPD) measured before initiation of study drug between Day 1 (Visit 1) and Day 4 (Visit 2) and between Day 1 (Visit 1) and Day 7 (Visit 3).	4 days and 7 days of study drug treatment
Change in Nasal Potential Difference With Perfusion of a Solution Containing Amiloride	Change in the nasal potential difference response (in mV) with perfusion of a solution containing amiloride from baseline to Days 4 and 7.	4 and 7 days
Change in Nasal Potential Difference During Perfusion With a Low Chloride Solution Containing Amiloride	Change in nasal potential difference (in mV) with perfusion of a low chloride solution containing amiloride from baseline to Days 4 and 7.	4 and 7 days
Change in Nasal Potential Difference With a Low Chloride Solution Containing Amiloride Plus the Change With a Low Chloride Solution Containing Amiloride and Isoproterenol	Change in Nasal Potential Difference (in mV} with perfusion of a low chloride solution (containing amiloride) followed by the low chloride solution containing amiloride and Isoproterenol from baseline to Days 4 and 7.	4 and 7 days
Change in FEV1	Change in FEV1 from baseline to Days 4 and 7.	7 days
Safety and Tolerability - Electrolytes (Meq/L)	Electrolytes are presented in meq/L. Mean and SD reported at Screening and V4.	14 days
Safety and Tolerability-Liver Function-Total Bilirubin	Total Bilirubin on a comprehensive metabolic panel obtained from a serum sample and reported in mg/dl.	14 days
Safety and Tolerability - Liver Function-Liver Enzymes	Hepatic enzymes obtained from a serum sample -AST and ALT in units/L.	14 days
Safety and Tolerability - Liver Function-Alkaline Phosphatase (IU/L)	Alkaline Phosphatase obtained on a Comprehensive Metabolic Panel (IU/L).	14 days
Safety and Tolerability - Blood Protein Biomarkers (g/dl)	Safety and Tolerability - serum protein biomarkers in g/dl.	14 days
Safety and Tolerability - Blood Cell Counts (K/ul)	White blood cells, red blood cells, and platelet cell counts from a complete blood cell count panel (K/ul).	14 days
Safety and Tolerability - Blood Cell Counts (%)	White blood cells are fractionated into different types of white blood cells and presented as the fraction of total white blood cells counted.	14 days
Safety and Tolerability - Erythrocyte Sedimentation Rate (mm/hr)	Erythrocyte sedimentation rate is an indicator of inflammation that measures the rate at which red blood cells settle to the bottom of a test tube in mm/hr.	14 days
Safety and Tolerability - Serum Glucose (mg/dl)	Serum glucose was obtained in a comprehensive metabolic panel in mg/dl.	14 days
Safety and Tolerability - Blood Waste Metabolites (mg/dl)	Blood urea nitrogen (BUN), serum creatinine, and serum uric acid were obtained in a comprehensive metabolic panel in mg/dl.	14 days
Safety and Tolerability - Blood Biomarker of Inflammation (mg/dl)	C reactive protein (cRP) is a systemic marker of inflammation and was measured in mg/dl.	14 days
Safety and Tolerability - Hematocrit (%)	Hematocrit is resulted as the fraction of red blood cells in total volume of blood from which they are measured.	14 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) Studies	Concentration of PBA and PAA in blood over time	4 days

Collaborators and Investigators

• Sponsor: National Jewish Health
• Collaborators: Johns Hopkins University; Children's Hospital of Philadelphia; University of Alabama at Birmingham; Horizon Pharma Ireland, Ltd., Dublin Ireland
• Investigators: Principal Investigator: Pamela L Zeitlin, MD, PhD, National Jewish Health

Publications and helpful links

Helpful Links

• Johns Hopkins CF research office

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2018
• Primary Completion (Actual): March 1, 2022
• Study Completion (Actual): March 1, 2022

Study Registration Dates

• First Submitted: December 18, 2014
• First Submitted That Met QC Criteria: December 18, 2014
• First Posted (Estimated): December 23, 2014

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: cystic fibrosis; nasal potential difference; glycerol phenylbutyrate; corrector
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cystic Fibrosis; Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Cryoprotective Agents; glycerol phenylbutyrate
• Other Study ID Numbers: GPBA; FD-R-0005380 (Other Grant/Funding Number: FDA Office of Orphan Products Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No