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

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ClinicalTrials.gov Identifier: NCT02323100
Recruitment Status : Recruiting
First Posted : December 23, 2014
Last Update Posted : July 15, 2019
Sponsor:
Collaborators:
University of Alabama at Birmingham
Children's Hospital of Philadelphia
Johns Hopkins University
Horizon Pharma Ireland, Ltd., Dublin Ireland
Information provided by (Responsible Party):
Pam Zeitlin, National Jewish Health

Tracking Information
First Submitted Date  ICMJE December 18, 2014
First Posted Date  ICMJE December 23, 2014
Last Update Posted Date July 15, 2019
Actual Study Start Date  ICMJE December 2, 2018
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2017)
The primary biological endpoint will be the change in average measurement of nasal potential difference between day 7 and baseline. [ Time Frame: 7 days ]
chloride and sodium transport in nasal epithelium
Original Primary Outcome Measures  ICMJE
 (submitted: December 18, 2014)
PRIMARY ENDPOINT [ Time Frame: 7 days ]
The primary biological endpoint will be the change in average measurement of nasal potential difference between day 7 and baseline.
Change History Complete list of historical versions of study NCT02323100 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2017)
  • 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 ]
    change between date and baseline in sodium and chloride transport
  • Change in average sweat chloride measurement between days 4, 7, 14 and baseline. [ Time Frame: 14 days ]
    change between study time point and baseline in sweat chloride
  • Safety and tolerability. [ Time Frame: 14 days ]
    standard safety and tolerability lab values
  • Efficacy of PERT on absorption of Ravicti®. [ Time Frame: 14 days ]
    quantification of exogenous pancreatic enzyme effects on release of active drug from the pro-drug triglyceride form
Original Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2014)
  • SECONDARY ENDPOINTS [ Time Frame: 14 days ]
    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.
  • SECONDARY ENDPOINTS [ Time Frame: 14 days ]
    Change in average sweat chloride measurement between days 4, 7, 14 and baseline.
  • SECONDARY ENDPOINTS [ Time Frame: 14 days ]
    Safety and tolerability.
  • SECONDARY ENDPOINTS [ Time Frame: 14 days ]
    Efficacy of PERT on absorption of Ravicti®.
Current Other Pre-specified Outcome Measures
 (submitted: February 28, 2017)
  • Plasma will be sampled for pharmacokinetics (PK) studies [ Time Frame: 14 days ]
    blood pharmacokinetics
  • Safety labs: hematology, complete metabolic panel (CMP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), uric acid. Sputum microbiology and spirometry will be performed. [ Time Frame: 14 days ]
    blood counts, metabolic measures, CRP
Original Other Pre-specified Outcome Measures
 (submitted: December 18, 2014)
  • OTHER EVALUATIONS [ Time Frame: 14 days ]
    Plasma will be sampled for PK studies on Visit 1 at time 0 (+ 5 min) (delivery of first dose), 1 hour (+/-5 min), 2 hour (+/-10min), and 4 hour (+/-10 min) post dose. The sampling will be repeated on day 4, Visit 2, as a trough level prior to dose administration and again at 1 hour (+/-5 min), 2 hour (+/-10 min), and 4 hour (+/-10 min). The PK blood sampling done on Visits 3, Visit 4 and Early WD will include single post dose trough plasma levels. A single urine PK sample will be obtained at Visits 2, 4 and Early WD. Urine will be collected over 24 hours on Visit 1 and Visit 3.
  • SAFETY EVALUATIONS [ Time Frame: 14 days ]
    Safety labs consisting of standard hematology, CMP, CRP, ESR and uric acid, sputum microbiology, and spirometry will be performed. Assessment of safety will include clinical observations, laboratory evaluations, and monitoring of subjects. AEs will be recorded on the CRFs from the Screening Visit thorough Day 14 Visit or Early Withdrawal Visit.
 
Descriptive Information
Brief Title  ICMJE Glycerol Phenylbutyrate Corrector Therapy For CF (Cystic Fibrosis)
Official Title  ICMJE A Double Blind, Placebo Controlled, Dose Escalation Trial of Glycerol Phenylbutyrate Corrector Therapy for Cystic Fibrosis
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 (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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE
  • Drug: Ravicti low dose
    8 am, 4pm and midnight
    Other Name: Ravicti, glycerol phenylbutyrate
  • Drug: Ravicti high dose
    8 am, 4pm and midnight
    Other Name: Ravicti, glycerol phenylbutyrate
  • Drug: Placebo
    8 am, 4pm and midnight
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Ravicti low dose
  • Active Comparator: Ravicti high dose
    Ravicti® oral liquid at 9ml (9.9 gm)at 8 am and 8.25ml (9.08 gm) at 4pm and midnight for 7 days.
    Intervention: Drug: Ravicti high dose
  • Placebo Comparator: Placebo
    Matching placebo taken at 8am, 4pm and midnight for 7 days.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 18, 2014)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2021
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jennifer Brandorff 303-398-1811 brandorffJ@NJHealth.org
Contact: Britany Zeglin, BS 443-287-8983 bzeglin1@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02323100
Other Study ID Numbers  ICMJE GPBA
FD-R-0005380 ( Other Grant/Funding Number: FDA Office of Orphan Products Development )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Pam Zeitlin, National Jewish Health
Study Sponsor  ICMJE National Jewish Health
Collaborators  ICMJE
  • University of Alabama at Birmingham
  • Children's Hospital of Philadelphia
  • Johns Hopkins University
  • Horizon Pharma Ireland, Ltd., Dublin Ireland
Investigators  ICMJE
Principal Investigator: Pamela L Zeitlin, MD, PhD National Jewish Health
PRS Account National Jewish Health
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP