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Phenylbutyrate/Genistein Duotherapy in Delta F508-Homozygous(for Cystic Fibrosis)

Primary Purpose

Cystic Fibrosis

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Sodium 4-Phenylbutyrate (4PBA)
Unconjugated Isoflavones 100 (PTI G-4660, 87% Genistein)
Placebo
Sponsored by
Children's Hospital of Philadelphia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Cystic Fibrosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Able to communicate with pertinent staff, able to understand and willing to comply with the requirements of the trial, and able and willing to give informed consent. Willing to practice a reliable and study-accepted method of contraception during the study. Diagnosis of cystic fibrosis consisting of both: clinical manifestations of cystic fibrosis and cystic fibrosis genotype homozygous for Delta F508 and sweat sodium or chloride > 60 mEq/L Oxyhemoglobin saturation greater than or equal to 92% while breathing room air Exclusion Criteria: Underlying diseases likely to limit life span and/or increase risk of complications: Cancer requiring treatment in the past 5 years, with the exception of cancers that have been cured, or in the opinion of the investigator, carry a good prognosis such as non-melanoma skin cancer, papillary thyroid carcinoma, and cervical cancer in situ. GI disease i. Inflammatory bowel disease requiring treatment in the past year ii. elevations in ALT or AST levels to greater than 3 times the upper limit of normal Conditions or behaviors likely to affect the conduct of the study Current or anticipated participation in another intervention research project Recent (with 2 months) sinus surgery or nasal polypectomy Currently pregnant or less than 3 months post-partum Currently nursing or within 6 weeks of having completed nursing Unwilling to undergo pregnancy testing or to report possible or confirmed pregnancy promptly during the course of the study Unwilling to use a reliable contraceptive method for two months after the completion of the study. Major psychiatric disorder, which, in the opinion of the investigators, would impede conduct of the study, e.g., alcoholism Other condition, which, in the opinion of the investigators, would impede conduct of the study. Glucocorticoids other than topical, ophthalmic, and inhaled preparations. Conditions that would place the patient at an increased risk for complications: Pneumothorax within the last 12 months Uncontrolled diabetes Asthma or allergic bronchopulmonary aspergillosis requiring systemic glucocorticoid therapy within the last two months Sputum culture growing a pathogen that does not have in vitro sensitivity to at least two types of antibiotics which could be administered to the patient History of major hemoptysis: (Greater than 240 mL of blood within a 24-hour period within the last 12 months). Medication use or conditions not specifically mentioned above, including severe or end stage CF lung disease, that may serve as criteria for exclusion at the discretion of the investigators. History of significant cardiovascular disease, such as myocardial infarction, congestive heart failure, unstable arrhythmia, or uncontrolled hypertension.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    1

    2

    Arm Description

    Subjects will be randomized to receive either the Phenylbutyrate or placebo tablets for 4 days Every participant will receive Genistein during the NPD.

    Outcomes

    Primary Outcome Measures

    The basis of analysis for the primary outcome measure will be the comparison of data from both the standard CF NPD protocol compared to a modified NPD protocol including the perfusion of Genistein.

    Secondary Outcome Measures

    Interval history, physical and mental status examination.
    Laboratory Evaluations
    Spirometry Data

    Full Information

    First Posted
    May 31, 2001
    Last Updated
    January 8, 2009
    Sponsor
    Children's Hospital of Philadelphia
    Collaborators
    Cystic Fibrosis Foundation, National Center for Research Resources (NCRR)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00016744
    Brief Title
    Phenylbutyrate/Genistein Duotherapy in Delta F508-Homozygous(for Cystic Fibrosis)
    Official Title
    A Pilot Trial of Phenylbutyrate/Genistein Duotherapy in Delta F508-Homozygous Cystic Fibrosis Patients
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    January 2009
    Overall Recruitment Status
    Completed
    Study Start Date
    September 2001 (undefined)
    Primary Completion Date
    October 2005 (Actual)
    Study Completion Date
    October 2005 (Actual)

    3. Sponsor/Collaborators

    Name of the Sponsor
    Children's Hospital of Philadelphia
    Collaborators
    Cystic Fibrosis Foundation, National Center for Research Resources (NCRR)

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    We are testing a new combination of medicines, to determine if they could be used to treat cystic fibrosis (CF). Subjects with CF who have two copies of the most common mutation (change) found in patients with CF called DF508. CF is caused by a lack of chloride movement in the nose, sinuses, lungs, intestines, pancreas and sweat glands. We are conducting this study to determine the safety of using a combination of two medicines, Phenylbutyrate and Genistein, to improve the ability of the cells lining the nose to regulate movement of salt (chloride) and water in people with CF. Phenylbutyrate has been extensively used to treat patients with rare metabolic diseases (which are very different from CF), Phenylbutyrate is an investigational drug for the purpose of this study. Genistein is a naturally occurring substance that is found in food products such as soy and tofu, but is also an investigational drug for this study. Both drugs may be able to restore normal chloride movements in body organs and glands. We will be studying salt and water in the nose movement by a technique called nasal transepithelial potential difference (NPD).
    Detailed Description
    Subjects will be randomized to receive either the Phenylbutyrate or placebo tablets for 1 week, with a 2 out of 3 chance of receiving Phenylbutyrate at a standard adult dose, with visits on study days 1, 4, and 7. The study will last an additional 2 weeks to determine whether the effects of the Phenylbutyrate or Placebo persist for any length of time, with visits on study days 14 and 21. Every participant will receive the Genistein during the NPD on days 1 and 7. The dose of Genistein used will not be escalated and will be the same for every participant. Safety evaluations at each visit will include a history, and physical exam and mental status exam, blood and urine tests, and lung function tests. The main physiologic outcome of the trial will be the assessment of salt and water transport NPD. In this way, we will assess whether genistein enhances the effect of phenylbutyrate to improve chloride transport in the nose by topical application of genistein to the nasal mucosa during the NPD procedure on study days 1 and 7.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Cystic Fibrosis

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    12 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    1
    Arm Type
    Active Comparator
    Arm Description
    Subjects will be randomized to receive either the Phenylbutyrate or placebo tablets for 4 days Every participant will receive Genistein during the NPD.
    Arm Title
    2
    Arm Type
    Placebo Comparator
    Intervention Type
    Drug
    Intervention Name(s)
    Sodium 4-Phenylbutyrate (4PBA)
    Intervention Description
    The standard oral adult dose is 20g/day (tablets) for 4 days.
    Intervention Type
    Drug
    Intervention Name(s)
    Unconjugated Isoflavones 100 (PTI G-4660, 87% Genistein)
    Intervention Description
    Every participant will be administered a perfusion of 50 MicroM of Genistein during the modified NPD procedure.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    The placebo dose will match the oral tablets in arm 1, maintaining the study blind.
    Primary Outcome Measure Information:
    Title
    The basis of analysis for the primary outcome measure will be the comparison of data from both the standard CF NPD protocol compared to a modified NPD protocol including the perfusion of Genistein.
    Time Frame
    All visits
    Secondary Outcome Measure Information:
    Title
    Interval history, physical and mental status examination.
    Time Frame
    Every visit
    Title
    Laboratory Evaluations
    Time Frame
    Every visit
    Title
    Spirometry Data
    Time Frame
    Every visit

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Able to communicate with pertinent staff, able to understand and willing to comply with the requirements of the trial, and able and willing to give informed consent. Willing to practice a reliable and study-accepted method of contraception during the study. Diagnosis of cystic fibrosis consisting of both: clinical manifestations of cystic fibrosis and cystic fibrosis genotype homozygous for Delta F508 and sweat sodium or chloride > 60 mEq/L Oxyhemoglobin saturation greater than or equal to 92% while breathing room air Exclusion Criteria: Underlying diseases likely to limit life span and/or increase risk of complications: Cancer requiring treatment in the past 5 years, with the exception of cancers that have been cured, or in the opinion of the investigator, carry a good prognosis such as non-melanoma skin cancer, papillary thyroid carcinoma, and cervical cancer in situ. GI disease i. Inflammatory bowel disease requiring treatment in the past year ii. elevations in ALT or AST levels to greater than 3 times the upper limit of normal Conditions or behaviors likely to affect the conduct of the study Current or anticipated participation in another intervention research project Recent (with 2 months) sinus surgery or nasal polypectomy Currently pregnant or less than 3 months post-partum Currently nursing or within 6 weeks of having completed nursing Unwilling to undergo pregnancy testing or to report possible or confirmed pregnancy promptly during the course of the study Unwilling to use a reliable contraceptive method for two months after the completion of the study. Major psychiatric disorder, which, in the opinion of the investigators, would impede conduct of the study, e.g., alcoholism Other condition, which, in the opinion of the investigators, would impede conduct of the study. Glucocorticoids other than topical, ophthalmic, and inhaled preparations. Conditions that would place the patient at an increased risk for complications: Pneumothorax within the last 12 months Uncontrolled diabetes Asthma or allergic bronchopulmonary aspergillosis requiring systemic glucocorticoid therapy within the last two months Sputum culture growing a pathogen that does not have in vitro sensitivity to at least two types of antibiotics which could be administered to the patient History of major hemoptysis: (Greater than 240 mL of blood within a 24-hour period within the last 12 months). Medication use or conditions not specifically mentioned above, including severe or end stage CF lung disease, that may serve as criteria for exclusion at the discretion of the investigators. History of significant cardiovascular disease, such as myocardial infarction, congestive heart failure, unstable arrhythmia, or uncontrolled hypertension.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Ronald Rubenstein, M.D., PhD.
    Organizational Affiliation
    Children's Hospital of Philadelphia
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    33331662
    Citation
    Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3.
    Results Reference
    derived

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    Phenylbutyrate/Genistein Duotherapy in Delta F508-Homozygous(for Cystic Fibrosis)

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