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

NCT00590538 | Terminated Phase 1 Results DMC

• 2 other identifiers: 2002-10-3023RUBENS01A0
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to test a new combination of medicines, Phenylbutyrate and Genistein, to determine if they could be used to treat cystic fibrosis (CF). The most common genetic mutation found in patients with CF is called Delta F508. Due to this mutation, there is a lack of salt (chloride) movement in your nose, sinuses, lungs, intestines, pancreas and sweat glands. This lack of movement causes the clinical manifestations of the disease. Although Phenylbutyrate has been extensively used to treat patients with rare metabolic diseases, 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. When used together, both drugs may be able to restore normal chloride and salt (water) movements in body organs and glands in people with CF. We will be studying salt and water movement in the nose by a technique called nasal transepithelial potential difference (NPD).

Conditions

Cystic Fibrosis

Outcome Measures

Primary Outcomes (1)

• Change in Voltage (mVolt) in Nasal Epithelium

  The basis of analysis for the primary outcome measure will be the comparison of data from both the standard CF Nasal Potential Difference (NPD) Protocol compared to a modified NPD protocol including the perfusion of Genistein. The NPD response will be compared from baseline to after study drug. NPD responses will then be compared between the Phenylbutrate group and the placebo group.

  Baseline and 2 weeks

Secondary Outcomes (4)

• Change in FEV1 (Forced Expiratory Volume in 1 Second) in Spirometry.

  baseline and 2 weeks

• Change in FVC (Forced Vital Capacity)in Spirometry.

  baseline and 2 weeks

• Number of Participants With Adverse Events

  up to 2 weeks

• Number of Participants With Abnormal Laboratory Safety Tests

  up to 2 weeks

Study Arms (2)

Phenylbutyrate

ACTIVE COMPARATOR

The standard oral adult dose is 20 g/day for 4 days. Every participant will receive Genistein during the NPD.

Drug: Sodium 4-Phenylbutyrate; Drug: Genistein (Unconjugated Isoflavones 100)

Placebo

PLACEBO COMPARATOR

The placebo is given to match the active comparator for 4 days. Every participant will receive Genistein.

Drug: Genistein (Unconjugated Isoflavones 100); Drug: Placebo

Interventions

Sodium 4-Phenylbutyrate DRUG

The standard oral adult dose is 20 g/day (tablets) for 4 days.

Also known as: 4PBA

Phenylbutyrate

Genistein (Unconjugated Isoflavones 100) DRUG

Every participant will be administered a perfusion of 50 MicroM of Genistein (Unconjugated Isoflavones 100) during the modified NPD procedure.

Also known as: PTI G-4660, 87% Genistein

Phenylbutyrate; Placebo

Placebo DRUG

The placebo is given to match the active comparator for four days.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• either cystic fibrosis genotype heterozygous for Delta F508 with a second identified CFTR mutation, or cystic fibrosis genotype with one Delta F508 allele and one unidentified allele and sweat sodium or chloride \> 60 mEq/L
• Oxyhemoglobin saturation greater than or equal to 92% while breathing room air

You may not qualify if:

• 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:

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• Cystic Fibrosis Foundation: collaborator

Study Sites (1)

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (2)

• Heneghan M, 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. 2023 Nov 20;11(11):CD010966. doi: 10.1002/14651858.CD010966.pub4.

  PMID: 37983082 DERIVED

• 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.

  PMID: 33331662 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

4-phenylbutyric acid; Genistein

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Isoflavones; Flavonoids; Chromones; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

No analysis was completed on data collected; More clinically efficacious compounds have been identified which suggested that completion of this study might not be as critical as when initially proposed; therefore, the study was terminated by PI.

Results Point of Contact

• Title: Ronald Rubenstein, MD, PhD
• Organization: The Children's Hospital of Philadelphia

rubensteinr@email.chop.edu

1-215-590-1281

Study Officials

• Ronald Rubenstein, M.D., PhD.

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 27, 2007
• First Posted: January 10, 2008
• Study Start: February 1, 2003
• Primary Completion: December 1, 2008
• Study Completion: December 1, 2008
• Last Updated: June 30, 2011
• Results First Posted: June 30, 2011

Record last verified: 2011-06

Locations

US (1)