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

NCT00016744 | Completed Phase 1 DMC

• 2 other identifiers: NCRR-M01RR00240-1765IRB#2000-10-2189
• Study Type: interventional
• Target: 12
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Cystic Fibrosis

Outcome Measures

Primary Outcomes (1)

• 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.

  All visits

Secondary Outcomes (3)

• Interval history, physical and mental status examination.

  Every visit

• Laboratory Evaluations

  Every visit

• Spirometry Data

  Every visit

Study Arms (2)

1

ACTIVE COMPARATOR

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

Drug: Sodium 4-Phenylbutyrate (4PBA); Drug: Unconjugated Isoflavones 100 (PTI G-4660, 87% Genistein)

2

PLACEBO COMPARATOR

Drug: Unconjugated Isoflavones 100 (PTI G-4660, 87% Genistein); Drug: Placebo

Interventions

Sodium 4-Phenylbutyrate (4PBA) DRUG

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

1

Unconjugated Isoflavones 100 (PTI G-4660, 87% Genistein) DRUG

Every participant will be administered a perfusion of 50 MicroM of Genistein during the modified NPD procedure.

1; 2

Placebo DRUG

The placebo dose will match the oral tablets in arm 1, maintaining the study blind.

2

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
• 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

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
• National Center for Research Resources (NCRR): collaborator

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

Study Officials

• Ronald Rubenstein, M.D., PhD.

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

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: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: May 31, 2001
• First Posted: June 4, 2001
• Study Start: September 1, 2001
• Primary Completion: October 1, 2005
• Study Completion: October 1, 2005
• Last Updated: January 9, 2009

Record last verified: 2009-01