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

A Pilot Trial of Phenylbutyrate/Genistein Duotherapy in Delta F508-Heterozygous Cystic Fibrosis Patients

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).

Study Overview

• Status: Terminated
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Sodium 4-Phenylbutyrate; Drug: Genistein (Unconjugated Isoflavones 100); Drug: Placebo

Detailed Description

This protocol is investigating novel pharmaceutical agents (Phenylbutyrate and Genistein), which are aimed at improving the physiologic function of mutant Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CFTR is absent or dysfunctional in cystic fibrosis. Nasal epithelial CFTR function will be assessed by the NPD procedure.

We will test the hypotheses that:

1. Phenylbutyrate given orally for 4 days will be safe in adult Delta F508- heterozygous subjects with CF and will result in small improvements in nasal epithelial CFTR function.
2. Topical administration of Genistein to the nasal epithelia of Phenylbutyrate treated Delta F508-heterozygous CF subjects will be safe and lead to augmentation of the improved nasal epithelial CFTR function observed during Phenylbutyrate treatment, but not during placebo treatment.

Study Flow If eligibility is confirmed at the screening visit, there will be an additional 3 outpatient visits over a 1-2 week period, lasting 2-4 hours each.

Visit 1, all study related safety evaluations will be completed. There will also be a Nasal Potential Difference (NPD) measurement performed. To measure nasal potentials, or voltages, a small butterfly needle will be placed in the skin of the forearm and connected by a thin plastic tube to a monitoring device. A very small soft plastic catheter or tube will be placed against the inner surface of the nose. This catheter will pump a very small amount of saltwater onto the nose and it will connect to the monitoring machine. This machine senses very small electrical voltages that are generated by the body. It does not and cannot send electricity or shocks to the subject. A measurement is made and then the fluid pumped into the nose is changed to one containing a drug called amiloride. Amiloride changes the makeup of salt transported in the nose and reduces the electrical voltage. Then the fluid is changed to saltwater that does not contain chloride. The fluid is then changed to one that has the drug isoproterenol. Isoproterenol causes the cells in subjects without CF to move chloride. The doses of amiloride and isoproterenol used in this study are much lower than those typically used in patients for other reasons. Finally, the fluid will be changed to one containing the experimental drug Genistein.

Subject will then be randomized and given a 4-day supply of the study drug.

Visit 2, subject will have safety evaluations and NPD performed in the same manner as previous visit. No more study drug after this visit.

Visit 3, subject will have safety evaluations and NPD performed without the perfusion of Genistein.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. 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.
2. Willing to practice a reliable and study-accepted method of contraception during the study.

3. Diagnosis of cystic fibrosis consisting of both:

   1. clinical manifestations of cystic fibrosis and
   2. 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
4. Oxyhemoglobin saturation greater than or equal to 92% while breathing room air

Exclusion Criteria:

1. Underlying diseases likely to limit life span and/or increase risk of complications:

   1. 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.
   2. 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

2. Conditions or behaviors likely to affect the conduct of the study

   1. Current or anticipated participation in another intervention research project
   2. Recent (with 2 months) sinus surgery or nasal polypectomy
   3. Currently pregnant or less than 3 months post-partum
   4. Currently nursing or within 6 weeks of having completed nursing
   5. Unwilling to undergo pregnancy testing or to report possible or confirmed pregnancy promptly during the course of the study
   6. Unwilling to use a reliable contraceptive method for two months after the completion of the study.
   7. Major psychiatric disorder, which, in the opinion of the investigators, would impede conduct of the study, e.g., alcoholism
   8. Other condition, which, in the opinion of the investigators, would impede conduct of the study.
3. Glucocorticoids other than topical, ophthalmic, and inhaled preparations.

4. Conditions that would place the patient at an increased risk for complications:

   1. Pneumothorax within the last 12 months
   2. Uncontrolled diabetes
   3. Asthma or allergic bronchopulmonary aspergillosis requiring systemic glucocorticoid therapy within the last two months
   4. 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
   5. History of major hemoptysis: (Greater than 240 mL of blood within a 24-hour period within the last 12 months).
5. 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.
6. History of significant cardiovascular disease, such as myocardial infarction, congestive heart failure, unstable arrhythmia, or uncontrolled hypertension.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Phenylbutyrate; The standard oral adult dose is 20 g/day for 4 days. Every participant will receive Genistein during the NPD.	Drug: Sodium 4-Phenylbutyrate; The standard oral adult dose is 20 g/day (tablets) for 4 days.; Other Names: 4PBA; Drug: Genistein (Unconjugated Isoflavones 100); Every participant will be administered a perfusion of 50 MicroM of Genistein (Unconjugated Isoflavones 100) during the modified NPD procedure.; Other Names: PTI G-4660, 87% Genistein
Placebo Comparator: Placebo; The placebo is given to match the active comparator for 4 days. Every participant will receive Genistein.	Drug: Genistein (Unconjugated Isoflavones 100); Every participant will be administered a perfusion of 50 MicroM of Genistein (Unconjugated Isoflavones 100) during the modified NPD procedure.; Other Names: PTI G-4660, 87% Genistein; Drug: Placebo; The placebo is given to match the active comparator for four days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FEV1 (Forced Expiratory Volume in 1 Second) in Spirometry.	Outcome measure will be obtained from standard Pulmonary Function testing.	baseline and 2 weeks
Change in FVC (Forced Vital Capacity)in Spirometry.	Outcome measure will be obtained from standard Pulmonary Function testing.	baseline and 2 weeks
Number of Participants With Adverse Events	Adverse Events will be assessed and outcome measure obtained by completion of Interval history, physical and mental status examinations of every participant.	up to 2 weeks
Number of Participants With Abnormal Laboratory Safety Tests	Outcome measure will be obtained by completion of routine metabolic and hematological laboratory parameters for every participant. Metabolic testing willl include a CMP (comprehensive metabolic panel, ALT (alanine aminotransferase test), GGT (gamma-glutamyl transpeptidase), and Uric Acid; Hematological testing will include a complete blood count (CBC), and partial thromboplastin (PT/PTT).	up to 2 weeks

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Cystic Fibrosis Foundation

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2003
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: December 27, 2007
• First Submitted That Met QC Criteria: December 27, 2007
• First Posted (Estimate): January 10, 2008

Study Record Updates

• Last Update Posted (Estimate): June 30, 2011
• Last Update Submitted That Met QC Criteria: June 29, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Estrogens, Non-Steroidal; Estrogens; Protein Kinase Inhibitors; Anticarcinogenic Agents; Phytoestrogens; Genistein; 4-phenylbutyric acid
• Other Study ID Numbers: 2002-10-3023; RUBENS01A0 (Other Identifier: Children's Hospital of Philadelphia)