Cystic FibrosisPhase 1/2NCT00590538
Phenylbutyrate/Genistein Duotherapy in Delta F508-Heterozygotes (for Cystic Fibrosis)
A Phase 1/2 study testing Sodium 4-Phenylbutyrate and Genistein (Unconjugated Isoflavones 100) in people with Cystic Fibrosis, run by Children's Hospital of Philadelphia at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cystic Fibrosis
- What is being tested?
- Sodium 4-Phenylbutyrate and Genistein (Unconjugated Isoflavones 100)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2003to Dec 2008
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
- 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
Show all 22Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
About this study
Official title: 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).
Read the 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:
- 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.
- 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.
- Conditions
- Cystic Fibrosis
- Being tested
- Sodium 4-Phenylbutyrate, Genistein (Unconjugated Isoflavones 100), Placebo
- Medical subject headings
- Cystic Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium 4-PhenylbutyrateDrug
Also called 4PBA
The standard oral adult dose is 20 g/day (tablets) for 4 days.
Genistein (Unconjugated Isoflavones 100)Drug
Also called PTI G-4660, 87% Genistein
Every participant will be administered a perfusion of 50 MicroM of Genistein (Unconjugated Isoflavones 100) during the modified NPD procedure.
PlaceboDrug
The placebo is given to match the active comparator for four days.
| Study group | Role | What they receive |
|---|---|---|
| Phenylbutyrate | Active comparator | The standard oral adult dose is 20 g/day for 4 days.
Every participant will receive Genistein during the NPD. Receives: 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. Receives: Drug: Genistein (Unconjugated Isoflavones 100); Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and 2 weeks
Secondary outcomes (4)
Change in FEV1 (Forced Expiratory Volume in 1 Second) in Spirometry.
Outcome measure will be obtained from standard Pulmonary Function testing.
Measured: baseline and 2 weeks
Change in FVC (Forced Vital Capacity)in Spirometry.
Outcome measure will be obtained from standard Pulmonary Function testing.
Measured: 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.
Measured: 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).
Measured: up to 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jan 2008 (estimated)
- Study startFeb 2003
- Primary completionDec 2008
- Study completionDec 2008
Why it stopped: 12/15/2008 Voluntarily placed on inactive status-requested by the PI
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- More trials run by Children's Hospital of PhiladelphiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital of Philadelphia
- Sponsor type
- University, hospital or other
- Collaborators
- Cystic Fibrosis Foundation
- Investigators
- Ronald Rubenstein, M.D., PhD., Principal investigator, Children's Hospital of Philadelphia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00590538
- Sponsor's protocol ID
- 2002-10-3023
- Other IDs
- RUBENS01A0
- Status last verified
- Jun 2011
- First submitted
- 27 Dec 2007
- Last updated
- 30 Jun 2011
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 37983082Southern 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.
PubMed 33331662
Study at a glance
From the registry record, last updated by the sponsor on 30 Jun 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Trial of Phenylbutyrate/Genistein Duotherapy in Delta F508-Heterozygous Cystic Fibrosis Patients
- ClinicalTrials.gov ID
- NCT00590538
- Acronym / sponsor ID
- 2002-10-3023
- Conditions
- Cystic Fibrosis
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: 12/15/2008 Voluntarily placed on inactive status-requested by the PI
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Children's Hospital of PhiladelphiaUniversity, hospital or other
- Collaborators
- Cystic Fibrosis Foundation
- Study start
- Feb 2003
- Primary completion
- Dec 2008 (actual)
- Study completion
- Dec 2008 (actual)
- First posted
- 10 Jan 2008 (estimated)
- Results
- Posted 30 Jun 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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:
- 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.
- 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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phenylbutyrate | Active comparator | Drug: Sodium 4-Phenylbutyrate, Drug: Genistein (Unconjugated Isoflavones 100)The standard oral adult dose is 20 g/day for 4 days. Every participant will receive Genistein during the NPD. |
| Placebo | Placebo comparator | Drug: Genistein (Unconjugated Isoflavones 100), Drug: PlaceboThe placebo is given to match the active comparator for 4 days. Every participant will receive Genistein. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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:
- Oxyhemoglobin saturation greater than or equal to 92% while breathing room air
Key exclusion criteria (22 listed)
- Underlying diseases likely to limit life span and/or increase risk of complications:
- Conditions or behaviors likely to affect the conduct of the study
- Glucocorticoids other than topical, ophthalmic, and inhaled preparations.
- Conditions that would place the patient at an increased risk for complications:
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sodium 4-PhenylbutyrateAlso: 4PBAThe standard oral adult dose is 20 g/day (tablets) for 4 days. | Drug | Phenylbutyrate |
| Genistein (Unconjugated Isoflavones 100)Also: PTI G-4660, 87% GenisteinEvery participant will be administered a perfusion of 50 MicroM of Genistein (Unconjugated Isoflavones 100) during the modified NPD procedure. | Drug | Phenylbutyrate, Placebo |
| PlaceboThe placebo is given to match the active comparator for four days. | Drug | Placebo |
Primary outcome
Change in Voltage (mVolt) in Nasal Epithelium
Time frame: Baseline and 2 weeks
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.
4 secondary outcomes
Change in FEV1 (Forced Expiratory Volume in 1 Second) in Spirometry.
Time frame: baseline and 2 weeks
Change in FVC (Forced Vital Capacity)in Spirometry.
Time frame: baseline and 2 weeks
Number of Participants With Adverse Events
Time frame: up to 2 weeks
Number of Participants With Abnormal Laboratory Safety Tests
Time frame: up to 2 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jun 2011.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37983082Heneghan 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.
- Derived from this study: PubMed 33331662Southern 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ronald Rubenstein, M.D., PhD. principal investigator
Children's Hospital of Philadelphia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Sodium 4-Phenylbutyrate and Genistein (Unconjugated Isoflavones 100) in people with Cystic Fibrosis, run by Children's Hospital of Philadelphia at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 30 Jun 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Jun 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Voltage (mVolt) in Nasal Epithelium (time frame: Baseline and 2 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00590538, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jun 2011.