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Efficacy and Safety Study of EGCG/Tocotrienol in 18 Patients With Splicing-mutation-mediated Cystic Fibrosis (CF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2012 by Hadassah Medical Organization
Sponsor:
Information provided by (Responsible Party):
Kerem Eithan, Hadassah Medical Organization
ClinicalTrials.gov Identifier:
NCT00889434
First received: April 20, 2009
Last updated: November 11, 2012
Last verified: November 2012
  Purpose
  • Working Hypothesis: EGCG and Tocotrienol can act as genetic modifiers and increase the level of correctly spliced CFTR transcripts.
  • Aims of the Study: To determine in patients with CF if oral administration of EGCG and Tocotrienol, both separate and in combination, modify CFTR splicing towards normal splicing as evaluated by improved Transepithelial Potential Difference (TEPD) assessment of chloride secretion.

To assess the effect of EGCG and Tocotrienol, both separate and in combination, on (1) additional TEPD measures of ion channel activity, (2) levels of correctly spliced CFTR mRNA in nasal mucosa, (3) cytokine levels in sputum and (4) changes in pulmonary function over the course of the study.

  • Potential Implications to Medicine: Alternative splicing mechanisms are a common cause of genetic disease as ~15% of all known human mutations result in defective pre-mRNA splicing. Therapies based on augmenting the levels of full length or fully functioning proteins may have a substantial impact on the treatment of patients with genetic diseases.
  • Contribution of the expected outcome to society Today genetic diseases can be treated but not healed. This proposal may be a step in the direction of finding a cure for patients carrying splicing mutations.

Condition Intervention
Cystic Fibrosis
Dietary Supplement: ECGC
Dietary Supplement: Tocotrienol
Dietary Supplement: EGCG + Tocotrienol

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Single-site, Open-label, Dose-ranging, Efficacy, and Safety Study of EGCG/Tocotrienol in 18 Patients With Splicing-mutation-mediated CF

Resource links provided by NLM:


Further study details as provided by Hadassah Medical Organization:

Primary Outcome Measures:
  • Changes in nasal chloride secretion as assessed by TEPD, with assessment of mean changes in TEPD by drug compared to baseline and the proportion of patients with a chloride secretion response by drug compared to baseline [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pulmonary function testing: forced expiratory volume in 1 sec [FEV1], forced vital capacity [FVC], and maximal expiratory flow25-75 [MEF25-75] [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 18
Study Start Date: September 2009
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: EGCG
Two cycles comprising 28 days of continuous daily treatment with EGCGgiven 2 times/6 soft gel capsules (total 600 mg) /day (BID) in the morning and in the evening with food followed by a 14 day wash out period without drug.
Dietary Supplement: ECGC
1 cycle will comprise 28 days of continuous daily treatment with EGCG given once/day(total 375 mg) /day in the morning with food followed by a 14 day wash out period without drug.
Active Comparator: Tocotrienol Dietary Supplement: Tocotrienol
One cycle will comprise 28 days of continuous daily treatment with Tocotrienol given 2 times/6 soft gel capsules (total 600 mg) /day (BID) in the morning and in the evening with food followed by a 14 day wash out period without drug.
EGCG + Tocotrienol
Combination of both arms
Dietary Supplement: EGCG + Tocotrienol
combination of both arms 375 mg EGCG + 600mg/day Tocotrienol

Detailed Description:

Background: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF trans-membrane conductance regulator protein. Despite substantial progress achieved in the understanding of the molecular basis and physiopathology of CF, a cure is not available. Mutation specific therapy is a novel approach to overcome the molecular defect in CF. We have previously shown that gentamicin and PTC 124 can induce read-through of nonsense CFTR mutations, and lead to functional CFTR. In addition we have shown that in vitro treatment with (-)epigallocatechin gallate (EGCG) and or Tocotrienol of cells harboring splicing mutations can augment production of full-length transcripts of affected proteins.

Working hypothesis and aims: EGCG and tocotrienol can act as genetic modifiers and increase the level of correctly spliced CFTR transcripts. Aim: To determine in CF patients if oral administration of EGCG and/or Tocotrienol, will modify CFTR splicing, as assessed by (1) Transepithelial Potential Difference (TEPD) as a measurement of ion channel activity, (2) levels of correctly spliced CFTR mRNA in nasal mucosa, (3) cytokine levels in sputum and (4) pulmonary function (FEV1).

Methods: Patients with CF carrying splicing mutations will be treated with EGCG 200 mg/day, Tocotrienol 600mg/day or both for 28 day cycles. Clinical parameters (TEPD, FEV1 and cytokine levels in sputum) and molecular parameters (mRNA levels,) will be analyzed to determine the effectiveness of the treatment.

Expected results: In vitro studies with cell cultures derived from CF patients have shown positive results; therefore an improvement in TEPD will be an indication for CFTR expression. An increase in mRNA levels and changes in FEV1, and cytokine levels will confirm the results.

Importance: Genetic therapy has encountered many technical difficulties. It is therefore of importance to develop alternative molecular strategies that will lead to an improvement or to a cure of genetic diseases.

Probable implications to Medicine: Alternative splicing mechanisms are a common cause of genetic disease as ~15% of all known human mutations result in defective pre-mRNA splicing. Therapies based on augmenting the levels of full length or fully functioning proteins may have a substantial impact on the treatment of patients with genetic diseases.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Confirmed diagnosis of CF.
  2. Abnormal chloride secretion as measured by TEPD (a less than -5 mV TEPD assessment of chloride secretion with chloride-free amiloride and isoproterenol).
  3. Presence of a splicing mutation in at least one allele of the CFTR gene.
  4. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures (including TEPD measurements, clinical laboratory tests,), and study restrictions.
  5. Ability to provide written informed consent.
  6. Evidence of personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.

Exclusion Criteria:

  1. Prior or ongoing medical condition (e.g., concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the patient, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
  2. Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment.
  3. History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment.
  4. Abnormalities on screening chest x-ray suggesting clinically significant active pulmonary disease other than CF, or new, significant abnormalities such as atelectasis or pleural effusion which may be indicative of clinically significant active pulmonary involvement secondary to CF.
  5. Abnormal liver function (serum ALT, AST, GGT, alkaline phosphatase, LDH, or total bilirubin > 2 times upper limit of normal). Abnormal renal function (serum creatinine >1.5 times upper limit of normal).
  6. Pregnancy or breast-feeding.
  7. History of solid organ or hematological transplantation.
  8. Ongoing participation in any other therapeutic clinical trial or exposure to another investigational drug within 14 days prior to start of study treatment.
  9. Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 14 days prior to start of study treatment.
  10. Change in treatment with systemic or inhaled corticosteroids within 14 days prior to start of study treatment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00889434

Contacts
Contact: Eitan Kerem, MD 972-2-5844430/1 kerem@hadassah.org.il
Contact: Hadas Lemberg,, PhD 972 2 6777572 lhadas@hadassah.org.il

Locations
Israel
Hadassah Medical Organization, Mount Scopus Recruiting
Jerusalem, Israel, 91240
Contact: Eitan Kerem, MD    972-2-5844430/1    kerem@hadassah.org.il   
Principal Investigator: Eitan Kerem, MD         
Sub-Investigator: Michael Wilschanski, MD         
Sub-Investigator: Thea Pugatsch, PhD         
Sub-Investigator: Hela Elyashar-Eiron         
Sponsors and Collaborators
Hadassah Medical Organization
Investigators
Principal Investigator: Eitan Kerem, MD Hadassah Medical Organization
  More Information

No publications provided

Responsible Party: Kerem Eithan, Head, Pediatrics division Hadassah Medical Center, Hadassah Medical Organization
ClinicalTrials.gov Identifier: NCT00889434     History of Changes
Other Study ID Numbers: ECGC-TOC-HMO-CTIL
Study First Received: April 20, 2009
Last Updated: November 11, 2012
Health Authority: Israel: Israeli Health Ministry Pharmaceutical Administration

Keywords provided by Hadassah Medical Organization:
Cystic fibrosis
splicing mutations
molecular therapy
EGCG
Tocotrienol
Splicing-mutation-mediated Cystic Fibrosis

Additional relevant MeSH terms:
Tocopherols
Tocotrienols
Vitamin E
Cystic Fibrosis
Fibrosis
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases
Pancreatic Diseases
Pathologic Processes
Respiratory Tract Diseases
Antioxidants
Growth Substances
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Vitamins

ClinicalTrials.gov processed this record on November 27, 2014