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

NCT00889434 | Completed

• 1 other identifier: ECGC-TOC-HMO-CTIL
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

• 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.

Conditions

Cystic Fibrosis

Keywords

Cystic fibrosis; splicing mutations; molecular therapy; EGCG; Tocotrienol; Splicing-mutation-mediated Cystic Fibrosis

Outcome Measures

Primary Outcomes (1)

• 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

  3 months

Secondary Outcomes (1)

• Pulmonary function testing: forced expiratory volume in 1 sec [FEV1], forced vital capacity [FVC], and maximal expiratory flow25-75 [MEF25-75]

  3 months

Study Arms (3)

EGCG

ACTIVE COMPARATOR

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

Tocotrienol

ACTIVE COMPARATOR

Dietary Supplement: Tocotrienol

EGCG + Tocotrienol

OTHER

Combination of both arms

Dietary Supplement: EGCG + Tocotrienol

Interventions

ECGC DIETARY_SUPPLEMENT

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.

EGCG

Tocotrienol DIETARY_SUPPLEMENT

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.

Tocotrienol

EGCG + Tocotrienol DIETARY_SUPPLEMENT

combination of both arms 375 mg EGCG + 600mg/day Tocotrienol

EGCG + Tocotrienol

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• 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.
• Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment.
• History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment.
• 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.
• 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).
• Pregnancy or breast-feeding.
• History of solid organ or hematological transplantation.
• Ongoing participation in any other therapeutic clinical trial or exposure to another investigational drug within 14 days prior to start of study treatment.
• Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 14 days prior to start of study treatment.
• Change in treatment with systemic or inhaled corticosteroids within 14 days prior to start of study treatment.

Sponsors & Collaborators

• Hadassah Medical Organization: lead

Study Sites (1)

Hadassah Medical Organization, Mount Scopus

Jerusalem, 91240, Israel

Location

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Tocotrienols; epigallocatechin gallate

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)

Vitamin E; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Eitan Kerem, MD

  Hadassah Medical Organization

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2009
• First Posted: April 28, 2009
• Study Start: November 1, 2011
• Primary Completion: April 16, 2015
• Study Completion: April 16, 2015
• Last Updated: November 30, 2017

Record last verified: 2017-02

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)