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

Primary Purpose

Cystic Fibrosis

Status

Completed

Phase

Not Applicable

Locations

Israel

Study Type

Interventional

Intervention

ECGC

Tocotrienol

EGCG + Tocotrienol

About this trial

This is an interventional treatment trial for Cystic Fibrosis focused on measuring Cystic fibrosis, splicing mutations, molecular therapy, EGCG, Tocotrienol, Splicing-mutation-mediated Cystic Fibrosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Sites / Locations

Hadassah Medical Organization, Mount Scopus

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Other

Arm Label

EGCG

Tocotrienol

EGCG + Tocotrienol

Arm Description

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.

Combination of both arms

Outcomes

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

Secondary Outcome Measures

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

Full Information

NCT ID

NCT00889434

First Posted

April 20, 2009

Last Updated

November 29, 2017

Sponsor

Hadassah Medical Organization

1. Study Identification

Unique Protocol Identification Number

NCT00889434

Brief Title

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

Official Title

Single-site, Open-label, Dose-ranging, Efficacy, and Safety Study of EGCG/Tocotrienol in 18 Patients With Splicing-mutation-mediated CF

Study Type

Interventional

2. Study Status

Record Verification Date

February 2017

Overall Recruitment Status

Completed

Study Start Date

November 1, 2011 (Actual)

Primary Completion Date

April 16, 2015 (Actual)

Study Completion Date

April 16, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hadassah Medical Organization

4. Oversight

Data Monitoring Committee

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cystic Fibrosis

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

EGCG

Arm Type

Active Comparator

Arm Description

Arm Title

Tocotrienol

Arm Type

Active Comparator

Arm Title

EGCG + Tocotrienol

Arm Type

Other

Arm Description

Combination of both arms

Intervention Type

Dietary Supplement

Intervention Name(s)

ECGC

Intervention Description

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.

Intervention Type

Dietary Supplement

Intervention Name(s)

Tocotrienol

Intervention Description

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.

Intervention Type

Dietary Supplement

Intervention Name(s)

EGCG + Tocotrienol

Intervention Description

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

Primary Outcome Measure Information:

Title

Time Frame

3 months

Secondary Outcome Measure Information:

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Eitan Kerem, MD

Organizational Affiliation

Hadassah Medical Organization

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hadassah Medical Organization, Mount Scopus

City

Jerusalem

ZIP/Postal Code

91240

Country

Israel

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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