Back to results

Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome

Primary Purpose

Long QT Syndrome

Status

Completed

Phase

Not Applicable

Locations

Israel

Study Type

Interventional

Intervention

Moxifloxacin

Grapefruit group

About this trial

This is an interventional diagnostic trial for Long QT Syndrome

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Inclusions Criteria - healthy volunteers

Healthy volunteers between 18 and <65 years of age.
Subjects within BMI 18.0-29.0 calculated as Weight (Kg)/Height (m)2.
No known history of significant neurological (including history of seizures or EEG abnormalities), renal, cardiovascular (including known structural cardiac abnormalities or hypertension), respiratory (asthma), endocrinological, gastrointestinal, hepatic or hematopoietic disease, neoplasm, psychological (marked anxiety, tension or agitation) or any other clinically significant medical disorder, which in the investigator's judgment contraindicate administration of the study medications.
No significant abnormalities in screening physical examination
No known allergy to Fluoroquinolone (Moxifloxacin)
Subjects must provide written informed consent to participate in the study
No significant abnormalities in the electrocardiogram prior to the first dosing day.

Inclusions Criteria - LQTS patients:

LQTS patients between 18 and <65 years of age.
Subjects within BMI 18.0-29.0 calculated as Weight (Kg)/Height (m)2.
No known history of significant neurological (including history of seizures or EEG abnormalities), renal, cardiovascular (including known structural cardiac abnormalities or hypertension), respiratory (asthma), endocrinological, gastrointestinal, hepatic or hematopoietic disease, neoplasm, psychological (marked anxiety, tension or agitation) or any other clinically significant medical disorder, which in the investigator's judgment contraindicate administration of the study medications.
No significant abnormalities in screening physical examination.
Subjects must provide written informed consent to participate in the study.

Exclusion Criteria:

Exclusions Criteria - healthy volunteers:

Subjects with any clinically significant abnormality upon physical examination or in the clinical laboratory test values (CBC, electrolytes, renal function and liver enzymes).
Subjects with a history of clinically defined GERD, peptic ulcer or any gastrointestinal surgery other than appendectomy or herniotomy, or with any gastrointestinal disorder likely to influence drug absorption, or with any history of severe gastrointestinal narrowing, or frequent nausea or emesis, regardless of etiology.
Subjects with significant allergic response to other drugs or history of food allergies deemed clinically significant or exclusionary for the study.
Previous episode of syncope or seizures.
Supine heart rate < 45 beats per minute after 5 minutes rest.
QTc prolongation (defined as QTc >450 msec for healthy volunteers) in the electrocardiogram on screening examination.
Significant abnormalities in the electrocardiogram prior to the first dosing day. Patients with sinus arrhythmia will be excluded.
Subjects with an inability to communicate well with the investigators and staff (i.e., language problem, poor mental development or impaired cerebral function).
Subjects with any acute medical situation (e.g. acute infection) within 48 hours of study start, which is considered of significance by the Principal Investigator.
Subjects who are non-cooperative or unwilling to sign consent form.

Exclusions Criteria - LQTS patients:

Subjects with any clinically significant abnormality upon physical examination or in the clinical laboratory test values (CBC, electrolytes, renal function and liver enzymes).
Subjects with a history of clinically defined GERD, peptic ulcer or any gastrointestinal surgery other than appendectomy or herniotomy, or with any gastrointestinal disorder likely to influence drug absorption, or with any history of severe gastrointestinal narrowing, or frequent nausea or emesis, regardless of etiology.
Subjects with significant allergic response to other drugs or history of food allergies deemed clinically significant or exclusionary for the study.
Previous episode of syncope or seizures.
Supine heart rate < 45 beats per minute after 5 minutes rest.
QTc prolongation (defined as QTc >500 msec for LQTS patients) in the electrocardiogram on screening examination.
Subjects with an inability to communicate well with the investigators and staff (i.e., language problem, poor mental development or impaired cerebral function).
Subjects with any acute medical situation (e.g. acute infection) within 48 hours of study start, which is considered of significance by the Principal Investigator.
Subjects who are non-cooperative or unwilling to sign consent form.

Sites / Locations

Sourasky medical center (Ichilov)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Positive control group

Grapefruit group

Arm Description

subjects will receive a single 400 mg tablet of Moxifloxacin - the most commonly used positive control in "thorough" QTc (TQT) studies. Subjects will be continuously recorded by a Holter monitor for 24 hours

subjects will drink one liter of fresh pink-grapefruit juice as fast as possible. The pink-grapefruit juice will be squeezed in the morning of the experiment in the cardiology department. ECG will be performed immediately pre dose and at 1, 2, 3, 4, 6, 8, 12, 24 after fresh pink-grapefruit juice administration. In addition, subjects will be continuously recorded by a Holter monitor for 24 hours

Outcomes

Primary Outcome Measures

QT measurements

ECG will be performed after fresh pink-grapefruit juice administration. In addition, subjects will be continuously recorded by a Holter monitor for 24 hours QT interval, RR and QTc will be evaluated

Secondary Outcome Measures

Full Information

NCT ID

NCT02680080

First Posted

January 28, 2016

Last Updated

May 22, 2019

Sponsor

Tel-Aviv Sourasky Medical Center

Collaborators

Tel Aviv Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT02680080

Brief Title

Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome

Official Title

The Effect of Pink Grapefruit Juice on the QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome

Study Type

Interventional

2. Study Status

Record Verification Date

May 2019

Overall Recruitment Status

Completed

Study Start Date

December 1, 2016 (Actual)

Primary Completion Date

June 12, 2018 (Actual)

Study Completion Date

May 22, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Tel-Aviv Sourasky Medical Center

Collaborators

Tel Aviv Medical Center

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The list of medications that prolong the QT interval and can provoke torsade de pointes keeps expanding. This list includes not only antiarrhythmic drugs, but also medications with no cardiac indications. All these medications prolong the QT interval because they block a specific potassium channel on the myocardial cell membrane: the channel for the rapid component of the delayed rectifier potassium current or "IKr". The risk for developing torsade de pointes for patients taking any of the medications with IKr blockade capabilities varies from >4% for antiarrhythmic drugs to <0.01% for non-cardiac medications. The risk depends on the strength of IKr blockade, but also on specific patient characteristics. The majority of patients who develop torsade de pointes from non-cardiac medications have identifiable risk factors. In this regard, patients with a congenital long QT syndrome are prone to develop torsade de pointes when treated with QT-prolonging medications. This is because, due to their genetically defective ion channels, patients with Long QT Syndrome (LQTS) have impaired ventricular repolarization and reduced "repolarization reserve." Therefore, it is common medical practice to strongly advise patients with congenital LQTS to avoid all medications that have IKr channel blocker capabilities. it was reported that some flavonoids contained in pink-grapefruit juice block the IKr channel. These investigators also reported that drinking 1 liter of pink-grapefruit juice causes QT prolongation in healthy volunteers. The magnitude of the QT prolongation provoked by grapefruit juice was small However, drugs causing minor QT prolongation in healthy volunteers may provoke major QT prolongation in rare or sick individuals who are then at risk for developing torsade de pointes. Consequently, one could argue that, until proven otherwise, pink-grapefruit should be added to the list of "drugs" that are forbidden for patients with LQTS

Detailed Description

The list of medications that prolong the QT interval and can provoke torsade de pointes keeps expanding. This list includes not only antiarrhythmic drugs, but also medications with no cardiac indications (like several antibiotics, antihistamines or antipsychotic medications). All these medications prolong the QT interval because they block a specific potassium channel on the myocardial cell membrane: the channel for the rapid component of the delayed rectifier potassium current or "IKr". The risk for developing torsade de pointes for patients taking any of the medications with IKr blockade capabilities varies from >4% for antiarrhythmic drugs to <0.01% for non-cardiac medications. The risk depends on the strength of IKr blockade, but also on specific patient characteristics. In fact, the majority of patients who develop torsade de pointes from non-cardiac medications have identifiable risk factors. In this regard, patients with a congenital long QT syndrome (LQTS) are prone to develop torsade de pointes when treated with QT-prolonging medications. This is because, due to their genetically defective ion channels, patients with LQTS have impaired ventricular repolarization and reduced "repolarization reserve." Therefore, it is common medical practice to strongly advise patients with congenital LQTS to avoid all medications that have IKr channel blocker capabilities. Zitron et al reported that some flavonoids contained in pink-grapefruit juice block the IKr channel. These investigators also reported that drinking 1 liter of pink-grapefruit juice causes QT prolongation in healthy volunteers. The magnitude of the QT prolongation provoked by grapefruit juice was small (12.5 ± 4.2 msec). However, drugs causing minor QT prolongation in healthy volunteers may provoke major QT prolongation in rare or sick individuals who are then at risk for developing torsade de pointes. Consequently, one could argue that, until proven otherwise, pink-grapefruit should be added to the list of "drugs" that are forbidden for patients with LQTS. This is a single center, open-label, randomized, crossover study. Subjects will be admitted to the cardiology department on the day before the first dose and will remain there until study completion. After performing a baseline electrocardiogram and baseline blood tests (Complete Blood Count, chemistry - up to 10 ml of blood) subjects will be continuously recorded by a Holter monitor for 24 hours (baseline Holter). On the next day subjects will be randomly divided into two experimental therapies (one after the other in a random order to the same group of patients

6. Conditions and Keywords

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

Long QT Syndrome

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

25 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Positive control group

Arm Type

Active Comparator

Arm Description

Arm Title

Grapefruit group

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Moxifloxacin

Intervention Description

a single 400 mg tablet of Moxifloxacin

Intervention Type

Dietary Supplement

Intervention Name(s)

Grapefruit group

Intervention Description

one liter of fresh pink-grapefruit juice

Primary Outcome Measure Information:

Title

QT measurements

Description

ECG will be performed after fresh pink-grapefruit juice administration. In addition, subjects will be continuously recorded by a Holter monitor for 24 hours QT interval, RR and QTc will be evaluated

Time Frame

up to 24 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Inclusions Criteria - healthy volunteers Healthy volunteers between 18 and <65 years of age. Subjects within BMI 18.0-29.0 calculated as Weight (Kg)/Height (m)2. No known history of significant neurological (including history of seizures or EEG abnormalities), renal, cardiovascular (including known structural cardiac abnormalities or hypertension), respiratory (asthma), endocrinological, gastrointestinal, hepatic or hematopoietic disease, neoplasm, psychological (marked anxiety, tension or agitation) or any other clinically significant medical disorder, which in the investigator's judgment contraindicate administration of the study medications. No significant abnormalities in screening physical examination No known allergy to Fluoroquinolone (Moxifloxacin) Subjects must provide written informed consent to participate in the study No significant abnormalities in the electrocardiogram prior to the first dosing day. Inclusions Criteria - LQTS patients: LQTS patients between 18 and <65 years of age. Subjects within BMI 18.0-29.0 calculated as Weight (Kg)/Height (m)2. No known history of significant neurological (including history of seizures or EEG abnormalities), renal, cardiovascular (including known structural cardiac abnormalities or hypertension), respiratory (asthma), endocrinological, gastrointestinal, hepatic or hematopoietic disease, neoplasm, psychological (marked anxiety, tension or agitation) or any other clinically significant medical disorder, which in the investigator's judgment contraindicate administration of the study medications. No significant abnormalities in screening physical examination. Subjects must provide written informed consent to participate in the study. Exclusion Criteria: Exclusions Criteria - healthy volunteers: Subjects with any clinically significant abnormality upon physical examination or in the clinical laboratory test values (CBC, electrolytes, renal function and liver enzymes). Subjects with a history of clinically defined GERD, peptic ulcer or any gastrointestinal surgery other than appendectomy or herniotomy, or with any gastrointestinal disorder likely to influence drug absorption, or with any history of severe gastrointestinal narrowing, or frequent nausea or emesis, regardless of etiology. Subjects with significant allergic response to other drugs or history of food allergies deemed clinically significant or exclusionary for the study. Previous episode of syncope or seizures. Supine heart rate < 45 beats per minute after 5 minutes rest. QTc prolongation (defined as QTc >450 msec for healthy volunteers) in the electrocardiogram on screening examination. Significant abnormalities in the electrocardiogram prior to the first dosing day. Patients with sinus arrhythmia will be excluded. Subjects with an inability to communicate well with the investigators and staff (i.e., language problem, poor mental development or impaired cerebral function). Subjects with any acute medical situation (e.g. acute infection) within 48 hours of study start, which is considered of significance by the Principal Investigator. Subjects who are non-cooperative or unwilling to sign consent form. Exclusions Criteria - LQTS patients: Subjects with any clinically significant abnormality upon physical examination or in the clinical laboratory test values (CBC, electrolytes, renal function and liver enzymes). Subjects with a history of clinically defined GERD, peptic ulcer or any gastrointestinal surgery other than appendectomy or herniotomy, or with any gastrointestinal disorder likely to influence drug absorption, or with any history of severe gastrointestinal narrowing, or frequent nausea or emesis, regardless of etiology. Subjects with significant allergic response to other drugs or history of food allergies deemed clinically significant or exclusionary for the study. Previous episode of syncope or seizures. Supine heart rate < 45 beats per minute after 5 minutes rest. QTc prolongation (defined as QTc >500 msec for LQTS patients) in the electrocardiogram on screening examination. Subjects with an inability to communicate well with the investigators and staff (i.e., language problem, poor mental development or impaired cerebral function). Subjects with any acute medical situation (e.g. acute infection) within 48 hours of study start, which is considered of significance by the Principal Investigator. Subjects who are non-cooperative or unwilling to sign consent form.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ehud Chorin, MD

Organizational Affiliation

Tel Aviv MC

Official's Role

Principal Investigator

Facility Information:

Facility Name

Sourasky medical center (Ichilov)

City

Tel-Aviv

Country

Israel

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

31075442

Citation

Chorin E, Hochstadt A, Granot Y, Khoury S, Schwartz AL, Margolis G, Barashi R, Viskin D, Ghantous E, Schnapper M, Mekori T, Fourey D, Guevara-Valdivia ME, Marquez MF, Zeltzer D, Rosso R, Viskin S. Grapefruit juice prolongs the QT interval of healthy volunteers and patients with long QT syndrome. Heart Rhythm. 2019 Aug;16(8):1141-1148. doi: 10.1016/j.hrthm.2019.04.039. Epub 2019 May 8.

Results Reference

derived

Learn more about this trial

Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome

We'll reach out to this number within 24 hrs