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

NCT02680080 | Completed

• 1 other identifier: TASMC-15-EC-15-0728-TLV-CTIL
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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

Conditions

Long QT Syndrome

Outcome Measures

Primary Outcomes (1)

• 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

  up to 24 hours

Study Arms (2)

Positive control group

ACTIVE COMPARATOR

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

Drug: Moxifloxacin

Grapefruit group

ACTIVE COMPARATOR

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

Dietary Supplement: Grapefruit group

Interventions

Moxifloxacin DRUG

a single 400 mg tablet of Moxifloxacin

Positive control group

Grapefruit group DIETARY_SUPPLEMENT

one liter of fresh pink-grapefruit juice

Grapefruit group

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.
• 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.
• 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).

Sponsors & Collaborators

• Tel-Aviv Sourasky Medical Center: lead
• Tel Aviv Medical Center: collaborator

Study Sites (1)

Sourasky medical center (Ichilov)

Tel Aviv, Israel

Location

Related Publications (1)

• 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.

  PMID: 31075442 DERIVED

MeSH Terms

Conditions

Long QT Syndrome

Interventions

Moxifloxacin

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ehud Chorin, MD

  Tel Aviv MC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director. Research & development, Tel-Aviv Sourasky Medical Center

Study Record Dates

• First Submitted: January 28, 2016
• First Posted: February 11, 2016
• Study Start: December 1, 2016
• Primary Completion: June 12, 2018
• Study Completion: May 22, 2019
• Last Updated: May 24, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)