Effects of Three Single Oral Doses of Trazodone on the QTc Interval Duration in Healthy Volunteers

Aziende Chimiche Riunite Angelini Francesco S.p.A20 enrolled

Overview

The present study has been designed to evaluate the effect of three doses of trazodone (20, 60 and 140 mg), in comparison to placebo, on the QT/QTc interval of healthy volunteers. Trazodone oral drops 6% formulation has been selected in order to evaluate the three doses using the same formulation, because the lowest available strength for the tablet formulations is 50 mg. According to the E14 guideline on the evaluation of QT/QTc interval prolongation and proarrhythmic potential of antiarrhytmic drugs, a negative control (placebo) and a positive control (moxifloxacin) will also be assessed.

Twenty (20) healthy volunteers (about 50% males and 50% females) will be randomised. Primary end-point: * Evaluation of the relationship between the plasma concentration of trazodone (free base) and the change from baseline in QTc, placebo-adjusted and corrected for HR based on the Fridericia correction method (QTcF) method (∆∆QTcF). * Trazodone can be declared to have no influence on QTc if the null hypothesis, that the upper bound of the two-sided 90% CI of the predicted mean placebo corrected change from baseline for QTcF is greater than 10 msec at the observed mean Cmax for the therapeutic dose of trazodone, can be rejected.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

DOUBLE

Enrollment

Conditions

Healthy

Eligibility

Sex: ALLMin age: 20 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

Main Inclusion Criteria: * Sex and Age: males/females, 20-50 years old inclusive * Body mass index (BMI): 18.5-28 kg/m2 inclusive * Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest (supine) * Contraception and fertility (females only): females of child-bearing potential must be using at least one of the following reliable methods of contraception: 1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit 2. A non-hormonal intrauterine device \[IUD\] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit 3. A male sexual partner who agrees to use a male condom with spermicide 4. A sterile sexual partner Main Exclusion Criteria: * ECG (12-leads, supine position): any of the following conditions: Heart rate \<50 or \>90 bpm; PR \<120 or \>200 msec; QRS \>110 msec; QTcF males \>430 msec, females \>450 msec; Any qualitative/morphological abnormality except: sinus arrhythmia, isolated premature atrial complexes/premature ventricular complexes; T-wave/U-wave characteristics making determination of the end of the T-wave difficult such as biphasic T-waves, U-waves of width greater than 1/3 the width of the preceding T-wave * Diseases: history of additional risk factors for torsade de pointes (e.g. heart failure, hypokalaemia, family history of long QT syndrome); history of significant renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study * Medications: any medications, including over the counter (OTC) medications and herbal products, and in particular medications that prolong the QT/QTc interval and potentially hepatotoxic drugs or hepatic/gastric enzyme inducers (i.e. phenobarbital, phenitoine, carbamazepine, chlorzoxazone and rifampicin) for 2 weeks before the start of the study and during the study duration. Hormonal contraceptives for females will be allowed * Physical findings: clinically significant abnormal physical findings * Laboratory analyses: clinically significant abnormal laboratory values * Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. * Blood donation: blood donations for 3 months before this study * Drug, alcohol, caffeine, tobacco: history of drug and/or alcohol dependence \[alcohol abuse defined as \>1 drink/day for females and \>2 drinks/day for males, defined according to USDA Dietary Guidelines 2015-2020\]; caffeine abuse (\>5 cups coffee/tea/day) or tobacco abuse (more than 10 cigarettes/day) * Drug test: positive result at the drug test at screening or day -1 * Alcohol test: positive alcohol breath test at day -1 * Grapefruit juice: grapefruit juice consumption within 2 weeks of the administration of the study treatments * Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women

Outcomes

Primary Outcomes

Relationship between trazodone plasma concentration and QTc

Evaluation of the relationship between the plasma concentration of trazodone (free base) and the change from baseline in QTc, placebo-adjusted and corrected for HR based on the Fridericia correction method (QTcF) method (∆∆QTcF).

Time frame: pre-dose (-0.25 hours) and at 0.0833, 0.1666, 0.3333, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.

Influence of trazodone on QTc

Trazodone can be declared to have no influence on QTc if the null hypothesis, that the upper bound of the two-sided 90% CI of the predicted mean placebo corrected change from baseline for QTcF is greater than 10 msec at the observed mean Cmax for the therapeutic dose of trazodone, can be rejected.