Concentration-QT Study of Paroxetine in Healthy Adults

Study Overview
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Brief Summary
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The primary purpose of the study is to evaluate the potential effect of paroxetine on QTc interval following escalating doses in healthy participants. Participants with no history of cardiac abnormalities or mood disorders will be enrolled. During the study, participants will take paroxetine at three incremental dose levels. Participants will attend the clinic at screening, baseline, at the end of each dose level administration week, and a final study exit visit. While on treatment outside of clinic visits, participants will be followed-up via video-call. A concentration-QTc analysis will assess any potential correlation between paroxetine plasma concentration and QTc prolongation. In addition, the occurrence of any side-effects will be compared between on and off treatment.

Official Title
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An Open-Label, Single Arm, Dose Escalating Concentration-QT Study to Investigate the Cardiac Effects and Safety of Paroxetine in Healthy Adult Participants

Conditions
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Anxiety Disorders

Intervention / Treatment
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* Drug: Paroxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants, both male and female, aged between 18 to 65 years, at the time of signing the informed consent. Participants determined as healthy based on medical evaluation by an experienced physician. A female participant is eligible to participate if she is of: Nonchildbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. Child-bearing potential and agrees to use one of the contraception methods for an appropriate time as mentioned in the study protocol. Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin ≤ 1.5x (Upper Limit of Normal) ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Body weight ≥ 45 kilogram (kg) and Body Mass Index (BMI) within the range 18 to 29.5 kilogram per metre square (kg/m2) (inclusive). No significant abnormality on 12-lead Electrocardiogram (ECG) at Screening in supine position, including the following specific requirements: Heart rate ≥ 40 beats per minute PR interval ≤ 220 milliseconds (msec) (For PR, QRS and QTcF interval, and Q wave, the mean of triplicate ECGs will be used) Q waves < 50 msec (For PR, QRS and QTcF interval, and Q wave, the mean of triplicate ECGs will be used) QRS interval to be ≥ 60msec and < 120msec (For PR, QRS and QTcF interval, and Q wave, the mean of triplicate ECGs will be used) The waveforms must enable the QT interval to be clearly defined QTcF interval must be < 450msec (machine or manual reading). A signed and dated written informed consent obtained from participants capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Non-smokers (never smoked or not smoking for >6 months with <10 pack years history (Pack years = (cigarettes per day smoked/20) x number of years smoked) or light smokers (less than 5 cigarettes per day). Exclusion Criteria: History or presence of any medically significant disease that may cause additional risk or interfere with the study procedures or outcome. History of symptomatic arrhythmias. History of hypersensitivity to paroxetine and excipients History of abnormal coagulation parameters, bleeding disorders or conditions which may predispose to bleeding. History of, or active suicidal ideation. Includes assessment using the Columbia Suicide Severity Rating Scale (C-SSRS) Must not have a pre-diagnosed mood disorder Participant is mentally or legally incapacitated. A supine blood pressure that is persistently higher than 140/90 millimetres of mercury (mmHG) at Screening. A supine heart rate outside the range 50-90 beats per minute (bpm) at Screening. A positive screening Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. Current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones). A positive drug/alcohol screen at screening or prior to dosing. A positive test for Human Immune Virus (HIV) antibody at Screening. History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint ( 240 millilitre [ml]) of beer, 1 glass (125ml) of wine or 1 (25 ml) measure of spirits. The participant has participated in a clinical trial and has received an investigational product within the following time prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Use of the following medications within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of the study medication: monoamine oxidase inhibitors (including linezolid), thioridazine, pimozide, serotonergic drugs (including L-tryptophan, triptans, tramadol, selective serotonin reuptake inhibitors, lithium and fentanyl, tamoxifen, anti-coagulants, clozapine, phenothiazines, tricyclic antidepressants, acetylsalicylic acid, non-steroidal anti-inflammatory drugs, Cox-2 inhibitors, antiarrhythmics, quinolone antibiotics, macrolides (including clarithromycin and erythromycin), ketoconazole and itraconazole Use of non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication. No current use of any medication other than paracetamol (doses ≤2 grams/day). Consumption of Seville oranges, pummelos (members of the grapefruit family) or grapefruit juice from 7 days prior to the first dose of study medication. Where participation in the study would result in donation of blood or blood products more than 500 mL within a 3-month period. Pregnant females as determined by positive serum β-HCG test at screening or serum/ urine beta-Human chorionic gonadotropin (HCG) prior to dosing. Lactating females. Unwillingness or inability to follow the procedures outlined in the protocol. Participants with unsuitable veins for cannulation and repeat venepuncture.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paroxetine<br> | Drug: Paroxetine<br>* Paroxetine will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in QTc interval |  | Baseline (Day minus 1) up to Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in vital signs: Systolic blood pressure and Diastolic Blood Pressure (millimetres of mercury [mmHg]) |  | Baseline (Day minus 1) up to Day 48 | 
| Change from baseline in vital signs: heart rate (beats per minute[bpm]) |  | Baseline (Day minus 1) up to Day 48 | 
| Change from baseline in vital signs: oral body temperature (Celsius) |  | Baseline (Day minus 1) up to Day 48 | 
| Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Up to Day 48 | 
| Number of Participants with Abnormalities in haematological, clinical laboratory parameters, vital signs, and physical examination |  | Up to Day 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose escalation, QTc Interval, Paroxetine, Healthy Adults