Concentration-QT Study of Paroxetine in Healthy Adults

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

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.

Study Overview

• Status: Completed
• Conditions: Anxiety Disorders
• Intervention / Treatment: Drug: Paroxetine

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, HA1 3UJ
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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:

  1. Heart rate ≥ 40 beats per minute
  2. PR interval ≤ 220 milliseconds (msec) (For PR, QRS and QTcF interval, and Q wave, the mean of triplicate ECGs will be used)
  3. Q waves < 50 msec (For PR, QRS and QTcF interval, and Q wave, the mean of triplicate ECGs will be used)
  4. QRS interval to be ≥ 60msec and < 120msec (For PR, QRS and QTcF interval, and Q wave, the mean of triplicate ECGs will be used)
  5. The waveforms must enable the QT interval to be clearly defined
  6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paroxetine	Drug: Paroxetine; Paroxetine will be administered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Corrected QT Interval by Fridericia (QTcF Interval)	A standard 12-lead electrocardiogram (ECG) were recorded in a participant using an ECG machine after 10 minutes rest in the supine position. Baseline was defined as the sample obtained on Day -1. Change from Baseline was calculated by subtracting Baseline value from post dose value.	Baseline (Day -1); 0.25 Hours Pre-dose on Day 1; 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12 Hours Post-dose on Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	SBP and DBP were measured in the supine position using a semi-automatic blood pressure recording device with an appropriate cuff size after at least 5 minutes of rest. Baseline was defined as the sample obtained on Day -1. Change from Baseline was calculated by subtracting Baseline value from post dose value. Mean and standard deviation (SD) values of vital sign assessments at Day 48 are reported.	Baseline (Day -1) and Day 48
Change From Baseline in Vital Sign: Pulse Rate	Pulse rate was measured in the supine position using a semi-automatic recording device with an appropriate cuff size after at least 5 minutes of rest. Baseline was defined as the sample obtained on Day -1. Change from Baseline was calculated by subtracting Baseline value from post dose value. Mean and SD values of vital sign assessments at Day 48 are reported.	Baseline (Day -1) and Day 48
Change From Baseline in Vital Sign: Body Temperature	Body temperature measurements were performed in participants. Baseline was defined as the sample obtained on Day -1. Change from Baseline was calculated by subtracting Baseline value from post dose value. Mean and SD values of vital sign assessments at Day 48 are reported.	Baseline (Day -1) and Day 48
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose, results in death; was life threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or any other situation as determined per medical and scientific judgment.	Up to Day 48
Number of Participants With Clinically Significant Findings for Hematology, Clinical Chemistry and Coagulation Laboratory Parameters	The laboratory measurements included hematology, clinical chemistry and coagulation parameters. The parameters evaluated were Basophil, Eosinophil, Erythrocyte Mean Corpuscular Volume, Erythrocytes, Hematocrit, Hemoglobin, Lymphocyte, Monocyte, Neutrophils, Platelets, Reticulocytes, Alanine Aminotransferase, Alkaline phosphatase, Aspartate Aminotransferase, Bilirubin, Calcium, Creatinine, Direct Bilirubin, Potassium, Sodium, Creatinine kinase, Prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ration (INR). Clinical significance was determined by the investigator. Number of participants with clinically significant findings in hematology, clinical chemistry and coagulation were reported.	Up to Day 48
Number of Participants With Clinically Significant Findings for Vital Signs	Vital signs included systolic and diastolic blood pressure, pulse rate and body temperature. Blood pressure and pulse rate were measured with the participant in supine position after at least 5 minutes rest. Clinical significance was determined by the investigator. Number of participants with clinically significant findings in vital signs were reported.	Up to Day 48
Number of Participants With Clinically Significant Findings for Physical Examinations	Physical examinations included assessment of skin, lungs, cardiovascular system, and abdomen (liver and spleen). Clinical significance was determined by the investigator. Number of Participants with clinically significant findings for physical examinations were reported.	Up to Day 48

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2023
• Primary Completion (Actual): January 8, 2024
• Study Completion (Actual): January 8, 2024

Study Registration Dates

• First Submitted: September 26, 2023
• First Submitted That Met QC Criteria: September 26, 2023
• First Posted (Actual): October 4, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: October 29, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Dose escalation; Healthy Adults; Paroxetine; QTc Interval
• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Cytochrome P-450 Enzyme Inhibitors; Neurotransmitter Uptake Inhibitors; Antidepressive Agents; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Paroxetine
• Other Study ID Numbers: 219882

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
• IPD Sharing Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• IPD Sharing Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No