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Effect of Therapeutic and Supratherapeutic Oral Doses of GSK3640254 on Cardiac Conduction Compared to Placebo and a Single Oral Dose of Moxifloxacin

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04563845
Recruitment Status : Not yet recruiting
First Posted : September 25, 2020
Last Update Posted : September 25, 2020
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
This study will aim to evaluate the effect of therapeutic and supratherapeutic oral doses of GSK3640254 on cardiac conduction compared to placebo and a single oral dose of Moxifloxacin in healthy adult participants. The study has 2 parts: Part 1 will determine the supratherapeutic dose for Part 2, which will be the main corrected QT interval (QTc) study. Part 1 consists of 2 sequential cohorts: Sentinel Cohort 1 will evaluate once daily (QD) dosing of GSK3640254 or placebo for 7 days and Sentinel Cohort 2 will evaluate twice daily (BID) dosing of GSK3640254 or placebo for 7 days. Part 2 will investigate the safety, tolerability and Pharmacokinetics (PK) of GSK3640254 doses on cardiac conduction as compared to placebo and a single oral dose of Moxifloxacin in healthy adult participants. Moxifloxacin will be included as a positive control. All doses of study intervention will be administered under fed conditions and will receive a moderate-fat meal 30 minutes prior to dosing. The total duration of the study is approximately 91 days. Approximately 58 participants will be enrolled in the study.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: GSK3640254 Drug: Placebo Drug: Moxifloxacin Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Study to Evaluate the Effect of Therapeutic and Supratherapeutic Oral Doses of GSK3640254 on Cardiac Conduction as Assessed by 12-Lead Electrocardiogram Compared to Placebo and a Single Oral Dose of Moxifloxacin in Healthy Adult Participants
Estimated Study Start Date : October 15, 2020
Estimated Primary Completion Date : March 30, 2021
Estimated Study Completion Date : March 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Part 1: Sentinal Cohort 1
Participants will be randomized in a 3:1 ratio to evaluate QD dosing of GSK3640254 or placebo. Participants will be administered GSK3640254 500 milligram (mg) or placebo with approximately 240 milliliters (mL) of water following ingestion of a moderate fat meal.
Drug: GSK3640254
GSK3640254 will be available as 100 mg oral tablet for therapeutic dose. The Supratherapeutic dose will be determined based on the results of preliminary data from sentinel cohort(s).

Drug: Placebo
Placebo will be available as GSK3640254 matching oral tablets.

Experimental: Part 1: Sentinal Cohort 2
Participants will be randomized in a 3:1 ratio to evaluate BID dosing of GSK3640254 or placebo. The maximum dose would be GSK3640254 500 mg BID or placebo BID with approximately 240 mL of water following ingestion of a moderate fat meal.
Drug: GSK3640254
GSK3640254 will be available as 100 mg oral tablet for therapeutic dose. The Supratherapeutic dose will be determined based on the results of preliminary data from sentinel cohort(s).

Drug: Placebo
Placebo will be available as GSK3640254 matching oral tablets.

Placebo Comparator: Part 2: Main QTc Study
Participants will be randomized to 1:1:1:1 ratio to receive Treatment T- Therapeutic dose of GSK3640254 (100 mg QD) on Days 1 through 7 or Treatment ST- Supratherapeutic dose of GSK3640254 (to be determined from Part 1) on Days 1 through 7 or Treatment P- Placebo for GSK3640254 on Days 1 through 7 or Treatment M- Moxifloxacin (GSK3640254 placebo Days 1 through 6 and a single dose of Moxifloxacin [400 mg] on Day 7 in 4 treatment periods. There will be at least 7 days wash out period between each period.
Drug: GSK3640254
GSK3640254 will be available as 100 mg oral tablet for therapeutic dose. The Supratherapeutic dose will be determined based on the results of preliminary data from sentinel cohort(s).

Drug: Placebo
Placebo will be available as GSK3640254 matching oral tablets.

Drug: Moxifloxacin
Moxifloxacin will be available as 400 mg oral capsule.




Primary Outcome Measures :
  1. Part 1: Area under the plasma concentration-time curve from time zero to time t (AUC[0-t]) of GSK3640254 [ Time Frame: Up to Day 9 of each cohort ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  2. Part 1: AUC from time zero to the end of the dosing interval at steady state (AUC[0-tau]) of GSK3640254 [ Time Frame: Up to Day 9 of each cohort ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  3. Part 1: Maximum observed concentration (Cmax) of GSK3640254 [ Time Frame: Up to Day 9 of each cohort ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  4. Part 1: Plasma concentration at the end of the dosing interval (Ctau) of GSK3640254 [ Time Frame: Up to Day 9 of each cohort ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  5. Part 1: Time of maximum observed concentration (Tmax) of GSK3640254 [ Time Frame: Up to Day 9 of each cohort ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  6. Part 1: Plasma concentrations of GSK3640254 and its major metabolite [ Time Frame: Up to Day 9 of each cohort ]
    Blood samples will be collected for measurement of plasma concentrations of GSK3640254 and its major metabolite.

  7. Part 1: Number of participants with adverse events (AEs) and serious AEs (SAEs) [ Time Frame: Up to Day 9 of each cohort ]
    All AEs and SAEs will be assessed.

  8. Part 1: Number of participants with abnormal laboratory parameters [ Time Frame: Up to Day 9 of each cohort ]
    Blood samples will be collected for the assessment of hematology and chemistry parameters.

  9. Part 1: Number of participants with abnormal urinalysis parameters [ Time Frame: Up to Day 9 of each cohort ]
    Urine samples will be collected for the assessment of urinalysis parameters.

  10. Part 1: Number of participants with abnormal electrocardiogram (ECG) parameters [ Time Frame: Up to Day 9 of each cohort ]
    Number of participants with abnormal ECG parameters will be assessed.

  11. Part 1: Number of participants with abnormal vital signs [ Time Frame: Up to Day 9 of each cohort ]
    Number of participants with abnormal vital signs will be assessed.

  12. Part 2: Placebo-corrected change from Baseline in QT interval corrected for heart rate using Fridericia's formula (QTcF) following administration of GSK3640254 (Milliseconds [ms]) [ Time Frame: Baseline (Day -1) and up to Day 51 ]
    Placebo-corrected change from Baseline in QTcF will be analyzed.

  13. Part 2: Plasma concentrations of GSK3640254 and its major metabolite [ Time Frame: Up to Day 51 ]
    Blood samples will be collected for measurement of plasma concentrations of GSK3640254 and its major metabolite.


Secondary Outcome Measures :
  1. Part 2: Change from Baseline in heart rate (HR) (Beats per minute [bpm]) [ Time Frame: Baseline (Day -1) and up to Day 51 ]
    Change from Baseline in heart rate will be analyzed.

  2. Part 2: Change from Baseline in QTcF, PR interval and QRS interval (ms) [ Time Frame: Baseline (Day -1) and up to Day 51 ]
    Change from Baseline in QTcF, PR interval and QRS interval will be analyzed.

  3. Part 2: Placebo-corrected change from Baseline in HR (bpm) [ Time Frame: Baseline (Day -1) and up to Day 51 ]
    Placebo-corrected change from Baseline in HR will be analyzed.

  4. Part 2: Placebo-corrected change from Baseline in QTcF, PR interval and QRS interval (ms) [ Time Frame: Baseline (Day -1) and up to Day 51 ]
    Placebo-corrected change from Baseline in QTcF, PR interval and QRS interval will be analyzed.

  5. Part 2: Number of participants with abnormal HR, QTcF, PR interval and QRS interval [ Time Frame: Up to Day 51 ]
    Number of participants with abnormal HR, QTcF, PR interval and QRS interval will be assessed.

  6. Part 2: Number of participants with treatment emergent changes of T-wave morphology [ Time Frame: Up to Day 51 ]
    Number of participants with treatment emergent changes of T-wave morphology will be evaluated.

  7. Part 2: Number of participants with presence of U-wave [ Time Frame: Up to Day 51 ]
    Number of participants with presence of U-wave will be evaluated.

  8. Part 2: Placebo-corrected change from Baseline in QTcF following administration of Moxifloxacin (ms) [ Time Frame: Baseline (Day -1) and up to Day 51 ]
    Placebo-corrected change from Baseline in QTcF will be analyzed.

  9. Part 2: AUC(0-t) of GSK3640254 [ Time Frame: Up to Day 51 ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  10. Part 2: AUC(0-tau) of GSK3640254 [ Time Frame: Up to Day 51 ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  11. Part 2: Cmax of GSK3640254 [ Time Frame: Up to Day 51 ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  12. Part 2: Ctau of GSK3640254 [ Time Frame: Up to Day 51 ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  13. Part 2: Tmax of GSK3640254 [ Time Frame: Up to Day 51 ]
    Blood samples will be collected at the indicated time points for PK analysis of GSK3640254.

  14. Part 2: Cmax of Moxifloxacin [ Time Frame: Up to Day 51 ]
    Blood samples will be collected at the indicated time points for PK analysis of Moxifloxacin.

  15. Part 2: Tmax of Moxifloxacin [ Time Frame: Up to Day 51 ]
    Blood samples will be collected at the indicated time points for PK analysis of Moxifloxacin.

  16. Part 2: Number of participants with AEs and SAEs [ Time Frame: Up to Day 51 ]
    All AEs and SAEs will be assessed.

  17. Part 2: Number of participants with abnormal laboratory parameters [ Time Frame: Up to Day 51 ]
    Blood samples will be collected for the assessment of hematology and chemistry parameters.

  18. Part 2: Number of participants with abnormal urinalysis parameters [ Time Frame: Up to Day 51 ]
    Urine samples will be collected for the assessment of urinalysis parameters.

  19. Part 2: Number of participants with abnormal ECG parameters [ Time Frame: Up to Day 51 ]
    Number of participants with abnormal ECG parameters will be assessed.

  20. Part 2: Number of participants with abnormal vital signs [ Time Frame: Up to Day 51 ]
    Number of participants with abnormal vital signs will be assessed.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

  • Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
  • Participants who are healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination (including cardiopulmonary examination), laboratory tests, and cardiac monitoring (history and ECG).
  • Body weight more than or equal to (>=)50.0 kilograms (kg) (110 pounds [lbs]) for men and >=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 31.0 kilograms per square meter (kg/m^2) (inclusive).
  • Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Male or female participants:

    1. Male participants should not engage in intercourse while confined in the clinic. There is no need for an extended period of double barrier use or prolonged abstinence after study discharge.
    2. Female participants:

    (i) A female participant is eligible to participate if she is not pregnant, planning to become pregnant within the next 6 months, or breastfeeding, and at least 1 of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and using a non-hormonal contraceptive method that is highly effective, with a failure rate of less than (<)1 percent (%) for 28 days before intervention, during the intervention period, and for at least 28 days after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

(ii) A WOCBP must have a negative highly sensitive serum pregnancy test at Screening and Check-in.

  • Capable of giving signed informed, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol.

Exclusion criteria:

  • Participants with current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A pre-existing condition interfering with normal Gastrointestinal (GI) anatomy or motility (for example [e.g.], gastro-esophageal reflux disease, gastric ulcers, gastritis), hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study intervention or render the participant unable to take oral study intervention.
  • Prior cholecystectomy (prior appendectomy is acceptable).
  • Clinically significant illness, including viral syndromes, within 3 weeks of dosing.
  • A participant with known or suspected active Coronavirus Disease-2019 (COVID-19) infection OR contact with an individual with known COVID-19, within 14 days of study enrollment (World Health Organization [WHO] definitions).
  • Any history of significant underlying psychiatric disorder, including, but not limited to, schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder.
  • Any history of major depressive disorder with or without suicidal features, or anxiety disorders that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (more than [>]6 months) outpatient treatment. Participants with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy (<6 months) without inpatient treatment and are currently well-controlled clinically or resolved may be considered for entry after discussion and agreement with the ViiV Healthcare/GlaxoSmithKline (VH/GSK) Medical Monitor.
  • Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the investigator (with or without psychiatric evaluation), could interfere with the participant's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the participant.
  • Medical history of cardiac arrhythmias, prior myocardial infarction in the past 3 months, or cardiac disease or a family or personal history of long QT syndrome.
  • History indicative of an increased risk of a cardiac arrhythmia or cardiac disease, including the following:

    1. History of symptomatic cardiac arrhythmias or palpitations associated with pre-syncope or syncope, or history of unexplained syncope.
    2. History of cardiac arrest.
    3. History of clinically relevant cardiac disease including symptomatic or asymptomatic arrhythmias (including but not limited to ventricular fibrillation, ventricular tachycardia, any degree of atrioventricular block, Brugada syndrome, Wolff-Parkinson-White Syndrome, and sinus bradycardia, defined as HR less than 50 bpm based on vital signs or ECG), presyncope or syncopal episodes, or additional risk factors for torsades de pointes (e.g., heart failure).
    4. History of clinically relevant structural cardiac disease including hypertrophic obstructive cardiomyopathy.
    5. History of hypokalemia.
  • History of heart disease (e.g., coronary heart disease, angina).
  • Presence of hepatitis B surface antigen at Screening or within 3 months prior to starting study intervention.
  • Positive hepatitis C antibody test result at Screening or within 3 months prior to starting study intervention.
  • Positive Human Immunodeficiency virus (HIV)-1 and -2 antigen/antibody immunoassay at Screening.
  • Alanine aminotransferase (ALT) >=1.5 times upper limit of normal (ULN). A single repeat of ALT is allowed within a single Screening period to determine eligibility.
  • Bilirubin >=1.5 times ULN (isolated bilirubin >=1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). A single repeat of any laboratory abnormality is allowed within a single Screening period to determine eligibility.
  • Any acute laboratory abnormality (including hypokalemia, hypercalcemia, or hypomagnesemia) at Screening which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.
  • Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of lipid abnormalities (e.g., total cholesterol, triglycerides), and ALT (previously described), will exclude a participant from the study unless the investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the sponsor. A single repeat of any laboratory abnormality is allowed within a single Screening period to determine eligibility.
  • Urine drug screen positive (showing presence of): amphetamines, barbiturates, cocaine, Methylenedioxymethamphetamine (MDMA), cannabinoids, methamphetamines, phencyclidine, or non-prescribed opiates, oxycodone, benzodiazepines, methadone, or tricyclic antidepressants at screening or before dosing of study intervention.
  • Unable to refrain from the use of prescription or nonprescription drugs including vitamins, herbal and dietary supplements (including Saint [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 intervention and for the duration of the study.
  • Treatment with any vaccine within 30 days prior to receiving study intervention.
  • Unwillingness to abstain from consumption of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days prior to the first dose of study intervention(s) until the end of the study.
  • Participation in another concurrent clinical study or prior clinical study (with the exception of imaging trials) prior to the first dosing day in the current study: 30 days, 5 half-lives, or twice the duration of the biological effect of the study intervention (whichever is longer).
  • Prior exposure to GSK3640254 in this or another clinical study.
  • Prior intolerance to Moxifloxacin.
  • Prior participation in this clinical study (participants may not participate in both Part 1 and Part 2 of the study).
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
  • Any positive (abnormal) response confirmed by the investigator on a screening clinician- or qualified designee-administered Columbia-Suicide Severity Rating Scale (C-SSRS).
  • A sustained supine systolic blood pressure >150 millimeters of mercury (mm Hg) or <90 mm Hg or a supine diastolic blood pressure >95 mm Hg or <50 mm Hg at Screening or Check-in (Day -2). Blood pressure may be retested once in the supine position. The blood pressure abnormality is considered sustained if either the systolic or the diastolic pressure values are outside the stated limits after 2 assessments, in which case the participant may not be randomized.
  • A resting HR of <50 bpm or >100 bpm when vital signs are measured at Screening or Check-in (Day -2). A HR from 100 to 110 bpm can be rechecked by ECG or vital signs within up to 2 hours to verify eligibility.
  • An uninterpretable ECG or any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the past 3 months, significant pathological Q-waves (defined as Q-wave >40 ms or depth greater than 0.4-0.5 millivolts [mV], symptomatic bradycardia, non-sustained or sustained atrial arrhythmias, ventricular pre-excitation, non-sustained or sustained ventricular tachycardia, any degree of atrioventricular block, complete left bundle branch block, or conduction abnormality) which, in the opinion of the investigator or VH/GSK Medical Monitor, will interfere with the safety of the individual participant.
  • Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility determination):

    (i) HR: <50 or >100 bpm (ii) QTcF interval1: >450 ms (iii) QRS interval: >110 ms (iv) PR interval: >200 ms

  • Screening Holter (24 hours) with any of the following:

    (i) Sinus bradycardia less than or equal to (<=)35 bpm or junctional arrhythmia >60 bpm for 10 seconds or longer.

(ii) Non-sustained ventricular tachycardia or more than 30 ventricular premature depolarizations during an hour.

(iii) Atrial arrhythmia >100 bpm for 3 seconds or longer or more than 40 atrial premature depolarizations during an hour.

  • History of alcoholism and/or drug/chemical abuse or regular alcohol consumption within 6 months of screening, defined as an average weekly intake of >14 units. One unit is equivalent to 8 grams of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 (25 mL) measure of spirits.
  • Unable to refrain from tobacco or nicotine-containing products within 3 months prior to Screening and for the duration of the study.
  • History of sensitivity to any of the study medications or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04563845


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Sponsors and Collaborators
ViiV Healthcare
Investigators
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Study Director: GSK Clinical Trials ViiV Healthcare
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Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT04563845    
Other Study ID Numbers: 213053
First Posted: September 25, 2020    Key Record Dates
Last Update Posted: September 25, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the 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 can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ViiV Healthcare:
GSK3640254
Moxifloxacin
Electrocardiogram
Cardiac Conduction
Supratherapeutic dose
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Moxifloxacin
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents