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GSK3640254 First Time in Human (FTIH) Study in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT03231943
Recruitment Status : Completed
First Posted : July 27, 2017
Last Update Posted : September 14, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
Human immuno deficiency virus 1 (HIV-1) infections continues to be a serious health threat throughout the world and development of medicines with new mechanism of action have an important role to play. GSK3640254 is a maturation inhibitor (MI) and can be effective in HIV-1 treatment. This randomized, 2-part, single and repeat increasing dose study will collect information on safety, tolerability and drug levels in the body of in healthy subjects for GSK3640254. The information collected in this study will help in further clinical development of GSK3640254, including a Phase IIA Proof of Concept (PoC) study in HIV-infected subjects. Approximately 16 healthy subjects will be randomized to receive single oral dose of GSK3640254 and placebo in Part 1 and approximately 56 healthy subjects will be randomized to receive repeat oral dose of GSK3640254 or placebo in Part 2. All doses will be given immediately after a moderate fat meal. Maximum duration of study participation will be approximately 12 weeks.

Condition or disease Intervention/treatment Phase
Infection, Human Immunodeficiency Virus Drug: GSK3640254 Drug: Placebo Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This is a dose-escalation study and dose will be escalated based on the safety data of the initial dose.
Masking: Double (Participant, Investigator)
Masking Description: This will be a double-blind study with subjects and the site-staff blinded and sponsor unblinded.
Primary Purpose: Treatment
Official Title: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK3640254 in Healthy Participants
Actual Study Start Date : September 19, 2017
Actual Primary Completion Date : September 5, 2018
Actual Study Completion Date : September 9, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Subjects in cohort 1-2: Part 1
Eligible subjects will participate in cohort 1 or 2 and each of these two cohorts will contain up to four escalating doses of GSK3640254. In each cohort, 6 subjects will be randomized to receive single oral dose of GSK3640254 and 2 subjects will be randomized to receive placebo. Hence, each subject in cohort 1 and 2 will receive up to 3 escalating doses of GSK3640254 and one placebo in crossover manner.
Drug: GSK3640254
GSK3640254 is a capsule available in 1 milligram (mg), 10 mg and 100 mg dosing strength. GSK3640254 capsule will be given via oral route during each dosing day with approximately 240 mL of water.

Drug: Placebo
Placebo capsule matching to the study treatment will be given via oral route during each dosing day with approximately 240 mL of water.

Experimental: GSK3640254 receivers (cohort 3-6 and expansion): Part 2
Eligible subjects will participate in one of the 4 cohorts (3,4,5,6). In each cohort, 6 subjects will be randomized to receive a once-daily oral dose of GSK3640254 for 14 days. After the safety data of cohort 3-6 is available, 18 eligible subjects will be randomized to receive once daily oral dose of GSK3640254 for 14 days in expansion cohort.
Drug: GSK3640254
GSK3640254 is a capsule available in 1 milligram (mg), 10 mg and 100 mg dosing strength. GSK3640254 capsule will be given via oral route during each dosing day with approximately 240 mL of water.

Placebo Comparator: Subjects receiving placebo (cohort 3-6): Part 2
Eligible subjects will participate in one of the 4 cohorts (3,4,5,6). In each cohort, 2 subjects will be randomized to receive a once-daily oral dose of placebo for 14 days. After the safety data of cohort 3-6 is available, 6 eligible subjects will be randomized to receive once daily oral dose of placebo for 14 days in expansion cohort.
Drug: Placebo
Placebo capsule matching to the study treatment will be given via oral route during each dosing day with approximately 240 mL of water.




Primary Outcome Measures :
  1. Number of subjects with adverse events (AEs) and serious AEs (SAEs): Part 1 [ Time Frame: Up to Week 14 ]
    An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

  2. Number of subjects with abnormal laboratory findings: Part 1 [ Time Frame: Up to Week 14 ]
    Serum chemistry, hematology and urine analysis parameters will be evaluated for single dose of GSK3640254

  3. Number of subjects with abnormal vital sign values: Part 1 [ Time Frame: Up to Week 14 ]
    Vital signs including tympanic temperature, pulse rate, respiratory rate and systolic and diastolic blood pressure will be evaluated for single dose GSK3640254.

  4. Number of subjects with abnormal electrocardiogram (ECG) findings: Part 1 [ Time Frame: Up to Week 14 ]
    12-lead ECGs will be obtained at each time point and number of subjects with abnormal ECG findings will be evaluated for single dose of GSK3640254.

  5. Number of subjects with adverse events (AEs) and serious AEs (SAEs): Part 2 [ Time Frame: Up to 4 weeks in each cohort ]
    An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

  6. Number of subjects with abnormal laboratory findings: Part 2 [ Time Frame: Up to 4 weeks in each cohort ]
    Serum chemistry, hematology and urine analysis parameters will be evaluated for repeat dose of GSK3640254.

  7. Number of subjects with abnormal vital sign values: Part 2 [ Time Frame: Up to 4 weeks in each cohort ]
    Vital signs including tympanic temperature, pulse rate, respiratory rate and systolic and diastolic blood pressure will be evaluated for repeat dose of GSK3640254.

  8. Number of subjects with abnormal ECG findings: Part 2 [ Time Frame: Up to 4 weeks in each cohort ]
    12-lead ECGs will be obtained at each time point and number of subjects with abnormal ECG findings will be evaluated for repeat dose of GSK3640254.


Secondary Outcome Measures :
  1. Area under the plasma concentration time curve (AUC) from zero to 24 hour (AUC[0-24]) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the Pharmacokinetic (PK) profile of GSK3640254 given as a single dose.

  2. AUC from zero to time of last sample taken (AUC[0-Tlast]) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  3. AUC from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  4. Maximum observed concentration (Cmax) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  5. Concentration of GSK3640254 at 24 hours (C24): Part 1 [ Time Frame: 24 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  6. Time of occurrence of Cmax (Tmax) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  7. Lag time (Tlag) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  8. Apparent terminal phase half-life (T1/2) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  9. Last measurable concentration (Clast) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  10. Time to reach Clast (Tlast) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  11. Apparent oral clearance (CL/F) of GSK3640254: Part 1 [ Time Frame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24,48,72 and 96 hours post-dose in each treatment period for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as a single dose.

  12. AUC(0-24) of GSK3640254: Part 2 Day 1 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose on Day 1 for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given on Day 1.

  13. Cmax of GSK3640254: Part 2 Day 1 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose on Day 1 for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given on Day 1.

  14. C24 of GSK3640254: Part 2 Day 1 [ Time Frame: 24 hours post-dose on Day 1 for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given on Day 1.

  15. Tmax of GSK3640254: Part 2 Day 1 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose on Day 1 for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given on Day 1.

  16. Tlag of GSK3640254: Part 2 Day 1 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose on Day 1 for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given on Day 1.

  17. AUC from pre-dose to the end of the dosing interval at steady state (AUC[0-tau): Part 2 Day 14 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as repeat dose.

  18. Cmax of GSK3640254: Part 2 Day 14 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as repeat dose.

  19. Plasma trough concentration (Ctau) of GSK3640254: Part 2 Day 14 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as repeat dose.

  20. Tmax of GSK3640254: Part 2 Day 14 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as repeat dose.

  21. T1/2 of GSK3640254: Part 2 Day 14 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as repeat dose.

  22. Cl/F of GSK3640254: Part 2 Day 14 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose for each cohort ]
    Blood sample will be collected at given time points to study the PK profile of GSK3640254 given as repeat dose.

  23. Accumulation ratio of AUC(0-tau) (R [AUC{0-TAU}]): Part 2 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours post-dose on Day 14 for each co ]
    Accumulation will be evaluated for each treatment by determining the ratio of Day 14 (Part 2) to Day 1 for AUC (0-tau).

  24. Accumulation ratio of Cmax (R [CMAX]): Part 2 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours post-dose on Day 14 for each cohort ]
    Accumulation will be evaluated for each treatment by determining the ratio of Day 14 (Part 2) to Day 1 for Cmax

  25. Accumulation ratio of C(tau) (R[CTAU]): Part 2 [ Time Frame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours post-dose on Day 14 for each cohort ]
    Accumulation will be evaluated for each treatment by determining the ratio of Day 14 (Part 2) to Day 1 for C(tau)

  26. Pre-dose concentration of GSK3640254: Part 2 [ Time Frame: Pre-dose on Days 2,3,4,6,8,10,12 and 14 for each cohort ]
    Attainment of steady-state will be assessed by estimating the slope of pre-dose concentrations for GSK3640254 on Days 2-14 (Part 2)



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.


Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
  • Subjects who are overtly healthy as determined by medical evaluation including medical history and psychiatric history, physical examination, laboratory tests, and 24 hour Holter monitoring.
  • Body weight >=50.0 kilogram (kg) (110 pounds) for men and 45.0kg (99 pounds) for women and body mass index (BMI) within the range 18.5-32.0 kg per meter square (kg/m^2) (inclusive).
  • Male or female subjects. A male subject must agree to use contraception during the treatment period and for at least 14 weeks following the last dose, corresponding to the time needed to eliminate study treatment for potential genotoxic and teratogenic study treatments plus an additional 90 days (spermatogenesis cycle). In addition, male subjects must refrain from donating sperm during this period. A female subject is eligible to participate if she is not a woman of childbearing potential (WOCBP).
  • Capable of giving signed informed consent.

Exclusion Criteria:

  • Alanine transaminase (ALT) >1.5 into upper limit of normal (ULN).
  • Bilirubin >1.5 into ULN (isolated bilirubin >1.5 into ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
  • Pre-existing clinically relevant, in the opinion of the primary investigator (PI), gastro-intestinal pathology or diagnosis - example irritable bowel syndrome, inflammatory bowel disease, and/or significant Baseline signs and symptoms.
  • Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
  • Any known or suspected pre-existing psychiatric condition.
  • Any other clinical condition (including but not limited to active substance use) or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study; unable to comply with dosing requirements; or unable to comply with study visits; or a condition that could affect the absorption, distribution, metabolism or excretion of the drug.
  • Unable to refrain from the use of prescription or non-prescription drugs (with the exception of paracetamol), 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 and for the duration of the study, unless in the opinion of the Investigator and ViiV Healthcare Sponsor and medical monitor, the medication will not interfere with the study medications, procedures, or compromise subject safety.
  • Unwillingness to abstain from ingestion of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos within 7 days prior to the first dose of study treatment(s) or 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 investigational product (whichever is longer).
  • Where participation in the study would result in donation of blood or blood products in excess of 500 milliliter (mL) within 56 days.
  • Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
  • A positive pre-study drug/alcohol screen.
  • A positive test for a diagnostic HIV-1 polymerase chain reaction (PCR).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • Exclusion criteria for screening ECG: Heart rate <45 or >100 beats per minute (bpm) for males and <50 or >100 bpm for females; PR interval <120 or >220 millisecond (msec); QRS duration <70 or >120 msec; the Fridericia's QT correction formula (QTcF) interval >450 msec.
  • Evidence of previous myocardial infarction (does not include ST segment changes associated with re-polarization).
  • Any conduction abnormality (including but not specific to left or right complete bundle branch block, Atrioventricular block [2nd degree or higher], Wolff-Parkinson-White [WPW] syndrome).
  • Sinus Pauses >3 seconds.
  • Any significant arrhythmia which, in the opinion of the Investigator or GlaxoSmithKline/ViiV medical monitor, will interfere with the safety for the individual subject.
  • Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular ectopic beats).
  • History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 gram of alcohol: a half-pint approximately 240 mL of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • Regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
  • 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): NCT03231943


Locations
United Kingdom
GSK Investigational Site
Cambridge, United Kingdom, CB2 2GG
Sponsors and Collaborators
ViiV Healthcare
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT03231943     History of Changes
Other Study ID Numbers: 207187
First Posted: July 27, 2017    Key Record Dates
Last Update Posted: September 14, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ViiV Healthcare:
FTIH
Healthy
Tolerability
Dose-escalation
HIV-1
Safety
PK
GSK3640254
Maturation inhibitor

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases