| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of human immunodeficiency virus-1 (HIV-1) |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of human immunodeficiency virus-1 (HIV-1) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the antiviral activity of GSK3640254 in HIV-1-infected participants during 10 days of monotherapy |
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| E.2.2 | Secondary objectives of the trial |
•To assess the safety and tolerability of GSK3640254 when administered as monotherapy over 10 days in HIV-1 infected participants
•To characterize the pharmacokinetics of GSK3640254 dosing for 10 days in HIV-1 infected patients
•To explore the relationship between GSK3640254 exposure and change in plasma HIV-1 RNA
•To estimate GSK3640254 accumulation following administration of GSK3640254 for 10 days in HIV-1 infected patients.
•To examine dose proportionality of GSK3640254 PK parameters following dosing for 10 days |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2.Participants who are healthy (other than HIV infection) as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, laboratory tests, and cardiac monitoring.
3.Screening CD4+ T-cell count ≥350 cells/mm3
4.Documented HIV infection and Screening plasma HIV-1 RNA ≥5000 copies/mL. A single repeat of this test is allowed within a single Screening period to determine eligibility.
5.Treatment-naïve: No ARVs (in combination or monotherapy) received after the diagnosis of HIV-1 infection.
Weight
6.Body weight ≥50.0 kg (110 lbs.) for men and ≥45.0 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive).
Sex
7.Male or female:
a.Male participants:
A male participant with a female partner of child-bearing potential or who is breastfeeding or pregnant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment phase 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 participants must refrain from donating sperm during this period.
b.Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 5 of protocol ), not breastfeeding, and not a woman of childbearing potential (WOCBP) as defined in Appendix 5 of protocol.
Informed Consent
8.Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and stated in the protocol.
Other
9.For participants enrolled in France: a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
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|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to starting study treatment
2.Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment AND positive on reflex to Hepatitis C RNA
•NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C RNA test is obtained (central lab will automatically reflex to HCV RNA on positive HCVAb)
3.Alanine aminotransferase (ALT) >2 x upper limit of normal (ULN). A single repeat of ALT is allowed within a single Screening period to determine eligibility.
4.Bilirubin >1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
5.Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones);
6.A pre-existing condition interfering with normal gastrointestinal anatomy or motility (e.g., gastroesophageal reflux disease [GERD], gastric ulcers, gastritis), hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs or render the subject unable to take oral study treatment.
7.Any acute laboratory abnormality at screen which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.
8.Any Grade 2-4 laboratory abnormality at Screen, with the exception of creatine phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides, etc), and ALT (described above), 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 lab abnormality is allowed within a single Screening period to determine eligibility.
9.Any pre-existing physical or 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.
10.Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
Prior/Concomitant Therapy
11.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.
Prior/Concurrent Clinical Study Experience
12.The participant has participated in a clinical trial and has received an investigational product within the 30 days prior to the first dosing day in the current study.
Diagnostic assessments
13.Any positive (abnormal) response confirmed by the investigator on a Screening clinician- (or qualified designee-) administered C-SSRS.
14.Any positive result for illicit drug use (e.g., cocaine, heroin) at Screening. A positive screen for marijuana is not exclusionary, though if positive for THC, see Section 6.3.2 for guidance to be given to the participant.
15.Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
16.Exposure to more than four new investigational drugs or vaccines within 12 months prior to the first dosing day.
17.Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or anticipated need for such treatment within the study.
18.Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; or other localized malignancies require agreement between the investigator and the study medical monitor for inclusion of the subject prior to randomization.
19.Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration.
20.An active Center for Disease Control and Prevention (CDC) Category C disease except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the trial.
21.Treatment with any vaccine within 30 days prior to receiving study medication.
Refer other exclusion points mentioned in the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Maximum change from baseline (Day 1) in plasma HIV-1 ribonucleic acid (RNA) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
GSK3640254 safety and tolerability parameters: adverse events(AE); post-baseline values and changes over time of clinical laboratory evaluations, vital signs, and electrocardiogram (ECG) parameters
• GSK3640254 PK parameters at the following dose administration:
Day 1: area under the plasma concentration time curve from zero to 24 (AUC [0-24]), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), concentration at 24 hours post dose (C24), absorption lag time (tlag)
Following repeat administration: Area under the curve (Area under the plasma drug concentration-time curve from pre-dose to the end of the dosing interval at steady state (AUC [0-τ]), Cmax, tmax, pre-dose concentration (C0), concentration at end of dosing interval (Cτ), apparent terminal phase half-life (t1/2), and apparent oral clearance (CL/F), if data permit.
GSK3640254 repeat-dose PK parameters AUC(0-τ), Cmax, Cτ with maximum HIV-1 RNA change from baseline
Accumulation: GSK3640254 PK accumulation ratios (R): repeat -dose AUC (0-τ), Cmax, and Cτ compared to Day 1 AUC (0-24), Cmax, C24, respectively
Relationship between Day 1 AUC (0-24), Cmax, C24, and repeat-dose AUC (0-τ), Cmax and Cτ and GSK3640254 dose levels
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Russian Federation |
| South Africa |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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