| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus Type-1 (HIV-1) |
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| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 antiviral efficacy of GSK3640254 + DTG, relative to DTG + 3TC at Week 24 in HIV-1 infected, ART-naïve participants |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the antiviral activity of GSK3640254 + DTG relative to DTG + 3TC at Week 48;
• To evaluate safety and tolerability of GSK3640254 when given in combination with DTG, relative to DTG + 3TC;
• To assess the development of viral resistance to GSK3640254 and other on-study ART in participants experiencing virologic failure through Week 48;
• To assess the steady-state exposure of GSK3640254 when given in combination with DTG. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age:
1. Participants must be 18 years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics:
2. Treatment-naïve, defined as no ARVs (in combination or monotherapy) received after a known diagnosis of HIV-1 infection;
NOTE: Use of PrEP (prior to known HIV-1 infection) is allowed and still meets inclusion. PrEP is used by individuals who are not infected with HIV-1 but who are at high risk for acquiring the virus. PrEP alone is not sufficient to treat HIV and the use of PrEP is stopped if/when a diagnosis of HIV is made.
3. Documented HIV infection and Screening plasma HIV-1 RNA ≥1000 c/mL;
4. Screening CD4+ T-cell count ≥300 cells/mm3;
Weight:
5. Body weight ≥50.0 kg (110 lbs.) for men and ≥45.0 kg (99 lbs) for women and body mass index (BMI) > 18.5 kg/m2. Calculations will utilize sex assigned at birth;
Sex:
Sex and Contraceptive/Barrier Requirements:
6. Male and female
a. Participants who are male at birth: There are no contraceptive requirements for participants who are male at birth
b. Participants who are female at birth:
Contraceptive use by participants who are female at birth should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• A participant who is female at birth is eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies:
o Is not a participant of childbearing potential (PONCBP) as defined in Section 10.4.
OR
o Is a POCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in Section 10.4 during the study intervention period and until after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
o If a hormonal method is selected, the participant is required to be clinically stable on it for at least one month prior to starting treatment in the study.
• A POCBP must have a negative highly sensitive serum pregnancy test at Screening and a negative urine pregnancy test at Day 1 before starting study intervention .
o If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are located in Section 8.2.5 Pregnancy Testing.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a participant with an early undetected pregnancy Informed Consent:
7. Capable of giving signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Other:
8. 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.
|
|
| E.4 | Principal exclusion criteria |
1. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring systemic therapy;
2. 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;
3. Presence of primary HIV infection, evidenced by acute retroviral syndrome (e.g., fever, malaise, fatigue, etc) and/or evidence of recent (within 3 months) documented viremia without antibody production and/or evidence of recent (within 3 months) documented seroconversion;
4. Known history of liver cirrhosis with or without viral hepatitis co-infection;
5. Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment)
6. History of ongoing or clinically relevant hepatitis within the previous 6 months;
7. History of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation;
8. Any history of significant underlying psychiatric disorder, in the opinion of the Investigator or Medical Monitor, including but not limited to schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder; or a clinical assessment of suicidality based on the responses on the CSSRS.
9. 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 (>6 months) outpatient treatment;
10. Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the Investigator or Medical Monitor (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;
11. A pre-existing condition, in the opinion of the Investigator or Medical Monitor, that could interfere with normal gastrointestinal anatomy or motility (e.g., gastroesophageal reflux disease [GERD], gastric ulcers, gastritis, inflammatory bowel disease), hepatic and/or renal function, or with the absorption, metabolism, and/or excretion of the study interventions or render the participant unable to take oral study treatment;
12. Myocardial infarction, acute coronary syndrome, unstable angina, stroke, transient ischemic attack, or intermittent claudication in the past 3 months;
13. Familial or personal history of long QT syndrome or sudden cardiac death;
14. Medical history, current or historical, of significant cardiac arrhythmias or ECG findings which, in the opinion of the Investigator or Medical Monitor, will interfere with the safety of the participant;
15. Active treatment for a viral infection other than HIV-1, such as Hepatitis B, with an agent that is active against HIV-1 (were known to be infected with HIV-1 after treatment for Hepatitis B was completed);
16. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
17. Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, any systemic immune suppressant;
18. Participants receiving any protocol-prohibited medication and who are unwilling or unable to switch to an alternate medication;
19. Participants who require concomitant medications known to be associated with a prolonged QTc.
20. Exposure to an experimental drug, human blood product, monoclonal antibody, or vaccine (which does not have emergency, conditional, or standard market authorization) within 28 days prior to the first dose of study treatment;
21. Current enrollment or past participation within the last 30 days before signing of consent in any other clinical study involving an investigational study intervention (including an investigational COVID vaccine) or any other type of medical research.
22. Historical evidence (prior to study screening period) of the presence of resistance-associated mutations gag A364V or A364A/V
23. Creatinine Clearance <50 mL/min;
24. ALT ≥ 3x ULN or ALT ≥ 2x ULN and total bilirubin ≥ 1.5x ULN (upper limit of normal);
25. Evidence of Hepatitis B virus (HBV) infection based on the results of testing for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antibody (anti-HBs) and reflex HBV DNA;
For full list of exclusion criteria, please refer to the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 24 using the FDA snapshot algorithm |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 48 using the FDA snapshot algorithm;
• Absolute values and changes from baseline in HIV-1 RNA through Weeks 24 and 48;
• Absolute values and changes from baseline in CD4+ T-cell counts through Weeks 24 and 48;
• Frequency of SAEs, Deaths and AEs leading to Discontinuation through Weeks 24 and 48;
• AEs of special interest (AESIs) through Weeks 24 and 48;
• Changes in genotypic and/or phenotypic profiles of virus compared to baseline;
• The steady-state plasma PK parameters of GSK3640254 will be assessed based on Sparse PK sampling through Week 48
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the time period specified in E.5.2 Secondary end point section. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Resistance profile, Viral Genotyping and Phenotyping Analyses |
|
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
| Canada |
| Puerto Rico |
| Russian Federation |
| South Africa |
| United States |
| France |
| Germany |
| Italy |
| Poland |
| Portugal |
| Spain |
| Argentina |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if the participant has completed all phases of the study including the last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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