HIV-1 Infection

To demonstrate the non-inferior antiviral activity of switching to dolutegravir (DTG) plus rilpivirine (RPV) once daily compared to continuation of current antiretroviral regimen (CAR) over 48 weeks in HIV-1 infected antiretroviral therapy (ART)-experienced subjects

Dolutegravir、Rilpivirine

Dolutegravir
Rilpivirine

tablet

25
50

 The primary endpoint will be the proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot algorithm for the ITT-E population.

1. Main inclusion criteria:

Eligible subjects must:
• be able to understand and comply with protocol requirements, instructions, and restrictions;
• be likely to complete the study as planned;
• be considered appropriate candidates for participation in an investigative clinical trial with oral medication (e.g., no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country, etc.).

Source documentation to verify entry criteria must be reviewed by the Principal Investigator or designee prior to randomization. Source documents from other medical facilities must be located/received during the 14 day screening period (or up to 28 days) and under no circumstances may the subject be randomized in the absence of source documentation.
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. HIV-1 infected men or women ≥18 years of age;
2. Must be on uninterrupted current regimen (either the initial or second cART regimen) for at least 6 months prior to Screening
Any prior switch to a second cART regimen, defined as a change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability and/or safety concerns or access to medications, or convenience/simplification.
Acceptable stable cART regimens prior to Screening include 2 NRTIs plus:
• INI (either the initial or second cART regimen)
• NNRTI (either the initial or second cART regimen)
• Boosted PI (or atazanavir [ATV] unboosted) (must be initial cART regimen; one within class switch permitted for tolerability)
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening;
4. Plasma HIV-1 RNA <50 c/mL at Screening;
5. A female, may be eligible to enter and participate in the study if she:
a. is of non-child-bearing potential either defined as post-menopausal (12 months of spontaneous amenorrhea and ≥45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or,
b. is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:
• Complete abstinence from intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all study medications;
• Male condom/spermicide, male condom/diaphragm, diaphragm/spermicide;
• Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see the SPM for a listing describing criteria of approved IUDs);
• Male partner sterilization prior to the female subject’s entry into the study and this male is the sole partner for that subject;
• Approved hormonal contraception for subjects randomly assigned to DTG + RPV arm or approved hormonal contraception plus a barrier method for subjects assigned to CAR (see the SPM for a listing of examples of approved hormonal contraception);
• Any other method with published data showing that the expected failure rate is <1% per year.
Any contraception method must be used consistently, in accordance with the approved product label during treatment with IP and for at least 2 weeks after discontinuation of study drug.
All subjects participating in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.
6. Subject is willing and able to understand requirements of study participation and provide signed and dated written informed consent prior to Screening.
7. For subjects enrolled in France: a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

2. Main exclusion criteria:
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
Exclusionary Criteria prior to Screening or Day 1
1. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement 50 c/mL;
2. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL;
3. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, 2 or more plasma HIV-1 RNA measurements 50 c/mL;
4. Any drug holiday during the window between initiating first HIV ART and 6 months prior to Screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns;
5. Any switch to a second line regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV 1 RNA measurement 400 c/mL after initial suppression to <50 c/mL while on first line HIV therapy regimen);
Exclusionary medical conditions
6. Women who are pregnant, breastfeeding or plan to become pregnant during the study;
7. Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease. Exceptions include cutaneous Kaposi’s sarcoma not requiring systemic therapy and historic CD4+ lymphocyte counts of <200 cells/mm3;
8. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh Classification C
9. Unstable liver disease (as defined by the presence of any of the following: ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
10. 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), and antibodies against Hepatitis B surface antigen (anti-HBsAg) as follows:
• Subjects positive for HBsAg are excluded;
• Subjects positive for anti-HBc (negative HBsAg status) and negative for anti HBsAg are excluded.
11. Subjects with an anticipated need for any Hepatitis C virus (HCV) therapy during the Early Switch Phase and for interferon-based therapy for HCV throughout the entire study period;
12. History or presence of allergy to the study drugs or their components or drugs of their class;
13. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject prior to randomization;
14. Subjects who in the investigator’s judgment pose a significant suicidality risk. Subject’s history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk;
15. Any pre-existing physical or mental condition (including substance abuse disorder) which, in the opinion of the Investigator, may interfere with the subject’s ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the subject;
16. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the subject unable to take oral medication;
Exclusionary Treatments prior to Screening or Day 1
17. Use of medications which are associated with Torsades de Pointes. (See SPM for a list of relevant medications);
18. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
19. Treatment with any of the following agents within 28 days of Screening: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses (a list of examples is provided in the SPM);
20. Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of investigational product (IP);
21. Subjects who are currently participating in any other study or are anticipated to be selected to participate in any other interventional study after randomization (NOTE: subjects who are already enrolled into another interventional study at time of screening may be eligible after consultation with the GSK study team prior to randomization. Considerations include subject’s ability to attend all visits on schedule, and possible drug and study procedure compatibility);
22. A history of use of any regimen consisting of only single NNRTI therapy (even if only for peri-partum treatment), or only single or dual NRTI therapy prior to starting cART;
23. Current or prior history of ETR use;
24. Current use of tipranavir/ritonavir or fosamprenavir/ritonavir;
25. Subjects receiving any prohibited medication listed in Section Error! Reference source not found. and who are unwilling or unable to switch to an alternate medication. Note: Any prohibited medications listed in Section Error! Reference source not found. that decrease DTG or RPV concentrations should be discontinued for a minimum of four weeks or a minimum of three half-lives (whichever is longer) prior to the first dose and any other prohibited medications should be discontinued for a minimum of two weeks or a minimum of three half-lives (whichever is longer) prior to the first dose (see Section Error! Reference source not found. for details of prohibited medications);

Exclusionary Laboratory Values or Clinical Assessments at Screening
26. Evidence of viral resistance based on the presence of any resistance associated major PI, INI, NRTI, or NNRTI mutation [Error! Reference source not found., 2014] and integrase (IN) resistance associated substitution R263K in any available prior resistance genotype assay results;
Note: Any prior genotypic resistance testing must be provided to GSK, after screening and before randomization according to guidance in the SPM, to provide direct evidence of no pre-existing major resistance mutations. You must wait for the study virologists to confirm the lack of major resistance mutations, which will be provided before the screening window closes. Details regarding baseline or prior resistance data must be noted in the source documentation.
27. Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid abnormalities. A single repeat test is allowed during the Screening period to verify a result;
28. Any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the subject’s participation in the study of an investigational compound;
29. Alanine aminotransferase (ALT) 5 × ULN, or ALT 3 × ULN and bilirubin ≥1.5 × ULN (with >35% direct bilirubin);
30. Corrected QT interval (QTc (Bazett)) >450 msec or QTc (Bazett) >480 msec for subjects with bundle branch block.
The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB).
To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the IB and supplements, approved product labels, and/or local prescribing information for detailed information regarding warnings, precautions, contraindications, AEs, drug interactions, and other significant data pertaining to the study drugs.