| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HIV-1-infected adult participants |
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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 | 10008922 |
| E.1.2 | Term | Chronic infection with HIV |
| 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 select an intramuscular dosing regimen of CAB LA plus RPV LA based on a comparison of the Week 32 antiviral activity, tolerability, and safety of two IM dosing regimens, relative to CAB 30 mg plus ABC/3TC orally once daily. |
|
| E.2.2 | Secondary objectives of the trial |
* Evaluate antiviral activity,tolerability,safety of CAB 30mg + ABC/3TC orally once daily through Induction and Maintenance Periods.
*Evaluate efficacy,tolerability,safety of CAB LA 400mg IM + RPV LA 600mg IM every 4 weeks and CAB LA 600mg IM + RPV LA 900mg every 8 weeks, relative to CAB 30mg + ABC/3TC orally once daily in maintenance Period.
*Characterize CAB LA and RPV LA PK to explore PK-PD relationships.
* Evaluate change in treatment satisfaction for participants in both the long-acting injectable and oral regimens through Week 32 of Maintenance Period.*
Assess development of viral resistance in participants experiencing protocol defined virologic failure.
* Explore the effect of various demographic Baseline characteristics and adherence on virologic response of CAB and RPV over time.
*Evaluate treatment satisfaction for participants on LA injectable regimens with those on oral regimen through Week 96 of the Maintenance Period.
*Evaluate medication adherence over time. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In general, participants screened for this study must:
* be able to understand and comply with protocol requirements, instructions, and restrictions,
* be likely to complete the study as planned,
* understand the long term commitment to the study,
* and be considered appropriate candidates for participation in an investigative clinical trial with oral and intramuscularly injectable medications (e.g., no active substance abuse, acute major organ disease).
Participants eligible for enrollment in the study must meet all of the following criteria:
1. HIV-1 infected participants ≥18 years of age.
2. A female participant is eligible to enter and participate in the study if she:
a. is of non-child-bearing potential defined as either 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 first day of the Induction Period and agrees to use one of the following methods of contraception to avoid pregnancy 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all oral study medications and for at least 52 weeks after discontinuation of CAB LA and RPV LA:
* Complete abstinence from intercourse (where this is the participant’s preferred and usual lifestyle).
* Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide).
* Approved hormonal contraception (see the SPM for a listing of examples of approved hormonal contraception).
* 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 study procedures manual [SPM] for specifics).
* Male partner sterilization prior to the female participant’s entry into the study, and this male is the sole partner for that participant.
* Any other method with published data showing that the lowest expected failure rate is <1% per year.
* Any contraception method must be used consistently and in accordance with the approved product label.
ALL participants participating in the study must be counseled on safer sexual practices including the use of effective barrier methods to minimize risk of HIV transmission.
3. HIV-1 infection as documented by Screening plasma HIV-1 RNA ≥1000 c/mL.
4. CD4+ cell count ≥200 cells/mm3 (or higher as local guidelines dictate).
5. ART-naive defined as having no more than 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection. Any previous exposure to an HIV integrase inhibitor or non-nucleoside reverse transcriptase inhibitor will be exclusionary.
French participants: 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 meeting any of the following criteria must not be enrolled:
1. Women who are breastfeeding.
2. Any evidence at screening of an active Centers for Disease and Prevention Control (CDC) Category C disease [Centers for Disease Control and Prevention (CDC), 1993], except cutaneous Kaposi’s sarcoma not requiring systemic therapy.
3. Participants with known moderate to severe hepatic impairment.
4. Any pre-existing physical or mental condition (including substance abuse disorder) which, in the opinion of the Investigator, may interfere with the participant’s ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant.
5. Participant who, in the investigator's judgment, poses a significant suicide risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk.
6. The participant has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.
7. History of ongoing or clinically relevant hepatitis within the previous 6 months, including chronic hepatitis B virus (HBV) infection (HBsAg positive).
8. Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; participants who are anticipated to require such therapy must be excluded.
9. History of liver cirrhosis with or without hepatitis viral co-infection.
10. Ongoing or clinically relevant pancreatitis.
11. History of the following cardiac diseases: myocardial infarction, congestive heart failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia.
12. Personal or known family history of prolonged QT syndrome.
13. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the participant unable to receive study medication.
14. History/presence of allergy or intolerance to the study drugs or their components or drugs of their class. In addition, if heparin is used during PK sampling, participants with a history of sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled.
15. Current or anticipated need for chronic anti-coagulation.
Exclusionary Laboratory Values at Screening (a single repeat to determine eligibility is allowed)
16. Any evidence of primary resistance based on the presence of any major resistanceassociated mutation [IAS-USA, 2013] in the Screening result or, if known, any historical resistance test result. Note: re-tests of Screening genotypes are allowed only at the discretion of the study virologist.
17. Any verified Grade 4 laboratory abnormality.
18. Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the participant’s participation in the study of an investigational compound.
19. Participant has estimated creatinine clearance <50 mL/min via Cockcroft-Gault [Cockcroft, 1976] method.
20. Alanine aminotransferase (ALT) ≥5 times ULN. Participants with ALT > 2xULN but <5xULN may participate in the study, if in the opinion of the Investigator and GSK medical monitor the lab abnormality will not interfere with the study procedures or compromise participant safety.
21. Alanine aminotransferase (ALT) ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin).
22. Any clinically significant finding on screening or Baseline electrocardiograph (ECG), specifically - Please refer to protocol section 4.3 (21)
23. Participants who are HLA-B*5701 positive and unable to use an alternative NRTI backbone (participants who are HLA-B*5701 positive may be enrolled if they use an alternative NRTI backbone that does not contain abacavir).
Exclusionary Treatments prior to Screening or First Day of Induction Period
24. Exposure to an experimental drug and/or experimental vaccine within 28 days or 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 IP.
25. Treatment with any of the following agents within 28 days of Screening:
* radiation therapy *cytotoxic chemotherapeutic agents
* tuberculosis therapy * Immunomodulators that alter immune responses (such as systemic corticosteroids, interleukins, or interferons) Note: Participants using short-term (<10 day) steroid tapers, topical, inhaled and intranasal corticosteroids are eligible for enrollment.
26. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
27. Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 within 28 days of the first dose of IP. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of participants with HIV-1 RNA <50 c/mL at Maintenance Week 32 based on intent to treat-maintenance exposed (ITT-ME) population using the Missing, Switch, or Discontinuation = Failure (MSDF) algorithm.
Proportion of participants with protocol defined virologic failures over time
Incidence and severity of AEs and laboratory abnormalities over time. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Maintenance Week 32 (following 20 Week Induction) |
|
| E.5.2 | Secondary end point(s) |
-Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL over time.
-Absolute values and change from Baseline in plasma HIV-1 RNA.
-Absolute values and changes from Baseline in CD4+ cell counts.
-Incidence of disease progression (HIVassociated conditions, acquired immunodeficiency syndrome [AIDS] and death).
-Incidence and severity of AEs and laboratory abnormalities over time.
-Absolute values and changes in laboratory parameters over time.
-Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL over time.
-Proportion of participants with protocol defined virologic failures over time.
-Absolute values and change from Baseline in plasma HIV-1 RNA.
-Absolute values and changes from Baseline in CD4+ cell counts.
-Incidence of disease progression (HIVassociated conditions, acquired immunodeficiency syndrome [AIDS] and death.
-Incidence and severity of AEs and laboratory abnormalities over time.
-Absolute values and changes in laboratory parameters over time.
-Plasma PK parameters for CAB LA and RPV LA (Ctrough and concentrations post dose [~Cmax]) during the Maintenance Period.
-Plasma CAB and RPV trough concentrations will be used to determine when steady state is achieved for each CAB LA and RPV LA regimen.
-Relationship between plasma PK parameters and plasma HIV-1 RNA, CD4+ cell counts and/or occurrence of adverse events [AEs] through Week 48 of the Maintenance Period will be explored.
-Incidence of treatment emergent genotypic and phenotypic resistance to CAB, RPV, and other on-study ART.
-Proportion of participants with plasma HIV-1 RNA <50 c/mL over time.
-Summarize treatment satisfaction using the HIV Treatment Satisfaction Questionnaire Status (HIVTSQ(s)) over time.
-Measure change in treatment satisfaction using the HIV Treatment Satisfaction Questionnaire Change (HIVTSQ(c)) over time.
-Summarize participant reported medication adherence using the HIV Medication Questionnaire (HIVMQ) over time. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints to be assessed at various timepoints in the study |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| CAB 30 mg plus ABC/3TC orally to IM regimens |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| France |
| Germany |
| Spain |
| United States |
|
| 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
|
LVLS but date depend on if/when CAB is approved and commercially available
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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