This is a Phase 3 study (efficacy, safety and tolerability study) of two experimental drugs against HIV 1 infection.

The full names are:

1. Cabotegravir Long Acting (Oral and Parenteral)

2. Rilpivirine Long Acting (Oral and Parenteral)

This study is also known as CARES

The study Drugs are developed by ViiV Healthcare’s group of companies who make the Cabotegravir Combination and Janssen Research & Development, a division of Janssen Pharmaceutical NV who make the Rilpivirine combination

The combination regimen has been developed for maintenance of viral suppression (HIV-1 RNA <50 copies/mL) in HIV-1 infected individuals previously treated with standard-of-care antiretroviral therapy.

The study will enroll about 512 participants in three sites in Africa that is Kenya, Uganda and South Africa.

The purpose of the study is to learn if:

The study drug is not worse than the active standard of care treatment available for HIV

The study drugs are safe, effective and tolerable

The study drug make people adhere to medication

The study drug can maintain viral suppression after switching from the standard of care treatment ARV’S

The study drug can cause viral resistance to those participating in the study

Phase 3b, Randomized, Multicenter, Open-Label Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Long-Acting Cabotegravir Plus Long-Acting Rilpivirine From Current Antiretroviral Regimen in HIV-1 Infected, Virologically Suppressed Adults in Sub-Saharan Africa

Cabotegravir And Rilpivirine: Efficacy and Safety (CARES) Study

Long-acting (LA) injectable therapy for the treatment of Human Immunodeficiency Virus (HIV)-1 infection offers a reduced dosing frequency and an additional option to the currently available two-drug oral combinations. A parenteral LA formulation of rilpivirine (RPV) for intramuscular (IM) injection in combination with ViiV Healthcare’s parenteral. LA formulation of the integrase inhibitor cabotegravir (CAB) may offer a better tolerability and resistance profile, as well as improved adherence and treatment satisfaction in virologically suppressed patients. The combination regimen has been developed for maintenance of viral suppression (HIV-1 RNA <50 copies/mL) in HIV-1 infected individuals previously treated with standard-of-care antiretroviral therapy.

OBJECTIVES

Primary

• To demonstrate the non-inferior antiviral activity of switching to IM RPV LA+CAB LA administered every 2 months compared with continuation of cART administered daily over 12 months in HIV-1 infected participants in a resource limited setting.

Secondary

• To demonstrate the antiviral and immunologic activity of switching to IM RPV LA+CAB LA every 2 months compared to continuation of cART over 12 and 24 months of follow-up
• To evaluate the safety and tolerability of switching to RPV LA+CAB LA every 2 months compared to continuation of cART.
• To assess viral resistance in participants experiencing protocol-defined confirmed virologic failure (plasma HIV-1 RNA ≥200 c/mL).
• To assess the incidence of on-treatment genotypic resistance to CAB, RPV and other on-study cART up to Month 12 and 24.
• To evaluate adherence to treatment.

Hypothesis

The antiviral effect of switching to RPV LA+CAB LA is non-inferior (margin -10%) to continuation of first-line treatment with daily triple drug oral cART at Month 12 in HIV-1

infected, virologically suppressed participants.

OVERALL DESIGN

CARES is a randomized, open-label, active-controlled, multicenter, interventional study in virologically

suppressed (<50 c/mL) HIV-1 infected adult participants to demonstrate that the antiviral effect of

switching to IM RPV LA+CAB LA is non-inferior to continuation of first-line cART containing 2

non-nucleoside reverse transcriptase inhibitor (NRTIs; tenofovir [TDF] plus either lamivudine [3TC] or

emtricitabine [FTC]) plus an INI (dolutegravir [DTG]) or a non-nucleoside reverse transcriptase inhibitors

(NNRTI) (efavirenz [EFV] or nevirapine [NVP]) at Month 12. After providing written informed consent,

participants will be evaluated for eligibility during the 28-day screening period. On Day 1, participants will

be randomized to either continue cART or to discontinue cART and begin therapy with RPV LA+CAB LA

administered every 2 months. Baseline assessments will be performed on Day 1. Participants randomized

to the RPV LA+CAB LA group will be given the option of a 4-week Oral Lead-in (OLI) Phase with oral

RPV and oral CAB, or to directly receive the injectable RPV LA+CAB LA. This decision to dose with or

without an OLI Phase will be determined by the study participant following informed consent discussions

with the investigator.

Starting Day 1, the total duration of the study will be 24 months. Any participant who has received at least

a single dose of RPV LA+CAB LA and discontinues the regimen for any reason before Month 24 must

start suppressive cART within 2 months of the last LA injection. Investigators must discuss the choice of

the follow-up cART regimen with the lead scientist/chief investigator prior to initiating the new regimen

with the participant. The participants must remain in the study unless consent is withdrawn, and complete

their scheduled assessments up to the Month 24 visit.

NUMBER OF PARTICIPANTS

A target of 512 participants will be enrolled in this study and randomized 1:1 to continue cART or switch

to the RPV LA+CAB LA for a treatment period of 24 months. Participants will be recruited across 8 sites

from 3 countries (3 sites in Uganda, 3 sites in Kenya and 2 sites in South Africa).

INTERVENTION GROUPS AND DURATION

The interventions received are as follows:

cART Group: Participants will take a regimen of 2 NRTIs (TDF 300 mg + [3TC 300 mg/FTC 200 mg]) +

DTG (50 mg)/EFV (600 mg)/NVP (200 mg), as a single tablet or Fixed-Dose Combination regimen as per

local country guidelines up to Month 24. Participants will be permitted to switch cART drugs in case of

toxicity or for treatment optimization and convenience after viral load testing.

RPV LA+CAB LA Group: The participants who opt for the OLI Phase will receive the study intervention

in 2 phases:

Oral Lead-in Phase : Starting on Day 1, participants will receive RPV 25 mg + CAB 30 mg once daily for

4 weeks to be taken at approximately the same time each day with a meal. The purpose of the optional

OLI Phase is to allow an opportunity, when desired, for participants to assess tolerability of the combination

prior to administration of RPV LA+CAB LA.

Maintenance Phase: After the 4-week OLI Phase, participants will return for the Month 1 visit to take the

last dose of oral CAB+RPV at the study-site, and to receive the first IM RPV LA 900 mg + CAB LA

600 mg initiations injections. The second initiation injections with RPV LA 900 mg + CAB LA 600 mg

will be administered at Month 2, and then continuation injections will be administered every 2 months

thereafter.

Participants who opt for direct RPV LA+CAB LA (ie, without the OLI Phase) injections will remain on

cART for 4 weeks after randomization on Day 1, and will receive the first initiation injection of

RPV LA+CAB LA at the Month 1 visit. The second initiation injections with RPV LA+CAB LA will be

administered at Month 2, followed by continuation injections of RPV LA+CAB LA every 2 months

thereafter.

The total duration of the study will be 24 months. At the end of their participation in the study, participants

from the RPV LA+CAB LA group who have completed the study and are benefiting from the study

intervention, as determined by their investigator, will be able to receive continued access to both CAB LA

and RPV LA up to 2 years after study completion or until the participant no longer derives clinical benefit,

the participant meets a protocol-defined reason for discontinuation, until RPV LA and CAB LA are

registered and reimbursed in the country, or until either CAB LA or RPV LA development program is

terminated, whichever occurs earlier. The participant will then be transitioned to a SOC regimen based on

the investigator’s clinical judgment and local country guidelines. Participants in the cART group will