| Protocol No: | ECCT/21/06/13 | Date of Protocol: | 22-11-2020 |
| Study Title: |
A 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
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| A 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 | ||||||||||
| A 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 | ||||||||||
| Study Objectives: |
Primary
Secondary
Exploratory
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| Laymans Summary: | A 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. 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 oral combinations. |
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| 1 | he protocol was amended to add additional exploratory endpoints to determine the prevalence of hepatitis B surface antibody (anti-HBs) positivity and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) among the study participants, and to provide the background and rationale on the same. Other changes included modifications to the inclusion and exclusion criteria and Schedule of Activities (SoA). | |||||||||
| 2 | The Amendment was done to provide clarity on the timepoints used in the protocol and details on continued access to the study intervention following the end of the study | |||||||||
| Abstract of 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
Secondary
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
continue to receive cART medications as part of the national program.
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| 1 | 1.1 synopsis 3 objectives and end Points The following exploratory objectives were added: - To determine the prevalence HBV DNA among participants on stable combination antiretroviral therapy (cART)containing nucleoside reverse transcriptase inhibitors (NRTI)who test negative for HBsAg and positive for hepatitis B core antibodies (anti-HBc)at screening. - To determine the prevalence of anti-HBs positivity among participants on stable cART containing NRTI who test negative for hepatitis B surface antigen (HBsAg)and positive for anti-HBc at screening. The following exploratory endpoints were added: - Proportion of participants who test negative for HBsAg and positive for anti-HBc with a detectable HBVviral load at screening. - Proportion of participants at screening who test positive for anti-HBs among those who test negative for HBsAg and positive for anti-HBc at screening Section 1.3 Schedule of Activities The following assessments were added to the SoA along with the corresponding footnotes: - Concomitant medication at Month 2 - Urine pregnancy test at Screening - Plasma storage at Screening: Footnote ‘k’ was added for plasma storage at screening: Plasma stored (4ml EDTA) at screening for batched testing for HBV DNA. - Serum storage at Screening: Footnote ‘l’ was added: serum stored (4ml redtop) at screening for batched testing for anti-HBs. To capture assessments that were omitted in the Schedule of Activities. - The HIV Treatment Satisfaction Questionnaire - Change (HIVTSc) was added to the table. - Medical resource utilization survey was added at Month 12 2.3.4 significance of anti HBc positivity Among Screen Failures A new section was added to discuss the rationale for the additional HBV assessments in participants positive for anti-HBc at screening and the potential impact on anti-HBc positive participants treated with CAB+RPV 8.5 Additional Stored Blood Samples for Characterization of HBV Profile in Screen Failures Based on HBV Serology A new section was added to detail to provide a rationale for additional exploration of HBV profile, and storage procedures for plasma and serum samples from participants who test negative for HBsAg and positive for anti-HBc at screening. 5.4 Screen Failure The following text was added to the section: Screen failures who tested negative for HBsAg but positive for anti-HBc, and did not have a sample stored at screening, will be invited for a repeat blood sampling for the testing ofHBV DNA and anti-HBs. Informed consent will be obtained from these participants for the repeat blood sampling. 5.1 Inclusion Criteria Inclusion criterion 1: modified to include ‘males or females as determined at birth’. to Inclusion criterion 5: modified from ‘confirmed plasma HIV-1 RNA measurement >200 c/mL at any time’ Inclusion criterion 7: the definitions of non-reproductive potential was modified to pre-menopausal women with a history oftubal ligation, stereoscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, hysterectomy or bilateral oophorectomy. 5.2 Exclusion criteria Exclusion criterion 7: modified from ‘more than one seizure within one year….’ to: Either: Has had one or more seizures within one year (defined as within 365 days) prior to entry, or unstable or poorly controlled seizure disorder, as determined by the investigator or designee, based on available medical records or Participants determined by the Investigator to have a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. A participant with a prior history of seizure may be considered for enrolment if the Investigator believes the risk of seizure recurrence is low. 6.8.3 Prohibited Medications with CAB and/or RPV A note was added to proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. Must not be administered during oral intake of CAB or RPV; no contraindication for injectable formulation 1.1 Synopsis 1.3 Schedule of Activities 8.1.4 Patient-reported Outcomes A treatment preference question was added to the SoA along with the timepoints of the assessments. Further details were added to the patient-reported outcomes section: To understand the choice and lived experiences of participants randomized to the CAB LA+RPV LA arm receiving OLI versus those directly transitioning to injectable CAB LA+RPV, in-depth interviews (IDIs) will be carried out to understand individual perspectives of participants and focus group discussions (FGDs) will be used to capture group perspectives. FGDs may include 6 to 10 participants including both males and females, or segregated gender groups. Informed consent will be obtained from the participants for the collection of this data. Additionally, treatment preference will be assessed among participants in the CAB LA+RPV LA arm at the timepoints detailed in the Schedule of Activities. A detailed survey on medical resource utilization will also be done at Month 12 at selected sites. 10.2 Appendix 2: Clinical Laboratory Tests % Reticulocytes was deleted from RBC indices in the protocol-required safety laboratory assessments. Throughout the protocol “RPV LA+CAB LA” was changed to “CAB LA + RPV LA”. Throughout the protocol Minor grammatical, formatting, or spelling changes were made. | |||||||||
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