Clinical trial NCT05546242: Improving HIV-1 Control in Africa with Long Acting Antiretrovirals
Official title: A Phase 3b Randomised, Multicentre, Open-label Study Evaluating the Effectiveness of Switching to Two-monthly Long-acting Injectable Cabotegravir and Rilpivirine from First-line Oral Antiretroviral Therapy in HIV-1 Positive Virologically Suppressed Adults with a History Of, or At Risk Of, Sub-optimal HIV Control in Sub-Saharan Africa
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: HIV-1-infection
Lead sponsor: MRC/UVRI and LSHTM Uganda Research Unit
Sponsor class: OTHER
Collaborators: name: Janssen Pharmaceuticals
First posted: 2022-09-19
Enrollment: 540
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: parallel open-label phase 3b study. Participants will be randomised to continuing current therapy or switching to injectable therapy.
Primary purpose: TREATMENT

Brief summary: IMPALA is a randomized, open-label, multicenter, interventional study of 540 virologically suppressed HIV-1 infected adults who have a history of sub-optimal adherence to daily oral ART and/or engagement in HIV care. The study will seek to demonstrate non-inferior antiviral effectiveness of the 2-monthly long-acting injectable combination of cabotegravir/rilpivirine as compared to continuation of first line oral antiretroviral therapy.

Detailed description: IMPALA is a randomized, open-label, multicenter, interventional study of 540 virologically suppressed (\<200 c/mL) HIV-1 infected adults (18 years or older) who have a history of sub-optimal adherence to daily oral ART and/or engagement in HIV care. IMPALA seeks to demonstrate the non-inferior antiviral effectiveness of switching to long acting injectable rilpivirine (RPV LA) plus long acting injectable cabotegravir (CAB LA) given every 2 months (Q2M CAB LA + RPV LA) by IM compared to the continuation of first-line daily oral ART containing 2 nucleoside reverse transcriptase inhibitor (NRTIs) plus an integrase strand transfer inhibitor (INSTI; dolutegravir \[DTG\]).

After providing written informed consent, participants will be evaluated for eligibility during the screening period. Participants who are viremic (HIV VL \>200 c/mL) at the time of screening will be virologically suppressed (for \>3 months) on a regimen of 2 NRTIs plus DTG prior to randomization. On Day 1 virologically suppressed (\<200 c/mL for at least 3 months) individuals will be randomized 1:1 to either continue daily oral ART (2 NRTI + DTG, control arm), or switch to Q2M CAB LA + RPV LA IM, the intervention arm. Those randomized to the intervention arm will be offered either optional oral lead-in (OLI) of 1 month daily oral CAB and RPV or a direct to injection (DTI) approach. This decision to dose with or without an OLI Phase will be determined by the study participant following the informed consent discussion with the investigator. The total duration of the study will be 24 months. Any participant who has received at least a single dose of CAB LA + RPV LA and discontinues the regimen for any reason before Month 24 must start suppressive daily oral ART within 2 months of the last injection. There will be an optional real-world extension phase, provided the regimen is deemed to be non-inferior at Month 12 and 24.

Eligibility criteria: Inclusion Criteria:

1. 18 years of age and above
2. HIV-1 infection confirmed in clinic records or by study team.
3. Two consecutive HIV-1 VL \<200 copies/mL ≥3 months apart prior to randomization.
4. On an oral regimen of 2NRTI + DTG as part of first line ART
5. Is identified as a participant with a history of, sub-optimal ART adherence or engagement in care based on one or more of the following criteria:

   1. Documented detectable HIV-1 VL (\>1000 c/mL) on all-oral ART (EFV/NVP or DTG-based) in the prior 2 years despite being ART-experienced for

      ≥3 months.
   2. History of being lost to follow-up from care (\>4 weeks elapsed since a missed scheduled clinic appointment or refill in the prior 2 years).
   3. Failed to link to HIV care despite ≥3 months elapsed since HIV diagnosis.
6. Females: human chorionic gonadotrophin (HCG) negative and willing to use one highly effective form of contraception if woman of reproductive potential
7. Must sign informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
8. Willing and able to attend all clinic appointments.

Exclusion Criteria:

1. Not virologically suppressed (VL\<200 c/mL) for ≥3 months at the end of the screening process.
2. Previous use, or intention to use, protease inhibitor-based ART at any time.
3. Evidence of prior HIV-1 resistance test with NNRTI drug resistance mutations (other than K103N) and/or INSTI drug resistance mutations.
4. Unwillingness to receive 2 injections on a 2 monthly basis.
5. Unwilling to use a form of contraception.
6. Pregnant, breastfeeding or planning to become pregnant during the study period.
7. Requires tuberculosis therapy or other drug with clinically relevant drug interaction
8. High risk of seizures, including participants with an unstable or poorly controlled seizure disorder.
9. Has active TB or other mycobacterial disease and requires treatment.
10. Advanced liver disease, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or history of cirrhosis.
11. Chronic Hepatitis C with planned or anticipated use of Hep C therapy
12. Evidence of hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis B surface antibody (HBsAb) as follows:

    * Participants positive for HBsAg are excluded
    * Participants negative for HBsAg but positive for HBcAb, with no evidence of HBsAb are excluded NOTE: Participants positive for HBcAb due to prior infection (negative HBsAg status) and with evidence of HBsAb have some immunity to HBV and have low risk of reactivation so are not excluded.
13. Current or anticipated need for chronic anticoagulation therapy.
14. Previous use of oral or injectable CAB or RPV.
15. Any Grade 4 laboratory abnormality at the conclusion of screening process.
16. Creatinine clearance (CrCl) \<50 mL/min/1.732 by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation.
17. Alanine aminotransferase (ALT) \> 3×upper limit of normal (ULN).
18. Has a tattoo or other dermatological condition overlying the gluteus region that may interfere with interpretation of ISRs.
19. Has ongoing or clinically significant medical conditions that in the opinion of the investigator may interfere with the absorption, distribution, metabolism or excretion of the study interventions or could affect participant safety.
20. Has pre-existing physical or mental condition 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.
21. Known allergies, hypersensitivity, or intolerance to cabotegravir or rilpivirine or its excipients.
22. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 30 days before the planned first dose of study intervention or is currently enrolled in another interventional study.
23. Has received any prohibited medication listed in Section 6.8.2, Prohibited Medications and Non-drug Therapies and is unwilling or unable to switch to an alternate medication.
24. Has been treated with any of the following agents within 28 days of Screening:

    1. Radiation therapy.
    2. Cytotoxic chemotherapeutic agents.
    3. Tuberculosis therapy with the exception of isoniazid (isonicotinyl hydrazid, INH).
    4. Anticoagulation agents (e.g., warfarin and direct oral anticoagulants).
25. Is using immunomodulators that alter immune responses (such as chronic systemic corticosteroids, interleukins, or interferons). Note: Participants using short-term steroid tapers, topical, inhaled and intranasal corticosteroids, topical imiquimod are eligible for enrolment.
26. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
27. QTc interval \>450 ms (if QTc interval is \>450 ms on the ECG read out, then it should be corrected according to Fridericia; https://www.mdcalc.com/corrected-qt-interval-qtc) within 90 days prior to study entry.

Primary outcomes:
measure: HIV-1 viral load at 12 months
timeFrame: 12 months
Secondary outcomes:
measure: Confirmed virologic failure on 2 consecutive occasions
timeFrame: 12 months
measure: Confirmed virologic failure on 2 consecutive occasions
timeFrame: 24 months
measure: Lost to follow up
timeFrame: 12 months
measure: Lost to follow up
timeFrame: 24 months
measure: HIV-1 viral load <200c/mL
timeFrame: 12 months
measure: Virologic response
timeFrame: 12 months and 24 months
measure: Virologic non-response
timeFrame: 24 months
measure: Change in CD4+ T cell count
timeFrame: 12 months
measure: Change in CD4+ T cell count
timeFrame: 24 months
measure: HIV disease progression
timeFrame: 24 months
measure: Adverse Events
timeFrame: 12 months
measure: Adverse Events
timeFrame: 24 months
measure: Grade 3 and 4 Adverse Events
timeFrame: 12 months
measure: Grade 3 and 4 Adverse Events
timeFrame: 24 months
measure: Injection Site Reactions
timeFrame: 24 months
measure: Resistance Emergence
timeFrame: 12 months and 24 months
Other outcomes:
measure: Change in health-related quality of life
timeFrame: 12 months and 24 months
measure: Change in health-related quality of life
timeFrame: 12 months and 24 months
measure: Change in health-related quality of life
timeFrame: 6 months, 12 months and 18 months
measure: Treatment satisfaction
timeFrame: 12 months and 24 months
measure: Treatment preference
timeFrame: 12 months and 24 months
measure: Medical resource utilisation
timeFrame: 24 months
measure: Medical resource utilisation
timeFrame: 24 months
measure: Medical resource utilisation
timeFrame: 24 months
measure: Programmatic acceptability of Q2M CAB LA + RPV LA
timeFrame: 24 months
measure: Treatment adherence
timeFrame: 24 months
Locations:
city: Kisumu
country: Kenya
facility: Jaramogi Oginga Odinga Teaching & Referral Hospital
city: Nairobi
country: Kenya
facility: Kenyatta National Hospital
city: Cape Town
country: South Africa
facility: Desmond Tutu Health Foundation
city: Durban
country: South Africa
facility: CAPRISA
city: Entebbe
country: Uganda
facility: Entebbe Grade A Hospital
city: Fort Portal
country: Uganda
facility: JCRC Fort Portal
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
Study officials:
affiliation: MRC/UVRI & LSHTM
name: Fiona Cresswell, MBChB, PhD
role: PRINCIPAL_INVESTIGATOR
References: