Clinical trial NCT06747507: Ndovu RCT: Investing the Optimal Management of Dolutegravir Resistance
Official title: Investigating the Optimal Management of Dolutegravir Resistance: an Open-label Randomised Controlled Trial of Maintaining Dolutegravir or Switch to Ritonavir-boosted Darunavir
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: HIV-1-infection
Keywords: HIV
Dolutegravir
Treatment failure
Drug resistant mutations
Dolutegravir resistance
Re-suppression
Lead sponsor: University of Nairobi
Sponsor class: OTHER
Collaborators: name: Instituto Nacional de Saúde, Mozambique
name: Muhimbili University of Health and Allied Sciences
name: SolidarMed
name: London School of Hygiene and Tropical Medicine
First posted: 2024-12-24
Enrollment: 392
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a phase 3b, multi-country, open-label, two-arm, active-controlled randomized clinical trial over 12 months describing the efficacy and safety of switching from DTG to DRV/r among PLWH age ≥ 3 years who are failing DTG-based ART with HIV-1 RNA ≥ 200 copies/mL and ≥ 1 major DTG-associated DRM (substitution at codon 66K, 92Q, 118R, 138K/A/T, 140S/A/C, 148H/R/K, 155H or 263K ), and most recent prior HIV-1 RNA ≥1,000 copies/mL after at least 6 months on DTG-based ART.
Primary purpose: TREATMENT

Brief summary: This clinical trial will address the gap in published data on the effect of dolutegravir (DTG)-associated drug-resistant mutations on viral suppression among people remaining on DTG-based antiretroviral therapy. It will also address the gap in the optimal management strategy for this population.

Detailed description: BACKGROUND:

The majority of people living with HIV (PLWH) on first-line antiretroviral therapy (ART) in low- and middle-income countries are on dolutegravir (DTG)-containing regimens. Different countries have adopted different approaches in the management of people on DTG-based first-line ART with repeat HIV viral load (VL) of \> 1,000 copies/mL after 3 months of enhanced adherence counselling. For example, Kenya recommends a drug resistance test (DRT) to guide on switch and the optimal second-line regimen; Mozambique and Tanzania recommend switch to 2 nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) without drug resistance testing; South Africa does not recommend switch from DTG or DRT for those who are on first-line DTG-containing regimens within the first 2 years of treatment, after which management is guided by possible DRT and expert opinion. The World Health Organization has recognised the role of drug resistance testing (DRT) in a treatment failure algorithm for people living with HIV receiving DTG-based treatment to minimise unnecessary switches from this regimen. The switch to PI has disadvantages including higher cost, higher pill burden, less convenient administration (often should be taken with food), more potential drug-drug interactions, poorer tolerability and more long-term toxicities.

GOAL:

To assess the efficacy and safety of remaining on DTG compared to switching to DRV/r among people failing DTG-based ART with at least one major DTG DRM.

METHODS:

This is a phase 3b, multi-country, open-label, two-arm, active-controlled randomized clinical trial (RCT) over 12 months describing the efficacy and safety of switching from DTG to DRV/r among PLWH age ≥ 3 years who are failing DTG-based ART with HIV-1 RNA ≥ 200 copies/mL and ≥ 1 major DTG-associated DRM (and most recent prior HIV-1 RNA ≥ 1,000 copies/mL after at least 6 months on DTG-based ART). The primary efficacy endpoint is the proportion of participants with HIV-1 RNA \< 200 copies/mL at month 6. The study will be conducted in 9 sites in Kenya, Mozambique, Tanzania and Lesotho targeting 392 participants including 30 children aged between 3 and 14 years old. The primary efficacy analysis will assess the difference in the proportion of participants with viral suppression at month 6 using the Cochran-Mantel-Haenszel method. This RCT is nested within an observational cohort study describing HIV-1 viral suppression of people with HIV-1 RNA value of ≥ 1,000 copies/mL after at least six months on DTG-based ART.

Eligibility criteria: Inclusion Criteria:

* Enrolled in the Ndovu cohort study
* Able and willing to understand and comply with the protocol requirements, instructions and restrictions
* Able and willing to provide informed consent for the nested clinical trial (assent as appropriate and legal guardian consent if \< 18 years)
* Age ≥ 3 years
* Most recent HIV-1 RNA ≥ 200 copies/mL
* At least one major DTG-associated DRM (substitution at codon 66K, 92Q, 118R, 138K/A/T, 140S/A/C, 148H/R/K, 155H or 263K)

Exclusion Criteria:

* Pregnant or breastfeeding
* Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
* WHO stage 3 or 4 opportunistic infection which would prevent randomisation to either arm (e.g. due to drug interactions or significant liver or renal injury) within 4 weeks prior to RCT screening
* Investigator opinion that the potential participant should discontinue DTG immediately for clinical reasons
* Investigator opinion that the potential participant should not switch to DRV/r for clinical reasons

Primary outcomes:
measure: Proportion of participants with HIV-1 RNA of <200 copies/mL at 6 months
timeFrame: 6 months
Secondary outcomes:
measure: Proportion of participants with HIV-1 RNA of <200 copies/mL at 12 months
timeFrame: 12 months
measure: Superiority of switch to DRV/r
timeFrame: 6 months
measure: Viral suppression with cut-off of 50 copies/mL
timeFrame: 6 and 12 months
measure: Viral suppression with cut-off of 1,000 copies/mL
timeFrame: 6 and 12 months
measure: Viral suppression by age strata
timeFrame: 6 and 12 months
measure: Viral suppression by sex at birth
timeFrame: 6 and 12 months
measure: Incidence of adverse events by study arm
timeFrame: 6 and 12 months
measure: Association between adherence and suppression
timeFrame: 6 months
measure: Incidence of drug resistant mutations (DRMs)
timeFrame: 6 and 12 months
measure: Patterns of accumulated drug resistant mutations (DRMs)
timeFrame: 6 and 12 months
measure: Drug resistant mutations (DRM) patterns associated with non-suppression
timeFrame: 6 and 12 months
measure: Predictors of DTG-associated drug resistant mutations (DRMs)
timeFrame: 6 and 12 months
measure: Viral suppression by pre-enrolment nucleoside reverse transcriptase inhibitor (NRTI)
timeFrame: 6 and 12 months
measure: Viral suppression by tenofovir disoproxil fumarate versus tenofovir alafenamide
timeFrame: 6 and 12 months
measure: Change in cluster of differentiation 4 (CD4) Count
timeFrame: 6 and 12 months
measure: Patient satisfaction as measured using the HIV Treatment Satisfaction Questionnaire - Status version (HIVTSQs) which scores 10 variables on a 7-point likert score ranging from 0 to 6 with a higher score representing a better outcome
timeFrame: 6 months
measure: Change in patient satisfaction as measured using the HIV Treatment Satisfaction Questionnaire - Change version (HIVTSQc) which scores 10 variables on a 7-point likert score ranging from -3 to +3 with a higher score representing a better outcome
timeFrame: Month 6
Other outcomes:
Locations:
city: Kisumu
country: Kenya
facility: Jaramogi Oginga Odinga Teaching and Referral Hospital
city: Mombasa
country: Kenya
facility: Bomu Hospital
city: Nairobi
country: Kenya
facility: Kenyatta National Hospital
city: Butha-Buthe
country: Lesotho
facility: Butha-Buthe District Hospital
city: Mokhotlong
country: Lesotho
facility: Mokhotlong District Hospital
city: Beira
country: Mozambique
facility: CS Ponta Gea
state: Sofala
city: Maputo
country: Mozambique
facility: CS Machava II
city: Maputo
country: Mozambique
facility: CS Ndlavela
city: Dar Es Salaam
country: Tanzania
facility: MUHAS Clinical Trial Unit
Study officials:
affiliation: University of Nairobi
name: Loice A Ombajo, MMed, MSc
role: PRINCIPAL_INVESTIGATOR
References: