Clinical trial NCT03988452: Nucleosides And Darunavir/Dolutegravir In Africa
Official title: Nucleosides And Darunavir/Dolutegravir In Africa (NADIA): a Randomised Controlled Trial of Darunavir Versus Dolutegravir and Tenofovir Versus Zidovudine in Second-line Antiretroviral Therapy Regimens for the Public Health Approach in Sub-Saharan Africa
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Human Immunodeficiency Virus
Lead sponsor: Makerere University
Sponsor class: OTHER
Collaborators: name: Infectious Diseases Institute, Uganda
First posted: 2019-06-17
Enrollment: 465
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: This trial evaluates options for second-line antiretroviral therapy in patients failing on a non-nucleoside reverse transcriptase inhibitor (NNRTI) and tenofovir (TDF)-based first-line regimen in the setting of the public health approach in sub-Saharan Africa (with assumed substantial nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance). The trial tests two hypotheses. Firstly that a regimen of dolutegravir (DTG) with two NRTIs is non-inferior to a regimen of ritonavir-boosted darunavir (DRV/r) with two NRTIs. Secondly that continuing an NRTI regimen of TDF and lamivudine (3TC) is non-inferior to switching to zidovudine (ZDV) and 3TC.

The trial is a parallel group, open-label, multi-centre, factorial (2X2) randomised, controlled trial. Patients will be randomised to either DTG or DRV/r with a second randomisation to ZDV and 3TC or TDF and 3TC. Treatment efficacy will be monitored by testing viral load (VL). Analyses will compare DRV/r with DTG; and ZDV/3TC with TDF/3TC by intention to treat analysis on the primary outcome parameter of plasma VL below 400 copies/ml at 48 weeks. Trial follow-up will continue to 96 weeks.


Eligibility criteria: Inclusion Criteria:

1. Male or female, age 12 years and above
2. Body weight at least 40kg
3. Taking a tenofovir plus lamivudine/emtricitabine plus NNRTI-based regimen continuously for a total period of at least 6 months
4. Good adherence to ART, defined as missing medication on no more than 3 days in the one month prior to screening. \[Patients who do not have good adherence should be given adherence counselling and re-assessed after an interval of not less than 4 weeks\].
5. HIV treatment failure defined by virological criteria (modified from WHO 2016 criteria); Viral load ≥ 1000 copies/ml at screening AND EITHER Viral load ≥ 1000 copies/ml on the previous test, taken after at least 6 months on ART, and at no more than 6 months prior to screening and at no less than 4 weeks prior to screening, with adherence counselling given after the previous test OR Viral load ≥ 1000 copies/ml on a confirmatory test taken no less than 4 weeks after screening with adherence counselling given after the screening test
6. If a woman of childbearing potential, must be willing to use effective contraception. \[Childbearing potential is defined as being not premenarchal; not post-menopausal (\> 12 months of spontaneous amenorrhea and ≥45 years of age); and not permanently sterilised\].
7. Willing and able to provide written informed consent
8. Able to attend regular study follow-up visits

Exclusion Criteria:

1. Prior use of protease inhibitor or integrase inhibitor therapy
2. Requirement for concomitant medication with known major interactions with study drugs for which drug substitutions or dose alterations are not available or acceptable (if the patient requires rifamycin-based TB treatment, rifabutin must be available at the site).
3. Women who are currently pregnant or breastfeeding.
4. Severe hepatic impairment (with ascites and/or encephalopathy)
5. ALT \> 5 times upper limit of normal
6. Estimated glomerular filtration rate (eGFR) \< 50 ml/min/1.73m2 at screening calculated using the CKD-EPI equation
7. Current participation in another clinical trial or research protocol (may be permitted in some circumstances; but must first be discussed with the NADIA Chief Investigator)
8. Life expectancy of less than one month in the opinion of the treating physician

Primary outcomes:
measure: Plasma viral load < 400 copies/ml at 48 weeks
timeFrame: 48 weeks
Secondary outcomes:
measure: Plasma viral load < 1000 copies/ml
timeFrame: 48 and 96 weeks
measure: Plasma viral load < 400 copies/ml at 96 weeks
timeFrame: 96 weeks
measure: Plasma viral load < 50 copies/ml
timeFrame: 48 and 96 weeks
measure: Plasma viral load rebound (≥ 1000 copies/ml, confirmed)
timeFrame: 48 and 96 weeks
measure: Plasma viral load rebound (≥ 400 copies/ml, confirmed)
timeFrame: 48 and 96 weeks
measure: Plasma viral load rebound (≥ 50 copies/ml, confirmed)
timeFrame: 48 and 96 weeks
measure: Viral load rebound (≥ 1000 copies/ml, confirmed) with ≥ 1 major resistance mutation (IAS list) to DRV or DTG
timeFrame: 48 and 96 weeks
measure: Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to DRV or DTG
timeFrame: 48 and 96 weeks
measure: Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to both zidovudine and tenofovir
timeFrame: 48 and 96 weeks
measure: CD4+ cell count change from baseline
timeFrame: 48 and 96 weeks
measure: Incident (new or recurrent) WHO stage 4 event
timeFrame: 48 and 96 weeks
measure: Incident serious non-AIDS event
timeFrame: 48 and 96 weeks
measure: Death
timeFrame: 48 and 96 weeks
measure: Time to new or recurrent WHO Stage 4 event, serious non-AIDS event, or death
timeFrame: 96 weeks
measure: Grade 3 or 4 clinical adverse events
timeFrame: 48 and 96 weeks
measure: Grade 3 or 4 clinical adverse events (possibly, probably or definitely related to ART)
timeFrame: 48 and 96 weeks
measure: Serious Adverse Events
timeFrame: 48 and 96 weeks
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
Study officials:
affiliation: National University of Singapore
name: Nicholas Paton, MD
role: STUDY_DIRECTOR
References:
citation: Paton NI, Musaazi J, Kityo C, Walimbwa S, Hoppe A, Balyegisawa A, Asienzo J, Kaimal A, Mirembe G, Lugemwa A, Ategeka G, Borok M, Mugerwa H, Siika A, Odongpiny ELA, Castelnuovo B, Kiragga A, Kambugu A; NADIA Trial Team. Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial. Lancet HIV. 2022 Jun;9(6):e381-e393. doi: 10.1016/S2352-3018(22)00092-3. Epub 2022 Apr 20.
citation: Paton NI, Musaazi J, Kityo C, Walimbwa S, Hoppe A, Balyegisawa A, Kaimal A, Mirembe G, Tukamushabe P, Ategeka G, Hakim J, Mugerwa H, Siika A, Asienzo J, Castelnuovo B, Kiragga A, Kambugu A; NADIA Trial Team. Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV. N Engl J Med. 2021 Jul 22;385(4):330-341. doi: 10.1056/NEJMoa2101609.