Nucleosides And Darunavir/Dolutegravir In Africa (NADIA)

• ClinicalTrials.gov Identifier: NCT03988452
• Recruitment Status: Unknown
• First Posted: June 17, 2019
• Last Update Posted: July 30, 2020
• Sponsor: Makerere University
• Collaborator: Infectious Diseases Institute, Uganda
• Information provided by (Responsible Party): Makerere University

Tracking Information

• First Submitted Date: June 13, 2019
• First Posted Date: June 17, 2019
• Last Update Posted Date: July 30, 2020
• Actual Study Start Date: July 30, 2019
• Estimated Primary Completion Date: September 30, 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 13, 2019): Plasma viral load < 400 copies/ml at 48 weeks [ Time Frame: 48 weeks ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 13, 2019)

• Plasma viral load < 1000 copies/ml [ Time Frame: 48 and 96 weeks ]
• Plasma viral load < 400 copies/ml at 96 weeks [ Time Frame: 96 weeks ]
• Plasma viral load < 50 copies/ml [ Time Frame: 48 and 96 weeks ]
• Plasma viral load rebound (≥ 1000 copies/ml, confirmed) [ Time Frame: 48 and 96 weeks ]
• Plasma viral load rebound (≥ 400 copies/ml, confirmed) [ Time Frame: 48 and 96 weeks ]
• Plasma viral load rebound (≥ 50 copies/ml, confirmed) [ Time Frame: 48 and 96 weeks ]
• Viral load rebound (≥ 1000 copies/ml, confirmed) with ≥ 1 major resistance mutation (IAS list) to DRV or DTG [ Time Frame: 48 and 96 weeks ]
• Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to DRV or DTG [ Time Frame: 48 and 96 weeks ]
• Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to both zidovudine and tenofovir [ Time Frame: 48 and 96 weeks ]
• CD4+ cell count change from baseline [ Time Frame: 48 and 96 weeks ]
• Incident (new or recurrent) WHO stage 4 event [ Time Frame: 48 and 96 weeks ]
• Incident serious non-AIDS event [ Time Frame: 48 and 96 weeks ]
• Death [ Time Frame: 48 and 96 weeks ]
• Time to new or recurrent WHO Stage 4 event, serious non-AIDS event, or death [ Time Frame: 96 weeks ]
• Grade 3 or 4 clinical adverse events [ Time Frame: 48 and 96 weeks ]
• Grade 3 or 4 clinical adverse events (possibly, probably or definitely related to ART) [ Time Frame: 48 and 96 weeks ]
• Serious Adverse Events [ Time Frame: 48 and 96 weeks ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Human Immunodeficiency Virus

Intervention

• Drug: Darunavir
  Antiretroviral therapy
• Drug: Ritonavir
  Antiretroviral therapy
• Drug: Dolutegravir
  Antiretroviral therapy
• Drug: Zidovudine
  Antiretroviral therapy
• Drug: Tenofovir
  Antiretroviral therapy
• Drug: Lamivudine
  Antiretroviral therapy

Study Arms

• Active Comparator: Darunavir/r Zidovudine Lamivudine
  Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
  Interventions:

  • Drug: Darunavir
  • Drug: Ritonavir
  • Drug: Zidovudine
  • Drug: Lamivudine
• Experimental: Darunavir/r Tenofovir Lamivudine
  Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
  Interventions:

  • Drug: Darunavir
  • Drug: Ritonavir
  • Drug: Tenofovir
  • Drug: Lamivudine
• Experimental: Dolutegravir Zidovudine Lamivudine
  Dolutegravir 50mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
  Interventions:

  • Drug: Dolutegravir
  • Drug: Zidovudine
  • Drug: Lamivudine
• Experimental: Dolutegravir Tenofovir Lamivudine
  Dolutegravir 50mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
  Interventions:

  • Drug: Dolutegravir
  • Drug: Tenofovir
  • Drug: Lamivudine

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: July 28, 2020): 465
• Original Estimated Enrollment (submitted: June 13, 2019): 440
• Estimated Study Completion Date: September 30, 2021
• Estimated Primary Completion Date: September 30, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Uganda

Administrative Information

• NCT Number: NCT03988452
• Other Study ID Numbers: JC3218
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Makerere University
• Original Responsible Party: Same as current
• Current Study Sponsor: Makerere University
• Original Study Sponsor: Same as current
• Collaborators: Infectious Diseases Institute, Uganda

Investigators

• Study Director: Nicholas Paton, MD; National University of Singapore

• PRS Account: Makerere University
• Verification Date: July 2020