Back to resultsNucleosides And Darunavir/Dolutegravir In Africa (NADIA)
Primary Purpose
Human Immunodeficiency Virus
Status
Unknown status
Phase
Phase 3
Locations
Uganda
Study Type
Interventional
Intervention
Darunavir
Ritonavir
Dolutegravir
Zidovudine
Tenofovir
Lamivudine
Sponsored by
About this trial
This is an interventional treatment trial for Human Immunodeficiency Virus
Eligibility Criteria
Inclusion Criteria:
- Male or female, age 12 years and above
- Body weight at least 40kg
- Taking a tenofovir plus lamivudine/emtricitabine plus NNRTI-based regimen continuously for a total period of at least 6 months
- 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].
- 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
- 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].
- Willing and able to provide written informed consent
- Able to attend regular study follow-up visits
Exclusion Criteria:
- Prior use of protease inhibitor or integrase inhibitor therapy
- 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).
- Women who are currently pregnant or breastfeeding.
- Severe hepatic impairment (with ascites and/or encephalopathy)
- ALT > 5 times upper limit of normal
- Estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73m2 at screening calculated using the CKD-EPI equation
- 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)
- Life expectancy of less than one month in the opinion of the treating physician
Sites / Locations
- Infectious Diseases Institute
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Experimental
Experimental
Experimental
Arm Label
Darunavir/r Zidovudine Lamivudine
Darunavir/r Tenofovir Lamivudine
Dolutegravir Zidovudine Lamivudine
Dolutegravir Tenofovir Lamivudine
Arm Description
Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
Dolutegravir 50mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
Dolutegravir 50mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
Outcomes
Primary Outcome Measures
Plasma viral load < 400 copies/ml at 48 weeks
Secondary Outcome Measures
Plasma viral load < 1000 copies/ml
Plasma viral load < 400 copies/ml at 96 weeks
Plasma viral load < 50 copies/ml
Plasma viral load rebound (≥ 1000 copies/ml, confirmed)
Plasma viral load rebound (≥ 400 copies/ml, confirmed)
Plasma viral load rebound (≥ 50 copies/ml, confirmed)
Viral load rebound (≥ 1000 copies/ml, confirmed) with ≥ 1 major resistance mutation (IAS list) to DRV or DTG
Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to DRV or DTG
Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to both zidovudine and tenofovir
CD4+ cell count change from baseline
Incident (new or recurrent) WHO stage 4 event
Incident serious non-AIDS event
Death
Time to new or recurrent WHO Stage 4 event, serious non-AIDS event, or death
Grade 3 or 4 clinical adverse events
Grade 3 or 4 clinical adverse events (possibly, probably or definitely related to ART)
Serious Adverse Events
Full Information
NCT ID
NCT03988452
First Posted
June 13, 2019
Last Updated
July 28, 2020
Sponsor
Makerere University
Collaborators
Infectious Diseases Institute, Uganda
1. Study Identification
Unique Protocol Identification Number
NCT03988452
Brief Title
Nucleosides And Darunavir/Dolutegravir In Africa
Acronym
NADIA
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
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Unknown status
Study Start Date
July 30, 2019 (Actual)
Primary Completion Date
September 30, 2020 (Anticipated)
Study Completion Date
September 30, 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Makerere University
Collaborators
Infectious Diseases Institute, Uganda
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
465 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Darunavir/r Zidovudine Lamivudine
Arm Type
Active Comparator
Arm Description
Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
Arm Title
Darunavir/r Tenofovir Lamivudine
Arm Type
Experimental
Arm Description
Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
Arm Title
Dolutegravir Zidovudine Lamivudine
Arm Type
Experimental
Arm Description
Dolutegravir 50mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
Arm Title
Dolutegravir Tenofovir Lamivudine
Arm Type
Experimental
Arm Description
Dolutegravir 50mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
Intervention Type
Drug
Intervention Name(s)
Darunavir
Intervention Description
Antiretroviral therapy
Intervention Type
Drug
Intervention Name(s)
Ritonavir
Intervention Description
Antiretroviral therapy
Intervention Type
Drug
Intervention Name(s)
Dolutegravir
Intervention Description
Antiretroviral therapy
Intervention Type
Drug
Intervention Name(s)
Zidovudine
Intervention Description
Antiretroviral therapy
Intervention Type
Drug
Intervention Name(s)
Tenofovir
Intervention Description
Antiretroviral therapy
Intervention Type
Drug
Intervention Name(s)
Lamivudine
Intervention Description
Antiretroviral therapy
Primary Outcome Measure Information:
Title
Plasma viral load < 400 copies/ml at 48 weeks
Time Frame
48 weeks
Secondary Outcome Measure Information:
Title
Plasma viral load < 1000 copies/ml
Time Frame
48 and 96 weeks
Title
Plasma viral load < 400 copies/ml at 96 weeks
Time Frame
96 weeks
Title
Plasma viral load < 50 copies/ml
Time Frame
48 and 96 weeks
Title
Plasma viral load rebound (≥ 1000 copies/ml, confirmed)
Time Frame
48 and 96 weeks
Title
Plasma viral load rebound (≥ 400 copies/ml, confirmed)
Time Frame
48 and 96 weeks
Title
Plasma viral load rebound (≥ 50 copies/ml, confirmed)
Time Frame
48 and 96 weeks
Title
Viral load rebound (≥ 1000 copies/ml, confirmed) with ≥ 1 major resistance mutation (IAS list) to DRV or DTG
Time Frame
48 and 96 weeks
Title
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
Title
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
Title
CD4+ cell count change from baseline
Time Frame
48 and 96 weeks
Title
Incident (new or recurrent) WHO stage 4 event
Time Frame
48 and 96 weeks
Title
Incident serious non-AIDS event
Time Frame
48 and 96 weeks
Title
Death
Time Frame
48 and 96 weeks
Title
Time to new or recurrent WHO Stage 4 event, serious non-AIDS event, or death
Time Frame
96 weeks
Title
Grade 3 or 4 clinical adverse events
Time Frame
48 and 96 weeks
Title
Grade 3 or 4 clinical adverse events (possibly, probably or definitely related to ART)
Time Frame
48 and 96 weeks
Title
Serious Adverse Events
Time Frame
48 and 96 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female, age 12 years and above
Body weight at least 40kg
Taking a tenofovir plus lamivudine/emtricitabine plus NNRTI-based regimen continuously for a total period of at least 6 months
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].
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
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].
Willing and able to provide written informed consent
Able to attend regular study follow-up visits
Exclusion Criteria:
Prior use of protease inhibitor or integrase inhibitor therapy
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).
Women who are currently pregnant or breastfeeding.
Severe hepatic impairment (with ascites and/or encephalopathy)
ALT > 5 times upper limit of normal
Estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73m2 at screening calculated using the CKD-EPI equation
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)
Life expectancy of less than one month in the opinion of the treating physician
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicholas Paton, MD
Organizational Affiliation
National University of Singapore
Official's Role
Study Director
Facility Information:
Facility Name
Infectious Diseases Institute
City
Kampala
Country
Uganda
12. IPD Sharing Statement
Citations:
PubMed Identifier
35460601
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.
Results Reference
derived
PubMed Identifier
34289276
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.
Results Reference
derived
Learn more about this trial
Nucleosides And Darunavir/Dolutegravir In Africa
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