Nucleosides And Darunavir/Dolutegravir In Africa

NCT03988452 | Unknown Phase 3 DMC

• 1 other identifier: JC3218
• Study Type: interventional
• Target: 465
• Locations: 1 country
• Sites: 1

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.

Conditions

Human Immunodeficiency Virus

Outcome Measures

Primary Outcomes (1)

• Plasma viral load < 400 copies/ml at 48 weeks

  48 weeks

Secondary Outcomes (17)

• Plasma viral load < 1000 copies/ml

  48 and 96 weeks

• Plasma viral load < 400 copies/ml at 96 weeks

  96 weeks

• Plasma viral load < 50 copies/ml

  48 and 96 weeks

• Plasma viral load rebound (≥ 1000 copies/ml, confirmed)

  48 and 96 weeks

• Plasma viral load rebound (≥ 400 copies/ml, confirmed)

  48 and 96 weeks

Study Arms (4)

Darunavir/r Zidovudine Lamivudine

ACTIVE COMPARATOR

Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks

Drug: Darunavir; Drug: Ritonavir; Drug: Zidovudine; Drug: Lamivudine

Darunavir/r Tenofovir Lamivudine

EXPERIMENTAL

Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks

Drug: Darunavir; Drug: Ritonavir; Drug: Tenofovir; Drug: Lamivudine

Dolutegravir Zidovudine Lamivudine

EXPERIMENTAL

Dolutegravir 50mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks

Drug: Dolutegravir; Drug: Zidovudine; Drug: Lamivudine

Dolutegravir Tenofovir Lamivudine

EXPERIMENTAL

Dolutegravir 50mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks

Drug: Dolutegravir; Drug: Tenofovir; Drug: Lamivudine

Interventions

Darunavir DRUG

Antiretroviral therapy

Darunavir/r Tenofovir Lamivudine; Darunavir/r Zidovudine Lamivudine

Ritonavir DRUG

Antiretroviral therapy

Darunavir/r Tenofovir Lamivudine; Darunavir/r Zidovudine Lamivudine

Dolutegravir DRUG

Antiretroviral therapy

Dolutegravir Tenofovir Lamivudine; Dolutegravir Zidovudine Lamivudine

Zidovudine DRUG

Antiretroviral therapy

Darunavir/r Zidovudine Lamivudine; Dolutegravir Zidovudine Lamivudine

Tenofovir DRUG

Antiretroviral therapy

Darunavir/r Tenofovir Lamivudine; Dolutegravir Tenofovir Lamivudine

Lamivudine DRUG

Antiretroviral therapy

Darunavir/r Tenofovir Lamivudine; Darunavir/r Zidovudine Lamivudine; Dolutegravir Tenofovir Lamivudine; Dolutegravir Zidovudine Lamivudine

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Makerere University: lead
• Infectious Diseases Institute, Uganda: collaborator

Study Sites (1)

Infectious Diseases Institute

Kampala, Uganda

Location

Related Publications (2)

• 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.

  PMID: 35460601 DERIVED

• 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.

  PMID: 34289276 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Darunavir; Ritonavir; dolutegravir; Zidovudine; Tenofovir; Lamivudine

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Thymidine; Pyrimidine Nucleosides; Pyrimidines; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Organophosphonates; Organophosphorus Compounds; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Zalcitabine; Deoxycytidine; Cytidine

Study Officials

• Nicholas Paton, MD

  National University of Singapore

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2019
• First Posted: June 17, 2019
• Study Start: July 30, 2019
• Primary Completion: September 30, 2020
• Study Completion: September 30, 2021
• Last Updated: July 30, 2020

Record last verified: 2020-07

Locations

UG (1)