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D²EFT: Dolutegravir and Darunavir Evaluation in Adults Failing Therapy

Sponsor
Kirby Institute (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03017872
Collaborator
UNITAID (Other), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), National Health and Medical Research Council, Australia (Other), ViiV Healthcare (Industry), Janssen Pharmaceutica (Industry)
813
Enrollment
28
Locations
3
Arms
80.2
Anticipated Duration (Months)
29
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

D²EFT is a randomised, open-label study in HIV-1 infected patients failing first-line antiretroviral therapy (ART). The study compares 2 regimens of second-line ART (dolutegravir and darunavir pharmaco-enhanced with ritonavir and dolutegravir and 2 prespecified NRTIs) with the WHO recommended regimen of 2NRTIs plus a ritonavir-boosted PI (Standard of Care (SOC)). 1,010 participants from 14 predominantly low-middle income countries will be followed for 96 weeks with the primary endpoint at week 48. The design is based on the hypothesis that one or both of the new regimens will be non-inferior to SOC in terms of virologic control while being easier to take, economically viable and affording simplification of treatment programs.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

Consenting participants will be screened and within 45 days randomly allocated to receive either dolutegravir and darunavir/ritonavir, dolutegravir and 2 prespecified NRTIs or the SOC regimen. Participants will be seen four weeks after their randomisation (week 0) visit and then at weeks 12, 24, 48 and 96. Consenting participants will have storage samples collected and cryopreserved at their week 0, 48 & 96 visits. This repository will be used in future for central baseline resistance testing, pharmacogenomic testing (separate consent required) and has inherent value for later studies of HIV pathogenesis. A 1-time PK sample will be collected at week four for future testing and any participants failing therapy at 24 weeks will have a plasma sample stored for future genotypic resistance testing.

A number of secondary outcomes will be considered in order to compare the performance of the two study treatment regimens. Secondary analyses will focus on virological, immunological, safety, antiretroviral treatment change and medication adherence. A comparison of costs and estimates of cost-effectiveness for the randomised comparison will be a critical component of this study. ART costs will be assessed across study arms. Health-care utilisation will be self-reported and then used to estimate costs. Safety data, viral loads and quality of life data will also be analysed.

The open label nature of the study allows routine care to be undertaken and the use of objective endpoints limit potential bias. The study has well defined and integrated clinical data collection and patient management systems that have been shown to be effective in a wide range of clinical settings.

The choice of NRTIs in the SoC regimen is based on clinical judgement and may be guided by resistance testing if locally available, while those used with dolutegravir are predetermined (tenofovir and lamivudine or emtricitabine). The NRTIs are not provided via the study. At the end of 96 weeks (completion of the protocol) study drug can be offered to all participants for a further 48 weeks as informed by the 48-week study results and clinical judgement. After 144 weeks study drug will no longer be available and composition of the participant's post-study regimen will be the clinician's decision.'

Study Design

Study Type:
Interventional
Actual Enrollment :
813 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
A third arm has been incorporated using a multi-arm, multi-stage (MAMS) design. This design allows for the 2-arm study (DTG+DRV/r vs DRV/r+2NRTI) to continue accrual while preparation of the new arm (DTG+2NRTI) is begun in parallel. Once that arm is ready, accrual to it begins and the study switches to the second stage. All participants accrued to Arm 1 and 2 throughout the trial are contemporaneous and can be compared, while the subjects accrued to Arm 3 are compared only to their contemporaries in Arms 1 and 2. The size of Arm 3 is sufficient to allow adequate power comparisons, and stage effects are minimized while non-contemporaneous control data are not required.A third arm has been incorporated using a multi-arm, multi-stage (MAMS) design. This design allows for the 2-arm study (DTG+DRV/r vs DRV/r+2NRTI) to continue accrual while preparation of the new arm (DTG+2NRTI) is begun in parallel. Once that arm is ready, accrual to it begins and the study switches to the second stage. All participants accrued to Arm 1 and 2 throughout the trial are contemporaneous and can be compared, while the subjects accrued to Arm 3 are compared only to their contemporaries in Arms 1 and 2. The size of Arm 3 is sufficient to allow adequate power comparisons, and stage effects are minimized while non-contemporaneous control data are not required.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase IIIB/IV Randomised Open-label Trial Comparing Dolutegravir With Pharmaco-enhanced Darunavir Versus Dolutegravir With Predetermined Nucleosides Versus Recommended Standard of Care ART Regimens in Patients With HIV-1 Infection Failing First Line Therapy.
Actual Study Start Date :
Nov 23, 2017
Anticipated Primary Completion Date :
Jul 31, 2023
Anticipated Study Completion Date :
Jul 31, 2024

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Standard of Care (SoC) arm

2 x NRTIs + darunavir/ritonavir 800mg/100mg po od

Drug: NRTIs
In SOC arm, choice of NRTIs determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection. In D2N arm, NRTIs are predetermined.
Other Names:
  • Nucleoside/Nucleotide Reverse Transcription Inhibitors

    • Drug: Darunavir
    800mg tablet by mouth once daily for 96 weeks.
    Other Names:
  • Prezista

    • Drug: Ritonavir
    100mg tablet by mouth once daily for 96 weeks.
    Other Names:
  • Norvir

    		•
    Experimental: Dolutegravir arm

    Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od

    Drug: Dolutegravir
    50mg tablet by mouth once daily for 96 weeks.
    Other Names:
  • Tivicay

    • Drug: Darunavir
    800mg tablet by mouth once daily for 96 weeks.
    Other Names:
  • Prezista

    • Drug: Ritonavir
    100mg tablet by mouth once daily for 96 weeks.
    Other Names:
  • Norvir

    		•
    Experimental: Dolutegravir 2NRTI arm (D2N)

    Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)

    Drug: NRTIs
    In SOC arm, choice of NRTIs determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection. In D2N arm, NRTIs are predetermined.
    Other Names:
  • Nucleoside/Nucleotide Reverse Transcription Inhibitors

    • Drug: Dolutegravir
    50mg tablet by mouth once daily for 96 weeks.
    Other Names:
  • Tivicay

    		•

    Outcome Measures

    Primary Outcome Measures

    1. The proportion of participants in each arm whose plasma viral load is <50 copies/mL at 48 weeks by intention to treat. [At 48 weeks]

    Secondary Outcome Measures

    1. Proportion with plasma viral load <200 copies/mL [At 48 and 96 weeks]

    2. Proportion with plasma viral load <50 copies/mL where those stopping randomised therapy for any reason are classified as plasma viral load >50 copies/mL [At 48 and 96 weeks]

    3. Mean change in CD4+ cell count from baseline [At 48 and 96 weeks]

    4. Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides) [At 48 and 96 weeks]

    5. Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs [At 48 and 96 weeks]

    6. Total number of opportunistic diseases (AIDS events), deaths and serious non-AIDS defining events and the cumulative incidence of these [At 48 and 96 weeks]

    7. Adverse events associated with cessation of randomly assigned therapy [At 48 and 96 weeks]

    8. Categorisation of neuropsychological adverse events [At 48 and 96 weeks]

    9. Proportion who stopped randomised therapy by reason for stopping [At 48 and 96 weeks]

    10. Patterns of genotypic HIV resistance associated with virological failure [At 48 and 96 weeks]

    11. Adherence assessment using participant 7-day recall self-report questionnaire [At week 4]

    12. Quality of life and anxiety & depression assessed by participant questionnaire [At 48 and 96 weeks]

    13. Health care utilisation assessed by participant questionnaire [At 48 and 96 weeks]

    14. Cost of care assessment [At 48 and 96 weeks]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. HIV-1 positive by licensed diagnostic test

    2. Aged ≥16 years of age (or minimum age as determined by local regulations or as legal requirements dictate)

    3. Failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) + 2N(t)RTI combination therapy according to virological criteria, defined as at least two consecutive (≥7 days apart) pVL results >500 copies/mL after a minimum period of exposure to continuous NNRTI + 2N(t)RTI first-line therapy of 24 weeks (only the second pVL result needs to be within 45 days of randomisation)

    4. For women of child-bearing potential, willingness to use appropriate contraception

    5. Able to provide written informed consent

    Exclusion Criteria:

    1. The following laboratory variables:

    2. absolute neutrophil count (ANC) <500 cells/µL

    3. haemoglobin <7.0 g/dL

    4. platelet count <50,000 cells/µL

    5. AST and/or ALT ≥5xULN OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)

    6. Change in antiretroviral therapy within 12 weeks prior to randomisation

    7. Prior exposure to HIV protease inhibitors and/or HIV integrase inhibitors

    8. Patients with chronic viral hepatitis B infection defined by positive serum hepatitis B surface antigen

    9. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy (INR >2.3), hypoalbuminemia (serum albumin <2.8g/dL), esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

    10. Anticipated need for Hepatitis C virus (HCV) therapy during the study

    11. Subject has creatinine clearance of <50 mL/min via CKD-EPI equation

    12. Current use of rifabutin or rifampicin

    13. Use of any contraindicated medications (as specified by product information sheets)

    14. Intercurrent illness requiring hospitalization

    15. An active opportunistic disease not under adequate control in the opinion of the investigator

    16. Pregnant or nursing mothers

    17. Patients with current alcohol or illicit substance use that in the opinion of the investigator might adversely affect participation in the study

    18. Patients deemed unlikely by the investigator to be able to remain in follow-up for the protocol-defined period

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hospital G de Agudos JM Ramos Mejia Buenos Aires Ciudad De Buenos Aires Argentina C1221ADC
    2 Hospital Dr Diego Paroissien Isidro Casanova Provincia De Buenos Aires Argentina 1765
    3 CAICI Rosario Provincia De Santa Fe Argentina S2000PBJ
    4 Hospital Interzonal de Agudos San Juan de Dios La Plata Argentina 1900
    5 Laboratório de Pesquisa Clinica Em Hiv/Aids - Instituto Nacional de Infectologia - Fiocruz Rio de Janeiro Brazil 21040-360
    6 Hospital San Borja-Arriaran Santiago Chile 8360159
    7 ASISTENCIA Cientifica De Alta Complejidad S.A.S. Bogota Colombia 110010
    8 Centre de traitementambulatoire de Donka ( Hopital de jour) Conakry Guinea BP:5845
    9 CART CRS, VHS Hospital Chennai Tamil Nadu India 600113
    10 Dr. Cipto Mangunkusumo Hospital Jakarta Indonesia 10320
    11 RSUP Dr. Wahidin Sudirohusodo Makassar Indonesia 90241
    12 Dr. Soetomo Hospital Surabaya Indonesia 60285
    13 Dr Sardjito Hospital Yogyakarta Indonesia 55284
    14 Hospital Pulau Pinang George Town Pulau Pinang Malaysia 10450
    15 University of Malaya Medical Centre Kuala Lumpur Malaysia 59100
    16 University of Sciences, Techniques and Technologies of Mali, University Clinical Research Center (UCRC) Bamako Mali
    17 Morales Vargas Centro de Investigacion SC León Guanajuato Mexico 37000
    18 Hospital Civil de Guadalajara Guadalajara Jalisco Mexico 44280
    19 Instituto Nacional de Ciencias Medicas y Nutriciòn Salvador Zubiran Mexico City Mexico 14080
    20 Institute of Human Virology, Nigeria (IHVN) Abuja Nigeria 9396
    21 Desmond Tutu HIV Foundation Cape Town South Africa 7925
    22 Clinical HIV Research Unit (CHRU), Wits Health Consotium (Pty) Ltd Johannesburg South Africa 2041
    23 Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital Soweto South Africa 1864
    24 HIV-NAT (The HIV Netherlands Australia Thailand Research Collaboration), Thai Red Cross AIDS Research Centre Bangkok Thailand 10330
    25 Chiangrai Prachanukroh Hospital Chiang Rai Thailand 57000
    26 Srinagarind Hospital, Khon Kaen University Khon Kaen Thailand 40002
    27 Bamrasnaradura Infectious Diseases Institute Nonthaburi Thailand 11000
    28 University of Zimbabwe Clinical Research Centre Harare Zimbabwe +263

    Sponsors and Collaborators

    • Kirby Institute
    • UNITAID
    • National Institute of Allergy and Infectious Diseases (NIAID)
    • National Health and Medical Research Council, Australia
    • ViiV Healthcare
    • Janssen Pharmaceutica

    Investigators

    • Principal Investigator: Gail Matthews, MD, Kirby Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Kirby Institute
    ClinicalTrials.gov Identifier:
    NCT03017872
    Other Study ID Numbers:
    • D2EFT
    • 18Q065
    • 19Q120
    First Posted:
    Jan 11, 2017
    Last Update Posted:
    Jun 22, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Kirby Institute
    HIV, second-line
    Additional relevant MeSH terms:
    Infections
    Ritonavir
    Darunavir
    Dolutegravir

    Study Results

    No Results Posted as of Jun 22, 2022