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Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D²EFT)

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ClinicalTrials.gov Identifier: NCT03017872
Recruitment Status : Recruiting
First Posted : January 11, 2017
Last Update Posted : February 5, 2020
Sponsor:
Collaborators:
UNITAID
National Institute of Allergy and Infectious Diseases (NIAID)
National Health and Medical Research Council, Australia
ViiV Healthcare
Janssen Pharmaceutica
Information provided by (Responsible Party):
Kirby Institute

Tracking Information
First Submitted Date  ICMJE January 2, 2017
First Posted Date  ICMJE January 11, 2017
Last Update Posted Date February 5, 2020
Actual Study Start Date  ICMJE November 23, 2017
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2017)
The proportion of participants in each arm whose plasma viral load is <50 copies/mL at 48 weeks by intention to treat. [ Time Frame: At 48 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2017)
  • Proportion with plasma viral load <200 copies/mL [ Time Frame: At 48 and 96 weeks ]
  • 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 [ Time Frame: At 48 and 96 weeks ]
  • Mean change in CD4+ cell count from baseline [ Time Frame: At 48 and 96 weeks ]
  • Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides) [ Time Frame: At 48 and 96 weeks ]
  • Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs [ Time Frame: At 48 and 96 weeks ]
  • Total number of opportunistic diseases (AIDS events), deaths and serious non-AIDS defining events and the cumulative incidence of these [ Time Frame: At 48 and 96 weeks ]
  • Adverse events associated with cessation of randomly assigned therapy [ Time Frame: At 48 and 96 weeks ]
  • Categorisation of neuropsychological adverse events [ Time Frame: At 48 and 96 weeks ]
  • Proportion who stopped randomised therapy by reason for stopping [ Time Frame: At 48 and 96 weeks ]
  • Patterns of genotypic HIV resistance associated with virological failure [ Time Frame: At 48 and 96 weeks ]
  • Adherence assessment using participant 7-day recall self-report questionnaire [ Time Frame: At week 4 ]
  • Quality of life and anxiety & depression assessed by participant questionnaire [ Time Frame: At 48 and 96 weeks ]
  • Health care utilisation assessed by participant questionnaire [ Time Frame: At 48 and 96 weeks ]
  • Cost of care assessment [ Time Frame: At 48 and 96 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2017)
  • Proportion with plasma viral load <200 copies/mL [ Time Frame: At 48 and 96 weeks ]
  • 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 [ Time Frame: At 48 and 96 weeks ]
  • Mean change in CD4+ cell count from baseline [ Time Frame: At 48 and 96 weeks ]
  • Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides) [ Time Frame: At 48 and 96 weeks ]
  • Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs [ Time Frame: At 48 and 96 weeks ]
  • Total number of opportunistic diseases (AIDS events), deaths and serious non-AIDS defining events and the cumulative incidence of these [ Time Frame: At 48 and 96 weeks ]
  • Adverse events associated with cessation of randomly assigned therapy [ Time Frame: At 48 and 96 weeks ]
  • Categorisation of neuropsychological adverse events [ Time Frame: At 48 and 96 weeks ]
  • Proportion who stopped randomised therapy by reason for stopping [ Time Frame: At 48 and 96 weeks ]
  • Patterns of genotypic HIV resistance associated with virological failure [ Time Frame: At 48 and 96 weeks ]
  • Adherence assessment using participant 7-day recall self-report questionnaire [ Time Frame: At week 4 ]
  • Quality of life assessed by participant questionnaire [ Time Frame: At 48 and 96 weeks ]
  • Health care utilisation assessed by participant questionnaire [ Time Frame: At 48 and 96 weeks ]
  • Cost of care assessment [ Time Frame: At 48 and 96 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dolutegravir and Darunavir Evaluation in Adults Failing Therapy
Official Title  ICMJE 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.
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV Infections
Intervention  ICMJE
  • 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 Name: Nucleoside/Nucleotide Reverse Transcription Inhibitors
  • Drug: Dolutegravir
    50mg tablet by mouth once daily for 96 weeks.
    Other Name: Tivicay
  • Drug: Darunavir
    800mg tablet by mouth once daily for 96 weeks.
    Other Name: Prezista
  • Drug: Ritonavir
    100mg tablet by mouth once daily for 96 weeks.
    Other Name: Norvir
Study Arms  ICMJE
  • Active Comparator: Standard of Care (SoC) arm
    2 x NRTIs + darunavir/ritonavir 800mg/100mg po od
    Interventions:
    • Drug: NRTIs
    • Drug: Darunavir
    • Drug: Ritonavir
  • Experimental: Dolutegravir arm
    Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od
    Interventions:
    • Drug: Dolutegravir
    • Drug: Darunavir
    • Drug: Ritonavir
  • Experimental: Dolutegravir 2NRTI arm (D2N)
    Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)
    Interventions:
    • Drug: NRTIs
    • Drug: Dolutegravir
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 8, 2018)
1010
Original Estimated Enrollment  ICMJE
 (submitted: January 9, 2017)
610
Estimated Study Completion Date  ICMJE December 28, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

    1. absolute neutrophil count (ANC) <500 cells/µL
    2. haemoglobin <7.0 g/dL
    3. platelet count <50,000 cells/µL
    4. AST and/or ALT ≥5xULN OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)
  2. Change in antiretroviral therapy within 12 weeks prior to randomisation
  3. Prior exposure to HIV protease inhibitors and/or HIV integrase inhibitors
  4. Patients with chronic viral hepatitis B infection defined by positive serum hepatitis B surface antigen
  5. 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)
  6. Anticipated need for Hepatitis C virus (HCV) therapy during the study
  7. Subject has creatinine clearance of <50 mL/min via CKD-EPI equation
  8. Current use of rifabutin or rifampicin
  9. Use of any contraindicated medications (as specified by product information sheets)
  10. Intercurrent illness requiring hospitalization
  11. An active opportunistic disease not under adequate control in the opinion of the investigator
  12. Pregnant or nursing mothers
  13. Patients with current alcohol or illicit substance use that in the opinion of the investigator might adversely affect participation in the study
  14. Patients deemed unlikely by the investigator to be able to remain in follow-up for the protocol-defined period
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Simone S Jacoby +61 2 9385 0900 ext 50919 sjacoby@kirby.unsw.edu.au
Listed Location Countries  ICMJE Argentina,   Brazil,   Chile,   Colombia,   Guinea,   India,   Indonesia,   Malaysia,   Mali,   Mexico,   Nigeria,   South Africa,   Thailand,   Zimbabwe
Removed Location Countries Peru
 
Administrative Information
NCT Number  ICMJE NCT03017872
Other Study ID Numbers  ICMJE D2EFT
18Q065 ( Other Grant/Funding Number: NIAID via Leidos )
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
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Kirby Institute
Study Sponsor  ICMJE Kirby Institute
Collaborators  ICMJE
  • UNITAID
  • National Institute of Allergy and Infectious Diseases (NIAID)
  • National Health and Medical Research Council, Australia
  • ViiV Healthcare
  • Janssen Pharmaceutica
Investigators  ICMJE
Principal Investigator: Mark Polizzotto, MD Kirby Institute
PRS Account Kirby Institute
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP