Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D²EFT)

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.

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.

Study Overview

• Status: Active, not recruiting
• Conditions: HIV Infections
• Intervention / Treatment: Drug: NRTIs; Drug: Darunavir; Drug: Ritonavir; Drug: Dolutegravir

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: Interventional
• Enrollment (Actual): 831
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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: 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; Drug: Dolutegravir; 50mg tablet by mouth once daily for 96 weeks.; Other Names: Tivicay
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
Proportion with plasma viral load <200 copies/mL	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	At 48 and 96 weeks
Mean change in CD4+ cell count from baseline	At 48 and 96 weeks
Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides)	At 48 and 96 weeks
Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs	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	At 48 and 96 weeks
Adverse events associated with cessation of randomly assigned therapy	At 48 and 96 weeks
Categorisation of neuropsychological adverse events	At 48 and 96 weeks
Proportion who stopped randomised therapy by reason for stopping	At 48 and 96 weeks
Patterns of genotypic HIV resistance associated with virological failure	At 48 and 96 weeks
Adherence assessment using participant 7-day recall self-report questionnaire	At week 4
Quality of life and anxiety & depression assessed by participant questionnaire	At 48 and 96 weeks
Health care utilisation assessed by participant questionnaire	At 48 and 96 weeks
Cost of care assessment	At 48 and 96 weeks

Collaborators and Investigators

• Sponsor: Kirby Institute
• Collaborators: National Health and Medical Research Council, Australia; National Institute of Allergy and Infectious Diseases (NIAID); ViiV Healthcare; UNITAID; Janssen Pharmaceutica
• Investigators: Principal Investigator: Gail Matthews, MD, Kirby Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2017
• Primary Completion (Actual): November 11, 2022
• Study Completion (Anticipated): October 31, 2023

Study Registration Dates

• First Submitted: January 2, 2017
• First Submitted That Met QC Criteria: January 9, 2017
• First Posted (Estimate): January 11, 2017

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 16, 2023
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: HIV, second-line
• Additional Relevant MeSH Terms: Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Darunavir; Dolutegravir
• Other Study ID Numbers: D2EFT; 18Q065 (Other Grant/Funding Number: NIAID via Leidos); 19Q120 (Other Grant/Funding Number: NIAID via Leidos)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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