Dolutegravir and Darunavir Evaluation in Adults Failing Therapy

HIV Infections Clinical Trial

— D²EFT  

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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03017872
• Other study ID #: D2EFT
• Secondary ID: 18Q06519Q120
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: November 23, 2017
• Est. completion date: October 31, 2023

Study information

• Verified date: September 2022
• Source: Kirby Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.'

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 831
• Est. completion date: October 31, 2023
• Est. primary completion date: November 11, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections
• Infections

Intervention

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.
• Dolutegravir
50mg tablet by mouth once daily for 96 weeks.
• Darunavir
800mg tablet by mouth once daily for 96 weeks.
• Ritonavir
100mg tablet by mouth once daily for 96 weeks.

Locations

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

Sponsors (6)

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

Countries where clinical trial is conducted

Argentina,  Brazil,  Chile,  Colombia,  Guinea,  India,  Indonesia,  Malaysia,  Mali,  Mexico,  Nigeria,  South Africa,  Thailand,  Zimbabwe, 

Outcome

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