Dolutegravir and Darunavir Evaluation in Adults Failing Therapy

Phase 4

Active, not recruiting

• Conditions: HIV Infections
• Interventions: Drug: NRTIs; Drug: Dolutegravir; Drug: Darunavir; Drug: Ritonavir

• Registration Number: NCT03017872
• Lead Sponsor: Kirby Institute

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 Timeline

• Study First Submitted: 2017-01-02
• Study First Submitted QC: 2017-01-09
• Study First Posted: 2017-01-11
• Study Start: 2017-11-23
• Status Verified: 2022-09
• Primary Completion: 2022-11-11
• Last Update Submitted: 2023-04-16
• Last Update Posted: 2023-04-18
• Study Completion: 2023-10-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 831

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dolutegravir 2NRTI arm (D2N)	NRTIs	Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)
Standard of Care (SoC) arm	NRTIs	2 x NRTIs + darunavir/ritonavir 800mg/100mg po od
Dolutegravir arm	Darunavir	Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od
Dolutegravir arm	Ritonavir	Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od
Dolutegravir arm	Dolutegravir	Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od
Standard of Care (SoC) arm	Darunavir	2 x NRTIs + darunavir/ritonavir 800mg/100mg po od
Standard of Care (SoC) arm	Ritonavir	2 x NRTIs + darunavir/ritonavir 800mg/100mg po od
Dolutegravir 2NRTI arm (D2N)	Dolutegravir	Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Adherence assessment using participant 7-day recall self-report questionnaire	At week 4
Proportion with plasma viral load <200 copies/mL	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
Proportion who stopped randomised therapy by reason for stopping	At 48 and 96 weeks
Health care utilisation assessed by participant questionnaire	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
Adverse events associated with cessation of randomly assigned therapy	At 48 and 96 weeks
Categorisation of neuropsychological adverse events	At 48 and 96 weeks
Patterns of genotypic HIV resistance associated with virological failure	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
Quality of life and anxiety & depression assessed by participant questionnaire	At 48 and 96 weeks
Cost of care assessment	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

Trial Locations

Locations (28)

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

CAICI; 🇦🇷 Rosario, Provincia De Santa Fe, Argentina

Hospital Interzonal de Agudos San Juan de Dios; 🇦🇷 La Plata, Argentina

Laboratório de Pesquisa Clinica Em Hiv/Aids - Instituto Nacional de Infectologia - Fiocruz; 🇧🇷 Rio de Janeiro, Brazil

Hospital San Borja-Arriaran; 🇨🇱 Santiago, Chile

ASISTENCIA Cientifica De Alta Complejidad S.A.S.; 🇨🇴 Bogota, Colombia

Centre de traitementambulatoire de Donka ( Hopital de jour); 🇬🇳 Conakry, Guinea

Dr. Cipto Mangunkusumo Hospital; 🇮🇩 Jakarta, Indonesia

RSUP Dr. Wahidin Sudirohusodo; 🇮🇩 Makassar, Indonesia

Dr. Soetomo Hospital; 🇮🇩 Surabaya, Indonesia

Dr Sardjito Hospital; 🇮🇩 Yogyakarta, Indonesia

Hospital Pulau Pinang; 🇲🇾 George Town, Pulau Pinang, Malaysia

University of Malaya Medical Centre; 🇲🇾 Kuala Lumpur, Malaysia

University of Sciences, Techniques and Technologies of Mali, University Clinical Research Center (UCRC); 🇲🇱 Bamako, Mali

Hospital Civil de Guadalajara; 🇲🇽 Guadalajara, Jalisco, Mexico

Instituto Nacional de Ciencias Medicas y Nutriciòn Salvador Zubiran; 🇲🇽 Mexico City, Mexico

Institute of Human Virology, Nigeria (IHVN); 🇳🇬 Abuja, Nigeria

Desmond Tutu HIV Foundation; 🇿🇦 Cape Town, South Africa

Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital; 🇿🇦 Soweto, South Africa

Clinical HIV Research Unit (CHRU), Wits Health Consotium (Pty) Ltd; 🇿🇦 Johannesburg, South Africa

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, Thailand

University of Zimbabwe Clinical Research Centre; 🇿🇼 Harare, Zimbabwe

CART CRS, VHS Hospital; 🇮🇳 Chennai, Tamil Nadu, India

Morales Vargas Centro de Investigacion SC; 🇲🇽 León, Guanajuato, Mexico