Clinical trial NCT03017872: Dolutegravir and Darunavir Evaluation in Adults Failing Therapy
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: HIV Infections
Keywords: HIV, second-line
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
Collaborators: name: UNITAID
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Health and Medical Research Council, Australia
name: ViiV Healthcare
name: Janssen Pharmaceutica
First posted: 2017-01-11
Enrollment: 831
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.'

Eligibility criteria: 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

Primary outcomes:
measure: The proportion of participants in each arm whose plasma viral load is <50 copies/mL at 48 weeks by intention to treat.
timeFrame: At 48 weeks
Secondary outcomes:
measure: Proportion with plasma viral load <200 copies/mL
timeFrame: At 48 and 96 weeks
measure: 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
timeFrame: At 48 and 96 weeks
measure: Mean change in CD4+ cell count from baseline
timeFrame: At 48 and 96 weeks
measure: Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides)
timeFrame: At 48 and 96 weeks
measure: Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs
timeFrame: At 48 and 96 weeks
measure: Total number of opportunistic diseases (AIDS events), deaths and serious non-AIDS defining events and the cumulative incidence of these
timeFrame: At 48 and 96 weeks
measure: Adverse events associated with cessation of randomly assigned therapy
timeFrame: At 48 and 96 weeks
measure: Categorisation of neuropsychological adverse events
timeFrame: At 48 and 96 weeks
measure: Proportion who stopped randomised therapy by reason for stopping
timeFrame: At 48 and 96 weeks
measure: Patterns of genotypic HIV resistance associated with virological failure
timeFrame: At 48 and 96 weeks
measure: Adherence assessment using participant 7-day recall self-report questionnaire
timeFrame: At week 4
measure: Quality of life and anxiety & depression assessed by participant questionnaire
timeFrame: At 48 and 96 weeks
measure: Health care utilisation assessed by participant questionnaire
timeFrame: At 48 and 96 weeks
measure: Cost of care assessment
timeFrame: At 48 and 96 weeks
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Hospital G de Agudos JM Ramos Mejia
state: Ciudad De Buenos Aires
city: Isidro Casanova
country: Argentina
facility: Hospital Dr Diego Paroissien
state: Provincia De Buenos Aires
city: Rosario
country: Argentina
facility: CAICI
state: Provincia De Santa Fe
city: La Plata
country: Argentina
facility: Hospital Interzonal de Agudos San Juan de Dios
city: Rio de Janeiro
country: Brazil
facility: Laboratório de Pesquisa Clinica Em Hiv/Aids - Instituto Nacional de Infectologia - Fiocruz
city: Santiago
country: Chile
facility: Hospital San Borja-Arriaran
city: Bogota
country: Colombia
facility: ASISTENCIA Cientifica De Alta Complejidad S.A.S.
city: Conakry
country: Guinea
facility: Centre de traitementambulatoire de Donka ( Hopital de jour)
city: Chennai
country: India
facility: CART CRS, VHS Hospital
state: Tamil Nadu
city: Jakarta
country: Indonesia
facility: Dr. Cipto Mangunkusumo Hospital
city: Makassar
country: Indonesia
facility: RSUP Dr. Wahidin Sudirohusodo
city: Surabaya
country: Indonesia
facility: Dr. Soetomo Hospital
city: Yogyakarta
country: Indonesia
facility: Dr Sardjito Hospital
city: George Town
country: Malaysia
facility: Hospital Pulau Pinang
state: Pulau Pinang
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Centre
city: Bamako
country: Mali
facility: University of Sciences, Techniques and Technologies of Mali, University Clinical Research Center (UCRC)
city: León
country: Mexico
facility: Morales Vargas Centro de Investigacion SC
state: Guanajuato
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara
state: Jalisco
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutriciòn Salvador Zubiran
city: Abuja
country: Nigeria
facility: Institute of Human Virology, Nigeria (IHVN)
city: Cape Town
country: South Africa
facility: Desmond Tutu HIV Foundation
city: Johannesburg
country: South Africa
facility: Clinical HIV Research Unit (CHRU), Wits Health Consotium (Pty) Ltd
city: Soweto
country: South Africa
facility: Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital
city: Bangkok
country: Thailand
facility: HIV-NAT (The HIV Netherlands Australia Thailand Research Collaboration), Thai Red Cross AIDS Research Centre
city: Chiang Rai
country: Thailand
facility: Chiangrai Prachanukroh Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital, Khon Kaen University
city: Nonthaburi
country: Thailand
facility: Bamrasnaradura Infectious Diseases Institute
city: Harare
country: Zimbabwe
facility: University of Zimbabwe Clinical Research Centre
Study officials:
affiliation: Kirby Institute
name: Gail Matthews, MD
role: PRINCIPAL_INVESTIGATOR
References: