Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D²EFT)
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| ClinicalTrials.gov Identifier: NCT03017872 |
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Recruitment Status :
Recruiting
First Posted : January 11, 2017
Last Update Posted : March 16, 2021
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| HIV Infections | Drug: NRTIs Drug: Dolutegravir Drug: Darunavir Drug: Ritonavir | Phase 4 |
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 (Clinical Trial) |
| Estimated Enrollment : | 1010 participants |
| 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 |
| 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. |
| Actual Study Start Date : | November 23, 2017 |
| Estimated Primary Completion Date : | December 31, 2022 |
| Estimated Study Completion Date : | December 31, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Standard of Care (SoC) arm
2 x NRTIs + darunavir/ritonavir 800mg/100mg po od
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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: 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 |
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Experimental: Dolutegravir arm
Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od
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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 |
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Experimental: Dolutegravir 2NRTI arm (D2N)
Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)
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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 |
- 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 ]
- 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 ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- HIV-1 positive by licensed diagnostic test
- Aged ≥16 years of age (or minimum age as determined by local regulations or as legal requirements dictate)
- 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)
- For women of child-bearing potential, willingness to use appropriate contraception
- Able to provide written informed consent
Exclusion Criteria:
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The following laboratory variables:
- absolute neutrophil count (ANC) <500 cells/µL
- haemoglobin <7.0 g/dL
- platelet count <50,000 cells/µL
- AST and/or ALT ≥5xULN OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)
- Change in antiretroviral therapy within 12 weeks prior to randomisation
- Prior exposure to HIV protease inhibitors and/or HIV integrase inhibitors
- Patients with chronic viral hepatitis B infection defined by positive serum hepatitis B surface antigen
- 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)
- Anticipated need for Hepatitis C virus (HCV) therapy during the study
- Subject has creatinine clearance of <50 mL/min via CKD-EPI equation
- Current use of rifabutin or rifampicin
- Use of any contraindicated medications (as specified by product information sheets)
- Intercurrent illness requiring hospitalization
- An active opportunistic disease not under adequate control in the opinion of the investigator
- Pregnant or nursing mothers
- Patients with current alcohol or illicit substance use that in the opinion of the investigator might adversely affect participation in the study
- Patients deemed unlikely by the investigator to be able to remain in follow-up for the protocol-defined period
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03017872
| Contact: Simone S Jacoby | +61 2 9385 0900 ext 50919 | sjacoby@kirby.unsw.edu.au |
Show 28 study locations
| Principal Investigator: | Mark Polizzotto, MD | Kirby Institute |
| Responsible Party: | Kirby Institute |
| ClinicalTrials.gov Identifier: | NCT03017872 |
| Other Study ID Numbers: |
D2EFT 18Q065 ( Other Grant/Funding Number: NIAID via Leidos ) 19Q120 ( Other Grant/Funding Number: NIAID via Leidos ) |
| First Posted: | January 11, 2017 Key Record Dates |
| Last Update Posted: | March 16, 2021 |
| Last Verified: | March 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| 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 |
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HIV, second-line |
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Infection Ritonavir Darunavir Dolutegravir HIV Protease Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors HIV Integrase Inhibitors Integrase Inhibitors |