<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03017872</url>
  </required_header>
  <id_info>
    <org_study_id>D2EFT</org_study_id>
    <secondary_id>18Q065</secondary_id>
    <secondary_id>19Q120</secondary_id>
    <nct_id>NCT03017872</nct_id>
  </id_info>
  <brief_title>Dolutegravir and Darunavir Evaluation in Adults Failing Therapy</brief_title>
  <acronym>D²EFT</acronym>
  <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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kirby Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>UNITAID</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Health and Medical Research Council, Australia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>ViiV Healthcare</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Janssen Pharmaceutica</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Kirby Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      D²EFT is a randomised, open-label study in HIV-1 infected patients failing first-line&#xD;
      antiretroviral therapy (ART). The study compares 2 regimens of second-line ART (dolutegravir&#xD;
      and darunavir pharmaco-enhanced with ritonavir and dolutegravir and 2 prespecified NRTIs)&#xD;
      with the WHO recommended regimen of 2NRTIs plus a ritonavir-boosted PI (Standard of Care&#xD;
      (SOC)). 1,010 participants from 14 predominantly low-middle income countries will be followed&#xD;
      for 96 weeks with the primary endpoint at week 48. The design is based on the hypothesis that&#xD;
      one or both of the new regimens will be non-inferior to SOC in terms of virologic control&#xD;
      while being easier to take, economically viable and affording simplification of treatment&#xD;
      programs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Consenting participants will be screened and within 45 days randomly allocated to receive&#xD;
      either dolutegravir and darunavir/ritonavir, dolutegravir and 2 prespecified NRTIs or the SOC&#xD;
      regimen. Participants will be seen four weeks after their randomisation (week 0) visit and&#xD;
      then at weeks 12, 24, 48 and 96. Consenting participants will have storage samples collected&#xD;
      and cryopreserved at their week 0, 48 &amp; 96 visits. This repository will be used in future for&#xD;
      central baseline resistance testing, pharmacogenomic testing (separate consent required) and&#xD;
      has inherent value for later studies of HIV pathogenesis. A 1-time PK sample will be&#xD;
      collected at week four for future testing and any participants failing therapy at 24 weeks&#xD;
      will have a plasma sample stored for future genotypic resistance testing.&#xD;
&#xD;
      A number of secondary outcomes will be considered in order to compare the performance of the&#xD;
      two study treatment regimens. Secondary analyses will focus on virological, immunological,&#xD;
      safety, antiretroviral treatment change and medication adherence. A comparison of costs and&#xD;
      estimates of cost-effectiveness for the randomised comparison will be a critical component of&#xD;
      this study. ART costs will be assessed across study arms. Health-care utilisation will be&#xD;
      self-reported and then used to estimate costs. Safety data, viral loads and quality of life&#xD;
      data will also be analysed.&#xD;
&#xD;
      The open label nature of the study allows routine care to be undertaken and the use of&#xD;
      objective endpoints limit potential bias. The study has well defined and integrated clinical&#xD;
      data collection and patient management systems that have been shown to be effective in a wide&#xD;
      range of clinical settings.&#xD;
&#xD;
      The choice of NRTIs in the SoC regimen is based on clinical judgement and may be guided by&#xD;
      resistance testing if locally available, while those used with dolutegravir are predetermined&#xD;
      (tenofovir and lamivudine or emtricitabine). The NRTIs are not provided via the study. At the&#xD;
      end of 96 weeks (completion of the protocol) study drug can be offered to all participants&#xD;
      for a further 48 weeks as informed by the 48-week study results and clinical judgement. After&#xD;
      144 weeks study drug will no longer be available and composition of the participant's&#xD;
      post-study regimen will be the clinician's decision.'&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 23, 2017</start_date>
  <completion_date type="Anticipated">October 31, 2023</completion_date>
  <primary_completion_date type="Actual">November 11, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The proportion of participants in each arm whose plasma viral load is &lt;50 copies/mL at 48 weeks by intention to treat.</measure>
    <time_frame>At 48 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion with plasma viral load &lt;200 copies/mL</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion with plasma viral load &lt;50 copies/mL where those stopping randomised therapy for any reason are classified as plasma viral load &gt;50 copies/mL</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean change in CD4+ cell count from baseline</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides)</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total number of opportunistic diseases (AIDS events), deaths and serious non-AIDS defining events and the cumulative incidence of these</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events associated with cessation of randomly assigned therapy</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Categorisation of neuropsychological adverse events</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion who stopped randomised therapy by reason for stopping</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patterns of genotypic HIV resistance associated with virological failure</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence assessment using participant 7-day recall self-report questionnaire</measure>
    <time_frame>At week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life and anxiety &amp; depression assessed by participant questionnaire</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health care utilisation assessed by participant questionnaire</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost of care assessment</measure>
    <time_frame>At 48 and 96 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">831</enrollment>
  <condition>HIV Infections</condition>
  <arm_group>
    <arm_group_label>Standard of Care (SoC) arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>2 x NRTIs + darunavir/ritonavir 800mg/100mg po od</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dolutegravir arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dolutegravir 2NRTI arm (D2N)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NRTIs</intervention_name>
    <description>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.&#xD;
In D2N arm, NRTIs are predetermined.</description>
    <arm_group_label>Dolutegravir 2NRTI arm (D2N)</arm_group_label>
    <arm_group_label>Standard of Care (SoC) arm</arm_group_label>
    <other_name>Nucleoside/Nucleotide Reverse Transcription Inhibitors</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dolutegravir</intervention_name>
    <description>50mg tablet by mouth once daily for 96 weeks.</description>
    <arm_group_label>Dolutegravir 2NRTI arm (D2N)</arm_group_label>
    <arm_group_label>Dolutegravir arm</arm_group_label>
    <other_name>Tivicay</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Darunavir</intervention_name>
    <description>800mg tablet by mouth once daily for 96 weeks.</description>
    <arm_group_label>Dolutegravir arm</arm_group_label>
    <arm_group_label>Standard of Care (SoC) arm</arm_group_label>
    <other_name>Prezista</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ritonavir</intervention_name>
    <description>100mg tablet by mouth once daily for 96 weeks.</description>
    <arm_group_label>Dolutegravir arm</arm_group_label>
    <arm_group_label>Standard of Care (SoC) arm</arm_group_label>
    <other_name>Norvir</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. HIV-1 positive by licensed diagnostic test&#xD;
&#xD;
          2. Aged ≥16 years of age (or minimum age as determined by local regulations or as legal&#xD;
             requirements dictate)&#xD;
&#xD;
          3. Failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) + 2N(t)RTI&#xD;
             combination therapy according to virological criteria, defined as at least two&#xD;
             consecutive (≥7 days apart) pVL results &gt;500 copies/mL after a minimum period of&#xD;
             exposure to continuous NNRTI + 2N(t)RTI first-line therapy of 24 weeks (only the&#xD;
             second pVL result needs to be within 45 days of randomisation)&#xD;
&#xD;
          4. For women of child-bearing potential, willingness to use appropriate contraception&#xD;
&#xD;
          5. Able to provide written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. The following laboratory variables:&#xD;
&#xD;
               1. absolute neutrophil count (ANC) &lt;500 cells/µL&#xD;
&#xD;
               2. haemoglobin &lt;7.0 g/dL&#xD;
&#xD;
               3. platelet count &lt;50,000 cells/µL&#xD;
&#xD;
               4. AST and/or ALT ≥5xULN OR ALT ≥3xULN and bilirubin ≥1.5xULN (with &gt;35% direct&#xD;
                  bilirubin)&#xD;
&#xD;
          2. Change in antiretroviral therapy within 12 weeks prior to randomisation&#xD;
&#xD;
          3. Prior exposure to HIV protease inhibitors and/or HIV integrase inhibitors&#xD;
&#xD;
          4. Patients with chronic viral hepatitis B infection defined by positive serum hepatitis&#xD;
             B surface antigen&#xD;
&#xD;
          5. Unstable liver disease (as defined by the presence of ascites, encephalopathy,&#xD;
             coagulopathy (INR &gt;2.3), hypoalbuminemia (serum albumin &lt;2.8g/dL), esophageal or&#xD;
             gastric varices, or persistent jaundice), known biliary abnormalities (with the&#xD;
             exception of Gilbert's syndrome or asymptomatic gallstones)&#xD;
&#xD;
          6. Anticipated need for Hepatitis C virus (HCV) therapy during the study&#xD;
&#xD;
          7. Subject has creatinine clearance of &lt;50 mL/min via CKD-EPI equation&#xD;
&#xD;
          8. Current use of rifabutin or rifampicin&#xD;
&#xD;
          9. Use of any contraindicated medications (as specified by product information sheets)&#xD;
&#xD;
         10. Intercurrent illness requiring hospitalization&#xD;
&#xD;
         11. An active opportunistic disease not under adequate control in the opinion of the&#xD;
             investigator&#xD;
&#xD;
         12. Pregnant or nursing mothers&#xD;
&#xD;
         13. Patients with current alcohol or illicit substance use that in the opinion of the&#xD;
             investigator might adversely affect participation in the study&#xD;
&#xD;
         14. Patients deemed unlikely by the investigator to be able to remain in follow-up for the&#xD;
             protocol-defined period&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gail Matthews, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kirby Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital G de Agudos JM Ramos Mejia</name>
      <address>
        <city>Buenos Aires</city>
        <state>Ciudad De Buenos Aires</state>
        <zip>C1221ADC</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Dr Diego Paroissien</name>
      <address>
        <city>Isidro Casanova</city>
        <state>Provincia De Buenos Aires</state>
        <zip>1765</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CAICI</name>
      <address>
        <city>Rosario</city>
        <state>Provincia De Santa Fe</state>
        <zip>S2000PBJ</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Interzonal de Agudos San Juan de Dios</name>
      <address>
        <city>La Plata</city>
        <zip>1900</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Laboratório de Pesquisa Clinica Em Hiv/Aids - Instituto Nacional de Infectologia - Fiocruz</name>
      <address>
        <city>Rio de Janeiro</city>
        <zip>21040-360</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital San Borja-Arriaran</name>
      <address>
        <city>Santiago</city>
        <zip>8360159</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASISTENCIA Cientifica De Alta Complejidad S.A.S.</name>
      <address>
        <city>Bogota</city>
        <zip>110010</zip>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre de traitementambulatoire de Donka ( Hopital de jour)</name>
      <address>
        <city>Conakry</city>
        <zip>BP:5845</zip>
        <country>Guinea</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CART CRS, VHS Hospital</name>
      <address>
        <city>Chennai</city>
        <state>Tamil Nadu</state>
        <zip>600113</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr. Cipto Mangunkusumo Hospital</name>
      <address>
        <city>Jakarta</city>
        <zip>10320</zip>
        <country>Indonesia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>RSUP Dr. Wahidin Sudirohusodo</name>
      <address>
        <city>Makassar</city>
        <zip>90241</zip>
        <country>Indonesia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr. Soetomo Hospital</name>
      <address>
        <city>Surabaya</city>
        <zip>60285</zip>
        <country>Indonesia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Sardjito Hospital</name>
      <address>
        <city>Yogyakarta</city>
        <zip>55284</zip>
        <country>Indonesia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Pulau Pinang</name>
      <address>
        <city>George Town</city>
        <state>Pulau Pinang</state>
        <zip>10450</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Malaya Medical Centre</name>
      <address>
        <city>Kuala Lumpur</city>
        <zip>59100</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Sciences, Techniques and Technologies of Mali, University Clinical Research Center (UCRC)</name>
      <address>
        <city>Bamako</city>
        <country>Mali</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Morales Vargas Centro de Investigacion SC</name>
      <address>
        <city>León</city>
        <state>Guanajuato</state>
        <zip>37000</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Civil de Guadalajara</name>
      <address>
        <city>Guadalajara</city>
        <state>Jalisco</state>
        <zip>44280</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Nacional de Ciencias Medicas y Nutriciòn Salvador Zubiran</name>
      <address>
        <city>Mexico City</city>
        <zip>14080</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Human Virology, Nigeria (IHVN)</name>
      <address>
        <city>Abuja</city>
        <zip>9396</zip>
        <country>Nigeria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Desmond Tutu HIV Foundation</name>
      <address>
        <city>Cape Town</city>
        <zip>7925</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical HIV Research Unit (CHRU), Wits Health Consotium (Pty) Ltd</name>
      <address>
        <city>Johannesburg</city>
        <zip>2041</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital</name>
      <address>
        <city>Soweto</city>
        <zip>1864</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HIV-NAT (The HIV Netherlands Australia Thailand Research Collaboration), Thai Red Cross AIDS Research Centre</name>
      <address>
        <city>Bangkok</city>
        <zip>10330</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chiangrai Prachanukroh Hospital</name>
      <address>
        <city>Chiang Rai</city>
        <zip>57000</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Srinagarind Hospital, Khon Kaen University</name>
      <address>
        <city>Khon Kaen</city>
        <zip>40002</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bamrasnaradura Infectious Diseases Institute</name>
      <address>
        <city>Nonthaburi</city>
        <zip>11000</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Zimbabwe Clinical Research Centre</name>
      <address>
        <city>Harare</city>
        <zip>+263</zip>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Brazil</country>
    <country>Chile</country>
    <country>Colombia</country>
    <country>Guinea</country>
    <country>India</country>
    <country>Indonesia</country>
    <country>Malaysia</country>
    <country>Mali</country>
    <country>Mexico</country>
    <country>Nigeria</country>
    <country>South Africa</country>
    <country>Thailand</country>
    <country>Zimbabwe</country>
  </location_countries>
  <removed_countries>
    <country>Peru</country>
  </removed_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>January 2, 2017</study_first_submitted>
  <study_first_submitted_qc>January 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <last_update_submitted>April 16, 2023</last_update_submitted>
  <last_update_submitted_qc>April 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HIV, second-line</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Darunavir</mesh_term>
    <mesh_term>Dolutegravir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03017872
org study id: D2EFT
secondary id: 18Q065
secondary id: 19Q120
nct id: NCT03017872
lead sponsor: 
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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.'
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.
primary purpose: Treatment
masking: None (Open Label)
measure: 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
measure: Proportion with plasma viral load <200 copies/mL
time frame: 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
time frame: At 48 and 96 weeks
measure: Mean change in CD4+ cell count from baseline
time frame: At 48 and 96 weeks
measure: Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides)
time frame: At 48 and 96 weeks
measure: Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs
time frame: 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
time frame: At 48 and 96 weeks
measure: Adverse events associated with cessation of randomly assigned therapy
time frame: At 48 and 96 weeks
measure: Categorisation of neuropsychological adverse events
time frame: At 48 and 96 weeks
measure: Proportion who stopped randomised therapy by reason for stopping
time frame: At 48 and 96 weeks
measure: Patterns of genotypic HIV resistance associated with virological failure
time frame: At 48 and 96 weeks
measure: Adherence assessment using participant 7-day recall self-report questionnaire
time frame: At week 4
measure: Quality of life and anxiety & depression assessed by participant questionnaire
time frame: At 48 and 96 weeks
measure: Health care utilisation assessed by participant questionnaire
time frame: At 48 and 96 weeks
measure: Cost of care assessment
time frame: At 48 and 96 weeks
arm group label: Standard of Care (SoC) arm
arm group type: Active Comparator
description: 2 x NRTIs + darunavir/ritonavir 800mg/100mg po od
arm group label: Dolutegravir arm
arm group type: Experimental
description: Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od
arm group label: Dolutegravir 2NRTI arm (D2N)
arm group type: Experimental
description: Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)
intervention type: Drug
intervention name: NRTIs
description: 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.
arm group label: Dolutegravir 2NRTI arm (D2N)
arm group label: Standard of Care (SoC) arm
other name: Nucleoside/Nucleotide Reverse Transcription Inhibitors
intervention type: Drug
intervention name: Dolutegravir
description: 50mg tablet by mouth once daily for 96 weeks.
arm group label: Dolutegravir 2NRTI arm (D2N)
arm group label: Dolutegravir arm
other name: Tivicay
intervention type: Drug
intervention name: Darunavir
description: 800mg tablet by mouth once daily for 96 weeks.
arm group label: Dolutegravir arm
arm group label: Standard of Care (SoC) arm
other name: Prezista
intervention type: Drug
intervention name: Ritonavir
description: 100mg tablet by mouth once daily for 96 weeks.
arm group label: Dolutegravir arm
arm group label: Standard of Care (SoC) arm
other name: Norvir
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gail Matthews, MD
role: Principal Investigator
affiliation: Kirby Institute
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country: Argentina
country: Brazil
country: Chile
country: Colombia
country: Guinea
country: India
country: Indonesia
country: Malaysia
country: Mali
country: Mexico
country: Nigeria
country: South Africa
country: Thailand
country: Zimbabwe
country: Peru
responsible party type: Sponsor
mesh term: Infections
mesh term: Ritonavir
mesh term: Darunavir
mesh term: Dolutegravir
sharing ipd: No