Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D²EFT)

Study Description

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Brief Summary:

D²EFT is a randomised, open-label study in HIV-1 infected patients failing first-line antiretroviral therapy (ART). The study compares a novel regimen of second-line ART (dolutegravir and darunavir pharmaco-enhanced with ritonavir) with the WHO recommended regimen of 2(t)NRTIs plus a ritonavir-boosted PI (Standard of Care (SOC)). 610 participants from 10 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 the new regimen will be non-inferior to SOC in terms of virologic control while being easier to take, economically viable and affording simplification of treatment programs.

Condition or disease	Intervention/treatment	Phase
HIV Infections	Drug: N(t)RTIs; Drug: Dolutegravir; Drug: Darunavir; Drug: Ritonavir	Phase 4

Detailed Description:

Consenting participants will be screened and within 45 days randomly allocated to receive either dolutegravir and darunavir/ritonavir or the SOC regimen. Participants will be seen four weeks after their randomisation (week 0) visit and then at weeks 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 N(t)RTIs in the SoC regimen is based on clinical judgement and may be guided by resistance testing if locally available. 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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	610 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase IIIB/IV Randomised Open-label Trial to Compare Dolutegravir + Pharmaco-enhanced Darunavir Versus Recommended Standard of Care Antiretroviral Regimens in Patients With HIV Infection Who Have Failed Recommended First Line Therapy.
Actual Study Start Date :	November 1, 2017
Estimated Primary Completion Date :	September 30, 2019
Estimated Study Completion Date :	December 30, 2020

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Standard of Care (SoC) arm; 2 x NRTIs + darunavir/ritonavir 800mg/100mg po od	Drug: N(t)RTIs; Choice of N(t)RTI determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection.; 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
Experimental: Dolutegravir arm; Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od	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

Outcome Measures

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Primary Outcome Measures :

1. 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 ]

Secondary Outcome Measures :

1. Proportion with plasma viral load <200 copies/mL [ Time Frame: At 48 and 96 weeks ]
2. 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 ]
3. Mean change in CD4+ cell count from baseline [ Time Frame: At 48 and 96 weeks ]
4. Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides) [ Time Frame: At 48 and 96 weeks ]
5. Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs [ Time Frame: At 48 and 96 weeks ]
6. 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 ]
7. Adverse events associated with cessation of randomly assigned therapy [ Time Frame: At 48 and 96 weeks ]
8. Categorisation of neuropsychological adverse events [ Time Frame: At 48 and 96 weeks ]
9. Proportion who stopped randomised therapy by reason for stopping [ Time Frame: At 48 and 96 weeks ]
10. Patterns of genotypic HIV resistance associated with virological failure [ Time Frame: At 48 and 96 weeks ]
11. Adherence assessment using participant 7-day recall self-report questionnaire [ Time Frame: At week 4 ]
12. Quality of life and anxiety & depression assessed by participant questionnaire [ Time Frame: At 48 and 96 weeks ]
13. Health care utilisation assessed by participant questionnaire [ Time Frame: At 48 and 96 weeks ]
14. Cost of care assessment [ Time Frame: At 48 and 96 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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. 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 with interferon 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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Simone S Jacoby	+61 2 9385 0900 ext 50919	sjacoby@kirby.unsw.edu.au

Locations

Argentina
Hospital G de Agudos JM Ramos Mejia	Not yet recruiting
Buenos Aires, Ciudad De Buenos Aires, Argentina, C1221ADC
Contact: Marcelo Losso 5411 4127 0276 mlosso@hivramos.org.ar
Contact: Guillermo Viloria 5411 4931 5252 gviloria@hivramos.org.ar
Principal Investigator: Marcelo Losso, M.D.
Hospital Nacional Prof Alejandro Posadas	Not yet recruiting
El Palomar, Provincia De Buenos Aires, Argentina, 1684
Contact: Lucia Esther Daciuk, M.D. 54 11 1544962605 luciadaciuk@yahoo.com.ar
Contact: Hector Laplume, M.D. 54 11 1560426461 hectorlaplume@gmail.com
Principal Investigator: Lucia Esther Daciuk, M.D.
Hospital Dr Diego Paroissien	Not yet recruiting
Isidro Casanova, Provincia De Buenos Aires, Argentina, 1765
Contact: Eduardo Warley 5411 1541 897 181 eduwarley@yahoo.com.ar
Contact: Maria Ines Vieni 5411 1136 877 377 ext 3340 inesvieni@gmail.com
Principal Investigator: Eduardo Warley, M.D.
CAICI	Not yet recruiting
Rosario, Provincia De Santa Fe, Argentina, S2000PBJ
Contact: Sergio Lupo 54 9 341 515 7704 drsergiolupo@gmail.com
Contact: Luciana Peroni 54 341 424 8045 administracioncaici@gmail.com
Principal Investigator: Sergio Lupo, M.D.
Hospital Interzonal de Agudos San Juan de Dios	Not yet recruiting
La Plata, Argentina, 1900
Contact: Martha Michaan +54 9221 5765 131 mgmichaan@yahoo.com.ar
Principal Investigator: Martha Michaan, M.D.
Chile
Hospital San Borja-Arriaran	Not yet recruiting
Santiago, Chile, 8360159
Contact: Marcelo Wolff 562- 555 6206 marcewolff@yahoo.com
Contact: Gladys Allendes 562-555-6206 gladys_allendes@yahoo.es
Principal Investigator: Marcelo Wolff, MD
Colombia
ASISTENCIA Cientifica De Alta Complejidad S.A.S.	Not yet recruiting
Bogota, Colombia, 110010
Contact: Otto Sussmann 57-1- 5107600 ext 104 osussmann@gmail.com
Contact: Ana Julia Rojas 57-1-5107600 ext 128 coord.investigaciones@asistenciacientifica.com
Principal Investigator: Otto Sussmann, M.D.
India
YRG Care	Not yet recruiting
Chennai, Tamil Nadu, India, 600113
Contact: Nagalingeswaran Kumarasamy 91 917 691 2007 kumarasamy@yrgcare.org
Contact: Faith Beulah 91 44 39106811 beulah@yrgcare.org
Principal Investigator: Nagalingeswaran Kumarasamy, MD
Malaysia
University of Malaya Medical Centre	Not yet recruiting
Kuala Lumpur, Malaysia, 59100
Contact: Raja Iskandar Shah Raja Azwa 603-79493834 iskandar.azwa@gmail.com
Contact: Margaret Tan 603-79492622 margarettan455@gmail.com
Principal Investigator: Raja Iskandar Shah Raja Azwa, MBChB, MRCP
Mexico
Morales Vargas Centro de Investigacion SC	Not yet recruiting
León, Guanajuato, Mexico, 37000
Contact: Juan Luis Mosqueda Gomez +52 (477) 1310037 luis_mosqueda@yahoo.com
Contact: Jorge Morales Vargas +52 (477) 7160714 mnc.jorge@hotmail.com
Hospital Civil de Guadalajara	Not yet recruiting
Guadalajara, Jalisco, Mexico, 44280
Contact: Jaime Andrade-Villanueva jandradev@msn.com
Contact: Angeles González-Hernández 5233 3614 7586 angelesghdez1@gmail.com
Principal Investigator: Jaime Andrade-Villanueva, M.D.
Instituto Nacional de Ciencias Medicas y Nutriciòn Salvador Zubiran	Not yet recruiting
Mexico City, Mexico, 14080
Contact: Juan Sierra Madero 52 5556559675 jsmadero@yahoo.com
Contact: Izchel Loyo iz.inncm@outlook.com
Principal Investigator: Juan Sierra Madero, M.D.
South Africa
Desmond Tutu HIV Foundation	Recruiting
Cape Town, South Africa, 7925
Contact: Richard Kaplan Richard.Kaplan@hiv-research.org.za
Contact: Christie Heiberg 27 21 406 3621 Christie.Heiberg@hiv-research.org.za
Principal Investigator: Richard Kaplan, M.D.
Clinical HIV Research Unit (CHRU), Wits Health Consotium (Pty) Ltd	Recruiting
Johannesburg, South Africa, 2041
Contact: Noluthando Mwelase tmwelase@witshealth.co.za
Contact: Pauline Vunandala 27 11 276 8800 pvunandlala@witshealth.co.za
Principal Investigator: Noluthando Mwelase, MBCHB
Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital	Recruiting
Soweto, South Africa, 1864
Contact: Lerato Mohapi mohapil@hivsa.com
Contact: Debra Peters 27 11 989 9700 petersd@phru.co.za
Principal Investigator: Lerato Mohapi, BSc, MBBCh
Thailand
HIV-NAT (The HIV Netherlands Australia Thailand Research Collaboration), Thai Red Cross AIDS Research Centre	Recruiting
Bangkok, Thailand, 10330
Contact: Anchalee Avihingsanon +662 652 3040 ext 107 anchaleea2009@gmail.com
Contact: Kanitta Pussadee +662 652 3040 ext 202 kanitta.p@hivnat.org
Principal Investigator: Anchalee Avihingsanon, M.D.
Chiangrai Prachanukroh Hospital	Not yet recruiting
Chiang Rai, Thailand, 57000
Contact: Pacharee Kantipong 66818859195 pachareek@hotmail.com
Contact: Supawadee Pongprapass 66819616900 npudit@hotmail.com
Principal Investigator: Pacharee Kantipong, M.D.
Srinagarind Hospital, Khon Kaen University	Not yet recruiting
Khon Kaen, Thailand, 40002
Contact: Ploenchan Chetchotisakd 6643363168 ploencha@kku.ac.th
Contact: Anchalee Tiyabut 6643363169 atiyabut@yahoo.com
Principal Investigator: Ploenchan Chetchotisakd, M.D.
Bamrasnaradura Infectious Diseases Institute	Not yet recruiting
Nonthaburi, Thailand, 11000
Contact: Weerawat Manosuthi drweerawat@hotmail.com
Contact: Supeda Thongyen 6625903631 supeda_t@yahoo.com
Principal Investigator: Weerawat Manosuthi, M.D.
Zimbabwe
University of Zimbabwe Clinical Research Centre	Recruiting
Harare, Zimbabwe, +263
Contact: James G Hakim 263 772225489 Jhakim@mweb.co.zw
Contact: Shepherd Mudzingwa 263 4 701717 smudzingwa@yahoo.com
Principal Investigator: James G Hakim, M.D.

Sponsors and Collaborators

Kirby Institute

UNITAID

National Health and Medical Research Council, Australia

ViiV Healthcare

Janssen Pharmaceutica

Investigators

Study Director:	David A Cooper	Kirby Institute

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Kirby Institute
ClinicalTrials.gov Identifier:	NCT03017872 History of Changes
Other Study ID Numbers:	D2EFT
First Posted:	January 11, 2017
Last Update Posted:	January 12, 2018
Last Verified:	October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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

Keywords provided by Kirby Institute:

HIV, second-line

Additional relevant MeSH terms:

HIV Infections; Acquired Immunodeficiency Syndrome; Infection; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; 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