Dolutegravir and Darunavir Evaluation in Adults Failing Therapy

NCT03017872 | Unknown Phase 4 DMC

• 3 other identifiers: D2EFT18Q06519Q120
• Study Type: interventional
• Target: 831
• Locations: 14 countries
• Sites: 28

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.

Conditions

HIV Infections

Keywords

HIV, second-line

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (14)

• Proportion with plasma viral load <200 copies/mL

  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

• Mean/median changes from baseline in fasted lipids (Total cholesterol, LDL-c, HDL-c, and triglycerides)

  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

Study Arms (3)

Standard of Care (SoC) arm

ACTIVE COMPARATOR

2 x NRTIs + darunavir/ritonavir 800mg/100mg po od

Drug: NRTIs; Drug: Darunavir; Drug: Ritonavir

Dolutegravir arm

EXPERIMENTAL

Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od

Drug: Dolutegravir; Drug: Darunavir; Drug: Ritonavir

Dolutegravir 2NRTI arm (D2N)

EXPERIMENTAL

Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)

Drug: NRTIs; Drug: Dolutegravir

Interventions

NRTIs DRUG

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.

Also known as: Nucleoside/Nucleotide Reverse Transcription Inhibitors

Dolutegravir 2NRTI arm (D2N); Standard of Care (SoC) arm

Dolutegravir DRUG

50mg tablet by mouth once daily for 96 weeks.

Also known as: Tivicay

Dolutegravir 2NRTI arm (D2N); Dolutegravir arm

Darunavir DRUG

800mg tablet by mouth once daily for 96 weeks.

Also known as: Prezista

Dolutegravir arm; Standard of Care (SoC) arm

Ritonavir DRUG

100mg tablet by mouth once daily for 96 weeks.

Also known as: Norvir

Dolutegravir arm; Standard of Care (SoC) arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kirby Institute: lead
• UNITAID: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• National Health and Medical Research Council, Australia: collaborator
• ViiV Healthcare: collaborator
• Janssen Pharmaceutica: collaborator

Study Sites (28)

Hospital Dr Diego Paroissien

Isidro Casanova, Buenos Aires, 1765, Argentina

Location

Hospital G de Agudos JM Ramos Mejia

Buenos Aires, Buenos Aires F.D., C1221ADC, Argentina

Location

CAICI

Rosario, Santa Fe Province, S2000PBJ, Argentina

Location

Hospital Interzonal de Agudos San Juan de Dios

La Plata, 1900, Argentina

Location

Laboratório de Pesquisa Clinica Em Hiv/Aids - Instituto Nacional de Infectologia - Fiocruz

Rio de Janeiro, 21040-360, Brazil

Location

Hospital San Borja-Arriaran

Santiago, 8360159, Chile

Location

ASISTENCIA Cientifica De Alta Complejidad S.A.S.

Bogotá, 110010, Colombia

Location

Centre de traitementambulatoire de Donka ( Hopital de jour)

Conakry, BP:5845, Guinea

Location

CART CRS, VHS Hospital

Chennai, Tamil Nadu, 600113, India

Location

Dr. Cipto Mangunkusumo Hospital

Jakarta, 10320, Indonesia

Location

RSUP Dr. Wahidin Sudirohusodo

Makassar, 90241, Indonesia

Location

Dr. Soetomo Hospital

Surabaya, 60285, Indonesia

Location

Dr Sardjito Hospital

Yogyakarta, 55284, Indonesia

Location

Hospital Pulau Pinang

George Town, Pulau Pinang, 10450, Malaysia

Location

University of Malaya Medical Centre

Kuala Lumpur, 59100, Malaysia

Location

University of Sciences, Techniques and Technologies of Mali, University Clinical Research Center (UCRC)

Bamako, Mali

Location

Morales Vargas Centro de Investigacion SC

León, Guanajuato, 37000, Mexico

Location

Hospital Civil de Guadalajara

Guadalajara, Jalisco, 44280, Mexico

Location

Instituto Nacional de Ciencias Medicas y Nutriciòn Salvador Zubiran

Mexico City, 14080, Mexico

Location

Institute of Human Virology, Nigeria (IHVN)

Abuja, 9396, Nigeria

Location

Desmond Tutu HIV Foundation

Cape Town, 7925, South Africa

Location

Clinical HIV Research Unit (CHRU), Wits Health Consotium (Pty) Ltd

Johannesburg, 2041, South Africa

Location

Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital

Soweto, 1864, South Africa

Location

HIV-NAT (The HIV Netherlands Australia Thailand Research Collaboration), Thai Red Cross AIDS Research Centre

Bangkok, 10330, Thailand

Location

Chiangrai Prachanukroh Hospital

Chiang Rai, 57000, Thailand

Location

Srinagarind Hospital, Khon Kaen University

Khon Kaen, 40002, Thailand

Location

Bamrasnaradura Infectious Diseases Institute

Nonthaburi, 11000, Thailand

Location

University of Zimbabwe Clinical Research Centre

Harare, +263, Zimbabwe

Location

Related Publications (2)

• D2EFT Study Group. Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D2EFT): an open-label, randomised, phase 3b/4 trial. Lancet HIV. 2024 Jul;11(7):e436-e448. doi: 10.1016/S2352-3018(24)00089-4. Epub 2024 May 21.

  PMID: 38788744 DERIVED

• Nyein PP, Petoumenos K, Borok M, Eriobu N, Kumarasamy N, Avihingsanon A, Azwa I, Dao S, Cisse M, Dharan NJ, Hanson J, Matthews GV. Associations Between Antiretroviral Regimen and Changes in Blood Pressure: Results From the D2EFT Study. Clin Infect Dis. 2025 Feb 5;80(1):160-163. doi: 10.1093/cid/ciae256.

  PMID: 38721980 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Nucleosides; dolutegravir; Darunavir; Ritonavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Glycosides; Carbohydrates; Nucleic Acids, Nucleotides, and Nucleosides; Sulfonamides; Amides; Organic Chemicals; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles

Study Officials

• Gail Matthews, MD

  Kirby Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 2, 2017
• First Posted: January 11, 2017
• Study Start: November 23, 2017
• Primary Completion: November 11, 2022
• Study Completion: October 31, 2023
• Last Updated: April 18, 2023

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

CL (1); GU (1); TH (4); BR (1); AR (4); MA (1); IN (1); ID (4); ME (3); ZA (3); CO (1); MY (2); NG (1); ZI (1)