Inflammation and Co-Infections in D²EFT (i2-D²EFT)

November 8, 2020 updated by: Kirby Institute

The Impact of Co-infections on Inflammation in Patients Commencing Second-line Antiretroviral Therapy. A Sub-study of D²EFT (Dolutegravir and Darunavir Evaluation in Adults Failing Therapy)

i2-D²EFT substudy is an observational cohort nested within the parent D²EFT study (NCT03017872). D²EFT goal is to compare the standard of care second-line antiretroviral therapy in people living with HIV whose first-line non nucleoside reverse transcriptase-based regimen failed, to two simpler regimens. Approximately 1,000 participants will be enrolled in D²EFT.

Commencing a second-line ART is an important moment when the level of inflammation in participants may be elevated due to first-line ART failure; this level of inflammation should then decrease with the commencement of a new second-line treatment and would be expected to normalise by 48 weeks of second-line treatment, if successful.

The investigators propose to study other factors which can influence the decrease of inflammation. The investigators hypothesise that co-infections may play a role in persistent inflammation. The key-infections of interest will be common frequent infections encounter throughout the world: Human Herpes virus 8, Epstein-Barr virus, Cytomegalovirus and Human papillomavirus, tuberculosis, malaria and other key opportunistic infections. Possible changes of level of inflammation (using the serum level of Interleukin 6) in approximately 200 participants of the D²EFT study will be investigated and measured. The hypothesis is that the presence of other infections than HIV may influence the level of inflammation in participants in therapeutic success.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

i2-D²EFT substudy an observational cohort nested within the parent open label phase III/IV randomised controlled trial of simplified second-line therapy, D²EFT (NCT03017872). Participants consenting to D²EFT study will be randomised within the three arms: either ritonavir-boosted darunavir plus two nucleosides or dolutegravir plus two predetermined nucleosides (tenofovir disoproxil fumarate plus lamivudine or emtricitabine) or ritonavir-boosted darunavir plus dolutegravir. Enrolment into the i2-D²EFT substudy is voluntary and optional for participants in D²EFT. Parameters relevant to i2-D²EFT substudy including demographics, arm of randomised ART, HIV history, physical examination, immunological and virological results, episodes of co-infections and adverse events due to any infection or malignancies at required time points will be collected as part of D²EFT study. Substudy specific assessments performed at baseline and at weeks 48 include sample collection for IL-6 dosage plus EBV/CMV/HHV8 testing, and optional anal/cervical HPV screening.

Study Type

Interventional

Phase

  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Fulfil the eligibility criteria for D²EFT randomisation;
  • Being able to give a written informed consent for the i2-D²EFT sub-study.

Exclusion Criteria:

  • Unwilling to comply with the i2-D²EFT protocol requirements.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: SOC
darunavir/ritonavir 800/100mg + 2 NRTIs po od
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 Names:
  • Nucleoside/Nucleotide Reverse Transcription Inhibitors
Drug: Darunavir
800mg tablet by mouth once daily for 96 weeks.
Other Names:
  • Prezista
Drug: Ritonavir
100mg tablet by mouth once daily for 96 weeks.
Other Names:
  • Norvir
EXPERIMENTAL: DOL
darunavir/ritonavir 800/100mg + dolutegravir 50mg po od
Drug: Darunavir
800mg tablet by mouth once daily for 96 weeks.
Other Names:
  • Prezista
Drug: Ritonavir
100mg tablet by mouth once daily for 96 weeks.
Other Names:
  • Norvir
Drug: Dolutegravir
50mg tablet by mouth once daily for 96 weeks.
Other Names:
  • Tivicay
EXPERIMENTAL: D2N
dolutegravir 50mg + tenofovir + emtricitabine or lamivudine po od
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 Names:
  • Nucleoside/Nucleotide Reverse Transcription Inhibitors
Drug: Dolutegravir
50mg tablet by mouth once daily for 96 weeks.
Other Names:
  • Tivicay

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in IL-6 level at week 48
Time Frame: At week 0 and week 48
To compare the change of a biomarker of inflammation (IL-6) in participants who achieve HIV virological suppression (defined as peripheral blood viral load below 50 copies/mm3 at week 48) across the three study arms according to the presence (or not) of active key-co-infections (HHV8, EBV, CMV, HPV) at baseline and week 48, and the occurrence (or not) within these 48 weeks of any infection (co-infections or opportunistic infections).
At week 0 and week 48
Change from baseline of presence/absence of active key co-infections at week 48
Time Frame: At week 0 and week 48
Active key-co-infections (HHV8, EBV, CMV, HPV) at baseline and week 48, and the occurrence (or not) within these 48 weeks of any infection (co-infections or opportunistic infections).
At week 0 and week 48

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of HHV8, EBV and CMV and of cervical and anal HPV
Time Frame: At week 0
To describe the prevalence of HHV8, EBV and CMV (defined by serological assays) and of cervical and anal HPV (defined by tissue HPV deoxyribonucleic acid (DNA) detection) at baseline, in the D2EFT cohort, by geographic region, route of HIV transmission, and other demographic and disease variables.
At week 0
Occurrence of active HHV8, EBV and CMV
Time Frame: At week 48
To compare the occurrence of active HHV8, EBV and CMV (defined by a detectable peripheral blood viral load) in participants with and without HIV virological suppression at 48 weeks, across the three arms of D²EFT.
At week 48
Change from baseline in rates of detection of cervical and anal HPV infection at week 48
Time Frame: At week 0 and week 48
To compare rates of detection of cervical and anal HPV infection (defined by tissue HPV DNA detection) between baseline and week 48 in participants with and without HIV virological suppression at 48 weeks across the three arms of D²EFT.
At week 0 and week 48

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kirby Institute

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
ViiV Healthcare
UNITAID
Janssen Pharmaceutica
Frederick National Laboratory for Cancer Research

Investigators

  • Principal Investigator: Mark Polizzotto, MD, PhD, Kirby Institute, UNSW Sydney, Australia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

February 1, 2021

Primary Completion (ANTICIPATED)

December 19, 2022

Study Completion (ANTICIPATED)

December 19, 2022

Study Registration Dates

First Submitted

November 28, 2019

First Submitted That Met QC Criteria

November 28, 2019

First Posted (ACTUAL)

December 3, 2019

Study Record Updates

Last Update Posted (ACTUAL)

November 10, 2020

Last Update Submitted That Met QC Criteria

November 8, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2019-10-i2-DEFT
  • 18Q065 (Other Grant/Funding Number: NIAID via Leidos)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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