Ignite Creation Date:
2024-05-06 @ 3:11 PM
Last Modification Date:
2024-10-26 @ 1:45 PM
Study NCT ID:
NCT04553081
Status:
RECRUITING
Last Update Posted:
2024-02-28
First Post:
2020-05-29
Brief Title:
2DR Versus 3DR in a Prospective Randomized Controlled Switch Trial
Sponsor:
University Hospital Ghent
Organization:
University Hospital Ghent
Study Overview
Official Title:
Virological and Immunological Assessment in HIV Positive Participants on 2DR Versus 3DR in a Prospective Randomized Controlled Switch Trial
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
2DR
Brief Summary:
The aim of this study is to monitor virological and immunological markers in participants who are switching from a classic triple drug regimen 3DR to dual therapy 2DR We aim to monitor whether this has an influence on different parameters such as severity of HIV disease evaluated by viral load and viral reservoir size presence of non-AIDS related health complications impact the phenotype and function of the immune system
By conducting this study we want to assess whether switching from 3DR to 2DR implies an increased risk for subclinical failure We especially want to make sure that this switch does not increase the HIV reservoir does not increase inflammation or immune exhaustion in patients living with HIV and that it can be considered as a safe long term alternative for the classic 3DR
The primary objective is to demonstrate non inferiority at W48 of the 2DR DTG3TC Dovato regimen compared to BICTAFFTC Biktarvy in terms of the amount of intact replication competent HIV sequences with a non-inferiority margin of 12 quantified by the fraction intact HIV viral sequences quantified by an intact proviral DNA assay present in blood CD4 cells
By conducting this study we want to assess whether switching from 3DR to 2DR implies an increased risk for subclinical failure We especially want to make sure that this switch does not increase the HIV reservoir does not increase inflammation or immune exhaustion in patients living with HIV and that it can be considered as a safe long term alternative for the classic 3DR
The primary objective is to demonstrate non inferiority at W48 of the 2DR DTG3TC Dovato regimen compared to BICTAFFTC Biktarvy in terms of the amount of intact replication competent HIV sequences with a non-inferiority margin of 12 quantified by the fraction intact HIV viral sequences quantified by an intact proviral DNA assay present in blood CD4 cells
Detailed Description:
In HIV care we have been facing a paradigm change over the last years reaching an ultimatum with the reimbursement of a 2DR regimen both in naïve as in switch patients
The rationale behind dual therapy is interesting namely lower cost less side-effects more preserved treatment options less interactions
However from a patient and clinicians perspective this requires a paradigm change after an era of successful treating patient with 3DR
In the past 2DR and even 1DR treatments have been proposed as an alternative for 3DR however results were often disappointing and these regimens were only suitable for a selection of patients often requiring intensification of follow-up
Recently dual therapy with integrase inhibitor dolutegravir has shown very promising results both in switch TANGO study with no virological failure related to this regimen over 48 weeks and in naïve patients GEMINI study with no resistance mutations at 96 weeks Moreover time to undectability was statistically not different from the 3DR group and the small amount of data available on in depth analysis of the reservoir and immunological parameters were reassuring
Comparative data however on immunological and virological parameters are lacking therefore we want to conduct the present clinical trial to further elaborate on this important question
Recent data show that newer ARVs among which integrase inhibitors and TAF are associated with weight gain Further data is required to investigate the patterns of weight change with these ARVs and any associated metabolic impact
So far DTG3TC has been assessed in 3 phase III clinical trials GEMINI-1 GEMINI-2 and TANGO GEMINI-1 and GEMINI-2 are two large identically designed phase 3 studies that compare the 2DR DTG3TC once daily with a first-line recommended 3DR DTG 2 nucleoside reverse transcriptase inhibitors NRTIs tenofovir disoproxil TDFFTC once daily in treatment-naïve People living with HIV PLHIV Cahn 2019 The primary objective of TANGO is to demonstrate the non-inferior antiviral activity of switching to DTG3TC once daily compared to the continuation of TAF-based regimens TBR over 48 weeks in ART-experienced virologically suppressed PLHIV Van Wyk 2020 The primary results of these trials have been published Cahn 2019 Van Wyk 2020 while the trials continue in order to collect longer-term data
GEMINI-1 and GEMINI-2 are 2 twin phase 3 randomised double-blind active-controlled multicentre parallel-group noninferiority studies conducted in treatment-naive patients with HIV-1 RNA of 1000 to 500000 cmL at screening Patients are randomised 11 to receive DTG3TC once daily or DTG plus FDC tablet of TDFFTC once daily The results of GEMINI-1 GEMINI-2 and the pooled analysis demonstrated that DTG3TC has a high level of efficacy and safety and is noninferior to 3DR DTGTDFFTC In the pooled analysis 91 of patients in the DTG3TC arm and 93 of patients in the DTGTDFFTC arm achieved plasma HIV-1 RNA 50 cmL by Week 48 The Week 96 secondary efficacy analysis demonstrated that DTG3TC continued to provide a high level of clinical efficacy A similar proportion of subjects in each treatment group achieved the secondary efficacy endpoint of plasma HIV-1 RNA 50 cmL at Week 96 for GEMINI-2 and pooled analysis Based on the Food and drug administration FDA Snapshot algorithm DTG3TC is noninferior to DTGTDFFTC in the individual studies as well as the pooled analysis at Week 48 and at Week 96 The subgroup analyses further supported the noninferiority of DTG3TC at both Week 48 and Week 96 Moreover few patients experienced CVW by Week 48 with comparable rates across treatment arms 1 in each and fewer AEs were observed in the DTG3TC arm compared to DTGTDFFTC No treatment-emergent resistance mutation were observed in these patients up to Week 96 demonstrating DTG3TCs high barrier to resistance The incidence of drug-related AEs at Week 48 in the DTG3TC arm was low 126716 18 and lower than that in the DTGTDFFTC arm 169717 24 The most common 1 drug-related Grade 2-4 AE in both arms was headache 1 in both arms Low rates of drug-related AEs were also observed at Week 96 for both arms with slightly more but comparable overall AEs and slightly more drug-related AEs in the DTGTDFFTC arm compared with the DTG3TC arm
TANGO is a 200-week phase 3 randomised open-label active-controlled multicentre parallel-group study to assess the noninferior antiviral activity and safety of replacing a TBR with a 2DR of DTG3TC in HIV-infected adults who are virologically suppressed and stable on TBR Van Wyk 2020 The results of TANGO demonstrate that DTG3TC has a high level of efficacy and safety for patients switching from TBR Based on the FDA Snapshot virologic failure DTG3TC is noninferior to TBR at Week 24 Ait-Khaled 2019 Van Wyk 2020 Very few 1 patients experienced virologic failure in both treatment arms Only one patient in the TBR arm had a CVW by Week 24 A greater proportion of patients in the DTG3TC arm experienced Serious Adverse Events SAEs but not drug-related SAEs drug-related adverse events AEs and AEs leading to withdrawal from the study compared with the TBR arm in the first 24 weeks of the study as expected due to the switch study design
The various clinical trials ongoing and planned for DTG3TC are further supported by real-world evidence These real-world studies have findings consistent with the results observed in clinical trials
The primary objective is to demonstrate non inferiority at W48 of the 2DR DTG3TC Dovato regimen compared to BICTAFFTC Biktarvy in HIV-1 infected individuals in terms of the amount of intact replication-competent HIV-1 sequences with a non-inferiority margin of 12 quantified by the fraction intact HIV viral sequences quantified by IPDA present in blood CD4 cells
1 Quantification of immune activation markers in both arms will be explored as secondary objective and should not differ more than 20 The power calculation is however calculated based on the primary objective
Assessment at baseline W48 and W144
Inflammation markers IL-6 hs-CRP of CRP other IL_8 IP10 TNF B2M CXCL1 IL21 Hyaluric acid
Markers of coagulopathy D-Dimers
T cell activation markers HLA-DR CD38 on both CD4 and CD8 soluble markers sCD27 sCH40 ligand
T cell exhaustion markers PD-1 CD28 CD57
Markers of microbial translocation sCD14
CD4CD8 ratio
2 In addition the secondary objective is to assess impact of the DTG3TC vs BICFTCTAF on metabolic health Therefore as secondary endpoint metabolic health will be assessed through incidence of metabolic syndrome weightBMI change waist circumference and insulin resistance Finally dual-energy x-ray absorptiometry DXA scans will be performed to assess body composition and fat distribution and bone mineral density and FibroScans will be performed to assess liver steatosis and fibrosis
3 As a third secondary objective we will assess the impact of switching through a patient questionnaire
4 The fourth secondary objective is to demonstrate non inferiority at W144 of the 2DR DTG3TC Dovato regimen compared to BICTAFFTC Biktarvy in HIV-1 infected individuals in terms of the amount of intact replication-competent HIV-1 sequences with a non-inferiority margin of 12 quantified by the fraction intact HIV viral sequences quantified by IPDA present in blood CD4 cells
The rationale behind dual therapy is interesting namely lower cost less side-effects more preserved treatment options less interactions
However from a patient and clinicians perspective this requires a paradigm change after an era of successful treating patient with 3DR
In the past 2DR and even 1DR treatments have been proposed as an alternative for 3DR however results were often disappointing and these regimens were only suitable for a selection of patients often requiring intensification of follow-up
Recently dual therapy with integrase inhibitor dolutegravir has shown very promising results both in switch TANGO study with no virological failure related to this regimen over 48 weeks and in naïve patients GEMINI study with no resistance mutations at 96 weeks Moreover time to undectability was statistically not different from the 3DR group and the small amount of data available on in depth analysis of the reservoir and immunological parameters were reassuring
Comparative data however on immunological and virological parameters are lacking therefore we want to conduct the present clinical trial to further elaborate on this important question
Recent data show that newer ARVs among which integrase inhibitors and TAF are associated with weight gain Further data is required to investigate the patterns of weight change with these ARVs and any associated metabolic impact
So far DTG3TC has been assessed in 3 phase III clinical trials GEMINI-1 GEMINI-2 and TANGO GEMINI-1 and GEMINI-2 are two large identically designed phase 3 studies that compare the 2DR DTG3TC once daily with a first-line recommended 3DR DTG 2 nucleoside reverse transcriptase inhibitors NRTIs tenofovir disoproxil TDFFTC once daily in treatment-naïve People living with HIV PLHIV Cahn 2019 The primary objective of TANGO is to demonstrate the non-inferior antiviral activity of switching to DTG3TC once daily compared to the continuation of TAF-based regimens TBR over 48 weeks in ART-experienced virologically suppressed PLHIV Van Wyk 2020 The primary results of these trials have been published Cahn 2019 Van Wyk 2020 while the trials continue in order to collect longer-term data
GEMINI-1 and GEMINI-2 are 2 twin phase 3 randomised double-blind active-controlled multicentre parallel-group noninferiority studies conducted in treatment-naive patients with HIV-1 RNA of 1000 to 500000 cmL at screening Patients are randomised 11 to receive DTG3TC once daily or DTG plus FDC tablet of TDFFTC once daily The results of GEMINI-1 GEMINI-2 and the pooled analysis demonstrated that DTG3TC has a high level of efficacy and safety and is noninferior to 3DR DTGTDFFTC In the pooled analysis 91 of patients in the DTG3TC arm and 93 of patients in the DTGTDFFTC arm achieved plasma HIV-1 RNA 50 cmL by Week 48 The Week 96 secondary efficacy analysis demonstrated that DTG3TC continued to provide a high level of clinical efficacy A similar proportion of subjects in each treatment group achieved the secondary efficacy endpoint of plasma HIV-1 RNA 50 cmL at Week 96 for GEMINI-2 and pooled analysis Based on the Food and drug administration FDA Snapshot algorithm DTG3TC is noninferior to DTGTDFFTC in the individual studies as well as the pooled analysis at Week 48 and at Week 96 The subgroup analyses further supported the noninferiority of DTG3TC at both Week 48 and Week 96 Moreover few patients experienced CVW by Week 48 with comparable rates across treatment arms 1 in each and fewer AEs were observed in the DTG3TC arm compared to DTGTDFFTC No treatment-emergent resistance mutation were observed in these patients up to Week 96 demonstrating DTG3TCs high barrier to resistance The incidence of drug-related AEs at Week 48 in the DTG3TC arm was low 126716 18 and lower than that in the DTGTDFFTC arm 169717 24 The most common 1 drug-related Grade 2-4 AE in both arms was headache 1 in both arms Low rates of drug-related AEs were also observed at Week 96 for both arms with slightly more but comparable overall AEs and slightly more drug-related AEs in the DTGTDFFTC arm compared with the DTG3TC arm
TANGO is a 200-week phase 3 randomised open-label active-controlled multicentre parallel-group study to assess the noninferior antiviral activity and safety of replacing a TBR with a 2DR of DTG3TC in HIV-infected adults who are virologically suppressed and stable on TBR Van Wyk 2020 The results of TANGO demonstrate that DTG3TC has a high level of efficacy and safety for patients switching from TBR Based on the FDA Snapshot virologic failure DTG3TC is noninferior to TBR at Week 24 Ait-Khaled 2019 Van Wyk 2020 Very few 1 patients experienced virologic failure in both treatment arms Only one patient in the TBR arm had a CVW by Week 24 A greater proportion of patients in the DTG3TC arm experienced Serious Adverse Events SAEs but not drug-related SAEs drug-related adverse events AEs and AEs leading to withdrawal from the study compared with the TBR arm in the first 24 weeks of the study as expected due to the switch study design
The various clinical trials ongoing and planned for DTG3TC are further supported by real-world evidence These real-world studies have findings consistent with the results observed in clinical trials
The primary objective is to demonstrate non inferiority at W48 of the 2DR DTG3TC Dovato regimen compared to BICTAFFTC Biktarvy in HIV-1 infected individuals in terms of the amount of intact replication-competent HIV-1 sequences with a non-inferiority margin of 12 quantified by the fraction intact HIV viral sequences quantified by IPDA present in blood CD4 cells
1 Quantification of immune activation markers in both arms will be explored as secondary objective and should not differ more than 20 The power calculation is however calculated based on the primary objective
Assessment at baseline W48 and W144
Inflammation markers IL-6 hs-CRP of CRP other IL_8 IP10 TNF B2M CXCL1 IL21 Hyaluric acid
Markers of coagulopathy D-Dimers
T cell activation markers HLA-DR CD38 on both CD4 and CD8 soluble markers sCD27 sCH40 ligand
T cell exhaustion markers PD-1 CD28 CD57
Markers of microbial translocation sCD14
CD4CD8 ratio
2 In addition the secondary objective is to assess impact of the DTG3TC vs BICFTCTAF on metabolic health Therefore as secondary endpoint metabolic health will be assessed through incidence of metabolic syndrome weightBMI change waist circumference and insulin resistance Finally dual-energy x-ray absorptiometry DXA scans will be performed to assess body composition and fat distribution and bone mineral density and FibroScans will be performed to assess liver steatosis and fibrosis
3 As a third secondary objective we will assess the impact of switching through a patient questionnaire
4 The fourth secondary objective is to demonstrate non inferiority at W144 of the 2DR DTG3TC Dovato regimen compared to BICTAFFTC Biktarvy in HIV-1 infected individuals in terms of the amount of intact replication-competent HIV-1 sequences with a non-inferiority margin of 12 quantified by the fraction intact HIV viral sequences quantified by IPDA present in blood CD4 cells
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None