Ignite Creation Date:
2024-05-05 @ 10:11 PM
Last Modification Date:
2024-10-26 @ 10:15 AM
Study NCT ID:
NCT01049204
Status:
TERMINATED
Last Update Posted:
2011-11-01
First Post:
2010-01-12
Brief Title:
Impact of Maraviroc on the Immune Function in HIV-1 Infected Subjects Receiving Immunisation With Novel Antigens
Sponsor:
St Stephens Aids Trust
Organization:
St Stephens Aids Trust
Study Overview
Official Title:
Randomised Placebo Controlled Phase IV Safety and Exploratory Immunogenicity Study on Maraviroc an Oral ART CCR5 Inhibitor on the Intensification of Immune Function in HIV-1 Infected Subjects Receiving Immunisation With Novel Antigens
Status:
TERMINATED
Status Verified Date:
2011-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
The data from the first 48 patients recruited has now been analysed and it has been determined that it is sufficient to meet the study objectives
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Impact of Maraviroc a ART CCR5 inhibitor on the intensification of immune function in HIV-1 infected subjects receiving immunisation with novel antigens
The purpose of the study is to investigate the impact of adding Maraviroc an anti-HIV agent to a participants normal HIV medication on immune function As part of the study participants will also receive three different vaccinations and a skin test The study will also look at whether Maraviroc influences the bodys response to these
The vaccines are given to stimulate the bodys immune system so we can therefore evaluate the impact that Maraviroc has on this
The duration of the study will be just over 24 weeks plus a screening period up to 4 weeks prior to the start of the study
The purpose of the study is to investigate the impact of adding Maraviroc an anti-HIV agent to a participants normal HIV medication on immune function As part of the study participants will also receive three different vaccinations and a skin test The study will also look at whether Maraviroc influences the bodys response to these
The vaccines are given to stimulate the bodys immune system so we can therefore evaluate the impact that Maraviroc has on this
The duration of the study will be just over 24 weeks plus a screening period up to 4 weeks prior to the start of the study
Detailed Description:
Maraviroc is a CCR5 antagonist with potent anti-HIV-1 activity demonstrated in both treatment naïve and experienced settings Binding of maraviroc to CCR5 leads to the loss of receptor function Individuals with non-functioning CCR5 due to a 32 base pair deletion in the encoding gene are observed at a 1 frequency in the northern European Caucasian population These individuals have near normal immune function although differential response to renal transplant and West Nile virus have been reported relative to individuals with functional CCR5 The modest impact on immune function is indicative of a functional overlap between CCR5 and other CC chemokine receptors While the precise role of CCR5 has not been established data suggest a role in chemotaxis and inflammation
An excess of clinical events infective inflammatory or malignant have not been reported in persons receiving maraviroc relative to placebo or to efavirenz-based antiretroviral therapy over 48 weeks follow-up Indeed individuals randomized to maraviroc were noted in these studies to have modestly greater increases in CD4 T-cell numbers not accounted for by changes in lymphocyte counts or rates of viral suppression
The impact of inclusion of maraviroc in an antiretroviral treatment regimen on immune function has not been reported
In chronically infected HIV-1 individuals who progress to AIDS the full functionality of the anti-HIV-1 CD8 cytotoxic T lymphocyte response is progressively lost This is accompanied by diminished responses to neo- and recall antigens and skin anergy loss of DTH response This is likely dependent on the loss of function and numbers of HIV-1-specific CD4 helper T lymphocytes Appay and Sauce 2008 This process is apparently at least partially irreversible despite otherwise successful currently used antiretroviral drug regimens Accumulation of functionally inert anergic HIV-1-specific CD4 and CD8 CD28- CTLA-4hi T cells is observed which lack proliferative and IL-2 producing ability and cytolytic function despite maintaining the capacity to produce IFN-γ Deeks and Walker 2007 A balanced response in which the host responds appropriately to prevalent antigen such as HIV-1 Gag yet remains relatively quiescent may prove to be the strongest functional correlate of virologic control Imami et al 2002 Imami et al 2007
Recent work has shown that tetanus antibody responses are significantly impaired in HIV patients on successful ART Hart et al 2007 A recently identified CD4 T-cell subset known as follicular T cells TFH plays a crucial role in the development of humoral immune responses to protein antigens such as tetanus toxoid King et al 2008 Follicular CD4 T cells express a chemokine receptor called CXCR5 a protein called inducible co-stimulatory factor ICOS and are readily identified in peripheral blood Follicular CD4 T cells are prone to activation induced cell death which is believed to be a major mechanism of CD4 T-cell depletion in chronic HIV-1 infection and therefore could be a vulnerable target in retroviral disease A reduction in circulating CD4 TFH numbers andor function may account for the failure of HIV-1 patients to respond to tetanus vaccination
The aims of this study are to investigate the impact of the addition of maraviroc to a successful HIV-1 treatment regimen on in vitro lymphoproliferative ELISpot assays and in vivo response to subcutaneous and GI administered vaccination by antibody and skin tests as applicable immune function and to assess function of CD4 TFH cells by measuring cytokine and co-stimulatory protein expression in this T-cell subset
This 92 patient randomized blinded placebo controlled trial plans to investigate the impact of the addition of maraviroc to on-going successful PIr based ART with regards to multiple immunology markers including markers of activation CD4 and CD8 T-cell subsets immune function Elispot and lymphoproliferative responses to HIV-1 and recall antigens andor peptides Gag TTox CMV and antibody response to oral cholera and deep subcutaneousIM meningococcus neoantigens and recall antigens Tetanus toxoid and to assess function of CD4 TFH cells by measuring cytokine and co-stimulatory protein expression in this subset Delayed type hypersensitivity will be tested at baseline and week 24 and read 48 hours post administration of the Mantoux test
Participants will be stratified by CD4 nadir with 50 of patients having a CD4 nadir 200 cellsµl blood
Maraviroc will be administered to patients at a dose level of 150mg BID This dose is approved for use in the UK
An excess of clinical events infective inflammatory or malignant have not been reported in persons receiving maraviroc relative to placebo or to efavirenz-based antiretroviral therapy over 48 weeks follow-up Indeed individuals randomized to maraviroc were noted in these studies to have modestly greater increases in CD4 T-cell numbers not accounted for by changes in lymphocyte counts or rates of viral suppression
The impact of inclusion of maraviroc in an antiretroviral treatment regimen on immune function has not been reported
In chronically infected HIV-1 individuals who progress to AIDS the full functionality of the anti-HIV-1 CD8 cytotoxic T lymphocyte response is progressively lost This is accompanied by diminished responses to neo- and recall antigens and skin anergy loss of DTH response This is likely dependent on the loss of function and numbers of HIV-1-specific CD4 helper T lymphocytes Appay and Sauce 2008 This process is apparently at least partially irreversible despite otherwise successful currently used antiretroviral drug regimens Accumulation of functionally inert anergic HIV-1-specific CD4 and CD8 CD28- CTLA-4hi T cells is observed which lack proliferative and IL-2 producing ability and cytolytic function despite maintaining the capacity to produce IFN-γ Deeks and Walker 2007 A balanced response in which the host responds appropriately to prevalent antigen such as HIV-1 Gag yet remains relatively quiescent may prove to be the strongest functional correlate of virologic control Imami et al 2002 Imami et al 2007
Recent work has shown that tetanus antibody responses are significantly impaired in HIV patients on successful ART Hart et al 2007 A recently identified CD4 T-cell subset known as follicular T cells TFH plays a crucial role in the development of humoral immune responses to protein antigens such as tetanus toxoid King et al 2008 Follicular CD4 T cells express a chemokine receptor called CXCR5 a protein called inducible co-stimulatory factor ICOS and are readily identified in peripheral blood Follicular CD4 T cells are prone to activation induced cell death which is believed to be a major mechanism of CD4 T-cell depletion in chronic HIV-1 infection and therefore could be a vulnerable target in retroviral disease A reduction in circulating CD4 TFH numbers andor function may account for the failure of HIV-1 patients to respond to tetanus vaccination
The aims of this study are to investigate the impact of the addition of maraviroc to a successful HIV-1 treatment regimen on in vitro lymphoproliferative ELISpot assays and in vivo response to subcutaneous and GI administered vaccination by antibody and skin tests as applicable immune function and to assess function of CD4 TFH cells by measuring cytokine and co-stimulatory protein expression in this T-cell subset
This 92 patient randomized blinded placebo controlled trial plans to investigate the impact of the addition of maraviroc to on-going successful PIr based ART with regards to multiple immunology markers including markers of activation CD4 and CD8 T-cell subsets immune function Elispot and lymphoproliferative responses to HIV-1 and recall antigens andor peptides Gag TTox CMV and antibody response to oral cholera and deep subcutaneousIM meningococcus neoantigens and recall antigens Tetanus toxoid and to assess function of CD4 TFH cells by measuring cytokine and co-stimulatory protein expression in this subset Delayed type hypersensitivity will be tested at baseline and week 24 and read 48 hours post administration of the Mantoux test
Participants will be stratified by CD4 nadir with 50 of patients having a CD4 nadir 200 cellsµl blood
Maraviroc will be administered to patients at a dose level of 150mg BID This dose is approved for use in the UK
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| EudraCT No 2008-006769-95 | OTHER | EU Clinical Trials database | None |