HIV InfectionsPhase 4NCT00925756
CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery
A Phase 4 study testing Maraviroc in people with HIV Infections, run by University of California, San Diego at 3 sites in United States.
Trial summary
CCTG 590 is a open-label study to evaluate the impact of therapy intensification with Maraviroc (MVC) (a CCR5 inhibitor) to a stable suppressive HIV antiretroviral regimen on the rate of CD4+ T-cell recovery and gene expression profiles. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV Infections
- What is being tested?
- Maraviroc
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 3 sitesUnited States
- Study dates
- 20 Oct 2008to 11 Apr 2014
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- HIV-1 infection
- All available CD4+ T cell counts within the last 12 months of screening below 350 cells/mm3 (minimum of 3 values obtained > 30 days apart).
- HIV treatment with a stable (for at least 6 months) antiretroviral regimen consisting of at least 2 NRTIs and either a protease inhibitor boosted with low dose ritonavir or an NNRTI. A stable regimen is defined as no additions or deletions for more than 14 cumulative days.
- Patient considered to be receiving initial HIV regimen (history of medication substitution for toxicity is allowed).
- All available plasma HIV RNA levels within the last 12 months are below the level of detection. Isolated values that are detectable but < 1000 copies will be allowed as long as the plasma HIV RNA levels before and after this detectable time point are undetectable - The subject should have a minimum of 3 values obtained > 30 days apart.
- Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
- Men and women age ≥ 18 years.
Who cannot join
- Current antiretroviral regimen contains tenofovir disoproxil fumarate AND didanosine in combination.
- History of chronic hepatitis C (defined as HCV antibody positive and HCV RNA detectable).
- History of chronic active hepatitis B (defined as surface antibody negative, surface antigen positive and HBV DNA detectable).
- Concurrent use of G-CSF or GM-CSF.
- Prior or concurrent use of IL-2.
- Prior or concurrent use of a CCR5 inhibitor.
Show all 14Show fewer
- Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
- Use of any immunomodulator, HIV vaccine, or investigational therapy within 30 days of study entry.
- Use of human growth hormone within 30 days prior to study entry.
- Initiation of testosterone or anabolic steroids within 30 days prior to study entry. (Exception: Chronic replacement dosages in patient's with diagnosed hypogonadism is allowed).
- Evidence of splenic sequestration or suppressed bone marrow function:
- Clinical or radiographic evidence of significant splenomegaly.
- History of leukemia or lymphoma.
- History of myelosuppressive chemotherapy or irradiation
Trial locations and contacts
3 sites in 1 country.
United States3 sites
University Southern California
Los Angeles, California, 90033
University California San Diego
San Diego, California, 92103
Harbor-UCLA
Torrance, California, 90502
About this study
Official title: The Impact of CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery and Gene Expression Profiles in HIV-Infected Patients With Viral Suppression
CCTG 590 is a open-label study to evaluate the impact of therapy intensification with Maraviroc (MVC) (a CCR5 inhibitor) to a stable suppressive HIV antiretroviral regimen on the rate of CD4+ T-cell recovery and gene expression profiles. Patients on a stable first-line HIV regimen with continued viral suppression and sub-optimal CD4+ T-cell counts will be eligible for this study. Those who are found to be eligible will have MVC (dose-adjusted to background HIV regimen) added to their current HIV regimen for 24 weeks. After the 24 week intensification, the MVC will be discontinued, the original antiretroviral regimen will be continued and the subjects will be followed for an additional 12 weeks.
The investigators hypothesize that MVC will improve the rate of CD4 recovery. This improved CD4 recovery will be associated with favorable changes in gene expression profiles of genes involved with CD4 maintenance and circulation.
Read the detailed description
Blunted CD4+ T-cell responses during viral control may be a consequence of on-going T-cell destruction in the regenerative phase of CD4 recovery from activation-induced apoptosis and/or reduced production from decreased thymic output. Maraviroc, a CCR5 inhibitor, may improve the clinical status of HIV-infected by two distinct mechanisms. First, by blocking HIV entry into CD4+ T-cells, CCR5 inhibitors have direct antiviral activity. Second, as the pro-inflammatory state of HIV infection up-regulates CCR5 ligands and receptors, this CCR5 receptor antagonist may abrogate immune activation and resultant T-cell apoptosis. Importantly, MVC binds CCR5 receptors without inducing intracellular signaling or altering cell-surface expression. Potentially, MVC intensification during viral suppression with ART may further decrease persistent activation-induced apoptosis and improve repair and remodeling of lymphoid tissue leading to increased CD4+ T-cell recovery and function.
The aim of this study is to evaluate a potentially therapeutic immunomodulatory effect of MVC. Several measures of immune homeostasis will be determined in this study, including functional genomic analysis and extended T-cell phenotyping. Genes responsive to MVC therapy will be identified and categorized into functional groups. Based upon existing literature of the identified genes and observed immune responses (change in CD4/CD8 subsets) during MVC therapy, a model of CCR5 responsive-genes and potential impact on immune recovery will be outlined. Potentially, individuals experiencing immune discordance during suppressive ART may be better treated by MVC antiretroviral intensification.
- We hypothesize that expression will decrease among genes involved in immune activation (NF-kB, MAPK, nuclear factor of activated T-cells, MYD88 and STAT1), apoptosis (Fas ligand and TRAIL) and trafficking/repopulation of T-cells (CCR5, MIP-1α, MIP-1β and RANTES) and increase among genes involved in tissue repair (platelet-derived growth factor, insulin-like growth proteins and osteoblast-specific transcription factor).
- The gene expression profiles induced by MVC will be associated with a favorable increase in the rate of CD4+ T-cell recovery.
- The rate of CD4 recovery (cells/month) will be greater during MVC compared to before.
- The proportion of cells expressing activation/ apoptosis markers will decrease from baseline and this decrease will be associated with improved CD4 recovery.
- The proportion of naïve cells will increase from baseline and this increase will be associated with improved CD4 recovery.
- The rate of CD4 recovery will be greater among those subjects receiving PI-containing treatment regimens compared to those receiving NNRTI-containing treatment regimen.
- Conditions
- HIV Infections
- Being tested
- Maraviroc
- Keywords
- HIV, low CD4 recovery, Low CD4 recovery despite HIV control, Treatment experienced
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MaravirocDrug
Also called Selzentry
Maraviroc will be given dose-adjusted to background HIV treatment (150 mg, 300 mg, or 600 mg twice daily)
| Study group | Role | What they receive |
|---|---|---|
| Maraviroc 150 mg, 300 mg, or 600 mg twice daily | Experimental | This was a single arm study where Maraviroc was added for 24 weeks.
Maraviroc was dose-adjusted for concomitantly administered HIV medications according to the manufacture's recommendations:
150 mg twice daily with strong CYP3A4 inhibitors, including:
* Protease inhibitors (except tipranavir/ ritonavir)
* Delavirdine
* ketoconazole, itraconazole, clarithromycin, nefazadone, telithromycin
* Darunavir/r + etravirine
300 mg twice daily with non-inducers/ non-inhibitors of CYP3A4, including:
* Tipranavir/ ritonavir
* Nevirapine
* All NRTIs
* Enfuvirtide
600 mg twice daily with strong CYP3A4 inducers, including:
* Efavirenz, etravirine
* rifampin Receives: Drug: Maraviroc |
What is being measured
The primary outcome is the main question the study is designed to answer.
Differences in Gene Expression Profiles Obtained at Baseline and Week 4 and Week 24.
To determine differential gene expression in T-Cells due to MVC exposure between week 0, 4 and 24 weeks.
Repeated measures (RM) ANOVA was used to identify genes whose expression changed over the course of MVC administration. Multivariate permutation tests under default settings (80% confident no more than 10% false positives) were performed using BRB-Array Tools. Gene assignment to temporal profiles was performed using a non- parametric clustering algorithm in Short Time-series Expression Miner (STEM)
Measured: Baseline to Week 24
Secondary outcomes (2)
CD4+ T-cell Absolute Count and Percentage at Baseline, Weeks 4 and 24.
To compare the CD4+/CD8+ T-cell absolute count and percentage change at Weeks 4 and 24 from Baseline. Wilcoxon signed rank test was used to assess changes in T cell counts, percentages, CD4+ T cell recovery slopes and changes in T cell phenotypes measured by flow cytometry.
Measured: Baseline to Week 24
Change in CD4+/CD8+ T-cell Immune Activation, Maturation, Regulatory and Apoptosis Markers at Baseline and Weeks 4 and 24.
To compare the percent change of CD4+/CD8+ T-cell
Measured: Baseline to Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jun 2009 (estimated)
- Study start20 Oct 2008
- Primary completion2 May 2012
- Study completion11 Apr 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by University of California, San DiegoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Diego
- Sponsor type
- University, hospital or other
- Collaborators
- University of California, Los Angeles, University of Southern California, Pfizer, California HIV/AIDS Research Program
- Responsible party
- Principal investigator, Sheldon Morris, University of California, San Diego
- Investigators
- Sheldon Morris, MD, Study chair, UC San Diego AntiViral Research Center (AVRC)Richard Haubrich, MD, Principal investigator, University of California, San Diego
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00925756
- Sponsor's protocol ID
- CCTG 590
- Status last verified
- Aug 2020
- First submitted
- 18 Jun 2009
- Last updated
- 19 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Impact of CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery and Gene Expression Profiles in HIV-Infected Patients With Viral Suppression
- ClinicalTrials.gov ID
- NCT00925756
- Acronym / sponsor ID
- CCTG 590
- Conditions
- HIV Infections
- Keywords
- HIV, low CD4 recovery, Low CD4 recovery despite HIV control, Treatment experienced
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- University of California, San DiegoUniversity, hospital or other
- Collaborators
- University of California, Los Angeles, University of Southern California, Pfizer, California HIV/AIDS Research Program
- Study start
- 20 Oct 2008 (actual)
- Primary completion
- 2 May 2012 (actual)
- Study completion
- 11 Apr 2014 (actual)
- First posted
- 22 Jun 2009 (estimated)
- Results
- Posted 19 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
CCTG 590 is a open-label study to evaluate the impact of therapy intensification with Maraviroc (MVC) (a CCR5 inhibitor) to a stable suppressive HIV antiretroviral regimen on the rate of CD4+ T-cell recovery and gene expression profiles. Patients on a stable first-line HIV regimen with continued viral suppression and sub-optimal CD4+ T-cell counts will be eligible for this study. Those who are found to be eligible will have MVC (dose-adjusted to background HIV regimen) added to their current HIV regimen for 24 weeks. After the 24 week intensification, the MVC will be discontinued, the original antiretroviral regimen will be continued and the subjects will be followed for an additional 12 weeks.
The investigators hypothesize that MVC will improve the rate of CD4 recovery. This improved CD4 recovery will be associated with favorable changes in gene expression profiles of genes involved with CD4 maintenance and circulation.
Detailed description
Blunted CD4+ T-cell responses during viral control may be a consequence of on-going T-cell destruction in the regenerative phase of CD4 recovery from activation-induced apoptosis and/or reduced production from decreased thymic output. Maraviroc, a CCR5 inhibitor, may improve the clinical status of HIV-infected by two distinct mechanisms. First, by blocking HIV entry into CD4+ T-cells, CCR5 inhibitors have direct antiviral activity. Second, as the pro-inflammatory state of HIV infection up-regulates CCR5 ligands and receptors, this CCR5 receptor antagonist may abrogate immune activation and resultant T-cell apoptosis. Importantly, MVC binds CCR5 receptors without inducing intracellular signaling or altering cell-surface expression. Potentially, MVC intensification during viral suppression with ART may further decrease persistent activation-induced apoptosis and improve repair and remodeling of lymphoid tissue leading to increased CD4+ T-cell recovery and function.
The aim of this study is to evaluate a potentially therapeutic immunomodulatory effect of MVC. Several measures of immune homeostasis will be determined in this study, including functional genomic analysis and extended T-cell phenotyping. Genes responsive to MVC therapy will be identified and categorized into functional groups. Based upon existing literature of the identified genes and observed immune responses (change in CD4/CD8 subsets) during MVC therapy, a model of CCR5 responsive-genes and potential impact on immune recovery will be outlined. Potentially, individuals experiencing immune discordance during suppressive ART may be better treated by MVC antiretroviral intensification.
- We hypothesize that expression will decrease among genes involved in immune activation (NF-kB, MAPK, nuclear factor of activated T-cells, MYD88 and STAT1), apoptosis (Fas ligand and TRAIL) and trafficking/repopulation of T-cells (CCR5, MIP-1α, MIP-1β and RANTES) and increase among genes involved in tissue repair (platelet-derived growth factor, insulin-like growth proteins and osteoblast-specific transcription factor).
- The gene expression profiles induced by MVC will be associated with a favorable increase in the rate of CD4+ T-cell recovery.
- The rate of CD4 recovery (cells/month) will be greater during MVC compared to before.
- The proportion of cells expressing activation/ apoptosis markers will decrease from baseline and this decrease will be associated with improved CD4 recovery.
- The proportion of naïve cells will increase from baseline and this increase will be associated with improved CD4 recovery.
- The rate of CD4 recovery will be greater among those subjects receiving PI-containing treatment regimens compared to those receiving NNRTI-containing treatment regimen.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Maraviroc 150 mg, 300 mg, or 600 mg twice daily | Experimental | Drug: MaravirocThis was a single arm study where Maraviroc was added for 24 weeks. Maraviroc was dose-adjusted for concomitantly administered HIV medications according to the manufacture's recommendations: 150 mg twice daily with strong CYP3A4 inhibitors, including: * Protease inhibitors (except tipranavir/ ritonavir) * Delavirdine * ketoconazole, itraconazole, clarithromycin, nefazadone, telithromycin * Darunavir/r + etravirine 300 mg twice daily with non-inducers/ non-inhibitors of CYP3A4, including: * Tipranavir/ ritonavir * Nevirapine * All NRTIs * Enfuvirtide 600 mg twice daily with strong CYP3A4 inducers, including: * Efavirenz, etravirine * rifampin |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- HIV-1 infection
- All available CD4+ T cell counts within the last 12 months of screening below 350 cells/mm3 (minimum of 3 values obtained > 30 days apart).
- HIV treatment with a stable (for at least 6 months) antiretroviral regimen consisting of at least 2 NRTIs and either a protease inhibitor boosted with low dose ritonavir or an NNRTI. A stable regimen is defined as no additions or deletions for more than 14 cumulative days.
- Patient considered to be receiving initial HIV regimen (history of medication substitution for toxicity is allowed).
- All available plasma HIV RNA levels within the last 12 months are below the level of detection. Isolated values that are detectable but < 1000 copies will be allowed as long as the plasma HIV RNA levels before and after this detectable time point are undetectable - The subject should have a minimum of 3 values obtained > 30 days apart.
Key exclusion criteria (14 listed)
- Current antiretroviral regimen contains tenofovir disoproxil fumarate AND didanosine in combination.
- History of chronic hepatitis C (defined as HCV antibody positive and HCV RNA detectable).
- History of chronic active hepatitis B (defined as surface antibody negative, surface antigen positive and HBV DNA detectable).
- Concurrent use of G-CSF or GM-CSF.
- Prior or concurrent use of IL-2.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MaravirocAlso: SelzentryMaraviroc will be given dose-adjusted to background HIV treatment (150 mg, 300 mg, or 600 mg twice daily) | Drug | Maraviroc 150 mg, 300 mg, or 600 mg twice daily |
Primary outcome
Differences in Gene Expression Profiles Obtained at Baseline and Week 4 and Week 24.
Time frame: Baseline to Week 24
To determine differential gene expression in T-Cells due to MVC exposure between week 0, 4 and 24 weeks. Repeated measures (RM) ANOVA was used to identify genes whose expression changed over the course of MVC administration. Multivariate permutation tests under default settings (80% confident no more than 10% false positives) were performed using BRB-Array Tools. Gene assignment to temporal profiles was performed using a non- parametric clustering algorithm in Short Time-series Expression Miner (STEM)
2 secondary outcomes
CD4+ T-cell Absolute Count and Percentage at Baseline, Weeks 4 and 24.
Time frame: Baseline to Week 24
Change in CD4+/CD8+ T-cell Immune Activation, Maturation, Regulatory and Apoptosis Markers at Baseline and Weeks 4 and 24.
Time frame: Baseline to Week 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sheldon Morris, MD study chair
UC San Diego AntiViral Research Center (AVRC)
Richard Haubrich, MD principal investigator
University of California, San Diego
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Maraviroc in people with HIV Infections, run by University of California, San Diego at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Differences in Gene Expression Profiles Obtained at Baseline and Week 4 and Week 24. (time frame: Baseline to Week 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2020.