Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00735072
• Collaborator: Pfizer (Industry), amfAR, The Foundation for AIDS Research (Other), Stanford University (Other), Case Western Reserve University (Other), Rush University (Other)
• Enrollment: 45
• Locations: 4
• Arms: 2
• Duration (Months): 21.9
• Patients Per Site: 11.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Many people with HIV fail to regain normal CD4 counts despite effectively suppressing HIV replication with medications. Blocking the "co-receptor" for HIV might decrease inflammation of the immune system, potentially providing an immune benefit. The goal of the current trial is to determine whether adding maraviroc, a new CCR5 "co-receptor" blocker, decreases inflammation, providing an immune benefit for patients with low CD4 counts despite undetectable viral loads on HIV medications.

In this study, HIV-infected patients who are receiving antiretroviral therapy for HIV will receive either maraviroc or a placebo (sugar pill) each day for 24 weeks. After 24 weeks, the study medication will be stopped and all subjects will be followed for 12 more weeks. Blood tests measuring the extent of inflammation, low-level viremia, and immune function will be measured throughout the trial and compared between treatment arms.

Condition or Disease	Intervention/Treatment	Phase
HIV Infection	Drug: Placebo; Drug: Maraviroc	Phase 4

Detailed Description

Our primary hypothesis is that CCR5 inhibitors may have protective immunomodulatory effects independent of their impact on HIV replication. Specifically, we predict that maraviroc will reduce the persistent T cell activation that prevents normal immune reconstitution during HAART-mediated viral suppression. This hypothesis will be tested in the context of a placebo controlled pilot study assessing the impact of maraviroc in antiretroviral-treated patients with a CD4+ T cell count less than 350 cells/mm3. In order to address the immunologic activity of this drug independent of plasma HIV RNA levels, we will study individuals who have undetectable viral loads (< 75 copies RNA/mL). Subjects will be randomized to maraviroc for 24 weeks or matching placebo for 24 weeks, followed by a 12 week washout period. We will use as our primary endpoint the proportion of CD8+ T cells that co-expresses CD38 and HLA-DR, as these outcomes have been well validated in prior studies. The primary outcome will be change in the percentage of activated CD8+ T cells at week 24. Change in CD4+ T cell counts, HIV RNA levels (using ultra-sensitive techniques), and other more experimental immunologic measurements will be assessed as secondary outcomes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Maraviroc Maraviroc (dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Drug: Maraviroc; Dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.; Other Names: Selzentry
Placebo Comparator: Placebo Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Drug: Placebo; Dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.; Other Names: Placebo for Maraviroc

Outcome Measures

Primary Outcome Measures

1. Week 24 Change in Percentage of CD8+ T Cells That Co-express CD38 and HLA DR (Week 24 %CD38+HLA-DR+ CD8+ T Cells Minus Baseline %CD38+HLA-DR+ CD8+ T Cells) [Baseline and Week 24]

Secondary Outcome Measures

1. Change in CD4+ T Cell Count [Baseline and Week 24]

2. Change in Ultra-sensitive Plasma HIV RNA Level (Single Copy/ml Assay) [Baseline and Week 24]

3. Change in Brachial Artery Flow-mediated Dilatation (UCSF Site Only) [Baseline and Week 24]

4. Change in Gut-associated Lymphoid Tissue HIV RNA Level (UCSF Site Only) [Baseline and Week 24]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.

2. Stable antiretroviral therapy for at least 12 months

3. Screening CD4+ T cell count below 350 cells/mm3

4. All available CD4+ T cell counts in the last year and at screening < 350 cells/mm3

5. Screening plasma HIV RNA levels below level of detection (< 50 copies RNA/mL using Roche Amplicor or < 75 copies/mL using Bayer bDNA)

6. All available plasma HIV RNA levels within past year below the level of detection. Isolated values that are detectable but < 500 copies will be allowed as long as the plasma HIV RNA levels before and after this time point are undetectable.

7. 90% adherence to therapy within the preceding 30 days, as determined by self-report.

8. Both male and female subjects are eligible. 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.

9. Ability and willingness of subject or legal guardian/representative to provide informed consent

Exclusion Criteria:

1. Increase in CD4 count of > 100 cells/mm3 in past year.

2. Patients who are intending to modify antiretroviral therapy in the next 24 weeks for any reason.

3. Serious illness requiring hospitalization or parental antibiotics within preceding 3 months.

4. Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in past 16 weeks.

5. HBVsAg+ or active hepatitis C or hepatitis B which will require treatment in the subsequent 24 weeks.

6. Prior exposure to CCR5 inhibitors

7. Screening absolute neutrophil count <1,000 cells/mm3, platelet count <50,000 cells/mm3, hemoglobin < 8mg/dL, estimated creatinine clearance <40 mL/minute.

8. Pregnant or breastfeeding women

9. Use of both Tenofovir and Didanosine in current antiretroviral therapy regimen.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco - San Francisco General Hospital	San Francisco	California	United States	94110
2	Stanford University	Stanford	California	United States	94305
3	Rush University - Stroger Hospital of Cook County	Chicago	Illinois	United States	60612
4	Case Western Reserve University	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

• University of California, San Francisco
• Pfizer
• amfAR, The Foundation for AIDS Research
• Stanford University
• Case Western Reserve University
• Rush University

Investigators

• Principal Investigator: Peter W Hunt, MD, University of California, San Francisco
• Principal Investigator: Steven G Deeks, MD, University of California, San Francisco
• Principal Investigator: Nancy Shulman, MD, Stanford University
• Principal Investigator: Robert Shafer, MD, Stanford University
• Principal Investigator: Michael Lederman, MD, Case Western Reserve University
• Principal Investigator: Toyin Adeyemi, MD, Rush University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00735072
• Other Study ID Numbers: GA9001DE
• First Posted: Aug 14, 2008
• Last Update Posted: Aug 17, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by University of California, San Francisco: HIV infection; T cell activation; Antiretroviral Therapy; CCR5; Maraviroc
• Additional relevant MeSH terms: HIV Infections; Maraviroc

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the HIV clinics at San Francisco General Hospital, Stanford University, Case Western Reserve University, and Rush University/CORE Center between September, 2008, and December, 2009.
Pre-assignment Detail	All 45 enrolled patients were assigned to study intervention. We over-enrolled by 3 subjects given 2 premature treatment discontinuations and one subject with unavailable baseline peripheral blood mononuclear cell (PBMC) samples available for analysis.

Arm/Group Title	Maraviroc	Placebo
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
Period Title: Overall Study
STARTED	23	22
COMPLETED	22	21
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Maraviroc	Placebo	Total
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Total of all reporting groups
Overall Participants	23	22	45
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	23 100%	21 95.5%	44 97.8%
>=65 years	0 0%	1 4.5%	1 2.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50 (8)	50 (10)	50 (9)
Sex: Female, Male (Count of Participants)
Female	0 0%	2 9.1%	2 4.4%
Male	23 100%	20 90.9%	43 95.6%
Region of Enrollment (participants) [Number]
United States	23 100%	22 100%	45 100%

Outcome Measures

1. Primary Outcome

Title	Week 24 Change in Percentage of CD8+ T Cells That Co-express CD38 and HLA DR (Week 24 %CD38+HLA-DR+ CD8+ T Cells Minus Baseline %CD38+HLA-DR+ CD8+ T Cells)
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Maraviroc	Placebo
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
Measure Participants	23	22
Median (Inter-Quartile Range) [%CD38+ HLA-DR+ CD8+ T cells]	2.2	-0.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maraviroc, Placebo
	Comments	Null hypothesis: there will be no difference in the week 24 change in %activated CD8+ T cells between arms. Assuming a standard deviation as high as 3.5% and a Type I error of 5%, with 21 subjects in each treatment arm we would have 80% statistical power to detect a mean 3 percentage-point difference in the percent of activated CD8+ T cells between the active drug and placebo groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Change in CD4+ T Cell Count
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Maraviroc	Placebo
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens). Maraviroc: Dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.	Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens). Placebo: Dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.
Measure Participants	22	21
Mean (95% Confidence Interval) [cells/mm^3 over 24 weeks]	17	17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maraviroc, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Change in Ultra-sensitive Plasma HIV RNA Level (Single Copy/ml Assay)
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Data available only on the 35 participants with at least 7 mL of plasma available as reported here.

Arm/Group Title	Maraviroc	Placebo
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
Measure Participants	18	17
Mean (95% Confidence Interval) [percent change from baseline]	-52	-48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maraviroc, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Change in Brachial Artery Flow-mediated Dilatation (UCSF Site Only)
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

These data were collected from participants enrolled at the UCSF site only, as reported here.

Arm/Group Title	Maraviroc	Placebo
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
Measure Participants	10	9
Mean (95% Confidence Interval) [percent change from baseline]	1.0	0.3

5. Secondary Outcome

Title	Change in Gut-associated Lymphoid Tissue HIV RNA Level (UCSF Site Only)
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

These data were collected from participants enrolled at the UCSF site only, as reported here.

Arm/Group Title	Maraviroc	Placebo
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).	Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
Measure Participants	6	6
Median (Inter-Quartile Range) [percent change from baseline]	-11	-3

Adverse Events

Time Frame	36 weeks
Arm/Group Title	Maraviroc		Placebo
Arm/Group Description	Maraviroc (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).		Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
All Cause Mortality
	Maraviroc		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/22 (0%)
Serious Adverse Events
	Maraviroc		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Maraviroc		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/23 (17.4%)		2/22 (9.1%)
Hepatobiliary disorders
Indirect Hyperbilirubinemia (on atazanavir-based ART)	2/23 (8.7%)		1/22 (4.5%)
HBV flare, transaminitis	0/23 (0%)		1/22 (4.5%)
Infections and infestations
Prolonged Fever	1/23 (4.3%)		0/22 (0%)
Metabolism and nutrition disorders
Triglyceride Elevation	1/23 (4.3%)		0/22 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.