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Downmodulating Monocyte Activation for HIV-1 Associated Neurocognitive Disorders (HAND)

Primary Purpose

HIV Dementia

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Atorvastatin (generic Lipitor)

placebo

About this trial

This is an interventional treatment trial for HIV Dementia focused on measuring HIV, monocytes, CD16+, statins, mcp1, inflammation

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Chronic HIV-1 infected individuals on HAART (with no change in treatment within 4 weeks of study entry) and willing to continue therapy for the duration of the study.
HIV viral load less than 200 copies/ml for more than 6 months at time of screening.
Nadir CD4 count less than 350 and current CD4 counts greater than 100 cells/ul.
Hs-CRP levels above 2mg/L.
Willingness to use a method of contraception during the study period.
Willingness to comply with study evaluations for LP sub-study.
Karnofsky performance score of 80 or higher.
If female, willing to undergo pregnancy testing on a monthly basis and not breastfeeding.
Hemoglobin greater than or equal to 9.0 g/dL for female and 10.0 g/dL for male subjects.
men and women 18 years or older.

Exclusion Criteria:

Concomitant use of fibric acid derivatives or other lipid lowering agents including patients on statins and Ezetimibe.
Use of any anti-inflammatory drugs (OTC or prescription) on a daily basis.
Pregnancy or breastfeeding
Active drug use or alcohol abuse/dependence which in the opinion of researchers will interfere with the patients' ability to participate in the study.
Allergy or hypersensitivity to Atorvastatin or any of its components.
History of myositis or rhabdomyolysis with use of any statins.
Patients who are on concurrent immunomodulatory agents, including systemic corticosteroids (nasal or inhaled) will be ineligible for 3 months after completion of therapy with the agent.
History of inflammatory muscle disease such a poly or dermatomyositis.
Serious intercurrent illness requiring systemic treatment and/or hospitalization within 30 days of entry.
Evidence of active opportunistic infections requiring treatment or neoplasms that require chemotherapy during study period.
CPK greater than 3 times the ULN.
Known active liver disease or AST/ALT greater than 3 times the ULN.
Renal insufficiency, indicated by serum creatinine greater than 2mg/dL.
Absolute neutrophil counts less than 1000/ul; hemoglobin less than 10g/dL for males and less than 9g/dL for females; platelet counts less than 100,000/mm3.
Documented HCV infection.
NYHA class III or IV congestive heart failure.
Active IV drug use within 1 year prior to entry.
For LP sub-study, allergy to Lidocaine.
Coronary artery disease or equivalent including Diabetes mellitus.

Sites / Locations

University of Pennsylvania School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Atorvastatin

Placebo

Arm Description

Participants were given atorvastatin for 12 weeks at various doses based on their specific HAART treatment.

Participants were given Placebo tablets for 12 weeks.

Outcomes

Primary Outcome Measures

Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CD16 at 12 Weeks, as a Result of Treatment.

Whole blood drawn from participants were stained with fluorochrome tagged antibodies to the surface markers. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the change in percentage of monocytes expressing the specific marker (CD16) at 12 wk versus 0wk within each Period. Data is shown as fold change over 12 weeks, in percent positive monocytes expressing surface markers. Change in primary outcome measures in each treatment arm is expressed as fold change (at week 12 versus week 0). For eg. outcome measure CD14+CD16+ in atorvastatin arm shows a mean value of 1.14. This means at 12 weeks there is an increase of 0.14 fold in the percent monocyte population expressing CD14+CD16+ marker, versus 0 week. Similarly in the placebo group. If fold change in atorvastatin group is smaller than in placebo group, then the treatment had no effect.

Change From Baseline Within Each Period in Levels of Plasma Inflammatory Marker MCP-1 in Chronic HIV+/ HAART+ Subjects Over 12 Weeks.

Monocyte specific inflammatory soluble factor MCP-1 was measured by Luminex in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following treatment (atorvastatin or placebo). Data is shown as fold change in concentration of MCP-1 over 12wks within each treatment period.

Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CD163 at 12 Weeks, as a Result of Treatment.

Whole blood drawn from participants were stained with fluorochrome tagged antibodies to the surface marker CD163. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the change in percentage of monocytes expressing the specific marker (CD163) at 12 wk versus 0wk within each Period. Data in each treatment arm is shown as 'mean difference' at 12 weeks versus 0 week, in percent positive monocytes expressing surface marker CD163. Data is expressed as the difference of the mean values at week 12 and week 0. The negative values mean that the mean values at 12 week were lower than the mean values at 0 week.

Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CCR2 at 12 Weeks, as a Result of Treatment.

Whole blood drawn from participants were stained with fluorochrome tagged antibodies to the surface marker CCR2. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the change in percentage of monocytes expressing the specific marker (CCR2) at 12 wk versus 0wk within each Period. Data in each treatment arm is shown as fold change over 12 weeks, in percent positive monocytes expressing surface marker CCR2.

Change From Baseline Within Each Period in Levels of Plasma Inflammatory Marker sCD14 in Chronic HIV+/ HAART+ Subjects Over 12 Weeks.

Monocyte specific inflammatory soluble factor sCD14 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following treatment (atorvastatin or placebo). Data is shown as fold change in concentration of sCD14 over 12wks within each treatment period.

Secondary Outcome Measures

Change From Week 0 to Week 12 in Percentage of Blood Monocytes Expressing Surface Marker Tissue Factor (TF), Following Treatment.

Whole blood drawn from participants were stained with fluorochrome tagged antibodies to the surface marker TF. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the change in percentage of monocytes expressing the specific marker TF at 12 wk versus 0wk within each Period. Data are expressed as fold change.

Change From 0 Week in Levels of Plasma Inflammatory Marker hsCRP in Chronic HIV+/ HAART+ Subjects Over 12 Weeks, Following Treatment.

Monocyte specific inflammatory soluble factor hsCRP was measured by Quest in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following treatment (atorvastatin or placebo). Data shown as fold change at week 12 versus week 0.

Change From Week 0 to Week 12 in Percentage of Blood Monocytes Expressing Surface Marker CD38, Following Treatment.

Whole blood drawn from participants were stained with fluorochrome tagged antibodies to the surface marker CD38. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the change in percentage of monocytes expressing the specific marker CD38 at 12 wk versus 0wk within each Period. Data are expressed as fold change at 12 week versus week 0.

Change From Week 0 in Plasma sCD163 Levels, at Week 12 Following Treatment.

Monocyte specific inflammatory soluble factor sCD163 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following treatment (atorvastatin or placebo). Data are expressed as fold change at 12 week versus week 0.

Full Information

NCT ID

NCT01600170

First Posted

May 14, 2012

Last Updated

October 28, 2020

Sponsor

University of Pennsylvania

1. Study Identification

Unique Protocol Identification Number

NCT01600170

Brief Title

Downmodulating Monocyte Activation for HIV-1 Associated Neurocognitive Disorders (HAND)

Official Title

Statin Modulation of Monocyte/Macrophage Activation for HAND Treatment

Study Type

Interventional

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Completed

Study Start Date

January 2013 (undefined)

Primary Completion Date

October 2017 (Actual)

Study Completion Date

October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Pennsylvania

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

HIV associated neurological disorders (HAND), are a major problem even in ART treated people. HAND results from chronic inflammation which is largely attributed to expansion and activation of monocytes. These activated monocytes, some of which also carry virus to the brain, invade the CNS and release cytokines / chemokines resulting in further recruitment of monocytes, as well as release viral proteins which injure neurons and cause activation of other brain cells. Persistent monocyte/macrophage activation is thus a potential critical target for adjunctive therapy to treat or prevent HAND. The investigators therefore propose to study the effects of a statin drug (Atorvastatin), which has anti-inflammatory functions, on the monocyte activation status in ART treated HIV+ individuals. The investigators objectives are based on the hypothesis that Atorvastatin treatment will reduce the inflammatory and activated phenotype and function of monocytes which have been linked to HIV associated neuropathogenesis and occur in HIV infected subjects despite ART. In this study the investigators propose to 1) define the effect of Atorvastatin on monocyte activation in HIV infected / ART treated subjects in a double blind, placebo controlled crossover study

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Dementia

Keywords

HIV, monocytes, CD16+, statins, mcp1, inflammation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Atorvastatin

Arm Type

Active Comparator

Arm Description

Participants were given atorvastatin for 12 weeks at various doses based on their specific HAART treatment.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants were given Placebo tablets for 12 weeks.

Intervention Type

Drug

Intervention Name(s)

Atorvastatin (generic Lipitor)

Intervention Description

Atorvastatin is an FDA approved prescription drug which is frequently used to lower cholesterol levels.It is available in the form of tablets ranging in dose from 10-80mg.

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

A substance containing no medication and prescribed or given to reinforce a patient's expectation to get well.

Primary Outcome Measure Information:

Title

Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CD16 at 12 Weeks, as a Result of Treatment.

Description

Time Frame

Week 0 and week 12

Title

Change From Baseline Within Each Period in Levels of Plasma Inflammatory Marker MCP-1 in Chronic HIV+/ HAART+ Subjects Over 12 Weeks.

Description

Time Frame

Week 0 and week 12

Title

Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CD163 at 12 Weeks, as a Result of Treatment.

Description

Time Frame

week 0 and week 12

Title

Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CCR2 at 12 Weeks, as a Result of Treatment.

Description

Time Frame

week 0 and week 12

Title

Change From Baseline Within Each Period in Levels of Plasma Inflammatory Marker sCD14 in Chronic HIV+/ HAART+ Subjects Over 12 Weeks.

Description

Time Frame

0 week and 12 week

Secondary Outcome Measure Information:

Title

Change From Week 0 to Week 12 in Percentage of Blood Monocytes Expressing Surface Marker Tissue Factor (TF), Following Treatment.

Description

Time Frame

0 week and 12 week

Title

Change From 0 Week in Levels of Plasma Inflammatory Marker hsCRP in Chronic HIV+/ HAART+ Subjects Over 12 Weeks, Following Treatment.

Description

Time Frame

0 week and 12 week

Title

Change From Week 0 to Week 12 in Percentage of Blood Monocytes Expressing Surface Marker CD38, Following Treatment.

Description

Time Frame

0 week and 12 week

Title

Change From Week 0 in Plasma sCD163 Levels, at Week 12 Following Treatment.

Description

Time Frame

0 week and 12 week

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Chronic HIV-1 infected individuals on HAART (with no change in treatment within 4 weeks of study entry) and willing to continue therapy for the duration of the study. HIV viral load less than 200 copies/ml for more than 6 months at time of screening. Nadir CD4 count less than 350 and current CD4 counts greater than 100 cells/ul. Hs-CRP levels above 2mg/L. Willingness to use a method of contraception during the study period. Willingness to comply with study evaluations for LP sub-study. Karnofsky performance score of 80 or higher. If female, willing to undergo pregnancy testing on a monthly basis and not breastfeeding. Hemoglobin greater than or equal to 9.0 g/dL for female and 10.0 g/dL for male subjects. men and women 18 years or older. Exclusion Criteria: Concomitant use of fibric acid derivatives or other lipid lowering agents including patients on statins and Ezetimibe. Use of any anti-inflammatory drugs (OTC or prescription) on a daily basis. Pregnancy or breastfeeding Active drug use or alcohol abuse/dependence which in the opinion of researchers will interfere with the patients' ability to participate in the study. Allergy or hypersensitivity to Atorvastatin or any of its components. History of myositis or rhabdomyolysis with use of any statins. Patients who are on concurrent immunomodulatory agents, including systemic corticosteroids (nasal or inhaled) will be ineligible for 3 months after completion of therapy with the agent. History of inflammatory muscle disease such a poly or dermatomyositis. Serious intercurrent illness requiring systemic treatment and/or hospitalization within 30 days of entry. Evidence of active opportunistic infections requiring treatment or neoplasms that require chemotherapy during study period. CPK greater than 3 times the ULN. Known active liver disease or AST/ALT greater than 3 times the ULN. Renal insufficiency, indicated by serum creatinine greater than 2mg/dL. Absolute neutrophil counts less than 1000/ul; hemoglobin less than 10g/dL for males and less than 9g/dL for females; platelet counts less than 100,000/mm3. Documented HCV infection. NYHA class III or IV congestive heart failure. Active IV drug use within 1 year prior to entry. For LP sub-study, allergy to Lidocaine. Coronary artery disease or equivalent including Diabetes mellitus.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ronald G Collman, MD

Organizational Affiliation

University of Pennsylvania

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Pennsylvania School of Medicine

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

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Downmodulating Monocyte Activation for HIV-1 Associated Neurocognitive Disorders (HAND)

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