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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Atorvastatin | Active Comparator | Participants were given atorvastatin for 12 weeks at various doses based on their specific HAART treatment. |
|
| Placebo | Placebo Comparator | Participants were given Placebo tablets for 12 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Atorvastatin (generic Lipitor) | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Week 0 and week 12 |
| 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. | Week 0 and week 12 |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ronald G Collman, MD | University of Pennsylvania | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pennsylvania School of Medicine | Philadelphia | Pennsylvania | 19104 | United States |
Participants that met the inclusion criteria were randomly assigned to 12weeks of atorvastatin (or placebo) in the first period followed by a 4week washout and then in the second period on placebo (or atorvastatin) for 12 weeks followed by washout (4weeks). Therefore each subject served as their own control.
Chronic HIV infected individuals on HAART (with no changes in treatment within 4 weeks of study entry), were recruited using the Penn CFAR Clinical Core database. Subject were consented by the study nurse coordinating the project. Of 46 screened subjects, 11 fulfilled the inclusion criteria and were enrolled in the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Atorvastatin, Then Placebo | Participants were assigned atorvastatin at different conc. (20, 40 or 60mg / day) based on HAART for 12 wks. After a washout period of 4 weeks participants received placebo tablets (matching atorvastatin), for 12 weeks followed by another washout period of 4 weeks. |
| FG001 | Placebo, Then Atorvastatin | Participants were assigned placebo tablets for 12 wks. After a washout period of 4 weeks participants received atorvastatin tablets at different conc.(20, 40 or 60mg / day) based on HAART, for 12 weeks followed by another washout period of 4 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
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| Period 2 |
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| ID | Title | Description |
|---|---|---|
| BG000 | Atorvastatin Then Placebo | Participants were given Atorvastatin followed by a washout period then placebo.
|
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Subjects received Atorvastatin or placebo for 12wks followed by 4wk washout period then switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold change | Week 0 and week 12 |
Participants were observed for the duration of the study enrollment period, i.e. 36 weeks.
Participants were routinely assessed for any adverse events with regular laboratory testing, and study Investigator and study nurse assessment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Atorvastatin | Participants were given Atorvastatin for 12 weeks based on HAART
|
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This study had a very small sample size of 11 subjects and did not reach target recruitment (30 subjects) due to stringent study Inclusion criteria. Therefore due to lack of power the data is largely inconclusive.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ronald G Collman | University of Pennsylvania School of Medicine | 215-898-0913 | collmanr@pennmedicine.upenn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 7, 2014 | Aug 20, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D015526 | AIDS Dementia Complex |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D000069059 | Atorvastatin |
| ID | Term |
|---|---|
| D011758 | Pyrroles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| placebo | Drug | A substance containing no medication and prescribed or given to reinforce a patient's expectation to get well. |
|
| week 0 and week 12 |
| 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. | week 0 and week 12 |
| 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. | 0 week and 12 week |
| 0 week and 12 week |
| 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. | 0 week and 12 week |
| 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. | 0 week and 12 week |
| 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. | 0 week and 12 week |
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| BG001 | Placebo Then Atorvastatin | Participants were administered Placebo tablets followed by a washout period and then Atorvastatin.
|
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Number | participants |
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| Region of Enrollment | Number | participants |
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| ID | Title | Description |
|---|---|---|
| OG000 | Atorvastatin | Participants were given Atorvastatin depending on their HAART
|
| OG001 | Placebo | Participants were administered Placebo tablets for 12 weeks. |
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| Primary | 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. | Subjects received Atorvastatin or placebo for 12wks followed by 4wk washout period then switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold change | Week 0 and week 12 |
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| Primary | 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. | Subjects received Atorvastatin or placebo for 12wks followed by 4wk washout period then switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Percentage of monocytes | week 0 and week 12 |
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| Primary | 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. | Subjects received Atorvastatin or placebo for 12wks followed by 4wk washout period then switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold Change | week 0 and week 12 |
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| Primary | 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. | Subjects received Atorvastatin or placebo for 12wks followed by 4wk washout period then switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold Change | 0 week and 12 week |
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| Secondary | 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. | Subjects were assigned to Atorvastatin or placebo for 12wks followed by 4wk washout period then subjects switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold change | 0 week and 12 week |
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| Secondary | 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. | Subjects were assigned to Atorvastatin or placebo for 12wks followed by 4wk washout period then subjects switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold change | 0 week and 12 week |
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| Secondary | 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. | Subjects were assigned to Atorvastatin or placebo for 12wks followed by 4wk washout period then subjects switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold Change | 0 week and 12 week |
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| Secondary | 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. | Subjects were assigned to Atorvastatin or placebo for 12wks followed by 4wk washout period then subjects switched treatment for 12 wks followed again by a washout period. The same 11 subjects were analyzed in each group. | Posted | Mean | 95% Confidence Interval | Fold Change | 0 week and 12 week |
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| 0 |
| 11 |
| 0 |
| 11 |
| 0 |
| 11 |
| EG001 | Placebo | Participants were administered Placebo tablets for 12 weeks. | 0 | 11 | 0 | 11 | 0 | 11 |
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| D015229 |
| Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006538 |
| Heptanoic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |