A Phase 4 interventional study of Atorvastatin (generic Lipitor) and placebo in HIV Dementia, sponsored by University of Pennsylvania. Completed at 1 site in United States. Open to participants aged 18 Years to 60 Years. Per ClinicalTrials.gov, last updated 2020-11-23.
Sponsored by University of Pennsylvania · Phase 4, Interventional, and Treatment
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
Exclusion Criteria:
Participants were given atorvastatin for 12 weeks at various doses based on their specific HAART treatment.
Drug: Atorvastatin (generic Lipitor)
Participants were given Placebo tablets for 12 weeks.
Drug: placebo
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.
A substance containing no medication and prescribed or given to reinforce a patient's expectation to get well.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 0 week and 12 week
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 0 week and 12 week
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.
| Milestone | Atorvastatin, Then Placebo | Placebo, Then Atorvastatin |
|---|---|---|
| Started | 6 | 5 |
| Completed | 6 | 5 |
| Not completed | 0 | 0 |
| Milestone | Atorvastatin, Then Placebo | Placebo, Then Atorvastatin |
|---|---|---|
| Started | 6 | 5 |
| Completed | 5 | 5 |
| Not completed | 1 | 0 |
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.
| Fold change | Atorvastatin | Placebo |
|---|---|---|
| Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CD16 at 12 Weeks, as a Result of Treatment. | 1.14 (0.73 to 1.77) | 1.51 (0.88 to 2.59) |
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.
| Fold change | Atorvastatin | Placebo |
|---|---|---|
| Change From Baseline Within Each Period in Levels of Plasma Inflammatory Marker MCP-1 in Chronic HIV+/ HAART+ Subjects Over 12 Weeks. | 0.96 (0.82 to 1.13) | 0.87 (0.67 to 1.12) |
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.
| Percentage of monocytes | Atorvastatin | Placebo |
|---|---|---|
| Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CD163 at 12 Weeks, as a Result of Treatment. | -0.06 (-9.17 to 9.05) | -5.14 (-11.94 to 1.65) |
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.
| Fold Change | Atorvastatin | Placebo |
|---|---|---|
| Change From Week 0 in Percentage of Blood Monocytes Expressing Surface Marker CCR2 at 12 Weeks, as a Result of Treatment. | 1.60 (0.80 to 3.21) | 0.78 (0.52 to 1.18) |
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.
| Fold Change | Atorvastatin | Placebo |
|---|---|---|
| Change From Baseline Within Each Period in Levels of Plasma Inflammatory Marker sCD14 in Chronic HIV+/ HAART+ Subjects Over 12 Weeks. | 0.95 (0.80 to 1.12) | 1.04 (0.94 to 1.16) |
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.
| Fold change | Atorvastatin | Placebo |
|---|---|---|
| Change From Week 0 to Week 12 in Percentage of Blood Monocytes Expressing Surface Marker Tissue Factor (TF), Following Treatment. | 1.18 (0.57 to 2.42) | 1.52 (0.75 to 3.09) |
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.
| Fold change | Atorvastatin | Placebo |
|---|---|---|
| Change From 0 Week in Levels of Plasma Inflammatory Marker hsCRP in Chronic HIV+/ HAART+ Subjects Over 12 Weeks, Following Treatment. | 0.94 (0.61 to 1.44) | 1.70 (0.85 to 3.39) |
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.
| Fold Change | Atorvastatin | Placebo |
|---|---|---|
| Change From Week 0 to Week 12 in Percentage of Blood Monocytes Expressing Surface Marker CD38, Following Treatment. | 0.98 (0.86 to 1.12) | 1.04 (0.86 to 1.27) |
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.
| Fold Change | Atorvastatin | Placebo |
|---|---|---|
| Change From Week 0 in Plasma sCD163 Levels, at Week 12 Following Treatment. | 1.08 (0.97 to 1.2) | 1.02 (0.85 to 1.22) |
Collected over Participants were observed for the duration of the study enrollment period, i.e. 36 weeks.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Atorvastatin | 0/11 (0%) | 0/11 (0%) | 0/11 (0%) |
| Placebo | 0/11 (0%) | 0/11 (0%) | 0/11 (0%) |
| Age, Continuous(years) | Atorvastatin Then Placebo | Placebo Then Atorvastatin | Total |
|---|---|---|---|
| Mean | 43.3 ± 13.8 | 47.9 ± 12.0 | 45.4 ± 12.6 |
| Sex: Female, Male(Participants) | Atorvastatin Then Placebo | Placebo Then Atorvastatin | Total |
|---|---|---|---|
| Female | 2 | 1 | 3 |
| Male | 4 | 4 | 8 |
| Race/Ethnicity, Customized(participants) | Atorvastatin Then Placebo | Placebo Then Atorvastatin | Total |
|---|---|---|---|
| White | 0 | 1 | 1 |
| African American | 6 | 4 | 10 |
| Ethnicity: Non Hispanic / Latino | 6 | 5 | 11 |
| Region of Enrollment(participants) | Atorvastatin Then Placebo | Placebo Then Atorvastatin | Total |
|---|---|---|---|
| United States | 6 | 5 | 11 |
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University of Pennsylvania