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

NCT01600170 | Completed Phase 4 Results DMC

• 1 other identifier: IRB Protocol # 815512
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

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

Conditions

HIV Dementia

Keywords

HIV; monocytes; CD16+; statins; mcp1; inflammation

Outcome Measures

Primary Outcomes (5)

• 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.

  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

Secondary Outcomes (4)

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

  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.

  0 week and 12 week

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

  0 week and 12 week

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

  0 week and 12 week

Study Arms (2)

Atorvastatin

ACTIVE COMPARATOR

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

Drug: Atorvastatin (generic Lipitor)

Placebo

PLACEBO COMPARATOR

Participants were given Placebo tablets for 12 weeks.

Drug: placebo

Interventions

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.

Atorvastatin

placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

AIDS Dementia Complex; Inflammation

Interventions

Atorvastatin

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Neurocognitive Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Limitations and Caveats

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.

Results Point of Contact

• Title: Ronald G Collman
• Organization: University of Pennsylvania School of Medicine

collmanr@pennmedicine.upenn.edu

215-898-0913

Study Officials

• Ronald G Collman, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2012
• First Posted: May 16, 2012
• Study Start: January 1, 2013
• Primary Completion: October 1, 2017
• Study Completion: October 1, 2017
• Last Updated: November 23, 2020
• Results First Posted: November 23, 2020

Record last verified: 2020-10

Locations

US (1)