Clinical Trial of CNS-targeted HAART (CIT2)
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Purpose
CIT2 is a strategy for targeting HAART (Highly Active Antiretroviral Therapy) to the CNS (Central Nervous System) in patients with HIV associated neurocognitive impairment (HNCI).
The primary goal of this study is to evaluate the effectiveness of CNS-targeted (CNS-T) as compared to non-CNS-targeted (non-CNS-T) HAART in treating HNCI globally and in different domains of functioning known to be affected by HIV.
It is hypothesized that participants in the CNS-T arm will have greater improvement in neurocognitive functioning than those in the non-CNS-T arm.
The secondary goal of the study is to compare participants assigned to CNS-T and non-CNS-T HAART on measures of CNS and systemic HIV suppression (undetectable CSF and plasma VL).
It is also hypothesized that although CSF viral suppression will be more frequent in the CNS-T arm, plasma viral suppression will be similar in the two treatment arms.
| Condition | Intervention | Phase |
|---|---|---|
| HIV Infections | Drug: FDA Approved Antiretroviral Therapy (see list below) | Phase 2 Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Single (Participant) Primary Purpose: Treatment |
| Official Title: | HIV Neurocognitive Disorders: A Randomized Clinical Trial of CNS-Targeted HAART |
- Neuropsychological Performance Change [ Time Frame: Baseline and 16 weeks ]The outcome measure is change in performance from baseline to 16 weeks as measured by the global deficit score (GDS). The GDS is calculated by averaging the individual deficit scores from each neurocognitive test. Deficit scores for each test were calculated from age-, education-, gender-, and ethnicity-adjusted raw scores by methods that capture unexpectedly poor performance while ignoring better than expected performance. The GDS ranges in value from 0-5; higher scores indicate poorer cognitive functioning. Subjects with scores greater than or equal to 0.5 are considered cognitively impaired.
| Enrollment: | 59 |
| Study Start Date: | March 2007 |
| Study Completion Date: | June 2012 |
| Primary Completion Date: | February 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: CNS-targeted
CNS-T will comprise two components: 1) initial selection of agents to optimize CNS penetration of the overall regimen; and 2) modification of the regimen if an interim pharmacokinetic (PK) assessment determines that plasma ARV exposure is not appropriate (overdosing, under dosing). Possible regimens include combinations of these FDA approved antiretroviral agents: Efavirenz/Emtricitabine/Tenofovir, Lamivudine/Zidovudine, Emtricitabine, Lamivudine, Abacavir/Lamivudine, Zidovudine, Abacavir/Lamivudine/Zidovudine, Emtricitabine/Tenofovir, Tenofovir, Abacavir, Etravirine, Delavirdine, Efavirenz, Nevirapine, Amprenavir, Tipranavir, Saquinavir, Lopinavir/ritonavir, Fosamprenavir, Ritonavir, Darunavir, Atazanavir, Nelfinavir, Enfuvirtide, Maraviroc, Raltegravir |
Drug: FDA Approved Antiretroviral Therapy (see list below)
Combinations of FDA approved antiretroviral agents: Atripla, Combivir, Emtriva, Epivir, Epzicom, Retrovir, Trizivir, Truvada, Viread, Ziagen, Intelence, Rescriptor, Sustiva, Viramune, Agenerase, Aptivus, Invirase, Kaletra, Lexiva, Norvir, Prezista, Reyataz, Viracept, Fuzeon, Selzentry, Isentress Generic names: Efavirenz/Emtricitabine/Tenofovir, Lamivudine/Zidovudine, Emtricitabine, Lamivudine, Abacavir/Lamivudine, Zidovudine, Abacavir/Lamivudine/Zidovudine, Emtricitabine/Tenofovir, Tenofovir, Abacavir, Etravirine, Delavirdine, Efavirenz, Nevirapine, Amprenavir, Tipranavir, Saquinavir, Lopinavir/ritonavir, Fosamprenavir, Ritonavir, Darunavir, Atazanavir, Nelfinavir, Enfuvirtide, Maraviroc, Raltegravir Other Names:
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|
Active Comparator: non-CNS-targeted
Subjects in the non-CNS-T (Comparison) arm will be randomized to receive a regimen (see list of FDA approved antiretrovirals listed below) designed to suppress plasma Viral Load, but not expected to have targeted CNS penetration. Combinations of FDA approved antiretroviral agents: Efavirenz/Emtricitabine/Tenofovir, Lamivudine/Zidovudine, Emtricitabine, Lamivudine, Abacavir/Lamivudine, Zidovudine, Abacavir/Lamivudine/Zidovudine, Emtricitabine/Tenofovir, Tenofovir, Abacavir, Etravirine, Delavirdine, Efavirenz, Nevirapine, Amprenavir, Tipranavir, Saquinavir, Lopinavir/ritonavir, Fosamprenavir, Ritonavir, Darunavir, Atazanavir, Nelfinavir, Enfuvirtide, Maraviroc, Raltegravir |
Drug: FDA Approved Antiretroviral Therapy (see list below)
Combinations of FDA approved antiretroviral agents: Atripla, Combivir, Emtriva, Epivir, Epzicom, Retrovir, Trizivir, Truvada, Viread, Ziagen, Intelence, Rescriptor, Sustiva, Viramune, Agenerase, Aptivus, Invirase, Kaletra, Lexiva, Norvir, Prezista, Reyataz, Viracept, Fuzeon, Selzentry, Isentress Generic names: Efavirenz/Emtricitabine/Tenofovir, Lamivudine/Zidovudine, Emtricitabine, Lamivudine, Abacavir/Lamivudine, Zidovudine, Abacavir/Lamivudine/Zidovudine, Emtricitabine/Tenofovir, Tenofovir, Abacavir, Etravirine, Delavirdine, Efavirenz, Nevirapine, Amprenavir, Tipranavir, Saquinavir, Lopinavir/ritonavir, Fosamprenavir, Ritonavir, Darunavir, Atazanavir, Nelfinavir, Enfuvirtide, Maraviroc, Raltegravir Other Names:
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Detailed Description:
"HIV Neurocognitive Disorders: A Randomized Clinical Trial of CNS-targeted HAART" is a randomized, controlled clinical trial to assess the efficacy of a strategy for targeting highly active antiretroviral therapy (HAART) to the CNS in patients with HIV associated neurocognitive impairment (HNCI). Contemporary cohort studies have consistently demonstrated that HNCI remains a prevalent disorder in patients receiving HAART. HNCI is a significant burden to persons living with HIV infection, caregivers, and the healthcare system. Thus the development of effective treatment strategies is of critical public health importance.
This study is based on findings from a previous study. Briefly, among individuals with HNCI who initiated a new antiretroviral (ARV) therapy regimen, those receiving more highly CNS-penetrating ARV regimens were more likely to successfully suppress cerebrospinal fluid (CSF) viral load (VL), and those who achieved CSF suppression (VL < 50 c/mL) had better neurocognitive (NC) outcomes. These findings suggest that NC outcomes of ART may be enhanced by the planned application of an ARV selection and clinical monitoring strategy designed to optimize the treatment of CNS infection. In the future it will become increasingly important to consider CNS penetration issues in selecting ART regimens. The randomized clinical trial proposed here would provide the level of evidence needed to formulate ART guidelines specific to HNCI.
Subjects eligible for this trial will be individuals with HNCI who anticipate initiation of a new ARV regimen or substitution of their existing regimen following contemporary treatment guidelines. A total of 120 patients at 3 study sites will be randomized 1:1 to receive a CNS-targeted (CNS-T) ARV strategy versus a non-CNS-targeted (Comparison) strategy. The primary outcome, change in global neuropsychological (NP) performance, will be assessed at 16 weeks. CNS-T will comprise two components: 1) initial selection of agents to optimize CNS penetration of the overall regimen; and 2) modification of the regimen if an interim pharmacokinetic (PK) assessment determines that plasma ARV exposure is not appropriate (overdosing, underdosing).
Eligibility
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| Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- HIV infected- confirmed by ELISA or 2 prior viral loads >2000
- 18 years or older
- Under consideration to initiate or change their HAART regimens (based on current consensus treatment guidelines) as directed by their primary care physicians.
- Measurable HIV Neurocognitive Impairment (HNCI)
- Willing and able to undergo at least 3 lumbar punctures safely during the course of the study.
- Potential subjects must have a Karnofsky score of > or = to 60 within 60 days prior to study entry.
- Potential subjects must have a CD4 cell count obtained within 60 days prior to study entry.
Exclusion Criteria:
- Presence of serious illness, including HIV-related opportunistic infections, requiring systemic treatment and/or hospitalization until candidate either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 14 days prior to study entry.
- Presence of neurologic disorders other than HIV judged to be the principal cause of neurocognitive impairment.
- Presence of active, severe psychiatric disorders (e.g., major depression, schizophrenia) that would interfere with interpretation of the study evaluations or adherence to the study protocol or that might make their participation in the study problematic or unsafe.
- Presence of active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
- Use of any immunomodulator (interferons, interleukins, cyclosporine), vaccine, or investigational therapy including dexamethasone within 30 days prior to study entry.
- Inability to provide informed consent.
- Enrollment in other ARV treatment studies, unless the study is: 1) observational; 2) a compassionate use study that predated the current study; 3) one that does not require specific interventions (or one that does not dictate the regimen); or 4) one that does not include NP testing.
- A positive serum or urine pregnancy test, if female and of reproductive potential.
Contacts and Locations
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00624195
| United States, California | |
| HIV Neurobehavioral Research Center, University of California San Diego | |
| San Diego, California, United States, 92103 | |
| University of California, San Francisco | |
| San Francisco, California, United States, 94110 | |
| United States, Maryland | |
| Johns Hopkins University- School of Medicine | |
| Baltimore, Maryland, United States, 21287 | |
| United States, Missouri | |
| Washington University | |
| St. Louis, Missouri, United States, 63110 | |
| United States, New York | |
| Mount Sinai Medical Center | |
| New York, New York, United States, 10024 | |
| Principal Investigator: | Ronald J Ellis, MD, PhD | UCSD HIV Neurobehavioral Research Center |
More Information
Additional Information:
Publications:
| Responsible Party: | Ronald J Ellis, Principal Investigator, University of California, San Diego |
| ClinicalTrials.gov Identifier: | NCT00624195 History of Changes |
| Other Study ID Numbers: |
060154 R01MH058076-09A2 ( U.S. NIH Grant/Contract ) |
| First Submitted: | February 15, 2008 |
| First Posted: | February 27, 2008 |
| Results First Submitted: | December 9, 2013 |
| Results First Posted: | April 23, 2014 |
| Last Update Posted: | April 23, 2014 |
| Last Verified: | March 2014 |
Keywords provided by Ronald J Ellis, University of California, San Diego:
|
HIV Dementia HAART Cognitive Impairment |
Antiretroviral Regimen Viral Load CNS Drug Penetration |
Additional relevant MeSH terms:
|
HIV Infections Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Ritonavir Lopinavir Darunavir Atazanavir Sulfate Nelfinavir Saquinavir |
Fosamprenavir Amprenavir Tenofovir Lamivudine Raltegravir Potassium Emtricitabine Zidovudine Maraviroc Nevirapine Abacavir Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination Tipranavir Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination Enfuvirtide Lamivudine, zidovudine drug combination |