Clinical Trial of CNS-targeted HAART (CIT2)

NCT00624195 | Completed Phase 2 Results DMC

• 2 other identifiers: 060154R01MH058076-09A2
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

HIV Infections

Keywords

HIV Dementia; HAART; Cognitive Impairment; Antiretroviral Regimen; Viral Load; CNS Drug Penetration

Outcome Measures

Primary Outcomes (1)

• Neuropsychological Performance Change

  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.

  Baseline and 16 weeks

Study Arms (2)

CNS-targeted

EXPERIMENTAL

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)

non-CNS-targeted

ACTIVE COMPARATOR

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)

Interventions

FDA Approved Antiretroviral Therapy (see list below) DRUG

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

Also known as: 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

CNS-targeted; non-CNS-targeted

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV infected- confirmed by ELISA or 2 prior viral loads \>2000
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, San Diego: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Mental Health (NIMH): collaborator

Study Sites (5)

HIV Neurobehavioral Research Center, University of California San Diego

San Diego, California, 92103, United States

Location

University of California, San Francisco

San Francisco, California, 94110, United States

Location

Johns Hopkins University- School of Medicine

Baltimore, Maryland, 21287, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Mount Sinai Medical Center

New York, New York, 10024, United States

Location

Related Publications (3)

• May S, Letendre S, Haubrich R, McCutchan JA, Heaton R, Capparelli E, Ellis R. Meeting practical challenges of a trial involving a multitude of treatment regimens: an example of a multi-center randomized controlled clinical trial in neuroAIDS. J Neuroimmune Pharmacol. 2007 Mar;2(1):97-104. doi: 10.1007/s11481-006-9057-8. Epub 2007 Jan 10.

  PMID: 18040832 BACKGROUND

• Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ; CHARTER Group. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008 Jan;65(1):65-70. doi: 10.1001/archneurol.2007.31.

  PMID: 18195140 BACKGROUND

• Ellis RJ, Letendre S, Vaida F, Haubrich R, Heaton RK, Sacktor N, Clifford DB, Best BM, May S, Umlauf A, Cherner M, Sanders C, Ballard C, Simpson DM, Jay C, McCutchan JA. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder. Clin Infect Dis. 2014 Apr;58(7):1015-22. doi: 10.1093/cid/cit921. Epub 2013 Dec 18.

  PMID: 24352352 RESULT

Related Links

• University of California, San Diego HIV Neurobehavioral Research Center Public Website

MeSH Terms

Conditions

HIV Infections; AIDS Dementia Complex; Cognitive Dysfunction

Interventions

Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; lamivudine, zidovudine drug combination; Emtricitabine; Lamivudine; abacavir, lamivudine drug combination; Zidovudine; abacavir, lamivudine, and zidovudine drug combination; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Tenofovir; abacavir; etravirine; Delavirdine; efavirenz; Nevirapine; amprenavir; tipranavir; Saquinavir; lopinavir-ritonavir drug combination; fosamprenavir; Ritonavir; Darunavir; Atazanavir Sulfate; Nelfinavir; Enfuvirtide; Maraviroc; Raltegravir Potassium

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Drug Combinations; Pharmaceutical Preparations; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Zalcitabine; Dideoxynucleosides; Thymidine; Piperazines; Indoles; Pyridines; Isoquinolines; Quinolines; Thiazoles; Sulfur Compounds; Azoles; Sulfonamides; Amides; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Furans; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Peptide Fragments; HIV Envelope Protein gp41; Viral Fusion Proteins; Membrane Fusion Proteins; Membrane Proteins; Proteins; HIV Antigens; Antigens, Viral; Viral Proteins; env Gene Products, Human Immunodeficiency Virus; Gene Products, env; Retroviridae Proteins; Human Immunodeficiency Virus Proteins; Viral Envelope Proteins; Viral Structural Proteins; Antigens; Biological Factors; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Triazoles; Pyrrolidinones; Pyrrolidines

Results Point of Contact

• Title: Dr. Ron Ellis
• Organization: UCSD

roellis@ucsd.edu

619-543-5079

Study Officials

• Ronald J Ellis, MD, PhD

  UCSD HIV Neurobehavioral Research Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 15, 2008
• First Posted: February 27, 2008
• Study Start: March 1, 2007
• Primary Completion: February 1, 2012
• Study Completion: June 1, 2012
• Last Updated: April 23, 2014
• Results First Posted: April 23, 2014

Record last verified: 2014-03

Locations

US (5)