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Effect of Cenicriviroc on HIV Neurocognitive Impairment

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02128828
Recruitment Status : Completed
First Posted : May 1, 2014
Last Update Posted : March 16, 2017
Sponsor:
Collaborator:
Tobira Therapeutics, Inc.
Information provided by (Responsible Party):
Cecilia Shikuma, University of Hawaii

Tracking Information
First Submitted Date  ICMJE September 4, 2013
First Posted Date  ICMJE May 1, 2014
Last Update Posted Date March 16, 2017
Study Start Date  ICMJE April 2014
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 29, 2014)
Change from baseline to week 24 in Neuropsychological Performance utilizing a battery of neuropsychological tests [ Time Frame: baseline, week 24 ]
To assess 24 week change in global and domain-specific neuropsychological performance following CVC intensification
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2017)
  • Number of participants who experience temporary or permanent study drug discontinuation due to intolerability [ Time Frame: Up to 24 weeks ]
  • Cenicriviroc plasma drug levels [ Time Frame: week 2 ]
    plasma levels on dosage selected for patient
  • Change in plasma HIV RNA from baseline to week 24 [ Time Frame: Baseline, week 4, week 24 ]
  • Change in CD4 count from baseline to week 24 [ Time Frame: Baseline, week 24 ]
  • Change in fasting metabolic parameters (glucose, insulin, total, LDL and HDL cholesterol, triglycerides) [ Time Frame: baseline, week 24 ]
  • Number of participants who experience grade 2 or higher adverse events [ Time Frame: Up to 28 weeks ]
  • Change in total numbers of activated monocytes by flow cytometry phenotype [ Time Frame: baseline to week 24 ]
    Activated monocytes, defined by flow cytometry as blood cells bearing the CD14 surface receptor (indicating monocytes) and bearing the CD16 surface receptor (indicating activation)
Original Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2014)
  • Number of participants who experience temporary or permanent study drug discontinuation due to intolerability [ Time Frame: Up to 24 weeks ]
  • Cenicriviroc plasma drug levels [ Time Frame: week 2 ]
    plasma levels on dosage selected for patient
  • Change in plasma HIV RNA from baseline to week 24 [ Time Frame: Baseline, week 4, week 24 ]
  • Change in CD4 count from baseline to week 24 [ Time Frame: Baseline, week 24 ]
  • Change in fasting metabolic parameters (glucose, insulin, total, LDL and HDL cholesterol, triglycerides) [ Time Frame: baseline, week 24 ]
  • Number of participants who experience grade 2 or higher adverse events [ Time Frame: Up to 28 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Cenicriviroc on HIV Neurocognitive Impairment
Official Title  ICMJE Randomized, Placebo-Controlled, Double-Blind, Pilot Study of CCR5/CCR2 Inhibitor Cenicriviroc (CVC) for HIV Associated Neurocognitive Disorder (HAND)
Brief Summary The study hypothesis is that cenicriviroc will improve cognition in HIV infected individuals with cognitive impairment. The investigators will study the effect of cenicriviroc on cognition in 24 subjects over a 24 week period.
Detailed Description

HIV-associated neurocognitive disease (HAND), particularly in its milder form, is estimated to occur in greater than 30% of HIV infected individuals in the era of potent antiretroviral therapy. As even mild disease leads to functional consequences with decreased ability to live independently, HAND is of substantial public health concern. HIV-induced immune activation/inflammation of monocytes (MO) may be primarily responsible for the development of HAND.

Cenicriviroc is a combined CCR5 and CCR2 chemokine co-receptor antagonist. The investigators hypothesize that dual CCR5 and CCR2 blockade with the use of CVC will lead to measurable reductions in MO activation and lead to cognitive improvement by decreasing HIV infection of MO and by interrupting the trafficking of such MO into the central nervous system.

The investigators propose a single arm, 24-week trial of CVC in 24 subjects with HIV-1 infection suppressed on ART (plasma HIV RNA < 50 copies/ml) for 1 year or more with mild to moderate cognitive impairment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • AIDS Dementia Complex
  • HIV-1-Associated Cognitive Motor Complex
  • Human Immunodeficiency Virus
Intervention  ICMJE Drug: cenicriviroc
cenicriviroc given once daily for 24 weeks; number of pills dependent on recommended modifications based on patient's other antiretroviral medications and certain other medications anticipated to interact with cenicriviroc
Other Name: TBR-652
Study Arms  ICMJE Experimental: cenicriviroc
cenicriviroc 50 mg tablets, number of tablets adjusted for other antiretroviral medications or other drugs, given once daily
Intervention: Drug: cenicriviroc
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 14, 2017)
20
Original Estimated Enrollment  ICMJE
 (submitted: April 29, 2014)
24
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 4.2.1.1 Documentation of HIV-1 infection by an FDA approved test at any time prior to study entry
  • On ARV medication uninterrupted for > 1 year leading up to the screening period
  • Screening plasma HIV RNA < 50 copies/ml within 3 months of entry
  • Willingness for males and females of childbearing potential to utilize 2 effective contraception methods (2 separate forms, one of which must be an effective barrier method), be non-heterosexually active or have a an exclusive vasectomized partner from screening throughout the duration of the study treatment and for 30 days following the last dose of study drugs.
  • Age 18 to 70 years
  • Ability and willingness to provide written informed consent
  • Mild to moderate cognitive impairment with global neuropsychological (NP) test (NPZglobal) score of < -0.5 or a neurocognitive abnormality (<-0.5) in at least one cognitive domain known to be typically affected by HIV OR unimpaired
  • On antiretroviral (ARV) therapy consisting of nucleoside reverse transcriptase inhibitors, atazanavir with/or without ritonavir, darunavir plus ritonavir, dolutegravir, raltegravir or efavirenz.

Exclusion Criteria:

  • Receiving or used a CCR5 antagonist within 6 months of study entry
  • Plasma HIV RNA > 100 copies/ml within 6 mo. of screening
  • HIV-2
  • Chronic hepatitis B (positive hepatitis B surface antigen)
  • Chronic hepatitis C (positive hepatitis C antibody), except with proof of viral clearance and normal liver function tests
  • Active or chronic liver disease
  • Active or inadequately treated tuberculosis infection, or inadequate treatment for a positive purified protein derivative test. Adequate treatment meets current recommendations of the Center for Disease Control, NIH and the HIV Medicine Association of the Infectious Diseases Society of America (IDSA) guidelines or other Center for Disease Control recommendations if patient was treated before the current recommendations or before coinfection with HIV.
  • Prior/current diagnosis with other intracellular pathogens (Listeria monocytogenes, Toxoplasma gondii, and Cryptococcus neoformans).
  • Uncontrolled seizures
  • Current or past malignancies excluding basal cell cancer and Kaposi's sarcoma (skin).
  • Immunomodulator, HIV vaccine, any other vaccine, or investigational therapy within 30 days of entry.
  • Requirement for acute therapy for AIDS-defining or other serious medical illnesses within 14 days of entry.
  • Other chronic illnesses including hematologic, pulmonary, autoimmune diseases and endocrinopathies, except for stable controlled diabetes or cardiovascular disease in the view of the investigator and stable testosterone or thyroid therapy.
  • Known hypersensitivity to CVC or its excipients
  • Anticipated need for prescription medication not allowed in the study. Unwilling to stop eating grapefruit or using St. John's wort).
  • Chronic use of over the counter medications unless approved by Study Investigator
  • Hemoglobin < 8.5; Absolute neutrophil count < 1000; Platelet count < 100,000; serum glutamate oxaloacetate and pyruvate transaminase > 2.5x upper limit of normal ; Lipase > 2.0 x upper limit of normal
  • Estimated creatinine clearance < 30 mL/min(Cockcroft and Gault 1979)
  • Bradycardia, sinus rhythm <50 beats/min (bpm).
  • Presence of any condition that would interfere with the absorption, distribution, metabolism, or excretion of the drug
  • Current active illicit substance or alcohol use or abuse which, in the judgment of the Investigator, will interfere with the patient's ability to comply with protocol requirements
  • Pregnancy or breast-feeding
  • History of moderate (Child-Pugh class B) or severe (Child-Pugh C) hepatic impairment
  • Patients, who, in the opinion of the Investigator, are unable to comply with the dosing schedule and protocol evaluation or for whom the study may not be advisable
  • For MRI substudy [impaired]: Any factor that precludes MRI scan including presence of metal or exposure to metal work (e.g. metal grinder/worker) and claustrophobia
  • For MRI substudy [impaired]: Any central nervous system pathology which, in the judgment of the investigator, will interfere with the ability to assess study change in magnetic resonance spectroscopy
  • 4.2.2.28 For lumbar puncture substudy: Thrombocytopenia or other bleeding disorders (including ongoing anticoagulant therapy), suspected increased intracranial pressure or spinal epidural abscess, or any other factor which would increase risk of complications following lumbar puncture
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02128828
Other Study ID Numbers  ICMJE H020
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Cecilia Shikuma, University of Hawaii
Study Sponsor  ICMJE University of Hawaii
Collaborators  ICMJE Tobira Therapeutics, Inc.
Investigators  ICMJE
Principal Investigator: Cecilia Shikuma, MD University of Hawaii - Hawaii Center for AIDS (HICFA)
PRS Account University of Hawaii
Verification Date March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP