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Effect of Cenicriviroc on HIV Neurocognitive Impairment

This study has been completed.
Sponsor:
Collaborator:
Tobira Therapeutics, Inc.
Information provided by (Responsible Party):
Cecilia Shikuma, University of Hawaii
ClinicalTrials.gov Identifier:
NCT02128828
First received: September 4, 2013
Last updated: March 14, 2017
Last verified: March 2017
  Purpose
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.

Condition Intervention Phase
AIDS Dementia Complex
HIV-1-Associated Cognitive Motor Complex
Human Immunodeficiency Virus
Drug: cenicriviroc
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Randomized, Placebo-Controlled, Double-Blind, Pilot Study of CCR5/CCR2 Inhibitor Cenicriviroc (CVC) for HIV Associated Neurocognitive Disorder (HAND)

Resource links provided by NLM:


Further study details as provided by University of Hawaii:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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)


Enrollment: 20
Study Start Date: April 2014
Study Completion Date: June 2016
Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: cenicriviroc
cenicriviroc 50 mg tablets, number of tablets adjusted for other antiretroviral medications or other drugs, given once daily
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02128828

Locations
United States, Hawaii
Clint Spencer Clinic
Honolulu, Hawaii, United States, 96813
Sponsors and Collaborators
University of Hawaii
Tobira Therapeutics, Inc.
Investigators
Principal Investigator: Cecilia Shikuma, MD University of Hawaii - Hawaii Center for AIDS (HICFA)
  More Information

Responsible Party: Cecilia Shikuma, Professor, Dept of Medicine, University of Hawaii
ClinicalTrials.gov Identifier: NCT02128828     History of Changes
Other Study ID Numbers: H020
Study First Received: September 4, 2013
Last Updated: March 14, 2017

Keywords provided by University of Hawaii:
AIDS Dementia Complex
HIV-1-Associated Cognitive Motor Complex
Human Immunodeficiency Virus

Additional relevant MeSH terms:
Dementia
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
AIDS Dementia Complex
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
TAK-652
CCR5 Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on March 29, 2017