Effect of Cenicriviroc on HIV Neurocognitive Impairment
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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 Names:
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline to Week 24 in Global Neuropsychological Performance [baseline, week 24]
Raw scores from individual performance on 14 validated neuropsychological tests meant to assess various cognitive domains were converted into standardized z-scores adjusted for age, sex, and education. Z-scores from all tests were aggregated and averaged to determine each subject's Global Neuropsychological Performance Score; NPZ-Global). Z-scores follow a normal distribution with scores < '0' identifying poorer cognition than 'average' and scores > "0" identifying better cognition than average with -1 and +1 represented 1 SD below or higher than average.
Eligibility Criteria
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
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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.
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Prior/current diagnosis with other intracellular pathogens (Listeria monocytogenes, Toxoplasma gondii, and Cryptococcus neoformans).
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Uncontrolled seizures
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Current or past malignancies excluding basal cell cancer and Kaposi's sarcoma (skin).
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Immunomodulator, HIV vaccine, any other vaccine, or investigational therapy within 30 days of entry.
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Requirement for acute therapy for AIDS-defining or other serious medical illnesses within 14 days of entry.
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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.
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Known hypersensitivity to CVC or its excipients
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Anticipated need for prescription medication not allowed in the study. Unwilling to stop eating grapefruit or using St. John's wort).
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Chronic use of over the counter medications unless approved by Study Investigator
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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
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Estimated creatinine clearance < 30 mL/min(Cockcroft and Gault 1979)
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Bradycardia, sinus rhythm <50 beats/min (bpm).
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Presence of any condition that would interfere with the absorption, distribution, metabolism, or excretion of the drug
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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
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Pregnancy or breast-feeding
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History of moderate (Child-Pugh class B) or severe (Child-Pugh C) hepatic impairment
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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
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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
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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
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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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 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)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H020
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Cenicriviroc |
|---|---|
| Arm/Group Description | cenicriviroc 50 mg tablets, number of tablets adjusted for other antiretroviral medications or other drugs, given once daily 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 |
| Period Title: Overall Study | |
| STARTED | 20 |
| COMPLETED | 17 |
| NOT COMPLETED | 3 |
Baseline Characteristics
| Arm/Group Title | Cenicriviroc |
|---|---|
| Arm/Group Description | cenicriviroc 50 mg tablets, number of tablets adjusted for other antiretroviral medications or other drugs, given once daily 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 |
| Overall Participants | 17 |
| Age (years) [Median (Inter-Quartile Range) ] | |
| Median (Inter-Quartile Range) [years] |
55
|
| Sex: Female, Male (Count of Participants) | |
| Female |
1
5.9%
|
| Male |
16
94.1%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
1
5.9%
|
| Asian |
3
17.6%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
7
41.2%
|
| More than one race |
6
35.3%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| United States |
17
100%
|
Outcome Measures
| Title | Change From Baseline to Week 24 in Global Neuropsychological Performance |
|---|---|
| Description | Raw scores from individual performance on 14 validated neuropsychological tests meant to assess various cognitive domains were converted into standardized z-scores adjusted for age, sex, and education. Z-scores from all tests were aggregated and averaged to determine each subject's Global Neuropsychological Performance Score; NPZ-Global). Z-scores follow a normal distribution with scores < '0' identifying poorer cognition than 'average' and scores > "0" identifying better cognition than average with -1 and +1 represented 1 SD below or higher than average. |
| Time Frame | baseline, week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cenicriviroc |
|---|---|
| Arm/Group Description | cenicriviroc 50 mg tablets, number of tablets adjusted for other antiretroviral medications or other drugs, given once daily 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 |
| Measure Participants | 17 |
| Median (Inter-Quartile Range) [units on a scale] |
.24
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cenicriviroc |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0079 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Cenicriviroc | |
| Arm/Group Description | cenicriviroc 50 mg tablets, number of tablets adjusted for other antiretroviral medications or other drugs, given once daily 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 | |
All Cause Mortality |
||
| Cenicriviroc | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Cenicriviroc | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/20 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Cenicriviroc | ||
| Affected / at Risk (%) | # Events | |
| Total | 9/20 (45%) | |
| Gastrointestinal disorders | ||
| Loose stools | 2/20 (10%) | |
| General disorders | ||
| Fatigue | 4/20 (20%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 3/20 (15%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Cecilia Shikuma |
|---|---|
| Organization | University of Hawaii |
| Phone | 808 692-1328 |
| shikuma@hawaii.edu |
- H020