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Mental Ability Challenge Study in Adults With and Without HIV

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: NCT03244488
Recruitment Status : Completed
First Posted : August 9, 2017
Last Update Posted : February 25, 2019
Sponsor:
Information provided by (Responsible Party):
Asante Kamkwalala, Vanderbilt University Medical Center

Brief Summary:
It is estimated that by 2016, nearly 50% of HIV-positive individuals in the US will be aged 50 or older, and up to 60% of those will experience some degree of cognitive impairment as they age. The purpose of this study is to evaluate the contribution of the neuronal cholinergic receptor system to the cognitive impairments seen in adults aging with chronic HIV Infection. By using anti-cholinergic challenge drugs to reversibly "stress" cognitive functioning, the investigators hope to understand whether the presence of the HIV virus in the brain impairs the neural system necessary for normal cognition, more than would be expected from normal cognitive aging.

Condition or disease Intervention/treatment
HIV-1-infection Aging, Premature Cognitive Impairment Memory Impairment HIV-Associated Cognitive Motor Complex Drug: Scopolamine Injectable Product Drug: Mecamylamine Pill

Detailed Description:
This study is intended to evaluate the involvement of the neuronal cholinergic receptor system in the accelerated cognitive aging profile seen in adults living with chronic HIV-1 infection. It is estimated by the CDC that by the year 2016, nearly 50% of the US' HIV-positive population will be 50 or older. The HIV-1 virus is known to enter the CNS very rapidly after initial infection, and cause a pattern of persistent neural inflammation, which is deleterious to neurons and glia. This damage is believed to be the basis of cognitive impairment associated with long-term chronic HIV infection, known as HIV-Associated Neurocognitive Disorders (HAND). Successful introduction of Anti-Retroviral Treatment (ART) has greatly reduced the likelihood of progressing to the most severe category of HAND (HIV-Associated Dementia), however the mild and moderate forms (Asymptomatic Neurocognitive Impairment and Mild Neurocognitive Disorder, respectively) are still fairly common even in adults declared "virally suppressed", with little to no detectable peripheral viral DNA/RNA. Prior studies have shown that over the lifetime, more than 50% of adults diagnosed with HIV will experience some degree of cognitive impairment as they age. Some of these changes may be due to cholinergic dysfunction. The acetylcholinergic receptor system is necessary for normal cognitive performance, and is active during working memory, executive functioning, attention, and learning tasks. It has been shown that as the human brain ages, cognitive ability begins to decline, and correlates with declining acetylcholinergic activity. The cholinergic theory of cognitive aging postulates that this loss of activity at cholinergic receptors with age is at least partly responsible for poorer cognitive performance in aging. I will use this model to examine the impact of HIV infection on cholinergic system functioning. This study will use a well-established anti-cholinergic drug challenge model to evaluate cognitive performance in domains of cognitive functioning relevant to cholinergic functioning. Under conditions of temporary muscarinic or nicotinic blockade, or a combination of both, I aim to explore the contribution of putative cholinergic receptor dysfunction to the observed symptoms of HAND. I also intend to determine whether age and HIV-status interact to produce an accelerated pattern of cholinergic cognitive aging that would indicate that older adults with HIV are at higher risk for more rapid cognitive aging than HIV-negative individuals. If successful, the outcome of this study would support the future exploration of novel pro-cholinergic medications to treat cognitive symptoms of HAND, which may improve quality of life for adults living with chronic HIV infection, as they survive into old age.

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Study Type : Observational
Actual Enrollment : 22 participants
Observational Model: Case-Crossover
Time Perspective: Cross-Sectional
Official Title: Cholinergic Correlates of Impaired Cognitive Ability in HIV-Associated Neurocognitive Disorders
Actual Study Start Date : December 2015
Actual Primary Completion Date : December 2018
Actual Study Completion Date : December 2018


Group/Cohort Intervention/treatment
HIV-Positive
Patients will be administered each of 4 possible treatments: high dose (5 mcg/kg) scopolamine, high dose (20 mg) mecamylamine, a low dose combination (2.5mcg/kg and 10 mg) of scopolamine and mecamylamine, or placebo.
Drug: Scopolamine Injectable Product
2.5 or 5 mcg/kg of scopolamine via IV

Drug: Mecamylamine Pill
10 or 20mg of mecamylamine orally

HIV-Negative
Patients will be administered each of 4 possible treatments: high dose (5 mcg/kg) scopolamine, high dose (20 mg) mecamylamine, a low dose combination (2.5mcg/kg and 10 mg) of scopolamine and mecamylamine, or placebo.
Drug: Scopolamine Injectable Product
2.5 or 5 mcg/kg of scopolamine via IV

Drug: Mecamylamine Pill
10 or 20mg of mecamylamine orally




Primary Outcome Measures :
  1. Cognitive Outcome - Lower verbal memory score [ Time Frame: 2 hours ]
    Cognitive performance will be more significantly impaired by study medications in HIV-positive participants relative to HIV-negative participants, indicating impairment of cholinergic neurotransmitter system.


Secondary Outcome Measures :
  1. Age and HIV-Status Interaction - Slower CRTreaction time [ Time Frame: 2 hours ]
    Older age and positive HIV status will interact to more significantly impair cognitive performance as measured by reaction time on the Choice Reaction Time task under the influence of study medications, than either variable alone.


Biospecimen Retention:   Samples With DNA
Blood samples collected from all participants for routine screening labs and APOE genotyping.


Information from the National Library of Medicine

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Ages Eligible for Study:   35 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
HIV-Positive Healthy older adults and HIV-Negative Healthy older adults
Criteria

Inclusion Criteria:

  1. 35 years of age or older;
  2. HIV-Positive (must be on ART's for at least 6 months, most recent viral load (within 6 months) <50, CD4+ count >200, must be diagnosed HIV-positive at least 5 years) or HIV-Negative, At-Risk Individuals
  3. Able and willing to give written informed consent
  4. Negative urine pregnancy test
  5. Adequate visual and auditory acuity to allow neuropsychological testing.

Exclusion Criteria:

  1. Unmanaged HIV Infection, identified by no current medication regimen or the presence of one or more AIDS-defining conditions
  2. Fagerstrom cigarettes per day (CPD) score of '2' indicating heavy use of nicotine
  3. An ART regimen including a Protease Inhibitor Medication
  4. A documented history of cardiac disease or abnormal ECG at Screening
  5. Current alcohol or substance abuse, particularly intravenously
  6. Current use of psychoactive medications (antipsychotics, benzodiazepines, etc.)
  7. Current Axis I or Axis II psychiatric disorder
  8. History of myocardial infarction in the past year or unstable or severe cardiovascular disease

Information from the National Library of Medicine

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): NCT03244488


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37212
Sponsors and Collaborators
Vanderbilt University Medical Center
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Responsible Party: Asante Kamkwalala, Graduate Research Assistant, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03244488    
Other Study ID Numbers: 150929
First Posted: August 9, 2017    Key Record Dates
Last Update Posted: February 25, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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AIDS Dementia Complex
Aging, Premature
Neurocognitive Disorders
Mental Disorders
HIV Infections
Blood-Borne Infections
Communicable Diseases
Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Mecamylamine
Scopolamine
Butylscopolammonium Bromide
Adjuvants, Anesthesia
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Mydriatics