Effect of Galantamine on Inflammation and Cognition

Study Overview
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Brief Summary
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This study tests whether galantamine (GAL) reduces HIV-related inflammation and cognitive deficits. In this double-blind placebo-controlled crossover study, HIV-infected individuals (N=120; 60 smokers and 60 non-smokers) will be randomized to 12 weeks of GAL or placebo, followed by a 4-week washout, then 12 weeks of GAL or placebo (arms switched). Outcomes are monocyte/macrophage and T cell activation and neurocognitive performance.

Detailed Description
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Although anti-retroviral therapy (ART) enhances life expectancy and overall quality of life (QoL), HIV-infected individuals are increasingly vulnerable to non-AIDS-related diseases including HIV-associated neurocognitive disorders (HAND). Inflammation is a primary mechanism in the pathogenesis of HAND and tobacco use may further exacerbate inflammation. Conversely, nicotine alone has anti-inflammatory effects suggesting that stimulating the cholinergic pathway via pharmacological treatment [e.g., galantamine (GAL)] may suppress inflammation and reverse or prevent neurocognitive deficits in HIV-1 infection. In this double-blind, placebo-controlled crossover study, HIV-infected individuals (N=120; 60 smokers, 60 nonsmokers) will be randomized to 12 weeks of GAL or placebo, followed by a 4-week washout, then 12 weeks of GAL or placebo (arms switched). All subjects will be stable on ART and the GAL dose will follow FDA guidelines. At the beginning and end of each treatment phase, inflammatory biomarkers and viral load will be assessed. Monocyte transcriptomics will also be assessed on a subset of the sample (n=60; 30/group). Neurocognition and clinical outcomes (e.g., QoL) will be measured at baseline and at 4-week intervals during each treatment phase. The primary outcomes are monocyte/macrophage and T-cell activation (CD16, CD163, and CC chemokine receptor type 2 or CCR2 expression; plasma CC chemokine ligand type 2 or CCL2 [MCP-1 or monocyte chemoattractant protein-1], sCD14; CD38/HLA-DR [cluster of differentiation 38/Human Leukocyte Antigen- antigen D Related] on CD8 [cluster of differentiation 8] cells) and neurocognitive performance (processing speed, verbal learning/memory, executive function). Exploratory outcomes include monocyte gene expression patterns and broad plasma cytokine analysis. This study will provide insight into the interactions among nAChR activation, HIV immune activation and pathogenesis, and tobacco use and has translational and therapeutic implications that could improve health outcomes among HIV-infected individuals.

Official Title
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Targeting the Cholinergic Pathway in HIV-associated Inflammation and Cognitive Dysfunction

Conditions
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HIV Associated Cognitive Motor Complex

Intervention / Treatment
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* Drug: Galantamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible subjects will be males and females: At least 30 years old Diagnosed with HIV-1 infection On stable ART regimens (no changes to treatment within 4 weeks of Intake visit) Viral load of less than or equal to 200 copies/mL Current cluster of differentiation (CD4) counts greater than 200 If current or past diagnosis of bipolar disorder, eligible if: No psychotic features Montgomery-Asberg Depression Rating Scale (MADRS): total score less than 8 (past 4 weeks), suicidal item score less than 1 (past 4 weeks) Young Mania Rating Scale (Y-MRS): total score less than 8 (past 4 weeks), irritability, speech content, disruptive or aggressive behavior items score less than 3 (past 4 weeks) No psychiatric hospitalization or Emergency Room visits for psychiatric issues in the past 6 months No aggressive or violent acts or behavior in the past 6 months Able to communicate in English and provide written informed consent Will be residing in the geographic area for at least 7 months Not currently trying to quit smoking Smoking Status Smokers (HIV+S) will report at least 5 instances of smoking per day, on average for the past year and provide a breath carbon monoxide (CO) sample greater than 5 ppm at Intake and at the beginning of each treatment period Non-smokers (HIV+NS) will report smoking fewer than 100 cigarettes in their lifetime, or less than 5 pack years of smoking and no cigarettes in the last year. They will self-report no current use of any tobacco or nicotine product and will provide a CO sample of less than 3 ppm at Intake and at the beginning of each treatment period. If CO sample does not reflect self-report, the PI will be consulted to determine eligibility. Exclusion Criteria: Subjects who present with and/or self-report the following criteria will not be eligible to participate in the study. Smoking Behavior Current enrollment or plans to enroll in another smoking cessation program in the next 7 months. Regular (daily) use of electronic cigarettes, chewing tobacco, snuff, snus, cigars, cigarillos, or pipes. Current use or plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) or smoking cessation treatments in the next 7 months. Alcohol/Drug Use Current untreated and unstable diagnosis of substance abuse or dependence (if past use and if receiving treatment and stable for at least 30 days, eligible) Positive urine drug screen for cocaine, methamphetamines, phencyclidine (PCP), barbiturates, ecstasy (MDMA), at Intake or Lab visits. Those who screen positive for amphetamines, benzodiazepines, methadone, oxycodone, and/or opiates (low level cut-off 300 ng/mL) and who are prescribed these medications will be reviewed on a case-by-case basis by the study physician and PIs (see Measures and Table 1 for details). Participants believed to have a false-positive result on the drug screen may continue in the study, with investigator approval. Medical/Psychiatric Conditions Women who are pregnant, planning a pregnancy or lactating Current diagnosis of unstable and untreated major depression (if stable for at least 30 days, eligible) Current or past diagnosis of psychotic disorder Cancer diagnosis within the past 6 months (except basal cell carcinoma) Major heart disease or stroke within the past 6 months Uncontrolled hypertension (systolic blood pressure greater than 160 or diastolic blood pressure greater than 100). Medical conditions contraindicated for use with galantamine: Diagnosis of Alzheimer's disease or dementia Epilepsy or other seizure disorder Bladder outflow obstruction Active HCV co-infection (if cured, requires study physician approval) Liver function tests more than 20% outside of the normal range; Gamma-glutamyl transpeptidase (GGT) values more than 20% outside of the normal range. If Albumin/Globulin ratios are 20% outside of normal range the abnormal value will be evaluated for clinical significance by the Study Physician and eligibility will determined on a case-by-case basis. Renal disease or renal dysfunction (e.g., serum creatinine levels greater than 1.5 X upper limit of normal). Those with moderate hepatic impairment or creatinine clearance 9 to 59 mL/min shall not exceed the 16 mg/day dose. Peptic ulcer disease (requires study physician approval) Suicide risk as indicated by at least one of the following on the Columbia Suicide Severity Rating Scale (the PI and/or study psychologist will be consulted to assess safety and determine eligibility in cases close to the eligibility cutoffs): Current suicidal ideation (within 30 days of enrollment) Two or more lifetime suicide attempts or episodes of suicidal behavior Any suicide attempt or suicidal behavior within 2 years of enrollment Medication Current use or discontinuation within the last 14 days of: Quit smoking medications including varenicline (Chantix), bupropion (Wellbutrin) Anti-psychotic medications (e.g., Zyprexa, Clozaril, Seroquel, Risperdal). If used to treat psychotic symptoms. Other uses may be eligible pending physician approval). Systemic Steroids (e.g., Prednisone). Alzheimer's disease medications (e.g., Acetylcholinesterase inhibitors (ACIs), Aricept/donepezil, Exelon/rivastigmine, Tacrine, or memantine) Irritable bowel syndrome medication (e.g., Dicyclomine/Bentyl) Heart medications (e.g., quinidine). Muscle relaxants (e.g., Anectine/succinylcholine) Anti-seizure medications (e.g. Ativan, Banzel, Carbatrol, Dilantin, Lamictal, Gabitril, Lyrica, Neurontin, Tegretol, Topomax) if used to treat a seizure disorder or epilepsy. Other uses may be eligible. Urinary retention medications (e.g., Duvoid/bethanechol, Proscar/finasteride, Avodart/dutasteride, Dibenzyline/ phenoxybenzamine, Regitine/phentolamine) Daily use of: Opiate-containing medications for chronic pain (Duragesic/fentanyl patches, Percocet, Oxycontin). Smokers who report taking opiate-containing medications on an as-needed basis will be instructed to refrain from use until their study participation is over and that they will be tested to ensure they have complied with this requirement. Chronic obstructive pulmonary disease (COPD) medication (e.g., Atrovent/Ipratropium Bromide) Known allergy to study medication. Subjects will be instructed to refrain from using any study prohibited drugs/medications (both recreational and prescription) throughout their participation in the study.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Galantamine<br>This study follows the FDA-recommended dosing regimen for galantamine extended release (GAL ER): 4 weeks at 8 mg (once a day), 4 weeks at 16 mg (once a day), and 4 weeks at 24 mg (once a day). The University of Pennsylvania Investigational Drug Service (IDS) will oversee the randomization of all study medication, purchase study medication, manufacture matched placebo, encapsulate and package them in blister packs to maintain double-blind procedures. | Drug: Galantamine<br>* The study will be performed using the 8mg, 16mg and 24mg doses of galantamine hydrobromide-ER. The dosing regimen will be an initial 4 weeks of drug run-up at the lowest 8mg q.d. dose, followed by 16mg q.d. for the following 4 weeks, and the dose will be increased for the last 4 weeks to 24mg. Participants will be instructed to take one 8mg 16mg or 24mg pill (galantamine-ER or placebo) every morning, preferably with food.<br>* Other names: Razadyne ER;|
| Placebo Comparator: Placebo<br>12-week placebo-controlled medication period Placebo ingredients will be purchased, encapsulated, and packaged into blister packs by the IDS at the University of Pennsylvania. Both active medication and placebo will look identical. The study medication assignments for each participant in this project is randomized and counterbalanced. This means that approximately 50% of participants will take galantamine during the first medication period, followed by the placebo in the second medication period. Alternatively, approximately 50% of participants will take the placebo during the first medication period, followed by galantamine during the second medication period. | Drug: Placebo<br>* Matched placebo will be made in-house using lactulose filler in gel capsules. Participants will be instructed to take one pills every morning for 12 weeks.<br>* Other names: Sugar Pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cognition | Cognitive function will be assessed 8 times throughout study participation at Lab Visits and Mid-treatment Visits. Participants will complete measures of executive function, verbal learning and memory and response inhibition. The primary outcome is the change from baseline cognitive function after 12 weeks of treatment. Because this is a within-subject crossover study, change in cognition will be measured during each treatment arm. | Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28) | 
| Change in Inflammation | Cellular markers of immune activation will be measured in whole blood and soluble markers of immune activation will be measured in plasma at Lab Visits. The primary outcome is the change in monocyte and T cell surface activation and soluble markers after 12 weeks of treatment. Because this is a within-subject crossover study, changes in cellular markers will be measured during each treatment arm. | Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monocyte Transcriptomics | Monocytes will be isolated from blood samples and analyzed for differences in monocyte expression between smoking and non-smoking groups and between treatment arms. Gene expression patterns will also be correlated with soluble and cell surface markers of inflammation. | Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Neurocognition, Inflammation, Galantamine, Nicotine, Tobacco Use