Effect of Galantamine on Inflammation and Cognition

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03384784

Acronym

CHI

Enrollment

Registered

2017-12-27

Start date

2017-10-30

Completion date

2022-05-31

Last updated

2024-10-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Associated Cognitive Motor Complex

Keywords

HIV, Neurocognition, Inflammation, Galantamine, Nicotine, Tobacco Use

Brief summary

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

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.

Interventions

DRUGGalantamine

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.

DRUGPlacebo

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.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

30 Years to No maximum

Healthy volunteers

Inclusion criteria

Eligible subjects will be males and females: 1. At least 30 years old 2. Diagnosed with HIV-1 infection 3. On stable ART regimens (no changes to treatment within 4 weeks of Intake visit) 4. Viral load of less than or equal to 200 copies/mL 5. Current cluster of differentiation (CD4) counts greater than 200 6. If current or past diagnosis of bipolar disorder, eligible if: 1. No psychotic features 2. Montgomery-Asberg Depression Rating Scale (MADRS): total score less than 8 (past 4 weeks), suicidal item score less than 1 (past 4 weeks) 3. 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) 4. No psychiatric hospitalization or Emergency Room visits for psychiatric issues in the past 6 months 5. No aggressive or violent acts or behavior in the past 6 months 7. Able to communicate in English and provide written informed consent 8. Will be residing in the geographic area for at least 7 months 9. Not currently trying to quit smoking 10. Smoking Status 1. 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 2. 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 1. Current enrollment or plans to enroll in another smoking cessation program in the next 7 months. 2. Regular (daily) use of electronic cigarettes, chewing tobacco, snuff, snus, cigars, cigarillos, or pipes. 3. 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 1. 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) 2. 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 1. Women who are pregnant, planning a pregnancy or lactating 2. Current diagnosis of unstable and untreated major depression (if stable for at least 30 days, eligible) 3. Current or past diagnosis of psychotic disorder 4. Cancer diagnosis within the past 6 months (except basal cell carcinoma) 5. Major heart disease or stroke within the past 6 months 6. Uncontrolled hypertension (systolic blood pressure greater than 160 or diastolic blood pressure greater than 100). 7. Medical conditions contraindicated for use with galantamine: 1. Diagnosis of Alzheimer's disease or dementia 2. Epilepsy or other seizure disorder 8. Bladder outflow obstruction 9. Active HCV co-infection (if cured, requires study physician approval) 10. 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. 11. 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. 12. Peptic ulcer disease (requires study physician approval) 13. 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): 1. Current suicidal ideation (within 30 days of enrollment) 2. Two or more lifetime suicide attempts or episodes of suicidal behavior 3. Any suicide attempt or suicidal behavior within 2 years of enrollment Medication 1. Current use or discontinuation within the last 14 days of: 1. Quit smoking medications including varenicline (Chantix), bupropion (Wellbutrin) 2. Anti-psychotic medications (e.g., Zyprexa, Clozaril, Seroquel, Risperdal). If used to treat psychotic symptoms. Other uses may be eligible pending physician approval). 3. Systemic Steroids (e.g., Prednisone). 4. Alzheimer's disease medications (e.g., Acetylcholinesterase inhibitors (ACIs), Aricept/donepezil, Exelon/rivastigmine, Tacrine, or memantine) 5. Irritable bowel syndrome medication (e.g., Dicyclomine/Bentyl) 6. Heart medications (e.g., quinidine). 7. Muscle relaxants (e.g., Anectine/succinylcholine) 8. 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. 9. Urinary retention medications (e.g., Duvoid/bethanechol, Proscar/finasteride, Avodart/dutasteride, Dibenzyline/ phenoxybenzamine, Regitine/phentolamine) 2. Daily use of: 1. 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. 2. Chronic obstructive pulmonary disease (COPD) medication (e.g., Atrovent/Ipratropium Bromide) 3. 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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Cognition	Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28)	Cognitive function will be assessed 4 times at Lab Visits. Executive function was measured by the task switch cost from the Color shape task, measured in ms. Executive function was also measured via response time (ms) and accuracy (# correct) on an N-back working memory task. Verbal learning and memory were measured by the Total Recall and Delayed Recall, respectively, from the Hopkins Verbal Learning Test. Response inhibition was measured by the stop signal reaction time (ms) from the Stop Signal Task. A composite score will be created by computed standardized z-scores for each measure (where the mean is 0 and the standard deviation is 1) and then averaging the z-scores. Measures of response time were reverse coded such that higher z-scores indicate better cognitive performance. The primary outcome is the change from baseline cognitive function after 12 weeks of treatment. Change in cognition will be measured during each treatment arm.
Change in Inflammation (MCP-1)	Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28)	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.
Change in Inflammation (Percentage of CD14+ Monocytes Expressing CD8)	Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28)	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.
Change in Inflammation (CD14)	Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28)	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.
Change in Inflammation (Percentage of CD14+ Monocytes Expressing CD163)	Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28)	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.
Change in Inflammation (Percentage of CD14+ Monocytes Expressing CD16)	Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28)	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.

Countries

United States

Participant flow

Pre-assignment details

Because there was a gap between enrollment and assignment to group, some participants were lost to follow-up between those time points.

Participants by arm

Arm	Count
Galantamine First This is a crossover study such that all participants receive both placebo and galantamine. Participants were randomized to receive galantamine first and placebo second. Timepoints Week 0 through Week 12 represent the first period and Weeks 16 through 28 represent the second period. 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. Galantamine: 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.	28
Placebo First This is a crossover study such that all participants receive both placebo and galantamine. Participants were randomized to receive galantamine first and placebo second. Timepoints Week 0 through Week 12 represent the first period and Weeks 16 through 28 represent the second 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. Placebo: 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.	30
Total	58

Baseline characteristics

Characteristic	Galantamine First	Total	Placebo First
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	28 Participants	58 Participants	30 Participants
Age, Continuous	57.9 years STANDARD_DEVIATION 3.7	57.6 years STANDARD_DEVIATION 4.4	57.3 years STANDARD_DEVIATION 5.1
CD4 Levels at Intake	769.8 cells/microliter STANDARD_DEVIATION 311.2	687.9 cells/microliter STANDARD_DEVIATION 269.7	611.6 cells/microliter STANDARD_DEVIATION 201.1
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants	4 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	25 Participants	54 Participants	29 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	21 Participants	40 Participants	19 Participants
Race (NIH/OMB) More than one race	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	3 Participants	1 Participants
Race (NIH/OMB) White	4 Participants	14 Participants	10 Participants
Region of Enrollment United States	28 participants	58 participants	30 participants
Sex: Female, Male Female	5 Participants	13 Participants	8 Participants
Sex: Female, Male Male	23 Participants	45 Participants	22 Participants
Smoking History Current Smoker	18 Participants	26 Participants	8 Participants
Smoking History Non-Smoker	10 Participants	32 Participants	22 Participants
Viral Load at Intake Viral load < 50 copies/mL	25 Participants	53 Participants	28 Participants
Viral Load at Intake Viral load > = 50 copies/mL	3 Participants	5 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	1 / 52	0 / 49	0 / 48	0 / 47
other Total, other adverse events	2 / 52	4 / 49	2 / 48	3 / 47
serious Total, serious adverse events	1 / 52	0 / 49	2 / 48	2 / 47

Outcome results

Primary

Change in Cognition

Cognitive function will be assessed 4 times at Lab Visits. Executive function was measured by the task switch cost from the Color shape task, measured in ms. Executive function was also measured via response time (ms) and accuracy (# correct) on an N-back working memory task. Verbal learning and memory were measured by the Total Recall and Delayed Recall, respectively, from the Hopkins Verbal Learning Test. Response inhibition was measured by the stop signal reaction time (ms) from the Stop Signal Task. A composite score will be created by computed standardized z-scores for each measure (where the mean is 0 and the standard deviation is 1) and then averaging the z-scores. Measures of response time were reverse coded such that higher z-scores indicate better cognitive performance. The primary outcome is the change from baseline cognitive function after 12 weeks of treatment. Change in cognition will be measured during each treatment arm.