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Effect of Galantamine on Inflammation and Cognition (CHI)

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ClinicalTrials.gov Identifier: NCT03384784
Recruitment Status : Recruiting
First Posted : December 27, 2017
Last Update Posted : April 18, 2019
Sponsor:
Collaborator:
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
HIV Associated Cognitive Motor Complex Drug: Galantamine Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Targeting the Cholinergic Pathway in HIV-associated Inflammation and Cognitive Dysfunction
Actual Study Start Date : October 30, 2017
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : May 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Galantamine

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
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.
Other Name: Razadyne ER

Placebo Comparator: Placebo

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
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.
Other Name: Sugar Pill




Primary Outcome Measures :
  1. Change in Cognition [ Time Frame: 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 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.

  2. Change in Inflammation [ Time Frame: 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.


Secondary Outcome Measures :
  1. Monocyte Transcriptomics [ Time Frame: Period1 Lab 1 (Week 0), Period 1 Lab 2 (Week 12), Period 2 Lab 1 (Week 16), Period 2 Lab 2 (Week 28) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Breath alcohol concentration (BrAC) greater than 0.00 at Intake or Lab visits
  3. 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. A history or current diagnosis of cancer
  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 or recent hepatitis C virus (HCV) co-infection
  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 ernollment)
    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)
    10. Eye medication (e.g., Atropine)
  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.


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): NCT03384784


Contacts
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Contact: Rebecca L Ashare, PhD 215-746-5789 rlashare@pennmedicine.upenn.edu
Contact: Molly R Ruben, MPH 215-746-8420 molly.ruben@pennmedicine.upenn.edu

Locations
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United States, Pennsylvania
Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Molly R Ruben, MPH    215-746-8420    molly.ruben@pennmedicine.upenn.edu   
Contact: Kristin Tederstrom    215-746-7142    tederstr@pennmedicine.upenn.edu   
Sponsors and Collaborators
University of Pennsylvania
National Institute on Drug Abuse (NIDA)
Investigators
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Principal Investigator: Rebecca L Ashare, PhD University of Pennsylvania

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03384784     History of Changes
Other Study ID Numbers: 828125
R01DA044906 ( U.S. NIH Grant/Contract )
First Posted: December 27, 2017    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

The final dataset will include demographic and behavioral assessments and laboratory data bio-specimens. Because the dataset will contain personal health information, identifying information will be collected. Even though the final dataset will be stripped of identifiers prior to release for sharing, investigators will do the following to reduce the possibility confidentiality loss. We will make the data and associated documentation available to users only under a data-sharing agreement that provides for: (1) a commitment to using data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.

Transcriptomic data will be deposited with a public access database such as NCBI's Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/)

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data will be made available starting 6 months after the summary data are published or January 2024 (whichever comes first) and will be made available for 5 years.
Access Criteria: The PIs will review requests for data and all users must sign a data sharing agreement as described above.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Pennsylvania:
HIV
Neurocognition
Inflammation
Galantamine
Nicotine
Tobacco Use

Additional relevant MeSH terms:
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Inflammation
AIDS Dementia Complex
Pathologic Processes
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Neurocognitive Disorders
Mental Disorders
Galantamine
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Parasympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Nootropic Agents