Effects of Atomoxetine in Mild Cognitive Impairment

NCT01522404 | Completed Phase 2 Results DMC

• 3 other identifiers: IRB000543975U01AG010483ATX-001
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the safety of atomoxetine and its effect primarily on the biologic markers (substances that may indicate the presence of a disease) in the cerebrospinal fluid (CSF) of participants diagnosed with Mild Cognitive Impairment (MCI). Additionally, information will be gathered to identify the dose of atomoxetine that is most beneficial, and how taking this medication affects thinking and behavior, as well as imaging and blood biomarkers.The study will also explore rates of change in biomarkers of neurodegeneration (Aß, tau, brain atrophy rates). The results of this research will help determine if atomoxetine alters signs of inflammation and other biomarkers associated with Alzheimer's disease.

Conditions

Mild Cognitive Impairment

Keywords

Mild Cognitive Impairment; Memory Loss; Alzheimer's Disease

Outcome Measures

Primary Outcomes (4)

• Change in Interleukin 1 (IL 1-alpha) in Cerebrospinal Fluid (CSF) in Subjects With Mild Cognitive Impairment (MCI) Treated With Atomoxetine/Inactive Compound Compared to Subjects Treated With Inactive Compound / Atomoxetine

  This study will examine the effects of Atomoxetine and Inactive compound on biomarkers of inflammation by measuring and comparing the levels of Interleukin 1 (IL 1-alpha) using the assay of CSF at Baseline, Week 29 and Week 58 among the two groups. The study hypothesizes that the period that participants are treated with atomoxetine will have reductions in levels of these pro-inflammatory biomarkers among the two groups.

  Baseline, Week 29 and Week 58

• Change in Mean Level of Thymus-Expressed Chemokine (TECK) in Cerebrospinal Fluid (CSF) in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine

  This study will examine the effect of Atomoxetine and Inactive Compound on biomarkers of inflammation by measuring and comparing the mean levels of Thymus-Expressed Chemokine (TECK). These levels are measured using the assay of CSF at Baseline, Week 29 and Week 58. The study hypothesizes that the period that participants are treated with atomoxetine will have reduction in levels of these markers among both groups.

  Baseline, Week 29 and Week 58

• Number of All Adverse Events Among the Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine Compared to the Participants Treated With Placebo/Inactive Compound

  Safety was assessed by number of all adverse events among the participants treated with Atomoxetine compared to the participants treated with Placebo throughout the study. The Adverse Event assessment was done at each study visit through their participation in the study.

  Up to Week 58

• Number of Participants That Drop Out of the Study Among the Participants Treated With Atomoxetine When Compared to the Participants Treated With Inactive Compound (Placebo)

  Tolerability is measured by comparing the drop out rate among the participants treated with Atomoxetine to the participants treated with inactive compound (Placebo). Study predicts that treatment-associated (Atomoxetine Group) drop out rate will be \< 15% .

  Up to Week 58

Secondary Outcomes (2)

• Rate of Cerebral Blood Flow in Subjects With Mild Cognitive Impairment MCI Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine

  Baseline, Week 29, Week 58

• Change in FluoroDeoxyGlucose (FDG) Uptake in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine

  Baseline, Week 29 and Week 58

Study Arms (2)

Atomoxetine / Inactive Compound

EXPERIMENTAL

Participants in this arm received atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose for up to weeks 29 and are then crossed over to Inactive compound group

Drug: Atomoxetine; Drug: Placebo

Inactive compound / Atomoxetine

PLACEBO COMPARATOR

Subjects in this arm received a matching placebo that have inactive compound for up to weeks 29 and then are crossed over to receive active treatment of Atomoxetine

Drug: Atomoxetine; Drug: Placebo

Interventions

Atomoxetine DRUG

Subjects in this intervention will receive Atomoxetine up to 29 weeks, crossover, dose escalating (up to a maximum dose of 100 mg per day) of oral atomoxetine

Also known as: Strattera, Primary Outcome Measure

Atomoxetine / Inactive Compound; Inactive compound / Atomoxetine

Placebo DRUG

Subjects in this intervention will receive inactive compound up to weeks 29 and will cross over to the other group

Also known as: Inactive compound

Atomoxetine / Inactive Compound; Inactive compound / Atomoxetine

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must have a subjective memory concern as reported by subject, study partner or clinician.
• Meets Alzheimer's Disease Neuroimaging Initiative (ADNI) criteria for diagnosis of MCI. Subjects with amnestic (single or multi-domain) will be eligible, as both subtypes of MCI are at high risk for progression to AD.
• Abnormal memory function documented by assessment using the Logical Memory subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the maximum score is 25):
• \<11 for 16 or more years of education
• \<9 for 8-15 years of education
• \<6 for \<7 years of education
• Mini-Mental State Exam score between 24 and 30 (inclusive). Exceptions may be made for subjects with less than 8 years of education at the discretion of the PI.
• Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5.
• General cognition and functional performance sufficiently preserved such that a diagnosis of AD cannot be made by the physician at the time of the screening visit.
• Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screen.
• Stability of Permitted Medications for 4 weeks. In particular, subjects may washout from excluded medication for at least 4 weeks prior to screening.
• Geriatric Depression Scale (GDS) ≤ than 6.
• Male or female outpatients aged 50-90 (inclusive).
• Study partner has regular contact with the subject adequate to provide a reliable assessment of the subject's level of function, and can be available for all clinic visits, either in person or by telephone, for the duration of the study.
• Visual and auditory acuity adequate for neuropsychological testing.

You may not qualify if:

• Any significant neurologic disease other than MCI and suspected incipient AD, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, poorly controlled seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.
• Screening/baseline MRI scan with evidence of infection, large vessel infarction or other focal structural lesions that could account for the memory deficits. Subjects with multiple lacunes or lacunes in a critical memory structure are excluded.
• Contraindication to MRI due to presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body, or excessive weight.
• Major depression, bipolar disorder as described in DSM-IV within the past 1 year, or history of schizophrenia (DSM-IV). Psychotic features, agitation or behavioral problems within the last 3 months which could lead to difficulty complying with the protocol.
• History of alcohol or substance abuse or dependence within the past 2 years (DSM-IV criteria).
• Allergic to any component of atomoxetine (Strattera).
• Any uncontrolled medical condition that is expected to preclude completion of the study, or any medical condition which would represent a contraindication to atomoxetine pharmacotherapy (e.g. hepatic insufficiency, untreated hypertension, untreated cardiovascular or cerebrovascular disease).
• Known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems.
• History of narrow angle glaucoma.
• History of pheochromocytoma.
• Slow metabolizer of atomoxetine (i.e., CYP2D6 polymorphism).
• Women who are pregnant or lactating, or who plan to become pregnant during the study.
• Inability to obtain initial CSF sample.
• Use within 60 days of a monoamine oxidase inhibitor or a potent CYP2D6 inhibitor.
• Current use of anti-psychotic medication.

Sponsors & Collaborators

• Emory University: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

Emory University School of Medicine

Atlanta, Georgia, 30322, United States

Location

MeSH Terms

Conditions

Cognitive Dysfunction; Memory Disorders; Alzheimer Disease

Interventions

Atomoxetine Hydrochloride

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Dementia; Brain Diseases; Central Nervous System Diseases; Tauopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals

Limitations and Caveats

Sample size is small leading to some analytical limitations

Results Point of Contact

• Title: Allan I. Levey, MD, PhD
• Organization: Emory University

alevey@emory.edu

404-727-7220

Study Officials

• Allan I. Levey, MD, PhD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chair, Department of Neurology

Study Record Dates

• First Submitted: January 25, 2012
• First Posted: January 31, 2012
• Study Start: March 1, 2012
• Primary Completion: October 31, 2017
• Study Completion: June 30, 2018
• Last Updated: July 23, 2019
• Results First Posted: December 5, 2018

Record last verified: 2019-07

Locations

US (1)