Effects of Atomoxetine in Mild Cognitive Impairment
Condition: Mild Cognitive Impairment
MeSH terms: Cognitive Dysfunction
Intervention: Atomoxetine; Placebo
Intervention description: 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; Subjects in this intervention will receive inactive compound up to weeks 29 and will cross over to the other group
Intervention MeSH terms: Atomoxetine Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 39.0
Sex: All
Minimum age: 50 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: Mild Cognitive Impairment; Memory Loss; Alzheimer's Disease

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.
    

Eligibility criteria:

        Inclusion

          -  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.

          -  Good general health with no diseases expected to interfere with the study.

          -  For women of child-bearing potential (i.e., one who is biologically capable of
             becoming pregnant), must be willing to use a medically acceptable form or birth
             control or practice abstinence for the duration of her participation in the trial.
             Acceptable methods of birth control include: oral or patch contraception, or
             medroxyprogesterone (Depo-Provera®) or other intramuscular contraceptive injection, or
             implantation of levonorgestrel (Norplant®) system, an Intrauterine Device (IUD), a
             reliably-employed barrier method (e.g. diaphragm, cervical cap or condom), or a male
             partner who is surgically sterilized.

          -  Modified Rosen Hachinski ≤ 4.

          -  Completed six grades of education or has a good work history (sufficient to exclude
             mental retardation).

          -  Able to communicate in English with study personnel.

          -  Able to understand the nature of the study and must provide written informed consent
             prior to conduct of any study procedures.

          -  Willing to undergo repeated MRIs (3Tesla) and at least three Positron-Emission
             Tomography (PET) scans. No medical contraindications to MRI.

          -  Agrees to blood collection for Apolipoprotein (APOE) epsilon, CYP2D6 and biomarker
             testing.

          -  Agrees to lumbar puncture over the course of the study for the collection of CSF. CSF
             levels of Ab42, total Tau, and Tau phosphorylated at threonine 181 consistent with
             underlying AD pathology according to established threshold values at Emory and the
             ADNI Biomarker Core

        Exclusion

          -  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.

          -  Presence of clinically significant suicide risk, based on the Investigator's judgment
             informed by a structured clinician interview. Any suicide attempt within the past 1
             year of the screening visit is exclusionary.

          -  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.

          -  Clinically significant abnormal findings on screening laboratory tests or physical
             exam. Abnormalities in Vitamin B12 level, Thyroid Function Tests (TFTs) or Liver
             Function Tests (LFTs) that might interfere with the study. A low Vitamin B12 level is
             exclusionary, unless follow-up labs (homocysteine and methylmalonic acid indicate that
             it is not physiologically significant.

          -  Slow metabolizer of atomoxetine (i.e., CYP2D6 polymorphism).

          -  Women who are pregnant or lactating, or who plan to become pregnant during the study.

          -  Current use of warfarin (exclusionary for lumbar puncture).

          -  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.

          -  Current use of the following anti-depressant medications that act on NET: duloxetine,
             venlafaxine, desvenlafaxine, imipramine, or amitryptiline.

          -  Current participation in another clinical trial. Participation in clinical studies
             involving neuropsychological measures being collected more than one time per year.

          -  CSF profile is not consistent with underlying Alzheimer's Disease pathology.

          -  Reasonable likelihood for non-compliance with the protocol or any other reason, in the
             opinion of the investigator, prohibits enrollment of subject into the study.

          -  Exceptions to these guidelines may be considered on a case-by-case basis at the
             discretion of the protocol director.