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Effects of Atomoxetine in Mild Cognitive Impairment (ATX-001)

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ClinicalTrials.gov Identifier: NCT01522404
Recruitment Status : Completed
First Posted : January 31, 2012
Last Update Posted : August 6, 2018
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Allan I Levey, MD, Emory University

January 25, 2012
January 31, 2012
August 6, 2018
March 2012
October 31, 2017   (Final data collection date for primary outcome measure)
  • Change in Interleukin1 (IL1-alpha) in Cerebrospinal fluid (CSF) in subjects with Mild Cognitive Impairment MCI treated with Atomoxetine compared to subjects treated with Placebo [ Time Frame: Baseline, Week 29 and Week 55 ]
    This study will examine the effect of atomoxetine on biomarkers of inflammation by measuring the levels of IL1 alpha using the assay of CSF at Week 29 and Week 55.The study that subjects treated with atomoxetine have reductions in levels of these markers compared to the other group.
  • Change in Thymus-Expressed Chemokine (TECK) in Cerebrospinal fluid (CSF) in subjects with Mild Cognitive Impairment MCI treated with Atomoxetine compared to subjects treated with Placebo [ Time Frame: Baseline, Week 29 and Week 55 ]
    This study will examine the effect of atomoxetine on biomarkers of inflammation by measuring the levels of Thymus-Expressed Chemokine (TECK) using the assay of Week 29 and Week 55. The study that subjects treated with atomoxetine have reductions in levels of these markers compared to the other group.
  • Number of adverse events with Mild Cognitive Impairment MCI treated with Atomoxetine compared to subjects treated with Placebo [ Time Frame: Upto Week 55 ]
    Safety will be assessed by number of adverse events among the subjects treated with Atomoxetine compared to subjects treated with Placebo. The assessment will be done at each visit through their participation in the study.
  • Percentage of subject drop out rate that are treated with Atomoxetine [ Time Frame: Upto Week 55 ]
    Tolerability to Atomoxetine is measured by subject drop out rate that are treated with the drug. Study predicts that treatment-associated drop out rate will be < 15% .
  • Cerebrospinal fluid biomarkers of inflammation [ Time Frame: 6 months ]
  • Biomarkers of noradrenergic function [ Time Frame: 6 months ]
Complete list of historical versions of study NCT01522404 on ClinicalTrials.gov Archive Site
  • Change in rate of cerebral blood flow in subjects with Mild Cognitive Impairment MCI treated with Atomoxetine compared to subjects treated with Placebo [ Time Frame: Baseline, Week 29 and Week 55 ]
    Change in rate of cerebral blood flow is assessed by arterial spin labeling Magnetic Resonance Imaging (ASL-MRI) in subjects with Mild Cognitive Impairment MCI treated with Atomoxetine compared to subjects treated with Placebo. The rates from the Baseline are compared to week 29 and week 55 among the subjects treated with Atomoxetine compared to subjects treated with Placebo. All MRIs will be reviewed by the investigators and the investigator.
  • Change in Fluoro Deoxy Glucose [FDG] uptake in subjects with Mild Cognitive Impairment MCI treated with Atomoxetine compared to subjects treated with Placebo [ Time Frame: Baseline, Week 29 and Week 55 ]
    Cerebral metabolic rate for glucose as measured by fluorodeoxyglucose [FDG] uptake will be obtained by Positron Emission Tomography (PET) scan. The rates from the Baseline are compared to week 29 and week 55 among the subjects treated with Atomoxetine compared to subjects treated with Placebo.
  • Number of Adverse Events [ Time Frame: 6 months ]
  • Cerebrospinal fluid biomarkers of neurodegeneration [ Time Frame: 6 months ]
  • Imaging biomarkers of neurodegeneration [ Time Frame: 6 months ]
  • Cognitive measures [ Time Frame: 6 months ]
  • Behavioral symptoms [ Time Frame: 6 months ]
Not Provided
Not Provided
 
Effects of Atomoxetine in Mild Cognitive Impairment
A 6 Month, Phase II Randomized, Double-Blind, Placebo Controlled, Flexible Dosing, Crossover Trial of Atomoxetine in Subjects With Mild Cognitive Impairment.
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.

The Alzheimer's Disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. Advances in AD biomarker research have demonstrated changes in amyloid, brain metabolism, and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. Since MCI coincides with the onset of brain atrophy, this early stage of AD pathogenesis may offer a critical window of time to initiate novel therapies aimed at the secondary wave of events that lead to progressive neurodegeneration.

From recently emerged basic research in animal models of AD: loss of norepinephrine (NE) incites a pro-inflammatory condition that is neurotoxic and reduces Aß clearance, and remarkably, rescue of norepinephrine reverses these effects and slows neurodegeneration. This study seeks to extend this proof-of-concept to humans for the first time. The study proposes that atomoxetine, a selective norepinephrine transport inhibitor, is an ideal drug to translate these findings to humans because it is already FDA-approved and safe in the elderly

Subjects with mild cognitive impairment (amnestic or multi-domain subtypes) will be randomly assigned to treatment with placebo or flexible doses of the Norepinephrine Transporter (NET) inhibitor 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. Participants will be treated for 6 months, and will undergo venous blood draws and lumbar puncture for biomarker analyses at baseline and at 6 months. At the six month time point, subjects assigned to active treatment will crossover to placebo and those subjects who were initially randomized to placebo will initiate active treatment.

Participants who complete study are eligible to receive open-label Atomoxetine at the maximum-tolerated dose received during the double-blind phase of the trial. Subjects in the open label are seen every 6 months upto maximum of 2 years.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Mild Cognitive Impairment
  • Drug: Atomoxetine
    6 month, crossover, dose escalating (up to a maximum dose of 100 mg per day) of oral atomoxetine
    Other Names:
    • Statterra
    • Primary Outcome Measure
  • Drug: Placebo
    At the six-month timepoint, subjects who were taking placebo during the first six months will be placed on active study medication.
    Other Name: Inactive compound
  • Experimental: Atomoxetine
    Active treatment. Subjects in this arm will receive 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
    Intervention: Drug: Atomoxetine
  • Placebo Comparator: Inactive compound
    Subjects in this arm will receive a matching placebo that have inactive compound
    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
39
40
June 30, 2018
October 31, 2017   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
50 Years to 90 Years   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01522404
IRB00054397
5U01AG010483 ( U.S. NIH Grant/Contract )
ATX-001 ( Other Identifier: Other )
Yes
Not Provided
Not Provided
Allan I Levey, MD, Emory University
Emory University
National Institute on Aging (NIA)
Principal Investigator: Allan I. Levey, MD, PhD Emory University
Emory University
August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP