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Treatment of Psychosis and Agitation in Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT02129348
Recruitment Status : Recruiting
First Posted : May 2, 2014
Last Update Posted : October 25, 2017
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
Brief Summary:

Clinically, many patients with AD show no response or minimal response to antipsychotics for symptoms of agitation/aggression or psychosis, or they have intolerable side effects on these medications. Antipsychotics have a wide range of side effects, including the risk of increased mortality (60-70% higher rate of death on antipsychotic compared to placebo) that led to an FDA black box warning for patients with dementia; a more recent review and meta-analysis showed a 54% increased risk of mortality. In addition, some patients show only partial response to antipsychotics and symptoms persist. For these reasons, the investigators need to study alternative treatment strategies. Currently, there is no FDA-approved medication for the treatment of psychosis or agitation in AD.

The investigators innovative project will examine the efficacy and side effects of low dose lithium treatment of agitation/aggression with or without psychosis in 80 patients with AD in a randomized, doubleblind, placebo-controlled, 12-week trial (essentially a Phase II trial). The results will determine the potential for a large-scale clinical trial (Phase III) to establish the utility of lithium in these patients.


Condition or disease Intervention/treatment Phase
Alzheimer's Disease Psychosis Agitation Drug: Lithium Drug: Placebo Phase 2

  Show Detailed Description

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Treatment of Psychosis and Agitation in Alzheimer's Disease
Study Start Date : June 2014
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : April 2019


Arms and Interventions

Arm Intervention/treatment
Active Comparator: Lithium Treatment Group

The patient will be started on lithium 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on real lithium blood level. Blood will be drawn at each study visit. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects).

Patients who develop side effects, e.g., tremor, falls, will have their dose reduced.

Drug: Lithium
Other Name: lithium carbonate
Placebo Comparator: Placebo Group

The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects).

Patients who develop side effects, e.g., tremor, falls, will have their dose reduced.

Drug: Placebo


Outcome Measures

Primary Outcome Measures :
  1. Change in Neuropsychiatric Inventory (NPI) Score [ Time Frame: Screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Assessment used to examine behavioral issues and disturbances in patients with dementia. Each behavior is assessed for frequency and severity by the rater.


Secondary Outcome Measures :
  1. Clinical Global Impression (CGI) Global [ Time Frame: Screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Used to assess a patient's overall functioning prior to, and after taking the study medication (Lithium or placebo).

  2. Clinical Global Impression (CGI) Behavior [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Assessment used to determine changes in the patients behavior prior to, and after beginning study medication (Lithium or placebo).

  3. Young Mania Rating Scale [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Used to assess manic symptoms experienced by the patient in the prior two days. Each mania item on the scale is rated for severity.

  4. Treatment Emergent Signs and Symptoms (TESS) [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Scale used to assess if symptoms not present at screening emerge after treatment begins. Each symptom is assigned a "yes" or "no" response based on patient and caregiver report.

  5. Simpson-Angus Scale [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Five point scale used to assess pseudoparkinsonism in patients. Symptoms assess include gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation.

  6. Basic Activities of Daily Living (BADL) [ Time Frame: Week 4, Week 8, Week 10, Week 12 ]
    Assesses if the patient can perform six basic ADLs on his own. These include bathing, dressing, toileting, transferring, continence, and feeding.

  7. Zarit Caregiver Burden Interview [ Time Frame: Week 0, Week 4, Week 8, Week 10, Week 12 ]
    Twenty-two item questionnaire, where the caregiver is asked to rank statements on a 5-point scale (never to nearly always).

  8. Clinical Dementia Rating Scale (CDR) [ Time Frame: Week 0, Week 12 ]
    Scale used to rate the severity of dementia symptoms raging from 0-3.


Other Outcome Measures:
  1. Selective Reminding Test Immediate and Delayed Recall (SRT) [ Time Frame: Week 0, Week 12 ]
    Neuropsychological test used to assess a patient's ability to remember a list of 12 words. The patient is asked to name as many words as he can remember across 6 trials. After a 15 minute delay, the patient is asked to recall as many words as he can remember. The patient is visually cued for the words that he cannot recall.

  2. Folstein Mini-Mental Status Exam [ Time Frame: Screening, Week 12 ]
    30 item questionnaire used to assess degree of cognitive impairment. Orientation, registration, attention/calculation, recall, language, repetitions and commands are assessed,


Eligibility Criteria

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Ages Eligible for Study:   55 Years to 95 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 55-95 years
  2. Diagnosis of possible or probable AD by standard NIA criteria (McKahnn et al, 1984; McKhann et all, 2011)
  3. Folstein MMSE 5-26 out of 30
  4. Neuropsychiatric Inventory (NPI) agitation/aggression subscale score > 4. On each subscale (frequency X severity), a score higher than 4 represents moderate to severe symptoms.
  5. Female patients need to be post-menopausal
  6. Availability of informant; patients without an informant will not be recruited. Patients who lack capacity must have a surrogate.

Exclusion Criteria:

  1. Medical contraindication to lithium treatment or prior history of intolerability to lithium treatment.

    Contraindications to lithium in this study include: resting tremor causing functional impairment, history of falls in the last month, untreated thyroid disease or any abnormal thyroid function test (T3, T4, or TSH), creatinine level greater than 1.5 mg/100ml or a glomerular filtration rate less than 44ml/min/ 1.73m2; blood pressure > 150/90 mm Hg; heart rate < 50 bpm; unstable cardiac disease based on history, physical examination, and ECG.

  2. Medications, in combination with lithium, known to have adverse renal effects, including therapeutic or higher doses of diuretics, i.e. hydrochlorothiazide greater than 25mg daily or furosemide greater than 10mg daily. Whenever feasible, patients receiving concomitant antidepressants or antipsychotics will be washed off these medications for at least 24 hours before starting lithium. Patients who do not wish to discontinue antipsychotics or antidepressants, typically because of family member/caregiver objection, will be allowed to enter the trial provided there is no contraindication to concomitant lithium use with that specific psychotropic medication. During the trial, patients will be permitted to receive lorazepam as needed up to 2 mg/day for anxiety/insomnia, and non-benzodiazepine hypnotics, e.g., zolpidem.
  3. Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, or bipolar 1 disorder (DSM-IV TR criteria).
  4. Current or recent (past 6 months) alcohol or substance dependence (DSM-IV TR criteria).
  5. Current major depression or suicidality as assessed by the study psychiatrist.
  6. Suicidal behavior or dangerous behavior with serious safety risk or risk of physical harm to self or others.
  7. Parkinson's disease, Lewy body disease, multiple sclerosis, CNS infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder.
  8. Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (smallinfarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion.
  9. Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases will be excluded, but past history of successfully treated cancer will not lead to exclusion.
  10. QTc interval > 460 ms at the time of baseline EKG is an exclusion criterion for treatment.
  11. Hypernatremia as determined by serum sodium level > 150 meq/L.
Contacts and Locations

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): NCT02129348


Contacts
Contact: DP Devanand, MD 646 774 8658 ext 8658 dpd3@columbia.edu
Contact: Gregory H Pelton, MD 646 774 8669 ext 8669 ghp4@columbia.edu

Locations
United States, Florida
University of Miami Miller School of Medicine Recruiting
Miami, Florida, United States, 33136
Contact: Elizabeth Crocco, MD    305-355-9065    ecrocco@med.miami.edu   
United States, Massachusetts
McLean Hospital Recruiting
Belmont, Massachusetts, United States, 02478
Contact: Brent Forester, MD    617-855-3622    bforester@partners.org   
United States, New York
New York State Psychiatric Institute Recruiting
New York, New York, United States, 10032
Contact: Jesse Strickler, BA    646-774-8668 ext 8668    jesse.strickler@nyspi.columbia.edu   
Contact: Michaela Ciovacco, BA    646 774 7204    michaela.ciovacco@nyspi.columbia.edu   
Principal Investigator: DP Devanand, MD         
Sub-Investigator: Gregory Pelton, MD         
Sub-Investigator: Edward Huey, MD         
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75235
Contact: Mustafa Husain, MD    214-648-2806    mustafa.husain@utsouthwestern.edu   
Sponsors and Collaborators
New York State Psychiatric Institute
National Institute on Aging (NIA)
Investigators
Principal Investigator: DP Devanand, MD Columbia University
More Information

Publications:
Haddad P, Wieck A, Yarrow M, Denham P. 1999. The Lithium Side Effects Rating Scale (LISERS); development of a self-rating instrument. Eur Neuropsychopharmacol 9(s5): 231-232.

Responsible Party: New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT02129348     History of Changes
Other Study ID Numbers: #6915
1R01AG047146-01 ( U.S. NIH Grant/Contract )
First Posted: May 2, 2014    Key Record Dates
Last Update Posted: October 25, 2017
Last Verified: October 2017

Keywords provided by New York State Psychiatric Institute:
Alzheimer's disease
psychosis
agitation
aggression
Lithium
delusions
hallucinations

Additional relevant MeSH terms:
Alzheimer Disease
Psychotic Disorders
Mental Disorders
Psychomotor Agitation
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Dyskinesias
Neurologic Manifestations
Psychomotor Disorders
Neurobehavioral Manifestations
Signs and Symptoms
Lithium Carbonate
Antidepressive Agents
Psychotropic Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs