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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 : August 20, 2019
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Davangere P. Devanand, New York State Psychiatric Institute

Tracking Information
First Submitted Date  ICMJE April 29, 2014
First Posted Date  ICMJE May 2, 2014
Last Update Posted Date August 20, 2019
Study Start Date  ICMJE June 2014
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 1, 2014)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02129348 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 1, 2014)
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • Clinical Dementia Rating Scale (CDR) [ Time Frame: Week 0, Week 12 ]
    Scale used to rate the severity of dementia symptoms raging from 0-3.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 11, 2018)
  • 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,
  • Severe Impairment Battery [ Time Frame: Week 0, Week 12 ]
    Neuropsychological test used to assess a patient's cognitive ability. The patient is asked to complete small tasks such as drawing shapes and printing their name. They are also asked to remember certain names and objects, such as a cup and a spoon, and the evaluator's first name.
Original Other Pre-specified Outcome Measures
 (submitted: May 1, 2014)
  • 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.
  • 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,
 
Descriptive Information
Brief Title  ICMJE Treatment of Psychosis and Agitation in Alzheimer's Disease
Official Title  ICMJE Treatment of Psychosis and Agitation in Alzheimer's Disease
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.

Detailed Description

Symptoms of psychosis or agitation are common in Alzheimer's disease. These symptoms are associated with distress for the patient, an increased burden for caregivers, more rapid cognitive decline, greater risk of institutionalization and mortality, and increased health care costs. In a recent meta-analysis, caregiver education and behavior modification studies revealed a small to medium effect size in treating agitation in these patients. However, none of these studies were double-blind (difficult to achieve in such studies) and none had a control group that received the same amount of staff time as the intervention group, thereby biasing the results toward the active intervention.

Among the psychotropic medications that have been studied, only antipsychotics have shown superiority over placebo for the treatment of psychosis and agitation in patients with dementia.

However, most studies show only moderate superiority for antipsychotic over placebo and a few studies have been negative. The side effects of antipsychotic medications include sedation, extrapyramidal signs, tardive dyskinesia, weight gain, and the metabolic syndrome. A pooled analysis from 17 short-term trials showed that the mortality rate in patients with dementia receiving antipsychotic medications was 1.6 to 1.7 times as high (60-70% increase in mortality rate) as the mortality rate in patients receiving placebo. These findings led the FDA to issue a black-box warning for antipsychotic medication use in patients with dementia; a more recent meta-analysis reported a slightly lower odds ratio of 1.54 (54% increase in mortality rate).

Lithium has several different actions from anticonvulsants, though both are effective in bipolar disorder, especially mania. Lithium is not being proposed here to treat mania in AD though the investigators will monitor symptoms on the Young Mania Rating Scale. In patients with AD, lithium has been studied for its putative cognitive enhancing effects. A few reports suggest that chronic lithium use reduces the risk of dementia, but other data show increased dementia risk with lithium use. A placebo-controlled, single-blind lithium trial showed no cognitive effects in patients with AD, but a recent trial of lithium in 45 patients with mild cognitive impairment (MCI, which often leads to clinically diagnosable AD) showed a small advantage for lithium (n=24) over placebo (n=21) in attention and other cognitive domains. None of these studies with lithium were intended to treat psychosis or agitation in AD, and patients with these symptoms typically were excluded in these clinical trials.

There has been no systematic placebo-controlled trial of lithium to treat agitation/aggression with or without psychosis in AD even though lithium is a highly effective treatment for mania with psychosis and symptoms of agitation or aggression. Nonetheless, the published studies of lithium to treat cognitive decline in older patients show that low-dose lithium is safe in patients with MCI or AD.

Specific Aims and Hypotheses Specific Aim 1. To compare changes in agitation/aggression with or without psychosis in patients with AD who receive 12 weeks of randomized, double-blind treatment with lithium or placebo.

Primary Hypothesis. Over these 12 weeks, the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) will decrease significantly more on lithium than placebo.

Secondary Hypothesis. Over these 12 weeks, the proportion of responders on lithium will be significantly greater than the proportion of responders on placebo. Response is defined as a 30% decrease in NPI core score (defined as the sum of domains for agitation/aggression, delusions and hallucinations) plus a CGI Change score of much improved or very much improved (CGI based on these behavioral symptoms only). Exploratory hypothesis. Over these 12 weeks, the psychosis score, measured by the sum of the NPI domain scores for delusions and hallucinations, will decrease significantly more on lithium than placebo. Specific Aim 2. To evaluate the tolerability of low dose lithium by assessing emergent somatic side effects over the course of the 12-week trial on lithium compared to placebo. Specific Aim 3. To explore associations between improvement on lithium (decrease in agitation/aggression and psychosis scores) and serum brain-derived neurotrophic factor (BDNF) levels (baseline, 12 weeks), a SNP in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus, because these indices are associated with lithium response in bipolar disorder. The investigators do not postulate a specific mechanism of action for lithium in the investigators trial, but will evaluate these three potential predictors of lithium response with the aim of improving patient selection for personalized treatment. The investigators will examine BDNF serum levels as a biomarker correlate of lithium treatment by correlating change in BDNF levels with change in NPI agitation/aggression and psychosis scores.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Alzheimer's Disease
  • Psychosis
  • Agitation
Intervention  ICMJE
  • Drug: Lithium
    Other Name: lithium carbonate
  • Drug: Placebo
Study Arms  ICMJE
  • 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.

    Intervention: Drug: Lithium
  • 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.

    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 1, 2014)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2020
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male and female adults.
  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 1 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02129348
Other Study ID Numbers  ICMJE #6915
1R01AG047146-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Davangere P. Devanand, New York State Psychiatric Institute
Study Sponsor  ICMJE New York State Psychiatric Institute
Collaborators  ICMJE National Institute on Aging (NIA)
Investigators  ICMJE
Principal Investigator: DP Devanand, MD Columbia University
PRS Account New York State Psychiatric Institute
Verification Date August 2019

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