17TH ANNUAL GERIATRIC PSYCHIATRY SYMPOSIUM NOV. 6, … · escitalopram for agitation in...
Transcript of 17TH ANNUAL GERIATRIC PSYCHIATRY SYMPOSIUM NOV. 6, … · escitalopram for agitation in...
ESCITALOPRAM FOR AGITATION IN ALZHEIMER’S DISEASE (S-CITAD)
17TH ANNUAL GERIATRIC
PSYCHIATRY SYMPOSIUM
NOV. 6, 2019
DR. MAHTAB ASADABADI
SUMMARY
Placebo-controlled, masked, 24-week (with treatment for 12 weeks, and additional 12 weeks of safety and efficacy
follow-up), 24 – 30 sites, randomized clinical trial
Sponsored by the National Institute on Aging (NIA)
Enrolls participants with Alzheimer’s Disease (AD) from real world settings such as outpatient and assisted living facilities
Applies widely usable Psychosocial Intervention (PSI) in sequence with Escitalopram, an FDA-approved generic SSRI
RATIONALE FOR S-CITAD
Agitation in AD: Appropriate target for treatment but major gaps still remain
S-CitAD designed:
• To produce an effective treatment with larger effect sizes
• To explain how agitation phenotypes affect responses to treatment
S-CitAD results:
• Define those patients most likely to respond to components of the approach
• Provide clinicians with immediately implementable information given portability of the PSI and availability of
Escitalopram
• Provide investigators with information to define a well-documented and easily standardized evidence-based
algorithm that can be further studied over time
OBJECTIVES
Primary
Examine in a masked, randomized trial the efficacy & safety of Escitalopram, in combination with a PSI, for the treatment of agitation in participants with AD who fail to improve with a PSI, by comparing Escitalopram and placebo treatment groups
Secondary
Examine the predictors of response to Escitalopram therapy on AD participants with agitation who fail to show improvement on a PSI alone
Examine the predictors of relapse, the duration of response, and time-course of any subsequent relapse, in AD participants with agitation who improve on a PSI, with extended follow-up in parallel with the randomized participants
DESIGN
DESIGN - STUDY POPULATION & SAMPLE SIZE
Enrolling 588 participants who meet S-CitAD criteria for “AD and clinically significant agitation”
• In CitAD, 26% of placebo + PSI and 40% citalopram + PSI, demonstrated clinically significant improvement in agitation after 9 weeks of treatment, for a RR of 1.53.
• Assuming Escitalopram will have similar efficacy, a sample size of N=352 (176 per group) will have 80% power to detect a risk difference of 14 percent with setting the two-sided Type I error to be 0.05
• Allowing for 10% loss to follow-up, S-CitAD plans to randomize 392 participants to one of the two treatment arms in the randomized portion of the study (196 in each group)
ELIGIBILITY CRITERIA
Inclusion criteria
Alzheimer’s dementia (or mixed type) diagnosed clinically by NIA and Alzheimer’s Association
MMSE score of 5-28
Meets the IPA provisional criteria for agitation in cognitive disorders
Clinically significant agitation & aggression as assessed by Neuropsychiatric Inventory (NPI) for which either/or
• The frequency is “Very frequently”
• The frequency is “Frequently” AND the severity is “Moderate” or “Marked”
Caregiver availability; spending several hours per week with the participant, supervising their care, willing to accompany them to study visits, and willing to participate in the study
Stable (for ≥ 7 days) dosing of antipsychotics for agitation/psychosis, if being used at all
A medication for agitation is appropriate (in the opinion of the study physician)
ELIGIBILITY CRITERIA
Exclusion criteria
MDE in the past 90 days (based on DSM-V criteria)
Dementia due to another brain disease (e.g., brain vascular disease, PD, DLB, TBI, or MS)
Contraindication to treatment with escitalopram (e.g. recent (30 days) use of MAOIs)
Prior failed treatment attempt with citalopram/escitalopram for agitation
Indication for psychiatric hospitalization or acute suicidality
Recent (< 7 days) changes in symptoms requiring a new or change in antipsychotic treatment
Abnormal corrected QT interval on enrollment ECG (> 450 for M and > 470 for F)
ELIGIBILITY CRITERIA
Exclusion criteria
Recent (30 days) severe reduced renal function (GFR clearance < 30 ml/min) or reduced hepatic function
Current treatment (within 7 days) with any of the following:
• Anticonvulsants (other than Dilantin for seizures), Antidepressants (other than Trazodone, ≤ 50 mg/day at bedtime), Benzodiazepines (other than lorazepam), Psychostimulants
Recent (< 14 days) use of medical marijuana
Current participation in a study that may add a significant burden or affect neuropsychological outcomes
Significant communicative impairments that would affect participation in a clinical trial
AT THE ENROLLMENT VISIT:
Discuss the study and obtain consent
Record demographics information and obtain a medical history and current medications
Perform safety measures (vital signs and weight), collect basic metabolic panel (BMP), and perform an ECG
Collect assessments:
• Mini-Mental State Examination (MMSE)
• Neuropsychiatric Inventory /Agitation and Aggression domains (NPI/AA and NPI-C/AA)
• Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC)
• DSM-V Criteria for MDE
Provide the PSI to the participant and caregiver
MADCS-CGIC
Modified Alzheimer’s Disease Cooperative Study - Clinical Global Impression of Change
Systematic method, developed for the AD setting to assess clinically significant change in a patient’s
agitation
A trained clinician, uses a 7-point scale with measures ranging from marked improvement (score of 1)
to marked worsening (score of 7), based on an interview with the caregiver and examination of the
patient.
Assess different aspects of the agitation:
• Emotional agitation, mood lability/distress, psychomotor agitation, verbal aggression, and physical
aggression
PSYCHOSOCIAL INTERVENTION
Straightforward, easy to use, lasts 20-30 minutes and associated with known benefits in previous clinical trials
Consists of three components:
1. Counseling session for participant and caregiver
2. Provision of Education materials
3. 24-hour Availability to caregiver for after hours caregiving crises, with counselling over the telephone as appropriate
Each Counseling session consist of the following elements:
• Review and adjustment of the participant and caregiver supportive care plans
• Emotional support and opportunity to ventilate feelings
• Counseling regarding specific caregiving skills
• Assistance with problem solving of specific issues that the caregiver brings to the sessions
BASELINE VISIT PROCEDURES
Obtain a medical history and record current medications (Since 3wks will have passed between EN
and BL visit)
Perform safety measures: Vital signs and weight, Balance and gait stability
Collect assessments:
• CGI, NPI-C, Abbreviated NPI, ADCS-ADL, ZBI, CAS, MMSE, ADAS-cog, Digit Span, NBRS
Assess “run-in response” to PSI to determine eligibility for randomization using the definition of
clinically significant improvement in mADCS-CGIC
If “minimal improvement,” “no change,” “minimal worsening,” “moderate worsening,” or “marked
worsening” :
Eligible for Randomization
CONCOMITANT MEDICATIONS
Use of a wide variety of medications in all enrolled participants in order to represent usual clinical practice and increase real-world generalizability will be allowed;
AD medications– FDA approved Cholinesterase Inhibitors, Memantine
Antipsychotics – If the dose has not been changed in the 6 days prior to enrollment
Antidepressants – Low dose Trazodone, up to 50 mg per day or at bedtime
Benzodiazepines – Lorazepam, orally, with the lowest dose necessary “as needed” throughout the trial, up to a maximum of 0.5 mg/d, limited to 3 out of every 7 days
ASSESSMENT OF SUICIDALITY & NEED FOR HOSPITALIZATION
Suicidality will be assessed
• Using either the NPI-C, abbreviated NPI, or full NPI
• At Study enrollment, All in-person follow-up visits, Week 18 and week 24 telephone contacts
• Looking for: Severe hopelessness, passive death wish, suicidal statements, suicidal plan, or behavioral
indicators of risk for self-harm
Need for hospitalization:
• Imminent risk of harm due to agitation, such as refusal to eat, weight loss, violent behavior toward
the caregiver, or suicidality
PRIMARY OUTCOME MEASURE
Clinically significant improvement in Agitation over 12 weeks as measured by
‘Moderate’ or ‘Marked’ improvement in agitation on the mADCS-CGIC
among treatment group participants
We hypothesize that a higher proportion of Escitalopram + PSI
participants, compared to participants receiving placebo + PSI, will
experience clinically significant improvement
OTHER OUTCOME MEASURES
Efficacy:
Agitation over 12 weeks as measured by NPI-C/AA
• We hypothesize that Escitalopram + PSI will have lower sums of agitation and aggression NPI-C scores
Changes in behavior and psychological disturbances over 12 weeks as measured by an abbreviated NPI
• We hypothesize that Escitalopram + PSI will have lower abbreviated NPI scores
Functional performance over 12 weeks, assessed by ADCS-ADL
• We hypothesize that Escitalopram + PSI will have better ADL outcomes
Cogitative function over 12 weeks as assessed by MMSE
• We hypothesize that Escitalopram + PSI will have higher cognitive function
Caregiver burden over 12 weeks as assessed by ZBI
• We hypothesize that Escitalopram + PSI will have lower caregiver burden
OTHER OUTCOME MEASURES
Safety:
Vital signs (blood pressure, pulse, respiratory rate), and weight
Balance and gait stability as measured by the Get up and Go Test
Standardized electrocardiogram (ECG) monitoring, with special attention to the QTc interval
Adverse events (AE) and serious AEs (SAEs)
• We hypothesize that Escitalopram will be as well as tolerated as placebo on
these safety outcomes
RECENT UPDATE
ON
ENROLLMENT
STATUS
There have been 80 people enrolled to date.
At rate of the last 28 days, randomization target of 392 will be reached on 12/26/2023
Current Randomizations: 69 Participants (18% of Target)
There have been 7 people (4 between enrollment and baseline) enrolled in the observational cohort to date
QUESTIONS?