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?