Cholinesterase Inhibitor Discontinuation
Phase: PHASE2
Conditions: Dementia
Sponsor: VA Office of Research and Development

Study Protocol 
Cholinesterase Inhibitor Discontinuation (5/2/2019) 
NCT002248636 
 
 

 
Study Protocol 
Cholinesterase Inhibitor (CI) Discontinuation 
 5/2/2019 
PI:  Stephen Thielke 
 
Participant Identification 
 
Potential participants will be identified from automated pharmacy data.  A list will be 
produced of Veterans at the study sites who have received a prescription for either 
donepezil or galantamine for a period of 12 months. 
 
Review of CPRS records will establish whether each potential participant meets initial 
inclusion and exclusion criteria: 
 
Inclusion Criteria for All Participants:  
• Males and females ages 60 and older. 
• Taking stable dose of donepezil 5mg or greater per day, or galantamine 8mg or 
greater per day, for at least 1 year. 
Exclusion Criteria for All Participants: 
• Terminal medical condition for which life expectancy would be less than 6 months. 
• Unstable or uncontrolled medical condition that would jeopardize safety or 
interfere with participation in the study. 
• Receiving services from hospice. 
• Current prescription with more than one CI. 
• Receiving a medication in an investigational drug study. 
• Parkinson’s Disease or Lewy Body Dementia 
 
Participating Sites 
 
VA Puget Sound,  VA Boise, VA Bedford, and VA Little Rock will participate in 
recruitment.  The Puget Sound site is the coordinating cent 
 
Approach Letter / Brochures 
 
Potential participants will be mailed a letter and brochures describing the study, as well 
as a pre-stamped postcard.  One of the brochures is geared at caregivers and patients, and 
the other at providers.  The information in both is very similar, and can be understood by 
anyone with basic health literacy. 
 
Potential participants who could not be contacted during the initial recruitment (prior to 
March 2018) will be sent one more letter that includes the pre-stamped postcard allowing 
them to request information or to opt out.  Study staff may try once more to reach them 
by phone if the postcard is not received two weeks after sending the letter.  Potential 
participants who express interest on the postcard will be mailed a blank copy of the 
consent form, and contacted at their convenience. 
 

 
Case Review 
 
Based on the information from the chart review and interview, the study coordinator and 
PI will ascertain if the participant meets inclusion criteria. 
 
Phone Contact and Screening 
 
Study staff will wait two weeks for potential participants to return the postcard. 
 
The study coordinators or principal investigators will call potential participants who did 
not opt out and describe the purpose and process of the study with the Veteran and/or 
their caregiver.   
 
For those participants who remain interested, the study coordinators or principal 
investigators will gather further information from the caregiver: 
 
• Ensure presence of a primary caregiver who can assume responsibility for 
medication compliance, and can rate the patient's condition; OR residence in a VA 
nursing home with staffing capacity to address these issues 
• The caregiver and Veteran are willing to have the CI medication discontinued for 
up to 6 weeks (although it can be restarted at any time). 
 
Consent 
 
Once patients are identified who are willing to join the study, or if the returned postcard 
expresses interest, the study coordinator will send a consent form and a information 
statement to them in the mail.   If requested the study coordinator will arrange a time to 
go over the consent form with them over the phone.  A letter will be sent along with the 
consent asking the Veteran and their caregiver to call (206) 764-2815 if they have any 
questions.  The study coordinator will thoroughly explain all the details of the consent 
with the Veteran and their caregiver, including reading it to them if necessary.   
 
After any and all the Veteran and Caregiver’s questions have been answered, either the 
Veteran or their Caregiver will sign the consent form and send it back in a postage paid, 
self-addressed envelope.  If the Veteran is unable to sign for himself, consent will be 
obtained through the Veteran’s Durable Power Of Attorney and a copy of the DPOA 
paperwork will be kept on file with the consent.  The Caregiver and the DPOA do not 
have to be the same person, but the DPOA will always be kept abreast of the study 
procedures.  Once the study coordinator receives the signed consent back in the mail, 
they will mail a copy back to the Veteran.  The original signed consent will go in the 
study file. 
 
Boise will use their own site-specific consent form and information statement.  Bedford 
will use their own site-specific consent form for each the Veteran and Caregiver.  
 
 

Baseline Data Gathering 
 
After the consent has been obtained, the study coordinator will call the participant and 
caregiver.  This telephone visit will take about 30-45 minutes.  The following scales will 
be applied. 
 
Patient and disease variables 
 -Age, sex, race 
 -Duration of dementia symptoms / diagnosis (if relevant) 
 -Duration of treatment with CI 
 -Use of memantine (present / historical) 
 -Use of neuroleptic (present) 
 -Use of other psychotropic medication (present) 
 
Outcome measures 
-Cognition:  TICS (Veteran) 
-Functioning:  ADCS-ADL (caregiver) 
-Behaviors:  NPI-Q (caregiver) 
-Caregiver burden:  ZBI (caregiver) 
 
During this interview, the study coordinator will explain the process for medication 
administration during the study.  The caregiver will be asked to repeat back the process of 
taking the study pill instead of the previous CI medication, and that the participant and 
caregiver may, at any time and for any reason, return back to the previous dose of 
medication and stop the study medication.  At that point the participant is considered 
withdrawn from the study. 
 
Randomization 
 
Participants will be randomized to either Real Taper or Sham Taper, based on a 
randomization scheme generated by the study biostatistician. 
 
Documentation for Provider 
 
The participant’s primary care provider will be sent a letter informing them of the study, 
and requesting a call if there are any questions.  The participation will also be noted in 
CPRS. 
 
Medication Distribution 
 
Participants will receive the study medication by mail.  The pill bottle and instructions 
will specify that the study medication is to be taken instead of (not in addition to) the pre-
study CI.  The instructions will repeat that the participant can return back to the pre-study 
dose of medication, and stop the study medication, at any time and for any reason.  
Emergency contact information will be provided. 
 

The medication will take the form of two sets of pills:  those for the first three weeks, and 
those for the second three weeks.  The first three-week regimen involves either a half-
dose of the pre-study medication (real taper) or the full dose of the pre-study medication 
(sham taper).  The pharmacist may substitute formulations as needed.  The second three-
week regimen involves either placebo (real taper) or the full dose of the pre-study 
medication (sham taper). 
 
Emergency Procedures 
 
The consent form and the instructions sent with the medications both include contact 
information, including after-hours numbers, to address any study-related health issues. 
 
Withdrawal from study 
 
Participants may withdraw from the study at any time and for any reason, and return to 
their pre-study dose of medication. 
 
Assessment Contacts 
 
Every two weeks, the study coordinator will contact the caregiver by phone.  Any 
questions will be answered.  The following will be reviewed: 
 
1. Reiterate ability of the participant to return to the pre-study medication at any 
time, or for any reason. 
2. Document adverse events in prior 2 weeks (death, hospitalization, urgent medical 
visit, fall causing injury). 
3. Ascertain if study medication was stopped. 
4. Ascertain current CI medication (if non-study drug). 
 
Follow-Up Data Gathering 
 
At six weeks (at which point the medications will have been consumed), the study 
coordinator will contact the caregiver to complete the exit interview.  This interview will 
establish: 
 
Adverse events in prior 2 weeks (death, hospitalization, urgent medical visit, fall 
causing injury). 
Continuation or discontinuation of study medication. 
Current CI medication (if not taking study medication). 
 
Outcome measures 
-Cognition:  Six-Item Screener (Veteran) 
-Functioning:  ADCS-ADL (caregiver) 
-Behaviors:  NPI-Q (caregiver) 
-Caregiver burden:  ZBI (caregiver) 
 
Unblinding 

 
During or shortly after the exit interview the PI will call the subject and unblind the 
treatment arm (using information provided by the pharmacist).  The caregiver will be 
asked, based on this information, if they intend to return to the pre-study medication. 
 
Outcome measure 
-Decision to continue pre-study medication 
 
Follow-up 
 
At 12 weeks and 24 weeks from the start of the study, the study coordinator will contact 
the participant to ask what medication is being used (pre-study CI, no treatment, or 
other).  Any remaining questions will be answered. 
 
Data Transfer 
 
Data will be transferred between Seattle and Boise and Seattle and Bedford via placement 
in a secure research folder housed on the secure research drive through the Seattle VA.  
Only study staff members have access to this folder.   
 
Re-randomization 
 
In order to give participants more useful information about the effects of the medications, 
those who were initially in the “sham taper” arm will be offered the option of being re-
randomized to either real taper or sham taper.  They will be offered the re-randomization 
option after they have been unblinded.  If they choose to be re-randomized, the same data 
will be captured.  At the end of this period, the caregiver and Veteran will (as just above) 
be told which medication they had received.  The Veteran and Caregiver may, but are not 
required to re-enroll as many times as it takes to be randomized into the “Real Taper” 
arm in order to assess the effects of actual discontinuation. 
Study Flow Chart 

 
 
Background rates: 
 
In order to interpret the rates of discontinuation observed in different groups during the 
study, national pharmacy data from the study period will be analyzed in order to ascertain 
the following in the underlying population: 
1. The prevalence of different diagnoses among those who were prescribed 
cholinesterase inhibitors. 
2. The mean duration of cholinesterase inhibitor treatment among different groups, 
based on diagnoses, age, and number of medications. 
3. Discontinuation-free survival rates among different groups, based on diagnoses, 
age, and number of medications.