Clinical trial NCT02248636
Conditions: Dementia
Keywords: Alzheimer's disease Cholinesterase inhibitor Discontinuation
Sponsor: VA Office of Research and Development
Start date: 2015-01-22; Completion date: 2019-10-01
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study tries to determine if stopping certain medications that are used to treat dementia will cause worsening from the patient and family perspective.

All of the participants will take pills that look identical, and that may contain active drug or an inactive pill (a placebo). Half of the group will receive the same treatment they were taking before the study -- this is called the "sham discontinuation" arm. The other half will receive a reduced dose of their medication, and then an inactive pill (placebo) -- this is called the "real discontinuation" arm.

Participants will be able to return to their previous dose of medication at any time during the study. The percentage of people who return will be measured and compared. Other medical events and factors such as behaviors, thinking, and caregiver distress, will be measured and compared between the groups.

Detailed description:
There are no reliable findings from controlled trials about discontinuation of cholinesterase inhibitors from a patient and family perspective. It is unknown at what point these medications do not have effects, and how they can safely be discontinued.

The investigators will identify Veterans who have been taking a cholinesterase inhibitor (CI) (donepezil or galantamine) for at least one year. After informed consent, the investigators will randomize them to Real Taper (half-dose of the CI they had taken for 3 weeks, then placebo for 3 weeks), or Sham Taper (continued full dose of the CI they had taken for 6 weeks). The pills will be blinded by over-encapsulating of the drug or placebo.

An intake interview will ascertain history and measure behaviors, cognitive symptoms, and mood, as well as caregiver burden. Phone calls will assess treatment use and adverse events at week 2 and week 4. An exit interview at week 6 will measure the same variables as at baseline. Participants will be unblinded at that point so they will know which treatment had been used. A follow-up call at 12 weeks will ascertain ongoing treatment and any further adverse events.

At any point in the study, participants and caregivers will be able to return to their pre-study dose of medication.

The primary outcome is the percentage of participants who successfully complete a 6-week discontinuation. This will be compared between arms. Other outcomes related to medical events (e.g. hospitalizations, falls), symptoms (e.g. cognition, behaviors), and caregiver distress will be measured and compared.

Arms: arm 1: This group is tapered off their previous cholinesterase inhibitor medication. arm 2: This group receives their previous cholinesterase inhibitor medication, but in in placebo form.
Interventions: intervention 1: Cholinesterase inhibitor intervention 2: Sham discontinuation
Intervention descriptions: intervention 1: This group receives a half-dose of their previous cholinesterase inhibitor medication (in overencapsulated form) for two weeks, then receives placebo. intervention 2: This group receives their previous dose of cholinesterase inhibitor medication, but in overencapsulated form

Protocol documents:
Prot_000.pdf: 
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. 
 

SAP_001.pdf: 
Cholinesterase Inhibitor Discontinuation 
 
Statistical Analysis Plan (5/8/2014) 
 
NCT002248636 


Analytic Plan: 
The study is designed to test two hypotheses:  that the Sham Taper arm will 
have a higher successful discontinuation rate than the Real Taper arm, and that 
the rate of negative outcomes will be lower in the Sham Taper arm compared to 
the Real Taper arm.   This is a non-inferiority design.  The null hypothesis is that 
Real Taper is better than Sham Taper by a non-inferiority (or equivalence) limit.  
This limit can be defined in a number of ways, but the most straightforward in this 
setting is as the  “smallest value that would represent a clinically meaningful 
difference”. {Wiens, 2002 #75}  In the setting of dementia, we propose that a non-
inferiority limit of 25% is appropriate.  This is somewhat smaller than the limit 
used in other non-inferiority studies. 
 
The main threat of this design is a Type II error (falsely accepting that there is no 
difference between groups), which could happen if the sample was inadequate.  
As described further below, the sample size has been selected in order to ensure 
that the study would be adequately powered to detect a meaningful difference 
between groups.  For the main analyses, we will use a threshold of p < 0.05 to 
define statistical significance for the main analysis, and p <0.025 for the 
secondary analyses.  The more stringent threshold is selected for the latter 
because of multiple comparisons. 
 
Discontinuation Rates:  The primary outcome is the fraction of participants who 
completed a successful 6-week taper (either real or sham).  For instance, if half 
of the Real Taper and 65% of the Sham Taper group successfully discontinued 
the medication, then p(Real) = 0.5, and p(Sham) = 0.25.  The statistical 
significance of the difference between these proportions can be computed 
manually.  The variance of the estimate is 
𝑝∗(1−𝑝)
𝑛
, where p is the proportion and n 
is the total number of observations.  The difference between groups is p(Real) – 
p(Sham).  The pooled variance is var(Real) + var(Sham), and the standard 
deviation is the square root of this sum.  The z-score of the group difference is 
established using the mean variance relationship, as 
𝑀𝑒𝑎𝑛 𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒
𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝐷𝑒𝑣𝑖𝑎𝑡𝑖𝑜𝑛, and the z-
score can be converted into a p-value assuming a normal distribution.  This 
method will be used to assess both the primary study endpoint and the group 
differences at the interim analyses.  For instance, in the example of p(Real) = 0.5 
and p(Sham) = 0.65, if there were 100 in each group, the z-score of the 
difference would be 2.17, and a two-sided p-value for the difference would be 
0.038. 
 
Change in Cognitive, Functional, Behavioral, and Caregiver Outcomes:  For the 
four domains assessed at baseline and follow-up (cognition, functioning, 
behaviors, and caregiver burden), we will compare Real Taper and Sham Taper 
groups, using T-tests.  This will be an intent-to-treat analysis, including those who 
did or did not discontinue successfully.  If analysis of the sample suggests that 
the groups are unequally distributed based on patient or disease characteristics, 
then regression models controlling for these factors will be produced, examining 
the same outcomes. 


 
Unblinding and Post-Study Treatment Decision:  The treatment received will be 
unblinded for the caregiver and Veteran at the Completion Visit, and written 
information will be provided about what this means (i.e. exactly what medication 
the Veteran received).  This will be provided to both arms, since it is possible that 
even participants in the Sham Taper arm would desire to stop the CI medication.  
The unblinding will not be shared with the Study Coordinator, Research 
Assistant, or Investigators.  At week 12, study staff will contact the caregiver to 
ascertain what CI medication, if any, the Veteran is taking.  Because there is no 
comparison group, this will be a descriptive result rather than a group 
comparison. 
 
 
Sham 
taper 
Real taper 
p-value of 
difference 
% with successful 
discontinuation 
 
 
 
Change in Cognition (SCIP) 
 
 
 
Change in Functioning (ADCS-ADL) 
 
 
 
Change in Behaviors (BEHAVE-AD) 
 
 
 
Change in Caregiver burden (ZBI) 
 
 
 
Return to pre-study CI medication 
 
[Not applicable] 
 
Patient Factors Associated with Negative Outcomes:  For the 100 participants in 
the Sham Taper arm, we will explore which patient factors were associated with 
negative outcomes.  The main patient and disease variables (age, sex, race, 
duration of AD, duration of treatment, current or historical use of memantine, use 
of antipsychotic medication, use of other psychotropic medication) will be 
analyzed as predictors.  Each of the main outcomes described above (successful 
discontinuation; cognition; functioning; behavior; and caregiver burden) will be 
analyzed as outcomes, separately, using regression models. 
 
Interim Analyses:  There is the possibility that one of the arms could experience a 
greatly increased risk of negative outcomes.  Continuing the trial in this setting 
would be ethically unwarranted, by the principles of beneficence and 
nonmaleficence, since harm to Veterans could be prevented by either stopping or 
continuing the CI medication.  We therefore propose to conduct interim analyses 
every 6 months, starting 2 years after study initiation.  We will aggregate all the 
completed cases to date, and calculate differences between Real Taper and 
Sham Taper in (1) successful discontinuation, and (2) adverse events.  The 
Biostatistician will apply formal statistical methods to control for overall 
significance level and power of the trial, and will present summary results to the 
Principal Investigators if there is concern about excess harm in one treatment 
arm.{Pignon, 1994 #67}  If the interim analyses show a large relative risk 
reduction (>25%) in one arm, then the Biostatistician and Principal Investigators 
will weight the totality of the evidence and consider stopping the trial.