Conditions: Apathy Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 200
Healthy volunteers: no

Brief summary:
Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a Phase III, placebo-controlled, masked, 6 month, multi-center randomized clinical trial sponsored by National Institutes of Aging involving 200 participants with Alzheimer's disease (AD). ADMET 2 is designed to examine the efficacy and safety of methylphenidate as treatment for clinically significant apathy in AD participants. ADMET 2 will enroll participants from real world settings such as outpatient, nursing home, and assisted living facilities and will examine the effects of methylphenidate on apathy and cognition. ADMET 2 will also conduct careful safety monitoring.

Detailed description:
ADMET 2 will examine in a masked, randomized trial the efficacy of methylphenidate for the treatment of clinically significant apathy in participants with Alzheimer's dementia. Efficacy will be assessed as the change in Neuropsychiatric Inventory Apathy subscale (NPI apathy) from baseline to 6 months and score on the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (CGIC) scale at 6 months.

ADMET 2 will also examine the safety of methylphenidate for the treatment of clinically significant apathy in participants with Alzheimer's disease by measuring vital signs, electrolyte panels, adverse event reports, and electrocardiograms. Safety will also be measured by examining neuropsychiatric symptoms other than apathy using the Neuropsychiatric Inventory (NPI).

Changes from baseline to 6 months in other neuropsychological assessments as measured using the Dementia Apathy Interview and Rating (DAIR) scale will also be assessed.

Cost-effectiveness will be measured by assessing quality of life and economic assessment and cognitive changes using a cognitive battery that includes the Mini Mental State Exam (MMSE) and other scales.

A biomarker sub-study initiated part-way through the main trial will collect information on blood-based biomarkers, including microRNA, markers of oxidative stress, inflammation, neuronal loss and lipidomics.

Arms:
arm 1: Methylphenidate, target dose 20 mg per day (range 10-20 mg per day), in 5 mg over-capsulated tablets, and psychosocial intervention arm 2: Matching over-encapsulated placebo and psychosocial intervention

Interventions: intervention 1: Methylphenidate intervention 2: Placebo
Intervention descriptions: intervention 1: Two 5mg methylphenidate over-encapsulated drug taken twice a day for 6 months (total of 20 mg methylphenidate per day), and psychosocial intervention intervention 2: Two over-encapsulated placebo taken twice a day for 6 months and psychosocial intervention

Protocol document:
Prot_SAP_000.pdf: 
Apathy in Dementia Methylphenidate 
Trial 2 (ADMET 2) 
ADMET 2 Protocol 
Version 1.5 
Repository: 
ADMET 2 Coordinating Center 
Johns Hopkins University 
Bloomberg School of Public Health 
615 North Wolfe Street, E6138 
Baltimore, Maryland 21205 
(443) 287-3170
(443) 287-5797 (fax)
admet@jhu.edu
February 25, 2019 
NCT02346201


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
ii
 
 
 
 
 
 
 
 
 
 
 
 
 
Document distribution 
 
 
Version 
 
Version date 
 
Distribution 
 
Distribution date 
0 
11 Sep 2014 
Executive Committee, for review 
11 Sep 2014 
0 
2 Oct 2014 
Steering Committee, for review 
3 Oct 2014 
0 
20 Oct 2014 
Executive Committee, for review 
22 Oct 2014 
1.0 
26 Jan 2015 
Data Safety and Monitoring Committee, for review 
4 Feb 2015 
1.0 
5 Feb 2015 
Research Group, for IRB submission 
11 Feb 2015 
1.1 
3 Jun 2015 
Steering Committee, for review 
10 Jun 2015 
1.2 
9 Aug 2016 
Data Safety and Monitoring Committee, for review 
9 Aug 2016 
1.2 
11 Aug 2016 
Executive Committee, for review 
11 Aug 2016 
1.2 
11 Aug 2016 
Research Group, for IRB submission 
07 Sep 2016 
1.3 
02 May 2017 
Research Group, for IRB submission 
02 May 2017 
1.4 
10 Jul 2018 
Research Group, for IRB submission 
10 Jul 2018 
1.5 
25 Feb 2019 
Research Group, for IRB submission 
25 Feb 2019 
 
 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
iii
 
 
 
 
Document history 
 
 
Version 1.0 (5 Feb 2015); no history. Document developed from grant. 
 
Version 1.1 (3 June 2015) 
 
Numerous editorial and wording changes were made throughout document to improve clarity. Substantive 
modifications include: 
 
2 
Objectives 
 
Removed Apathy Evaluation Scale 
 
3 
Design 
 
Removed Apathy Evaluation Scale 
 
4 
Eligibility 
 
Revised inclusion criteria by: 
 
Adding the bolded statement to "Provision of informed consent for participation in the study 
by potential participant or surrogate (with participant assent if the potential participant is 
unable to provide informed consent) and caregiver" 
 
Removing primary in "Availability of caregiver, who spends greater than ten hours a week 
with the potential participant and supervises his/her care, to accompany the participant to 
study visits and to participate in the study" 
 
Adding the following criterion: "If female, woman must be post-menopausal for at least 2 
years or have had a hysterectomy" 
 
 
Revised exclusion criteria by: 
 
Adding the bolded statements to "Use of trazodone > 50mg or lorazepam > 0.5mg or for 
indications other than sleeping difficulties within the 30 days preceding randomization or a 
period of time equal to 5 half-lives of drug, whichever period of time is longer. Other 
benzodiazepines are prohibited in the past 30 days or within 5 half-lives, whichever period of 
time is longer 
 
Adding the following criterion: "Women with childbearing potential" 
 
5 
Randomization and masking 
 
Revised emergency unmasking method; clinic needs to request treatment assignment through 
data system instead of from the medical monitor 
 
Removed medical monitor from providing treatment assignment to participant and caregiver 
after 6-month follow-up and all collection is complete 
 
6.3 
Psychosocial treatment 
 
Revised the following to allow for clinic variability: "Psychosocial intervention may consist 
of three components: a counseling session, the provision of education materials, and 
availability for crises." 
 
Added "Dementia Care Guidelines for Families" to list of educational materials 
 
6.3 
Choice of methylphenidate formulation 
 
Added section to address formulation difference 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
iv
 
 
 
 
 
6.5 
Management and reporting of adverse events 
 
Removed "report of protocol violations" to the medical monitor duties 
 
Specified that investigators will notify the medical monitor and Coordinating Center within 
one day of learning of death or serious adverse event 
 
7.2 
Overview of consent issues 
 
Defined assent by the Alzheimer's Association and local IRB guidelines 
 
7.4 
Baseline visit procedures 
 
Provided time frame for baseline visit and added that ECG results should be reviewed prior to 
randomization (indicated by bolding): "The baseline visit may take place across more than 
one day, but must be completed within the two weeks preceding randomization. The clinical 
staff should perform and review results of the electrocardiogram (ECG) within the two weeks 
preceding randomization." 
 
Removed Apathy Evaluation Scale 
 
8.2 
Schedule in-person visits 
 
Removed Apathy Evaluation Scale 
 
8.6 
Data collection by visit 
 
Removed Apathy Evaluation Scale 
 
9.1 
Neuropsychology, neuropsychiatry, and other assessments 
 
Replaced 'blind to treatment assignment' with the following (indicated by bolding): "A 
trained clinician, not involved in collecting other assessments or procedures, will complete 
the CGIC using a 7-point Likert scale to rate each participant……" 
 
Removed Apathy Evaluation Scale 
 
9.2 
Cognitive assessments 
 
Removed statement that trail making test will be stopped after 5 errors 
 
10.2 Analysis for specific aims 
 
Added "As required by NIH policy, we will conduct valid subgroup analyses of the primary 
outcomes by gender and race/ethnicity subgroups to determine if there is possible subgroup 
differences (i.e., treatment interactions) in treatment effects. 
 
Added "As required by NIH policy, we will conduct valid subgroup analyses of the of the 
adverse event outcomes by gender and race/ethnicity subgroups to determine if there is 
possible subgroup differences (i.e., treatment interactions) in treatment effects." 
 
Removed Apathy Evaluation Scale 
 
Added that US and Canada will be analyzed for treatment effect differences 
 
11 
Data monitoring 
 
Added that NIA will approve DSMC member selection 
 
13.3 Consent procedures 
 
Defined assent by the Alzheimer's Association and local IRB guidelines 
 
13.4 Potential risks and benefits 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
v
 
 
 
 
 
Added information on 2013 FDA warning about relationship between priapism and 
methylphenidate use 
 
Added information on 2015 FDA warning about relationship between rhabdomyolysis and 
methylphenidate use 
 
13.5  Safety monitoring 
 
Removed "report of protocol violations" to the medical monitor duties 
 
Specified that investigators will notify the medical monitor and Coordinating Center within 
one day after learning of death or serious adverse event 
 
Appendix: Design summary 
 
Updated eligibility criteria to match revisions in section 4 
 
Removed Apathy Evaluation Scale 
 
Version 1.2 (22 August 2016) 
 
6.7 
Concomitant medications 
 
Clarified the procedures for reducing, discontinuing, and restarting the study drug when the 
participant is experiencing agitation or delusions:  
- Added “delusions” to the type of symptoms that may be present when treating 
participants with agitation. 
- Added that the study drug may be “temporarily” discontinued. 
- Removed that the study drug may be restarted within a month of stopping. 
- Added that if the participant is prescribed an SSRI/other medication, the SSRI/other 
medication may only be restarted “once the participant has stopped taking the 
SSRI/other medication for at least 30 days or 5 half-lives, whichever is longer.” 
 
Clarified the procedures for discontinuing and restarting the study drug when the participant 
is experiencing depression: 
- Added that the study drug may be “temporarily” discontinued until “the participant is 
on a stable dose of the SSRI for at least 30 days or 5 half-lives, whichever is longer.” 
 
7.4 
Baseline visit procedures 
 
Increased time frame for baseline visit (indicated by bolding): "The baseline visit may take 
place across more than one day, but must be completed within the three weeks preceding 
randomization. The clinical staff should perform and review results of the electrocardiogram 
(ECG) within the three weeks preceding randomization." 
 
9.1 
Neuropsychology, neuropsychiatry, and other assessments 
 
Decreased the maximum score for Dependence Scale from 20 to 15. 
 
13.5 Safety monitoring 
 
Increased time frame for baseline visit (indicated by bolding): “Therefore, an ECG must be 
performed no more than three weeks prior to randomization to allow the investigator to 
evaluate the clinical significance of potential findings.” 
 
Version 1.3 (02 May 2017) 
 
13.4 Potential risks and benefits 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
vi
 
 
 
 
 
Added information from 2017 FDA warning about relationship between serotonin syndrome 
and methylphenidate use 
 
 
Version 1.4 (10 Jul 2018) 
 
All sections 
 
Corrected spacing 
 
Referenced citations by (Author year) 
 
Document distribution 
 
Added “20” to the years 
 
Summary 
 
Added the goals of the blood-based biomarkers substudy 
 
1.7  Study rationale for Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) 
 
Added the goal of the biomarkers substudy 
 
2 
Objectives 
 
Added the objective of the biomarkers substudy 
 
3.1 
Overview 
 
Added the biomarkers substudy design of blood sample collection at baseline and 6 month 
follow-up 
 
3.2 
Sample size and power 
 
Added the biomarkers substudy has a convenience sample, based on availability. 
 
3.3 
Organization 
 
Added the Biomarkers executive committee 
 
7.4  Baseline study procedures 
 
Added the baseline blood-based biomarkers blood sample collection 
 
8.2 
Scheduled in-person visits 
 
Added the month 6 blood-based biomarkers blood sample collection 
 
8.6 
Data collection by visit 
 
Added the baseline and month 6 blood-based biomarkers blood sample collection 
 
10.1 Analysis overview 
 
Added a short description of the blood-based biomarkers analysis 
 
10.2 Analsysis for specific aims 
 
Added a description of the blood-based biomarkers analysis 
 
11 
Data monitoring 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
vii
 
 
 
 
 
Added that the CC will track collection, shipment, and receipt of blood-based biomarker 
samples 
 
13.3 Consent procedures 
 
Added that newly or currently enrolled participants will also be asked to consent to the blood-
based biomarkers substudy 
 
13.4 Potential risks and benefits 
 
Added a description of the risks to participants if they participate in the biomarks substudy 
blood draw 
 
13.6 Confidentiality of participant and caregiver data 
 
Added that blood samples will be de-identified with using only study ID codes 
 
14 
Blood-based biomarkers substudy 
 
Added this chapter 
 
15 
Literature cited 
 
Removed numbers on citations in this section  
 
Added new citations for blood-based biomarkers substudy 
 
Moved several citations to the correct alphabetical location 
 
Appendix: Design summary 
 
Added “(2015 to 2017)” to Banner Alzheimer’s Institute  
 
Added blood-based biomarker substudy objective 
 
Added blood-based biomarker substudy sample information 
 
Added blood-based biomarker substudy analysis information 
 
Version 1.5 (25 Feb 2019) 
 
2 
Objectives 
 
Added two secondary apathy outcomes. 
 
10.2  
Analysis for specific aims 
 
Added two secondary apathy outcomes. 
 
Appendix: Design summary 
 
Added two secondary apathy outcomes. 
 
Added “(2015 to 2019)” to Wake Forest University 
 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
viii
 
 
 
 
Document distribution .................................................................................................................................. ii 
Document history ......................................................................................................................................... iii 
Summary ....................................................................................................................................................... 1 
1. 
Background and significance ................................................................................................................ 2 
1.1.  
Public health significance ............................................................................................................. 2 
1.2.  
Neuropsychiatric symptoms of Alzheimer’s disease .................................................................... 2 
1.3.  
Apathy as a significant neuropsychiatric symptom ...................................................................... 2 
1.4.  
Etiology of apathy in AD .............................................................................................................. 3 
1.5.  
Treatments for apathy in AD ........................................................................................................ 4 
1.6.  
Methylphenidate as a possible treatment for apathy in AD .......................................................... 4 
1.7.  
Study rationale for Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) ........................... 5 
2. 
Objectives ............................................................................................................................................. 6 
3. 
Design ................................................................................................................................................... 7 
3.1. 
Overview ....................................................................................................................................... 7 
3.2.  
Sample size and power .................................................................................................................. 7 
3.3.  
Organization .................................................................................................................................. 8 
3.4.  
Policies .......................................................................................................................................... 8 
4. 
Eligibility criteria .................................................................................................................................. 9 
5. 
Randomization and masking ............................................................................................................... 11 
6. 
Treatment plan .................................................................................................................................... 12 
6.1.  
Treatment groups ........................................................................................................................ 12 
6.2.  
Treatment schedule and titration of study drug dose .................................................................. 12 
6.3.  
Choice of methylphenidate formulation ..................................................................................... 12 
6.4.  
Psychosocial treatment ................................................................................................................ 12 
6.5.  
Adherence to study treatment ..................................................................................................... 13 
6.6.  
Management and reporting of adverse events ............................................................................. 13 
6.7.  
Concomitant medications ............................................................................................................ 14 
6.8.  
Assessment of suicidality and need for acute hospitalization ..................................................... 14 
7. 
Baseline visit ....................................................................................................................................... 15 
7.1.  
Overview ..................................................................................................................................... 15 
7.2.  
Overview of consent issues ......................................................................................................... 15 
7.3.  
Review of medical history .......................................................................................................... 15 
7.4.  
Baseline visit procedures ............................................................................................................ 15 
8. 
Follow-up visits and telephone contacts ............................................................................................. 17 
8.1.  
Overview of follow-up visits and telephone contacts ................................................................. 17 
8.2.  
Scheduled in-person visits .......................................................................................................... 17 
8.3.  
Telephone contacts for data collection ........................................................................................ 18 
8.4.  
Telephone contacts for dose adjustments .................................................................................... 18 
8.5.  
Unscheduled follow-up visits and contacts ................................................................................. 18 
8.6. 
Data collection by visit ............................................................................................................... 19 
9. 
Outcomes assessments ........................................................................................................................ 20 
9.1.  
Neuropsychology, neuropsychiatry, and other assessments ....................................................... 20 
9.2.  
Cognitive assessments ................................................................................................................ 21 
9.3.  
Safety measurements .................................................................................................................. 22 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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10. 
Analysis........................................................................................................................................... 24 
10.1.  
Analysis overview ................................................................................................................... 24 
10.2.  
Analysis for specific aims ....................................................................................................... 24 
10.3.  
Additional considerations ....................................................................................................... 27 
11. 
Data monitoring .............................................................................................................................. 28 
12. 
Quality assurance and performance monitoring ............................................................................. 29 
12.1.  
Overview ................................................................................................................................. 29 
12.2.  
Certification of centers ............................................................................................................ 29 
12.3.  
Training of staff ...................................................................................................................... 29 
12.4.  
Certification of staff ................................................................................................................ 29 
12.5.  
Performance monitoring ......................................................................................................... 30 
12.6.  
Site visiting ............................................................................................................................. 30 
12.7.  
Error detection......................................................................................................................... 30 
13. 
Protection of human subjects .......................................................................................................... 31 
13.1.  
Human subjects ....................................................................................................................... 31 
13.2.  
Monitoring of Institutional Review Board (IRB) approvals ................................................... 31 
13.3.  
Consent procedures ................................................................................................................. 31 
13.4.  
Potential risks and benefits ..................................................................................................... 32 
13.5.  
Safety monitoring .................................................................................................................... 34 
13.6.  
Confidentiality of participant and caregiver data .................................................................... 35 
13.7.  
Data sharing ............................................................................................................................ 35 
14.  
Blood-based biomarkers substudy .................................................................................................. 36 
14.1. Title ............................................................................................................................................. 36 
14.2.  
Objectives ............................................................................................................................... 36 
14.3.  
Background and specific hypotheses ...................................................................................... 36 
14.4.  
Organization ............................................................................................................................ 40 
14.5.  
Eligibility criteria .................................................................................................................... 40 
14.6.  
Study design ............................................................................................................................ 40 
14.8.  
Biochemical analyses .............................................................................................................. 41 
14.9.  
Outcomes ................................................................................................................................ 42 
14.10.  
Justification of sample size ..................................................................................................... 42 
14.11.  
Data analysis ........................................................................................................................... 43 
14.12.  
Risk to participants and protections against risk ..................................................................... 44 
14.13.  
Data confidentiality ................................................................................................................. 44 
14.14.  
Biohazards ............................................................................................................................... 44 
15. 
Literature cited ................................................................................................................................ 45 
Appendix: Design summary ....................................................................................................................... 59 
 
 
 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
1
 
 
 
 
Summary 
 
Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a Phase III, placebo-controlled, masked, 6 
month, 10-center randomized clinical trial sponsored by National Institute of Aging involving 200 
participants with Alzheimer's disease (AD). ADMET 2 is designed to examine the efficacy and safety of 
methylphenidate as treatment for clinically significant apathy in AD participants. ADMET 2 will enroll 
participants from real world settings such as outpatient, nursing home, and assisted living facilities and 
will examine the effects of methylphenidate on apathy and cognition. ADMET 2 will also conduct careful 
safety monitoring. 
 
A substudy of blood-based biomarkers will also be conducted to understand biomarker correlates of 
change in apathy over time, and to identify possible predictors of treatment response. 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
2
 
 
 
 
1. 
Background and significance 
 
1.1.  
Public health significance 
 
Alzheimer's disease (AD) is a growing public health problem whose global burden is expected to exceed 
80 million cases by 2040 (Ferri 2005).  An estimated 5.1 million Americans have AD (Brookmeyer 
1998). Considering current demographic trends and recent improvements in the treatment of AD, the 
prevalence of this condition in the United States is expected to quadruple in the next 50 years 
(Brookmeyer 1998). AD debilitates patients and families both emotionally and economically (Rabins 
2006). Societal costs are about $100 billion per year in the US alone (Fillit 2000) and are expected to 
triple by 2040 (Fox 2001). 
 
1.2.  
Neuropsychiatric symptoms of Alzheimer’s disease 
 
While cognitive and functional decline are the hallmark of AD, neuropsychiatric symptoms (NPS) afflict 
almost all patients (Lyketsos 2007). NPS are sometimes referred to as "behavioral disturbances" or "non-
cognitive mental disturbances" which include agitation, delusions, hallucinations, depression, sleep 
disturbance, and problem behaviors. NPS add significant disability for patients and caregivers (Rabins 
2006). A range of associated adverse consequences have been reported including worse quality of life, 
greater disability, accelerated cognitive or functional decline, greater burden on caregivers, earlier 
institutionalization, and accelerated mortality (Rabins 2006). Practice guidelines developed for the 
treatment of AD consistently refer to management of NPS as central to the treatment of AD (e.g., 
American Psychological Association Practice Guidelines for the Treatment of AD (revised) (APA 2007); 
American Association for Geriatric Psychiatry Position Statement on Principles of Dementia Care, 2006) 
(Lyketsos 2006). The importance of NPS in the context of AD has also been recognized by the Food and 
Drug Administration (FDA), which is open to considering new indications for treatment of specific NPS 
in this context (Campbell 1997). Despite this, the empirical evidence supporting pharmacological and 
non-pharmacological interventions for NPS is sparse (Benoit 2004; Cummings 1994). 
 
1.3.  
Apathy as a significant neuropsychiatric symptom 
 
Apathy is one of the most prevalent NPS in AD. Clinically significant apathy is defined as a loss of will 
and initiative, lack of interest in activities, lack of productivity, as well as limited affective response to 
positive or negative events (Benoit 2003), and is present for at least four weeks. According to some 
studies, apathy affects approximately 50% of people with dementia (Steinberg 2006). While the 
prevalence of apathy increases with severity of dementia, it is a chronic and persistent problem at all 
stages of the illness (Mega 1996). A recent door-to-door epidemiological study conducted in Spain found 
that apathy was the most prevalent NPS in Alzheimer's patients, affecting 30% of study participants (Hill 
1963). More broadly, the study identified apathy as the most common NPS in all dementia types, 
affecting 54% of study participants (Fernandez 2007). An epidemiological study conducted in Brazil 
reported a similar prevalence of apathy. The researchers in this study observed apathy in 53% of AD 
patients (Tatsch 2006). Another study reported a lower, but still significant, prevalence of 36% in those 
with dementia (Lyketsos 2002). Apathy has devastating effects on the quality of life for both AD patients 
and their caregivers. Patients suffering from apathy experience decreased motivation, relying heavily on 
caregivers to initiate and oversee daily activities. One study found apathetic patients 2.8 times more likely 
than non-apathetic patients to struggle with at least one activity of daily living, such as dressing, bathing, 
and eating (Freels 1992). Thus, apathy compounds the negative effects of cognitive impairment, further 
degrading the quality of life of AD patients. In addition, caregivers who lack an understanding of apathy 
as a syndrome that accompanies AD may misinterpret apathetic patients as insensitive and uncaring 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
3
 
 
 
 
(Campbell 1997). Caregivers of apathetic AD patients report significant levels of distress and fewer 
positive experiences associated with caregiving than caregivers of non-apathetic AD patients (Greene 
1982; Kaufer 1998). Greater caregiver distress is linked with increased service utilization and accelerated 
institutionalization (Smyth 1997), which, in turn, creates a significant financial burden (Storga 1996; 
Herrmann 2006). Therefore, the management of apathy is a major priority in caring for patients with AD. 
 
1.4.  
Etiology of apathy in AD 
 
Post-mortem studies comparing AD patients with controls support the argument that disruptions in the 
dopaminergic system are common in AD (Nazarali 1992; Storga 1996). These studies reported that 
disruptions in the dopaminergic transporter and postsynaptic loss of striatal dopamine type 2 (D2) 
receptors were frequently found in AD patients (Joyce 1998). Furthermore, loss of striatal D2 receptors 
was prevalent among the 30% of AD patients who also exhibited extrapyramidal features (Joyce 1998; 
Pizzolato 1996). Moreover, neuroimaging studies suggest that disruptions in D2 receptor levels and 
metabolism became increasingly severe as cognitive impairment (Itoh 1994; Kemppainen 2000; Pizzolato 
1996) and NPS progressed (Tanaka 2003). This study suggests, however, that dopaminergic disruptions 
may not manifest themselves as general signs of disease progression, but may be specifically related to 
the onset of apathy. 
 
A recent study showed that apathy in AD correlates with decreased dopamine transporter density in the 
striatum (David 2007). Furthermore, Benoit et al (2004) reported that higher scores on the Apathy 
Inventory were associated with decreased orbito-frontal perfusion (using perfusion SPECT imaging) in 
AD patients. Specifically, they observed that perfusion patterns correlated with specific apathetic 
symptoms. For example, lack of initiative was associated with decreased right cingulate perfusion, lack of 
interest was associated with decreased right middle orbitofrontal perfusion, and emotional blunting was 
associated with decreased left orbitofrontal perfusion. Lanctôt et. al. (2007) reported similar findings.  
Using SPECT imaging, she found that apathetic AD patients have decreased perfusion in right 
orbitofrontal and left anterior cingulate cortex compared with non-apathetic AD patients. Marshall et al 
(2007) reported decreased bilateral anterior cingulate fluoro-D-glucose uptake in apathetic AD patients 
compared with non-apathetic AD patients. These findings are further supported by a recent 
neuropathologic report showing that chronic apathy in AD is associated with higher density of 
neurofibrillary tangles in the anterior cingulate (Marshall 2006). 
 
Further evidence for a relationship between apathy and dopaminergic disruption comes from studies of 
other neurodegenerative diseases with apathy as a syndrome. For example, a recent MRI study found that 
unmedicated schizophrenics show decreased activation of the ventral striatum during the presentation of 
reward-indicating cues. The authors suggest that the increased dopaminergic turnover observed in 
schizophrenia may increase brain reward system (BRS) "noise," resulting in impaired reward processing 
and anhedonia (Juckel 2006). Similarly, the high prevalence of apathy among cocaine dependent 
individuals suffering from withdrawal has been proposed to be a result of subcortical dopamine 
dysfunction (Kalechstein 2002; Volkow 1997). Degeneration of nigrostriatal dopamine neurons is key in 
the pathogenesis of Parkinson's disease (PD), leading some authors to suggest that it is an ideal clinical 
model for the study of the neuropsychiatric consequences of impaired BRS functioning. The prevalence 
of apathy in PD has been reported to be as high as 54% (Aarsland 2007), and treatment with 
dopaminergic agents, including L-DOPA (Czernecki 2002) and pramipexole (Lemke 2007), has been 
shown to improve both motor deficits and apathy in PD. In summary, these studies provide strong support 
for the hypothesis that apathy has a neurobiological basis and that it is associated with impaired perfusion 
patterns in the orbitofrontal and anterior cingulate cortices, which in turn results from damage to 
dopaminergic innervations from the progression of Alzheimer's pathology. 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
4
 
 
 
 
 
 
1.5.  
Treatments for apathy in AD 
 
Despite the high prevalence of apathy in AD and its serious consequences, there are no proven treatments 
for this condition. Clinicians familiar with AD care always prefer non-pharmacologic treatment strategies.  
The available data on non-pharmacologic treatments for AD, albeit scarce, suggest reliable but limited 
effects. Recently, pharmacologic options for the treatment of apathy have been explored. Antidepressant 
medications have been considered, but some evidence suggests they could be detrimental rather than 
helpful in the treatment of apathy in AD (Lemke 2007). Cholinesterase inhibitors (ChEIs) have also been 
studied. While these studies demonstrated a modest improvement in apathy (Cummings 2001; Feldman 
2001; Tariot 2001; Tariot 2000) with no clear differentiation between medications (Rosler 2002), about 
half of the patients showed no relief of apathetic symptoms following ChEI therapy (Cummings 2001).  
Furthermore, these studies were not tailored specifically for apathy. Generally, the trials did not recruit 
participants with clinically significant symptoms of apathy. Indeed, some apathetic patients were 
excluded since they tend to be less likely to participate in studies and less easily "engaged" in performing 
neuropsychological assessments. 
 
The evaluation of dopaminergic agents for the treatment of apathy is a feasible alternative approach. The 
rationale for the use of dopaminergic agents is based on the strong tie between activity of the 
dopaminergic mesolimbic brain reward system and the expression of motivated behaviors in brain 
damaged populations. Evidence for the use of dopaminergic agents also comes from case reports and 
small open-label studies in nondemented populations (Roccaforte 1990; Galynker 1997; Van Reekum 
1995; Corcoran 2004). Furthermore, preliminary data from a double blind, placebo-controlled, single-
center crossover pilot study suggest that the dopamine agonist methylphenidate is superior to placebo for 
the treatment of apathy in AD (Lanctot 2008). 
 
1.6.  
Methylphenidate as a possible treatment for apathy in AD 
 
Given the prevalence of apathy in this growing patient population, better pharmacologic options are 
needed. Unfortunately, there have been few randomized, placebo-controlled trials of dopamine agonists 
that address their efficacy for the treatment of apathy in AD. In 1990, Roccaforte (1990) conducted a 
comprehensive review of the literature on the use of psychostimulants in the elderly. Taken together, the 
studies, which began in 1956, included more than 800 patients with poor cognition, depression, and 
"amotivational syndromes." Doses of methylphenidate ranged from 10-60 mg/day, and one study used 5-
20 mg/day of amphetamine. In the dextroamphetamine study, a quarter of the patients dropped out due to 
side effects (aggression, confusion, delusions), but none of the methylphenidate patients were reported to 
have dropped out. Two patients were noted to have increased blood pressure and heart rate on 45 mg of 
methylphenidate, and several others noted "irritability." Overall, methylphenidate appeared to be well 
tolerated. It was not associated with any significant side effects. 
  
Long-acting methylphenidate is one treatment option. There have been two double-blind controlled trials 
evaluating the efficacy and safety of non-pediatric use of long-acting methylphenidate: A study by Jain et 
al. (2007) evaluated 50 patients between the ages of 18 and 60, while a separate study by Reimherr et al. 
(2007) evaluated 47 patients aged 18 and 65. Both studies describe similar efficacy between long- and 
short-acting methylphenidate for ADHD. Safety concerns included weight loss and alteration in blood 
pressure, which is of relevance in this population. Furthermore, there is no reported information on the 
use of long-acting methylphenidate in the 65 and over population, or in patients suffering from dementia.  
This is of substantial concern since in these patients, dosage, as well as metabolization issues, will need to 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
5
 
 
 
 
be further studied in normal elderly patients before the drug can be evaluated in a frail, demented 
population. 
 
From all possible dopamine-enhancing compounds available, short-acting methylphenidate has been one 
of the most studied compounds in the elderly and presents the best safety profile. However, the efficacy 
and safety of methylphenidate for the treatment of apathy in AD has not been definitively established.  
 
1.7.  
Study rationale for Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) 
 
Two small pilot randomized clinical trials showed a positive effect of methylphenidate for the treatment 
of apathy in AD. The first randomized, placebo-controlled trial of methylphenidate for the treatment of 
apathy in AD, conducted by Drs. Lanctôt, Herrmann, and Black, reported encouraging results (Lanctot 
2007; Lanctot 2008; Herrmann 2008). The results of this study suggest that methylphenidate is modestly 
effective in a subset of AD patients. They further suggest that improvement in apathy with 
methylphenidate can be predicted on the basis of attentional response to dextroamphetamine (d-amph) 
challenge. Response time variability, a measure of the "erraticness" of responses and a component of the 
Connors’ Continuous Performance Task inattention summary score, was also correlated with response to 
methylphenidate. While d-amph had no effect on the number or types of errors made, it negatively 
impacted the consistency in response times. The relationship between improvements in apathy with 
methylphenidate and greater inattention post-d-amph challenge may therefore reflect the behaviorally 
activating, rather than the subjective or cognitive effects, of psychostimulants in this population.   
 
This study demonstrated a significant benefit of methylphenidate over placebo for the treatment of apathy 
in AD in patients previously stabilized on a cholinesterase inhibitor. A positive relationship between the 
acute effects of d-amph was further related to methylphenidate treatment response, implicating a role for 
dopaminergic dysfunction in the development and treatment of apathy in AD. The study showed a clear 
efficacy signal at the tested dose as well a benign adverse event profile. The study reported that the two 
patients who experienced serious adverse events during the study also experienced significant behavioral 
disturbances, consisting of delusions, agitation, irritability, and appetite change prior to commencing 
methylphenidate treatment. Thus, patients presenting those symptoms at baseline will be excluded from 
ADMET 2. 
 
The original Alzheimer's Disease Methylphenidate Trial (ADMET) found that methylphenidate treatment 
of apathy in AD was associated with significant improvement in two of three efficacy outcomes and a 
trend toward improved global cognition with minimal adverse events, suggesting that methylphenidate 
might be a safe and efficacious treatment for apathy in AD. This trial studied 60 participants over 6-week 
period. 
 
The goal of ADMET 2 is to expand upon this information provided by these two pilot randomized trials 
by evaluating methylphenidate for the treatment of apathy in 200 AD participants over a 6-month period 
of time as well as collecting information on the safety of methylphenidate in this population. In addition, 
the goal of the substudy “Biomarkers of Apathy and Treatment Response” is to understand blood-based 
biomarker correlates of change in apathy over time, and to identify possible predictors of treatment 
response. 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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2. 
Objectives 
 
 
 
Primary objective 
 
To examine in a masked, randomized trial the efficacy of methylphenidate for the treatment of 
clinically significant apathy in participants with Alzheimer's dementia. Efficacy will be assessed 
as the change in Neuropsychiatric Inventory Apathy subscale (NPI apathy) from baseline to 6 
months and score on the Alzheimer’s Disease Cooperative Study - Clinical Global Impression of 
Change (CGIC) scale at 6 months.  
 
Additional objectives 
 
To examine the safety of methylphenidate for the treatment of clinically significant apathy in 
participants with Alzheimer’s disease. Safety will be measured using vital signs, electrolyte 
panels, adverse event reports, and electrocardiograms. Safety will also be measured by examining 
neuropsychiatric symptoms other than apathy using the Neuropsychiatric Inventory (NPI). 
 
To examine changes in other neuropsychological assessments, such as the Dementia Apathy 
Interview and Rating (DAIR) scale from baseline to 6 months.  
 
To examine cost-effectiveness by assessing quality of life and economic assessment from 
baseline to 6 months. 
 
To examine cognitive changes from baseline to 6 months using a cognitive battery that includes 
the Mini Mental State Exam (MMSE) and other scales.  
 
To understand blood-based biomarker correlates of change in apathy over time, and to identify 
possible predictors of treatment response (with the substudy “Biomarkers of Apathy and 
Treatment Response,” see Chapter 14) 
 
To assess efficacy as the change in NPI apathy and CGIC apathy from baseline to 2 months. 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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3. 
Design 
 
 
3.1. 
Overview 
 
This multi-center, parallel, randomized, double-blind, placebo-controlled Phase III, definitive trial will 
enroll 200 participants with clinically significant apathy from ten clinical centers. Primary outcome 
measures include the Neuropsychiatric Inventory Apathy subscale (NPI apathy) and the Clinical Global 
Impression of Change (CGIC). Additional outcome measures include the Dementia Apathy Interview and 
Rating (DAIR), AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), Dependence 
Scale, and Information on caregiver distress (NPI caregiver distress score). Cost-effectiveness will be 
measured using health related quality of life (HRQOL; EuroQol EQ-5D- 5L), and resource utilization 
(Resource Utilization in Dementia Lite, RUD-lite). A cognitive battery of tests will be assessed at 
baseline and at select in-person follow-up visits (every two months until 6 months) after randomization. 
Safety will be assessed by measuring vital signs, electrolytes, electrocardiograms (ECGs), and 
Neuropsychiatric Inventory (NPI). Adverse events reports will be completed as required at each follow-up 
visit. 
   
These assessments will be administered at baseline and at each in-person follow-up visit (monthly until 6 
months) after randomization.  
 
In addition, those participants who consent to participate in the blood-based biomarkers substudy to the 
main ADMET 2 study will provide a sample of blood biospecimen at baseline and 6 months after 
randomization according to this schedule: 
 
Baseline visit – miRNA, oxidative stress, inflammation (cytokines), neuronal loss, and 
lipidomics1 
 
6-month follow-up visit - oxidative stress, inflammation (cytokines), and lipidomics 
 
In addition, compliance checks will be conducted at in-person follow-up visits as well as by phone around 
days 15, 45, and 75 after randomization.  
 
3.2.  
Sample size and power 
 
Power calculations were conducted for the two primary outcomes: 1) mean difference in change from 
baseline to 6 months in the NPI apathy subscale scores; 2) odds of having a given rating or better on the 
ADCS-CGIC ratings at month 6. The power and sample size for the NPI apathy outcome were 
determined with standard two sample methods for comparing means using SAS 9.2 (Copyright © 2002-
2008 by SAS Institute Inc., Cary, NC, USA). The power and sample size for the ADCS-CGIC outcome 
were determined using the method of Whitehead (1993) for proportional odds logistic regression 
implemented by the ‘popower’ in the Hmisc package in R (2011). Both calculations assumed a type I 
error rate of 0.025 to preserve an overall type I error rate of 0.05 over both primary comparisons.   
 
The sample size calculations assume the difference in NPI apathy change scores (1.8 points) and standard 
deviation (3.2) of the change scores that was observed in the original ADMET study. The difference in 
NPI apathy is similar to the difference between mean change in moderate improvement and minimal 
improvement/no change in ADMET. The mean change in NPI apathy for those with CGIC rating of 
moderate improvement in ADMET was -5 and for those with minimal improvement or no change was -3. 
                                                     
1 MiRNA may be collected at any study visit. For those who enroll in the substudy after their baseline visit, these 
biospecimen may be collected up through the month 3 visit. 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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There were no deaths observed in the original ADMET; however, in the DIADS-2 study (Martin 2006), 
which included a similar AD population and was conducted by many of the same investigators proposed 
here, we observed 4 deaths with 131 participants (3%) that were followed for 6 months. We lost only 5% 
of the participants in the original ADMET before the final visit (none due to death) but losses may be 
higher in ADMET 2 due to the longer follow-up time. A sample size of 200 participants will ensure 
greater than 90% power to detect a difference of 1.8 points in change on the NPI apathy scale even if 15% 
of the participants are lost before the month 6 visit. We calculated the power for the ADCS-CGIC 
outcome assuming the overall proportions of ratings in each category from ADMET: 3.5% with marked 
improvement, 8.8% with moderate improvement, 29.8% with minimal improvement, 54.4% with no 
change, 3.5% with minimal worsening, 0% with moderate or marked worsening. Assuming an odds ratio 
for better ratings in methylphenidate of 2.75 (about 25% smaller than the odds ratio observed in ADMET) 
and 200 participants, the study will have 90% power to detect this odds ratio with 10% losses to follow-
up and greater than 85% power with 15% losses. 
 
For the blood-based biomarker substudy, the sample will be one of convenience, based on the availability 
of study participants in the trial. Possible effect sizes were estimated based upon the projected possible 
number of participants (see Section 14.10). 
 
3.3.  
Organization 
 
 
Operating units of ADMET 2 are the clinical and resource centers 
 
Primary decision-making bodies are the Executive and Steering Committees 
 
Data and safety monitoring will be conducted by an independent Data and Safety Monitoring 
Committee (DSMC) 
 
Additional committees are formed for special projects, as needed. These may include Training 
and certification committee, Quality assurance committee, Publications, presentations, and 
ancillary studies committee, Policy and protocol committee, and the Biomarkers executive 
committee.  
 
3.4.  
Policies 
 
Study policies include: 
 
Governance 
 
Data monitoring 
 
Publication  
 
Adverse events  
 
Ancillary studies 
 
Data sharing 
 
Conflict of interest 
 
Site replacement 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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4. 
Eligibility criteria 
 
 
Men and women, including those in minority groups, will be included with no specific age restrictions. 
No specific laboratory screenings will be required for inclusion. “Usual care” treatment with 
methylphenidate does not require laboratory monitoring. Laboratory tests for the purpose of qualifying a 
participant having Alzheimer’s disease (AD) (e.g., brain imaging, blood and urine test, etc.) will be 
obtained under usual care clinical practices prior to entry which is consistent with current clinical 
standards and guidelines. 
 
Inclusion criteria 
 
Possible or probable Alzheimer's disease (National Institute of Neurological and Communicative 
Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-
ADRDA) criteria), with Mini-Mental State Exam (MMSE) score of 10-28 inclusive 
 
Clinically significant apathy for at least four weeks for which either 
- the frequency of apathy as assessed by the Neuropsychiatric Inventory (NPI) is 'Very 
frequently', or 
- the frequency of apathy as assessed by the NPI is 'Frequently' or 'Often' AND the  
severity of apathy as assessed by the NPI is 'Moderate' or 'Marked' 
 
A medication for apathy is appropriate, in the opinion of the study physician 
 
Provision of informed consent for participation in the study by potential participant or surrogate 
(with participant assent if the potential participant is unable to provide informed consent) and 
caregiver 
 
Availability of caregiver, who spends greater than ten hours a week with the potential participant 
and supervises his/her care, to accompany the participant to study visits and to participate in the 
study 
 
Sufficient fluency, of both the potential participant and caregiver, in written and spoken English 
to participate in study visits, physical exams, and outcome assessments 
 
If female, woman must be post-menopausal for at least 2 years or have had a hysterectomy 
 
Exclusion criteria 
 
Currently meets criteria for Major Depressive Episode, by Diagnostic Statistical Manual of 
Mental Disorder - IV (TR) criteria 
 
Clinically significant agitation /aggression for which either 
- the frequency of agitation /aggression as assessed by the NPI is ‘Very frequently', or 
- the frequency of agitation /aggression as assessed by the NPI is ‘Frequently' AND the 
severity of the agitation as assessed by the NPI is ‘Moderate', or ‘Marked' 
 
Clinically significant delusions for which either 
- the frequency of delusions as assessed by the NPI is ‘Very frequently', or 
- the frequency of delusions as assessed by the NPI is ‘Frequently' AND the severity of the 
delusions as assessed by the NPI is ‘Moderate', or ‘Marked' 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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 
Clinically significant hallucinations for which either 
- the frequency of hallucinations as assessed by the NPI is ‘Very frequently', or 
- the frequency of hallucinations as assessed by the NPI is ‘Frequently' AND the severity 
of the hallucinations as assessed by the NPI is ‘Moderate', or ‘Marked' 
 
Change to AD medications within the 30 days preceding randomization, including starting, 
stopping, or dosage modifications 
 
Change in anti-depressant (except for trazodone used for sleeping difficulties as described below) 
use within the 30 days preceding randomization or a period of time equal to 5 half-lives of drug, 
whichever period of time is longer 
 
Use of trazodone > 50mg or lorazepam > 0.5mg or for indications other than sleeping difficulties 
within the 30 days preceding randomization or a period of time equal to 5 half-lives of drug, 
whichever period of time is longer. Other benzodiazepines are prohibited in the past 30 days or 
within 5 half-lives, whichever period of time is longer 
 
Failure of treatment with methylphenidate in the past for apathy after convincing evidence of an 
adequate trial as judged by study physician 
 
Currently taking any amphetamine product, an antipsychotic, bupropion, or any medication that 
would prohibit the safe concurrent use of methylphenidate, including but not limited to 
monoamine oxidase inhibitors and tricyclic antidepressants within the 30 days preceding 
randomization or a period of time equal to 5 half-lives of drug, whichever period of time is longer 
 
Need for acute psychiatric hospitalization or is suicidal in the opinion of the study physician 
 
Significant communicative impairments that would affect participation in clinical trial 
 
CNS abnormalities (e.g., cerebral aneurysm), seizures (convulsions, epilepsy), Tourette's 
syndrome or presence of motor tics, or abnormal EEGs 
 
Lack of appetite that results in significant unintentional weight loss as determined by the study 
physician in the last three months 
 
Uncontrolled hyperthyroidism 
 
Any cardiovascular or cerebrovascular abnormality deemed to be clinically significant by the 
study physician, tachycardia (heart rate ≥ 100 beats per minute), or uncontrolled hypertension 
(defined as medication non-compliance or past 3 months with a diastolic reading ≥ 105 mm Hg), 
at the time of screening 
 
Closed angle glaucoma or pheochromocytoma 
 
Women with childbearing potential  
 
Current participation in a clinical trial or study that may add significant burden or affect study 
outcomes 
 
Any condition that, in the opinion of the study physician, makes it medically inappropriate or 
risky for the potential participant to enroll in the trial, including, but not limited to, 
contraindication to treatment with methylphenidate 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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5. 
Randomization and masking 
 
The Coordinating Center (CC) will generate random treatment assignment schedules using a documented 
program in SAS. The randomization schedule will be designed to yield an expected assignment ratio of 
1:1 for methylphenidate and placebo. Assignments will be stratified by clinical center and schedules will 
employ permuted block designs, with block sizes to be determined and documented at the CC. 
Adjustment for residual or other imbalances in the baseline composition of the treatment groups, if 
needed, will be done using multiple regression techniques at the time of data analysis rather than through 
further stratification in the design. Treatment assignments will be masked to the participants and the 
personnel of the clinical centers, but not to a restricted set of personnel at the CC. The CC will also 
generate a list of randomly ordered medication identifiers which will be linked to the assignment 
schedule. Documentation of all these processes will be retained at the CC and shall be accessible only to 
authorized personnel. 
 
Treatments will be assigned using an online program accessible to the clinical centers through the data 
system.  After the entry of specified pre-randomization data, and confirmation of eligibility, each enrolled 
participant's ID will be irrevocably linked to the next unassigned treatment for that clinical center.  The 
clinical center will be directed to issue a medication kit containing the proper assigned treatment from 
among those kits available at the center. Treatment assignments will be e-mailed in real-time to the CC.  
The data system will also check for and prevent duplicate assignments (same participant randomized 
more than once). The treatment assignment tables in the data system will be encrypted to prevent 
inadvertent disclosures. 
 
The procedures related to randomization of participants at the clinical centers will be as follows: 
 
 
Eligibility and baseline data will be collected on paper forms and entered into the database at the 
clinical centers 
 
The data system will confirm eligibility and then issue the next assignment as described above; 
each assignment will also be e-mailed to the CC 
 
The data system will automatically store the date and time of assignment, the identity of the 
clinical center staff person making the assignment, the participant's ID, and the medication 
identifier to be issued 
 
Randomization materials, including a visit schedule and allowable time windows for visits, will 
be generated for the clinical center 
 
Emergency unmasking before the end of the treatment period is expected to be rare.  Clinical centers may 
request an emergency unmasking from the ADMET 2 data system. Clinical centers must contact the CC 
as soon as possible to report the emergency unmasking. 
 
Optional unmasking may occur for each participant after 6 months follow-up and all data collection is 
completed. This information will be provided to the participant and caregiver. Treatment assignment will 
not be revealed to the ADMET 2 staff at the clinical centers. 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
12
 
 
 
 
6. 
Treatment plan 
 
 
6.1.  
Treatment groups 
 
Participants will be assigned to one of the following groups: 
 
Methylphenidate, target dose of 20 mg per day, administered as two 5 mg over-encapsulated 
tablets twice a day, and psychosocial intervention 
 
Matching over encapsulated placebo and psychosocial intervention 
 
6.2.  
Treatment schedule and titration of study drug dose 
 
The target study dose will be 20 mg per day provided as two 10 mg doses administrated orally. 
Participants will start on 10 mg daily (i.e., 5 mg twice a day) for three days. Then the dose will be 
increased to 20 mg per day (i.e., 10 mg twice a day) for six months following a phone call to the 
participant and/or caregiver that is to occur at day 3. If necessary, study physicians will have the option of 
decreasing the daily dose preferably a minimum of 10 mg of study drug or placebo per day depending on 
tolerability. That is, some participants will have unacceptable side effects on 20 mg and will have to be 
reduced to a lower dose so as continue study treatment. Reductions of dose will only be allowed for 
clinically significant side effects. 
 
Unmasking for participants may occur after the 6 month visit for the purposes of clinical care. Unmasking 
before the end of the 6-month period is to occur only in emergency situations (see randomization and 
masking section 5 for more details). 
 
6.3.  
Choice of methylphenidate formulation 
 
Because the use of 5 mg allows for finer titration to the 20 mg daily intake and allows for reduction in 
dose due to possible side effects, the use of 5 mg tablets of methylphenidate is required. However, there is 
no 5 mg formulation of methylphenidate that is approved and available in both the United States and 
Canada. The drug will be purchased and distributed centrally in the nine US sites but will be purchased 
and distributed separately for the Canadian site. Therefore, two generic formulations will be used (one 
that is approved in the United States and one that is approved in Canada). This is a practical and 
pragmatic decision that will provide results that are more generalizable than using a formulation that is 
not approved in one of the countries. 
 
6.4.  
Psychosocial treatment 
 
All caregivers and the participants (if convenient) will be provided with a standardized psychosocial 
intervention modeled after the counseling strategies employed in Depression in Alzheimer’s Disease 
Study-2 (Martin 2006). The psychosocial intervention may consist of three components: a counseling 
session, the provision of education materials, and availability for crises. 
 
The counseling session, in which a trained study clinician will counsel the study caregiver and participant 
will take place at each study visit at and after the randomization visit. It will last approximately 20-30 
minutes. Each counseling session will consist of the following elements: 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
13
 
 
 
 
 
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 
 
Answers for questions regarding the educational materials 
 
The educational materials will consist of: 
 
A copy of the book The 36-Hour Day 
 
Dementia Care Guidelines for Families 
 
The caregiver also may be provided with 24-hour phone access to the study nurse or physician for 
assistance with crises that may arise after hours. 
 
6.5.  
Adherence to study treatment 
 
To ensure adherence, study medication will be administered to participants under the supervision of the 
caregivers involved in the study. Study physicians will assess the capacity of each participant to monitor 
and administer treatments and will involve caregivers as needed to ensure safe use of drug and proper 
adherence to the treatment protocol. Adherence to assigned treatment will be monitored via participant 
and/or caregiver interview at each visit and via pill counts. Participants and/or caregivers will be asked to 
return all study bottles with any unused capsules at each visit. Bottles are to be returned even if all study 
drug was used. 
 
6.6.  
Management and reporting of adverse events 
 
Management: All adverse events occurring after randomization and during the 6-month treatment period, 
regardless of adherence to study treatment, will be recorded at all contacts. A list of common side effects 
of methylphenidate will be used to monitor for adverse events. At scheduled visits, participants and their 
caregivers will be interviewed about whether the participant experienced any symptoms or side effects on 
the list since the last visit. Adverse events, other than those listed as common side effects, will still be 
recorded. If adverse events are noted, they will be rated as mild, moderate, or severe based on their 
clinical severity and frequency. Finally, participants and caregivers will be asked about visits to doctors, 
healthcare providers, and emergency departments for other than routine care. 
 
Center investigators will be responsible for monitoring the safety of participants. They will be responsible 
for appropriate medical care of participants during the study in connection with study procedures. Safety 
assessments will include physical exams, vital signs, monitoring of adverse events, and monitoring and 
maintenance of concurrent medication records. In addition, the medical monitor designated by the Chair’s 
office will provide consultation to all centers regarding medical monitoring. He/she will carry a beeper 
24-hours a day to receive protocol questions and serious or problematic adverse events that center 
investigators believe should be referred to him/her. 
 
Reporting: Supervising Institutional Review Boards (IRBs) will be notified by local investigators of 
adverse events occurring at their institution, according to their reporting requirements. Investigators also 
will notify the medical monitor and CC within one day of learning of a death or of an event that is life-
threatening, that results in hospitalization or prolongation of hospitalization, or that involves a persistent 
or significant disability or incapacity. Data collected regarding these serious adverse events will include 
the treatment provided, outcome, and presumed relationship to study drug and will be updated as new 
information becomes available; a narrative description also will be provided. CC personnel will review 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
14
 
 
 
 
the data and query the clinical centers for clarification, additional information, or supporting 
documentation as necessary. Reports and narratives will be forwarded to all investigators for submission 
to IRBs as necessary. In addition, this information will be provided to the Data and Safety Monitoring 
Committee (DSMC) as part of their safety review. 
 
Study-wide summary statistics (not broken down by treatment group) of adverse events will be available 
upon request to all centers on an annual basis for submission to their local IRB. 
 
6.7.  
Concomitant medications 
 
The use of a wide variety of medications will be allowed, because this study will attempt to represent 
usual clinical practice. Participants will remain on medications necessary to treat medical co-morbidities.  
Use of Alzheimer's disease medications will be allowed: (i) if there is no change to AD medications 
within the month preceding randomization, including, starting, stopping, or dosage modifications, (ii) if 
there are no current plans to change dosage or discontinue medication, and (iii) if the clinician believes 
that these medications are not causing or exacerbating the participant's apathy. Changes in Alzheimer's 
disease medications will be allowed only if the clinician supervising the participant's care determines the 
change to be clinically required. 
 
To make the efficacy comparison as straightforward as possible, any amphetamine product, antipsychotic, 
bupropion, or any medication that would prohibit the safe concurrent use of methylphenidate, including 
but not limited to monoamine oxidase inhibitors and tricyclic antidepressants, will not be allowed while 
participants are receiving masked study treatment. For the treatment of sleeping difficulties, trazodone up 
to 50 mg before sleep or lorazepam up to 0.5 mg before sleep may be used nightly, or as needed. Other 
benzodiazepines should not be used.  
 
If the participant experiences significant agitation (or delusions), the study drug dose can be reduced to 
one capsule twice a day (10 mg per day in the methylphenidate group). If symptoms persist after reducing 
the dose then study drug can be temporarily discontinued. If study drug is temporarily discontinued, it can 
be restarted if:  
a. The symptoms have improved, and  
b. The participant is able to stop taking any medications used to treat the symptoms (i.e., when study 
drug is restarted, the concomitant medications must meet baseline eligibility criteria).  
If the participant has been prescribed a selective serotonin reuptake inhibitor (SSRI) or other 
medication to treat the symptoms, the study drug may only be restarted once the participant has 
stopped taking the SSRI/other medication for at least 30 days or 5 half-lives, whichever is longer. 
 
If the participant requires initiation or change in an existing antidepressant (i.e. SSRIs) for treatment of 
depression any time during the study, study drug should be temporarily stopped until the participant is on 
a stable dose of the SSRI for at least 30 days or 5 half-lives, whichever is longer.  
 
Clinic staff should continue to conduct all participant visits and contacts per protocol regardless of 
whether the participant is taking study drug. 
 
6.8.  
Assessment of suicidality and need for acute hospitalization 
 
The assessment of suicidality or need for acute hospitalization will be based on psychiatric assessment at 
study screening. Specifically, suicidality will be assessed by participant and caregiver interview and by 
mental status examination of the participant. The examiner will assess for severe hopelessness, passive 
death wish, suicidal statements, suicidal plan, or behavioral indicators of risk for self-harm. Need for 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
15
 
 
 
 
acute hospitalization will be similarly assessed by a study physician. Acute hospitalization is typically 
indicated if there is imminent risk of harm. 
7. 
Baseline visit 
 
 
7.1.  
Overview 
 
Participants will be typical outpatients with Alzheimer’s disease, recruited from clinical settings at the 
study centers. Residents of nursing homes and assisted living facilities are also eligible. The use of 
diverse centers will promote representation from ethnic minority groups. The allowable range of cognitive 
impairment is as broad as possible, sufficient in the high end to establish dementia diagnosis, with 
sufficient residual on the low end to allow for the quantification of apathy symptoms. 
 
7.2.  
Overview of consent issues 
 
The participant and caregiver (if required by local IRB) are both to provide consent for this study. Issues 
of consent are important in this population of participants, as their capacity to give informed consent may 
be compromised. Consent is to be obtained from participants and their authorized legal representatives 
using procedures established by the individual centers and their overseeing Institutional Review Boards in 
accordance with local law. In all cases, prospective participants with dementia will first be assessed for 
their ability to provide informed consent. Capacity to give consent will be assessed in clinical interviews 
of participants by clinicians experienced in clinical dementia research. If a potential participant is found 
not capable of fully providing consent for participation, then his or her surrogate will provide consent and 
the participant will be asked to provide assent according to the Alzheimer’s Association3 or local IRB 
guidelines. Potential participants who are found to be able to provide informed consent will be asked to 
do so and their surrogates will co-sign the consent form as a witness. More details regarding the consent 
process can be found in the section on the protection of human subjects. 
 
7.3.  
Review of medical history 
 
A certified study physician must see the participant before randomization. The study physicians are 
responsible for fully assessing whether the participant has any of the conditions listed as contraindications 
for the use of methylphenidate, such as closed angle glaucoma, hyperthyroidism, or serious 
cardiovascular or heart rhythm problems (see exclusion criteria in section 4 for the complete list), through 
a thorough participant and family medical history or any other means that would be part of standard 
clinical care before prescribing methylphenidate to a participant. The presence of any contraindicated 
condition or medication, which are itemized in the baseline eligibility as well as medical history forms, 
constitutes an exclusion criterion for ADMET 2. 
 
7.4.  
Baseline visit procedures 
 
The baseline visit may take place across more than one day, but must be completed within the three 
weeks preceding randomization. The clinical staff should perform and review results of the 
electrocardiogram (ECG) within the three weeks preceding randomization.  
 
At the baseline visit, study staff will: 
 
Obtain the name and address of the participant's personal physician, if any 
 
Record participant and caregiver demographics 
 
Obtain a medical history and record current medications 
 
Administer research diagnostic criteria for apathy 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
16
 
 
 
 
 
Collect assessments: 
- Clinical Global Impression Worksheet (CGI) 
- Neuropsychiatric Inventory (NPI) 
- Dementia Apathy Interview and Rating (DAIR) 
- Dependence Scale 
- AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL)  
- Health related quality of life (HRQOL; EuroQol EQ-5D- 5L) 
- Resource Utilization in Dementia Lite (RUD-lite) 
 
Perform cognitive tests: 
- Mini Mental State Exam (MMSE) 
- Hopkins Verbal Learning Test - Revised (HVLT-R) 
- Digit Span 
- Trail Making Test (A and B) 
- Action Verbal Fluency Test from the PDCRS 
- Category Fluency Task-Animal Naming (from the VCIHS) 
- Short Boston Naming Test 
 
Perform safety measures: 
- Vital signs 
- Electrolyte panel 
- ECG 
- Gather baseline symptom information 
 
Obtain blood samples for biomarker analysis of miRNA, oxidative stress, inflammation 
cytokines), neuronal loss, and lipidomics (for those who consent to the blood-based 
biomarker substudy, see Chapter 14) 
 
Obtain the randomized treatment assignment 
 
Provide the psychosocial intervention 
 
Dispense study medication and review instructions for medication use 
 
Review visit schedule, compliance monitoring, and adverse event reporting 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
17
 
 
 
 
8. 
Follow-up visits and telephone contacts 
 
 
8.1.  
Overview of follow-up visits and telephone contacts 
 
Follow-up will include both scheduled and unscheduled visits and contacts. Scheduled follow-up 
includes: 
 
Scheduled in-person visits (monthly after randomization) 
 
Telephone contacts for data collection (days 15, 45, and 75 after randomization) 
 
Telephone contact for dose adjustments (day 3 and as needed) 
 
Target dates for follow-up visits are calculated from the date of randomization. 
 
8.2.  
Scheduled in-person visits 
 
At all scheduled in-person visits, study staff will: 
 
Review study procedures to verify ongoing consent 
 
Review interval medical history 
 
Review and record current medications 
 
Collect assessments: 
- Clinical Global Impression Worksheet (CGI) 
- Neuropsychiatric Inventory (NPI) 
- Dementia Apathy Interview and Rating (DAIR) 
 
Perform safety measures: 
- Vital signs 
- Electrolyte panel 
- ECG 
- Gather baseline symptom information 
 
Provide the psychosocial intervention 
 
Receive and record the amount of unused study drug 
 
Dispense a new supply of study drug (except month 6) 
 
Review visit schedule and compliance monitoring 
 
Refer the participant to a study physician or a primary care physician or specialist if the 
participant exhibits a notable change in condition or is medically unstable 
 
At months 2, 4, and 6, study staff will also  
 
Collect assessments: 
- Dependence Scale 
- AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) 
 
Perform cognitive tests: 
- Mini Mental State Exam (MMSE) 
- Hopkins Verbal Learning Test - Revised (HVLT-R) 
- Digit Span 
- Trail Making Test (A and B) 
- Action Verbal Fluency Test from the PDCRS 
– 
Category Fluency Task-Animal Naming 
– 
Short Boston Naming Test 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
18
 
 
 
 
 
At months 3 and 6, study staff will also 
 
Collect assessments: 
- Health related quality of life (EuroQol EQ-5D- 5L) 
- Resource Utilization in Dementia Lite (RUD-lite) 
 
If not obtained at baseline, at month 1, 2, or 3, study staff may also obtain blood samples for biomarker 
analysis of miRNA, oxidative stress, inflammation cytokines), neuronal loss, and lipidomics for those 
who consent to the blood-based biomarker substudy, see Chapter 14). 
 
At month 6, study staff will also obtain blood samples for biomarker analysis of oxidative stress, 
inflammation cytokines), and lipidomics (for those who consented to this substudy, see Chapter 14). 
 
8.3.  
Telephone contacts for data collection 
 
To ensure regular contact with study staff during the study, there will be telephone contacts with 
participants and their caregivers at day 15, 45, and 75 after randomization. The purpose of these contacts 
is to: 
 
Collect interim medical history 
 
Enhance compliance and retention 
 
Review visit schedule 
 
Provide medical monitoring 
 
Collect adverse events 
 
Medical information obtained from participants or caregivers is to be recorded for that contact. 
 
8.4.  
Telephone contacts for dose adjustments 
 
To aid participants and caregivers, a telephone contact should occur on day 3 or immediately before the 
day 4 dose adjustment, and at anytime when a dose adjustment is required for clinical purposes. The 
purpose is to remind the participant and caregiver to make the dose adjustment and to provide medical 
monitoring. No information will be captured for this contact unless there is a serious adverse event or 
treatment termination. 
 
8.5.  
Unscheduled follow-up visits and contacts 
 
In addition to the visits outlined in the above schedule, participants may also be asked to appear for other 
assessments as needed. Unscheduled clinic visits may occur to evaluate a new or altered medical 
condition, to assess side effects, to assist with compliance in complex cases, or to provide counseling and 
behavioral interventions as needed. 
 
Participants may contact the clinical center personnel between scheduled contacts regarding medical or 
cognitive problems that they are experiencing. Information will be recorded on the nature of the 
complaints and on any recommendation or referral made by clinical center personnel. 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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8.6. 
Data collection by visit 
 
 
BL 
T1 
F1 
T2 
F2 
T3 
F3 
F4 
F5 
F6 
Months from BL 
0 
0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
Procedures 
 
 
 
 
 
 
 
 
 
 
Consent 
 
 
 
 
 
 
 
 
 
 
History, or interim history 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion 
 
 
 
 
 
 
 
 
 
 
Psychosocial intervention 
 
 
 
 
 
 
 
 
 
 
Dispensing of study drug 
 
 
 
 
 
 
 
 
 
 
Review visit schedule 
 
 
 
 
 
 
 
 
 
 
Review of compliance 
 
 
 
 
 
 
 
 
 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
NPI 
 
 
 
 
 
 
 
 
 
 
CGIC 
 
 
 
 
 
 
 
 
 
 
DAIR 
 
 
 
 
 
 
 
 
 
 
ADL 
 
 
 
 
 
 
 
 
 
 
Dependence Scale 
 
 
 
 
 
 
 
 
 
 
Cognitive battery 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
RUD-lite 
 
 
 
 
 
 
 
 
 
 
Diagnostic Criteria for Apathy 
 
 
 
 
 
 
 
 
 
 
 
Safety measurements 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
Electrolyte panel 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
Review ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers blood collection* 
 
 
 
 
 
 
 
 
 
 
 
*For those participants consenting to the biomarkers substudy only: MicroRNA, oxidative stress, inflammation (cytokines), 
neuronal loss, and lipidomics are collected at BL (or F1, F2, or F3 if baseline visit already occurred); oxidative stress, 
inflammation, and lipidomics are collected also at F6. However, the mRNA portion may be collected at any in-person follow-up 
visit. 
 
BL = Baseline visit 
F=Scheduled follow-up visits 
T=Scheduled telephone contact 
NPI = Neuropsychiatric Inventory 
CGIC = Clinical Global Impression of Change 
DAIR= Dementia Apathy Interview and Rating 
ADL=Activities of Daily Living 
EQ-5D-5L= Euro Quality of Life 
RUD-lite= Resource Utilization in Dementia-Lite  
ECG = Electrocardiogram 
 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
20
 
 
 
 
9. 
Outcomes assessments 
 
 
The following instruments and measures will be used in ADMET 2. 
 
9.1.  
Neuropsychology, neuropsychiatry, and other assessments 
 
 
AD Cooperative Study - Clinical Global Impression of Change (CGIC) (Schneider 1997): The 
CGIC is a systematic method, developed for the Alzheimer’s disease (AD) setting to assess 
clinically significant change in a clinical trial as viewed by an independent, skilled, and 
experienced clinician. This will be applied to collect information on the level of apathy. Unlike a 
targeted symptom scale, this method takes into account the overall level of apathy with emphasis 
on clinically significant change since the pre-treatment baseline. A trained clinician, not involved 
in collecting other assessments or procedures, will complete the CGIC using a 7-point Likert 
scale to rate each participant along a continuum from "very much worse" (7) to "very much 
improved" (1) with a rating of 4 being "no change." Ratings will be based on an interview with 
the caregiver and an examination of the participant, without consulting other objective measures, 
such as cognitive test results. The CGIC requires the assessor to consider a number of aspects of 
apathy, such as level of initiative, level of interest, and emotional engagement. 
 
 
Neuropsychiatric Inventory (NPI) (Cummings 1997): The NPI is the most widely-used measure 
of NPS in dementia clinical trials. This inventory has a strong ability to distinguish medication 
groups from placebo groups. The NPI assesses type and severity of behavioral disturbances in 
dementia. The inventory evaluates 12 domains of neuropsychiatric symptoms (NPS): apathy, 
agitation, delusions, hallucinations, depression, euphoria, aberrant motor behavior, irritability, 
disinhibition, anxiety, sleeping, and eating. Frequency (1 = occasionally, less than once/week; 2 = 
often, about once per week; 3 = frequently, more than once a week; 4 = very frequently, once or 
more/day or continuously) and severity (1 = mild, 2 = moderate, 3 = severe) scales in each 
domain are scored based on responses from an informed caregiver involved in the participant's 
life. The NPI also includes a 5-point rating used to quantify caregiver distress with the 
participant's NPS symptoms. To obtain an NPI score for each domain, the severity score and the 
frequency score are multiplied, and the caregiver distress ratings of each domain are added up. In 
ADMET 2, the apathy domain score will be used as an entry criterion to define a level of apathy 
of moderate or greater severity. 
 
 
Dementia Apathy Interview and Rating (DAIR) (Strauss 2002): The DAIR is a 16-item, informant 
rated scale for the assessment of apathy in persons with mild to moderate AD. The DAIR has 
ability to discriminate apathy from lack of interest due to inability or longstanding, premorbid 
personality traits. The DAIR evaluates the change in motivation, engagement, and emotional 
response since disease onset. The minimum score is 0 and the maximum score is 48. 
 
 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
21
 
 
 
 
 
Dependence Scale (Stern 1994): This is a structured scale of the degree of dependence or 
assistance needed by a participant that was developed for longitudinal studies of AD and has been 
used as a predictor of nursing home placement. The interview is conducted a certified clinician 
with the caregiver. The minimum score is 0 and the maximum score is 15. Higher scores indicate 
increased levels of dependence. 
 
 
AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) (Galasko 1997): This 
measure is an ADL inventory developed by the ADCS to assess functional performance in 
patients with AD. In a structured interview format, informants are queried as to whether subjects 
attempted each of 24 items in the inventory during the prior 4 weeks and their level of 
performance. The scale discriminates well the stages of severity of AD, from very mild to 
severely impaired. 
 
 
EuroQol EQ-5D- 5L (Johnson 1998): This health related quality of life assessment will be 
collected at baseline, 3 months and endpoint. The EQ-5D-5L is a generic measure of health 
related quality of life that can be calibrated on a 0 to 1 scale and thus measures utility, allowing 
for the calculation of Quality Adjusted Life Years (QALYs). The standard EQ-5D measures 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression graded 
from level 1 (i.e., no problems) to level 5 (i.e., extreme problems). Use of the 5-levels (EQ-5D-
5L) rather than the standard 3 level EQ-5D (EQ-5D-3L) has led to less ceiling effect, greater 
discriminative ability, and potentially more power to detect differences between groups compared 
with EQ-5D-3L. 
 
 
Resource Utilization in Dementia-Lite (Wimo 2013): This is a validated instrument. The costing 
questionnaire will be generated by the research team, mapping from the resource utilization 
questionnaire to the costs of those services at fair market value today. The resource utilization 
questionnaire includes accommodation, informal care, community care, and hospitalizations, 
enabling estimation of both direct and indirect medical costs. 
 
 
 
9.2.  
Cognitive assessments 
 
The cognitive battery was selected to target tests that measure specific cognitive domains likely to be 
impacted by methylphenidate treatment. We have also selected measures of memory and naming/lexical 
retrieval, domains usually impaired in AD. In addition, it is our goal to create a limited efficient battery 
for practical considerations and to minimize the stress on participants (the battery was designed not to 
take more than 30 minutes to administer). The battery includes: 
 
 
Mini-Mental State Exam (MMSE) (Folstein 1975): This is a well-known cognitive screening test 
for the detection of dementia and estimation of its severity. The particular domains most often 
affected in AD (orientation, memory) are included in this instrument. Other items include those 
assessing working memory, naming, following verbal and written commands, spontaneously 
writing a sentence, and copying two overlapping pentagons. The MMSE has been used as a 
measure of toxicity in a number of studies evaluating treatments for NPS (Storga 1996). A second 
factor in choosing the MMSE as a safety measure rather than an efficacy measure was our 
intention to use separate tests to evaluate safety and efficacy in order to avoid bias and 
contamination by raters. Therefore, the MMSE will be used as a safety measure in this study. 
 
 
Hopkins Verbal Learning Test – Revised (HVLT-R) (Brandt 2001): The HVLT-R is used to 
measure verbal learning, recognition, and delayed recall. In this test, a list of twelve words—four 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
22
 
 
 
 
from each of three semantic categories—is read to participants. Three learning trials are followed, 
after 20 to 25 minutes, by a delayed recall trial and then a yes/no recognition trial. The minimum 
score is 0 and the maximum score is 12. Higher scores indicate better performance. 
 
 
Digit Span: The Wechsler Adult Intelligence Scale – Revised Digit Span subtest (Wheeler 1981) 
is used to assess auditory attention and working memory. Both forward and backward span is 
assessed. Both tests consist of six number sequences that the psychometrist reads aloud one at a 
time. After each sequence is read, the participant must repeat the digits back in the same 
(forward) or reverse (backward) order.  
 
 
Trail Making Test (A and B) (Stuss 2001): This timed test is used to measure attention, executive 
function, and visuo-motor tracking. To complete Trails Part A, the participant must draw lines to 
connect consecutively numbered circles. To complete Trails Part B, participants must connect 
consecutively numbered and lettered circles by alternating between the two sequences. The trail 
making test is discontinued after 5 minutes for both parts A and B. Shorter duration to complete 
the test and fewer number of errors indicate higher cognitive functioning in the domains tested. 
 
 
Action Verbal Fluency Test from the PDCRS  (Piatt 1999): This test measures executive function, 
working memory, and information processing speed. The Action Verbal Fluency Test from the 
Parkinson’s Disease–Cognitive Rating Scale (PDCRS) uses action verbal fluencies to 
differentiate between cognitive groups. The participant is asked to name verbs in 60 seconds 
without repetition or use of alternate form of verbs or with different endings.  
 
 
Category Fluency Task-Animal Naming (from the Vascular Cognitive Impairment Harmonization 
Standards) (Isaacs 1972): This is a test of executive function, working memory, set shifting, and 
executive control. It is one of the sensitive measures to distinguish normal aging from dementia. 
It is easy to use, has multiple normative forms, and can be used in different cross cultural settings. 
The participant is requested to generate words in 60 seconds. 
    
 
Short Boston Naming Test (Kaplan 1983; Franzen 1995): A modification of the Boston Naming 
Test measures expressive language. Participants are asked to name 15 line drawings of varying 
difficulty. The minimum score is 0 and the maximum score is 15. Higher scores indicate better 
control of expressive language. 
 
9.3.  
Safety measurements 
 
 
Vital signs, including blood pressure, pulse, respiratory rate, and weight, will be evaluated at 
every visit and will be measured using standard clinical procedures. Clinically significant changes 
will be reported as adverse events. 
 
 
Electrolyte panel will be assessed at baseline and monthly post-randomization. The panel will 
include sodium, potassium, chloride, bicarbonate, glucose, urea nitrogen, and creatinine levels. 
 
 
Adverse events including serious adverse events will be defined using standard approaches.  The 
occurrence of adverse events will be noted by the clinical center teams and recorded in the study 
documents for analytic purposes. 
 
 
Electrocardiogram (ECG): One of the potential adverse events of methylphenidate is an increase 
in heart rate. This increase could trigger previously undetected conduction problems.  Therefore, 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
23
 
 
 
 
we will evaluate ECGs at baseline to allow the investigator to evaluate the clinical significance of 
potential findings and decide on the inclusion or exclusion of the participant in the study. ECG 
assessments will also be conducted monthly to evaluate the potential effects of methylphenidate 
on heart conduction. If clinical manifestations of a cardiac condition are detected through the 
study, appropriate action will be taken at the investigator's discretion. 
    
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
24
 
 
 
 
10. 
Analysis 
 
 
10.1.  Analysis overview 
 
All data analyses will be conducted under the oversight of the biostatistician at the Coordinating Center 
(CC) at Johns Hopkins. All primary analyses will be based on the "intention to treat" principle. Every 
effort will be made to collect data at the protocol-defined measurement time points, even for participants 
who have discontinued the study for administrative reasons or due to adverse events. We will include all 
participants randomized in all analyses whenever possible. When data are not available, we will consider 
multiple imputation methods; however, in all such cases, these results will be contrasted to those 
employing participants with complete data. We will also compare participants who are lost to follow-up 
with those who complete the study on baseline characteristics and treatment assignment to assess 
characteristics of those who do not complete the study. Unless otherwise specified, tests are two-sided, 
with significance defined at the p = 0.05 level. 
 
Initial analyses will be descriptive in nature, using means, standard deviations, and proportions to 
describe baseline characteristics of the sample for all participants combined, and by intervention group. 
Distributions of continuous variables will be examined for symmetry, and transformations will be 
considered for seriously skewed variables. For continuous variables, t-tests will be used to compare the 
intervention groups on demographic and other baseline characteristics; the purpose is to assess 
comparability among the randomly assigned groups. For dichotomous or other categorical variables, chi-
square tests will be used to compare intervention groups, and enrolled/excluded groups. Non-parametric 
methods of comparison will be used for non-normally distributed variables (e.g., rank tests) or data will 
be transformed to achieve distributions closer to normal. Pearson correlation coefficients (or Spearman 
rank correlation) will be calculated to assess the strength of the associations among the various outcome 
measures, and to examine associations of other covariates with outcome measures; such potential 
confounding variables will be considered for inclusion in secondary analyses involving regression 
models. Further analyses will utilize general linear modeling approaches to adjust for covariates 
(especially any on which groups differ at baseline) for continuous variables, and logistic regression 
analysis for dichotomous variables controlling for within participant dependence. Comparisons also will 
be made, among treatment groups, of frequency and severity of adverse events, using ANOVA, logistic 
regression and Chi-square methods. Assuming that these events will be relatively rare, complex analyses 
will not be appropriate.  
 
For the blood-based biomarker substudy, expoloratory analysis will investigate if there is an association 
between any biomarker and either level of apathy or level of response to methylphenidate. 
 
10.2.  Analysis for specific aims 
 
Specific Aim 1 hypothesis: Methylphenidate will be superior to placebo for the treatment of clinically 
significant apathy. 
 
Primary Outcomes: Outcome measure 1: Difference in change from baseline to 6 months in the NPI 
apathy subscale scores as administered by certified personnel to the study caregiver at baseline and each 
monthly in-person visit. 
  
 
Analysis: A crude comparison of the difference in mean change scores from baseline to month 6 will be 
conducted using a t-test. We will also conduct longitudinal analyses of NPI apathy scores to compare 
treatment groups over time using a saturated means model (including indicators for each visit and each 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
25
 
 
 
 
visit-by-treatment interaction) adjusting for randomization stratification (clinic) by creating a linear mixed 
effects model with random intercept for each participant to account for multiple measurements over time. 
All available visit data for each participant will be incorporated into the model according to assigned 
treatment group. The primary comparison is difference in mean change from baseline to month 6. A 
transformation of the outcome will be used, if needed, to meet model assumptions. We will conduct 
planned subgroup analyses to see if treatment effects differ for 1.) The United States verses Canadian 
clinical centers; 2.) those meeting proposed diagnostic criteria for apathy at baseline verses those who do 
not meet criteria; 3.) apathy severity at baseline. Planned sensitivity analyses include comparing rate of 
change in NPI apathy scores over 6 months using target and actual visit times, using a subset of adherent 
participants in the original model, and comparing proportion of participants with greater than 30% 
reduction in NPI apathy scores at 6 months. As required by NIH policy, we will conduct valid subgroup 
analyses of the of the primary outcomes by gender and race/ethnicity subgroups to determine if there is 
possible subgroup differences (i.e., treatment interactions) in treatment effects.  
 
Outcome measure 2: Ratio of the odds of being at or better than a given category on the ADCS-CGIC at 
month 6 as evaluated by a study clinician who records his/her clinical impression of change from baseline 
on a seven-item scale at each in-person follow-up visit. 
 
Analysis: Proportional odds logistic regression will be used to compare the ADCS-CGIC ratings of 
change (ranging from “marked worsening” to “marked improvement” on a seven point scale) at month 6 
between the treatment groups.  
 
The categorical outcome on the ADCS-CGIC of each participant at month 6, which compares each 
participant's overall apathy outcome at endpoint to that at the baseline visit on a seven point scale 
(1=marked improvement, 2=moderate improvement, 3=minimal improvement, 4=no change, 5=minimal 
worsening, 6=moderate worsening and 7= marked worsening) will be compared by assigned 
randomization group. It is hypothesized that the proportion of participants with better scores on CGIC 
scale is higher for those assigned to methylphenidate compared with placebo. To capitalize on the ordered 
categories, the hypothesis will be evaluated with the proportional odds method. This method assumes that 
the odds ratios Ry are constant across the y categories, i.e. Ry =R. Although this assumption may not 
necessarily be exactly correct, this method has the correct type I error under the null hypothesis H0 of no 
treatment effect because, under H0, the proportional odds assumption is satisfied exactly with an odds 
ratio of 1 between treatment groups across all outcome categories. Moreover, this method is known to be 
considerably more powerful than unstructured methods for detecting ordered alternative hypotheses to 
H0, such as our research hypothesis, even when these alternatives do not exactly satisfy the proportional 
odds assumption. If the data do not meet the proportional odds assumption, a Wilcoxon rank-sum will be 
used to compare the CGIC ratings. Planned sensitivity analyses include imputation of missing 6 months 
CGIC outcomes and comparing the proportion of participants with marked or moderate improvement. We 
will perform the same subgroup analyses described in the previous section. 
 
Secondary Outcomes:  
 
 
Outcome measure 1: Difference in change from baseline to 2 months in the NPI apathy subscale 
scores as administered by certified personnel to the study caregiver at baseline and each monthly 
in-person visit. 
 
 
Outcome measure 2: Ratio of the odds of being at or better than a given category on the ADCS-
CGIC at month 2 as evaluated by a study clinician who records his/her clinical impression of 
change from baseline on a seven-item scale at each in-person follow-up visit. 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
26
 
 
 
 
 
These secondary outcomes will be analyzed as described above for the primary outcome. 
 
Specific Aim 2 hypothesis: Methylphenidate will be well tolerated. 
 
Safety Outcomes: Adverse events will be collected at each in-person visit using systematic, close-ended 
questions for known or expected side effects of methylphenidate and by open-ended questions for 
unexpected side effects, abnormal results of electrolyte or electrocardiogram results. Due to the possible 
association of anorexia with methylphenidate treatment, a weight loss of 7% or more from baseline at any 
time during the six months will be considered an adverse event. [The NPI will be measured at each in-
person visit and will be used to measure the severity of agitation and sleep difficulties; if there is evidence 
that there is a difference in effect of treatment on the agitation or sleep difficulties scores by dementia 
severity (i.e., treatment by baseline MMSE score interaction), we will report these adverse events by 
dementia severity.] Serious adverse events, including deaths, will be reported to the CC, study 
investigators and IRBs, regardless of presumed association with study treatment. The proportion of 
participants experiencing adverse events and serious adverse events will be compared between treatment 
groups using logistic regression or Fisher’s exact test, controlling for baseline imbalances if necessary. As 
required by NIH policy, we will conduct valid subgroup analyses of the of the adverse event outcomes by 
gender and race/ethnicity subgroups to determine if there are possible subgroup differences (i.e., 
treatment interactions) in treatment effects. 
 
Specific Aim 3 hypothesis: Methylphenidate will be superior to placebo with respect to several cognitive, 
functional and pharmacoeconomic outcomes. 
 
Secondary Outcomes: DAIR will be measured monthly at in-person visits. ADCS-ADL, Dependence 
Scale, caregiver distress, and caregiver time and the cognitive battery will be measured at baseline and 
months 2, 4 and 6. Change in the DAIR, ADCS-ADL, Dependence Scale, and cognitive sphere scores 
from baseline to month 6 will be calculated using a mixed effects model as described above. 
 
Pharmacoeconomic Analysis: EQ-5D-5L and RUD-lite will be assessed at baseline and months 3 and 6. 
Costs (direct, indirect and caregiver) will be summed in each treatment arm and compared using 
nonparametric tests as cost data are typically skewed. We will conduct a cost-utility analysis by 
comparing summed costs in each treatment arm with a summation of utilities derived from the EQ-5D-5L 
assessment to generate a cost per QALY analysis. This will provide an important assessment of the cost-
effectiveness of the intervention and we anticipate that treating with methylphenidate versus placebo will 
be economically attractive (i.e., potentially cost-saving if improved apathy is associated with lower 
overall costs and superior levels of functioning and quality-of-life). 
 
For the blood-based biomarkers substudy, data will be analyzed using both nonparametric and parametric 
statistics with correction for multiple comparisons. As a conservative approach, no assumptions will be 
made about the distribution of the data and a Wilcoxon rank-sum test will be used to compare MiRNA, 
oxidative stress, cytokines, neuronal loss, and lipidomics between responders and non-responders. P-
values less than 0.05 after adjustment for multiple comparisons will be considered significant. Analyses 
will also be performed on measures of MiRNA, oxidative stress, cytokines, neuronal loss, and lipidomics 
among all participants for an association with apathy. As a conservative approach, no assumptions will be 
made about the distribution of the data, a Spearman rank correlation will be used and the resulting 
significance adjusted for multiple comparisons. Subsequently, parametric testing will be performed where 
appropriate. 
 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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10.3.  Additional considerations 
 
Outcome Attrition: For study participants with any missing outcomes, multiple imputation (MI) will be 
considered, and analyses will follow the plans described above and the combination rules for MI. 
Multiple imputation has been recognized as superior to alternatives for addressing attrition in randomized 
trials because it combines (I) bias reduction, through its prediction of missing values; (ii) relatively low 
model influence, through the only imputed values; and (iii) accurate expression of uncertainty , through 
the multiplicity of imputations. To investigate sensitivity to missing values, study participants with and 
without missing values will be compared by background covariates, and any observed differences will be 
adjusted for in the analyses. 
 
Treatment non-adherence: Every effort will be made to minimize non-adherence in the trial. With non-
adherence, intention-to-treat analysis is unbiased for the effect of randomization, but is not unbiased for 
the effect of taking the treatment. In addition to the primary analyses, the effect of treatment may be 
evaluated with an "as treated" analysis, which compares study participants by the received treatment. This 
is not appropriate if participants who take treatment have different unmeasured prognostic factors 
independent of treatment, after adjusting prognostic factors. 
 
 


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11. 
Data monitoring 
 
 
The Data and Safety Monitoring Committee (DSMC) will act in an advisory capacity to the Steering 
Committee and the National Institute on Aging (NIA) to monitor participant safety and evaluate the 
efficacy of methylphenidate. The DSMC will have at least 3 and no more than 5 members who have a 
background in geriatrics and psychopharmacological research related to Alzheimer’s disease, including at 
least one clinician and at least one biostatistician. The Executive Committee, with approval of the NIA, 
will select the members. 
 
Monitoring reports of the accumulating data presented to the DSMC by the Coordinating Center (CC) 
will include treatment group comparisons of baseline characteristics, measures of apathy and cognition, 
and adverse events as well as clinic performance. DSMC members will not be masked to treatment 
assignment. The committee may recommend changes to the protocol for performance or safety concerns 
or early termination of the trial if they observe convincing evidence of a treatment difference in outcomes 
or safety issues. The DSMC will report to the Steering Committee chair, who will communicate with the 
rest of the team for reporting to local Institutional Review Boards. The DSMC will function as an 
independent entity and will be supported financially by the budget of the CC. The CC will develop a draft 
DSMC charter and the DSMC will refine its policies and procedures in accordance with federal 
regulations. 
 
The Coordinating Center will also track the collection, shipment, and receipt of blood-based biomarker 
samples collected in the study. See Chapter 14 for more information. 
 
 


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12. 
Quality assurance and performance monitoring 
 
 
12.1.  Overview  
 
Quality assurance strategies for ADMET 2 include design strategies and monitoring activities.  Design 
strategies include use of randomization to assign participants to treatment groups, masking data collectors 
to treatment assignment to the extent possible, requirement of certification of staff and centers, and formal 
training of staff in study procedures. Activities to monitor quality include performance monitoring, visits 
to clinical centers, and error detection procedures. 
 
12.2.  Certification of centers 
 
Study investigators will be required to complete a clinical center certification form that provides detailed 
information with regard to the space, facilities, and personnel at the center. One purpose of the form is to 
serve as a checklist for staff of the resources that need to be in place when participant activities begin.  
Additional items requested will be a copy of the Institutional Review Board (IRB) notice of approval and 
copies of the stamped consent statements to be used at the center. The information provided will be 
reviewed by CC staff prior to certification of a clinical center for data collection. 
 
12.3.  Training of staff 
 
Study personnel will train the physicians, coordinators, nurses, assessment raters, and data system 
operators in the standardized and uniform use of all assessment instruments and/or procedures prior to the 
randomization of participants in the trial. Training methods will include didactic instruction and clinical 
demonstrations. Clinicians who administer the psychosocial intervention will be trained in its application 
and will be provided with training materials. This training will occur at the start of the study and will be 
reviewed periodically. As appropriate, standardized methods for performing study procedures will be 
outlined in the handbook. 
 
12.4.  Certification of staff 
 
The purpose of the staff certification program is threefold. It identifies to the CC, the study group, and to 
the staff who will collect and/or record certain items of data for ADMET 2 and who will make decisions 
relating to eligibility. Second, it makes the data collector aware that he/she is a part of ADMET 2 and has 
a responsible and identifiable role in the trial. Third, it helps to document a minimum level of competency 
to perform the functions of the staff person's role. 
 
Personnel to be certified for ADMET 2 include study physicians/clinicians, study coordinators, cognitive 
assessment raters, psychosocial intervention administrators, and data system operators. Staff will be 
reminded of their duties and responsibilities to the participants, each other, and the public in adhering to 
high ethical standards in their interactions with participants and each other, in protecting the privacy of 
trial participants and the confidentiality of their records, in collecting accurate and reliable data, and in 
adhering to principles for the analysis and reporting of the data. They will be reminded of their duty to 
make known to proper authorities any suspicious or wrongful actions in relation to these processes.  Each 
member of the research group will be asked to sign a statement indicating a knowledge and understanding 
of the above and to voluntarily disclose any potential conflicts of interest. The next best set of assurances 
lies in the use of design strategies that protect the results from treatment-related biases.  Strategies 
proposed for this trial include random assignment to active treatment or placebo and masked data 


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collection and outcome assessment. Beyond these strategies, assurances depend on the documents, 
methods, and procedures used for data collection and monitoring. 
 
12.5.  Performance monitoring 
 
Performance monitoring will begin with the initiation of participant screening and will continue 
throughout the duration of the trial. Centers will be monitored on a regular basis regarding the following: 
 
Rate of enrollment 
 
Protocol deviations 
 
Missed visits 
 
Losses to follow-up 
 
Completeness of data 
 
Percentage of data items requiring edit queries 
 
Percentage of discrepancies found in audited data items 
 
Timing of visits 
 
Summaries of the above measures will be provided to the centers and to the DSMC on a regular basis.  
Review of performance data will be an agenda item for the annual investigators meetings. 
 
12.6.  Site visiting 
 
Site visits will be made to each of the clinical centers early in the course of recruitment and at other points 
in time as needed or desired for quality assurance purposes. The site visitors will review consent forms for 
enrolled participants and caregivers, study documents, IRB approvals, staffing, adverse event reports, 
protocol issues, forms management, data management, and study drug accounting records. 
 
12.7.  Error detection 
 
The study will employ double data entry and range checks to reduce the occurrence of errors. In addition, 
some logic checks will be done at the CC, and these checks may be updated throughout the trial to 
address new data problems as they are discovered. Edit queries will be made to the clinical centers on a 
regular basis regarding inconsistencies. Periodically, additional batch edits related to consistency of data 
across forms and over time will be generated. 
 
Periodic audits of subsets of the database will be conducted, both through visits to the centers and through 
a remote auditing procedure. At on-site visits, participant data will be chosen for verification from source 
documentation.  For the remote auditing procedure, the CC will periodically review participant form sets. 
 
 


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13. 
Protection of human subjects 
 
 
 
13.1.  Human subjects 
 
Participants will be adults, who meet clinical and research criteria for dementia of the Alzheimer's type, 
and their caregivers. There will be no restrictions to participation based on gender, race, ethnicity, or age.  
We expect to enroll participants who are representative of the ethnic and racial diversity of the geographic 
and populations of the participating institutions. Eligibility criteria are intended to be as inclusive as 
possible in order to obtain a clinical sample typical of the participants likely to receive study treatments in 
the usual clinical situation. 
 
13.2.  Monitoring of Institutional Review Board (IRB) approvals 
 
One of the requirements for certification of a center to begin participant activities will be submission to 
the CC of the center’s notice of IRB approval and a copy of each stamped consent form used at the center.  
These materials will be reviewed by CC staff for inclusion of appropriate elements. 
 
Centers that have obtained IRB approval for a previous version of the protocol will inform their IRB of 
changes to the protocol. Protocol amendments and changes to the consent form will be distributed from 
the CC via numbered memos. These amendments and changes will be submitted by the centers to their 
IRB in writing. 
 
Reporting local and study-wide adverse events will be done according to each local IRB's policy. A 
summary of study-wide adverse event data (not by treatment assignment) will be available upon request 
on an annual basis for submission to local IRBs. 
 
13.3.  Consent procedures 
 
Potential participants (or their legal proxies) and caregivers who may potentially fulfill study criteria will 
be approached by clinic or research staff to assess initial interest. If the potential participant and caregiver 
are interested, study personnel are to explain the study to them and obtain voluntary written informed 
consent, which is required for participation in this study. This consent will be obtained from potential 
participants with Alzheimer's disease (AD) (or authorized surrogates) and from the potential participant's 
caregiver (if required by local IRB) who will be providing data on themselves as a caregiver. There will 
also be an additional participant consent form for the blood-based biomarkers substudy for newly or 
currently enrolled participants. 
 
Even after a participant has provided initial consent to participate, we will obtain assent at each 
subsequent visit or during implementation of study procedures to assure continuing informed consent on 
the part of the proxy, to maintain assent by the participants, and to assess capacity. Potential participants 
and their authorized legal representatives will be included and consented at the study centers using local 
procedures established by the individual centers and their overseeing IRBs in accordance with local law.  
 
In all cases, prospective participants with dementia will first be assessed for their ability to provide 
informed consent. Capacity to give consent will be assessed in clinical interviews of potential participants 
by investigators experienced in clinical dementia research who will also be trained in obtaining consent 
for the study. In the course of these interviews, these investigators will assess the ability of potential 
participants to: 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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 
Comprehend the study and its consent form, by asking them to repeat the key elements of the 
research  
 
Understand the study and its consent form, by answering questions about the key elements of the 
research 
 
Appreciate the personal nature and consequences of what will or could happen to them should 
they agree to participate 
 
Interviews will take place in the presence of a person who may act as a surrogate research decision maker, 
if needed. The designation of a surrogate will be governed by local state and IRB rules. In general, this 
will be, in order of priority: a legal guardian, someone who holds a research advance directive for the 
participant, a healthcare agent by advance directive, or a healthcare surrogate decision maker by local law 
or custom, such as a spouse, adult child, or sibling. 
 
If in this process, a potential participant is found not capable of fully providing consent for participation, 
then the surrogate will provide consent in their place and the participant will be asked to provide assent.  
Assent is defined according to the Alzheimer’s Association (2004) or local IRB guidelines. The process 
of obtaining consent and assent will be documented in every case. If potential participants are able to 
provide informed consent, they will be asked to do so and their surrogates will co-sign the consent form 
as a witness. Caregivers will only be individuals who can provide informed consent for themselves and 
will be asked to provide informed consent for participation as informants and also to provide data on 
themselves as caregivers in the course of the study. Caregiver informed consent is required unless 
otherwise stated by the center’s local IRB. 
 
13.4.  Potential risks and benefits 
 
Potential risks 
 
The major risks of this study involve the potential adverse effects of methylphenidate and the risk of 
being assigned to placebo, thus prolonging discomfort and suffering. However, it is not currently 
knowable in advance whether methylphenidate is efficacious for a particular participant. Indeed, this is 
the main purpose of the trial. There is a risk that an individual may be initially assigned to placebo and 
may not improve, or his or her apathy may worsen as a result. However, these risks will be mitigated by 
the use of psychosocial intervention and the close monitoring of participants. The risk of being in the 
study with respect to medications is comparable to receiving medication in ordinary clinical settings. The 
optimal duration of treatment with an anti-apathy medication is not known. In this trial it is possible that 
some participants may be treated with medication for up to six months. It may be later discovered, as a 
result of the analysis of this trial and others, that this length of time is too long for some participants, and 
may have resulted in some unanticipated or unnecessary side effects. Nevertheless, the overall evaluation, 
clinical care, monitoring, and medication administration are likely to be more intensive and careful than 
usual clinical care, and to this extent participation in this trial may be associated with less risk. 
 
The dopamine agonist chosen for this study has been evaluated and approved by the Food and Drug 
Administration (FDA) for clinical use for the treatment of Attention Deficit Hyperactivity Disorder 
(ADHD) in children and young adults, and is generally well tolerated. Although there is no currently 
available indication for the treatment of apathy in Alzheimer's dementia, there have been a number of 
case reports of methylphenidate for the treatment of apathy among adults and elders with major 
depression (Padala 2005; Masand 1998); Parkinson's disease (Chatterjee 2002) and stroke (Storga 1996). 
One case report in AD (Kittur 1999) and an open label trial of methylphenidate in AD and vascular 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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dementia (Galynker 1997) also showed that methylphenidate is effective for the treatment of apathy in 
dementia. 
 
Despite these findings in 2006, the FDA has issued a warning about sudden death, aggression, and 
psychotic symptoms in participants with cardiac abnormalities who are taking methylphenidate for the 
treatment of Attention Deficit Disorder (FDA 2006). While the warning was not aimed at elderly 
participants, the proposed study will address this issue by closely evaluating cardiac function using 
electrocardiograms. In addition, participants with psychosis and aggression requiring treatment will be 
excluded from the study. The FDA also issued a warning about priapism in 2013. The clinic will inform 
male participants of the possible relationship between priapism and methylphenidate use and will advise 
them to seek medical care immediately if this condition occurs. 
 
In 2015, the FDA also released a warning about rhabdomyolysis, the breakdown of muscle tissue that 
leads to the release of muscle fiber contents into the blood. These substances can be harmful to the kidney 
and often cause kidney damage. The participant will be advised to monitor for general weakness, muscle 
stiffness or aching (myalgia), muscle tenderness, and changes in urine color (i.e., dark, red, or cola-
colored) or output (i.e., decreased) and to report these symptoms to the clinic and seek medical attention 
as soon as possible. 
 
In 2017, the FDA also released a warning about serotonin syndrome, which could result with the 
combined use of certain anti-depressant medications with methylphenidate. This rare side effect could 
result in the production of too much serotonin, causing mild symptoms such as confusion, restlessness, 
headache, nausea, or diarrhea. More severe symptoms could include high fever, or seizures, and lead to 
loss of consciousness or even death.    
 
For those participating in the blood-based biomarkers substudy, there is a small risk from providing a 
blood sample. Taking blood may cause discomfort, bleeding or bruising where the needle enters the body. 
In rare cases, it may cause fainting. There is a small risk of infection; these are outlined on the consent 
form. 
 
Potential benefits 
 
Participants will receive treatment for their apathy and will be closely monitored throughout their 
participation in the study. The participant and caregiver will receive a psychosocial intervention. It will 
consist of three parts: an educational component, a counseling component, and availability of clinical staff 
to help caregivers, provided by trained licensed clinicians (nurses, social workers, doctors). All 
participants and their caregivers will receive education regarding AD, its clinical course, symptomatic 
behaviors, behavioral management of apathy, and expectations for medication treatments. At the end of 
the study, an appropriate clinical referral will be made for continued management of dementia and apathy.  
Failure to achieve meaningful clinical improvement will result in changes in treatment designed to 
maximize the likelihood of such improvement. The benefits to society of this study will include important 
new data on the treatment of apathy occurring with dementia. 
 
 
Risk/benefit ratio 
 
Risks to the participants from the study medication will be similar to those encountered by other elderly 
participants with dementia who receive treatment with these drugs. Risks to the participants from lack of 
treatment efficacy will be minimized by the several regular assessments and by the investigators' abilities 
to discontinue or change medicines or to treat participants openly if they are not benefitting from their 
current protocol-specified treatment. The benefits that participants will receive in the form of free and 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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systematic treatment, in addition to the societal benefits of important treatment data concerning a disorder 
with substantial morbidity and mortality, outweigh the risks to participants. The projected outcomes 
following participation in this trial are similar to what the participants may expect in the absence of 
participation, except that treatment is likely to be monitored more carefully, and optimized. Therefore, the 
anticipated net benefits from participation are likely to be at least as great as those to be expected in the 
absence of participation. 
 
13.5.  Safety monitoring 
 
Study personnel will have frequent contact with participants both by phone and in-person. Participants 
will be monitored regularly for signs or symptoms of adverse effects. In addition, the DSMC will 
regularly review and evaluate accumulating safety data and may recommend termination of the trial if the 
risks become unacceptable.  
 
Methylphenidate has a short acting nature and, if unexpected adverse events emerge, the investigator will 
simply reduce or discontinue the use of the study medication. If the unexpected adverse events disappear, 
the participant will re-start the study medication under close clinical supervision, including inpatient care 
if necessary. If the symptoms continue, it will be concluded that it is unlikely that the symptoms are 
related to the study medication. In that case, the participant will be treated as deemed clinically 
appropriate by the treating physician. The continuation or discontinuation of the drug will be decided by 
the center investigator in conjunction with the treating clinician based on the risk benefit consideration for 
each individual participant. For this reason, there will be no "rescue medication" used in this study. 
 
The risks and benefits of methylphenidate, of specific-study procedures, and of the study as a whole will 
be explained in detail to participants, caregivers, and responsible parties. After a medical and psychiatric 
history, participants will undergo physical, neurological, and psychiatric examinations to assure the 
clinical appropriateness and safety of their participation. Close clinical monitoring will ensure the 
appropriateness and safety of their continued participation. Close monitoring will include several 
components: a) careful education of caregivers to monitor participants at home, including provision of 
written materials on how to contact the team and what side effects to look for (in lay language); b) in-
person visits or telephone contacts; c) contact with an experienced clinician, at minimum; d) in-clinic 
visits with a prescribing physician; and e) availability of the study team by 24-hour beeper for assistance 
with crises and urgent or emergent matters and for personal support. 
 
Center investigators will be responsible for appropriate medical care of participants during the study, in 
connection with study procedures, and for monitoring the safety of participants. The medical monitor will 
provide medical monitoring to all the centers. He/she or his/her physician designee, will carry a beeper 
24-hours a day for protocol questions and problematic or serious adverse events that center investigators 
believe should be referred to him. The medical monitor and the Coordinating Center will be notified using 
a special serious adverse event (SAE) report form within one working day by the investigative center via 
email and telephone and if any of the following events occur: (1) death, (2) hospitalization, (3) life-
threatening events, (4) unexpected event. Monitoring personnel will provide timely evaluation and 
turnaround of the initial SAE report to meet specifications and regulatory reporting requirements.  
Coordinating Center personnel will review SAE data and accompanying documents, and query centers for 
clarification or additional information. They will also consult with the center investigator to determine the 
event, any treatment provided, outcome, and causality, and to obtain necessary supporting documentation.  
A report with an SAE narrative will be generated and, following principal investigator review, sent to 
appropriate outside bodies, such as the sponsor. SAE data will be entered into a database, along with 
additional follow-up information and clarification obtained from the centers as they become available. 
 


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Specifically, safety assessments include the monitoring of: 
 
Change in vital signs from baseline:  Clinically significant changes will be reported as adverse 
events. 
 
Change in weight from baseline: weight loss greater than or equal to 7% of the participants’ 
baseline weight will be reported as an adverse event. 
 
Clinically significant change in Mini-Mental State Exam (MMSE) score from baseline: The 
MMSE has been used as a measure of toxicity in a number of studies evaluating treatments for 
neuropsychiatric symptoms. 
 
Change in Neuropsychiatric Inventory (NPI) scores from baseline: The NPI will be used to 
determine if methylphenidate causes an increase in neuropsychiatric symptoms other than apathy 
(such as hallucinations and delusions). 
 
Change in electrolytes from baseline: Clinically significant change in sodium, potassium, 
chloride, bicarbonate, glucose, blood urea nitrogen, or creatinine. 
 
Adverse events: Adverse events and serious adverse events will be defined using standard 
approaches as was the case with Clinical Antipsychotic Trials of Intervention Effectiveness and 
Depression of Alzheimer’s Disease Study-2 (Martin 2006). 
 
Change in electrocardiogram (ECG) from baseline: One of the potential adverse events of 
methylphenidate is an increase in heart rate. This increase could trigger conduction problems. 
Therefore, an ECG must be performed no more than three weeks prior to randomization to allow 
the investigator to evaluate the clinical significance of potential findings. ECG assessments will 
be conducted each month to evaluate the potential effects of methylphenidate on heart 
conduction. If clinical manifestations of a cardiac condition are detected during the study, 
appropriate action will be taken at the investigator's discretion. 
 
Compliance check: Between visits the first three months, there will be 10-minute telephone 
contacts to obtain information such as medication adherence and potential adverse events. 
 
13.6.  Confidentiality of participant and caregiver data 
 
Clinical centers will keep all participant and caregiver data and blood samples in a secure location. 
Passwords to the website or to access database functions will not be shared with other staff. Names, 
addresses, and other such personal data will not be part of the central database. Data and blood samples 
collected from study evaluations and interviews will be identified only by study ID codes, which will be 
the participant ID and 4-letter code assigned at eligibility evaluation. Caregivers also will be identified by 
an ID code. Any disclosure of potentially identifiable health information will be done in accordance with 
the law. 
 
13.7.  Data sharing  
 
The Coordinating Center will facilitate data sharing in accordance to NIH Data Sharing Policy. Study data 
will be provided to all ADMET-2 investigators after data collection is complete. In addition, a limited use 
dataset and documentation will be prepared for use by qualified investigators outside of the ADMET-2 
research group. Data supplied to outside parties will have personal health identifiers removed. Study 
participants will be informed about data sharing in the consent forms. 
 
 


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14.  Blood-based biomarkers substudy 
 
14.1. 
Title 
 
Biomarkers of apathy and treatment response 
 
14.2.  Objectives  
 
The objectives are to understand biomarker correlates of change in apathy over time, and to identify 
possible predictors of treatment response.  
 
14.3.  Background and specific hypotheses 
 
Apathy, one of the most common neuropsychiatric symptoms (NPS) in Alzheimer’s Disease (AD), has a 
documented negative impact on patients and caregivers including being associated with increased 
mortality (Spalletta 2015; Nijsten 2017). There are currently no approved treatments for this symptom. As 
previously mentioned, one promising potential treatment is methylphenidate, which, in a Phase II trial 
(ADMET), showed significant improvement in symptoms of apathy compared to placebo (Rosenberg 
2013). As outlined earlier in the protocol, the primary aim of the ADMET 2 study is to determine whether 
methylphenidate is effective in improving clinically significant apathy in patients with AD in a larger 
sample, over a longer treatment period. 
 
In the original ADMET trial, a distinct group of approximately one third of the sample had a dramatic 
response to treatment, but one third showed either minimal improvement or no change, and the final third 
had no benefit from treatment. Importantly, no significant clinical differences were found between those 
who responded and those who did not, suggesting that the variability in treatment response may have a 
biological basis. Personalized interventions, based on biomarkers or genetic information, are a key aspect 
of neuropsychiatric drug development. It is therefore critical to determine biomarkers that will help 
distinguish responders from non-responders. This substudy to ADMET 2 will investigate the following 
specific blood-based biomarkers.  
 
1. MicroRNA (miRNA) 
2. Markers of oxidative stress 
3. Markers of inflammation (cytokines) 
4. Markers of neuronal loss (S100B, NF-L) 
5. Lipidomics 
 
Background and specific hypotheses are as follows: 
 
miRNA. MicroRNAs (miRNAs) are endogenous, small (approximately 22 nucleotide) non-coding RNAs 
found in blood. However, several species of miRNA have been linked to dopamine transporter (DAT) 
expression and function and catecholamine metabolism, making them of special interest to the ADMET 2 
study. Many studies have shown that miRNA species may affect transporters or nuclear receptors and 
drug response, as summarized by Koturbash et al (2015). In particular, miRNA expression has been 
shown to influence DAT expression and subsequent dopaminergic function. Working in a human 
neuroblastoma cell culture model, Jia et al (2016) showed that miRNA-137 and miRNA-491 caused a 
marked reduction in the expression of DAT, altering neuronal dopamine transport. There was evidence 
that these miRNA species affected DAT expression at the post-transcriptional level. The effect of non-
coding RNA species on dopaminergic signaling in the CNS has been summarized by Carick et al (2016), 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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miRNAs-30b-5p, 1301, 1972, 6070 have been associated with miRNA binding sites located in 
polymorphic region of the DAT associated with attention deficit hyperactivity disorders, and miRNA 
binding sites located in polymorphic region of DAT associated with bipolar disorders include miRNAs-
762, 1266, 3127, 3192, and 4259.  
 
miRNA hypotheses:  
 
Blood levels of miRNA-137, 491,762, 1266, 3127, 3192, and 4259 will be associated with greater 
response to methylphenidate over placebo. miRNA-137, 491,762, 1266, 3127, 3192, and 4259 are 
involved in dopamine or dopamine agonist signaling.  
 
Blood levels of miRNA 208 will be associated with differential response to methylphenidate over 
placebo. Catecholamines increase miRNA 208 expression and will likely affect dopamine 
signaling.  
 
Oxidative stress markers: lipid peroxidase, malondialdehyde, 4-hydroxynonenal, and 8-isoprostane. 
Oxidative stress is an emerging mechanism related to both mood disorders and AD (Marcus 1998; 
Montine 1998; Vitek 1994; Ozcan 2004; Andreazza 2008). Importantly, oxidative stress and 
neuroinflammation, including activation of nicotinamide adenine dinucleotide phosphate (NADPH)-
dependent oxidases, play a major role in the progression of dopaminergic cell death (Labandeira-Garcia 
2012). The hypothesis that oxidative stress contributes to neurodegeneration in AD has been supported in 
studies of oxidative stress markers in serum lipid fractions and in cerebrospinal fluid (CSF), and by 
pathology series (Markesbery 1999; Schrag 2013; Zhao 2013). Evidence supports a role for oxidative 
stress in AD etiology and pathophysiology (Wang 2005; Sasaki 1998; Marcus 1998; Mecocci 1994; Sayre 
1997). Elevated oxidative DNA damage has been observed in mitochondrial and nuclear DNA in the 
temporal, frontal, and parietal lobes of post-mortem AD brain tissue (Wang 2005; Sayre 1997). 
Furthermore, increased levels of two biochemical markers for oxidative stress (malondialdehyde (MDA) 
and thiobarbituric acid reactive substances (TBARS)) concentrations were observed in the temporal lobe 
of AD brain tissue (Marcus 1998; Palmer 1994) and TBARS were also observed to be elevated in the 
frontal lobe and cerebellar cortex of AD brain tissue (Marcus 1998). Elevated oxidative stress products 
have also been observed in neurofibrillary tangles (Sayre 1997; Montine 1998) and senile plaques (Sasaki 
1998; Vitek 1994), two pathological hallmarks of AD. In addition, antioxidant enzyme activity, as 
measured by superoxide dismutase  and catalase activity, was observed to be significantly reduced in 
post-mortem AD brain tissue (Marcus 1998), suggesting reduced antioxidant capacity in these brains. 
Consistent with the emergence of apathy in late life and the strong evidence that apathy predicts AD, 
oxidative stress and subsequent cellular damage are thought to contribute to biological aging and late-life 
disorders  (Kregel 2007; Cadenas 2000; Reitz 2011).  
 
In support of a possible relationship with apathy, there is also evidence for a role of oxidative stress in 
mood disorders from observational studies (Ozcan 2004; Sarandol 2007; Bilici 2001; Atmaca 2004; 
Yanik 2004; Andreazza 2008). MDA, a product of lipid peroxidation of polyunsaturated fatty acids and a 
marker of oxidative stress, has been observed to be elevated in affective disorders (Ozcan 2004), major 
depressive disorder (MDD) (Sarandol 2007; Bilici 2001; Khanzode 2003), and social anxiety (Atmaca 
2004). Additional lipid peroxidation products such as 4-hydroxynonenal (4-HNE) and isoprostanes have 
also been observed to be elevated in MDD (Dimopoulos 2008; Selley 2004; Mazereeuw 2015). In bipolar 
disorder, peripheral concentrations of TBARS, another marker of lipid peroxidation, were found to be 
elevated (Andreazza 2008). Furthermore, antioxidant capacity might be diminished in mood disorders 
(Gawryluk 2011; Maes 2000; Cumurcu 2009; Andreazza 2009). This may directly result in 
neurodegenerative damage, as neurons are particularly susceptible to oxidative stress due to their high 
oxygen demand and high concentration of polyunsaturated fatty acids (Christen 2000), or reduced 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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antioxidant capacity might be a by-product of enhanced oxidative stress (Ozcan 2004). Indeed, ratios of 
peroxide products to antioxidant potential predicted depression severity (Yanik 2004). 
 
 
Oxidative stress hypotheses: 
 
Higher levels of lipid peroxidation markers will be associated with greater treatment response 
(decrease in apathy) in subjects receiving methylphenidate versus placebo.  
 
Decreased lipid peroxidation markers with treatment will be associated with decreased apathy. 
 
Inflammation (cytokines). Cytokines, chemical messengers between immune cells, have been observed 
to have direct actions on brain cells (Rothwell 2000; Kuno 2006), and serve as mediators between the 
immune and nervous systems (Kronfol 2000). Moreover, a bidirectional relationship exists where cells in 
the nervous system can have direct effect on immune cells via molecules such as neurotransmitters 
(Wrona 2006; Maier 1998). Cytokines can have pro-inflammatory or anti-inflammatory effects depending 
on the cell type and specific receptors (Rubio-Perez 2012; Scheller 2011). There is a substantial amount 
of evidence linking an imbalance in pro-inflammatory and anti-inflammatory cytokines to various 
psychological disease states including depression (Kohler 2017), bipolar disorder (Kim 2007), 
psychological stress, and sickness behavior (Anisman 2003). In major depressive disorder patients, meta-
analyses have shown that pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 
(IL)-1 (IL-1), and IL-6 are commonly elevated (Dowlati 2010; Howren 2009), leading to the hypothesis 
that elevated pro-inflammatory cytokines, acting as neuromodulators, are a cause of the behavioral and 
neurochemical features of these disorders (Schiepers 2005). Sickness behavior, characterized by a series 
of symptoms that include lethargy, amotivation, anhedonia, and sleep and appetite disturbances, has also 
been associated with elevated cytokines (Kronfol 2000). Importantly, reduced motivation is common in 
sickness behavior and may be responsible for reorganizing the organism’s priorities to facilitate recovery 
from infection and inflammation (Dantzer 2007; Bluthe 1994).  
 
Inflammatory and immune mechanisms involving cytokine production have been frequently reported to 
play a role in AD pathogenesis (Rubio-Perez 2012). Studies have shown that concentrations of IL-1 and 
IL-6 are elevated in both the CSF and serum of AD patients (Blum-Degen 1995; Swardfager 2010). In 
addition, meta-analytic evidence suggests that TNF-α, IL-12, and IL-18 are also elevated in the peripheral 
blood of individuals with AD (Swardfager 2010). Furthermore, amyloid-beta (Aβ) protein, a protein 
intimately linked to AD pathogenesis, has been shown to induce microglial expression of IL-1 in vitro, 
further suggesting a role of cytokines in the progression of AD (Araujo 1992). Moreover, both IL-1 and 
IL-6 have been implicated in the transition of diffuse plaques to neuritic plaques in the brain of AD 
patients (Hull 1996; Sheng 1997). Although cytokine dysregulation appears evident during different 
phases of progression of AD, it is unclear whether this is a consequence of the disease, a contributor to 
the disease, or both.  
 
Cytokines hypotheses: 
 
Higher levels of inflammatory markers will be associated with poorer response to 
methylphenidate. 
 
Decreased inflammatory markers with treatment will be associated with decreased apathy.  
 
Neuronal loss markers (S 100 calcium-binding protein B (S100B), neurofilament light chain protein 
(NF-L)). Patients with AD and significant apathy show increased neuropathological changes, including 
increased neuronal loss (Forstl 1993). Two common biomarkers of neuronal loss are S100B and NF-L. 
S100B is one of the most commonly used blood biomarkers for brain injury (Shahim 2016). Serum levels 
of S100B have been shown to have a positive correlation with disease severity in patients with AD 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
39
 
 
 
 
(Chaves 2010). S100B has also been shown to be increased in patients with depression and bipolar 
disorder (Rajewski-Rager 2016). NF-L has been suggested as a putative marker of progression in 
neurodegenerative diseases (Bacioglu 2016). NF-L, along with the neurofilament medium and heavy 
proteins, acts as scaffolding of the neural cytoskeleton, with important roles in axonal and dendritic 
branching and growth (Petzold 2005). Patients with AD have been shown to have a higher serum level of 
NF-L compared to control elderly patients without evidence of central nervous system damage (Gaiottino 
2013). In particular, patients with AD and Aβ pathologic features showed significantly higher levels of 
plasma NF-L (Mattsson 2017). Higher CSF levels of NF-L have also been found in patients with bipolar 
disorder (Jakobsson 2014). 
 
While no studies have looked at the relationship between S100B or NF-L and apathy in patients with AD, 
these markers may provide greater insight into the neurotoxic mechanisms behind apathy in AD. 
 
Neuronal loss hypothesis: 
 
Increased serum levels of S100B and NF-L (reflecting more brain injury) will be associated with 
poorer response of apathy to methylphenidate treatment in AD. 
 
Lipidomics. There is an increasing amount of published evidence that suggests brain lipid composition is 
altered in multiple dementias, and that these disease-associated modifications reflect underlying disease 
mechanisms. The brain is especially enriched in sphingolipids and membrane lipid composition regulates 
a variety of biologic processes including synaptic plasticity (Inokuchi 2009; Wheeler 2009; Yang 2000; 
Zhang 2002), neuronal survival (Arboleda 2009; Schneider 2006; Posse de Chavez 2006; Levonson 
2004), glial activation (Jung 2013; Antonucci 2012; Jana 2007; Bassi 2006), and the activity of amyloid 
processing enzymes such as α-, and β-secretase that regulate the physiological (α-secretase), and 
pathological (β-secretase) production of amyloid peptides (Li 2010; Puglielli 2003; Tamboli 2005). 
Animal models of disease and studies with human brain tissues and matched CSF/plasma have shown that 
circulating lipids appear to reflect changes in brain lipid composition (Cutler 2004a; Cutler 2004b; 
Haughey 2004), possibly through the release of lipid-rich exosomes from brain that enter into peripheral 
circulation (Dickens 2017). Characteristic changes in CSF lipid compositions have been associated with 
increased risk of incident AD (Mielke 2016; Mielke 2012), clinical progression (Mielke 2011), and have 
been correlated with Aβ and tau levels (Mielke 2014), and with white matter integrity (Gonzalez 2016; 
Proitsi 2015).  
 
We have a prime opportunity to explore blood-based lipid biomarkers as a surrogate measure for apathy 
in AD, and their association with the biological response to methylphenidate. As lipidomic methodology 
becomes more sophisticated and reproducible, we are starting to see replicable findings. For example, a 
preliminary report of six novel lipid markers reflecting disease state in AD was replicated along with the 
identification of new candidate lipids (Proitsi 2017). Lipid abnormalities have been shown to be 
associated with cognitive impairment in human immunodeficiency virus (HIV), AD, Multiple Sclerosis, 
Parkinson’s, and coronary artery disease (Cutler 2004; Haughey 2004; Mielke 2014; Bandaru 2007; 
Bandaru 2013; Bandaru 2009; Haughey 2008; Kooij 2012; Lu 2001; Mielke 2015; Mielke 2010a; Mielke 
2010b; Mielke 2013; Saleem 2013; Vidaurre 2014; Wheeler 2008). Furthermore, preliminary data 
suggests that severity of apathy is associated with alteration in plasma levels of specific ceramides. In a 
sample of 130 patients at risk for vascular cognitive impairment, 3 sphingolipids were associated with 
score on the apathy evaluation scale (AES): C22:1 (r=0.243, p=0.009), MHxC16:1 (r=0.219, p=0.018), 
and MHxC22:1 (r=0.207, p=0.026). In addition, baseline C22:1 concentration was associated with change 
in AES over 6 months (r=-0.218, p=0.031).  
 
Lipidomics hypotheses: 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
40
 
 
 
 
 
A lipid biosignature will be associated with apathy response to methylphenidate treatment in AD.  
 
Decreases in this lipid biosignature identified will be associated with decreased apathy. 
 
14.4.  Organization 
 
Five members, a subset of the ADMET 2 Executive Committee (EC) and Steering Committee (SC) 
members, will form the Biomarkers EC to oversee the substudy. One EC member will oversee the 
measurement of the five specific peripheral biomarker components described in this chapter. 
 
14.5.  Eligibility criteria  
 
Any person who is enrolled in the main study, may enroll in the substudy. All newly enrolled participants 
in the main study will be invited to participate in the substudy. Current participants already enrolled in the 
main study will be invited to enroll if they have not yet completed their month 3 visit. The substudy will 
only be conducted at those ADMET 2 clinics that have agreed to participate in the substudy. Participants 
will be asked to volunteer for this substudy. Whether or not they volunteer will not affect their ability to 
participate in the randomized trial. 
 
14.6.  Study design  
 
On newly enrolled participants to the main study, blood will be collected on consenting substudy 
participants at baseline for all blood-based biomarkers (although, miRNA may be collected at any in-
person study visit after baseline). Blood will also be collected at the last study visit (F6) for measurement 
of oxidative stress biomarkers, cytokines, and lipidomics as illustrated in the schedule of collection in 
Table 1a below.  
 
Table 1a: Schedule of substudy assessments for newly enrolled participants 
 
Baseline 
F6 
Months from baseline 
0 
6 
 miRNA 
 X* 
 
 Oxidative stress 
X 
X 
 Inflammation (cytokines) 
X 
X 
 Neuronal loss 
X 
 
 Lipidomics 
X 
X 
* The collection of miRNA may take place at any in-person visit after baseline, if need-be. 
 
On currently enrolled participants to the main study, who have already had their baseline visit, blood will 
be collected on consenting substudy participants at the month 1, month 2, or month 3 visits for all blood-
based biomarkers (although, miRNA may be collected at any in-person study visit). Blood will also be 
collected at the last study visit (F6) for measurement of oxidative stress biomarkers, cytokines, and 
lipidomics as illustrated in the schedule of collection in Table 1b below.  
 
 
 
 
 
 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
41
 
 
 
 
Table 1b: Schedule of substudy assessments for currently enrolled participants who have had their baseline 
visit but have not yet completed their month 3 visit 
 
F1, F2, or F3 
F6 
Months from baseline 
1, 2, or 3 
6 
 miRNA 
  X* 
 
 Oxidative stress 
X 
X 
 Inflammation (cytokines) 
X 
X 
 Neuronal loss 
X 
 
 Lipidomics 
X 
X 
* The collection of miRNA may take place at any in-person visit after baseline, if need-be. 
 
 
Each biomarker requires a specific collection and storage method as outlined in the ADMET 2 study 
handbook. All specimen are frozen on dry ice and shipped immediately or monthly to the designated 
laboratory for analysis.   
 
14.7.  Materials and shipments 
 
The ADMET 2 study handbook contains information on materials needed for blood collection as well as 
the Standard Operating Procedures (SOPs) to measure biomarkers and to obtain and interpret images. The 
handbook also contains detailed information on labeling and shipping of biospecimens.  
 
The CC will follow the normal quality control procedures including the tracking and monitoring of the 
collection of specimens. The CC is responsible for preparing and distributing kits containing materials 
needed by clinical centers to complete and store blood collection. The CC also tracks the acquisition and 
shipment of relevant biospecimens from clinical centers to the sites completing biochemical analyses. 
 
14.8.  Biochemical analyses 
 
Detailed methods to be used for biochemical analyses will be developed by the relevant laboratory and 
documented as an SOP. A summary of the approach for each biomarker is given here.  
 
Micro RNA. Methods for RNA extraction and miRNA quantitative reverse transcription polymerase 
chain reaction (qRT-PCR). RNA extraction will be based on published methods by Bekris et al (Bekris 
2013). Then DNA will be depleted using Qiagen deoxyribonucleic acid (DNA) elimination columns 
(Qiagen, Valencia, CA) and TURBO DNA-free™ Kit (Applied Biosystems, Austin, TX). 
  
Oxidative stress. Methods for measuring oxidative stress. Early-stage oxidative damage to lipids will be 
evaluated by measuring the levels of lipid hydroperoxide (LPH, Cayman Chemical; Item No. 705002) per 
manufacturer’s instructions. 
 
Late-stage oxidative damage to lipids will be evaluated by measuring MDA, 4-HNE, and 8-isoprostane 
(8-ISO, Cayman Chemical; Item No. 516351), which will be quantified using standard competitive 
sandwich enzyme-linked immunosorbent assays (ELISAs) for each marker.  
 
Inflammation (cytokines). Serum will be assessed for cytokine levels, including TNF-α, IL-1, and IL-6, 
by multiplex ELISA, using a commercial kit per the manufacturer’s instructions (Milliplex, Millipore 
#HMHMAG-34K - #HCYTOMAG-60K). 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
42
 
 
 
 
Neuronal loss. Serum S100B will be measured using an electrochemiluminescence immunoassay and 
NF-L will be measured using ELISA. 
 
Lipidomics. Lipid analysis is conducted using Data-Independent Lipid Analysis by MS/MSALL on a 
TripleTOFTM (TOF) 5600 (AB SCIEX, Redwood City, CA) mass spectrometer. This method will identify 
~1000 individual lipid species from 12 different classes of lipid that include: Ceramides, 
monohexosylceramides, dihexosylceramides, sphingomyelins, phospatidylcholine, phospatidylserine, 
phospatidylethanolamine, phospatidylglycerol, cholesterol esters, monoakayldiacylglyerides, 
diacylglycerides, and triacylglycersides. 
 
14.9.  Outcomes  
 
The endpoints in this substudy are the levels of each of the tested biomarkers (miRNA, oxidative stress 
biomarkers, inflammation (cytokines), neuronal loss (S100B, NF-L), and lipidomics). The relevant 
outcomes will include 1) the differences in mean biomarker level between responders and non-responders 
to the treatment methylphenidate and 2) the correlation between level of biomarker and level of apathy.  
 
14.10.  Justification of sample size  
 
Statistical Considerations. Each of the individual sections below contains a summary of the available 
evidence and rationale for studying the peripheral based biomarker in the ADMET 2 population. Insofar 
as hypothesized either to predict treatment response or change with apathy, the size of expected change, 
or of meaningful change remains unknown. Given that these differences would be required to make an 
accurate statistical power analysis, these aims should be considered exploratory and would likely need to 
be validated in further studies beyond ADMET 2. 
 
The discovery of peripheral based blood biomarkers of response of apathy in AD to pharmacotherapy 
would be a major advance in understanding the neurobiology of this NPS in AD. The current biomarker 
initiative is justified on this basis despite the lack of current data to help guide traditional power analyses. 
 
Power and Sample Size. We expect to enroll at least 60 subjects to measure these blood-based 
biomarkers. As we expect that for each measure some participant information may be incomplete due to 
measurement issues or loss to follow-up, we assume here a conservative 10% loss, so that each measure 
will have approximately 54 participants for analysis. For each, we are interested in comparing those 
responding to treatment with methylphenidate or placebo to those not responding to treatment. Among 54 
participants with complete information, we expect one third to have improvement in apathy (responders), 
and approximately one third to have worsening apathy over the course of the study (non-responders). 
With these 36 participants, we determined the detectable difference in Cohen’s d (mean 
difference/standard deviation) given the number of comparisons using a conservative Bonferroni 
adjustment (Witte 2000). The resulting detectable effect sizes are in Table 2 below. We also estimate the 
detectable association between each measure and a continuous valued treatment response among all 54 
participants with complete data, quantified by a correlation, likewise given the type one error rate 
adjusted by the number of comparisons using a Bonferroni adjustment (Table , below). 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
43
 
 
 
 
 
Table 2: Power, sample size, and detectable effect sizes for a type one error (alpha) of 0.05, assuming a test to compare 
non-responders to responders, when the sample is approximately one third responders and one third non-responders. 
Bonferroni adjustment is assumed for multiple comparisons. 
Measure 
Sample 
size 
Number of 
outcomes/ 
comparisons 
Expected 
drop out 
Effective 
sample 
size 
Effect size (Cohen’s d : 
mean difference / 
standard deviation) to 
compare two groups 
Power 
Supporting 
reference* 
MiRNA 
60 
50 (unique 
miRNA types) 
10% 
36 
1.50 
80% 
Ou 2016 
Oxidative stress 
60 
4 (1 early 
stage, 3 late 
stage) 
10% 
36 
1.20 
80% 
Andreazza 
2008 
Cytokines 
(inflammation) 
60 
3 
10% 
36 
1.15 
80% 
Spalletta 
2013 
S100B (neuronal 
loss) 
60 
1 
10% 
36 
0.95 
80% 
Schroeter 
2013 
NF-L (neuronal 
loss) 
60 
1 
10% 
36 
0.95 
80% 
Norgren 
2003 
Lipidomics 
60 
12 (classes) 
10% 
36 
1.35 
80% 
Gracia-
Garcia 2011 
* References shown support that the measure listed in Column 1 of this table is expected to have an effect size that 
is greater than or equal to the needed effect size as estimated in Column 6.  
 
Table 3: Power, sample size, and detectable effect sizes for a type one error (alpha) of 0.05, 
assuming a test for the association with a continuous-valued treatment response. A Bonferroni 
adjustment is assumed for multiple comparisons. 
Measure 
Sample 
size 
Number of 
outcomes/ 
comparisons 
Expected 
drop out 
Effective 
sample 
size 
Effect size 
(correlation) to 
detect association 
Power 
MiRNA 
60 
50 
10% 
54 
0.540 
80% 
Oxidative stress 
60 
4 (1 early stage, 
3 late stage) 
10% 
54 
0.450 
80% 
Cytokines 
(inflammation) 
60 
3 
10% 
54 
0.440 
80% 
S100B 
(neuronal loss) 
60 
1 
10% 
54 
0.385 
80% 
NF-L (neuronal 
loss) 
60 
1 
10% 
54 
0.385 
80% 
Lipidomics 
60 
12 (classes) 
10% 
54 
0.495 
80% 
 
14.11.  Data analysis  
 
Data will be analyzed using both nonparametric and parametric statistics with correction for multiple 
comparisons. As a conservative approach, no assumptions will be made about the distribution of the data 
and a Wilcoxon rank-sum test will be used to compare MiRNA, oxidative stress, cytokines, neuronal loss, 
and lipidomics between responders and non-responders. P-values less than 0.05 after adjustment for 
multiple comparisons (Benjamini 1995) will be considered significant. 
 
Analyses will also be performed on measures of MiRNA, oxidative stress, cytokines, neuronal loss, and 
lipidomics among all participants for an association with apathy. As a conservative approach, no 
assumptions will be made about the distribution of the data, a Spearman rank correlation will be used and 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
44
 
 
 
 
the resulting significance adjusted for multiple comparisons. Subsequently, parametric testing will be 
performed where appropriate.  
 
14.12.  Risk to participants and protections against risk  
 
Because obtaining and measuring biomarkers is an ancillary study to the main ADMET 2 study, a 
separate informed consent statement will be developed that will allow the study participant and caregiver 
to participate in the biomarkers substudy. The consent will notify potential participants that there is a 
small risk from blood draw (feeling slight discomfort or pain, with potential of feeling faint or bruising). 
 
14.13.  Data confidentiality 
 
As with the main study, clinics will keep all participant and caregiver data in a secure location. Names, 
addresses, and other such personal data will not be part of the central database. Samples collected from 
will be identified only by study ID codes, which will be the participant ID number and 4-letter code 
assigned at screening. Any disclosure of potentially identifiable health information will be done in 
accordance with the law. 
 
14.14.  Biohazards 
 
Blood will be collected for miRNA, lipidomics, neuronal loss, oxidative stress, and cytokines. All 
personnel involved in collecting and handling biologic specimens are to follow appropriate precautionary 
procedures as currently recommended by the CDC. Shipping of specimens are to be done in compliance 
with federal regulations. 
 
 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
45
 
 
 
 
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Appendix: Design summary 
 
 
Title 
 
Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) 
 
Objectives 
 
Primary objective 
 
To examine in a masked, randomized trial the efficacy of methylphenidate for the treatment of 
clinically significant apathy in participants with Alzheimer's dementia. 
 
Secondary objective 
 
To examine the safety of methylphenidate for the treatment of clinically significant apathy in 
participants with Alzheimer's disease, 
 
To examine changes in other neuropsychological and quality of life assessments, 
 
To examine economic assessments from baseline to 6 months, and 
 
To examine cognitive changes from baseline to 6 months.  
 
Blood-based biomarker substudy objective 
 
To understand biomarker correlates of change in apathy over time, and to identify possible 
predictors of treatment response 
 
Type of trial 
 
Phase III 
 
Randomized, multicenter clinical trial  
 
Two parallel treatment groups  
 
Double masked 
 
Design variables 
 
Neuropsychiatric Inventory Apathy subscale (NPI apathy) and Alzheimer's Disease Cooperative 
Study - Clinical Global Impression of Change (CGIC) Scale 
 
Outcomes 
 
Primary 
 
Mean change in NPI apathy from baseline to 6 months 
 
Odds of having a given CGIC rating or better for apathy at 6 months 
 
Secondary 
 
Apathy 
 
Mean change in Dementia Apathy Interview and Rating from baseline to 6 months  
 
Mean change in NPI apathy from baseline to 2 months 
 
Odds of having a given CGIC rating or better for apathy at 2 months 
 
Safety 
 
Mean change in Mini-Mental State Exam from baseline to 6 months 
 
Mean change in vital signs from baseline to 6 months 


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 
Number and proportion with abnormal electrocardiogram during follow-up 
 
Number and proportion with abnormal electrolytes during follow-up 
 
Number and proportion with significant unintentional weight loss (> 7%) 
 
Number and proportion of participants with adverse events at any time 
 
Other neuropsychological assessments 
 
Distribution of change in NPI sub-scale scores (excluding apathy) from baseline to 6 months 
 
Economic assessments 
 
Mean change in EuroQol 5D-5L from baseline to 6 months 
 
Mean change in Resource Utilization in Dementia-Lite from baseline to 6 months 
 
Cognitive tests 
 
Action Verbal Fluency Test from the PDCRS 
 
Category Fluency Task-Animal Naming  
 
Hopkins Verbal Learning Test – Revised 
 
Trail Making Test (A and B) 
 
Digit Span: The Wechsler Adult Intelligence Scale – Revised Digit Span subtest 
 
Short Boston Naming Test 
 
 
 
Study population 
 
200 participants who meet the criteria for apathy in Alzheimer's disease 
 
Participants enrolled in ADMET 2 are invited to join the blood-based biomarker substudy 
 
Sample size and power calculations 
 
Two-sided alpha = 0.025 for each co-primary outcome 
 
Power greater than 90% with 10% losses to follow-up 
 
NPI apathy 
– 
1.8 point difference in change in NPI apathy scores from baseline to month 6 
– 
Estimated standard deviation in NPI apathy of 3.2 
 
CGIC 
– 
Proportions assumed in each rating: 
 
3.5% marked improvement 
 
8.8% moderate improvement 
 
29.8% minimal improvement 
 
54.4% no change 
 
3.5% minimal worsening 
– 
Odds ratio = 2.75 
 
Randomization 
 
1:1 assignment ratio 
 
Stratification by clinic 
 
Data analysis 
 
Primary analysis by assigned treatment group (intention-to-treat principle) 
 
Initial descriptive analyses 
 
Regression methods for effect estimates 
 
Assessment of baseline variables for interaction or confounding 


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 
For blood-based biomarker substudy, exploratory analysis for association between biomarkers 
and apathy or methylphenidate response 
 
Treatments 
 
Methylphenidate, target dose 20 mg per day (range 10-20 mg per day), and psychosocial 
intervention 
 
Placebo and psychosocial intervention 
 
Masking 
 
Treatment assignment masked to participants and all personnel 
 
Duration of follow-up 
 
6 months 
 
Data collection schedule 
 
Scheduled in-person visits (monthly after randomization until month 6) 
 
Telephone contacts for data collection (day 15, 45, and 75 after randomization) 
 
Inclusion criteria 
 
Possible or probable Alzheimer's disease (National Institute of Neurological and Communicative 
Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-
ADRDA) criteria), with Mini-Mental State Exam (MMSE) score of 10-28 inclusive 
 
Clinically significant apathy for at least four weeks for which either 
– 
the frequency of apathy as assessed by the Neuropsychiatric Inventory (NPI) is 'Very 
frequently', or 
– 
the frequency of apathy as assessed by the NPI is 'Frequently' or 'Often' AND the severity 
of apathy as assessed by the NPI is 'Moderate' or 'Marked' 
 
A medication for apathy is appropriate, in the opinion of the study physician 
 
Provision of informed consent for participation in the study by potential participant or surrogate 
(with participant assent if the potential participant is unable to provide informed consent) and 
caregiver 
 
Availability of caregiver, who spends greater than ten hours a week with the potential participant 
and supervises his/her care, to accompany the potential participant to study visits and to 
participate in the study 
 
Sufficient fluency, of both the potential participant and caregiver, in written and spoken English 
to participate in study visits, physical exams, and outcome assessments 
 
If female, woman must be post-menopausal for at least 2 years or have had a hysterectomy 
 
Exclusion criteria 
 
Currently meets criteria for Major Depressive Episode, by Diagnostic Statistical Manual of 
Mental Disorder - IV (TR) criteria 
 
Clinically significant agitation /aggression for which either 
– 
the frequency of agitation /aggression as assessed by the NPI is ‘Very frequently', or 
– 
the frequency of agitation /aggression as assessed by the NPI is ‘Frequently' AND the 
severity of the agitation as assessed by the NPI is ‘Moderate', or ‘Marked' 
 
Clinically significant delusions for which either 
– 
the frequency of delusions as assessed by the NPI is ‘Very frequently', or 
– 
the frequency of delusions as assessed by the NPI is ‘Frequently' AND the severity of the 
delusions as assessed by the NPI is ‘Moderate', or ‘Marked' 


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 
Clinically significant hallucinations for which either 
– 
the frequency of hallucinations as assessed by the NPI is ‘Very frequently', or 
– 
the frequency of hallucinations as assessed by the NPI is ‘Frequently' AND the severity 
of the hallucinations as assessed by the NPI is ‘Moderate', or ‘Marked' 
 
Change to AD medications within the month preceding randomization, including starting, 
stopping, or dosage modifications 
 
Change in anti-depressant (except for trazodone used for sleeping difficulties as described below) 
use within the 30 days preceding randomization or a period of time equal to 5 half-lives of drug, 
whichever period of time is longer 
 
Use of trazodone > 50mg or lorazepam > 0.5mg or for indications other than sleeping difficulties 
within the 30 days preceding randomization or a period of time equal to 5 half-lives of drug, 
whichever period of time is longer. Other benzodiazepines are prohibited in the past 30 days or 
within 5 half-lives, whichever period of time is longer  
 
Failure of treatment with methylphenidate in the past for apathy after convincing evidence of an 
adequate trial as judged by study physician 
 
Currently taking any amphetamine product, an antipsychotic, bupropion, or any medication that 
would prohibit the safe concurrent use of methylphenidate, including but not limited to 
monoamine oxidase inhibitors and tricyclic antidepressants within the 30 days preceding 
randomization or a period of time equal to 5 half-lives of drug, whichever period of time is longer 
 
Need for acute psychiatric hospitalization or is suicidal in the opinion of the study physician 
 
Significant communicative impairments that would affect participation in clinical trial 
 
CNS abnormalities (e.g., cerebral aneurysm), seizures (convulsions, epilepsy), Tourette's 
syndrome or presence of motor tics, or abnormal EEGs 
 
Lack of appetite that results in significant unintentional weight loss as determined by the study 
physician in the last three months 
 
Uncontrolled hyperthyroidism 
 
Any cardiovascular or cerebrovascular abnormality deemed to be clinically significant by the 
study physician, tachycardia (heart rate ≥ 100 beats per minute), or uncontrolled hypertension 
(defined as medication non-compliance or past 3 months with a diastolic reading ≥ 105 mm Hg), 
at the time of screening 
 
Closed angle glaucoma or pheochromocytoma 
 
Women with childbearing potential  
 
Current participation in a clinical trial or study that may add significant burden or affect study 
outcomes 
 
Any condition that, in the opinion of the study physician, makes it medically inappropriate or 
risky for the participant to enroll in the trial, including, but not limited to, contraindication to 
treatment with methylphenidate. 
 
Participating sites 
 
Study Chair’s Office: Medical University of South Carolina (Charleston, SC) 
 
Coordinating Center: Johns Hopkins Bloomberg School of Public Health (Baltimore, MD) 
 
Clinical Centers 
– 
Banner Alzheimer’s Institute (Phoenix, AZ) (2015 to 2017) 
– 
Emory University (Atlanta, GA) 
– 
Johns Hopkins University (Baltimore, MD) 
– 
Roper–St. Francis Healthcare (Charleston, SC) 
– 
Sunnybrook Research Institute (Toronto, ON, Canada) 
– 
University Hospitals- Case Medical Center (Cleveland, OH) 


ADMET 2 Protocol rev 1.5, Feb 2019 
 
 
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– 
University of Arkansas (Little Rock, AR) 
– 
University of Rochester (Rochester, NY) 
– 
Wake Forest University (Winston-Salem, NC) (2015 to 2019) 
– 
Yale University (New Haven, CT)