Anti-viral Therapy in Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer Disease, Herpes Simplex 1, Herpes Simplex 2
Sponsor: Columbia University

Anti-viral Therapy in Alzheimer's Disease 
NCT03282916
July 14, 2025

2 
Introduction 
This multicenter project is funded by grant number R01AG055422 from the National Institute on Aging, 
P.I. Dr. Davangere P Devanand.  The recipient organization is Columbia University (CU). Since many
procedures are conducted at New York State Psychiatric Institute (NYSPI) through a Research
Foundation for Mental Hygiene (RFMH) subcontract, the term “NYSPI” is used to refer to CU/NYSPI
conduct of the protocol. By default, all policies and procedures refer to CU/NYSPI, and procedures
specific to the two other sites, New York University (NYU; PI Dr. Thomas Wisniewski) and Banner
Alzheimer’s Institute (BAI; PI Dr. Allison Perrin), are indicated accordingly.
In this study, we will be conducting the first controlled clinical trial to directly address the long-standing 
viral etiology hypothesis of Alzheimer’s disease (AD) which posits that viruses, particularly the very 
common herpes simplex virus-1 (HSV1) and herpes simplex virus-2 (HSV2), may be etiologic or 
contribute to the pathology of AD. 
The generic antiviral drug valacyclovir at 4 g per day, repurposed as an anti-AD drug, will be compared 
to matching placebo in the treatment of 130 patients (65 valacyclovir, 65 placebo) with mild AD in a 
randomized, double-blind, 18-month Phase II proof of concept trial.  Participants are required to be 
seropositive for HSV1 or HSV2.  The targeted number of participants was reduced from 130 to 120 (60 
valacyclovir, 60 placebo) because of delays due to the COVID pandemic and the funding timeline.  This 
change was approved by the DSMB and the sponsor, NIA. 
We hypothesize that patients treated with valacyclovir will show less decline in cognition and function 
compared to placebo; will show less amyloid accumulation than those on placebo using 18F-Florbetapir 
PET imaging, and less tau binding than those on placebo using 18F-MK-6240 tau PET Imaging.  
Background 
The viral hypothesis of Alzheimer’s disease (AD) posits that viruses in the brain, specifically herpes 
simplex virus-1 (HSV1) and to a lesser extent herpes simplex virus-2 (HSV2), may be etiologic or 
contribute to AD pathology. HSV has been implicated for several reasons. HSV1 and HSV2 can 
trigger amyloid aggregation and their DNA is common in plaques. Anti-HSV drugs reduce Aβ and 
P-tau accumulation in brains of mice infected with HSV1, and HSV1 reactivation is associated
with tau hyperphosphorylation. There is a strong association between HSV1 and amyloid plaques
in AD brains but not normal brains. After initial oral infection, HSV1 becomes latent in the
trigeminal ganglion and can enter the brain via retrograde axonal transport. Recurrent reactivation
with newly produced HSV viral particles, ‘drop by drop,’ is supported by amino acid homology
between human p-tau and VP22, a key target for phosphorylation.
Valacyclovir, a pro-drug of acyclovir, is a generic anti-viral drug. Acyclovir is converted by HSV viral 
thymidine kinase into monophosphate and triphosphate forms that inhibit DNA polymerase and this leads 
to HSV chain termination. Therefore, valacyclovir leads to death of infected cells but not non-infected 
cells and has efficacy against several herpes viruses.  
Valacyclovir may be both symptomatic and disease-modifying because chronic use leads to prolonged 
HSV suppression in patients with peripheral HSV infection. In a pilot clinical trial of 24 patients with 
schizophrenia with positive HSV1 antibody titers, valacyclovir 3 g daily was superior to placebo with a 
large effect size of around 1.0 on three cognitive tests of memory from the Penn battery. Valacyclovir has 
been tested in multiple sclerosis (MS) with equivocal results for changes in MRI lesions; cognition was 
not assessed in the MS trials. 

3 
 
 
 
 
 
 
 
 
 
 
 
Valacyclovir is the most widely used generic antiviral drug with over 20 years of worldwide use. It 
is approved for the treatment of HSV1, HSV2, varicella zoster (shingles), and chickenpox. No other 
available antiviral drug, e.g., acyclovir (intravenous), famciclovir and ganciclovir, has been shown 
to be superior to valacyclovir in the treatment of HSV1 and HSV2.  Recommended dose of oral 
valacyclovir for peripheral acute HSV infections is 1 to 3 g daily, and bioavailability is 54%. For 
long-term HSV suppression, the dose is 1 g daily. In patients with HIV infection and clinical AIDS, 
valacyclovir 8 g/day was associated with serious adverse events in 10% of patients including GI 
disturbances and headache, and thrombotic microangiopathy in a few cases. Doses of 6-8 g daily 
are tolerated in healthy young adults. The difficulty in obtaining efficacy for any drug in AD has 
led us to target a dose of valacyclovir 4 g daily in this proof-of-concept trial; 3 g is approved for 
peripheral HSV infection and was effective in the schizophrenia pilot trial.  
Based on our experience to date in the conduct of this protocol, which is consistent with U.S. 
prevalence rates, HSV1/HSV2 seropositivity rate is estimated to be 60-65%.  
Participants can continue on cholinesterase inhibitors and/or memantine, if doses are stable for 1 
month prior to study entry. Major neurological and psychiatric disorders are excluded.  
Psychotropic and other medications will be permitted. Medication dosage may be changed if 
indicated by the study physician. All medication changes will be documented using the National 
Alzheimer’s Coordinating Center (NACC) rating form for possible ancillary analyses. 
Valacyclovir does not have any major drug-drug/drug-food interactions. 
 
SPECIFIC AIMS.  
The aim is to evaluate valacyclovir, a repurposed generic antiviral drug, as a treatment for early AD. 
An additional aim is to evaluate the effect of valacyclovir on biomarkers of AD. VALAD is a Phase 
II, proof of concept (POC), randomized, double-blind, placebo-controlled, 18-month treatment trial 
with early AD and antibodies to HSV1 or HSV2. 
 
Hypothesis 1. Patients treated with valacyclovir will show smaller decline than patients treated with 
placebo on the ADAS-Cog11 (primary outcome; cognitive measure, 0 to 78 weeks). 
Hypothesis 2. Patients treated with valacyclovir will show smaller decline than patients treated with 
placebo on the ADCS-ADL (secondary outcome; function measure, 0 to 78 weeks). 
Hypothesis 3. Patients treated with valacyclovir will show less accumulation than patients on 
placebo in PET amyloid scans’ (18F-Florbetapir, 0 to 78 weeks) combining six ROIs (SUVR: 
cerebellar reference) that show increased uptake in AD: medial orbital frontal, anterior cingulate, 
parietal, temporal, posterior cingulate, precuneus. 
Hypothesis 4. From baseline to 78 weeks, patients treated with valacyclovir will show smaller 
increase in 18F-MK-6240 binding (SUVR: combining medial temporal, lateral temporal, prefrontal, 
parietal, and occipital regions of interest, ROIs, with cerebellar reference) than patients treated with 
placebo. 
18F-MK-6240 PET imaging was funded by a grant supplement within the first year after study 
initiation and conducted in a subset of the overall sample. 
 
In exploratory analyses, we will compare valacyclovir to placebo for changes in global cognition 
(MoCA), verbal memory (Craft story delayed verbatim recall), and examine age, sex and 
apolipoprotein E e4 genotype as a potential moderator of outcome.  We will explore the AD 
“signature” of regional cortical thinning and whole brain cortical thinning on MRI for 

4 
 
 
 
 
 
 
 
 
 
 
valacyclovir compared to placebo. We will evaluate plasma acyclovir levels.  In the subsample with 
CSF acyclovir levels, we will examine CSF acyclovir levels and if a sufficient number of 
participants has LPs done for CSF, plasma/CSF acyclovir correlations will be examined. 
 
Inclusion Criteria: 
 
1. Females must be postmenopausal defined as 12 consecutive months without 
menstruation. 
2. Diagnosis of probable AD by NIA clinical diagnostic criteria. 
3. Folstein Mini Mental State (MMSE) score 18 to 28 (inclusive) out of 30. 
4. Clinical Dementia Rating (CDR) score of 1 (mild dementia). 
5. A family member or other individual who is in contact with the patient and consents to serve as 
informant during the study. 
6. Patient retains capacity to consent for him/herself or retains the capacity to identify a surrogate 
who will consent on his/her behalf. 
7. At screening, patients must test positive for serum antibodies to HSV1 or HSV2. Patients that test 
equivocal (index between 0.90-1.09; < 0.90 is negative and > 1.09 is positive) will repeat the test 
within 6 weeks at a repeat visit. If the results are negative at the second test, the patient will not enter 
the study. If the results are equivocal or positive at the second test (first test was equivocal), we will 
enroll the patient in the study because “equivocal” indicates the presence of antibodies that do not 
reach the minimum threshold. 
8. Use of cholinesterase inhibitors and memantine, and concomitant psychotropic medications (other 
than high- dose benzodiazepines), will be permitted throughout the trial. Doses of these medications 
will need to be stable for at least 1 month prior to study entry. Any changes to the medication will be 
documented in the participant research chart. Medications given for other medical reasons, e.g., anti-
diabetic or antihypertensive medications, will not be altered for the purposes of this trial and the 
patient’s primary physician may adjust such medications as medically indicated throughout the trial. 
Details of concomitant medication use will be documented at all visits and will be available for 
statistical analysis. 
9. For patients diagnosed with Mild Cognitive Impairment and CDR score of 0.5 (questionable 
dementia), if these patients have biomarkers of AD neuropathology with either a positive amyloid 
PET scan, positive fluorodeoxyglucose (FDG) PET scan of the brain, or positive findings for AD in 
CSF (low ABeta42 and high tau, p-tau protein levels) they will be eligible for the study. This applies 
to patients who already had an amyloid PET scan, FDG PET scan of the brain, or lumbar puncture, 
prior to recruitment into the protocol. 
 
 
Exclusion Criteria: 
 
1. Caregiver and/or participant is unwilling or unable to comply with study instructions. 
2. Patient has dementia predominantly of non-Alzheimer’s type, including vascular dementia, 
frontotemporal dementia, Lewy body dementia, substance-induced dementia. 
3. Modified Hachinski scale score greater than 4 
4. Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, bipolar 
disorder or current major depression by DSM-5 criteria. Prior history of major depression will not be 
exclusionary (25% of older adults have a lifetime history of major depression). 
5. Active suicidal intent or plan based on clinical assessment. 

5 
 
 
 
 
 
 
 
 
 
 
6. Current or recent (past 6 months) alcohol or substance use disorder (DSM-5 criteria). 
7. Current diagnosis of other major neurological disorders, including Parkinson’s disease, multiple 
sclerosis, CNS infection, Huntington’s disease, and amyotrophic lateral sclerosis. 
8. Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (small 
infarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological 
deficits will not lead to exclusion. 
9. Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases in the 
last 12 months will be excluded, but past history of successfully treated cancer will not lead to 
exclusion. 
10. Sitting blood pressure > 160/100 mm Hg Physician Evaluation 
11. Renal failure as determined by an estimated Glomerular Filtration Rate (GFR) < 44 
ml/min/1.73m2. 
12. Serum vitamin B12 levels below the normal range. 
13. Patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome will be 
excluded. 
14. Use of benzodiazepines in lorazepam equivalent doses equal to or greater than 2 mg daily. 
15. For patients consenting to lumbar puncture (40% of sample), this procedure will be conducted if 
there is no lower spinal malformation or other contraindication to lumbar puncture. 
16. For MRI, metal implants and pacemaker, and claustrophobia such that the patient refuses MRI. 
In our experience, these exclusions occur in less than 5% of patients with mild AD. MRI is required 
for VALAD. 
17. Radiation exposure in the prior 12 months that, together with 18F- Florbetapir and 18F-MK-
6240 PET, will be above the FDA annual radiation exposure threshold. This will be determined 
through study staff ( i.e. Principal Investigator, Study Physician) discussion with potential subjects at 
Screening, documenting inquiry about radiation history. If there is any history of additional radiation 
exposure in the past year; it will be reviewed with PET Center staff for their approval before 
proceeding. The combined radiation exposure from the maximum doses used for 18F- Florbetapir 
and 18F-MK-6240 is within the FDA limits for annual radiation exposure and the second scan in 
each patient will be done 18 months after the initial PET scan (for both radioligands). 
18. Severe vision or hearing impairment that would prevent the participant from performing the 
psychometric tests accurately. This will be a clinical determination by the study physician without 
formal testing or audiometry. 
19. Olfaction component: current upper respiratory infection (patient tested as soon as this 
improves), current smoker > 1 pack daily (past smoking has been shown not to affect UPSIT scores, 
UPSIT score < 12/40 (10 out of 40 is scored by chance in this multiple-choice test) indicating 
congenital anosmia. In our experience, less than 3% of cases are excluded for having one or more of 
these exclusionary criteria. If a patient is excluded from the olfaction component, the patient will 
still be eligible for the main protocol and all other study procedures. 
 
 
In the study sample, we anticipate 55% female and 45% male participants, 25% minorities 
comprising 12% African American, 12% Hispanic and 1% Asian. 
 
 
 
 
 
 
 

6 
 
 
 
 
 
 
 
 
 
 
Table 1. Study Procedures for the 78-week valacyclovir-placebo (VALAD) trial 
 
Procedure 
Screening 
0 
weeks 
2 
weeks 
12 
weeks 
26 
weeks 
52 
weeks 
78 
weeks 
Clinical assessment/physical 
exam/vital signs 
X 
X 
X 
X 
X 
X 
X 
Diagnosis (Consensus Dx at Weeks 0, 
52,78) 
X 
X 
 
 
 
X 
X 
ADAS-Cog11 
 
X 
 
X 
X 
X 
X 
MMSE 
X 
 
 
 
 
 
 
MoCA 
 
 X 
 
 
 
     X 
     X 
CDR 
X 
 
 
X 
X 
X 
X 
ADCS-ADL 
 
X 
 
X 
X 
X 
X 
CIBIC-plus 
 
X 
 
X 
X 
X 
X 
NACC/UDS 
 
X 
 
 
 
X 
X 
Modified Hachinski (from NACC) 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Serum anti-HSV antibodies with 
quantitative IgG and IgM 
X 
 
 
 
 
 
X 
SMAC blood chemistry 
X 
 
 
X 
X  
X 
Complete Blood Count 
X 
 
 
X  
 
X 
Plasma acyclovir levels 
 
 
 
X  
 
X 
*CSF acyclovir levels 
 
 
 
X  
 
X 
*CSF Neurofilament Light (NFL), 
ABeta, tau, p-tau 
 
X 
 
X  
 
X 
UPSIT olfaction test 
 
X 
 
 
 
 
X 
Apolipoprotein E genotype 
 
X 
 
 
 
 
 
MRI scan of brain 
 
X 
 
 
 
 
X 
18F-Florbetapir Amyloid PET Scan 
 
X 
 
 
 
 
X 
18F-MK-6240 tau PET scan 
 
X 
 
 
 
 
X 
* patients who agree to CSF studies 
 
 
Statistical Analysis Plan 
 
1. Introduction. 
The aim of the study was to evaluate the efficacy of Valacyclovir treatment in a 78-weeks, 
multicenter, randomized, double-blind, placebo-controlled, parallel-group treatment trial in 
participants with early Alzheimer’s Disease (AD) and positive serum antibodies (IgG or IgM) to 
HSV1 or HSV2. 
This statistical analysis plan provides more detailed descriptions of the statistical analyses 
conducted in the paper.  
 
2. Study Design  
One hundred and twenty participants with clinical diagnosis of probable AD or mild cognitive 
impairment (MCI), confirmed by a positive amyloid PET or FDG PET scan or a CSF AD profile, 

7 
 
 
 
 
 
 
 
 
 
 
were randomized to Valacyclovir or placebo at 1:1 ratio. Block randomization with varying 
block sizes (2 and 4) was used to reduce the risk of treatment allocation prediction by clinicians. 
Participants were evaluated at five scheduled visits (weeks 0, 12, 26, 52, and 78).  As a proof-of-
concept study, the target dose of Valacyclovir was 4 g per day -- at the higher end of the usual 
oral dosing range. Treatment began at 2 g per day (1 g twice daily), with the dose increased by 1 
g per day every two weeks until reaching either 4 g per day or the participant’s maximum 
tolerated dose. 
 
3. Outcome Measures. 
1) Cognitive and functional measures:  
•  Alzheimer’s Disease Assessment Scale – Cognitive Subscale 11 (ADAS-Cog 11), 
assessed at weeks 0, 12, 26, 52, 78; scoring range 0-70, higher scores indicate greater 
cognitive impairment.  (Primary) 
• Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-
ADL), assessed at weeks 0, 12, 26, 52, 78; scoring range 0-78, higher scores indicate 
better daily functioning. (Secondary) 
• Craft story delayed verbatim recall, assessed at weeks 0, 52, 78; scoring range 0-44, 
higher scores indicating better memory. (Secondary) 
• Montreal Cognitive Assessment (MoCA), assessed at weeks 0, 52, 78; scoring range 0 
to 30, higher scores indicating better global cognition. (Secondary) 
For all cognitive and functional measures, the outcome of interest is the change from 
baseline at each follow-up time point. The primary endpoint is the change from baseline to 
78 weeks. 
 
2) Imaging measures: 
• 18FFlorbetapir PET SUVR: Mean standardized uptake value ratio (SUVR) from the 
medial orbitofrontal cortex, anterior cingulate, parietal lobe, posterior cingulate, temporal 
lobe, and precuneus, normalized to cerebellar gray matter. 
• 18FMK-6240 PET SUVR (Medial Temporal): SUVR averaged across medial temporal 
regions including the amygdala, hippocampus, entorhinal cortex, and parahippocampus. 
• 18FMK-6240 PET SUVR (Global Mean): SUVR global mean normalized to cerebellar 
gray matter. 
• MRI Cortical Thickness: Mean cortical thickness across nine predefined brain regions. 
• MRI Hippocampal Volume: Volume of the hippocampus. 
All imaging measures were collected at baseline and 78 weeks. The outcomes are defined as 
the change in each measure from baseline to 78 weeks. 
 
4. Sample Size Calculation. 
The sample size calculation was based on the primary outcome: change in ADAS-Cog11 scores 
from baseline to 78 weeks, using the RMASS program for longitudinal studies.  Assuming a 
within-subject correlation of r=0.3 (moderate correlation) for repeated measures and a uniform 
dropout rate reaching 15% by 78 weeks, a total sample size of 130 participants (65 per arm) was 

8 
 
 
 
 
 
 
 
 
 
 
originally projected to detect Cohen’s d of 0.50 with 80% power at 5% significance level.  With 
approval from sponsor (NIA) and DSMB, the recruitment target was reduced to 120 participants 
due to pandemic-related recruitment delays and required study completion within the extended 
funding timeline.  For n=120, the minimum detectable effect size increased slightly to a Cohen’s 
d of 0.52. 
 
5. Statistical analysis 
The analyses were conducted on the Intent-to-treat (ITT) sample, i.e., all randomized participants 
according to the treatment that they were assigned. All hypotheses were tested at level of 
significance of 5%.  There was no adjustment for multiple statistical comparisons in this trial.  
All analyses were conducted using R.   
 
We first examined patients’ baseline characteristics to ensure that covariates were balanced 
between treatment and placebo arms. Continuous variables were summarized using means and 
standard deviations, while categorical variables were summarized using counts and percentages. 
 
Linear mixed effects models were used to evaluate the efficacy of Valacyclovir as compared to 
placebo on cognitive and functional outcomes. Specifically, for each outcome measure, we 
considered the following model 
Δ𝑌!" = 𝛽# + 𝛽$ ∗𝐺𝑟𝑜𝑢𝑝! + 𝜶∗𝑇𝑖𝑚𝑒!" + 𝜸∗𝐺𝑟𝑜𝑢𝑝! ∗𝑇𝑖𝑚𝑒!" + 𝛿𝑌!# + 𝑏! + 𝜖!",         (1)    
where Δ𝑌!" is change of the outcome measure (week 𝑡 minus baseline) for subject 𝑖 at timepoint 
𝑡, 𝐺𝑟𝑜𝑢𝑝! is the treatment group indicator for subject 𝑖 (1= Valacyclovir and 0=placebo), 𝑇𝑖𝑚𝑒!" 
is the visit time point (treated as a categorical variable), 𝑌!# is baseline value of the outcome 
measure for subject 𝑖, 𝑏! is a subject-specific random intercept, and 𝜖!" is the unexplained 
residual error term.  (𝛽#, 𝛽$, 𝜶, 𝜸, 𝛿) are fixed effects parameters. The efficacy of Valacyclovir 
versus placebo at each time point was tested by forming contrasts of the fitted model. The model 
was further adjusted for key demographic and genetic variables, including age, sex, and 
apolipoprotein E ε4 carrier status. Missing data on outcome variables were dealt with by using 
(longitudinal) linear mixed effects models which do not require complete measurements under 
the “missing at random” assumption.  
 
For the primary outcome (ADAS-Cog 11), a series of sensitivity analyses were conducted to 
evaluate the robustness of the findings across key clinical subgroups and under different analytic 
assumptions. These included: 1) a per-protocol analysis limited to participants who completed 
the study; 2) a subgroup analysis of participants who received cholinesterase inhibitors or 
memantine; and 3) a subgroup analysis of participants with a baseline 18F-Florbetapir PET 
SUVR ≥ 1.15 (amyloid positive for AD). 
 
Linear regression analyses were performed to evaluate the effect of Valacyclovir on changes in 
imaging outcomes from baseline to 78 weeks. Each model included the baseline value of the 
corresponding imaging measure as a covariate to control for initial differences. The models were 

9 
 
 
 
 
 
 
 
 
 
 
further adjusted for key demographic and genetic variables, including age, sex, and 
apolipoprotein E ε4 carrier status. To assess the robustness of the findings and address potential 
bias due to missing data at follow-up, sensitivity analyses were conducted using weighted linear 
regression. In these models, the weights were calculated as the inverse probability of a subject 
being a completer, with probabilities estimated using logistic regression with ridge regularization 
to handle potential collinearity among baseline variables. 
 
To assess safety, adverse events were systematically evaluated. For each type of adverse event, 
number and proportion of participants who experienced the adverse event was reported and 
compared by treatment arms using Fisher’s exact test. In addition, plasma acyclovir and CSF 
acyclovir concentrations obtained at 12 weeks and 78 weeks were summarized using means and 
standard deviations. 
 
 
Coordination of Trial: 
 
The National Institute on Aging (NIA) has issued funding for the project to Dr. Devanand at Columbia 
University (CU).  CU is the prime recipient with subcontracts to RFMH, NYU and BAI.  Procedures are 
conducted at both CU and NYSPI, as well as at NYU and BAI as described in this manual. The research teams 
at NYSPI, NYU and BAI are responsible for the proper conduct of project and data management. Coordinating 
Center (CU/NYSPI) staff will oversee all research operations in collaboration with NYU and BAI. NYSPI 
staff will be responsible for communications with the NYSPI Institutional Review Board (IRB), Data 
Coordinating Center (DCC), Research Pharmacy, and other involved personnel and organizations.  
 
The project began before NIH instituted sIRB requirements for NIH-supported multicenter trials.  Therefore, 
the three sites at Columbia/NYSPI, NYU and Banner have their own IRBs for each of their sites participating 
in this protocol. 
 
NYU staff will be responsible for communication with the NYU IRB on an independent basis (with 
notification/report provided to the Coordinating Center team before and after their IRB submissions. 
Coordinating Center staff will notify the NYU team of any new material or amendment to be submitted to the 
NYU IRB.) The team at NYU will first communicate with the program manager and other team members at 
Coordinating Center in order to establish that there is any question or issue requiring the collaboration of the 
DCC, Research Pharmacy, and other involved personnel and organizations. As the Coordinating Center, 
Columbia University/NYSPI must be made aware of any issues transpiring at a subsite in order to oversee and 
collaborate on the appropriate solution.  
 
BAI staff will be responsible for communication with the WIRB on an independent basis (with 
notification/report provided to the Coordinating Center team before and after their IRB submissions. 
Coordinating Center staff will notify the BAI team of any new material or amendment to be submitted to the 
WIRB.) The team at BAI will first communicate with the program manager and other team members at 
Coordinating Center in order to establish that there is any question or issue requiring the collaboration of the 
DCC, Research Pharmacy, and other involved personnel and organizations. As the Coordinating Center, 
Columbia University/NYSPI must be made aware of any issues transpiring at a subsite to oversee and 
collaborate on the appropriate solution.  
 
Regulatory compliance 
 

10 
 
 
 
 
 
 
 
 
 
 
ALCOA-C principles are implemented. When errors are made on source documents or CRFs, corrections 
should be made using a single line through, signed, and dated. Investigators should sign and date source 
documents in wet ink; signature stamps or signature images generated in Word or other software programs 
should not be utilized.  
 
All research staff will be required to complete courses on the following NYSPI internal website, including the 
course on “Essential Documentation and Regulatory Binders”.  
• 
OMH HRPP Research Education Course Library: intranet.nyspi.org/research/hrpp/education  
 
Specific trainings for the PI, study physicians, and other patient-interfacing research staff (research assistants, 
research coordinators, program managers) are listed as follows: 
• 
PI: CITI training, HRPP training, RFMH C-SSRS Training, IRB protocol training 
• 
Study physician: CITI training, HRPP training, RFMH C-SSRS Training, IRB protocol 
training 
• 
Other staff: CITI training, HRPP training, RFMH C-SSRS Training, neuropsychological 
assessment training, phlebotomy training, MRI training, PET training, IRB protocol training 
 
 
 
NYSPI Institutional Review Board 
The NYSPI Institutional Review Board (IRB) will review this protocol on an annual basis and must be kept up 
to date on any changes made to protocol throughout the lifecycle of the study (from start up to close out). 
Serious Adverse Event (SAE) reports and follow-up correspondence relevant to SAE reports will need to be 
submitted as well. Any reports from the Data Safety and Monitoring Board (DSMB) or significant 
notifications from sponsor/NIA program officer will need to be reviewed by the IRB.  The Columbia 
University IRB agreed to accept the transfer of this NYSPI protocol based on NYSPI IRB protocol approved 
procedures during the research pause that began in June 2023 due to circumstances unrelated to this protocol.  
The NYSPI IRB permitted this protocol to continue because this is a clinical trial with active participants but 
required the remaining active participants to be transferred to the NYU site to complete their final study visit 
procedures.  The Columbia University IRB agreed with this plan and all annual renewals will henceforth be 
done through the Columbia University IRB. 
 
For all IRB protocol submissions, all relevant documents must be attached when submitting the Protocol 
Summary Form (PSF) and consent forms. During the review process, coordinators should attach all documents 
previously submitted, to allow the IRB to consider the entire document history in the current review cycle. 
 
NYU Institutional Review Board 
The NYU IRB will review this protocol on an annual basis and must be kept up to date on any changes made 
to protocol throughout the lifecycle of the study (from start up to close out). Serious Adverse Event (SAE) 
reports and follow-up correspondence relevant to SAE reports will need to be submitted as well. Any SAE 
taking place with an NYU subject will first be reported to the NYU IRB, then to the NYSPI IRB (see “SAE” 
section for full details) if appropriate.  Any reports from the DSMB or significant notifications from 
sponsor/NIA Program Officer will need to be reviewed by the NYU IRB. NYU must send NYSPI stamped 
copies of all material approved by NYU IRB for this protocol. Though a single IRB will not be used, the 
NYSPI IRB may still request to review any and all documents approved by the NYU IRB.  
Since this protocol is now transferred to the Columbia IRB under WCG with a reliance agreement, annual IRB 
renewals will henceforth take place through Columbia and WCG. 
 
 
Western Institutional Review Board (WIRB, the IRB of record for BAI) 

11 
 
 
 
 
 
 
 
 
 
 
The WIRB will review this protocol on an annual basis and must be kept up to date on any changes made to 
protocol throughout the lifecycle of the study (from start up to close out). Serious Adverse Event (SAE) reports 
and follow-up correspondence relevant to SAE reports will need to be submitted as well. Any SAE taking 
place with BAI subjects will first be reported to the WIRB, then to the NYSPI IRB (see “SAE” section for full 
details) if appropriate.  Any reports from the DSMB or significant notifications from sponsor/NIA Program 
Officer will need to be reviewed by the WIRB. BAI must send NYSPI stamped copies of all material approved 
by WIRB for this protocol.  The NYSPI IRB may still request to review any and all documents approved by 
the WIRB. 
 
National Institute on Aging Progress Reports 
This trial is funded by a federal grant awarded by the National Institute on Aging (NIA). An annual grant 
progress report to the NIA will be generated by site staff each spring.  
Research coordinators (RC) are responsible for generating the following components of the NIA progress 
report and sending it to the program manager, who will edit the documents and send them to the PI. Sections 
can be copied from the prior progress report, if there was one, and there have not been major changes in 
project aims: 
 
1. Progress Report: 
a. Aims: This section should be copied verbatim from the grant and reviewed for accuracy against 
amendments to the protocol.  
b. Studies and Results: This section contains a detailed list of all substantial IRB-approved changes to 
the protocol. This information should be copied directly from the memos accompanying amendments 
submitted to the IRB and reviewed for accuracy. Summarize this section if it exceeds one page.  
c. Subject Recruitment: This section contains the number of subjects screened and recruited, as well as 
demographic information about recruited subjects. This section also includes information about SAEs 
and AEs. Specify SAEs in detail, summarize AEs.  
d. Significance: This section should be copied verbatim from the grant and reviewed for accuracy 
against amendments to the protocol. 
e. Plans: This section discusses plans for the next year; specifically pertaining to recruitment.  
f. 
Publications 
g. Project generated resources 
 
2. Human Subjects Section: This section of the grant must be reviewed for accuracy against amendments 
to the protocol.  
 
3. Inclusion Enrollment Report: Contains demographic information about enrolled patients. 
 
 
Contact information: 
 
NIA Program Officer: 
Laurie Ryan, PhD 
301-496-9350 
ryanl@mail.nih.gov 
NIA Research Program 
Analyst: 
Alvin McKelvy 
Phone: 301-827-5492 
alvin.mckelvy@nih.gov 
 
 
 

12 
 
 
 
 
 
 
 
 
 
 
Data Coordinating Center 
Dr. Howard Andrews will chair the DCC. Tejal Shah will also work as part of the Data Coordinating Center 
(DCC). The DCC will standardize the data entry procedures and provide consultation to all study staff during 
the trial. The DCC will have the following responsibilities: develop and implement data forms and collection 
procedures; lead data management and data security; carry out quality control for data entry; produce reports to 
the NIA, DSMB, and lead site; assist with statistical analyses; assist with trial closeout. 
 
Contact information:  
 
DCC chair: Howard Andrews, PhD 
646-774-5468 
andrews@nyspi.columbia.edu 
Tejal Shah 
732-668-7706 
tcs2113@cumc.columbia.edu 
 
Database Management 
Study coordinators at NYSPI, NYU and BAI will enter deidentified data collected in this study. Each study 
coordinator who will be entering data will have their own account login through the Citrix access gateway. The 
database for this study will be monitored and administrated by the DCC at NYSPI and the program manager. 
 
Data entry must be completed within 3-5 days of study visit completion. Data entry must be double checked 
and verified with the source documents by another coordinator and the program manager. The study 
coordinator running a second check of data entered should flag and correct any errors noted in the database 
and/or source documents. The second data check should be run 1-2 days after the initial data entry by the first 
RC. The program manager will run source document verification against what is entered into the database for 
all protocols on a rotating basis (acting as a third check) and log any discrepancies on a protocol specific 
spreadsheet. All discrepancies noted by the program manager will be followed up on within 3 days.   
 
Questions regarding the study database from NYSPI study coordinators should be directed to our contact at the 
DCC, Tejal Shah. Questions regarding the study database from NYU study coordinators should be directed to 
one of the NYSPI study coordinators, who will then reach out to Tejal Shah. There will be one NYSPI study 
coordinator delegated the task of consistently sending database queries from both NYSPI and NYU to Tejal. 
 
All changes to the database should be recorded in the ‘Changes to the ANTIVIRAL Database’ log kept in the 
geriatric psychiatry server, maintained by NYSPI staff.  
 
Data Safety and Monitoring Board 
Dr. Gary Small will chair the Data Safety and Monitoring Board (DSMB). The DSMB will consist of Dr. Gary 
Small (Hackensack Meridan Health), Dr. Jeffrey Cummings (Cleveland Clinic), and Dr. Richard Whitley 
(University of Alabama).  
The DSMB responsibilities are to:  
• 
Review the research protocol, amendment, informed consent documents and plans for data safety and 
monitoring; 
• 
advise the NIA on the readiness of the study staff to initiate recruitment; 
• 
evaluate the progress of the trial, including periodic assessments of data quality and timeliness, 
recruitment, accrual and retention, participant risk versus benefit, and other factors that can affect 
study outcome; 
• 
consider factors external to the study when relevant information becomes available, such as scientific 
or therapeutic developments that may have an impact on the safety of the participants, the ethics of the 
trial, or trial conduct; 
• 
review study performance, make recommendations and assist in the resolution of problems reported 
by the PI; 
• 
protect the safety of the study participants; 

13 
 
 
 
 
 
 
 
 
 
 
• 
report to NIA on the safety and progress of the trial;  
• 
make recommendations to the NIA and the PI concerning continuation, termination or modifications 
of the trial based on the observed beneficial or adverse effects of the treatment under study; 
• 
ensure the confidentiality of the study data and the results of monitoring; and,  
• 
assist the NIA by commenting on any problems with study conduct, enrollment, sample size and/or 
data collection. 
 
The DSMB will discharge itself from its duties when the last participant completes the study. 
 
The DCC will be responsible for preparing data and completing data analyses requested by the DSMB. The 
study team will hold teleconferences with the DSMB every 6 months (or more frequently based on subject 
recruitment and/or participant safety concerns) at the call of the chairperson and/or NIA program official. The 
DSMB will be notified of SAE reports from the study site on an ongoing basis. The program manager will be 
responsible for scheduling DSMB teleconferences as well as generating an agenda for those calls.  
 
To schedule DSMB teleconferences, the program manager will send a Doodle poll to all required attendees: 
Coordinating Center and sub-site PIs, Dr. Howard Andrews, NIA Program, DSMB Chair and members, as 
well as DSMB members’ assistants if needed (with the DSMB members cc’d in the initial scheduling email). 
Try to schedule at least 3 months out, as required staff tend to be very busy and often in different time zones. 
Either Dr. Laurie Ryan or Dr. Alvin McKelvy from NIA must be on the call. 
 
Contact information: 
 
Chair of DSMB 
Gary Small, MD 
Gary.Small@hmhn.org 
Hackensack Meridian Health 
30 Prospect Ave, Hackensack, 
NJ,07601 
Assistant: Melissa Fermin 
Melissa.Fermin@hmhn.org 
Melissa: 551-996-2008 
Dr. Small: 201-294-3132 
DSMB Member 
Jeffrey Cummings, MD 
cumminj@ccf.org 
Cleveland Clinic 
Las Vegas, NV 
cumminj@ccf.org 
Assistant: Mary Kay Tarkanian 
tarkanm@ccf.org 
702-701-7926 
DSMB Member 
Richard Whitley, MD 
rwhitley@peds.uab.edu 
University of Alabama 
Birmingham, AL 
rwhitley@peds.uab.edu 
Assistant: Sara Davis, 
sdavis@peds.uab.edu 
205-996-7804 
 
The study team is responsible for compiling a blinded report prior to each DSMB teleconference. This report 
needs to be approved by Dr. Devanand and submitted to Howard Andrews at least 2 weeks before the 
scheduled teleconference. This report will include: 
1. Project Summary 
a. Major Activities: This section lists all IRB-approved changes to the protocol since the previous 
teleconference.  
b. Subject Recruitment: This section contains the number of subjects screened and recruited, as well 
as demographic information about recruited subjects. 
2. Serious Adverse Events: Each SAE report must be included in its entirety, including any information 
from follow-up correspondence with the IRB after the initial report.  
3. Patient Flow Charts 
4. Recruitment Rate by Month 
5. Baseline Demographic and Clinical Summary Statistics: This section is completed by Dr. Howard 
Andrews from the database. 

14 
 
 
 
 
 
 
 
 
 
 
6. Unblinded DSMB report.  Dr. Howard Andrews generates the unblinded report directly to DSMB 
members with participant data by treatment assignment.  Blinded study staff are not privy to this 
information. 
 
DSMB Communications  
All key communications (including protocols, manual of procedures, reports, recommendations and other 
study-related correspondence) will be distributed by Dr. Devanand and/or the data management team led by 
Dr. Howard Andrews to DSMB board members and NIA program officials.  
In between meetings, the DSMB would like to be notified of, and review key changes to the protocol requiring 
IRB approval. These communications should be generated by site staff (i.e. NYSPI program manager, who 
will produce official reports for coordinating center and sub sites), reviewed by Dr. Devanand, then sent to the 
DSMB chair and members. An example of this would be amendment to protocol: the DSMB would like to be 
notified of any amendments to protocol after they have been submitted and approved by the local IRB. Report 
of amendment should be coalesced with supporting documentation for the DSMB’s review by the NYSPI 
program manager, reviewed by Dr. Devanand, then disseminated by NYSPI program manager to DSMB 
members in turn.  
In the case of an SAE, an expedited report of each SAE will be submitted by email to the DSMB chair and 
members, and NIH Program Officer, within 24 hours of the event being reported to the PI. 
A note on scheduling and confirming Dr. Howard Andrews for DSMB Teleconferences: To ensure Dr. 
Andrews’s timely attendance at DSMB Teleconferences, the study team members (lead by the program 
manager) should follow these steps: 
1. Send Dr. Andrews an Outlook invitation stating the date and time of the teleconference. Ensure Dr. 
Andrews accepts the invitation at least 2 weeks prior to the teleconference.  
2. Place 2 reminder calls to Dr. Andrews the week of teleconference (one call the day before, and another 
call 3 days before the conference. Ensure that you receive verbal confirmation from Dr. Andrews.  
3. Keep Dr. Andrews on all reminder emails pertaining to the teleconference. 
 
 
Recruitment: 
Recruitment is multifaceted and involves a variety of sources. Each source must be managed meticulously, and 
the relationships involved with each must be maintained accordingly. A focus on recruitment for this study is a 
high priority. 
 
At all stages of recruitment, two key points should be emphasized:  
1. This study has a simple two-step screening and consent process. Potential patients may not be eligible due 
to HSV seronegativity based on a blood draw in the clinic followed by the sample being assayed at Quest 
diagnostics for HSV1 IgG and IgM, and HSV2 IgG and IgM levels.   
2. Patients will have an hour to discuss the study procedures with a physician at their screening visit. 
 
 
Recruitment Sources (Recruitment Closed at this time) 
1. 
Advertisements (NY Daily News, NY Post,) (NYSPI and NYU) 
2. 
Community Advertising (NYSPI and NYU) 
3. 
DPO (Neurological Institute) Physician Referrals (NYSPI Specific) 
4. 
MDC (NYSPI Specific) 
5. 
CEAD (NYSPI Specific) 
6. 
TOPAD Cross Referral between Dr. Luchsinger/Yefrenia Henriquez and Dr. Devanand  
7. 
NIA Email Blast (NYSPI and NYU) 
8. 
Registries (NYSPI and NYU) 
9. 
NYU’s Primary Referral Sources 
• Advertisements 

15 
 
 
 
 
 
 
 
 
 
 
StudyKik **ended 05/10/2022** 
• Site: https://studykik.com/login  
• Accountable Party / Timeline: PM/monthly plan 
• Process: Reviews and sends Studykik rep IRB approved 
Ad language for listing -> Loop in Cileyn and Ed for 
payment -> Check if listing is active -> Review new sign-
up daily -> Assign potential participants to RAs for phone 
screen -> Check in with RA about contact status -> 
Update in Studykik & Recruitment tracker 
Contact: 
• Ricky May  
• 1315 Lincoln Blvd, Suite 270, Santa Monica, CA 90401 
• (919) 257-6675 
• ricky.may@studykik.com 
 
• Facebook (Qualtrics) **stopped 05/10/2022** 
• Site: https://login.qualtrics.com/login?lang=en  
• Accountable Party / Timeline: PM / Monthly  
• Process: Ads need to be renewed monthly-> PM reviews 
new sign up daily -> Assign potential participants to RAs 
for phone screen -> Check in with RA about contact 
status -> Update in recruitment tracker 
Contact:  
• Gabriella Dishy, MA  
• New York State Psychiatric Institute (NYSPI) 
• (646) 774-5388  
• gabriella.dishy@nyspi.columbia.edu 
 
Metro **stopped 05/10/22** 
• Accountable Party / Timeline: PM & BO / Monthly  
• Process: Ads need to be renewed monthly by email -> 
Betty’s desk phone number is on the ad, BO gets calls -> 
BO assigns potential participants to RAs for phone screen 
-> Check in with RA about contact status -> Update in 
recruitment tracker 
Contact: 
• Peter J. Blankenstein (Healthcare Sales Director Schneps 
Media) 
• One Metrotech Center North, Third Floor. Brooklyn, NY 
11201 
• Phone: (973) 454-2412 
• Email: peter.blankenstein@metro.us 
 
 
 
As with all studies in the Memory Disorders Clinic, we have created an advertisement for this Anti-viral study. 
Advertising is confirmed by the program manager and department administrator. All accounts are already in 
place. At the end of each month, the program manager will reach out to the primary contact for each respective 
newspaper to renew the advertisement for the following month. The frequency and size may be adjusted. Once 
the program manager has given the specifics, they will send an insertion order form (a one-page summary of 
the order). The program manager will have to print this form, sign it, scan it, and send it back to the primary 

16 
 
 
 
 
 
 
 
 
 
 
contact. Hard copies of all records will be maintained. The Metro financial teams will send an email at the end 
of each month with the invoice for the advertisements and the program manager is responsible for paying them 
in a timely manner.  
• Community Advertising: (NYSPI and NYU) 
Advertisement in the form of fliers, posters, print, etc. anti-viral RC will compose various advertising material 
(in English and Spanish) for review by Dr. Devanand then complete submission to NYSPI IRB. All fliers and 
brochures must be approved by NYSPI IRB first and must have an IRB stamp placed on them. Advertising 
material will be sent to sub sites from coordinating center for review and approval by sub site IRB. Sub sites 
will add their appropriate contact information to recruitment material prior to submission to IRB and once 
material is approved, post in locations as approved by institution.  
Ads (primarily the 1-page VALAD flier) should not be placed in the Neurological Institute (NI3) unless 
specifically approved by Dr. Lawrence Honig and team. They may be placed around PI, the AIM East Clinic, 
and approved areas in Presbyterian Hospital. They should also be handed out at any aging lecture. 
 
• DPO (Neurological Institute) Physician Referrals: (NYSPI Specific) 
Primary Contact: Lamprine N. Whitney (Nitsa) MS, RD, RN 
 
Email: lnw2109@cumc.columbia.edu Phone: (212) 342-5615 
 
 
Taub Recruitment and Referral Procedure: 
For referred patients who are potentially eligible for multiple studies: Taub staff will initiate contact, discuss 
options, and send study information to patients. Taub staff will offer patients the possibility of hearing more 
about the study from the study team. If the patient(s) agree to hear more, Taub staff will refer accordingly and 
will follow up on which study the patient(s) decided to participate in. 
For referred patients who are potentially eligible for one study: Taub staff will forward the referral directly 
to the study team to avoid multiple contacts. The Taub staff will follow up with the team regarding screening 
outcome. 
For patients who were identified as potentially eligible but were not referred to us: 
Taub staff will not contact the patient. If the clinician agreed that the study team may contact the patient(s), the 
study team will inform Taub staff prior to contacting the patient so that Taub staff can make sure that the 
patient is not being recruited or participating in other studies. No patient will be contacted without the 
knowledge of the treating clinician. Taub staff must be informed regarding the outcome of research staff 
contact to patient so that they may document and track study recruitment. 
For outside referrals: Taub staff will prescreen any interested participant, recruit for all potential studies, and 
refer to the study team accordingly, and will follow up on regrading which study the patient decided to 
participate in. 
Monthly updates to PI and study team: A monthly report will be sent to the PIs with the status of referred 
patients per study.  
 
In-person Recruitment 
When a referring physician has a potential research patient and their caregiver(s) in the office for a scheduled 
visit, they may call Dr. Devanand and/or the RC to come over and discuss the study. RC’s should always be 
ready for an in-person presentation as this is a highly effective resource for recruitment. Dr. Devanand and/or 
the RC will be ready with a consent packet and some basic screening forms including the MMSE and calendar. 
This is an opportunity to build rapport and explain the study in detail. We may find out that a patient/family is 
not interested, that they need more time to think about their involvement, or that they would like to schedule an 
evaluation as soon as possible. After this interview, the RC needs to follow up within the week and finalize the 
decision about whether the patient joins the study based on communications with the 
patient/caregiver/referring physician as appropriate. 
 
As a rule, if a patient with whom a RC has previously discussed the VALAD protocol (by phone, over email, 
etc.) is going to be seen at the NI3 for a DPO appointment, the coordinator who previously spoke with that 
patient must meet with the patient before or after their appointment, to follow up, further discuss VALAD 

17 
 
 
 
 
 
 
 
 
 
 
screening and plan an in-person screen. Consents and a 1-page ad will be brought to the patient for reference. 
We know when patients are being seen based on patient names reviewed during weekly pre-screening EPIC 
review, and corresponding email sent to Nitsa Whitney. If old medical records cannot be found in EPIC, 
CROWN records are still available for review. 
 
The RC will email or call the DPO provider 1-2 days prior to the patient’s appointment, and let the MD know 
that we would like a few minutes to discuss VALAD with the patient. If the MD isn’t interested in the RCs 
visit to NI3, we offer the patient the opportunity to come to NYSPI with us after their appointment, for an in-
person screen (patient must come with a caregiver in this case). Outcomes will be presented at the Tuesday 
Research Meeting. 
 
Prescreening 
To comply with the Health Insurance Portability and Accountability Act (HIPAA) regulations, the site applied 
for a partial waiver of HIPAA. The study team at NYSPI was granted a Request for HIPAA Waiver 
Authorization and/or Waiver of Consent. The NYSPI team was granted a partial waiver for telephone screens 
and a full waiver for the purpose of accessing an existing database or records to identify potential research 
subjects. Recruitment for this study depends on this waiver and ability to prescreen because it is not practical 
for the attending physicians to screen for their patients’ eligibility themselves. Therefore, the research study 
staff needs to identify potential research participants before suggesting that the attending physicians and Nitsa 
discuss the study with their patients.  Recruitment ended before IRB protocol transfer from the NYSPI IRB to 
the Columbia IRB.  Therefore, the Columbia IRB did not require their own HIPAA waiver documentation and 
approval for recruitment of participants in this protocol. 
 
Prescreening patients for potential eligibility is a necessary practice for effective recruitment in this study. 
What follows is a general description of how to prescreen based on practices at NYSPI.  
 
Procedure: Communication with Nitsa and DPO Providers  
• The RC reviews possible participants from lists of patients scheduled to see DPO Providers in the week to 
come. Pre-screen eligibility is determined through comparing EPIC records against key inclusion/exclusion 
criteria.  
Procedure: Responding to Direct Referrals from Physicians  
Note: This procedure applies when a physician directly emails patients to Dr. Devanand or a research 
coordinator. When physicians refer through Nitsa, all further communication and updates should follow the 
‘Communication with Nitsa and DPO Providers’ procedure above.  
1. First, review in EPIC whether or not the patient is eligible or close to being eligible. MMSEs from 18-28 
are acceptable.  
a. If a patient is clearly not eligible, include that in your response to the physician.  
b. If the patient is eligible, gather as much information as possible about the patient from EPIC. This 
includes where they live, who the informant is, and whether there are any practical issues affecting 
recruitment (e.g. the patient is living in Florida for 3 months).  
2. Respond to the physician email. 
   a. Dr. Devanand and all relevant study staff.  
b. Contact the patient/caregiver as appropriate.  
c. Update the provider within 24 hours regarding the patient’s status: the patient is not interested; the 
patient is scheduled for a screening visit; the patient is considering the study but has not made a final 
decision. 
d. For patients who are yet to make a final decision, the process of follow up (calls and email) needs to be 
completed within the week. The following steps are suggested: 

18 
 
 
 
 
 
 
 
 
 
 
• Inform the patient/caregiver that they may speak with an MD to discuss study participation if they wish.  
If patients would like to speak with the aforementioned providers, phone numbers will be provided. 
• For patients who do not wish to speak with an MD, inform them that you will reach out again in 3 days 
to follow up.  
• When reaching out 3 days later, be ready to answer any follow up questions. If the patient still needs 
more time, inform them that you will contact them again in 2 days. If the patient is still unsure at that 
point, defer to investigational staff regarding additional follow up and continued contact. We do not 
want to keep potential patients in a pending status for more than 5 business days.  
• In all phone calls, offer the option of coming in for a screening visit to meet with the research team and 
discuss any issues. We must always stress that we as the research team are here to address 
issues/concerns, whatever they may be. Be as specific as possible when offering to schedule the 
screening visit (i.e. “I have just had an opening free up for this Thursday at 1:00pm. Would you be 
available to come in for a screening visit then?”). In cases where the RC has not been able to schedule a 
screen for a patient despite reaching out on multiple occasions (at least 3 times with no success), the RC 
will send out a follow up letter with investigator approval. Ideally the screening visit should involve the 
patient and caregiver.  In some cases, the caregiver may want to come alone to discuss the study, and 
that is also acceptable. 
• Update the tracker accordingly and provide an update to the referring provider after each contact with an 
unsure patient (within 24 hours). When the research coordinator is unable to schedule a patient for a 
screening visit, the patient should be taken off the “Pending Screening” section of the tracker and moved 
onto the “Archived” tracker.  
Very important: When a DPO provider directly refers one of their patients to the VALAD study, we screen 
for VALAD first and do not consider the respective patient(s) for any other protocol at MDC. In the case of 
VALAD screen failure the RC must first ask the referring provider whether or not he/she approves of his/her 
patient being considered for any other study. We can query the referring provider about other protocols 
his/her patient may be eligible for as soon as VALAD screen failure is fully elucidated.  
 
Phone Screens: The following phone screening script will be used: 
*Verbal consent must be obtained before continuing with phone screening. All patients/informants who 
discuss participation in the trial need to be recorded on a phone-screen log. Coordinators should express to 
callers that we are offering a free screening evaluation to a research study without any initial commitment 
required. 
During the phone screen, staff must explain compensation details to subjects and/or caregivers. “We are 
required to mention the total compensation for participation in the protocol.  For subjects who complete 
Lumbar Puncture the total compensation will be $880.00; for those who do not complete LP, the total 
compensation will be $580.00. We will also reimburse for transportation.”   
 
Contact information for informants should be collected during phone screening as well, we will implement this 
by using and completing the “Patient Tracking Form” in full during in person screening. 
 
Whenever calling a patient directly the RC should ask the patient if they can also speak to their family member 
or other caregiver if applicable. If they say yes, then speak to the family member as well to make sure 
everyone is on board and to identify the informant and to confirm appointments, etc.  
 
 Initial Phone Call: 
First make sure that you are speaking to the correct person, or ask for the correct person, e.g., patient or 
patient’s spouse, at the start of your phone call. 
Hello. My name is ______. I am calling from Columbia University Medical Center (or NYU) I understand 
that you called in response to an advertisement for a research study for Alzheimer’s disease treatment. 

19 
 
 
 
 
 
 
 
 
 
 
If referred by another source, state that explicitly and start by identifying who you are in relation to the 
referral source, e.g., I work with Dr.______ as a research coordinator, and I understand that he spoke with 
you about our antiviral treatment study in patients with Azheimer’s disease. 
I am looking for Mr/Mrs/Ms._________. 
(We must identify who will be the interviewee: patient or caregiver? If caregiver, we need to state their name 
and relationship to the patient). 
Do you have a few minutes to discuss this with me? (if yes) 
Great, let me start by asking you a few brief questions related to you/your loved one’s health. If these 
questions are difficult to answer, or you need to take a break, please let me know.  
(if no) Ok, let me know a good time and number to call you back.  
 
The following scripted section applies to patients responding to advertisements only and should be 
skipped for patients referred from the DPO/other known evaluation source, e.g., MDC. 
Do you/your loved one have a diagnosis of Alzheimer’s disease?  
 
[If no, are you concerned about your memory?] 
 
[When did the concerns begin?] 
 
[Specific memory concerns:] 
Have you been evaluated by a neurologist? If so, for what reason?  
(If patient has completed neuropsych measures within 3 months, the scores can be used for initial visits 
in the study) 
Have you been evaluated by a psychiatrist? If so, For what reason? 
Are you taking any medications?  
 
[If yes, duration & reason:] 
MRI: Claustrophobia or metal implants 
If female: still menstruating? Approximate date for LMP? 
Do you ever use alcohol or other substances, including marijuana? I understand that some of these 
questions are very personal. All information discussed during this call is kept confidential.  
(If yes, how often?) 
Are you involved in any other research studies? 
(If yes, take note) 
 
For DPO/MDC/other known referral source:  
The conversation needs to be resumed here after skipping the above questions. Reminder: if speaking 
with a patient who comes from the DPO, state: “I work with Dr. Huey, Dr. Bell, etc.” or with whomever 
that patient sees clinically in DPO. There needs to be a sense of clinical cohesion set forth in script.  
 
Screening Script  
Based on our discussion today (or based on DPO referral), it seems like this study may be a good fit for you. 
Our screening and consent is a two-step process. The first step is simple. We can schedule you and your loved 
one (dependent upon if speaking with the patient directly or family member/caregiver) to come into our clinic 
for a simple blood test that checks whether you have been exposed to the common viruses treated by the 
antiviral medication used in this study. About half of the population is positive for the virus. If the results of the 
blood test are positive you may be eligible to participate in the study and a study physician will discuss the 
details with you. If the results are negative, you will not be eligible, and we will review other available studies 
for which you may be eligible, or we will give you an appropriate referral.  
If you are interested, we have the following appointment slots available for you (list 3 possible dates and 
times). Which one of these openings works best for you and your (insert either patient info or informant info 
depending on who is speaking)?  
 
Study description: 
In this study, which is funded by the National Institutes of Health, we are evaluating a new therapy for mild 
Alzheimer’s disease: valacyclovir, which is a widely used generic and safe, FDA approved anti-viral 
medication. We are conducting the first-ever clinical trial to address the theory that viruses, particularly 

20 
 
 
 
 
 
 
 
 
 
 
herpes simplex virus, may cause or contribute to the pathology of Alzheimer’s disease. Basic science studies 
show that anti-viral drugs are effective in lowering brain amyloid and tau, which are hallmarks of Alzheimer’s 
disease.   
 
The blurb below is only to be read to those patients who directly inquire regarding additional information: it is 
better to leave these points to be discussed in person and stick to the main points of the 2-part screen on the 
phone, seeing as the study design, procedures, and medications may not be relevant to those who won’t 
qualify, and could serve as a deterrent if miscommunicated or misunderstood): 
 
The study is a year and a half, involving roughly 9 visits to our clinic. During your visits, we will conduct 
neuropsychological assessments (memory testing, various pencil & paper tasks, remembering word lists, 
stories, etc.). You will also meet with physicians who will monitor your condition throughout the study. During 
some of your visits, you will have blood drawn, have an MRI, and PET-scanning. Visits may last from one to 
four hours at the beginning and end of the study, with shorter visits of one to two hours in the middle of the 
study. For the entirety of the study, you will be randomized (i.e. assigned by chance) to a daily dose of either 
valacyclovir or a placebo (i.e. inactive/sugar pill). Study staff will always be available to work with you and 
answer any questions you may have. 
 
We will leave mention of the LP for the in-person conversation with the study MD. If the patient/caretaker 
asks about it specifically, mention that he/she will be able to discuss this with the physician at the screening 
appointment. Know what you don’t know and leave specific conversations for the appropriate study team 
member.  
 
Completing the call  
Ask the patient/caretaker if they have any remaining questions, comments, or concerns. Remind them again of 
their appointment date and time/next steps for scheduling the screen. 
 
What to bring to the visit: 
The patient should bring a list of his/her current medications, his/her medical records (though not a limiting 
factor in scheduling a screen), a government issued photo ID and someone close to him/her, like a family 
member or friend, who will be able to answer questions about the patient’s memory and frequency of contact 
with the patient. 
a. 
Possible types of IDs: US passport or passport card, US Military ID (active duty or retired military 
and their dependents), Permanent Resident Card, Driver’s License or other state photo identity card 
issued by a Department of Motor Vehicles, a foreign government passport, Canadian provincial 
driver’s license or Indian and Northern Affairs Canada (INAC) card and US Government 
Employee ID with photo. Hospital‐issued identification is also acceptable and is generally obtained 
at the hospital registration desk. The ID must contain DOB and a photo.  
b. 
HSV Labs: If a patient is coming from out of state, or farther away in NY, they are free to go to an 
independent Quest Lab to have HSV labs drawn, to be ordered by their Primary Care Doctor. We 
will reimburse for this afterwards. Results should be faxed to us at 646-774-6398 and reviewed 
prior to the screening appointment.  
c. 
Routine Labs: We can accept routine labs completed externally, within 30 days of screening. 
d. 
Informant Proclivity: If the patient doesn’t have an informant or refuses one (and seems like a 
viable pre-screen) we should schedule them for an in-person visit to begin discussing the protocol 
and describe participation; though actual screening measures will not be carried out. This may 
slightly delay proceedings, but bringing the patient in to be introduced with staff and space is a step 
in the right direction to get a patient comfortable with the process and knowing there are qualified 
staff on site who are here to address their concerns.  
 
Another important point about informants: 
Our biggest concern is that informants provide quality reports; how frequently informants see patients isn’t as 
paramount. The informant can be family, a friend, a neighbor, home health aide, etc., really anyone who can 

21 
 
 
 
 
 
 
 
 
 
 
comment on the patient’s memory. RC should discuss anything that seems like an ethical violation or major 
issue in what they observe of the Patient-Informant relationship, but aside from that, the actual nature of the 
relationship we don’t query. We also do not inquire about the mental or physical status of the informant. 
 
 
 
• Memory Disorders Center (MDC) (primary contact Arlene Meija; am4717@cumc.columbia.edu)  
For patients co-enrolled in the ADRC protocol, and one of our protocols at MDC. 
 
• Center for Excellence in Alzheimer’s Disease (CEAD) (primary contact Priscilla Liriano: 212-305-
2473; pl2654@cumc.columbia.edu) 
Patients seen here are followed by Wendy Gonzalez, NP and Dr. Honig.  
 
• Cross Referral between Dr. Luchsinger/Dr. Devanand (NYSPI Specific) (Primary Contact: Charleny 
Escalante; cie2104@ cumc.columbia.edu) 
We will work with Charleny Escalante for the TOPAD study. 
 
• NIA Email Blast (NYSPI and NYU) Primary Contact: Carolyn Hirschman; 
email:  chirschman@jbsinternational.com; adear@mail.nih.gov 
The VALAD protocol is featured on the NIA’s monthly clinical trials recruitment email blast under the 
‘Drugs” section (every protocol included in this blast has a header under which the link to the protocol’s 
corresponding NIA website is featured). This initiative is managed by the program manager. 
 
• Registries (NYSPI and NYU) Primary Contact: For registry contacts, see program manager or visit 
corresponding registry website under “Contact Us” tab. 
We work with various registries including Antidote Bridge, PatientsLikeMe, Alzheimer’s Prevention 
Registry, Alzheimer’s Association Trial Match and other communities alike. These initiatives will be 
managed by the program manager. 
 
• 
BAI Primary Referral Sources: BAI will refer from investigator and co-investigator clinical patients.  
 
• NYU’s Primary Referral Sources: NYU will recruit from their ADRC and the Barlow Center. 
  

22 
 
 
 
 
 
 
 
 
 
 
Protocol Participation: 
 
Consent Procedures 
At all sites, participants referred to the study will undergo a screening process (MMSE and initial check for 
inclusion/exclusion criteria). If the patient appears eligible based on screening, an investigator at the site will 
confirm by patient interview that all inclusion/exclusion criteria are met and will go over the details of the 
study with the patient and the informant, as described in the informed consent form. Participants will also be 
informed that they need to have an informant available in person or by phone to be interviewed in order to be 
in the study. Patients will be given ample time to review the consent form and will be given the opportunity to 
ask questions of investigational staff prior to signing. 
 
NYU subjects and caregivers will sign both NYU and NYSPI consent forms. Dr. Devanand will sign all 
NYSPI consents with NYU subjects after meeting with NYU subjects briefly and discussing the protocol with 
them. This is required.  
 
Throughout the study, the study physicians at each site will cross-cover one another for patient assessments 
and management in the study. All study physicians are board certified psychiatrists or neurologists and their 
clinical role is to serve as the study physicians. 
 
Patients with mild AD with Folstein MMSE score 18-28 at screen will sign consent to participate in the 
protocol; all patients will be required to have the capacity to consent to the protocol, with IRB-approved PCS 
forms being completed. If the Folstein MMSE declines to below 18 out of 30 at any time-point during the trial, 
an independent assessment of capacity will be conducted. If the independent assessor determines that the 
patient retains the capacity to participate in the study, the patient will continue in the study. If the patient no 
longer retains the capacity to consent in the study, then the patient will be asked to assent to continued 
participation and to also agree that the surrogate designated by the patient will continue to act in this capacity. 
If both these criteria are met, the patient will continue in the study. If both these criteria are not met, the patient 
will be withdrawn from the protocol. 
 
Documenting Consent 
Voluntary written informed consent will be obtained from all patients. All patients will be assessed for 
capacity to consent and this will be documented in the chart. The consent form describes the nature of the 
procedures and time requirements, potential risks, the confidentiality of information, and the rights of research 
subjects, including their right to withdraw from the research at any time without loss of benefits to which they 
are otherwise entitled. It is made explicit that this protocol involves randomized double blinded treatment with 
valacyclovir or placebo with return visits at specified time points, and a description of the research 
assessments. The consent process also includes documentation of permission to obtain previous medical 
records.  
 
The informant must also provide written consent, via the caregiver consent form, indicating their 
understanding of the study, willingness to provide information about the patient, and complete questionnaires 
and interviews with the research staff.  
 
The IRB-approved forms for informed consent and for assessment of capacity are made part of the patient’s 
permanent medical record, with a copy being filed in the research chart. 
 
Patients and informants will sign every new version of consent form following the IRB approved amendment. 
 
 
Screening Eligibility (Inclusion/Exclusion Criteria: pages 4 to 5) 
The study sample will be composed of outpatient participants who have been diagnosed with probable AD by 
NIA clinical diagnostic criteria and test positive for serum antibodies to HSV1 or HSV2. RC and MD will 

23 
 
 
 
 
 
 
 
 
 
 
complete the inclusion/exclusion criteria form. Patients who do not meet all inclusion/exclusion criteria will 
not enter the study and will be considered a screen fail and noted as such on the corresponding log.  
 
Recruitment Logs: Logs to be kept at both study sites unless otherwise noted in description. 
The following logs will be used to track recruitment: 
 
1) Patient Tracker: This log includes the tracking of active study patients, patients who have been 
scheduled for a screening visit, patients who are pending screening evaluation (but not yet scheduled), 
and patients who are pending/we are unable to contact. The last seen/contacted column should be 
updated every time the patient or caregiver is contacted.  
 
NAME/ 
MRN 
Referral 
Source 
Study 
MD/ RC 
Referral 
Date 
Contact 
info 
Comm
ents 
Final 
Status 
 
 
2)  DPO Referral Tracker (This log is NYSPI specific): This log tracks DPO subjects who were 
elucidated to be interested or eligible in their EPIC chart (and whose names were sent to Dr. Devanand 
and Betina for pursuit by DPO providers) and their status in the referral process. This log also provides 
context as to why there was no referral (i.e. not interested or eligible after-all?) Context for this log 
comes from Betina as well as the patient’s last DPO provider note.  
 
Name 
DPO 
MRN 
DOB Age Dx 
Next  
Apt 
Date 
Pertinent 
Hx 
MMSE 
MMSE 
Date 
Eligible
? 
 
 
3) Screen Fails/Archived Subjects: This log tracks subjects who have come in for a screening visit but 
did not meet criteria to be enrolled in protocol.  
NAME/ 
MRN 
Referral 
Source 
Study 
MD/ RC 
Referral 
Date 
Contact 
info 
Comm
ents 
Final 
Status 
 
 
4) Phone Screening Log: This log is primarily for the tracking of advertising respondents. 
 
NAME/ 
MRN 
Referral 
Source 
Study 
MD/ RC 
Referral 
Date 
Contact 
info 
Comm
ents 
Final 
Status 
 
 
 
 
 
 
 

24 
 
 
 
 
 
 
 
 
 
 
Study Visits 
 
Prior to Screening Visit 
The screening visit encompasses completion of the screening packet to determine eligibility as well as all 
consent procedures. Research staff at NYSPI must schedule 4-6 screening visits per week, distributed amongst 
study physicians as follows:  
 
In any case where Dr. Deliyannides/Dr. Pelton are doubtful of a screening case (diagnosis), or have to make an 
initial diagnosis, they should call Dr. Devanand to consult prior to the patient departing from the clinic. If the 
physicians don’t reach out to Dr. Devanand themselves, one of the RCs will reach out to Dr. Devanand on their 
behalf.  
 
Ideally, screening visits are carried out on Mondays or Tuesdays as there is ample clinic availability. Screening 
visits are permitted on Wednesdays and Fridays despite limits on available clinic space. Scheduling research 
appointments is permitted on Monday, Tuesday, and Friday each week.  
 
Additional conference rooms can be booked for these days. The screening visit, including consent procedures, 
is estimated to take 1-1.5 hours on average.  In developing the schedule, allow up to 45 min for the study 
physician to obtain consent.  
 
Medical Records 
Prior to the visit, if the patient is an outside referral and/or called in from an advertisement, RCs should ensure 
that medical records are obtained from the subject’s primary care physician and/or neurologist. If medical 
records are not obtained this will not serve as a limiting factor on scheduling the screen; the patient should be 
brought in for screen anyway. Subjects may also bring their own records in person at screen but are 
encouraged to send records to the clinic prior to the visit to move the review process along faster. 
Subjects must come to the screening visit with the individual who will serve as their study informant. All 
patients and informants should be made aware of New York State law, which stipulates that the request and 
delivery of medical records to patient by provider must follow official, written and signed request. The 
physician must comply within a 24-hour turnaround time and provide records to the patient accordingly.   
 
If the patient is an internal (DPO-CUMC) referral, all available records should be printed from EPIC for 
reference at the visit. This includes labs, radiology/scan reports, and notes from the DPO provider. A 
coordinator should never exclude a patient for any reason based on the EPIC records, with the exception of 
MMSE (18-29 is acceptable for screening criteria; questionable if MMSE of 17). The only information that 
you do not need to print out: address and personal information, insurance information, other non-clinical and 
non-research information. 
 
It is a strict expectation that 24 hours prior to a VALAD screening visit the RC will review all records 
available in the EPIC chart, MDC chart, independent medical records sent in from external provider, etc. This 
is key to understanding who your patient is medically and personally.  
 
 
RC Responsibilities during Study Visits:  
From Screening until week 78, it is the expectation that the respective RC (ideally, the RC who conducted the 
phone screen with the patient) will be present in the exam room during all study visits, with patient and study 
MD, to preside over all activity and provide any relevant information, including self-reported measures such as 
the UPSIT. This will ensure that there are no gaps in knowledge or information shared throughout the duration 
of the patient’s protocol participation.  
 
The RC will always check all forms, both RC and MD, prior to the patient leaving the clinic, to ensure that all 
necessary measures were completed accurately. If another RC is present, they should cross check the forms. 
This should be done on the same date as the visit itself, no matter how late it gets. 

25 
 
 
 
 
 
 
 
 
 
 
 
Patients should take their regular medications prior to coming in for study visits. If they have medications that 
they take at lunchtime, they should bring them and take them at their regular dosing time when they are here. It 
is a good idea to take the patient’s chart, and particularly their list of medications, along with the patient when 
there are procedures outside our clinic (such as MRI, PET, LP).  Nurses or technicians at these other sites often 
wish to see the list of meds the patient is on and patients tend to lack reliability in reporting current medication 
administration.  
 
Screening Visit: Procedures  
 
NYU Capacity to Consent: 
Per PI agreement: NYU subjects will sign all consent forms even if deemed as “not having capacity” (per 
NYU’s standard, which is different from NYSPI’s standard and includes MMSE and subjective consent quiz). 
There will not be notes in the NYU subject chart about lacking capacity. NYU will continue to abide by 
NYU’s rules and standards NYU subjects lacking capacity will not undergo the LP. 
 
At screening, the patient meets with the study physician (or delegated staff at NYU and BAI) to be consented. 
The coordinator should be in the room to ensure their own understanding of the protocol and consent 
procedures and can supply physicians with necessary information. The physician will obtain signatures and 
sign the Patient and Caregiver Consent Forms, the PCS Cover Sheet and Form II, and the Consent Procedure 
Note with the patient and caregiver and review the inclusion/exclusion criteria. NYU and BAI will utilize their 
equivalent PCS Forms at the Screening visit. BAI patients only sign BAI consents.   
NYU subjects and caregivers will sign both NYU and NYSPI Patient and Caregiver consent forms to cover 
procedures performed at both NYU and NYSPI/CUMC facilities. 
 
The RC then completes a “Patient Tracking Form,” which outlines key information about subjects and 
caregivers.  The RC then takes vitals (BP, pulse) and completes the MMSE with the patient. If blood pressure 
is high or out of range, the RC should repeat BP twice, 10 minutes apart each time. Any pressure above either 
160 systolic or below 100 diastolic needs to be reported to an MD on site, for further instruction.   
 
For MMSE, use the three words in the second or third array since patients who have been undergoing regular 
neurological follow up for memory disorders tend to be familiar with “apple, table, penny.” This is necessary 
to ensure MMSE inclusion, barring circumstances where an MMSE has been documented in the previous 
month. The RC also completes the Informant FAQ if applicable per clinical standards, Metal Screening 
Questionnaire, and the Medical Records Release form with the patient and/or their caregiver.  
 
It is recommended that measures used for determining eligibility be completed earlier within a visit; should a 
subject screen fail on key criteria early in the visit, there is no need to complete other study measures because 
this patient has already been found to be ineligible. 
 
The patient then meets with the study physician again (or delegated staff at NYU and BAI) to discuss 
eligibility and review the inclusion/exclusion criteria again. 
 
For patients who sign consent, an RC will draw blood for SMAC, CBC, and HSV. If patients are “difficult 
draws” at NYSPI, the NYSPI phlebotomist (Manny de la Nuez; X8048) will be contacted.  
 
As patient and caregiver depart, let them know that the final blood results and follow up will be communicated 
to them by the coordinator in 3-4 business days.  
 
The RC will contact Quest Diagnostics to arrange pickup of the HSV sample. The RC will fill out the Quest 
requisition as described in the blood draw policy section of this manual. The requisition form and tube will be 
checked by the RC who filled them out and the back-up RC. Those who check will be looking to make sure the 
patient name, IRB number, correct collection time and date, language about research use only, and the 

26 
 
 
 
 
 
 
 
 
 
 
110014F HSV Box are checked on the form. They will then compare these to the tube to make sure all details 
are accurate and matching. The security guards on the first floor of NYSPI have the key to the Quest lockbox, 
which is located on the floor immediately in front of the mailboxes on the first floor.  
 
 
The RC centrifuges the red top (SMAC) tubes on centrifuge pre-setting 3 (3200 rpm, 20 minutes) after 
allowing the blood to clot in an upright position for 30 minutes. The RC does not centrifuge the purple top 
tube. The RC will fill out the NKI requisition (NYSPI) as described in the blood draw policy section of this 
manual. Staff at NYU will fill out the requisition for their local lab, which will be used to process both red and 
purple top tubes, as will BAI.  
 
The requisition form and tubes will be checked by the RC who filled them out and the back-up RC. Those who 
check will be looking to make sure the patient’s name, X number (NYSPI specific medical record number), 
sex, ward unit, facility name, date and time of draw, and proper tests requested are checked on the form and 
match the information on the tubes. The red top and purple top tubes are then left in the refrigerator in the lab 
on the 4th floor (Pardes Building at NYSPI) for processing by NKI. The NKI form should be time stamped by 
the machine located in the lab. The NKI form has 3 sheets: the first page (white) should be placed in the front 
sleeve of the specimen transport bag containing the tubes and put in the fridge, the second page (yellow) 
should be placed face-down in the tray in the lab, and the third page (pink) should be kept in the patient’s 
chart. NYU requisition forms will contain data to be collected and checked per participant as will BAI forms. 
 
A subject will not be considered eligible unless all inclusion/exclusion criteria are met. Inclusion/ exclusion 
criteria checklist will be signed at screen or baseline by both research coordinator and study physician.  
 
For BAI, NYU, and NYSPI subjects, HSV antibody results take 2-4 days to be posted online in the e- portal, 
Quanum/Care 360; so results are not immediately known. Once the initial results are published, the RC will 
print them for the subject’s chart and get signed by the study physician. Note: If the IgM results are “pending” 
from the results, the RC will continually monitor until the final results are published in Quanum/Care 360 to be 
printed and signed by the study physician.  
 
To access results in Quanum/Care 360: https://portal.care360.com/care360/care360.login 
Username: jpollina Password: Devy1600! 
 
Information concerning eligibility should be promptly communicated to the patient by the RC; for subjects 
who screen HSV negative, a study physician will have to reach out and inform of not only ineligibility but 
appropriate follow up. 
 
Documentation of communication (via progress note filled out by study physician) of screen failed subjects 
must be kept in each screen failure chart at all study sites. All of this information needs to be presented in the 
team Wednesday morning meeting for all active patients, and any questions should be raised with the team, 
e.g., referral for specific ineligible patients.  
 
 
Scheduling Baseline Measures: Procedures for NYSPI and NYU (BAI will follow this protocol with 
modification made per their site standard) 
 
All baseline measures (PET scans, optional LP, MRI) should be scheduled once HSV positivity has been 
confirmed for those patients with qualifying MMSEs. It is important that all key measures get on the books as 
soon as possible to avoid unnecessary back and forth with patients or caregivers and to simply move the 
protocol along in an expeditious manner. Note, we must confirm at screen that patients and caregivers are 
available to come in on either a Monday or Friday for their Tau PET (18F-MK-6240 tau ligand exclusively 
available M/F). If the caregiver is not available, study staff will offer to arrange dropping off and picking up 
the patient (from tau PET) and do what we can to make it work. This is applicable to NYSPI/CU and NYU, 
BAI will schedule per their site standard.  

27 
 
 
 
 
 
 
 
 
 
 
 
Priority must be given to scheduling the MRI. Once the MRI has been confirmed, the PET scans and LP can be 
officially scheduled to accommodate the MRI. 
 
If the patient would like to complete multiple procedures on the same day, schedule the MRI followed by 
amyloid PET on baseline day 1.  An alternative is MRI followed by LP on baseline day 1.  LP should be the 
last procedure for day 1. Theoretically, MRI followed by amyloid PET; followed by LP could be scheduled on 
the same day but this should be reserved for a highly cooperative and cognitively intact patient, with a 
sufficient gap of at least 2 hours between procedures to account for unanticipated delays for each procedure. 
The patient would still need to return a second day to complete the tau PET, which must be separated by at 
least 24 hours from the amyloid PET scan. When scheduling a PET scan and the LP on the same day: a gap of 
at least 4 hours if LP is done first, a gap of 1 hour if PET is done first.  
 
Ideally, all patients will complete all baseline measures as dictated per protocol, however, if a patient cannot 
complete one of the measures, for example, tau PET (due to failure on the part of the Kreitchman PET Center, 
failure to successfully produce the ligand, an unforeseen scheduling conflict on the patient’s part, etc.) we will 
not discontinue that patient from the protocol; instead, we will try to complete the procedure on another day. If 
that is not possible, write an exception or deviation, report to the IRB if needed, and continue the patient in the 
protocol.  
 
PET, MRI and LP will take place at CUMC/NYSPI. It will be the responsibility of the NYU RC to obtain 
patient availability for MRI, both PETs, and LP (if applicable) at the end of the patient’s screening visit and 
report to NYSPI staff within 24 hours. The NYU coordinator will email this availability (along with any forms 
such as PET Center Forms) to the NYPSI coordinator using patient ID, not name. Staff at NYSPI will schedule 
the patient for each respective procedure and will need the patient’s availability as soon as possible in order to 
schedule each procedure as per the patient’s request. The NYSPI coordinator will then communicate booked 
dates/times to the NYU team so they can communicate this information to their patient in timely manner. The 
MRI, PET scans, and LP should be scheduled by the NYSPI coordinator within one week of the NYU 
coordinators initial request.  
 
 
Research Pharmacy 
Ordering Study Drug/Randomization: Procedures for All Sites 
 
The New York State Psychiatric Institute pharmacy is the research pharmacy for the study.  The randomization 
code was generated by the study statistician when the study began and this code is maintained by the research 
pharmacy with Dr. Howard Andrews who leads the Data Coordinating Center for the study.  The research 
pharmacy updates the randomization table as participants enroll in the study and are dispensed study 
medication (valacyclovir or placebo) and sends the updated table to Dr. Howard Andrews on a monthly basis.  
Any discrepancies are resolved by the research pharmacy with Dr. Andrews.  
For all Columbia/NYSPI, NYU and BAI patients: The NYSPI research pharmacy will manage study drug kit 
generation and send these out for the entire duration of each patient’s protocol participation.  
 
NYSPI pharmacy dispenses kits for NYSPI subjects on-site at clinic visits and when needed through shipping 
the kits to the home of the patient or caregiver. Each subject’s first study drug kit will be dispensed by the 
NYSPI pharmacy to the study physician/research coordinator to be distributed at the baseline study visit. The 
pharmacy will send NYU/BAI kits to NYU/BAI RC’s for later distribution to subjects by staff on site.  NYSPI 
Pharmacy must include a receipt in every study drug shipment sent to sub sites, indicating what is included in 
each study drug shipment. These receipts are necessary for accession, filing and compliance purposes.  
 
At least two weeks before the patient’s scheduled Baseline visit, the Study Drug Order Form will be submitted 
to the NYSPI pharmacy by the NYSPI RC specifying kits for weeks 1-8 and 9-16. NYU and BAI coordinators 
will scan and send the study drug order form to NYSPI coordinators at least two weeks in advance, specifying 

28 
 
 
 
 
 
 
 
 
 
 
weeks 1-8 and 9-16.  As a reminder, the study drug order form should not be submitted until a study physician 
confirms eligibility, the patient is contacted, and the baseline MRI/PET scans are scheduled.  
 
Coordinators assign subject identification numbers for the protocol, ascending sequentially from 101 at 
NYSPI, from 1001 at NYU and from 2001 at BAI.  
 
Randomization is not officially completed until the first bottle of study medication is handed to a patient at 
their baseline visit. Subject IDs will not be reassigned, even if a patient does not come back after baseline 
(once randomized, always randomized). 
 
Study drug kits are broken down as follows: 
(NYSPI) For weeks 1-12: 644 total capsules. 
Week 1-2: 28 capsules x 2 bottles (2g per day, 1g morning (2 caps), 1g evening (2 caps) 
Week 3-4: 42 capsules x 2 bottles (3g per day, 1.5g morning (3 caps), 1.5g evening (3 caps) 
Week 5-8: 56 capsules x 4 bottles (4g per day, 2g morning (4 caps), 2g evening (4 caps) 
Week 9-16: 56 capsules x 8 bottles (4g per day, 2g morning (4 caps), 2g evening (4 caps) 
From then onward it’s 56 capsules x 8 bottles (4g per day, 2g morning (4 caps), 2g evening (4 caps), unless 
clinically indicated by the study physician. 
 
(NYU) For weeks 1-12: 644 total capsules. 
 Week 1-2: 28 capsules x 2 bottles (2g per day, 1g morning (2 caps), 1g evening (2 caps) 
Week 3-4: 42 capsules x 2 bottles (3g per day, 1.5g morning (3 caps), 1.5g evening (3 caps) 
Week 5-8: 56 capsules x 4 bottles (4g per day, 2g morning (4 caps), 2g evening (4 caps) 
Week 9-12: 56 capsules x 4 bottles (4g per day, 2g morning (4 caps), 2g evening (4 caps) 
Week 12-16: 56 capsules x 4 bottles (4g per day, 2g morning (4 caps), 2g evening (4 caps) 
From then onward it’s 56 capsules x 12 bottles (4g per day, 2g morning (4 caps), 2g evening (4 caps)), unless 
clinically indicated by the study physician. 
 
It will be the responsibility of each RC to track when each replenishment is due (there is a log in each subject 
chart for this) and complete the study drug order form. Given that NYSPI pharmacy will be sending kits out to 
NYU and BAI RC’s, it is the expectation that NYU and BAI coordinators scan and send a copy of the 
completed “Study Drug Kit Send Out Log” to coordinator(s) at NYSPI as a tracking and management tool. 
This will be done during the Baseline period. NYSPI, NYU and BAI kits will contain 4 months/16 weeks’ 
worth of valacyclovir/placebo. 
 
NYSPI, NYU and BAI RC’s will complete the study drug order form at least two weeks prior to subject 
replenishment due date. NYU and BAI coordinators will scan and send completed study drug order form to the 
NYSPI coordinator for distribution to NYSPI Pharmacy team. 
 
At all three sites, kits will be returned to coordinators at scheduled study visits so that compliance checks can 
be conducted in tandem with a check in with the patient regarding how they’re feeling (update of AE and Con 
Med Logs should be completed at this time based on result of conversation with patient). Coordinators must 
call patients once a month to check in with the patient regarding medication compliance, and any AEs and Con 
Med changes. 
 
Kits returned to NYU and BAI coordinators will be stored at respective pharmacy or other designated storage 
location, for later monitoring by the NYSPI team and eventual destruction at end of study.   
 
NYSPI Pharmacy Team: 
Robert Jung (Robert.Jung@nyspi.columbia.edu; Research Pharmacist) 
Kirwan Walsh (Kirwan.Walsh@nyspi.columbia.edu; Research Pharmacist) 
Francine Weber (Francine.Weber@nyspi.columbia,edu; Pharmacy Director) 
 

29 
 
 
 
 
 
 
 
 
 
 
Week 0 (Baseline) Visit: Procedures for NYSPI and NYU (BAI will follow this protocol with 
modification made per site facility standards) 
Details on MRI, PET scans, and LP procedures can be found in the specific Policy & Procedures 
Manual for each respective procedure located in the next section 
 
 
Participation Standards: The team will re-iterate expectations, as it pertains to participating in the study, 
with both subjects and caregivers. In brief, if subjects/caregivers agree to participate, the expectation is that 
they will remain in the protocol for the entire 78-week duration. 
 
Baseline measures will need to be completed over a span of a few days. Informants do not have to be present 
during all baseline study procedures, but the informant must drop off and pick up the subject (or make 
arrangements for this; research team staff can assist as well).  
 
Description of NYU staff activity at NYSPI for all procedures is included in this manual as NYU staff may 
need to be present at each procedure if necessary, per subject request.  
 
Prior to baseline, the RC will find out whether or not the subject has undergone any of the neuropsych testing 
that will be conducted per protocol. If so, any neuropsych test administered within the CUMC, NYU or BAI 
system 3 months or less prior to Baseline, can be used for the purposes of the protocol but this must first be 
checked with investigational staff for final approval. All data from historic neuropsych testing will be copied 
onto study specific CRFs, and entered into the VALAD database with the current, baseline date (not the date of 
original testing).   
 
The coordinator will take vital signs and administer the ADAS-COG 11 and NACC Neuropsychological 
Battery. The coordinator will administer the UPSIT. Finally, the coordinator will complete the initial NACC 
packet (the GDS and 3-page demographics form). Qualified/certified staff at NYU and BAI will complete the 
aforementioned NACC measures, coordinators will complete all other measures as dictated per protocol.  
 
The patient will then see the study physician, who will write a progress note and complete the MD NACC 
packet, the Concomitant Medications log, the CIBIC-Plus, and the CDR. The physician will also complete the 
ADCS-ADL with the informant. This informant interview can be done over the phone at a later time within the 
Baseline period, as well.  
 
The coordinator will then draw blood for APOE genotyping (yellow top), which is to be stored at the Human 
Genetics Resources Core (HGRC). Both NYU and NYSPI subjects will have APOE drawn at NYSPI during 
Baseline, as will BAI subjects. BAI staff will store APOE on site for later send out to the HGRC. The RC will 
fill out the HGRC form as described in the blood draw policy section of this manual. The form and tubes will 
be checked by the RC who filled them out and the back-up RC. They will sign the corresponding accuracy log. 
 
An extra serum tube (red top) will also be drawn for all subjects, processed, and stored in the -80 freezer on 
Pardes floor 4 (at NYSPI, BAI will store locally). Please see the Lab manual section for greater processing 
description.  
 
As described in the consent forms, all clinically applicable information collected during the trial will be 
disclosed to patients and their caregivers, as well as interpretation of baseline MRI, 18F-Florbetapir amyloid 
PET radiological read, and results from CSF analysis. 
 
After the baseline evaluation, the results of outcome measures specified in the hypotheses will not be 
disclosed. Apolipoprotein E genotyping results will not be disclosed nor will results from 18F-MK-6240 tau 
PET scan; tau PET imaging results are still in research development and there is no standardized method to 
make a clinical read and provide a report to the patient. 
 

30 
 
 
 
 
 
 
 
 
 
 
At both sites, the medication kit is dispensed when the study physician sees the patient and reviews the 
medication kit. 
 
After all procedures for the day are completed, follow-up visits are scheduled. The RC must review the 
Checklist for the visit and ensure that all forms listed in it are completed on the checklist page before the 
patient leaves the clinic.  The RC will double check that the study physician has completed all necessary 
forms, as well. After all verifications are complete, the patient and caregiver may be sent home.  
  
A few important notes to keep in mind at Baseline: 
A. The ADCS-ADL must be done by the study physician who sees the patient (At BAI, neuropsych and 
rating scales are completed per site standard with trained staff and raters).  It should be done at the end of 
the visit, i.e., after NACC and other forms are administered (specific forms will vary from visit to visit 
but ADCS-ADL should always be done at the end).  The ADCS-ADL should be administered to the 
informant but when the informant is not sure about the answer to a question, it can be done with the 
patient as well.  The study physician must fill it out completely based on the best information available, 
even if it seems to be spotty based on unclear patient and informant responses. 
B. We will use our own discretion in deciding whether subjects and caregivers should be compensated with 
Petty Cash, or through filling out a reimbursement form, which would result in a check being sent to the 
subject or caregiver’s place of residence. Reimbursement forms require collection of social security 
number and W9 completion from the payee.  
C. The RC must do the maximum, not the minimum, and know every detail about their patient(s) to truly 
make this a successful study. There needs to be an ongoing conversation about patient concerns, not just 
facts of the study. The single most important thing will be establishing a decent rapport with the study 
patient and making sure they (as well as their caregivers) know that we’re here to address their concerns 
and make participation in the study convenient for them. This will keep them coming back.   
 
 
Weeks 2 & 4 Phone Call/Visit 
● In-office or telephone call by study physician to assess subject study drug compliance and any patient 
history changes. This telephone call or in office visit should last approximately 10 minutes. 
● Physician will write note and RC will complete medication compliance form. 
 
Medication Compliance Calls: The RC will call the patients or caregivers once a month and medication 
compliance will be documented on a log upon query. These calls will occur throughout the subject’s 78 weeks 
of protocol participation. During phone contacts, patients should be reminded that they will be followed by a 
physician here. Patients should know exactly what they’ll be getting through participating in research. 
 
The following compliance script will be used when placing these calls: 
 
Hi Mr./Mrs. __________________. This is ________________ calling from Columbia about the “Antiviral 
therapy in Alzheimer’s disease” study that you/your family member is enrolled in. Do you have a few minutes 
to talk with me? I am just reaching out to check-in and see how you (and the patient) are doing. (If now is not 
a good time to speak, schedule a specific time when they know they will be available via phone. It is good to 
note in your personal tracking if there are certain days or times that are best for phone contact in the future) 
-person on the phone (patient or caregiver) should be where they have the study medication available 
  
(To complete over phone before the patient starts a new Study Drug Kit) 
 
The last kit you received had 8 study drug bottles. Can you tell me how many bottles have been finished? Can 
you count how many pills are left in the unfinished bottles? 
_________ finished bottles 
_________pills remaining 
 

31 
 
 
 
 
 
 
 
 
 
 
Now, let’s go over the kit you just received and will be starting on ________. Can you read me the labels on 
the bottles of the new kit? 
 
Thank you. As I mentioned, you will be starting the new box on ________. The pharmacy will ship you a new 
box by Fedex before this kit finishes. Please do not discard the old bottles. You can bring them with you in 
your next appointment. Feel free to reach out to me if you encounter any problems. 
 
The patient will be encouraged to come in if and when they believe it is necessary to be seen by study 
staff/medical team on protocol. AE and Con Med Logs to be updated based on information obtained at these 
calls.  
 
Week 12 Visit 
This visit should be completed in 2-4 hours.  
● Clinical assessment: Progress note, CDR, ADCS-ADL, and CIBIC-plus will be completed (Study 
Physician completes at NYSPI; PI or delegated/certified Sub-I at NYU and BAI). 
● Neuropsychiatric measures: ADAS-Cog11 (Research Coordinator completes at NYSPI, 
delegated/certified staff at NYU and BAI). 
● RC will record vitals. 
● RC draws blood for: SMAC blood chemistry (red top), complete blood count (lavender top) and plasma 
acyclovir levels (lavender top).   
▪ 
For SMAC blood chemistry and complete blood count, the RC will fill out the NKI 
requisition (NYSPI) or NYU Langone Lab req if NYU subject, and BAI specific lab req at 
BAI, as described in the blood draw policy section of this manual. The req and tubes will be 
checked by the RC who filled them out and the back-up RC. Those who check will be 
looking to make sure the patients name, X number (med rec number), sex, ward unit, facility 
name, date and time of draw and order, and proper boxes are checked on the form and 
match the information on the tubes.  
▪ 
Plasma acyclovir levels will be drawn, processed and stored for further analysis by the 
Acosta Lab at UAB. Plasma should be checked for: ID, draw time, date, date/time of most 
recent dose, valacyclovir/placebo, DOB, Dr. Devanand, IRB #.  
● 
For patients consenting to the LP, CSF (and plasma) will be collected (Dr. Bell performs the LP, NYSPI 
RC processes and stores specimens for both NYU and NYSPI LP subjects). The NYSPI RC will fill out 
the LP and Plasma forms and tubes according to the LP procedure section of this manual. The form/tubes 
will be checked by the RC, the back-up RC and the program manager.  
● 
Before the patient leaves, the RC will double check that the study physician completed all necessary 
forms. After verification is complete, the coordinator will confirm that all RC forms have been 
completed, as well. The RC must check the checklist for the visit, and ensure that all forms listed in it are 
completed and ticked off on the checklist page. Only after both of these checks have taken place can the 
patient and caregiver be sent home. 
Week 26 Visit 
The week 26 visit is estimated to take about 2-3 hours.  
● 
Neuropsychiatric measures: MMSE and ADAS-Cog11 (RC at NYSPI, delegated/certified staff at NYU 
and BAI).  
● 
Clinical assessment: Progress note, CDR, ADCS-ADL, and CIBIC-plus (study physician completes at 
NYSPI; PI or delegated/certified Sub-I at NYU and BAI). 
● 
SMAC blood chemistry (red top) will be collected to assess kidney function (RC completes). The RC 
will fill out the NKI requisition (NYSPI) or NYU Langone Lab req if NYU subject, BAI specific lab req 
if BAI subject; as described in the blood draw policy section of this manual. The req and tubes will be 
checked by the RC who filled them out, the back-up RC and the program manager. Those who check 
will be looking to make sure the patients name, X number (med rec number), sex, ward unit, facility 
name, date and time of draw and order, and proper boxes are checked on the form and match the 
information on the tubes.  
● 
Coordinator will record vital signs. 

32 
 
 
 
 
 
 
 
 
 
 
● 
Before the patient leaves, the RC will double check that the study physician completed all necessary 
forms. After verification is complete, the coordinator will confirm that all RC forms have been 
completed, as well. The RC must check the checklist for the visit and ensure that all forms listed in it are 
completed and ticked off on the checklist page. Only after both of these checks have taken place can the 
patient and caregiver be sent home. 
 
Week 52 Visit 
This visit will take 3-4 hours.  
● 
Re-evaluation of diagnosis, Progress note, CDR, ADCS-ADL, CIBIC-plus, and NACC packet (study 
physician completes at NYSPI; PI or delegated/certified Sub-I at NYU and BAI). 
● 
ADAS-Cog11, NACC neuropsychological battery, NACC RC questionnaire forms, vital signs. (RC 
completes at NYSPI, delegated/certified staff at NYU and BAI).  
● 
No blood will be drawn.  
● 
Before the patient leaves, the research coordinator will double check that the study physician completed 
all necessary forms. After verification is complete, the coordinator will confirm that all RC forms have 
been completed, as well. The RC must check the Checklist for the visit and ensure that all forms listed in 
it are completed and ticked off on the checklist page. Only after both of these checks have taken place 
can the patient and caregiver be sent home. 
 
Week 78 Visit or Endpoint (dropout) visit 
 
End of Study Procedures: We will not break the blind at Week 78. We will only break the blind after the 
entire clinical trial is over and the final subject enrolled completed all week 78 procedures. We will provide all 
test and procedure results to the referring MD, then let the referring MD decide what to do in terms of 
prescribing valacyclovir. The RC will need to summarize cognitive testing over protocol duration, in 
preparation. A full report inclusive of the subject’s experience in the study will be provided in addition to the 
cognitive testing summary (see below).  
 
These measures will span over 2-4 clinic visits.  
• This visit follows a very similar protocol to the week 0 visit, with the addition of blood drawn for SMAC, 
CBC, and HSV antibodies.  
• The RC will fill out the Quest forms and tubes as described in the blood draw policy section. The form and 
tubes will be checked by the RC who filled them out, the back-up RC and the program manager. Those who 
check will be looking to make sure the patient initials, IRB number, correct collection time and date, 
language about research use only, and the 6447 and 90849 HSV Boxes are checked on the form. They will 
then compare these to the tube to make sure all is accurate and matching.  
• NYSPI and NYU subjects will have MRI, PETs, and LP performed at NYSPI/CUMC as previously 
described in this manual and as described in each respective “Procedures” section. The NYSPI RC will fill 
out the LP and Plasma forms and tubes according to the LP procedure section of this manual. The form and 
tubes will be checked by the RC who filled them out, the back-up RC and the program manager.  
• The RC will draw blood for plasma (lavender top), SMAC (red top), CBC (lavender top), and HSV (marble 
top) antibodies. 
• The RC will fill out the NKI requisition (NYSPI) or NYU Langone Lab requisition if NYU subject or BAI 
specific lab req if BAI subject, as described in the blood draw policy section of this manual. The requisition 
and tubes will be checked by the RC who filled them out, the back-up RC and the program manager. Those 
who check will be looking to make sure the patients name, X number (med rec number), sex, ward unit, 
facility name, date and time of draw and order, and proper boxes are checked on the form and match the 
information on the tubes.  
• Re-evaluation of diagnosis, Progress note, CDR, ADCS-ADL, CIBIC-plus, NACC packet, and concomitant 
medications log. (Study physician completes at NYSPI; PI or delegated/certified Sub-I at NYU and BAI). 
• ADAS-Cog11, NACC neuropsychological battery, UPSIT, and vital signs. (RC completes at NYSPI, 
delegated/certified staff at NYU and BAI).  

33 
 
 
 
 
 
 
 
 
 
 
• Plasma acyclovir specimens, collected from all subjects, should be checked for: ID, draw time, date, 
date/time of most recent dose, valacyclovir/placebo, DOB, Dr. Devanand, IRB #.  
• Patients will have a final MRI and PET Scans, following the protocol of the baseline visit.  
• Patients who agreed to the LP will have a third and final LP, providing plasma and CSF specimens.  
• Adverse Events will be recorded on the Adverse Events Log (RC completes). 
• Medications will be recorded on the Concomitant Medications Log (Study physician completes). 
• A Protocol Exit form is completed (RC completes).  
 
Whenever a patient ends the protocol, regardless of time-point, the protocol exit form needs to be completed. If 
a patient terminates the protocol early for any reason, the patient needs to be brought back to complete all 
planned study visits and procedures under the intent-to-treat principle. Any intervening treatments or other 
changes will be documented but will not affect the assessments.  During this time, the patient should be 
instructed not to participate in any other treatment research protocol. Before the patient is free to go the RC 
should double check that the study physician has completed all necessary forms. After this is checked the 
coordinator should confirm that all RC forms have been completed. Only after both of these checks have taken 
place can the patient and caregiver be sent home. 
 
Study records (scan reports, lab results) for patients referred to VALAD by DPO Providers, will be dropped 
off in a manila folder, with Renata on NI3. These records will be dispersed to respective DPO provider. RC 
should compose a brief narrative of what exactly each manila folder contains, and which study visits have been 
completed to date.   
 
Biological Specimens and Scans: 
We will be collaborating with the following laboratories: 
1. Edward P. Acosta, Pharm.D. University of Alabama at Birmingham 
CSF Specimens and Plasma Specimens 
2. Dr. Leslie Shaw, Ph.D University of Pennsylvania 
CSF Specimens 
3. Marielba Zerlin-Esteves, Human Genetics Research Core (HGRC) CUMC 
CSF Specimens, APOE/DNA Specimens, Plasma Specimens 
4. Quest Diagnostics (HSV ½ IgG)/ARUP Lab (HSV ½ IgM) 
HSV1/HSV2 Testing 
5. Nathan Kline Institute (NKI) 
Routine Laboratory Testing 
6. NYU Langone Local Hospital Lab 
Routine Labs for NYU subjects 
7.   Banner Health Hospital Laboratory (BAI) 
Routine Labs for BAI subjects 
 
 
Lab Results 
All lab results need to be reviewed and signed by the study physician promptly after they are received. The 
physician should initial and date all results and indicate any clinically significant findings.  
 
 
Blood Draw Policy & Procedures       
 
 
Test 
Tube 
Visit 
Process 
SMAC 
Folate 
B12  
2 Red 
tops, 
Screen, Week 
12, Week 26, 
Week 78 
1.  Check off Chem 1, TSH, Folate, Vitamin B12 on NKI requisition form/ 
NYU Langone Lab Req or BAI Lab Req. 
2.  Invert 5 times. 

34 
 
 
 
 
 
 
 
 
 
 
8 mL 
Serum 
Sep clot 
activator 
Ref # 
455071P 
3. Stand up right for 30 minutes before centrifuge. 
4. Centrifuge for 20 minutes 
5. Fill entire label on tube (Ward 890, get X number from KIS-EMR or 
equivalent medical record number from NYU and BAI medical records 
interface) and make sure it matches requisition form. If the blood was 
drawn at baseline, check off “New Admission” under “Reason for Test”. 
If the blood was drawn at a follow up visit, check off “Other” and specify 
the study week.  
6. Submit to refrigerator with requisition form to room 4200 (NYSPI). NYU 
will submit these specimens to their lab or lab drop off site, as will BAI.  
7. 
RC’s and PM will check tubes and forms and confirm their accuracy.  
CBC 
1 
Lavender 
top,  
4mL 
K3EDTA 
Ref # 
454021 
Screen, Week 
12, Week 78 
 
1. Check off CBC on NKI requisition form or NYU Langone Lab Req or 
BAI Lab Req. 
2. Invert 10 times. 
3. Fill entire label on tube and make sure it matches requisition form. 
4. Submit to refrigerator with requisition form to room 4200. NYU will 
submit these specimens to their lab or lab drop off site, as will BAI. 
5. RC’s and PM will check tubes and forms and confirm their accuracy.  
 
 
 
Dr. Bell’s Directions 
● 
The CBC needs to include platelet count. 
● 
Patients on anticoagulants are not eligible for LP. 
● 
Patients on aspirin or NSAIDs need to stop 7 days before LP as long as 
they have their PCPs permission. 
● 
PT/INR not necessary since we are not taking people on 
anticoagulants.  
Extra 
Serum 
Specimen 
1 Red 
top, 8 mL  
Week 0 Only 
1. Invert 5 times. 
2. Stand up right for 30 minutes before centrifuge. 
3. Centrifuge for 20 minutes. 
4. Aliquot 1 mL of specimen into 2, 2 mL cryovials. 
5. Label cryovials with Subject ID, Date, PI, IRB Protocol Number, and 
time drawn.  
6. Store specimens in a Biohazard Bag, in the -80 freezer.  
ApoE 
1 Yellow 
top, 
8.5mL 
ACD 
solution 
A  
Ref # 
364606 
Week 0 
1. Put 1st of the 3 copies of the HGRC barcode stickers on the tube. 
2. 2nd sticker in ApoE binder log. 
3. 3rd sticker on ApoE completed HGRC form (make a copy). 
4. Give Marielba’s lab on PH19 a copy of HGRC form and have her sign 
the other to file in ApoE binder.  
5. RC’s and PM will check tubes and forms and confirm their accuracy. 

35 
 
 
 
 
 
 
 
 
 
 
HSV 1 & 2 
quantitativ
e IgG  
1 
red/grey 
speckled 
top, 
7.5mL 
serum 
separated  
Ref # 
367987 
(Order 
from 
Quest) 
Screen & 78 
1. 
Invert sample 10 times after collection. 
2. 
Put sample into a biohazard bag. 
3. 
Put patient’s initials on tube label with date and IRB #. 
4. 
Fill out Quest req form for account T46194 from office 1500A; BAI will 
complete this section with their BAI specific Quest account number. 
5. 
Only put the patient’s initials in the patient name section and indicate 
their sex, time/date of draw, and “non-fasting”. 
6. 
Put IRB #7537 (NYSPI) or NYU IRB# in Patient ID/MRN, or BAI IRB# 
in Patient ID/MRN. 
7. 
Put “For Research Only – Not Legal” in the Comments (to Print on 
Report) section in Specimen information. 
8. 
Check off test 6447 HSV1/2 IGG, Type AB Specific. 
9. 
Fill in 90849 HSV (IGM) W/RF at the bottom of the form and check it 
off. 
10. Place sticker with patient initials from the Req form onto tube. 
11. Get key for Quest drop-off box from security guard in the lobby of 
Pardes building 1st floor.  
12. Call Quest to pick up sample at 1051 Riverside Drive (866-697-8378) 
(they will ask for the account number T46194, need to call before 4PM 
for pick up; NYU will call Quest to their respective location as will BAI.  
13. Sample can stay at room temperature for 4 days. 
14. RC’s and PM will check tubes and forms and confirm their accuracy. 
Results take about 2-4 days and will be retrieved by RC online via Care 
360.  
HSV-1&2 
quantitativ
e IgM 
  
  
1 Red 
Top 
(8 mL 
Serum 
Sep clot 
activator) 
(Ref # 
455071P) 
1 ARUP 
LAB 4ml 
Plastic 
Transport 
tube 
Screen & 
Week 78 
When using a serum separator tube, follow these instructions:  
Note: Collect the specimen in a plain red-top tube containing no 
anticoagulants or preservatives. Transfer the serum with a pipette to 
an ARUP LAB 4ml plastic tube and place transport tube into a 
blue ARUP LAB frozen temperature specimen bag to be placed in our -80 
freezer. Serum should be clear and free from all red cells.  
Perform venipuncture as with any other blood collection device. 
1.   Invert the tube gently no more than eight times. Further inversion may 
cause alterations in sample integrity. 
2.   Place patient’s initials on tube label with date and IRB # 8089. 
3.   Do not remove the stopper at any time. Do not centrifuge immediately 
after drawing blood. Allow the blood to clot in an upright position for at 
least 30 minutes but not longer than 1 hour before centrifugation. 
4.   Centrifuge for at least 15 minutes at 2200-2500 RPM within one hour of 
collection. Ambient centrifuge will be used. 
5.   Transfer at least 1 mL of serum to an 4ml ARUP LAB plastic transport 
tube 
6.   Label tube with PT ID#, Date collected, Time collected. Time point: 
(Screen / Wk 52) and HSV 1&2 IgM 
7.   Place labeled ARUP Transport tube into Blue ARUP LAB frozen 
temperature specimen bag. Write account # on bag: VALAD: 496059. 
VALMCI: 496060 
8.   Place Blue ARUP lab bag in -80 freezer. Samples will be shipped 5 at a 
time. 

36 
 
 
 
 
 
 
 
 
 
 
9.    Add specimens’ information to biospecimen tracker as: ARUP HSV IgM 
Plasma 
  
3 
Lavender 
top, 4mL 
K3EDTA 
Ref # 
454021 
Weeks 12 & 
78 
 
If LP, 
specimen will 
be drawn at 
CRR  
1. Invert 10 times. Centrifuge the three 4mL lavender tops at 1000 x g for 
10 minutes to obtain plasma. 
2. Once samples have been centrifuged. Pipette 1-2 mL of plasma (at 
minimum, 1 mL) into four 2mL cryovials (to have a duplicate for UAB in 
case of shipping issues). 4mL tube should produce about 2.5 mL of 
plasma. 
3. Label two of the cryovials for UAB and fill out duplicate collection logs 
with ID, draw time, date, date/time of most recent dose, 
valacyclovir/placebo, DOB, Dr. Devanand, IRB # 
4. The two UAB samples should freeze in two separate boxes in an upright 
position immediately and be maintained in the 4930 freezer at -80°C until 
shipment.  
5. Another 2mL cryovial will be submitted to the HGRC same day of 
collection (3 copies of HGRC stickers, 1st: sample, 2nd: Plasma form for 
Marielba to sign, 3rd: Plasma binder log). BAI staff will store specimen 
on site for later send out to the HGRC. 
6. The 4th cryovial should be filled with the remaining specimen to be stored 
in the NYSPI freezer (or BAI freezer if BAI subject).  
7. RC’s and PM will check tubes and forms and confirm their accuracy via 
signature in the appropriate log 
8. Plasma for NYU patients who do not undergo LP will be drawn at NYU 
with NYSPI supervision. Specimens will be frozen and stored at NYU 
and then shipped to HGRC and UAB. 
 
 
Shipping Plasma to UAB: 
1. 
Batch ship (every 5 subjects) samples via FedEx, UPS or other overnight service with sufficient dry 
ice to keep samples frozen and adhere to IATA guidelines.  
2. 
Do not ship on Thursday or Friday or day before holiday. 
3. 
Notify UAB Antiviral pharmacology lab (205-975-2461, kedria@uab.edu) when shipment 
leaves with FedEx/UPS air bill number.  
4. 
Ship all samples with the collection log to: 
Edward P. Acosta, Pharm.D., Antiviral Laboratory Director 
Lab Contact: Kedria Walker, B.S. and 
Kevin Ryan J kjryan@uab.edu (Lab tech) 

37 
 
 
 
 
 
 
 
 
 
 
University of Alabama at Birmingham 
Division of Clinical Pharmacology 
1670 University Blvd., VH 270 
Birmingham, AL 35294 
 
Note: All specimens collected and processed for delivery to collaborating labs are to go through three 
checkpoints: 1.) the RC who drew and processed the specimen, 2.) the secondary RC  3.) the program 
manager. Each individual checking specimens will ensure accuracy of labeling (subject ID, DOB or initials, 
Visit, IRB#, Date) and that all specimens being shipped correspond to (and match with 100% accuracy) the 
logs they are being sent with.   
 
Blood Collection 
The following order-of-draw is recommended when drawing several specimens during a single venipuncture 
and is used to avoid possible test result error due to cross contamination from tube additives: (1) Blood culture 
tube (2) Serum tube with or without clot activator or 
gel separator (3) Heparin tube with or without gel separator (4) EDTA and (5) Glycolytic inhibitor. Always 
follow your facility’s protocol for order of draw. 
Scheduling the Lumbar Puncture (LP): Weeks 0, 12, and 78 (NYSPI/NYU Specific; BAI will apply this 
protocol with modification made per facility stanadard) 
 
The NYSPI coordinator will schedule Dr. Bell for a two-hour appointment with her scheduler, Terri Rivera 
(tr2454@cumc.columbia.edu). Terri should be emailed as soon as a subject confirms they will undergo the 
procedure. Dr. Bell’s availability will be released the month prior by Terri Rivera (NYSPI coordinator must 
email Terri the month prior asking for Dr. Bell’s LP availability for the following month). Dr. Bell should only 
be scheduled either 10:00am-11:00pm or 11:00am-12:00pm. NYU staff will communicate their subject’s 
availability, along with any relevant forms, to NYSPI coordinator within 1 day of successful screening and LP 
interest confirmation. Dr. Bell can be scheduled to see two patients in one day as she often has limited 
availability.  
 
When Dr. Bell is confirmed, the coordinator will email Elizabeth Guerrido (eg2414@cumc.columbia.edu) a 
formal CRR space request (see below), copying Ismael Castaneda (ic2444@cumc.columbia.edu) and Janelle 
Nunez (jn2531@cumc.columbia.edu. When emailing the CRR please attach the “CRR Outpatient 
Appointment Email Request Form”. Comments on this form:  
 
1. Please leave the first two questions that ask for EPIC MRN empty as we will not be enrolling our 
patients in EPIC. 
2. For the question that asks “Are there extenuating circumstances preventing you from registering this 
participant in EPIC?” Please select the “Yes” checkbox. 
3. “Eagle (CUIMC) MRN (7 digit number)” refers to their CROWN MRN. If the patient has never been 
see at Columbia and does not have a CROWN MRN please list “Needs to be assigned”  
4. We will be performing a blood draw for week 12 and week 78 LPs. Please indicate “Blood draw” on 
the form if it is one of these visits.  
5. We will not need any labels printed at the CRR for NYP Core Lab specimens. 
6. Under “Special Procedures” please check off “Lumbar Puncture”  
 
For NYU patients, the NYSPI coordinator will send a confirmation email to NYU staff as well when 
everything is confirmed.  
 
Participant Demographic 
Study Participant Name:      
DOB:  
Race/ethnicity:  

38 
 
 
 
 
 
 
 
 
 
 
Gender:  
MRN: (If available from EPIC)  
 
Study information 
Study CRR: CRR#2017-041  
PI: Davangere Devanand, MD, 646-774-8658, dpd3@cumc.columbia.edu 
Emergency MD: Study physician, Phone number, Email 
Coordinator: Coordinator, Phone number, Email 
Duration:  Two hours 
Room /space needed for the study visit: Exam room 5 
Blood draw: dependent on study week  
 
 
BEFORE THE LP 
10 DAYS BEFORE LP: Please ensure your patient is not on any blood thinners (aspirin included). If they are 
on any blood thinner, ensure this blood thinner is okay to be stopped with the study physician. If so, please 
note to call them 8 days before the LP to stop taking any blood thinner at least a week prior (last day taking the 
medication should be the day you call. Ensure that stopping the medication for a week is sufficient given the 
medication (confirm with NYSPI coordinators).  
2 DAYS BEFORE THE LP: Create a word document with your patient’s medication list on it. If there are 
any blood thinners list a discontinuation date. Create LP labels for all the LP vials (template can be found in 
the shared drive). Confirm you have all your supplies needed for the LP.  
 
LP Protocol (2 hours) 
 
Subject and informant will be seated in CRR outpatient waiting room. The RC will prep the room for LP, and 
instruct the subject to put on a gown using the procedure room bathroom. Once the LP begins, Dr. Bell and the 
RC will wear disposable surgical gown, gloves and surgical mask for the 20-30 minute LP procedure (disposal 
in CRR Biohazard bin when complete). After the subject has sufficiently recovered from LP (about 45 
minutes) and dressed, the research coordinator will disinfect the Procedure Room via Clorox wipe down. 
Subject and informant will depart directly for home from facility. Labs will be drawn by the CRR nurse. 
Biospecimens collected (CSF and blood) will be processed by RC at the CRR Lab. Coordinator will follow the 
CRR Lab’s infection control guidelines and will wear surgical mask gloves and lab coat while processing 
specimens, which will then be placed in a biohazard bag and cooler, to be transported to respective drop-off 
location. 
 
Procedure Preparation, CSF Collection, and Patient follow-up: 
1. 
Patient should eat breakfast and take all of their medications, as usual, prior to arrival.  
2. 
NYSPI: An RC will arrive 15 minutes prior to the appointment to set up and check the patient in at the 
front desk. NYU: RC and subject will arrive 30 minutes prior to the procedure (if the NYU 
coordinator joins, which isn't required). NYSPI coordinators will remain present for the entire 
procedure duration. NYSPI staff will process, store and ultimately ship specimens.  
3. 
RC will set up paper and pillowcase on the procedure table and lay out the patient gown.  
4. 
RC will set out all the materials for the procedure by the window and rolling tray: LP kit, betadine 
(found in CRR clinic room), alcohol, tubes, extra needles, bandages, sterile gloves (size 7.5), gauze, 
syringes, lidocaine. An image of how materials should be set up can be found in the LP Policy and 
Procedures Manual.  
5. 
RC will set up all the forms Dr. Bell needs by the desk: collection forms, progress note/continuation 
sheet, time out sheet. The protocol verification time out sheet and continuation forms can be found in 
the desk drawer. If these are running low notify Sonia to replenish. 
6. 
The patient’s chart should be present. The RC should pull out the patient’s medication list and signed 
consent form to be reviewed by Dr. Bell. 

39 
 
 
 
 
 
 
 
 
 
 
7. 
During the summer, the air conditioning should be turned on in the exam room prior to Dr. Bell’s 
arrival. 
8. 
The other RC will walk patient and caregiver to PH10 to meet Dr. Bell 15 minutes prior to their 
appointment time. The caregiver should wait in the waiting room throughout the procedure. 
9. 
During weeks 12 and 78, the patient will need to have their blood drawn and processed for plasma in 
the PH lab 15 minutes prior to the procedure. After the blood draw the subject can be escorted to the 
procedure room. 
10. 
Patient will need to remove their shirt, unbutton their pants, and put a gown on. 
11. 
Patient will be directed to lie on their side on the exam table and the RC help them to stay on the table. 
Dr. Bell may ask the patient to pull their legs closer to their chest or curl their chin towards their 
knees. The RC should ensure that the patient keeps their hands in front of them and does not reach 
towards their back. 
12. 
Dr. Bell will feel the patient’s lower back for the best spot and sterilize the skin with betadine. Dr. 
Bell will inject lidocaine 1% local anesthesia twice and then perform the LP with a 20-gauge sprotte 
spinal needle, filling 2 collection tubes once CSF is flowing. 
13. 
24 mL CSF will be withdrawn into 2, 12mL collection tubes, one research coordinator will take these 
tubes into the lab to begin processing. The other should remain with patient. 
14. 
Once all the CSF is collected Dr. Bell will clean off the betadine and place a bandage over the needle 
insertion site.  
15. 
The RC will help to roll the patient over onto their back. The patient must lie still on their back for at 
least 45 minutes. 
16. 
One RC will go to the waiting room and bring in the caregiver while Dr. Bell cleans up the procedure 
materials. 
17. 
Dr. Bell will explain the need for extra hydration and for the patient to remain off their feet for the 
next 2 days. Once she has spoken to the patient and caregiver and completed all the necessary forms, 
Dr. Bell will leave. The RC should remain with the patient until they are able to stand.  
18. 
After the patient has gotten up, they should change out of their gown and begin hydrating. 
19. 
The RC should collect all excess materials to bring back to NYSPI, throw out the paper on the exam 
table, and place all soiled linens in the bag in the hallway. 
20. 
The RC should walk the patient out of the hospital and back towards the most convenient building 
where they parked/took the train. 
21. 
A 24-hour follow up call will be placed to assess for any AEs. RCs will call their respective patients.  
22. 
As described below, reports from Baseline analysis of CSF AD Biomarkers will be provided to 
CUMC PI then shared with Dr. Wisniewski, who will provide report to NYU subjects.  
 
CSF Processing 
1. 
Processing the 24 mL of CSF collected from the patient: 
a. 2mL of CSF for HGRC: The RC should pipette 1mL of CSF into two, 2 mL cryogenic 
vials. 
 
b. 19mL of CSF for UPenn: The RC should pipette 9.5 mL of CSF into two, 12mL 
polypropylene clear capped transfer tubes. 
c. 1mL of CSF for UAB: the RC should pipette 1 mL of CSF into one, 2mL cryogenic vial. 
d. Any additional sample should be placed into 1.8 mL cryovials, labeled, and stored in the -
80 freezer on the 4th floor of NYSPI.  
 
Location 
Amount 
Type of Label  
HGRC 
1 mL into (1) 1.8 mL cryogenic vial  
1 mL into (1) 1.8 mL cryogenic vial 
Small barcode sticker on both 
cryovials 
Patient ID, IRB#, Devanand, CSF, 
date, time collected 
UPenn 
9.5 mL into (1) 12 mL propylene 
clear capped transfer tube 
Patient ID, IRB #, study visit, drug 
dose, last dose date, last dose time, 
date collected, time collected, 

40 
 
 
 
 
 
 
 
 
 
 
9.5 mL into (1) 12 mL propylene 
clear capped transfer tube 
method of collection, needle gauge, 
volume CSF and time frozen 
UAB 
1 mL into (1) 1.8 mL cryogenic vial 
patient ID, date collected, time 
collected, method of collection, 
volume CSF and time frozen 
Any additional sample 
Additional into (1) 1.8 mL cryogenic 
vial 
Patient ID, IRB#, Devanand, CSF, 
date, time collected 
 
 
2. 
Labeling tubes 
a. HGRC cryovials: small barcode stickers. Matching barcode numbers should be placed on 
both cryovials and the form submitted to HGRC. Another copy of this form should be 
placed in the HGRC binder. 
b. CSF tubes for UPenn: RC types labels for clear capped tubes to include patient ID, IRB 
#, study visit, drug dose, last dose date, last dose time, date collected, time collected, 
method of collection, needle gauge, volume CSF and time frozen. 
c. CSF for UAB: patient ID, date collected, time collected, method of collection, volume 
CSF and time frozen. 
 
CSF Storage & shipment: UAB and UPenn 
Storage of UAB and UPenn Samples 
a. Freeze the UAB and UPenn samples upright for at least 20 minutes on dry ice. Store/freeze the CSF 
in the two, 12 mL polypropylene clear capped UPenn tubes and 2mL UAB cryovial in -80°C freezer 
in room 4930 in respective UPenn and UAB boxes and/or bags.  
b. These tubes can be stored in the MDC freezer for 6 months, but we will batch ship specimens to both 
labs every 2-3 patients, every 5 patients max. Fill out corresponding shipment logs to match 
information listed on tubes/vials.  
 
Shipment of UAB and UPenn Samples: 
a. Each box log and tube should include ID, DOB, IRB #, and time/date of draw. 
b. If shipping that day, again, samples for UPenn and UAB need to be upright on dry ice for at least 20 
minutes before being packed. Do not allow samples to thaw at any point after they have been 
frozen. Never ship a sample that was not first frozen upright on dry ice for at least 20 minutes. All 
shipments are priority overnight. 
c. Place small pieces of dry ice in a bubble-wrap bag. 
d. Quickly transfer sample tube from dry ice to the bubble wrap bag. 
e. Seal the bag with the self-adhesive flap. 
f. 
Quickly place bubble bag with content into the zip lock bag. 
g. Place directly on dry ice in Styrofoam shipping box. 
h. Fill the box with dry ice and cover. Place container into cardboard box. 
i. 
Affix Federal Express shipping label and call for pick up.  
 
Address to ship to UPenn. Notify Dr. Shaw’s lab when shipment leaves; contact Magda 
(Magda.Brylska@uphs.upenn.edu) with FedEx air bill number. 215 662 6266 
Dr. Leslie Shaw, MD 
7 Maloney South, University of Pennsylvania Medical Center 
3400 Spruce Street, Philadelphia, PA 19104 
 
Notify UAB Antiviral pharmacology lab (205-975-2461, kedria@uab.edu) when shipment leaves with 
FedEx air bill number. 205-410-6358 (Kedria cell phone). Date and time. direct sig  
Ship all samples with this form to: 
Edward P. Acosta, Pharm.D., Antiviral Laboratory Director 
Lab Contact: Kedria Walker, B.S. 

41 
 
 
 
 
 
 
 
 
 
 
University of Alabama at Birmingham 
Division of Clinical Pharmacology 
1670 University Blvd., VH 270 Birmingham, AL 35294 
 
CSF Storage & shipment: HGRC 
1. 
HGRC vials will not be stored on site, they will be dropped off at the HGRC on the day of the LP. The 
CSF for the HGRC will NOT be frozen, the specimens are dropped off at the HGRC same day of the 
LP, so freezing isn’t necessary.  
2. 
There should be four copies of each barcode number on separate stickers. A small sticker should be 
placed on each of the two cryovials, another (larger sticker) should be placed on the bio sample form, 
and the last (larger sticker) should be placed on the CSF biological storage log in the bio samples 
binder. Subject ID, PI, Collection date, and IRB protocol number will also be included in the cryovials 
brought to the HGRC.  
3. 
The RC should fill out the CSF Bio Sample form from the HGRC with the information specified, 
including the matching barcode sticker. 
4. 
The RC should make a copy of this form and bring it to the HGRC. HGRC will keep the copy and 
sign the original. The signed original should then be copied. One copy of the form should be kept in 
the patient’s chart, and the other should be kept in the bio samples binder. 
 
 
CSF Analysis and Reports: UAB and UPenn 
a. 
UPenn: On a quarterly basis, tau, ptau, and AB42 will be analyzed and reported for all subjects. 
Neurofilament Light (NL) will be analyzed and reported on as well. The site will receive report of NL 
results, but these results will not be shared with subjects. Only baseline CSF analyses of tau, ptau and 
AB42 will be shared with subjects.  
b. 
UAB: At Weeks 12 and 78, plasma acyclovir levels will be drawn and analyzed for all subjects. On a 
quarterly basis, week 12 and 78 plasma acyclovir levels will be reported to the site, but not shared 
with subjects. This test isn’t clinically relevant but is of relevance to the research team as a check on 
randomization and subject drug compliance.  
 
 
 
18F-Florbetapir Amyloid PET Imaging Procedures (NYSPI/NYU specific, BAI will follow this protocol 
with modification made per facility standard) – Week 0 & Week 78 
 
Scheduling: 
a. NYSPI Coordinator uses iLab to fill out the time request form. Each participant will need a separate 
request (if there are 3 participants, 3 separate requests will need to be initiated). NYU staff will 
communicate subject availability and relevant forms to NYSPI coordinator within 1 day of successful 
screen being confirmed.   
b. Confirm if the available dates work with the subject's schedule. If not, follow up with potential dates. 
c. Coordinator officially requests a slot. Please note slots are first-come-first-serve. It is best to try to 
schedule as far in advance as you can per protocol. 
d. Coordinators will need to attach all the necessary forms including a scanned copy of the signed consent 
form, the scan requisition form, and the pregnancy attestation form.  
e. NYSPI coordinator will also need to create an order in EPIC for the PET scan, in tandem with iLab. Both 
the order in EPIC and the request in iLab are required to make an appointment. 
f. Amyloid PET scans are offered the following times on Thursdays: 14:00, 14:15, 14:30, 15:00, 15:15, and 
15:30. 
1) RPOs:  The scan requisition form can be downloaded directly in iLab or from the server. Note that there are 
separate forms for amyloid and tau scans. 
a. The date needs to be filled out in 01-Jan-2018 format. The scan requisition section needs to be digitally 
signed with a PDF editor. 

42 
 
 
 
 
 
 
 
 
 
 
b. Use military time when filling out the time request form. Military time will be calculated in 24 hours. 
12.00 am would be 0000 hours 12 pm would be 1200 hours and 11 pm would be 23 hours. 
2) Pregnancy: All female patients need to be sign documentation prior to scheduling their appointment. The 
patient will also need to indicate the year of their last menstrual period.  
a. You may want to contact Kim Goldner (kg2614@cumc.columbia.edu) regarding this process, she can 
also answer questions regarding the cancellation policy. 
 
 
 
PET PRE-SCAN PROCEDURES: 
1. 
During study screening:  
a. check for inability to cooperate/claustrophobia (sedation is not offered for this protocol), inability to 
lie on scanner bed for 20 minutes, inability to achieve venous access sufficient for tracer 
administration, and past radiation exposure.  
b. Have the patient sign the pregnancy attestation form if applicable. 
2. 
Schedule scan 2-3 weeks in advance on iLab (NYSPI). Scans need to be cancelled 48 hours in advance, 
otherwise we will be charged for the scan time.  
3. 
Create an order for the PET scan in EPIC, in tandem with iLab.  
4. 
Need to confirm appointment with patient and caregiver at least 3 times before 2-day cancellation 
window. The NYU team will have to communicate a cancelation to NYSPI as the team at NYSPI will 
then have to cancel both tracer and scan in iLab.  
5. 
Call patient and caregiver 10 days and 5 days before scan to confirm appointment. NYU staff must 
place these reminder calls to their subjects. 
a. If they do not pick up, leave voicemail for them to call back to confirm. 
b. If patient and caregiver do not confirm/do not pick up the phone, cancel PET scan. 
6. 
Call patient and caregiver 3 days and 1 day before scan to remind them of the appointment. 
7. 
NYSPI staff will contact Kim (kg2614@cumc.columbia.edu) to create an MRN for the patient if they 
do not already have one. 
8. 
Scanning can happen no earlier than 11:00am and no later than 4:00pm.  
 
Ordering Amyvid Dose from PETNET:  
As of 1/1/19, it is the responsibility of the study team to order Amyvid doses through PETNET Direct. 
Website:  https://apps.mipetsource.com/home/#/login Acct#: 147944 
1. At the far left-hand corner of the homepage, there is a link called "e-ordering." Please click the e-
ordering link.  
2. Once on the dose calendar, click the link on the far left-hand side called "Add Reserved Dose." 
3. When placing your orders for 18F-Florbetapir, reserve 12 mCi. We inject 10 mCi +/- 10% Also: Calibration 
time is the injection time, place patient ID (not name) in respective field, and name Dr. Devanand as the 
Referring Provider. 
4. Confirmation emails will be sent to the program manager, who will then forward the emails to RCs.  
5. Doses can be canceled up until 8am on the day the calibration is due. To cancel a dose, one must call 
PETNET Direct (1-877-473-8638). Cancelations will not be accepted electronically.  
 
ON THE DAY OF THE SCAN: 
1. Patient should eat breakfast and take all of their medications, as usual, prior to arrival at PET Center (RC 
will inform them at 24-hour confirmation). a patient has a long schedule for that day, the patient should 
bring all medications that they need to take during that time, e.g., medications typically taken during 
lunchtime if scans are scheduled before and after lunchtime. 
2. RC will schedule patient (or patient and coordinator if NYU patient and NYU coordinator joins for the 
scan) to meet her/him at the Memory Disorders Clinic 30-45 minutes before scan. NYSPI RC must remain 
present for all scanning procedures if running an NYU patient. Typically, the PET scan will not be the first 
thing a patient does at baseline or week 78, for these longer visits RC’s should keep their eye on the time to 

43 
 
 
 
 
 
 
 
 
 
 
ensure that they arrive at the PET center at least 15 minutes before their scan time to check them in at the 
front desk.  
3. NYSPI RC needs to bring the Pregnancy Attestation Form, a copy of the PET Requisition, and a copy of 
the signed consent or consents (NYU and NYSPI) if NYU subject. The PET center will keep all forms. All 
of these forms can be uploaded to iLab which eliminates the need for a hard copy. If the consent form has 
been changed between the patient’s week 0 visit and week 78 visit the patient must sign the updated 
consent and the NYU or NYSPI RC should bring this updated consent to week 78 PET scan. Always bring 
the entire subject chart with you if you feel this will be helpful in answering any question staff might pose. 
The subject will be asked to state his/her name and DOB, which should match the orders/scan request 
placed by the PI/coordinator.  
4. RC needs to bring her/his dosimetry badge. 
5. When checking in the person at reception will only need the IRB protocol number from the RC. Once the 
patient is checked in the RC will wait in the PET center with the patient and caregiver until they are called 
in. 
6. NYSPI RC will have all forms ready for review however the PET center will likely have the forms printed 
from the prior iLab submission. 
7. RC will make sure the patient has removed all metals from head – pins, clips, earrings.  
8. The PET technician will set up the patient on a bed with a blanket for them to relax during the uptake 
period.  
9. Once the patient is set up the RC will go to the waiting room to wait for the patient. If the patient does not 
have a caregiver with them the RC needs to remain in the room with the patient but sit at least 6 feet away. 
If the caregiver is present, they will remain with the patient until it is time for them to enter the scanner, 
then come out to the waiting room with the RC.  
10. Patient will be at the PET center for about 1.5 hours (scan acquisition time is 20 minutes and the uptake 
time is 50 minutes). The RC will go back to the scanner 5 minutes before the scan time is up to retrieve the 
patient and sign a copy of the PET checklist. 
11. Once the scan is done the RC will take the patient and caregiver back to the clinic to complete any other 
necessary measures or to the most convenient location to exit and head to their train or car, if NYU subject, 
they may leave at this time.  
 
POST SCAN PROCEDURES: 
1. Instruct patient that he/she can continue normal activities after PET scan. 
2. Patient is advised to drink several glasses of water and contact study physician if there is any persisting 
pain in his/her hand or arm (slight soreness and bruising is expected since a small tube was inserted into 
vein of arm).  
 
Obtaining Amyloid Scan Reads  
(completed through the PET Department’s Safety Read System in RedCap) : 
Amyloid reads will be completed by Dr. Akiva Mintz, MD (am4754@cumc.columbia.edu) and/or Dr. Mikhail 
Dobrouvin, MD (md2367@cumc.columbia.edu) Amyloid read reports are available in RedCap 1-10 days 
following amyloid PET scan.  
 
To access an Amyloid read: 
1. Website: https://radiosftp.cpmc.columbia.edu 
/redcap/redcap_v8.11.7/DataEntry/record_status_dashboard.php?pid=31&pagenum=2 
 
1. Navigate to "Record Status Dashboard" (on the left-hand side of the home-page) and all VALAD 
subjects are on the list of study subjects receiving reads that will automatically populate when one navigates 
to the Record Status Dashboard.  
2. Subjects are identified on this list by “NYSPI #7537” followed by respective Study ID.  
3. RCs must download a PDF the report with “saved data,” print, file in subject chart and obtain signature and 
date on the amyloid read by the patient’s study MD.  

44 
 
 
 
 
 
 
 
 
 
 
4. SUVR: Once the analysis and decisions about how to interpret SUVR are confirmed by Hengda He, we will 
decide how to communicate results to subjects and caregivers, with Drs. Mintz and Kreisl. Dr. Mintz would 
like to be informed of discrepant cases (between amyloid pos/neg status and SUVR AD Dx interpretation). 
 
Study physicians will review the amyloid read and SUVR results with the patient and caregiver when they 
come in for their next visit. If the patient wants the results sooner the physician may call to discuss but in-
person discussion is strongly preferred. Some reads may require immediate follow up. 
1. Prior to filing, PI or study physician will need to sign and date at the bottom of the report.  
2. Reports for NYU subjects will be sent to NYU from NYSPI coordinator via secure email after review by 
Dr. Devanand. Dr. Wisniewski will call NYU subjects with findings. 
 
18F-MK-6240 Tau PET Imaging Procedures (NYSPI/NYU specific, BAI will follow this protocol with 
modification made per facility standard) – Week 0 & Week 78 
General Note:  
a) For patients who have confirmed radiation exposure from the past year, contact Dr. Mintz via email for 
review of patient medical records/self-report of scanning as soon as you’ve been made aware of the issue. 
This information is captured on the Metal Screening Questionnaire and the Medical Screening Form. 
Prior research scans will count toward actual, calculated radiation exposure by Dr. Mintz but SOC scans 
will not. Dr. Mintz is to evaluate research scan radiation exposure prior to running PET scans. We should 
go ahead and book scans under the assumption that there will not be a significant delay in scanning, even 
for those patients who have had previous research scans; we will cancel/rebook if need be per Dr. Mintz.  
b) For the sake of IRB Compliance, the VALAD team will always email Dr. Mintz in regard to patients who 
have been exposed to radiation in the past year (SOC or research). Dr. Mintz will compose either a stock 
reply that piggy backs off of Dr. Weintraub’s decision that SOC scans will not count toward radiation 
exposure in this protocol, or a more pointed reply with pointed scan scheduling directions if a patient had 
a research scan(s) in the past year. IRB needs assurance that patients will not exceed 5 REM yearly 
allowable limit FDA guidelines. 
 
Scheduling: 
1. NYSPI Coordinator uses their own iLab account to fill out time request form. Each participant will need a 
separate request (if there are 3 participants, 3 separate requests will need to be initiated). NYU staff will 
communicate subject availability and relevant forms to NYSPI coordinator within 1 day of successful screen 
being confirmed.   
2. NYSPI Coordinator will create an order for the PET scan in EPIC, in tandem with iLab.  
3. Confirm if available dates work with subject’s schedule/follow-up with potential dates. 
4. Coordinator officially requests slot. Please note slots are first-come-first-serve. It is best to try to schedule as 
far in advance as you can per protocol. 
5. Coordinators will need to attach all the necessary forms including a scanned copy of the signed consent 
form, the scan requisition form, and the pregnancy attestation form.  
 
Please Note the following tau PET Scheduling Proclivities: 
Scheduling for MK-6240 will utilize the following time slots. We allow two tau dose synthesis failures before 
proceeding with randomization.  
 
1. MK-6240 injection times will be concentrated on Monday’s and Friday’s.  
2. MK-6240 will not be available on Tuesdays, Wednesdays, and Thursdays. 
3. The following injection times are available Monday’s and Friday’s: 14:00, 14:15, 14:30, 15:30, 15:45, and 
16:00 
4. The PET scan requisition form can be downloaded directly in iLab or from the server. Note that there are 
separate forms for amyloid and tau scans. 
a. The date needs to the filled out in 01-Jan-2020 format. The scan requisition section needs to be 
digitally signed with a PDF editor. 

45 
 
 
 
 
 
 
 
 
 
 
b. Use military time when filling out the time request form. Military time will be calculated in 24 
hours. 12.00 am would be 0000 hours 12 pm would be 1200 hours and 11 pm would be 23 hours. 
5. Pregnancy: All female patients need to be sign prior to scheduling their appointment. The patient will also 
need to indicate the year of their last menstrual period. 
a. You may want to contact Kim Goldner (kg2614@cumc.columbia.edu) regarding this process, 
she can also answer questions regarding the cancellation policy.  
 
 
PET PRE-SCAN PROCEDURES: 
1. During study screening:  
a. check for inability to cooperate/claustrophobia (sedation is not offered for this protocol), inability 
to lie on scanner bed for 40 minutes, inability to achieve venous access sufficient for tracer 
administration, and past radiation exposure.  
b. Complete pregnancy form if appicable 
2. Schedule scan 2-3 weeks in advance in iLab. Scans need to be cancelled 48 hours in advance, otherwise 
we will be charged for the scan time. Call patient and caregiver 10 days and 5 days before scan to confirm 
appointment. NYU staff must place these reminder calls to their subjects. 
a. If they do not pick up, leave voicemail for them to call back to confirm. 
b. If patient and caregiver do not confirm/do not pick up the phone cancel PET scan. 
3. Call patient and caregiver 3 days and 1 day before scan to remind them of appointment. 
 
ON THE DAY OF THE SCAN:  
1. Patient should eat breakfast and take all of their medications, as usual, prior to arrival at PET Center (RC 
will inform them at 24-hour confirmation). If a patient has a long schedule for that day, the patient should 
bring all medications that they need to take e.g., medications typically taken during lunchtime if scans are 
scheduled before and after lunchtime. 
2. NYSPI RC will schedule patient (or patient and coordinator if NYU patient) to meet her/him at the Memory 
Disorders Clinic 30 minutes before scan. NYSPI RC must be present for all scanning procedures if running 
an NYU patient. NYU RC’s presence is optional.  Typically, the PET scan will not be the first procedure a 
patient completes at baseline or week 78, for these longer visits RC’s should keep their eye on the time to 
ensure that they arrive at the PET Center at least 15 minutes before their scan time to check in at the front 
desk.  
3. NYSPI RC needs to bring the Pregnancy Attestation Form, a copy of the PET Center Checklist, and a copy 
of the signed consent or consents (NYU and NYSPI) if NYU subject. The PET center will keep all forms. If 
the consent form has been changed between the patient’s week 0 visit and week 78 visit, the patient must 
sign the updated consent and the RC should bring this updated consent to week 78 PET scan. Always bring 
the entire chart with you. This will be helpful in answering any question staff might pose. 
4. RC needs to bring her/his dosimetry badge. 
5. When checking in at reception, the RC will need the IRB protocol number. Once the patient is checked in 
the RC will wait at the PET center with the patient and caregiver until they are called in. 
6. NYSPI RC will give the consent form, and pregnancy attestation, subject ID, and RPO forms to the PET 
tech. 
7. RC will make sure the patient has removed all metals from head – pins, clips, earrings. 
8. Pre-injection vital signs (BP, heart rate, temperature, respirations) must be collected by the PET tech and 
recorded on the PET Center Checklist. The RC must check to ensure this has been done.  
9. RC(s) will remain with patient and caregiver during the injection process. RC and caregiver must sit or stand 
at least 6 feet away from the patient at all times to reduce exposure to radiation. The PET technician will set 
the patient up on a wheeling bed with a blanket during the uptake period. At this time, the caregiver should 
go and wait in the PET center waiting room unless the subject is anxious and needs the caregiver in room 
with them. 
10. The RC should remain with the patient and use this time to organize the patient’s chart and if the patient is 
in condition for measure administration, administer measures as required per protocol. Best use should be 

46 
 
 
 
 
 
 
 
 
 
 
made of the lengthy wait time for radioligand uptake. The RC should always be 6 feet away from the 
patient.  
11. Patient will be at the PET Center for 2 hours (scan acquisition time is 40 minutes and the uptake time is 80; 
120 minutes in total). The RC (s) will go back to the scanner 5 minutes before the scan time is up to 
retrieve the patient and review/sign a copy of the PET checklist. 
12. Post scan vital signs (BP, heart rate, temperature, respirations) must be collected on the PET center 
checklist, this will have to be checked by an RC every time an 18F-MK-6240 scan is completed. 
13. Room # and Scanner Type (ID) will need to be recorded on the PET center checklist and tracked per patient 
from baseline to 78 weeks to ensure consistency of scanner used. 
14. Once the scan is complete the RC will take the patient and caregiver back to the clinic to complete any 
other necessary measures. NYU subjects and coordinators may leave at this time.  
 
POST SCAN PROCEDURES: 
1. Instruct patient that he/she can continue normal activities after PET scan. 
2. Patient is advised to drink several glasses of water and contact study physician if there is any persisting pain 
in his/her hand or arm (slight soreness and bruising is expected since a small tube was inserted into vein of 
arm).  
3. 24 hours after the scan, the RC will place a follow up safety call to the patient or caregiver to assess for 
adverse events and/or pain. RCs will call respective subjects.  
4. Clinical reads will never be performed on tau scans. Performing clinical reads with non-FDA approved 
tracers is against federal regulations. 
 
Important Reminder for RCs: 
Dr. Devanand has advised of the following policy: if tau imaging procedures get canceled due to technical 
issues, the main goal is to keep the patient in the protocol. Therefore, the patient may not complete an imaging 
procedure, but continue in the protocol.  
 
If a patient is unwilling to do the tau PET scan, the patient will still be enrolled in the protocol and will be 
followed to 78 weeks. This will be a protocol deviation. Of course, this is only a final resort, and all decisions 
must be reviewed with the patient’s study physician and Dr. Devanand, if needed. 
 
Important Contact info for PET: 
Kim Goldner (Director of PET Center Technical Services): kg2614@cumc.columbia.edu; 212.342.2999 
Rodolfo Arevalo (Project Coordinator); ra2874@cumc.columbia.edu; 212.342.2999 
Akiva Mintz, MD (PET Center Director/Attending Radiologist): (am4754@cumc.columbia.edu)   
Mikhail Dubrouvin, MD (Attending Radiologist): (md2367@cumc.columbia.edu) 
 
 
MRI Protocol: NYSPI MRI Suite (BAI will follow this protocol with modification made per site 
standard) 
 
MRI PRE SCAN PROCEDURES: – Week 0 & Week 78 
1. 
After Recruitment and screening – complete the Metal Screening Questionnaire. All implants NEED TO 
BE CONFIRMED and reviewed with the MRI suite in tandem with the Metal Screening Questionnaire. 
** Obtaining MRI Clearance** If the patient checks ‘YES’ for any item on this questionnaire 
(examples include metal stents, wire mesh), clearance must be obtained prior to the MRI scan or the 
scan will not take place.  It is acceptable to schedule the scan prior to obtaining clearance. The 
coordinator must obtain the name of the patient’s implanting surgeon from the patient/caregiver as soon 
as possible. It is the coordinator’s responsibility to follow-up with the patient and/or surgeon to 
determine the presence or absence of a contraindication. The coordinator will then fax/email the 
surgeon’s office the MRI suite’s Request for Proof of MR-Safe Implants, including a signed Release of 
Information and a fax cover sheet with the patient’s name, DOB, and any other available information 

47 
 
 
 
 
 
 
 
 
 
 
about their surgery. This form must be completed and signed by the surgeon. The coordinator will email 
the completed form to Dr. Lawrence Kegeles (Larry.Kegeles@nyspi.columbia.edu) for clearance. The 
coordinator should print a hard copy of the Metal Screening Form, Request for Proof of MR-Safe 
Implants, and Dr. Kegeles’ clearance email to bring to the scan. If requested by Dr. Kegeles, the subject 
should be advised that there is a possibility of movement and overheating of the implant as a result of 
the scan. 
2. Ask about claustrophobia. 
3. Schedule an appointment in the Calpendo for 30 minutes (the actual scan takes 30-40 minutes + time for 
removing metal, wanding and paperwork, etc.) 
a. 
Schedule scans at least 24 hours in advance. 
b. NYU staff will communicate subject availability and relevant forms to NYSPI coordinator within 5 
days of successful screen being confirmed.   
c. 
Request the patient to be at least 30 minutes early. If NYU subject, both RC and subject will arrive 30 
minutes in advance of scan.  
d. Scan cancellation needs to be 95 hours (4 days) before scheduled scan. NYU staff will communicate 
cancelations to NYSPI staff so that the official cancelation can be made in Calpendo.  
 
 
ON THE DAY OF THE SCAN for Research Coordinator: 
1. Bring the subject in to the MRI suite along with caregiver if needed. The caregiver can wait in the waiting 
area. 
2. NYSPI RC will give the consent form and metal questionnaire (and clearance if needed) to the tech first. 
3. NYSPI RC will get billing form from Joe, check box to indicate we want a neuro read. Fill out the rest of 
the form and return to Joe. 
4. Make sure subjects remove all metals – pins, clips, credit cards etc. 
5. NYSPI RC will wand the patient to make sure there are no other metals. 
6. The tech will check and then take the subject into the scanner room. 
7. RC must go in to help place the subject in a comfortable position. 
8. RC should wait with the technician outside the scanning room and keep an eye on the patient throughout 
the duration of the scan. If the RC notices excessive movement, they should notify the tech about the 
possibility of re-running that scan section. 
9. The tech can instruct the subject over the intercom. 
 
AFTER THE SCAN: 
● 
The RC should enter the scan room and make sure that the subject gets out of the scanner carefully. 
● 
Let them collect their belongings and take them out of the MRI suite. 
● 
The study will be uploaded to XNAT (NYSPI). 
● 
Go to XNAT.nyspi.org and check in your projects and download when ready (NYSPI RC). 
● 
You can then download the scan to a PC or MAC and then send it over NYSPI - file transfer or burn on 
CDs and send them to the respective sites. 
● 
RC will print the MRI report for PI or study physician to review and sign it. PI or study physician will 
sign and date at bottom of page. Make sure this is completed in clear handwriting. 
● 
Pay attention to reading each report carefully, ensuring that the narrative structure of unremarkable reports 
are not identical.  
● 
Reports for NYU subjects will be sent to NYU from NYSPI coordinator via secure email after review by 
Dr. Devanand. Dr. Wisniewski will call NYU subjects with findings.  
 
Important MRI Contact info: 
 
Mathew Riddle MRI Unit Coordinator 
New York State Psychiatric Institute1051 Riverside Drive, Room SB315 New York, NY 10032 
Mathew.Riddle@nyspi.columbia.edu  
 

48 
 
 
 
 
 
 
 
 
 
 
Dr. Lawrence S. Kegeles Professor of Clinical Psychiatry (in Radiology), Psych Translational Imaging 
(Contact for MRI Implant Clearance) 
Larry.Kegeles@nyspi.columbia.edu 
 
 
MRI without contrast: Scan sequences: 
1. 3 Plane Localizer 
2. Accelerated Sagittal MPRAGE – IR-SPGR 
3. Sagittal 3D FLAIR 
4. Axial T2 STAR 
Note: As a general rule, we cannot accept data from outside MRI or PET scans for research purposes.   
 
MRI Protocol: Mind Brain Behavior Institute (BAI will follow this protocol with modification made per 
site standard) 
 
Informants will not be permitted to attend the actual MBBI MRI scan, and will wait in the facility waiting 
room, unless there is an emergency. RC will remain at MBBI MRI suite through completion of scan and will 
escort subjects/informants to exit and go home. 
 
MRI scans will be conducted in the Mind Brain Behaviour Institute (MBBI) scanner “Eve” when they are not 
cleared to complete a scan on the NYSPI scanner. Subjects scanned at MBBI for Baseline will need to be 
rescanned at MBBI for Week 78 (on the same scanner) as is the case for subjects scanned in the NYSPI 
scanner. 
 
Administrative points to keep in mind: 
1. Scanner to be used for this protocol: 
a. 
“Eve” Eve is fMRI machine; “June” is non-fMRI machine. 
Siemens Prisma 
3T, 60cm bore 
80 mT/m @ 200 T/m/s whole body gradients 
128 RF receiver channels 
2 RF transmit channels 
Multinuclear spectroscopy capable 
13 tons, 213 cm long 
Closed helium cryocooled (zero helium boil off) magnet 
Head, neck, body and spine coils come with system 
2. Certified MBBI Tech will run our scans. Availability during COVID-19 is only on Tuesdays and 
Wednesdays, and she will only assist up to 2 scans per day.  
3. Clinical Reads 
a. 
If there is an incidental finding on the clinical read, it is MBBI policy that a MD from Columbia 
Neurology do the incidental finding follow-up call with the patient. Our MDs will be notified of the 
findings via letter and perform follow up with subjects over the phone as well.  
b. 
RC’s need to complete the request for a clinical read in RedCap prior to the patient’s scan 
4. Medical Coverage 
a. 
If medical coverage is deemed necessary for a patient by Dr. Devanand (i.e. the patient is very 
impaired, on Lorazepam, or deemed “difficult”), the patient must be scheduled to be scanned on a 
Monday or Tuesday, as Dr. Devanand and Dr. Kerner indicated that those are the only days both are 
available for MBBI medical coverage (on site). In this case, Dr. Devanand and Dr. Kerner will be 
present at MBBI and sit in a counseling room adjacent to the MRI room, in case of a medical 
emergency.  
b. 
If no medical coverage is deemed necessary, Dr. Devanand and Dr. Kerner must be made aware of 
the date/time of a patient scan, so that he/she is available by phone/beeper. 
c. 
In the case of what staff deem to be “any major medical emergency,” MBBI calls 911 immediately.  

49 
 
 
 
 
 
 
 
 
 
 
d. 
To gain independent access to the building, MDs providing medical coverage must have M2 level 
training, else will have to be swiped in by their staff, which could pose an inconvenience. To sit in 
with patients (in the actual MRI scanning room), MDs must have M3 level access.  
5. Data Transfer 
a. 
All data is uploaded to FlyWheel, which is a cloud application accessible to those with a UNI. 
b. 
We will be able to do fMRI QC using FlyWheel. 
c. 
PM will be able to download the scan onto CDs, as she has been doing from XNAT. Dania can do 
this as well.  
6. Week 78 Scans 
a. 
Dr. Devanand confirmed that the patients scanned at MBBI at baseline must be scanned again at 
MBBI at Week 78.  
Procedures:  
1. All scans will be booked using iLAB (Devanand NYSPI Group) for 45 minutes.   
a. Kathleen confirmed that we already have an account set-up.  
b. There is a tau Chartstring which will be used for the billing of VALAD scans only.  
c. Use the tau Chartstring each time when booking a scan in iLAB. 
d. The scan must be booked by the PI research staff who will be accompanying the patient to the scan  
e. When booking the scan, ensure that MBBI Tech is available to run the scan.  
f. A RedCap record will be set up the day you schedule the scan so that the patient’s clinical read can be 
recorded in a timely manner. 
2. At the initial screening visit, the designated RC will complete MBBI’s Metal Screening Questionnaire. 
a. If needed, staff will obtain medical records pertaining to the patient’s implant and send to Dr. David 
Gultiken (dg3155@columbia.edu) 
3. On the day of scan: 
a. Designated RC will ensure that the patient’s chart is brought to MBBI. 
b. Designated RC will meet patient and MBBI Tech at MBBI (3227 Broadway) 30 minutes before the 
scheduled start-time of the scan. If NYU patient, NYSPI RC will meet outside MBBI 30 minutes prior 
to scan. NYU RC presence is optional.  
c. Designated RC will assist the patient in changing into scrubs provided by MBBI. 
d. Designated RC will complete wanding and all metal screening procedures with the participant.  
e. Designated RC will escort patient to MRI bed. 
f. Designated RC will provide ear plugs to the participant, per MBBI policy. 
g. Once scan is complete, RC will escort the patient out of the MRI scanner bed and bring him/her back 
to the dressing room.  
h. Dispose of scrubs in soiled linen basket. 
i. Complete subject payment form with the participant and schedule remaining baseline measures.  
4. After Scan/FlyWheel Procedures 
a. Lauren and MBBI Tech will be able to queue the MRI/fMRI QC post-scan using FlyWheel. 
b. Lauren will download scan onto three CDS (copy for:  CU, DU, QC) 
c. Research staff will obtain clinical read (RedCap) and review it with Study MD. 
i. If not listed, RC will include patient’s name, study ID, and date of birth on the document. RC is 
then required to initial and date the upper right-hand corner.  
ii. Study MD is required to initial and date the lower right-hand corner. 
d. Dr. Devanand or study MD will then sign IRB MRI Findings Letter. Letters will be sent to NYU RCs 
for report to NYU subjects by respective NYU study MD. 
e. RC to give the findings letter and clinical read document to patient at his/her next visit, or within a 
month of the scan date.  
5. Scan Cancellation Procedure/Policy 
a. Cancellations must be made 48-hours in advance in iLAB. 
b. If the cancellation must be made less than 48 hours prior to the scan, you must email Kathleen Durkin 
(kd2649@columbia.edu) directly. 
c. To cancel: 

50 
 
 
 
 
 
 
 
 
 
 
i. Login to iLAB. 
ii. Go to Zuckerman Mind Brain Behavior Institute (MBBI): MR Core along the left side, Core 
Facilities, Click Schedule Equipment. 
iii. Click view schedule for the scanner which you booked your scan on. 
iv. Find the reserved block, click on “details,” that appear to the left. 
v. On the screen that appears, there will be a “delete reservation” button in the lower-right corner. 
 
 
Additional Protocol Points: 
 
New Staff Communication: 
For emails regarding scheduling and procedures for an individual patient, communicate amongst coordinators 
for confirmation of correct language, phrasing, etc. 
For broader issues pertaining to the protocol or communication with people outside our core team, your draft 
email should be sent to both program managers specifically for review. In this draft email, you need to explain 
the context and include the sequence/chain of emails that led you to generate your draft email. For emails with 
broader implications, e.g., IRB protocol changes of significance, Dr. Devanand and the entire study team 
should be copied. 
Program Managers are to be CC’d on all key communication; when in doubt, CC a program manager as this 
will ensure that the proper material is always sent to the proper party covering questions within the email 
narrative such as Who, What, Where, When, and Why? 
 
Standing Communication Review Protocol: 
All communications to outside entities, e.g., DSMB, NIA should be presented for review in our Wednesday 
meeting and sent out only after that.  The exception is if Dr. Devanand has instructed you to do something 
immediately (in between our Wed meetings). 
For clinical and other emergencies, let Dr. Devanand know immediately. Otherwise, bring all pending issues 
and materials, including those that need signature, to the weekly meetings on Wednesday at 3:00pm in Room 
2001. 
 
Adverse Events and Serious Adverse Events: 
Adverse events (AE) and serious adverse events (SAE) will be carefully monitored, recorded, and reported in 
this study. An AE is an unexpected medical occurrence or worsening of symptoms, which does not necessarily 
have a causal relationship with study treatment. A SAE is a medically serious event, any event requiring 
hospitalization, and death. 
 
Each patient that has an AE or SAE reported will have an AE log filed in their research chart. Both AE and 
SAE are to be recorded on the AE log. AE logs are data forms for this study. Hardcopy AE forms are rewritten 
each time new information about the event is made available, with all revisions kept in paper research charts. 
However, the database AE form will only contain information reflecting the final resolved event or last 
recorded information once the patient has left the protocol. Information regarding the treatment provided, 
outcome, and presumed relationship to study drug will be updated as new information becomes available. Site 
PIs will sign the bottom of the AE logs for their own site once the patient has exited the protocol. 
 
SAEs are also logged on the AE form for data purposes in this study. For any SAE occurring at NYU or BAI, 
the SAE will first be reported to local IRB, then to NYSPI for local follow up reporting when applicable, as 
well as for follow up reporting to additional oversight bodies as described above (DSMB, IRB).    
 
All information obtained between visits by the study coordinator that may be an AE or SAE needs to be 
communicated to the study physician who will then decide if it is an AE or SAE, consulting with Dr. 
Devanand if necessary. Based on the decision, the study coordinator needs to ensure that the AE and SAE 

51 
 
 
 
 
 
 
 
 
 
 
forms and completed and submitted to the relevant agencies. Individual AEs need not be reported outside of 
the core research group and database team.  SAEs need to be reported to the IRB and DSMB and NIA. 
 
Protocol Deviations: 
If unavoidable deviations from the study protocol occur, they will be recorded on a protocol deviation form 
filed in the patient’s research chart. A protocol deviation log of all deviations throughout the protocol for every 
patient will be filed in the site’s regulatory binder. Site coordinators will keep a log of protocol deviations in an 
excel document for continual reference and recording.  
 
Protocol Exceptions: 
Requests for protocol exceptions are submitted to local IRB on a case by case basis.  
 
Caregiver Communications: 
Coordinators will log all clinically relevant communications with patients and their caregivers in the VALAD 
charts. The only communications that should not be recorded are those initiated by the coordinator, and those 
regarding scheduling.  
 
Study coordinators will call caregivers to confirm their appointments one day before the scheduled date. When 
calling to confirm an appointment, take the opportunity to remind caregivers to bring study medication bottles 
to the clinic and confirm that they have been administering the correct dosage to the patient. For screening or 
scanning visits remind the patient to bring a valid form of ID. 
 
Reimbursement/Payments: 
Patients will be paid $100 for each PET scan and $50 for each MRI scan; each patient will receive 4 PET and 2 
MRI scans. The patient will receive $100 for each lumbar puncture procedure.  Therefore, over 18 months 
subjects who complete LP will be compensated $800.00; and those who do not complete LP will be 
compensated $500.00. In addition, informants will receive $10 per hour or $200 for the entire study that 
requires approximately 20 hours of informant time during the one-year study. We will also cover 
transportation costs that we estimate at $80 per patient on average during the study. Petty cash will be used at 
NYSPI and payment cards at NYU.  
 
Monitoring Visits: 
NYSPI /CUMC will conduct Site Initiation, Interim Monitoring, and Close Out visits for any sub site 
completing work on this protocol. Monitoring visits will include review of sub site regulatory binders(s), 
source documents, subject charts, database data entry, pharmacy/pharmacy logs, lab space and equipment, any 
space where study visits are conducted, as well as scheduled time to meet with the site PI to discuss monitoring 
visit findings and protocol implementation. A detailed monitoring report inclusive of all findings and action 
items for the site will be generated 1-2 weeks after the visit.  
 
Research Charts: 
Study site coordinators are responsible for assembling and updating each patient’s research chart. Coordinators 
review each subject chart at the end of each subject’s visit for accuracy and completion of each form. A second 
coordinator will double check all forms. This instant checking and cross checking is designed to ensure 
protocol compliance and subject safety. Staff will follow local regulations for paper research charts, with 
special attention paid to regulations for proper storage of consent forms.  
 
It is recommended that the sections of a research chart be ordered as follows:  
1. 
Patient Tracker/Table of Study Procedures/AE log/Pill Log 
2. 
Consent 
3. 
Labs/Medical Records 
4. 
MRI 
5. 
PET (tau and amyloid) 
6. 
LP 

52 
 
 
 
 
 
 
 
 
 
 
7. 
Screen 
8. 
Week 0 
9. 
Week 2 
10. 
Week 4 
11. 
Week 12 
12. 
Week 26 
13. 
Week 52 
14. 
Week 78 
 
Forms and measures will be placed in the chart’s specific sections and visit weeks as specified in the “Study 
Visits: Measures to be Completed per Visit” section of this manual.  
 
Early Discontinuation and Alternate Scenarios: 
The reasons for early discontinuation of a patient from the study include the following: 
1. Intervening severe medical illness that either the PI or the Medical Monitor determines that it requires 
study discontinuation. 
2. Discontinuation of treatment with valacyclovir or placebo for more than 6 weeks. After an interruption 
of treatment for any reason, e.g., medical illness, the patient can resume the protocol if the interruption 
is less than 6 weeks. 
3. Based on the result of a blood draw at the week 26 visit, if the serum creatinine level increases to 
more than 1.5 or eGFR declines to less than 44 mL/min, we will lower the study medication to the 
minimum dose of 2g valacyclovir or placebo per day. Patients will then have blood collected and labs 
repeated at an additional visit at week 30. If, at week 30, kidney function is still abnormal based on the 
above criteria, study medication will be discontinued for this patient. The reduction in kidney function 
will be communicated to the patient's primary care physician. This is an intent-to treat protocol. 
Therefore, a patient who is discontinued early in the study due to the above reasons will be followed 
and evaluated (whenever feasible) until the Week 78 visit or until the patient withdraws his/her 
consent to participate. 
4. Patient moves their residence to a distant location. 
5. Side effects leading the subject to discontinue medication.  
6. Insufficient Clinical Response. 
7. Non-Compliance with study protocol and/or procedures. 
8. Withdrawal of consent. 
9. Death. 
 
Intent to Treat/ Dropouts and Missing Data:  
Dropout is estimated at 15%. In patients who discontinue study medication, reason for early exit will be 
documented and study visits will continue at scheduled time-points per the intent-to-treat (ITT) principle.  
 
The primary analyses will be on the ITT sample, i.e., all randomized subjects according to the treatment that 
they were assigned. Missing data on outcome variables will be dealt with by using (longitudinal) generalized 
linear mixed effects models that do not require complete measurements under the “missing at random” 
assumption. For MRI scan, 18F-Florbetapir PET scan, and 18F-MK-6240 tau PET scan, outcomes with just 
one pre and post measure, inverse probability weighting of cases with complete data will be used where 
weights are calculated based on the probability of a subject being a completer versus being a dropout. 
Sensitivity analysis will be performed to provide a range of plausible effect estimates that could arise due to 
non-ignorable missing data. 
 
Treatment interruption for up to 6 weeks will be allowed for medical/surgical intervening conditions. 
 
When a patient is at risk of dropping out:  
When a patient is at risk of dropping out, study staff should assess the concern and take action accordingly, and 
the study doctor for that patient needs to be informed about intervening to keep the patient in the study if 

53 
 
 
 
 
 
 
 
 
 
 
possible. Staff should keep all relevant blank paper work for the week 78 or Endpoint (dropout) visit in the 
subject’s chart at all times.  While the goal is ITT assessments up to 78 weeks, in some cases this may not be 
possible, e.g., patient does not wish to return, patient moves to a distant location and clinic visits are no longer 
possible.  In these instances, a final study visit should be completed whenever possible. This should be done 
even if not all procedures can be completed, e.g., patient is willing to come back for a final visit but does not 
wish to repeat the MRI or PET scan or LP.  In this instance, complete all available forms and record them in 
the database after consultation with Dr. Howard Andrews as to which time-point the data should be entered in 
the database.  
 
Assessment Instruments: 
For a full reference of all forms, measures, requisitions, and notes kept for subjects participating in this 
protocol, please refer to the Mock Chart, which is kept in room 1600A at NYSPI.  Testing materials for the 
ADAS-Cog11 and other procedures are stored in room 1600A. 
 
Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog11, modified version): Includes tests of 
attention, category fluency, episodic verbal memory, non-verbal memory, and naming. ADAS-cog has been 
used in virtually all FDA registration trials in AD, and we can compare our results with the literature. ADAS-
cog has three different/equivalent word list versions that will be given sequentially to reduce practice effects. 
 
ADCS-ADL: A research measure of daily functioning in AD that has been used in several major AD trials. It 
includes a large section on Instrumental Activities of Daily Living that are affected in mild AD. 
 
Clinical Dementia Rating (CDR): The formal CDR interview will be used to score 6 domains (boxes); sum 
of boxes. Overall score: 0=none, 0.5=questionable, 1=mild, 2=moderate, 3=severe dementia 
 
National Alzheimer’s Coordinating Centers (NACC) Forms: The physician will complete the NACC that 
takes 35-40 minutes and includes history, neurological exam with assessment of Parkinsonian signs, 
psychiatric assessment that includes the short version of the Geriatric Depression Scale and the 
Neuropsychiatric Inventory, Functional Activities Questionnaire (FAQ), vascular risk factors and the modified 
Hachinski ischemic scale. 
 
NACC-UDS Neuropsychological Test Battery (2015 version): Montreal Cognitive Assessment (MOCA), 
Number Span Test Forward and Backward, Category Fluency for animals and vegetables, Craft Story21 recall 
(and delayed), Benson Complex Figure Recall and delayed, Multilingual Naming Test, Verbal Fluency, 
Phonemic Test. These tests are given for diagnostic purposes only at baseline and 52 and 78 weeks. Drs. 
Devanand and Stern will make consensus diagnoses at baseline (done with ADRC), and at 52 and 78 weeks, 
based on clinical assessment and these cognitive tests. We considered the ADCS-PACC (composite score from 
4 tests) and the CogState C3 composite used in the A4 trial (PET amyloid-positive, cognitively intact subjects), 
but these scores were derived by examining the transition from cognitively normal to MCI; they have not yet 
been validated in AD clinical trials and hence we will not use them. 
 
Apolipoprotein E (ApoE): Apolipoprotein E will be genotyped (ε2, ε3, and ε4 alleles) by LCG genomics 
using SNPs rs429358 and rs7412. A portion of the blood will be sent out to Prevention Genetics for 
identification of APOE genotype. Using a standard protocol, DNA is amplified by the polymerase chase 
reaction (PCR). The genotypes are determined blind to subject status (patient or control) by the sizes of DNA 
fragments present. 
 
Olfaction Assessment/ The UPSIT (scratch-and-sniff odor identification test): Has been administered to 
several hundred thousand subjects around the world and its use is not associated with any known side effects. 
The UPSIT comprises synthetic odors and there is no risk of an allergic reaction with this procedure. If there is 
an acute upper respiratory infection, testing will be delayed until the participant has recovered.  
 
 
 

54 
 
 
 
 
 
 
 
 
 
 
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