Adherence to Antidepressant Treatment in Subjects With Depression
Phase: PHASE2
Conditions: Depression
Sponsor: Laureate Institute for Brain Research, Inc.

Adherence to Antidepressant Treatment in Subjects 
with Depression 
Protocol Identifying Number: 2017-007-00 
Principal Investigator: Martin P. Paulus 
Sponsor: Laureate Institute for Brain Research 
Funded by: The William K Warren Foundation 
Draft or Version Number:  v.1.0 
November 7, 2017 

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Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................................................... 1 
STATEMENT OF COMPLIANCE ...................................................................................................................... 1 
PROTOCOL SUMMARY .................................................................................................................................. 2 
SCHEMATIC OF STUDY DESIGN ..................................................................................................................... 3 
1 
KEY ROLES .......................................................................................................................................... 3 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................................. 5 
2.1 
Background Information .......................................................................................................... 5 
2.2 
Rationale .................................................................................................................................. 7 
2.3 
Potential Risks and Benefits..................................................................................................... 8 
2.3.1 
Known Potential Risks ............................................................................................ 8 
2.3.2 
Known Potential Benefits .................................................................................... 10 
3 
OBJECTIVES AND PURPOSE ............................................................................................................. 10 
4 
STUDY DESIGN AND ENDPOINTS ..................................................................................................... 10 
4.1 
Description of the Study Design ............................................................................................ 10 
4.2.1 
Primary Endpoint ................................................................................................. 11 
4.2.2 
Secondary Endpoints ........................................................................................... 11 
4.2.3 
Exploratory Endpoints ......................................................................................... 11 
5 
STUDY ENROLLMENT AND WITHDRAWAL ...................................................................................... 12 
5.1 
Participant Inclusion Criteria ................................................................................................. 12 
5.2 
Participant Exclusion Criteria ................................................................................................. 12 
5.3 
Strategies for Recruitment and Retention............................................................................. 12 
5.4 
Participant Withdrawal or Termination ................................................................................. 13 
5.4.1 
Reasons for Withdrawal or Termination ............................................................. 13 
5.4.2 
Handling of Participant Withdrawals or Termination .......................................... 13 
5.5 
Premature Termination or Suspension of Study ................................................................... 13 
6 
STUDY AGENT .................................................................................................................................. 14 
6.1 
Study Agent(s) and Control Description ................................................................................ 14 
6.1.1 
Acquisition ........................................................................................................... 14 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................ 14 
6.1.3 
Product Storage and Stability .............................................................................. 14 
6.1.4 
Preparation .......................................................................................................... 14 
6.1.5 
Dosing and Administration .................................................................................. 14 
6.1.6 
Route of Administration ...................................................................................... 14 
6.1.7 
Starting Dose and Dose Escalation Schedule ....................................................... 14 
6.1.8 
Dose Adjustments/Modifications/Delays ............................................................ 15 
6.1.9 
Duration of Therapy ............................................................................................. 15 
6.1.10 
Tracking of Dose .................................................................................................. 15 
6.1.11 
Device Specific Considerations ............................................................................ 15 
6.2 
Study Agent Accountability Procedures ................................................................................ 15 
7 
STUDY PROCEDURES AND SCHEDULE ............................................................................................. 15 
7.1 
Study Procedures/Evaluations ............................................................................................... 15 

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7.1.1 
Study specific procedures .................................................................................... 15 
7.1.2 
Standard of care study procedures...................................................................... 16 
7.2 
Laboratory Procedures/Evaluations ...................................................................................... 16 
7.2.1 
Clinical Laboratory Evaluations ............................................................................ 16 
7.2.2 
Other Assays or Procedures ................................................................................. 16 
7.2.3 
Specimen Preparation, Handling, and Storage .................................................... 16 
7.2.4 
Specimen Shipment ............................................................................................. 16 
7.3 
Study Schedule ...................................................................................................................... 17 
7.3.1 
Screening/enrollment/baseline ........................................................................... 17 
7.3.2 
Follow-up ............................................................................................................. 17 
7.3.3 
Final Study Visit .................................................................................................... 17 
7.3.4 
Early Termination Visit ......................................................................................... 18 
7.3.5 
Schedule of Events Table ..................................................................................... 18 
7.4 
Justification for Sensitive Procedures .................................................................................... 18 
7.5 
Concomitant Medications, Treatments, and Procedures ...................................................... 18 
7.5.1 
Precautionary Medications, Treatments, and Procedures .................................. 19 
7.6 
Prohibited Medications, Treatments, and Procedures.......................................................... 19 
7.7 
Prophylactic Medications, Treatments, and Procedures ...................................................... 19 
7.8 
Rescue Medications, Treatments, and Procedures ............................................................... 19 
7.9 
Participant Access to Study Agent at Study Closure .............................................................. 19 
8 
ASSESSMENT OF SAFETY ................................................................................................................. 19 
8.1 
Specification of Safety Parameters ........................................................................................ 19 
8.1.1 
Definition of Adverse Events (AE) ........................................................................ 19 
8.1.2 
Definition of Serious Adverse Events (SAE) ......................................................... 19 
8.1.3 
Definition of Unanticipated Problems (UP) ......................................................... 20 
8.2 
Classification of an Adverse Event ......................................................................................... 20 
8.2.1 
Severity of Event .................................................................................................. 20 
8.2.2 
Relationship to Study Agent ................................................................................ 20 
8.2.3 
Expectedness ....................................................................................................... 21 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up ....................................... 21 
8.4 
Reporting Procedures ............................................................................................................ 22 
8.4.1 
Adverse Event Reporting ..................................................................................... 22 
8.4.2 
Serious Adverse Event Reporting......................................................................... 22 
8.4.3 
Unanticipated Problem Reporting ....................................................................... 22 
8.4.4 
Events of Special Interest ..................................................................................... 23 
8.4.5 
Reporting of Pregnancy ....................................................................................... 23 
8.5 
Study Halting Rules ................................................................................................................ 23 
8.6 
Safety Oversight ..................................................................................................................... 23 
9 
CLINICAL MONITORING ................................................................................................................... 23 
10 
STATISTICAL CONSIDERATIONS ....................................................................................................... 23 
10.1 
Statistical and Analytical Plans .............................................................................................. 23 

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10.2 
Statistical Hypotheses ............................................................................................................ 24 
10.3 
Analysis Datasets ................................................................................................................... 24 
10.4 
Description of Statistical Methods ........................................................................................ 25 
10.4.1 
General Approach ................................................................................................ 25 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ....................................................... 25 
10.4.3 
Analysis of the Secondary Endpoint(s) ................................................................ 25 
10.4.4 
Safety Analyses .................................................................................................... 25 
10.4.5 
Adherence and Retention Analyses ..................................................................... 25 
10.4.6  
Baseline Descriptive Statistics ............................................................................. 25 
10.4.7 
Planned Interim Analyses .................................................................................... 26 
10.4.8 
Additional Sub-Group Analyses ........................................................................... 26 
10.4.9 
Multiple Comparison/Multiplicity ....................................................................... 26 
10.4.10 
Tabulation of Individual Response Data .............................................................. 26 
10.4.11 
Exploratory Analyses ............................................................................................ 27 
10.5 
Sample Size ............................................................................................................................ 27 
10.6 
Measures to Minimize Bias .................................................................................................... 27 
10.6.1 
Enrollment/ Randomization/ Masking Procedures ............................................. 28 
10.6.2 
Evaluation of Success of Blinding ......................................................................... 28 
10.6.3 
Breaking the Study Blind/Participant Code ......................................................... 29 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ........................................... 29 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 29 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 29 
13.1 
Ethical Standard ..................................................................................................................... 29 
13.2 
Institutional Review Board .................................................................................................... 29 
13.3 
Informed Consent Process ..................................................................................................... 29 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants 29 
13.3.2 
Consent Procedures and Documentation ............................................................ 30 
13.4 
Participant and Data Confidentiality ..................................................................................... 30 
13.4.1 
Research Use of Stored Human Samples, Specimens or Data............................. 30 
13.5 
Future Use of Stored Specimens ........................................................................................... 31 
14 
DATA HANDLING AND RECORD KEEPING ........................................................................................ 31 
14.1 
Data Collection and Management Responsibilities ............................................................... 31 
14.2 
Study Records Retention ....................................................................................................... 32 
14.3 
Protocol Deviations ................................................................................................................ 32 
14.4 
Publication and Data Sharing Policy ...................................................................................... 32 
15 
STUDY ADMINISTRATION ................................................................................................................ 32 
15.1 
Study Leadership ................................................................................................................... 32 
16 
CONFLICT OF INTEREST POLICY ....................................................................................................... 32 
17  
LITERATURE REFERENCES ................................................................................................................ 33 
APPENDIX .................................................................................................................................................... 34 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
GCP 
Good Clinical Practice 
US 
United States 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
QIDS-SR 
Quick Inventory of Depressive Symptomatology 
MPH 
Methylphenidate 
Mg 
Milligrams 
MEMS 
Medication Electronic Monitoring System 
BMQ 
Beliefs about Medicine Questionnaire 
MAR 
Medication Adherence Reasons 
LIBR 
Laureate Institute for Brain Research 
CGI 
Clinical Global Impression 
PDSQ  
Psychiatric Diagnostic Screening Questionnaire 
MHRP 
Mental Health Research Panel 
PHQ-9 
Patient Health Questionnaire (Depression) 
CTQ 
Childhood Trauma Questionnaire 
PANAS-X 
Positive and Negative Affect Schedule- Expanded Form 
WHO HPQ 
World Health Organization Health and Work Performance Questionnaire 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
CBC 
Complete Blood Count 
CMP 
Complete Metabolic Panel 
TSH 
Thyroid Stimulating Hormone 
STAR-D 
Sequenced Treatment Alternatives to Relieve Depression 
SDS 
Sheehan Disability Scale 
DF 
Degrees of Freedom 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with The International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP) as required by the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)   
• ICH E6 All key personnel (all individuals responsible for the design and conduct of this trial) have 
 completed Human Subjects Protection Training. 
• The principal investigator will assure that no protocol deviation from, or changes to the protocol take 
place without prior agreement from the sponsor and Institutional Review Board (IRB).  
 
Principal Investigator: _________Martin P. Paulus______________________  
 
Signed: _____________________ Date: ______11/07/2017________  

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PROTOCOL SUMMARY 
Title: 
The Effect of Methylphenidate on Adherence to Antidepressant Treatment 
in Subjects with Depression 
Précis: 
This study aims to determine whether a combination a first-line 
antidepressant plus methylphenidate (MPH) in a capsule relative to a first-
line antidepressant plus placebo in a capsule results in higher rates of 
medication adherence in individuals with moderate to severe depression.  
In this double-blind randomized placebo controlled trial, 100 individuals 
with a Quick Inventory of Depressive Symptomatology-Self Report (QIDS-
SR) scale score ≥ 14 will be enrolled to participate in an 8 week treatment 
study.  Participants will be randomized with a 1-1 ratio to receive 5 
milligrams (mg) MPH + 10 mg escitalopram or placebo + 10 mg 
escitalopram to be taken orally once per day. Participants will undergo a 3 
hour baseline evaluation visit at week 0, two 30-minute office visits (week 
2 and 4), one 60-minute office visit (week 8) and three 5-minute phone 
calls (weeks 1, 3, and 6) during which clinical assessments and measures 
will be obtained. The trial is designed with two stages: 20 participants in 
Stage 1 will be used to estimate the adherence effect size; Stage 2 is 
designed with an interim analysis to test our hypotheses. 
Objectives: 
 
Primary Objective: To determine whether MPH + escitalopram results in 
higher rates of medication adherence relative to placebo + escitalopram 
Secondary Objective: To determine whether MPH + escitalopram results in 
greater consistency of adherence relative to placebo + escitalopram 
Endpoint 
Primary Endpoint: 
• 
% Pill count = 100 * [number of prescribed pills – number of pills 
remaining]/[number of days between dispensing date and return 
date] 
Secondary Endpoint: 
• 
Medication Electronic Monitoring System (MEMS) (Aardex) - % of 
doses taken on schedule within 25% of the expected time interval, 
defined as ± 6 hours from participant’s breakfast time. 
 
Exploratory Endpoints: 
• 
Beliefs About Medicine Questionnaire (BMQ) – 
Accepting/ambivalent vs. indifferent/skeptical 
• 
Blood level monitoring – blood level outside the 75- 125% range of 
the therapeutic window 
• 
Revised Medication Adherence Reasons (MAR) scale  
• 
Response - Reduction in symptoms on the QIDS-SR 
• 
PROMIS Measures 
Population: 
Individuals with depression seeking treatment 
Phase: 
Proof of Concept (Phase 2a) 
Number of Sites 
enrolling participants: 
Single site – Laureate Institute for Brain Research (LIBR) 

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Description of Study 
Agent : 
Subjects will receive a compound capsule containing either (1) 5 mg MPH + 
10 mg escitalopram or (2) placebo + 10 mg escitalopram.  At week 4, the 
escitalopram dose may be increased to 20 mg, based on clinical 
evaluation. The capsule will be provided by a local compounding pharmacy 
(Tulsa, Oklahoma). 
Study Duration: 
3 years 
Participant Duration: 
2 months 
 
SCHEMATIC OF STUDY DESIGN 
 
1 
KEY ROLES 
Principal Investigator: 
Martin P. Paulus M.D. 
Scientific Director and President 
Laureate Institute for Brain Research 
6655 S Yale Ave Tulsa, OK 74136-3326 
Phone: 918 502 5120, FAX: 918 502 5135 
Email: mpaulus@laureateinstitute.org 
Web: http://www.laureateinstitute.org 
 
Sub-Investigator:  
Sahib S. Khalsa M.D., Ph.D. 
Director of Clinical Studies 
Laureate Institute for Brain Research 

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Assistant Professor, University of Tulsa, Oxley College of Health Sciences 
Tulsa, Oklahoma 
6655 S Yale Ave Tulsa, OK 74136-3326 
Phone: 918 502 5743 Fax: 918 502 5135 
Email: skhalsa@laureateinstitute.org 
 
Site investigators: 
Martin P. Paulus M.D. 
Scientific Director and President 
Laureate Institute for Brain Research 
6655 S Yale Ave Tulsa, OK 74136-3326 
Phone: 918 502 5120, FAX: 918 502 5135 
Email: mpaulus@laureateinstitute.org 
Web: http://www.laureateinstitute.org 
 
Sahib S. Khalsa M.D., Ph.D. 
Director of Clinical Studies 
Laureate Institute for Brain Research 
Assistant Professor, University of Tulsa, Oxley College of Health Sciences 
Tulsa, Oklahoma 
6655 S Yale Ave Tulsa, OK 74136-3326 
Phone: 918 502 5743 Fax: 918 502 5135 
Email: skhalsa@laureateinstitute.org 
 
Teresa A. Victor. Ph.D. 
Staff Scientist, Research Core 
Laureate Institute for Brain Research 
6655 South Yale Ave. 
Tulsa, Oklahoma USA 74136 
Phone: 918 502 5108 Fax: 918 502 5135 
Email: tvictor@laureateinstitute.org 
 
Biostatistician: 
Hung-wen Yeh Ph.D. 
Associate Investigator 
Laureate Institute for Brain Research 
6655 S Yale Ave 
Tulsa, OK 74136-3326 
Phone: 918 502 5119 
Fax: 918 502 5135 
Email: hyeh@laureateinstitute.org 
 

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Biostatistician: 
 
Wesley Thompson 
 
Statistical Consultant 
 
University of California, San Diego 
 
9500 Gilman Drive #0725 
 
La Jolla, CA 92093 
 
Phone: 858 534 6748 
 
Email: wkthompson@ucsd.edu 
 
 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND INFORMATION   
Adherence to treatment, i.e. the extent to which the patient's history of therapeutic engagement 
coincides with the prescribed treatment 1, is among the most important problems in mental health care 
2,3.  It is estimated that nearly half of all prescribed medications are not taken, that about 125,000 
deaths annually are attributable to non-adherence, and that non-adherence costs are estimated 
between $100 and $300 billion each year 4.  Thus, non-adherence is a profound clinical challenge that 
incurs adverse psychosocial consequences, enormous costs, and poor outcomes that are shared by 
patients, family members, providers, healthcare systems, payers, and society 5.  It is estimated that only 
one out of five patients comply with antidepressant treatment for over four months 6, and that the 
majority of patients discontinue antidepressant medication within the first 30 days 7. Some have 
estimated that the median time to discontinuation of an antidepressant is about two 8 to four months 9.  
Unfortunately, the majority of clinical trials do not report rates of adherence and for those that do only 
4 out of 5 participants adhere to the treatment regimen 10, which significantly affects reported efficacy 11 
and safety assessments 12. There are slight differences between antidepressant medication classes 13 but 
low adherence is not limited to medication treatment for depression 14, or even mental health 15,16. For 
example, there is evidence for 25-90% adherence rates for headache treatments 17.  Moreover, non-
adherence extends to other therapeutic modalities, with about 20% to 70% of individuals who initiate 
psychosocial mental health services discontinuing treatment prior to clinicians' recommendations 18.  
Whereas continued antidepressant treatment reduces recurrence risk 19, cardiovascular 20 and overall 
mortality 21,22 as well as suicide rates 23, non-adherence has profound consequences for the course of 
depression by increasing relapse 24 or recurrence 25.  Taken together, adherence to treatment has to be 
one of the most important targets of research seeking to improve therapeutic outcomes.  
There are numerous measures for adherence. Most are of moderate quality 26, and there is not one 
gold-standard approach for measuring and predicting adherence27.  For example, adherence scores 
reported by patients do not agree well with those obtained from physicians 28.  Moreover,  non-
adherence is not limited to initiation of antidepressant treatment but is also common among individuals 
on maintenance treatment 29.  A number of socio-demographic factors have been proposed to 
contribute to the rates of adherence, among them are age 30 (younger individuals are more likely to 
discontinue), gender (males are more likely to discontinue) 31, race (adherence to antidepressants is 40% 

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lower among African-Americans than Caucasians) 32, lower levels of education 31, employment 33, being 
from a lower-income neighborhood 30 or part of an immigrant group 34, lower levels of quality of life 8, 
and other psychosocial stressors 35.  Sexual side effects 36, substance use comorbidity and personality 
disorders also contribute to non-adherence of individuals with mood disorders 37.  However, recent data 
suggest that demographic or clinical factors 38 are not consistently associated with non-adherence 39.  
Unfortunately, there is little evidence from randomized controlled trials that educational 40,41 counseling 
42, coaching43, or other types of interventions improve adherence in general 44 and may have – at most – 
small effects 2.  Recently, however, based on a meta-analysis some have reported moderate effect size 
outcomes using multi-component, i.e. combining cognitive behavioral and educational aspects, 
interventions 3.   
These findings raise several issues about treatment non-adherence.  First, there is no optimal way to 
measure it. Second, socio-demographic characteristics are unlikely to provide single-subject level 
predictions for those individuals who are likely to be non-adhererent. Third, there is no “one-size-fits-
all” approach to characterizing and reducing non-adherence, particularly when it comes to 
psychoeducational interventions.  Therefore, further research into individual differences are likely to 
contribute substantially to our understanding of the underlying processes that influence adherence to 
treatment. 
Metacognition is an individual difference process which includes beliefs and attitudes about self-related 
events such as thoughts, feelings, memories, images, sensations, and perceptions 45.  The 'necessity-
concerns framework'46 is a metacognitive approach and provides a heuristic to understand patients' 
adherence behavior.  This framework proposes that the decision to take a medication is mediated by 
two opposing beliefs, i.e. beliefs about the necessity of taking the medication for a particular condition 
versus concerns about negative effects associated with taking medications.   Psychometric scales to 
measure these metacognitive aspects of adherence have identified several components. The revised 
Medication Adherence Reasons Scale (MARS) 47 (with Cronbach alphas ranging from 0.827 – 0.953) can 
identify between 50% to 70% of individuals taking medications. It comprises four medication related 
domains: practical issues, belief of necessity, forgetfulness, concerns over side effects. The Beliefs about 
Medicines Questionnaire (BMQ) 46 contains two sections: the BMQ-Specific, which assesses 
representations of medication prescribed for personal use such as beliefs about the necessity of the 
medication and beliefs about danger associated with a specific medication, and the BMQ-General, which 
assesses generic beliefs about medicines such as beliefs of harm and overuse.  Low scores in the BMQ-
Harm and -Concern subscales are associated with greater non-adherence to antidepressants48.  In a 
meta-analysis across different medical conditions and treatments, this framework significantly and 
differentially predicted rates of adherence 49.  For example, for each standard deviation increase in 
necessity beliefs, the odds of adherence increases by a factor of 1.7 and for each standard deviation 
increase in concerns, the odds of adherence decreases by a factor of 2 50.  Moreover, depression 51 has 
been shown to moderate this relationship 52 and influences particularly the concerns aspect of the 
framework 53.  The antidepressant-specific "necessity-minus-concerns" composite has been proposed as 
a predictor for adherence 54 and there is evidence that attitudes and beliefs are at least as important as 
side effects in predicting adherence 55. For example, those individuals who have higher levels of 

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concerns about antidepressant medications are less likely to be adherent 56 whereas those who report 
high initial expectations show greater adherence, even to placebo interventions 57.  Non-initiators also 
have lower belief scores for perceived impact of illness, intention to take medication, and positive 
attitude towards medication58.  Others have found that while intentional non-adherers had higher 
concerns scores unintentional non-adherers did not, which emphasizes the heterogeneity of non-
adherence59.  Moreover, those individuals who reported high necessity and high concern beliefs, i.e. 
were ambivalent, also showed lower levels of adherence 60.  Not surprisingly, greater non-adherence is 
related to higher depression scores at follow up 61.  These beliefs adjust dynamically during the course of 
treatment such that individuals who adhere to treatment have greater perceived benefit and reduced 
concerns 62.  Taken together, metacognition 45 is an individual difference metric that appears to play a 
central role in treatment adherence by providing self-relevant and value-based attributes to the actions 
that can guide policies for the individual, i.e. whether to take or not take a medication. 
2.2 
RATIONALE  
Building new habits is an important aspect of adherence to any treatment (medication or 
psychotherapy).  Successfully accomplishing this motivational feat basically means that new treatment 
related behaviors need to be changed from a reward-related to a habit-based strategy.  New habits can 
be typically reinforced either by an immediate positive outcome (positive reinforcement), or by the 
avoidance of a negative outcome (negative reinforcement).  Both processes are likely to involve top-
down prefrontal cortex control over hippocampal activity, and require the concerted establishment of a 
set of behavioral contingencies, heuristics, and internal representations of how the behavior positively 
affects the individual.  With respect to depression, there are several barriers to the formation of new 
treatment related habits (i.e., adherence behaviors).  First, depressed individuals have reduced hedonic 
processing mediated by the dopaminergic system, meaning they are less driven by what feels “good” or 
what is “good for the individual”.  Therefore, it is often difficult to utilize tools that may typically act as 
positive reinforcers in other individuals (e.g. financial payment).  Second, habits evolve from the strong 
association of a cue (situation or stimulus) with an action. The strengthening of a habit relies primarily 
on the degree to which a behavior is expressed “automatically” (without necessary thinking about it), 
occurs frequently, and is clearly self-identified. Successfully cemented habits are highly efficient 
behaviors, and usually associated with a lack of awareness, unintentionality, and uncontrollability during 
their performance. Habit-formation is therefore a complex process and is likely to take weeks. Prior 
research suggests that successful habit-formation likely involves a transition from reinforcement driven 
hippocampal circuit activity to stimulus-response driven basal ganglia driven circuit activity, indicating 
that it requires a broad shift in patterns of neural activity 63,64. Unfortunately, the functioning of these 
circuits is preferentially impaired in depressed individuals 65,66. It is presently unclear whether 
interventions capable of modulating activity in these same neural circuits can improve treatment related 
habit formation. Third, educational interventions to enhance adherence have failed to demonstrate a 
clear benefit on adherence and depression outcome 40.  Fourth, community pharmacy-based coaching 
program showed no intervention effect on adherence 43.  Based on these considerations, the current 
study aims to investigate the influence of pairing a pharmacological agent with an acute positive 

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reinforcing dopaminergic/noradrenergic effect with a standard antidepressant on the rates of 
medication treatment adherence. 
MPH has been widely used to treat attention-deficit/hyperactivity disorder (ADHD) for the last half 
century 67. The drug is a monoaminergic reuptake inhibitor, i.e. it blocks the blocking dopamine 
transporters 68 and increases dopamine and norepinephrine availability in the synaptic cleft 69. 
Methylphenidate has strong affinity at the norepinephrine transporter 70, which exceeds its affinity for 
the dopamine transporter. However, its ability to increase NE is much less than that of amphetamine 
and it has virtually no effect on serotonin 71.  Moreover, it does not produce a subjective euphoria, 
which has been related to its relatively weak ability to reduce D2 receptors in the striatum 72,73.  
However, it may have different properties after repeated administration 74.  Methylphenidate has 
weaker reinforcing properties  75 and has different pharmacokinetic profile 76 than amphetamines or 
cocaine, which lowers its relative abuse liability. In healthy volunteers, methylphenidate induced 
improvements in working memory performance 77, which were associated with reductions in rCBF in the 
dorsolateral prefrontal cortex and posterior parietal cortex, reduced the impact of emotionally arousing 
material on memory 78, however, it did not affect fear conditioning.  Interestingly, methylphenidate has 
long been considered as a potential treatment for anxiety based on human and animal studies.  
Moreover, there is a long history of using methylphenidate for treating mood, behavior, and cognitive 
symptoms in individuals with organic brain changes 79 and traumatic brain injury 80.  In particular, several 
studies have shown improvement of cognitive symptoms after treatment with methylphenidate in 
patients with acute brain injury 81 including speed of mental processing 82,83, response accuracy 84, 
improved shifts of attention 85, caregiver ratings of attention 86, level of depressive symptoms 87, 
however, its effects on sustained attention, distractibility, and memory are less clear 88,89. 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
A. 
Risks associated with the study medications:  
1. 
METHYPHENIDATE 
Common side effects: 
Nervousness, difficulty falling asleep or staying asleep, dizziness, nausea, vomiting, loss of 
appetite, stomach pain, diarrhea, heartburn, dry mouth, headache, muscle tightness, 
drowsiness, uncontrollable movement of a part of the body, restlessness, numbness, 
burning, or tingling in the hands or feet, decreased sexual desire 
Rare side effects: 
• 
Fast, pounding, or irregular heartbeat, chest pain, shortness of breath, excessive tiredness, 
slow or difficult speech, fainting, weakness or numbness of an arm or leg, seizures, changes 
in vision or blurred vision, agitation, believing things that are not true, feeling unusually 
suspicious of others, hallucinating (seeing things or hearing voices that do not exist), motor 

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tics or verbal tics, depression, abnormally excited mood, mood changes, frequent, painful 
erections, erection that lasts longer than 4 hours, numbness, pain, or sensitivity to 
temperature in the fingers or toes, skin color change from pale to blue to red in the fingers 
or toes, unexplained wounds on the fingers or toes, fever, hives, rash, blistering or peeling 
skin, itching, swelling of the eyes, face, lips, mouth, tongue, or throat, hoarseness, difficulty 
breathing or swallowing 
Methylphenidate may cause sudden death in children and teenagers, especially children or 
teenagers with heart defects or serious heart problems. This medication also may cause sudden 
death, heart attack or stroke in adults, especially adults with heart defects or serious heart 
problems. Development of substance use/dependence is a possible, but uncommon side 
effect.90 
2. 
ESCITALOPRAM 
Common side effects: 
Drowsiness, tired feeling, sleep problems (insomnia), mild nausea, diarrhea, constipation, 
upset stomach, dry mouth, cold/flu symptoms such as stuffy nose, sneezing, sore throat, 
cough, increased sweating or urination, dizziness, heart burn, increased appetite, weight 
changes, changes in sex drive or ability 
Rare side effects: 
Very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, 
tremors, agitation, hallucinations, overactive reflexes, nausea, vomiting, diarrhea, loss of 
coordination, feeling like you might pass out, headache with chest pain and severe dizziness, 
fainting, fast or pounding heartbeats; or headache, slurred speech, severe weakness, muscle 
cramps, feeling unsteady, seizure (convulsions), shallow breathing, serotonin syndrome, 
extrapyramidal symptoms, QT prolongation, hyponatremia, withdrawal symptoms on 
abrupt discontinuation, abrnomal bleeding, suicidality, paresthesia, anaphylaxis   
B. 
Risks Associated with Screening and Evaluation:  
The risks and discomforts of the screening evaluations are minimal.  Some of the questions in the 
interviews may be painful or uncomfortable to answer.  
C. 
Risks Associated with Blood Draw:  
The risks of blood drawing are minimal. Possible mild side effects include mild pain or bruising at the site 
of venipuncture. There is a very small risk of fainting or infection in the area of the needle insertion. 
D. 
Risks Associated with Delaying Treatment:  
Participants will NOT be asked to discontinue any medications for the purposes of this study and will be 
informed that they should not participate in the study if it will be difficult for them to delay treatment. 

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E. 
Risks Associated with Discontinuation 
Symptoms associated with discontinuation of Lexapro have been reported, including flu-like symptoms, 
insomnia, nausea, imbalance, paresthesias, and hyperarousal. Participants should be monitored for 
these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt 
cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the 
dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be 
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. 
At the time of consent and study visits 5 & 6, participants will be requested to follow-up with their 
primary care physician following completion of the study to continue receiving a prescription for 
escitalopram, if desired. Participants will be reminded to contact their primary care physician and 
possible side effects from abrupt cessation will be discussed. 
2.3.2 KNOWN POTENTIAL BENEFITS  
There may be no immediate personal or medical benefit derived from participation, as we do not expect 
every participant’s symptoms to improve. The results of these studies, however, will further the 
scientific community’s understanding of mood disorder pathophysiology and treatment adherence in 
depression. By increasing understanding of pathophysiology and adherence rates, this study the 
potential to improve treatment modalities, diagnostic capabilities, and methods of adherence 
compliance. The study may aid in de-stigmatizing psychiatric illness and convincing noncompliant 
patients that medications are likely to be helpful. As such, participants may derive personal satisfaction 
from their contribution to the discovery process. 
3 
OBJECTIVES AND PURPOSE 
 
Primary Objective: To determine whether MPH + escitalopram results in higher rates of adherence 
relative to placebo + antidepressant. 
Secondary Objective: To determine whether MPH + escitalopram results in greater consistency of 
adherence relative to placebo + escitalopram. 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This Phase 2a randomized placebo-controlled clinical trial will include two principal study arms, with an 
option to escalate the dose of escitalopram at week 4 (see 6.1.7): 
1) Study Drug A: 5mg placebo + 10mg escitalopram (encapsulated into one capsule) 
2) Study Drug B: 5mg methylphenidate (MPH) + 10mg escitalopram (encapsulated into one 
capsule) 

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In the proposed protocol, 100 MDD subjects will be randomized to one of the two conditions: 
escitalopram with placebo (n=10) or escitalopram with methylphenidate (n=10) in Stage 1 and 
escitalopram with placebo (n=40) or escitalopram with methylphenidate (n=40) in Stage 2. Participants 
randomized to either condition will be prescribed medication over the course of 8 weeks, with in-person 
follow-up visits at weeks 0, 2, 4 and 8, with follow-up phone calls on weeks 1, 3 and 6. 
Participants randomized to each condition will continue receive will receive usual care as defined by the 
individual clinician, with the restriction that participants in this group will not be allowed to receive 
certain new treatments during the study period. 
4.2.1 PRIMARY ENDPOINT 
Adherence 91: 
• 
% Pill count = 100 * [number of prescribed pills – number of pills remaining]/[number of days 
between dispensing date and return date] 
 
4.2.2 SECONDARY ENDPOINTS 
Secondary Outcome (STAR-D 92) 
• 
Medication Electronic Monitoring System (MEMS) (Aardex) - % of doses taken on schedule 
within 25% of the expected time interval, defined as ± 6 hours from participant’s breakfast time. 
 
4.2.3 EXPLORATORY ENDPOINTS 
 
• 
BMQ46 – Accepting/ambivalent vs. indifferent/skeptical 
• 
Blood level monitoring – blood level outside the 75 – 125% range of the therapeutic window 
• 
MAR93 scale 
• 
Remission - a score of 5 on the QIDS-SR 
• 
Response - 50% reduction in symptoms on the QIDS-SR 
PROMIS Measures 94,95: 
• 
PROMIS Anxiety 
• 
PROMIS Depression 
• 
PROMIS Anger 
• 
PROMIS/Neuro-QOL Positive Affect and Well-being 
• 
PROMIS Cog Abilities 
• 
PROMIS Cog General 
• 
PROMIS Fatigue 
• 
PROMIS Sleep Disturbance 
• 
PROMIS Sleep-related Impairment 
• 
PROMIS Social Satisfaction DSA 
• 
PROMIS Social Satisfaction Role 

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• 
PROMIS Ability to Participate Social 
• 
PROMIS Emotional Support 
• 
PROMIS Information Support 
• 
PROMIS Satisfaction Roles Activities 
• 
PROMIS Social Isolation 
• 
PROMIS Physical Function 
• 
PROMIS Pain Interference 
• 
PROMIS PAIN Behavior 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
Participants must meet all of the following inclusion criteria to be considered eligible to participate in 
the study (closely matched on STAR-D): 
• 
Baseline QIDS-SR > 14 (moderate depression 96) 
• 
Age 18 – 65 
• 
Written Informed Consent 
• 
MDD single-episode/recurrent, not in remission 
 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from study 
participation:  
• 
MPH-related exclusions 97 
o Uncontrolled hyperthyroidism 
o Glaucoma 
o Motor tics 
o MAOI treatment 
o Serious coronary artery disease, cardiomyopathy, serious cardiac arrhythmias 
o Uncontrolled HTN 
o Peripheral vasculopathy 
o Pregnancy 
• 
Bipolar Disorder 
• 
Psychotic Disorder 
• 
History of intolerability of study medications 
• 
Currently taking psychiatric medications 
• 
Current Substance Use Disorder (other than nicotine) 
• 
Current Alcohol Use Disorder 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 

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Study participants will be recruited through the clinical services of the Laureate Psychiatric Clinic and 
Hospital (LPCH), local service providers for behavioral health and mental health (e.g. Family and 
Children’s Services, local psychiatrist and physician offices), and through online, newspaper, flyer, radio 
or other media advertisements in the Tulsa metropolitan area. Participants will also be recruited 
through a pre-approved LIBR Screening protocol (WIRB #20101611) and through the Laureate Institute 
for Brain Research REDCap database.  Informed Consent will be obtained by members of the research 
team that have received training from the PI to obtain consent for this study.  All participant interactions 
including consenting will be conducted in private interview/exam rooms.  These exam rooms at LIBR are 
secured from public areas via combination locked doors that are only accessible to authorized 
personnel.  
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
Efforts will be made to continue follow-up of withdrawn or terminated participants or participants who 
prematurely discontinue assigned study intervention but remain in the study for follow-up. Follow-up 
efforts will include contacting participants to complete the 8-week in-person follow-up assessment. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the PI, and study sponsor. If the study is prematurely 
terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) for the 
termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants   
• 
Demonstration of efficacy that would warrant stopping   
• 
Insufficient compliance to protocol requirements   

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• 
Data that are not sufficiently complete and/or evaluable   
• 
Determination of futility   
If suspended, the study may resume once concerns about safety, protocol compliance, and/or data 
quality are addressed and satisfy the sponsor, and/or IRB. 
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
The study medications will be acquired through a local compounding pharmacy in Tulsa, Oklahoma. 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The study medications will be formulated into identical compound capsules containing either (1) 5 mg 
MPH + 10 mg escitalopram, (2) placebo + 10 mg escitalopram, (3) 5 mg MPH + 20 mg of escitalopram, 
(4) placebo + 20 mg escitalopram. The study medications will be packaged in standard bottles with a 
MEMS tracking cap. The bottles will be labeled with “Study Drug A”, “Study Drug B”, “Study Drug C” or 
Study Drug D”, the number of capsules in the bottle and the administration date. At the 4-week visit, 
participants will have the option to increase the escitalopram dose to 20 mg based on clinical 
improvement assessed by the study psychiatrist.  
6.1.3 PRODUCT STORAGE AND STABILITY 
The study medications will be stored behind at least two differently keyed locks at all times. The 
medication will be stored in a safe or steel cabinet of substantial construction. If the safe or cabinet is 
less than 750 pounds, it will be mounted or secured to a wall, floor or base embedded in concrete. The 
safe/cabinet will have an inner and outer door with the locks for each door keyed differently. The room 
where the safe/cabinet will be stored will also be lockable and locked after hours. 
6.1.4 PREPARATION 
 A compounding pharmacy will dispense and label the individual bottles of study medication. A study 
psychiatrist will provide the medication to the subject at each in-house study visit.  
6.1.5 DOSING AND ADMINISTRATION 
 The dosing and administration method are detailed below (see 6.1.7). 
6.1.6 ROUTE OF ADMINISTRATION 
Participants will receive the study medication in a compound capsule for oral administration. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 

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The compound capsules will contain either (1) 5 mg MPH + 10 mg escitalopram, (2) placebo + 10 mg 
escitalopram, (3) 5 mg MPH + 20 mg of escitalopram or (4) placebo + 20 mg escitalopram. At the 4-week 
visit, participants will have the option to increase the escitalopram dosage to 20 mg based on clinical 
improvement assessed by the study psychiatrist. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
Dose adjustments, modifications and delays will be determined by the study psychiatrist at the 4 week 
time point. 
6.1.9 DURATION OF THERAPY 
The expected duration of the study will be 8 weeks of treatment, plus a screening visit for eligibility that 
may occur up to one week prior to study start. 
6.1.10 TRACKING OF DOSE 
The dose will be tracked by the study coordinator and Principal Investigator and included in the study’s 
REDCAP database. 
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
NONE 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
A separate and current record will be maintained for the storage and use of each controlled substance 
(use meaning to administer, dispense, professionally use, or otherwise dispose of), indicating the date, 
building and room, specific research  experiment, controlled substance’s application in the research, and 
type, strength and quantity of each controlled substance use. The record must also include the name 
and address of the person to whom, or for whose use, the substances were administered or dispensed.  
By noting starting quantity of substance, each use is a subtraction from the starting quantity, and the 
running (decreasing) amount should equal the total amount remaining on-hand. 
Each record of use must be signed by the person working with the controlled substance. The inventory 
should also include a detailed list of any controlled substances lost, destroyed, or stolen, including the 
type, strength, and quantity of such substances, and the date of the discovery of such loss, destruction, 
or theft. The record of use will be stored on a LIBR computer with daily back-up and password protected 
access by designated research personnel. 
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  

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• Medical and psychiatric history – obtained by self-report questionnaire and from review of medical 
records 
• Medication history – only medications currently taken should be included; this includes prescription 
and over-the-counter medications. Assessment of eligibility will include a review of permitted and 
prohibited medications. 
• Vital sign assessment – temperature, heart and respiratory rate, systolic and diastolic blood pressure, 
echocardiogram (EKG), height and weight. 
• Oral administration of the study medication: either (1) 5 mg MPH + 10 mg escitalopram or (2) placebo 
+ 10 mg escitalopram. At week 4, the escitalopram dose may be increased to 20 mg, based on clinical 
evaluation. 
• Assessment of study medication adherence – conducted during scheduled visits and phone calls and 
by MEMS tracking cap 
• Administration of questionnaires or other instruments for patient­reported outcomes  
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
All participants in each study arm will continue to receive usual care from their primary care provider  
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS 
• Safety labs: CBC, CMP and TSH levels will be determined by blood collection prior to dispensing the 
study medication at Week 0 and collected again at Week 8.  
• Blood levels of study medications: At the Week 8 visit, levels of escitalopram will be determined by 
blood collection. 
• Pregnancy test: Conducted during screening evaluation. If positive, participants will be excluded from 
further study participation. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
NONE 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
The blood collection will be obtained in appropriate Vacutainer tubes by a trained phlebotomist using 
sterile techniques and transported to Saint Francis Hospital Outreach Laboratory for processing. The 
pregnancy test will be obtained by a trained LIBR staff member.  
7.2.4 SPECIMEN SHIPMENT 

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Blood samples will be transported to Saint Francis Hospital Outreach Laboratory. 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING/ENROLLMENT/BASELINE 
Screening/Enrollment Visit (Week 0, 3 hours):  
• Obtain informed consent of potential participant verified by signature on written informed consent 
form for screening and study consent form. 
• Record vital signs including temperature, heart rate, systolic and diastolic blood pressure.  
• Record height and weight. 
• Collect urine for evaluation of pregnancy status (if applicable). 
• Obtain demographic information, medical history, medication history, alcohol and tobacco use history. 
• Review medical history and medications history to determine eligibility based on inclusion/exclusion 
criteria. 
• Collect self-report scales  
• Collect blood safety labs (CBC, CMP, TSH)  
• Schedule study visits for participants who are eligible and available for the duration of the study. 
• Provide participants with instructions for taking the study medication 
7.3.2 FOLLOW-UP  
Weeks 1, 3 and 6 (phone call) 
• 
Administer the QIDS-SR and MAR questionnaires 
Weeks 2 and 4 (in person visits) 
• 
Verify inclusion/exclusion criteria.  
• 
Record vital signs including temperature, heart rate, systolic and diastolic blood pressure.  
• 
Record current medications and interim medical procedures 
• 
Collect self-report scales including QIDS-SR and medication adherence measures 
• 
Dispense the study medication 
7.3.3 FINAL STUDY VISIT 
Final Visit (Week 8, 1 hour):  
• 
Verify inclusion/exclusion criteria.  
• 
Record vital signs including temperature, heart rate, systolic and diastolic blood pressure.  
• 
Record current medications and interim medical procedures 
• 
Collect self-report scales and medication adherence measures 
• 
Collect blood levels of the antidepressant medication and repeat of safety labs obtained at 
Week 0. 

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7.3.4 EARLY TERMINATION VISIT 
If early termination occurs and the participant is willing, schedule a final visit to collect follow-up visit 
measures. 
7.3.5 SCHEDULE OF EVENTS TABLE 
 
Procedures 
Screening 
Week 0 
Week 1 
Week 2 
Week 3 
Week 4 
Week 6 
Week 8 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment: Medical 
History and Diagnosis, 
Physician Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Assessment 
Toolkit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion: QIDS-SR 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Psychiatric Diagnostic 
Screening 
Questionnaire (PDSQ) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Self-Report Measures: 
Demographics and 
Mental Health Tier 1 
and 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco, Alcohol and 
Substance Use 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
Self- Report Measures: 
PHQ-9, CTQ, PANAS-X, 
SDS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CGI 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
BMQ 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
Pill Count 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Blood Level of Study 
Medication 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
MEMS Monitoring 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
MAR Scale 
 
X X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
PROMIS Measures 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Safety Labs 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Escitalopram levels 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  

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Data pertaining to concomitant medications, treatments, and/or procedures utilized by participants will 
be collected during each in-person visit.  
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
The addition of psychoactive medications that affect brain function or evidence-based behavioral 
interventions will be prohibited during the duration of the study. Participants will be instructed to tell 
the study psychiatrist of any change in medication or treatment.  
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
See 7.5.1. above. 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Participants will no longer have access to the study medications at the study closure. Participants 
desiring to continue accessing this type of intervention will be instructed to contact their primary care 
physician and/or given information on treatment centers and physicians in their local area.  
 
8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
This study involves the use to two FDA-approved medications (MPH and escitalopram). 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, or a persistent or significant incapacity or 

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substantial disruption of the ability to conduct normal life functions. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
This study will use the OHRP definition of UP. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
An example of an adverse event (AE) that might conceivably occur as a result of the oral administration 
of the study medications due to side effects that would require treatment in an emergency room. 
All AEs will be assessed by the clinician using the following guidelines to describe severity. 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
8.2.2 RELATIONSHIP TO STUDY AGENT 

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For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below.   
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
should be clinically plausible. The event must be phenomenologically definitive, with use of a 
satisfactory rechallenge procedure if necessary.  
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable 
time after administration of the intervention, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.  
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the study intervention). However, other factors may 
have contributed to the event (e.g., the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related ” as appropriate.   
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did not occur 
within a reasonable time after administration of the intervention) and in which other drugs or chemicals 
or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments).   
Not Related – The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician.   
8.2.3 EXPECTEDNESS  
The study Principal Investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention.  
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the 

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appropriate RF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study intervention (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while 
on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution.  Any medical condition that is present at the time that the participant is screened 
will be considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. UPs will be recorded in the data 
collection system throughout the study.  Changes in the severity of an AE will be documented to allow 
an assessment of the duration of the event at each level of severity to be performed. AEs characterized 
as intermittent require documentation of onset and duration of each episode.  The PI will record all 
reportable events with start dates occurring any time after informed consent is obtained until 7 (for 
non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization.   
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
The study investigator shall complete an Unanticipated Adverse Event Form and submit to the study 
sponsor and to the reviewing IRB as soon as possible, but in no event later than 10 working days after 
the investigator first learns of the effect. The study sponsor contact information is provided in Section 1, 
Key Roles.   
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
All immediately life-threatening events, whether related or unrelated, will be recorded on the SAE Form 
and submitted to the IRB and study sponsor within 24 hours of site awareness. See Section 1, Key Roles 
for contact information.   
Other SAEs regardless of relationship, will be submitted to the IRB and study sponsor within 72 hours of 
site awareness. All SAEs will be followed until satisfactory resolution or until the site investigator deems 
the event to be chronic or the adherence to be stable.   
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the OHRP criteria for Unanticipated Problems (UPs) require the creation 
and completion of an UP report form. It is the site investigator’s responsibility to report UPs to their IRB 
and to the study sponsor. The UP report will include the following information:  
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number;   
A detailed description of the event, incident, experience, or outcome;   

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An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP.  
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
UPs that are SAEs will be reported to the IRB and to the study sponsor within 10 working days of the 
investigator becoming aware of the event.   
Any other UP will be reported to the IRB and to the study sponsor within 10 working days of the 
investigator becoming aware of the problem.   
All UPs should be reported to appropriate institutional officials (as required by an institution’s written 
reporting procedures), the supporting agency head (or designee), and study sponsor within 10 working 
days of the IRB’s receipt of the report of the problem from the investigator.   
8.4.4 EVENTS OF SPECIAL INTEREST  
Not applicable 
8.4.5 REPORTING OF PREGNANCY  
Any participants found to be pregnant on screening will be informed and excluded from further study 
participation.  
8.5 
STUDY HALTING RULES  
Administration of study agent will be halted when three grade 3 AEs determined to be “probably 
related” are reported to the IRB.  
8.6 
SAFETY OVERSIGHT 
Safety oversight will be under the direction of the Western IRB, via monitoring of study information 
provided by the PI.  
9 
CLINICAL MONITORING 
Monitoring for this study will be performed by the study PI. The study PI will engage in weekly 
discussions of the study progress with the clinical research coordinator, perform random reviews of 
study endpoint, safety, and other key data to verify completeness of data acquisition.  
10 
STATISTICAL CONSIDERATIONS  
 
10.1 
STATISTICAL AND ANALYTICAL PLANS 

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This Phase 2a trial contains 2 stages. Stage 1 aims to estimate dropout rate and the effect size of 
outcome measures, while Stage 2 aims to evaluate for statistical significance the primary, secondary, 
and exploratory endpoints. Stage 2 is designed with an interim analysis.  Hence, there will be two 
Go/No-Go decisions: one at the end of Stage 1, and the other in the middle (the interim analysis) of 
Stage 2.  Depending on the results of Stage 1, the trial may or may not proceed to Stage 2. If dropout 
rate and/or the effect size suggest 80 participants for Stage 2 (100 total study participants) is under-
powered, the study will be discontinued. Even if the study proceeds to Stage 2, the trial may still be 
terminated if the interim analysis suggests the trial to be futile.  To avoid biased decision-making, data 
will be analyzed by two statisticians: (1) the consultant statistician Dr. Thompson will analyze Stage 1 
data to obtain effect size and attrition rate, (2) before initiation of Stage 2, the primary statistician Dr. 
Yeh will re-evaluate the power/sample size of Stage 2 based on the effect size and attrition rate 
provided by Dr. Thompson from Stage 1, (3) if Stage 2 procedes, Thompson will conduct the interim 
analysis, and (4) if the interim analysis is inconclusive and Stage 2 proceeds to the end, Dr. Yeh will 
perform the final analysis. For statistical details, see Section 10.4. 
10.2 
STATISTICAL HYPOTHESES 
[For Stage 2 only]  
1. Individuals treated with antidepressant + MPH relative to antidepressant + placebo will show a 
lower % Pill count at the end of the study. 
 
2. Individuals treated with antidepressant + MPH relative to antidepressant + placebo will show a 
higher % of doses taken on schedule within 25% of the expected time interval. 
 
3. Individuals treated with antidepressant + MPH relative to antidepressant + placebo will show 
higher accepting/ambivalent vs. indifferent/skeptical on the Beliefs About Medicine 
Questionnaire at the end of the study. 
 
4. Individuals treated with antidepressant + MPH relative to antidepressant + placebo will show 
lower blood level for escitalopram at study endpoint. 
 
5. Individuals treated with antidepressant + MPH relative to antidepressant + placebo will show 
higher Revised Medication Adherence Reasons (MAR) scale at study endpoint. 
 
6. Individuals treated with antidepressant + MPH relative to antidepressant + placebo will show 
greater reduction in symptoms on the QIDS-SR at study endpoint. 
 
7. Individuals treatment with antidepressant + MPH relative to antidepressant + placebo will show 
greater outcome improvement as measured by the PROMIS scales. 
 
10.3 
ANALYSIS DATASETS 

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We will use the full analysis set which includes data of all participants who meet inclusion/exclusion 
criteria, provide consent form, and are randomized to either treatment arm.  The only exception is that 
participants will be excluded from the analysis set only if they have no single follow-up visit.   
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
At the end of Stage 1, effect size of the primary outcome measure for group difference at Week 8 will be 
expressed as Hedges’ G, and non-parametric bootstrap will be applied to obtain its 95% confidence 
interval (CI); attrition rate and its exact 95% CI will also be estimated. These two measures will be used 
to re-evaluate the power of Stage 2 before initiation of Stage 2. If no combinations of Hedges’ G and 
attrition rate within their 95% CI ranges provide 80% power in Stage 2 based on the proposed 80 
participants, the trial will be terminated, otherwise we will proceed to Stage 2. If the study proceeds to 
Stage 2, an interim analysis will be performed once we reach half completers of Stage 2 (n=40). All 
outcome measures will be analyzed in their continuous scales without dichotomization.   
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
For this study, the primary “efficacy” endpoint is an adherence measure—specifically, the pill count 
percentage at Week 8.  If the trial proceeds to Stage 2, group differences will be evaluated by 2-sample 
t-test first at the interim analysis (10 placebo + escitalopram, 10 methylphenidate + escitalopram) and at 
the final analysis if the trial proceeds to the end (also see Section 10.4.7).  Regardless of whether and/or 
when the trial is terminated, we will compute 95% confidence intervals for group differences using all 
available data including those from Stage 1 to maximize precision. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary endpoints will be analyzed in the same way as the primary endpoint in 10.4.2. 
10.4.4 SAFETY ANALYSES 
 
Adverse events leading to premature discontinuation from the study and/or serious 
treatment-emergent AEs will be presented in either a table or a listing. 
  
10.4.5 ADHERENCE AND RETENTION ANALYSES 
Because the primary outcome is adherence, only retention will be discussed here. The 8-week retention 
rate will be computed for each group and for both groups combined, and the corresponding 95% 
confidence interval will be estimated by the exact binomial method.  The 8-week retention rate will be 
compared between two groups by the “mid-P” value method instead of the conservative Fisher exact 
test98. 
10.4.6  BASELINE DESCRIPTIVE STATISTICS 

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For each group, demographic variables and baseline characteristics will be summarized in a table by 
mean and standard deviation for continuous variables or by frequency and percentage for categorical 
variables.  Following the CONSORT guideline, Item 15, baseline characteristics will be described but not 
tested between groups 99. 
10.4.7 PLANNED INTERIM ANALYSES  
Stage 2 is designed with an interim analysis, which will be performed when we achieve half completers. 
Assuming the primary endpoint follows a Gaussian distribution, we controlled overall Type I error rate at 
0.05 two-sided level using the Hwang-Shih-DeCani spending function 100 with 𝛾 parameter -4 for the 
upper bound and -2 for the binding lower bound. This analysis was conducted using R gsDesign package, 
version 3.0-1, function gsDesign(k=2, test.type=3, alpha=0.025, beta=0.2) where alpha is 1-sided.  The 
resulting lower and upper bounds for the interim z-statistic are 0.4 and 2.75, respectively.  Because we 
will use t-tests instead of z-tests for unknown variance, the lower and upper bounds of the z-statistic will 
be converted to corresponding quantiles in t-distribution using the quantile substitution method 101 and 
the actual number of available observations (e.g. the bounds will be 0.404 and 2.960 if we have 32 
participants or 30 degrees of freedom); if the t-statistic falls below the lower bound, we will terminate 
the trial for futility; if it falls above the upper bound, the trial will be claimed as successful; if the interim 
t-statistic falls between bounds, then Stage 2 will be continued to the end.  
10.4.7.1 SAFETY REVIEW 
Safety endpoints such as the occurrence and frequency of AEs or SAEs will be monitored. For action 
plans related to the safety review, see Section 5.5, Premature Termination or Suspension of Study and 
Section 8.5 Study Halting Rules. 
10.4.7.2 
EFFICACY REVIEW 
The primary endpoint will be evaluated with an interim analysis. 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
Not proposed. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
Considering this proof-of-concept trial, no adjustment will be implemented for multiple secondary and 
exploratory endpoints. 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
In addition to tables and graphs representing group data, individual response data and other relevant 
study information will be presented in tables.  The data listings accompanying the report will include, for 
each patient, a patient identifier, all measured or observed values of critical measurements, including 
baseline measurements, with notation of the time during the study (e.g., days on therapy and time of 
day, if relevant) when the measurements were made, the drug/dose at the time, measures of 

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adherence, and any concomitant medications at the time of, or close to the time of, measurement or 
assessment. 
10.4.11 
EXPLORATORY ANALYSES 
As an exploratory analysis, linear mixed-effect models (LMM) will be used to compare group differences 
across time points, using group and time and their interaction as fixed-effects and a patient-specific 
intercept. We will conduct post hoc comparisons to assess how early the treatment effect may start to 
appear. 
10.5 
SAMPLE SIZE 
We propose 20 participants for Stage 1 and 80 participants for Stage 2, both in 1:1 ratio for the two 
groups.   
In Stage 1, the proposed sample size of 10 patients per group will provide an estimate of mean with 
margin of error equivalent to 𝑡10−1,0.975√1/10 = 0.72 times of standard deviation for each group at 
95% confidence, or 𝑡10+10−2,0.975√1/10 + 1/10 = 0.94 times of common standard deviation for 
between-group difference.  Assuming 20% dropout rate for both groups at Week 8, the margin of error 
for the between-group difference becomes 𝑡8+8−2,0.975√1/8 + 1/8 = 1.07 times of common standard 
deviation. 
Stage 2 is designed with an interim analysis.  Assuming the primary endpoint follows a Gaussian 
distribution, we control overall Type I error rate at 0.05 two-sided level using the Hwang-Shih-DeCani 
spending function _ENREF_96 with 𝛾 parameter -4 for the upper bound and -2 for the binding lower 
bound. We propose a sample size of 40 patients per group and anticipate 20% dropout rate at Week 8, 
giving 32 patients per group or 64 in total. We set n.fix in gsDesign() to 62 instead of 64 to obtain a final 
sample size of 64.  Because gsDesign() uses 1-sample z-statistic for continuous endpoint, the resulting 
effect size 𝜃= 0.3558 needs be converted to 2-sample Hedges’ G by a factor of 2, i.e., 𝑔≈0.71.  For 
the maximum sample size of 64, this design leads to an expected sample size of 54.7 under this 
alternative hypothesis, or 42.8 under null hypothesis. Also, the variance of the primary endpoint is 
unknown and will be estimated from the sample, so z-tests will be replaced with t-tests in analyses and 
the bounds will need to be revised accordingly.  Based on the quantile substitution method 101, the 
interim boundaries 0.40 and 2.75 for z-distribution are converted to 0.404 and 2.960 for t-distribution 
with 32-2=30 degrees-of-freedom (df), and the critical z-value 1.96 for the final analysis be converted to 
1.999 for t-distribution with 64-2=62 df.  We evaluated these boundaries by 10,000-run simulation and 
confirmed that (1) under null hypothesis, there will be a 65.5% chance to stop the trial for futility and 
0.3% chance to claim it successful at interim analysis, and 0.024 one-sided Type I error rate at final 
analysis; (2) under alternative hypothesis with an effect size of Hedges’ G 0.714, there will be only 5.4% 
chance to stop the trial for futility and 19.8% chance for success at the interim analysis, and 80.1% 
power at the final analysis.  
10.6 
MEASURES TO MINIMIZE BIAS 

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10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Enrollment: To achieve the proposed sample size of 100 patients and to complete the study within the 
18-month study window, we will aim for an enrollment rate of 7 to 8 patients/month.  The figure below 
shows the monthly and cumulative enrollment.  The first 20 patients for Stage 1 will be enrolled within 
the first 2.5 months, followed by 8 weeks or 2 months of intervention for the 20th participant, and then 
another 2 weeks or 0.5 months for data preparation, cleaning, and analysis (including power re-
evaluation for Stage 2).  Thus, Stage 1 is planned to be finished within 5 months (the blue dashed line).  
If a satisfactory effect size and retention rate are suggested by Stage 1 data, another 80 patients will be 
recruited over the next 10.5 months.  Half of target participants for Stage 2 (40) will be enrolled at 
Month 10.2.  Followed by 2 months of intervention, an interim analysis will be performed between 
Months 12.2 and 12.7 (the red dashed line). If the interim analysis reveals the trial to be futile, the trial 
will be abandoned; at this point, we will have enrolled around 80 participants.  If the interim analysis 
suggests otherwise, enrollment will continue and end at Month 15.5.  Followed by another 2 months for 
intervention and 0.5 months for analysis, the whole trial will be completed within 18 months. 
 
Randomization/Masking: Participants who meet inclusion and exclusion criteria and sign the consent 
form will be randomized to receive either 5 mg MPH + 10 mg escitalopram or placebo + 10 mg 
escitalopram.  To ensure balance in-group size, we will use block randomization with block size two.  The 
randomization sheet will be provided by the primary statistician (Yeh) directly to the pharmacist. 
Investigators and participants will be kept blinded during the study window until data collection and 
analysis are completed.    
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
All study physicians, nurses and research assistants who work directly with participants will be blinded 
to treatment allocation. The study statistician and one additional staff member who will be assigned to 
work with the compounding pharmacy will be unblinded. Participants will be asked to guess their 
treatment assignment and indicate their degree of certainty and reasoning at each in-person visit 
(Weeks 0, 2, 4 and 8). 

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10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
During interviews or any time during the study, subjects may report psychological distress, suicidal 
ideation, or intent to harm self or others.  If this occurs, Dr. Paulus, or his licensed designee, will be 
contacted immediately to ensure appropriate care and compliance with mandated reporting to 
authorities.  Subjects may be referred for professional intervention and the blind may be broken to 
provide necessary information about study participation, as deemed appropriate, including calling 
emergency personnel (911) if needed.  A current list of local mental health programs will be available for 
all participants.  Information reported will be kept in confidence with the exception that disclosure of 
suicidality, homicidality, or child or elder abuse that warrants reporting to appropriate authorities. 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
LIBR will maintain appropriate medical and research records for this trial, in compliance with LIBR’s 
institutional requirements for the protection of confidentiality of participants.  
 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
The study PI will be responsible for addressing Quality Assurance issues (e.g., correcting procedures that 
are not in compliance with the protocol). The research coordinator will be responsible for Quality 
Control issues (e.g. correcting errors in data entry). 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 
ETHICAL STANDARD  
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6.  
13.2 
INSTITUTIONAL REVIEW BOARD  
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Western IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to the 
consent form will be IRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented.  
13.3 
INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 

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A separate screening consent may be used in order to register and track potential participants within 
LIBR’s screening protocol. If a separate screening procedure is not used, the study consent must be 
signed prior to conducting study screening procedures.  
Written informed consent is required for all participants. In obtaining and documenting informed 
consent, the investigator should comply with applicable regulatory requirements posed by LIBR and the 
Western IRB. Prior to the beginning of the trial, the PI should have the IRB’s written approval for the 
protocol and the written informed consent form(s) and any other written information to be provided to 
the participants.  
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to an individual agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator will 
explain the research study to the participant and answer any questions that may arise. All participants 
will receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, 
and potential risks of the study and of their rights as research participants. Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study.  
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  The study participant’s contact information will be securely 
stored at each clinical site for internal use during the study. At the end of the study, all records will 
continue to be kept in a secure location for as long a period as dictated by local IRB and Institutional 
regulations.  
Participant confidentiality will be assured via multiple measures: data will be coded so that identifying 
features are unlinked. The key for this code will be kept in a password-protected database. Any data 

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shared in publications and/or with other researchers will maintain the anonymity of participants, and 
will only link them according to their code.  
No human samples or specimens will be stored as a result of this study. Data related to this study will be 
retained, and stored in a password-protected database.  
13.5 
FUTURE USE OF STORED SPECIMENS  
 
 Not applicable. 
 
14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported.  
Electronic data capture will represent the primary source data. Any paper source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data. Black ink is required to 
ensure clarity of reproduced copies. When making changes or corrections, cross out the original entry 
with a single line, and initial and date the change.  
Copies of the electronic case report forms (eCRF) will be provided for use as source documents and 
maintained for recording data for each participant enrolled in the study. Data reported in the eCRF 
derived from source documents should be consistent with the source documents or the discrepancies 
should be explained and captured in a progress note and maintained in the participant’s official 
electronic study record.  
Clinical data (including self-report scales, AEs, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into the RedCap electronic data capture system 
provided by LIBR. Data will be collected using a HIPAA compliant interface. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate.  
All research documents containing Personally Identifiable Information (PII) and collected research data 
will be stored electronically on the LIBR Network and/or REDCap. Access to the LIBR network and to 
REDCap is granted only to authorized personnel. The LIBR Network is protected by the Palo Alto PA-5250 
Layer 7 firewall with licenses for Wildfire, AV, Threat Prevention, and URL filtering. All LIBR network data 
is stored on site. REDCap is a secure web application for building and managing online surveys and 
databases. While REDCap can be used to collect virtually any type of data (including 21 CFR Part 11, 
FISMA, and HIPAA-compliant environments), it is specifically geared to support online or offline data 
capture for research studies and operations. The REDCap Consortium, a vast support network of 

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collaborators, is composed of thousands of active institutional partners in over one hundred countries 
who utilize and support REDCap in various ways. 
14.2 
STUDY RECORDS RETENTION  
Study documents will be retained for a minimum of 3 years.  
14.3 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice, or 
Manual of Procedure requirements. The noncompliance may be on the part of either the participant, 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a 
clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any 
research project that prospectively assigns human subjects to intervention or concurrent comparison or 
control groups to study the cause-and-effect relationship between a medical intervention and a health 
outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, 
process-of-care changes, and the like. Health outcomes include any biomedical or health-related 
measures obtained in patients or participants, including pharmacokinetic measures and adverse events. 
The ICMJE policy, and the Section 801 of the Food and Drug Administration Amendments Act of 2007, 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine. Other biomedical journals are considering adopting 
similar policies. For interventional clinical trials performed under NIH IC grants and cooperative 
agreements, it is the grantee’s responsibility to register the trial in an acceptable registry, so the 
research results may be considered for publication in ICMJE member journals. The ICMJE does not 
review specific studies to determine whether registration is necessary; instead, the committee 
recommends that researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish. 
In accordance with these policies, the study PI will register the study with clinicaltrials.gov prior to data 
collection, so the research results may be considered for publication in ICMJE member journals. 
15 
STUDY ADMINISTRATION 
 
15.1 
STUDY LEADERSHIP 
This study will be led by the LIBR PIs.  
16 
CONFLICT OF INTEREST POLICY 

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The independence of this study from any actual or perceived influence, such as by the biomedical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. The study leadership has established policies 
and procedures (which mirror the policies for managing such conflicts proposed by the NIH) for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest.  
17  
LITERATURE REFERENCES  
Please see below. 
 
 

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APPENDIX 
 
Version 
Date 
Significant Revisions  
 
 
 
 
 
 
 
 
1. 
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Health Organization;2003. 
2. 
Pai AL, McGrady M. Systematic review and meta-analysis of psychological interventions to promote 
treatment adherence in children, adolescents, and young adults with chronic illness. Journal of pediatric 
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3. 
Kahana S, Drotar D, Frazier T. Meta-analysis of psychological interventions to promote adherence to 
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Bosworth HB, Granger BB, Mendys P, et al. Medication adherence: a call for action. Am Heart J. Sep 
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5. 
Bosworth HB, Fortmann SP, Kuntz J, et al. Recommendations for Providers on Person-Centered 
Approaches to Assess and Improve Medication Adherence. J Gen Intern Med. Jan 2017;32(1):93-100. 
6. 
Serna MC, Cruz I, Real J, Gasco E, Galvan L. Duration and adherence of antidepressant treatment (2003 to 
2007) based on prescription database. Eur Psychiatry. May 2010;25(4):206-213. 
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Olfson M, Marcus SC, Tedeschi M, Wan GJ. Continuity of antidepressant treatment for adults with 
depression in the United States. Am J Psychiatry. Jan 2006;163(1):101-108. 
8. 
Novick D, Montgomery W, Moneta V, Peng X, Brugnoli R, Haro JM. Antidepressant medication treatment 
patterns in Asian patients with major depressive disorder. Patient preference and adherence. 2015;9:421-
428. 
9. 
Milea D, Guelfucci F, Bent-Ennakhil N, Toumi M, Auray JP. Antidepressant monotherapy: A claims 
database analysis of treatment changes and treatment duration. Clinical therapeutics. Nov 
2010;32(12):2057-2072. 
10. 
Zhang Z, Peluso MJ, Gross CP, Viscoli CM, Kernan WN. Adherence reporting in randomized controlled 
trials. Clinical trials (London, England). Apr 2014;11(2):195-204. 
11. 
Satpute S, Mehta M, Bhete S, Kurle D. Assessment of adherence to the statistical components of 
consolidated standards of reporting trials statement for quality of reports on randomized controlled trials 
from five pharmacology journals. Perspectives in clinical research. Jul-Sep 2016;7(3):128-131. 
12. 
Dodd S, White IR, Williamson P. Nonadherence to treatment protocol in published randomised controlled 
trials: a review. Trials. Jun 18 2012;13:84. 
13. 
Poluzzi E, Piccinni C, Sangiorgi E, et al. Trend in SSRI-SNRI antidepressants prescription over a 6-year 
period and predictors of poor adherence. European journal of clinical pharmacology. Dec 
2013;69(12):2095-2101. 

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14. 
Corrigan PW, Rusch N, Ben-Zeev D, Sher T. The rational patient and beyond: implications for treatment 
adherence in people with psychiatric disabilities. Rehabilitation psychology. Feb 2014;59(1):85-98. 
15. 
Marengoni A, Onder G, Esposti LD, et al. Adherence to Selective Serotonin and Serotonin-Norepinephrine 
Reuptake Inhibitor Prescriptions Affects Overall Medication Adherence in Older Persons: Evidence From 
the Italian Nationwide OsMed Health-DB Database. J Clin Psychiatry. Dec 2016;77(12):1712-1718. 
16. 
Dupclay L, Eaddy M, Jackson J, Raju A, Shim A. Real-world impact of reminder packaging on 
antihypertensive treatment adherence and persistence. Patient preference and adherence. 2012;6:499-
507. 
17. 
Ramsey RR, Ryan JL, Hershey AD, Powers SW, Aylward BS, Hommel KA. Treatment adherence in patients 
with headache: a systematic review. Headache. May 2014;54(5):795-816. 
18. 
Gearing RE, Townsend L, Elkins J, El-Bassel N, Osterberg L. Strategies to Predict, Measure, and Improve 
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