Clinical trial NCT02960763
Conditions: Treatment Resistant Depression Major Depressive Disorder Treatment-Refractory Depression Late Life Depression Geriatric Depression
Keywords: Comparative Effectiveness Research Pragmatic Clinical Trials Patient-Centered Outcomes Research
Sponsor: Washington University School of Medicine
Start date: 2017-02-24; Completion date: 2021-09-01
Enrollment: 742 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to assess which antidepressants work the best in older adults who have treatment-resistant depression (TRD).

Detailed description:
Older adult participants with treatment-resistant depression will be randomly assigned to a Step 1 medication strategy.

* Adding aripiprazole to current antidepressant medication
* Adding bupropion to current antidepressant medication
* Replacing current antidepressant medication with bupropion

If depression is not relieved at the end of 10 weeks, or if participants do not qualify for Step 1, participants will be randomly assigned to a Step 2 medication strategy:

* Adding lithium to current antidepressant medication
* Replacing current antidepressant medication with nortriptyline

All medication strategies will be offered in collaboration with participants' own physicians with the the research team providing support and guidance.

After treatment in Step 1 and/or Step 2, participants will enter the Continuation Phase to assess long term follow-up outcomes for 12 months.

Participants in this clinical trial will also be asked to participate in an additional study to gather imaging and biomarker data.

Arms: arm 1: Augment current antidepressant treatment with aripiprazole (tablets), titrated from 2-15 mg daily based on symptom severity and side effects. arm 2: Augment current antidepressant treatment with bupropion once-daily extended release, titrated from 150-300 mg daily based on symptom severity and side effects. arm 3: Taper from current antidepressant therapy. Start bupropion once-daily extended, titrated from 150-300 mg daily based on symptom severity and side effects. arm 4: Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 meQ/L. arm 5: Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml.
Interventions: intervention 1: Aripiprazole Augmentation intervention 2: Bupropion Augmentation intervention 3: Switch to bupropion intervention 4: Lithium Augmentation intervention 5: Switch to nortriptyline
Intervention descriptions: intervention 1: Augment current antidepressant treatment with aripiprazole (tablets). Start at 2 mg daily; increase every two weeks (i.e., to 5, 7, 10 mg) to a maximum of 15 mg daily based on symptom severity and side effects. intervention 2: Augment current antidepressant treatment with bupropion once-daily extended release, starting at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects. intervention 3: Taper from current antidepressant therapy. Start bupropion once-daily extended release at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects. intervention 4: Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 meQ/L. intervention 5: Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml

Protocol documents:
SAP_004.pdf: 
Statistical Analysis Plan 
OPTIMUM 
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Statistical Analysis Plan 
1. Administrative information
1.1. Title and Trial Registration 
Full study title: Optimizing Outcomes of Treatment-Resistant Depression in Older Adults 
Acronym: OPTIMUM 
ClinicalTrials.gov identifier: NCT02960763 
Washington University in St. Louis IRB ID number: 201609085 
PCORI Contract number: TRD-1511-33321 
Additional funding by NIMH (“OPTIMUM NEURO” collaborative R01) 
SAP version: 4.1 
Study protocol version: 3.0 (3/4/2019) 
SAP version history: 1.0 (12/26/2019), 2.0(2/3/2020), 3.0 (5/26/2020), 4.0 (11/2/2021), 4.1 (5/26/2022)
SAP version justification: Version 4.1 clarifies some aspects of the moderators analysis (based on 
decisions made in May 2022). All other analyses are unchanged from Version 4.0.
SAP Revision timing: Revision will be conducted after reviewing by PI and biostatistician. As per 
above, Version 4.1 includes some modifications made in May 2022 of the description of the moderator 
analysis.  
1.2. Roles and Responsibility 
Author: Lei Yang, Statistical Data Analyst 
Biostatistician: J. Philip Miller 
Principal investigator: Eric Lenze, MD 
SAP contributors and roles: Michael Yingling, Data Manager 
      Vy Pham, Statistical Data Analyst 
      Emily Lenard, Study Coordinator 
Affiliations: 1. Washington University in St. Louis, Missouri, USA 
2. University of California Los Angeles, California, USA
3. University of Pittsburgh, Pennsylvania, USA
4. Columbia University, New York, USA
5. University of Toronto, Ontario, Canada


Statistical Analysis Plan 
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Table of contents 
1. Administrative information ................................................................................................................... 1 
1.1. Title and Trial Registration ............................................................................................................ 1 
1.2. Roles and Responsibility .................................................................................................................. 1 
Table of contents ......................................................................................................................................... 2 
Abbreviation ................................................................................................................................................ 4 
2. Introduction ............................................................................................................................................. 5 
2.1. Background and Rationale: ............................................................................................................ 5 
2.2. Objectives.......................................................................................................................................... 5 
2.2.1. Objectives and study aims ........................................................................................................ 5 
2.2.2.    Hypothesis ............................................................................................................................... 5 
2.2.3.      Scope ...................................................................................................................................... 6 
3. Study Methods ......................................................................................................................................... 6 
3.1. General Study Design and Plan: ..................................................................................................... 6 
3.2. Randomization ................................................................................................................................. 6 
3.3. Sample Size ....................................................................................................................................... 7 
3.4. Framework ....................................................................................................................................... 7 
3.5. Statistical interim analyses and stopping guidance ....................................................................... 7 
3.6. Timing of final analysis ................................................................................................................... 7 
3.7. Timing of outcome assessment ........................................................................................................ 7 
4. Statistical principles ................................................................................................................................ 7 
4.1. Confidence intervals and p values .................................................................................................. 7 
4.2. Adherence and protocol deviations ................................................................................................ 7 
4.2.1. Definitions of protocol deviations ............................................................................................ 7 
4.2.2. Adherence and protocol deviations to be summarized .......................................................... 8 
4.2.3. Electronic Data Capture ........................................................................................................... 8 
4.3. Analysis populations ........................................................................................................................ 8 
5. Trial Population ...................................................................................................................................... 8 
5.1. Screening data .................................................................................................................................. 8 
5.2. Eligibility ........................................................................................................................................... 8 
5.2.1. 
Inclusion Criteria (Steps 1 & 2) ......................................................................................... 8 
5.2.2. 
Exclusion Criteria (Steps 1 & 2) ........................................................................................ 9 
5.2.3. 
Exclusions to Enter Step 2 .................................................................................................. 9 


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5.3. Recruitment .................................................................................................................................... 10 
5.4. Withdrawal/follow-up .................................................................................................................... 10 
5.4.1. General withdrawal rules ....................................................................................................... 10 
5.5. Baseline participant characteristics ............................................................................................. 11 
5.5.1. List of baseline characteristics ............................................................................................... 11 
5.5.2. Descriptive summarization of baseline participant characteristics .................................... 11 
6.  Analysis ................................................................................................................................................. 12 
6.1. Outcome definitions ....................................................................................................................... 12 
6.1.1. Primary and secondary outcomes ......................................................................................... 12 
6.1.2. Outcome measurements ......................................................................................................... 12 
6.2. Analysis methods ............................................................................................................................ 13 
6.3. Missing data .................................................................................................................................... 13 
6.5. Harms .............................................................................................................................................. 14 
6.6. Statistical software ......................................................................................................................... 14 


Statistical Analysis Plan 
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Abbreviation 
*ADM
Antidepressant Medication 
AE
Adverse Event 
ATHF
Antidepressant Treatment History Form 
*CFR
Code of Federal Regulations 
CIRS-G
Cumulative Illness Rating Scale-Geriatric 
DAST-10
Drug Abuse Screening Test 
DSMB
Data Safety and Monitoring Board 
EMR
Electronic Medical Record 
*E-CRF
Electronic Case Report Form 
EKG/ECG
Electrocardiogram  
*FDA
Food and Drug Administration 
GCP
Good Clinical Practice 
*HIPAA
Health Insurance Portability and Accountability Act 
*ICF
Informed Consent Form 
IRB
Institutional Review board 
ITT
Intention-to-treat 
MADRS
Montgomery-Asberg Depression Rating Scale 
MD – (1-5)
Standards for Preventing and Handling Missing Data 
MDD
Major Depressive Disorder 
MDE
Major Depressive Episode 
MINI
Mini-International Neuropsychiatric Interview 
*NMS
Neuroleptic Malignant Syndrome 
OPTIMUM
Optimizing Outcomes of Treatment-Resistant Depression in Older Adults 
PCORI
Patient Centered Outcomes Research Institute 
PHQ-9
Patient Healthcare Questionnaire 
PI
Principal Investigator 
PROMIS
Patient Reported Outcome Measurement Information System 
RCT
Randomized Controlled Trial 
REDCap
Research Electronic Data Capture 
SAB
Stakeholder Advisory Board 
SAE
Serious Adverse Event 
TRD
Treatment-Resistant Depression 
*Appeared in the protocol, but not in the SAP


Statistical Analysis Plan 
 
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2. Introduction 
2.1. Background and Rationale:  
One-half or more of older adults fail to remit with antidepressant pharmacotherapy. Treatment-resistant 
depression (TRD) in older adults is highly deleterious because persistence of depression is a leading cause 
of disability, suicide, dementia, and premature mortality. Making it worse is the lack of evidence-
supported treatments at a stage in life when medications’ benefit vs. risk ratio crucial.  
The Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) study will 
provide the evidence that older adults need to get an effective treatment that works best for them, 
improving their quality of life while minimizing risks of medications. 
2.2. Objectives 
2.2.1. Objectives and study aims 
The study aims to close the evidence gap on late-life depression in three ways. First, we will examine the 
comparative benefits and risks of antidepressant strategies (augmentation and switching) in older adults 
with TRD. In addition to looking at rates of depression remission, we will focus on the effects on the 
outcomes that also matter to older adults, like well-being, adverse events, and falls. Secondly, we will 
explore how aging changes the balance of benefits vs. risks. With aging comes a decline in brain and 
systemic health that may alter the benefit/risk ratio of antidepressant strategies. Third, we will maximize 
stakeholder engagement by conducting semi-structured qualitative interviews of patients and providers 
and convening a Stakeholder Advisory Board (SAB) to guide the study and ensure its relevance to 
patients and providers Armed with the knowledge of differential benefits and risks, stakeholders could 
provide personalized precision care that maximizes the benefits of TRD treatment strategies for older 
adults with minimizing risks. 
2.2.2.    Hypothesis 
Theme 1: Benefits and risks of antidepressants: outcomes that matter for patients and clinicians  
1. Effectiveness. Augmentation arms will show greater improvement than monotherapy arms for 
effectiveness outcomes. 
a. Wellness outcome: Improved psychological well-being. (H1a) 
b. Symptom outcome: Remission from depression (defined as MADRS ≤10 at Step end). 
(H1b) 
2. Safety. Augmentation arms will have more tolerability and safety concerns (i.e., more serious 
adverse events) than monotherapy arms. 
a. Serious adverse events (H2a), falls, and fall-related injuries (H2b) are the safety 
outcomes.  
The primary analytic strategy is a test of specific treatment strategies (e.g., aripiprazole augmentation).  
More recently, a report on these strategies in mixed-age veterans with TRD (Mohamed et al, JAMA 2017) 
has suggested that augmentation approaches yield higher remission rates than does switch.  The TRD 
field has, likewise, converged on the overarching question of whether augmentation is superior to switch, 
more so than the specific question of which augmentation approach is superior (e.g., Ruberto, Jha, & 
Murrough, “Pharmacological treatments for patients with treatment-resistant depression”, 
Pharmaceuticals 2020; Voineskos, Daskalakis & Blumberger, “Management of treatment-resistant 
depression”, Neuropsychiatr Dis Treat 2020) with a recent Cochrane systematic review (Davies et al, 
2019) determining that augmentation strategies appeared efficacious while switch strategies had uncertain 
efficacy.   


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For this reason, a secondary analysis of each hypothesis will test the overall strategy of augmentation vs. 
switch. The two augmentation arms in Step 1 will be summed and compared to the switch arm.  
Theme 2: Aging influences the balance of benefits and risks of antidepressant strategies. 
3.
Moderator analyses (Heterogeneity of Treatment Effect). Exploratory analysis (HT-1):
Effectiveness and safety differences between treatment arms will be moderated by age. 
Specifically, with increasing age effectiveness differences between treatment arms will decrease, 
and safety differences between treatment arms will increase. In addition, the following potential 
moderators will be assessed: executive function, co-morbid medical burden, co-morbid anxiety, 
and degree of treatment resistance.
2.2.3.      Scope 
This Statistical Analysis Plan will be the guiding document for the quantitative analyses that will be 
conducted in the OPTIMUM study.  
3. Study Methods
3.1. General Study Design and Plan: 
Participants will be recruited from five regions with diverse and representative populations encompassing 
approximately 708 adults. The five regions are: St. Louis and rural Missouri; Los Angeles City and 
County; Pittsburgh and Western Pennsylvania; New York City; and Toronto and rural Ontario. 
Participants will be non-demented adults aged 60+, with equal proportions aged 60-70 and 70+, with 
current major depression that has failed to respond to 2+ adequate antidepressant trials. Two-thirds of the 
sample will be women and 86% White, 7% Black, 8% Latino/Hispanic, and 4% other racial groups.  
All recruited adults will be randomized to 10 weeks of one of three Step 1 strategies: aripiprazole 
augmentation, bupropion augmentation, or switch to bupropion. Those who do not attain remission in 
Step 1 or those who do not qualify for Step 1 will be randomized to 10 weeks of one of two Step 2 
strategies: lithium augmentation or switch to nortriptyline. Those who complete acute treatment will be 
followed in a one-year continuation, with assessments every four months. This pragmatic RCT will be 
carried out in real-world clinical settings. Primary care and mental health clinical partners will provide 
treatments, with decision support from the study team.  
Patients will be identified from clinical networks at each of the five participating centers. Our two primary 
mechanisms of recruitment will be through screening and referrals. We will screen through clinical 
networks using Electronic Medical Records (EMR) and will contact all patients in practices aged 60 and 
older who in the recent past were prescribed or are currently taking antidepressants. Referrals will be 
elicited from practitioners and through advertisements to patients and their caregivers.  
An additional mechanism of recruitment will be through IRB-approved hospital network registries and 
social media advertisements and posts on Facebook and Instagram. Potential participants who see Facebook 
ads and want to participate in the study can click on the Facebook ad and it will direct them to a secure and 
encrypted survey website using Redcap to collect name, phone number, and email address. Research study 
staff will contact the potential participants to screen them for study eligibility. 
3.2. Randomization 
Randomization of participants will be implemented in REDCap, using a randomized block design by 
alternating blocks of 3 and 6 within strata by site (i.e., St Louis vs. Pittsburgh), referral source (primary 
care vs. specialty mental health) and age (<70 vs >70).  


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Only assessors of outcome measures will be blinded. Assessors will be instructed to not ask, and 
participants instructed to not share the treatment to which they were assigned. Participants, providers, and 
other research staff will not be blinded to treatment conditions. 
In this pragmatic design where all levels of adherence are allowed, participants will be considered 
randomized assuming they meet the eligibility requirements at screening (including any safety screens as 
applicable) and they have been given a randomization assignment (i.e., even if participants never took a 
dose of the randomized medication, they will be included in the analysis). 
3.3. Sample Size 
Our original proposal was to randomize 1,500 patients in Step 1 and 800 for Step 2. This was adjusted 
mid-study when it became clear that recruitment efforts would not achieve this sample size. Newly 
adjusted sample size is 708 (estimated mid-study), including 123 participants who were enrolled into step 
2 without first participating in step 1.   
3.4. Framework 
Hypothesis testing framework: H0 and H1 with confidence intervals for differences. 
3.5. Statistical interim analyses and stopping guidance 
No interim analysis is planned. As there is no placebo and all treatments are FDA-approved and 
frequently used in older adult, no contingency plans for early stopping because of futility or safety are 
planned. 
3.6. Timing of final analysis 
Analyses will ensue after recruitment is completed and all participants have finished their acute phase.  
This statistical analysis plan was added to the study protocol at clinicaltrials.gov, before the closure of the 
database and before any analyses had been conducted. Independent study monitoring was conducted in 
adherence to the Good Clinical Practice(GCP) guidelines. The statistician will be blind to treatment 
assignments during the analysis. 
3.7. Timing of outcome assessment 
Outcome assessment will be conducted at the end of the acute phase for both step 1 and step 2. During the 
continuation phase, assessments will be conducted at month 4, month 8, and month 12.  
4. Statistical principles 
4.1. Confidence intervals and p values 
To test our primary hypothesis (H1a), a significance level of .05/3 will be considered as statistically 
significant in Step 1. A significance level of .05 will be considered statistically significant in Step 2. If the 
significance level is greater than .05, we will emphasis the increased chance of a type I error. Results will 
be presented with their values (e.g. regression coefficients, standard deviation, etc.) with 95% confidence 
intervals. 
4.2. Adherence and protocol deviations 
4.2.1. Definitions of protocol deviations 
Any alteration or modification to the IRB-approved research without prospective IRB approval.  The term 
research encompasses all IRB-approved materials and documents including the detailed protocol, IRB 


Statistical Analysis Plan 
 
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application, consent form, recruitment materials, questionnaires/data collection forms, and any other 
information relating to the research study. 
4.2.2. Adherence and protocol deviations to be summarized 
As a pragmatic study, all levels of adherence are allowed. Compliance with the study-recommended 
medication and dosing will be assessed at each decision support call using the Protocol Adherence Form. 
Reasons for non-compliance will be documented. 
4.2.3. Electronic Data Capture 
This study will utilize REDCap-based electronic Case Report Forms (e-CRF’s) for data capture and 
storage. Source documents, including laboratory values, medical records and physician communications 
will be maintained at each site to verify adherence to protocol, inclusion/exclusion criteria, and data 
accuracy. 
4.3. Analysis populations 
We will follow the intention-to-treat (ITT) principle. In other words, patients who receive co-prescribed 
medications, stop randomized medication, or switch to a different medication will continue to be 
followed. To confirm that ITT findings represent the “true” data on effectiveness, safety, and tolerability 
of management strategies, we will conduct a sensitivity analysis that will compare ITT to per-protocol 
findings.1 
5. Trial Population 
5.1. Screening data 
Potential participants identified through each site’s IRB-approved recruitment plans will be screened for 
eligibility. Staff and PI’s at each site are responsible for verifying that participants at their site meet all 
eligibility criteria before being randomized to acute treatment. We anticipate differences between sites in 
which assessments may be obtained in pre-screening (pre-written consent) versus screening (post written 
consent).  Despite these potential differences, the following assessments must be conducted prior to 
randomization to ensure eligibility (see also Section 5.2.1 and 5.2.2 for Inclusion and Exclusion Criteria):  
• 
PHQ-9 
• 
MINI MDE Module 
• 
Screening questions for treatment resistance and medical exclusions  
• 
Short Blessed Test 
• 
ATHF 
• 
CIRS-G 
 
5.2. Eligibility 
All participants will meet the following eligibility criteria:  
5.2.1. Inclusion Criteria (Steps 1 & 2) 
a) Men and women aged 60 and older. 
 
1 In the course of conducting analyses of effectiveness, the research team noted that many participants had a prior trial of one of 
the randomized medications.  This was allowed per the study protocol.  Because of these, a sensitivity analysis was conducted 
examining remission rates and change in depression scores for only those participants who had not had a prior trial of one of the 
randomized treatments.  This was only done for Step 1, because Step 2 treatments were rarely used in prior trials. 


Statistical Analysis Plan 
 
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b) Current Major Depressive Disorder (MDD), single or recurrent, as diagnosed by DSM-5 criteria. 
c) Failure to respond adequately to two or more antidepressant treatment trials of recommended dose and 
length (approximately 12 weeks; minimum 4 weeks at adequate dose). 
d) PHQ-92 score of 10 or higher. 
5.2.2. Exclusion Criteria (Steps 1 & 2) 
a) Inability to provide informed consent. 
b) Dementia, as defined by Short Blessed ≥10 and/or clinical evidence of dementia. Patients screened out 
due to possible dementia will be referred to a local Memory Clinic or back to their clinician for evaluation 
to clarify the presence or absence of dementia. 
c) Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform 
disorder, delusional disorder, or current psychotic symptoms. A recommendation for psychiatric referral 
will be made in these cases. 
d) High risk for suicide (e.g., active suicide ideation and or current/recent intent or plan) and unable to be 
managed safely in the clinical trial, such as unwilling to be hospitalized). Urgent psychiatric referrals will 
be made in these cases. 
e) Contraindication to proposed study medications, as determined by study physician including history of 
intolerance or non-response to proposed medications. 
f) Non-correctable, clinically significant sensory impairment (e.g., cannot hear well enough to cooperate 
with interview). 
g) Unstable medical illness, including delirium, uncontrolled diabetes mellitus, hypertension, 
hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are not under medical management. 
This will be determined based on information from the patient’s personal physician’s and study physician 
clinical judgment. Referral to the patient’s personal physician or to a general practitioner will be made in 
these cases. 
h) Moderate to severe substance or alcohol use disorder, as determined by study physician. Referral to 
appropriate treatment will be made in these cases.  
i) Seizure disorder.3 
j) Parkinson’s Disease3 
No exclusion criteria are based on race, ethnicity, or gender. 
5.2.3. Exclusions to Enter Step 24 
The following conditions are contraindications to Step 2 medications. Participants with them will not be 
eligible for Step 2 participation (but may be considered for Step 1 provided they meet criteria outlined in 
study protocol Sections 2.a & 2.b.) 
 
2 Initially the investigators used a score of 6 or greater but, per discussion with PCORI methodology team, changed 
this to 10 or greater during the study. 
3 When participants were allowed direct entry to Step 2, exclusion criteria i) and j) were exclusion for Step 1 only. 
4 The investigators allowed eligible individuals to directly enter Step 2 (i.e. if ineligible for Step 1). Thus, 
participants could enter from Step 1 or directly from initial consent into the study. 


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a) QTC prolongation or Wide QRS on EKG 
b) Active Ischemic Heart Disease as evidenced by angina or requiring treatment (e.g., nitrates) for 
ischemic attacks.  Patients with history of prior MI, stent, or bypass may be included who have had no 
symptoms of ischemia (e.g., no chest pain) for 2 years.  
c) Acute or chronic renal insufficiency (as indicated by creatinine clearance below 30 mL/min; suspected 
if creatinine above 1.5 mg/dL; per PI and/or clinician discretion)  
d) Narrow-angle glaucoma 
5.3. Recruitment  
A Consort diagram will be used to visualize the flow of patients. We will report the number of eligible 
participants and the number of screened participants. The reasons for lack of eligibility will be 
enumerated. The number randomized will be reported as well as the reasons for non-randomization. The 
number randomized into each of the three arms (augmentation with aripiprazole, augmentation with 
bupropion, and switch to bupropion) will be reported. For those who do not remit under step 1 will be 
randomized in step 2 to one of 2 arms (augmentation with lithium and switch to nortriptyline). See Figure 
1.  
Figure 1. 
 
*sample size estimated mid-study 
 
5.4. Withdrawal/follow-up 
5.4.1. General withdrawal rules 
Participants will be asked to continue in the study for follow-up regardless of their and their physician’s 
adherence to the medication recommendations from the study team. Participants who discontinue study 
medications for tolerability reasons will be asked to complete the appropriate Acute Phase End 
Assessments for their phase of the study. Participants who end Step 1 treatment early due to tolerability 
issues will be invited to proceed to Step 2 after completing Acute Phase End Assessments. 
Participants who choose to withdraw from the study early will be asked to complete the appropriate final 
visit for their phase of the study (Step 1 acute endpoint, Step 2 acute endpoint, or Continuation Month 
12).  


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Withdrawal from the study for any reason, including study completion, will be documented in the 
Electronic Case Report Form. 
Participants’ reasons for withdrawal will be summarily reviewed by each site’s IRB at Continuing Review 
and at DSMB meetings. 
5.5. Baseline participant characteristics 
5.5.1. List of baseline characteristics 
Informed consent forms will be signed by participants at baseline. Local research team assessments 
elements collected during baseline: 
o MINI MDD & Bipolar Modules 
o PHQ-9 (If more than 7 days has elapsed since the PHQ-9 was done at pre-screen.) 
o Suicide History, Risk & Protective Factors 
o Baseline Side Effects 
o Expectations for Adherence 
o Falls & Fall-related Injuries (history) 
o Height and Weight (self-reported) 
o If indicated by pre-screen: DAST-10  
o If indicated by pre-screen: AUDIT 
o NIH Toolbox Psychological Well Being (general life satisfaction and positive affect scales) 
o PROMIS Physical Function 
o PROMIS Social Participation 
o PROMIS Anxiety 
o NIH Cognition and Motor Batteries (in-person assessments - may be foregone for participants 
living in remote locations) 
o ATHF 
o CIRS-G 
o Medical Conditions and Medication List (study doctor to review before randomization) 
o MADRS 
The key variables being used in the study include: 
o Age 
o Gender 
o Race 
o Ethnicity 
o CIRS-G (cumulative medical comorbidity) 
o MADRS 
o PHQ-9 
o ATHF 
5.5.2. Descriptive summarization of baseline participant characteristics 
We will list general patient characteristics in a baseline characteristics table. Data will be presented as 
mean with standard deviation (SD) when normally distributed or as median with interquartile range in 
case of skewed data. Dichotomous and categorical data will be presented in proportions.  


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6.  Analysis 
6.1. Outcome definitions 
6.1.1. Primary and secondary outcomes 
Primary: Psychological well-being is the patient-centered effectiveness outcome (H1a) and remission 
from depression is the clinician-focused effectiveness outcome (H1b). Safety will be monitored through 
serious adverse events (H2a) as well as falls and fall-related injuries (H2b). 
Secondary: Secondary tests of effectiveness will examine changes in other aspects of quality of life: 
physical function, social participation, changes in depressive symptoms (i.e., MADRS scores), and 
antidepressant response (i.e., 50% or more reduction from baseline MADRS). 
Continuation phase analyses (all are considered secondary):  
In the continuation phase, we will explore the long-term effectiveness and safety of antidepressants: 
• 
We will examine long-term changes/stability of psychological well-being and other quality of life 
variables, and depressive symptoms, by mixed-effects repeated measures models. 
• 
We will also test for sustained remission (among those who achieved remission at the end of the acute 
step) by measuring relapse in each arm. Relapse will be defined as meeting DSM 5 criteria for a major 
depressive episode, as determined by an Independent Evaluator – who will identify all remitted 
participants who then have a criterion-based (ie PHQ9 score of 2-3 for items 1-8, 1-3 for item 9) and 
who will confirm the diagnosis by conferring with a study investigator.  We will carry out Cox models 
examining time to relapse (primary: meeting PHQ-9 criteria for a current MDE; secondary: MADRS 
≥15).and time to drop out, to examine for treatment inferiority (i.e., whether one antidepressant 
strategy produces poorer long-term outcomes).   
• 
In the continuation phase, we will also explore the long-term safety of antidepressants. Serious adverse 
events are the safety outcome in both acute and continuation phases. Cox models examining time-to-
event (with Anderson & Gill extensions for repeated events) will compare the treatment arms during 
continuation in terms of serious adverse events. Since falls and fall-related injuries information were 
not collected during the acute phase, the safety endpoint has changed. A time-to-event analysis will not 
be appropriated. Hence, a generalized linear model with logistic link function will be used. 
 
We will also compute rates of side effects in each arm, as specifically recommended by patient 
stakeholders.  These data are not hypothesis-testing, but they support the patient-centered goal of allowing 
clinicians and patients to know what to expect in terms of side effects from treatment. 
As well, the study will test how aging influences the relative benefits and risks of antidepressants for 
TRD.  Additionally, a qualitative study of patient and clinician partners will provide the lived experience 
of TRD and antidepressant strategies. 
6.1.2. Outcome measurements 
H1a outcome will be measured by NIH Toolbox (Psychological Well-being), and the secondary outcome 
will be measured by PROMIS (Physical function, Social participation). 
H1b outcome will be assessed by independent (blind) raters via phone interview to assess the MADRS 
score.  
H2a outcome will be measured when SAE occurs.  
H2b outcome will be assessed by independent raters. 


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6.2. Analysis methods 
To test hypothesis H1a (psychological well-being), a repeated measure of 2*2*3 ANOVA with age (60 – 
70, > 70), time (baseline, end of Active phase of Step 1) by treatment group (3 levels) will be used. 
Specific time * treatment group contrasts will compare the changes across pairs of treatment groups. 
These tests will be conducted with a Hochberg Step-down procedure. If the comparison with the lowest p-
value < 0.05/3 it is significant. If the second lowest p-value is also < 0.05/2 then it also will be significant 
and if the third p-value is < 0.05 then it also will be significant. We will include site as strata in all 
analyses.5 For those who proceed to Step 2, analogous repeated measures 2*2*2 ANOVA will be used 
with a significance level of .05 for the time*treatment group comparison. 
To test hypothesis H1b (remission), a corresponding 2*3 (age by treatment group) generalized linear 
models with a logit link function will be computed for the dichotomous outcome of remission. Pairwise 
treatment groups will be compared as in H1a. 
To test hypothesis H2a (serious adverse events), Cox models will be used to examine time to event (with 
Anderson & Grill extensions for repeated events) will compare the treatment arms during both the acute 
phase and the continuation in terms of serious adverse events. Pairwise comparison between treatment 
groups will be tested. 
To test hypothesis H2b (falls and fall-related injuries), a repeated measures generalized linear model with 
a cumulative logistic link function. The factors will be treatment group and time (week 2, 4,  6, 8 or 10). 
The age group (<70 vs.>70) and clinic stratification variables will be included in the model as well as the 
fall history obtained at baseline. Pairwise comparisons between the treatment group pairs will be formally 
tested. The same model with a simple logistic link function will be conducted during each 2-week period 
where the response is a fall-related injury or not.  
In terms of the exploratory hypothesis 3, we will include the treatment by age group (<70 vs >70) by time 
interaction to the linear models described above to test for both the benefits and risks for the treatment 
alternatives. Additionally, we will fit a model with age as a continuous variable. 
6.3. Missing data 
Missing data can occur from patient dropout (unit non-response), failure to provide data (item non-
response), or administrative issues. We will minimize missing data by closely monitoring accumulating 
data for missingness and implementing procedures to reduce it when identified (MD-16). The distribution 
of patients with missing data for each variable will be thoroughly investigated (MD-15). When a patient 
drops out of the study, we will document the reason for dropout and who made the dropout decision (MD-
47). We will compare patients with complete data to those with missing data to assess potential biases. 
Our approach will depend on both the pattern and the magnitude of the missing data, following strategies 
recommended by PCORI methodology standards and the National Research Council. For example, we 
 
5 Senn S. Testing for baseline balance in clinical trials. Stat Med. Sep 15 1994;13(17):1715-1726. 
6 Describe methods to prevent and monitor missing data. 
7 Describe how you will record and report all reasons for dropout and missing data, and account for all patients in 
reports. 


Statistical Analysis Plan 
 
OPTIMUM 
14 
 
will conduct sensitivity analyses (MD-58) based on different assumptions (MD-29, MD-310) including 
multiple imputations. 
Our specific plan for handling missing data with the MADRS (at baseline or endpoint) is as follows: for 
those missing a centrally-administered MADRS, we will accept a locally administered one.  For MADRS 
missing at baseline or at endpoint in completers, we will impute a MADRS score.  For those who stop 
Step 1 (acute) or Step 2 (acute) early, prior to week 10, and do not have a MADRS score, we will treat 
them as non-remitters with respect to the primary effectiveness analysis. 
6.5. Harms 
Adverse events assessment is one of our research outcomes. During the study, regular assessments for 
side effects will be conducted. If present, they will be assessed by a physician. Similarly, we will make 
recommendations to clinicians that appropriate metabolic parameters (glucose, lipids), EKG, thyroid, 
renal, drug level, and other safety tests be monitored throughout the study. At any time during the study, 
if a participant is judged to be experiencing serious side effects, the research team will provide decision 
support so that clinicians can provide prompt management, including dose reduction, stopping treatment, 
or clinical referral. 
6.6. Statistical software 
Data cleaning and statistical analyses will be performed using SAS (SAS Institute, Cary NC) and R (The 
R Foundation for Statistical Computing; Vienna, Austria).  
 
8 Describe how you will examine sensitivity of inferences to missing data methods and assumptions, and incorporate 
into interpretation. 
9 Describe statistical methods to handle missing data. 
10 Describe plans to use validated methods to deal with missing data that properly account for statistical uncertainty 
due to missingness. 

Prot_002.pdf: 
 
 
 
 
 
 
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OPTIMUM Protocol Version 3.0 2019-03-04 Final Version 
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OPTIMUM: Optimizing Outcomes of Treatment- 
Resistant Depression in Older Adults 
Study Protocol: Final Version 
 
 
 
Principal Investigator:  Eric Lenze, MD 
WUSTL IRB ID#  201609085 
PCORI Contract # TRD-1511-33321 
ClinicalTrials.Gov Identifier NCT02960763 
 
 
 
 
 
Version #3.0: 3/4/2019 


 
 
 
 
 
 
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TABLE OF CONTENTS 
 
A 
INTRODUCTION ............................................................................................................................... 5 
A1 STUDY ABSTRACT .............................................................................................................................. 5 
A2 PURPOSE OF THE STUDY PROTOCOL ................................................................................................... 6 
B 
BACKGROUND .................................................................................................................................. 6 
C 
STUDY OBJECTIVES........................................................................................................................ 7 
C1 AIM 1: EFFECTIVENESS ...................................................................................................................... 7 
C2 AIM 2: EFFECTS OF AGING ................................................................................................................. 7 
C3 AIM 3: MAXIMIZE STAKEHOLDER ENGAGEMENT ............................................................................... 7 
C4 RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ............................................................... 7 
D 
STUDY DESIGN ................................................................................................................................. 8 
D1 OVERVIEW OR DESIGN SUMMARY ..................................................................................................... 8 
D2 D2 SUBJECT SELECTION AND WITHDRAWAL ..................................................................................... 8 
2.a 
Inclusion Criteria (Steps 1 & 2) ............................................................................................... 9 
2.b 
Exclusion Criteria (Steps 1 & 2)............................................................................................... 9 
2.c 
Exclusions to Enter Step 2 ........................................................................................................ 9 
2.d 
Ethical Considerations ............................................................................................................10 
2.e 
Informed Consent ....................................................................................................................10 
2.f 
Subject Recruitment Plans and Consent Process ....................................................................11 
2.g 
Randomization Method and Blinding ......................................................................................11 
2.h 
Potential Risks .........................................................................................................................11 
2.i 
Potential Benefits .....................................................................................................................13 
2.j 
Early Withdrawal of Subjects ..................................................................................................13 
E 
MEDICATION STRATEGIES AND DECISIONAL SUPPORT ..................................................13 
1.a 
Description of Decisional Support ..........................................................................................13 
1.b 
Treatment Group Assignment ..................................................................................................14 
1.c 
Aripiprazole Augmentation Prescribing Information ..............................................................14 
1.d 
Bupropion Switch and Augmentation Prescribing Information ...............................................15 
1.e 
Lithium Augmentation Prescribing Information ......................................................................15 
1.f 
Nortriptyline Switch Prescribing Information .........................................................................16 
1.g 
Safety Labs and Monitoring .....................................................................................................16 
i 
Recommended baseline labs ................................................................................................................... 16 
ii 
Recommended labs prior to aripiprazole augmentation .......................................................................... 17 
iii 
Required labs prior to Lithium augmentation ......................................................................................... 17 
iv 
Blood Level testing for Lithium Augmentation ...................................................................................... 17 
v 
Required labs prior to Nortriptyline switch............................................................................................. 17 
vi 
Blood Level testing for Nortriptyline switch .......................................................................................... 17 
vii 
Recommended Follow-up Labs for Continuing on aripiprazole ............................................................. 18 
viii 
Recommended Follow-up Labs for Continuing on nortriptyline ....................................................... 18 


 
 
 
 
 
 
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ix 
Recommended Follow-up Labs for Continuing on lithium..................................................................... 18 
1.h 
Preparation and Administration of Study Drug .......................................................................19 
1.i 
Subject Compliance Monitoring ..............................................................................................19 
1.j 
Prior and Concomitant Therapy ..............................................................................................19 
F 
STUDY PROCEDURES ....................................................................................................................19 
F1 
SCREENING FOR ELIGIBILITY.............................................................................................................20 
1.a 
Screening Log ..........................................................................................................................20 
F2 
SCHEDULE OF MEASUREMENTS ........................................................................................................21 
F3 
BASELINE ..........................................................................................................................................22 
F4 
DECISION SUPPORT CALLS ................................................................................................................22 
F5 
ACUTE PHASE END ASSESSMENTS ....................................................................................................23 
F6 
CONTINUATION ASSESSMENTS ..........................................................................................................23 
F7 
GENETIC TESTING .............................................................................................................................23 
7.a 
Processing of DNA: .................................................................................................................24 
F8 
QUALITATIVE INTERVIEWS ...............................................................................................................24 
G 
SAFETY AND ADVERSE EVENTS ................................................................................................24 
1.a 
Safety Monitoring ....................................................................................................................24 
1.b 
Definitions of Adverse Events ..................................................................................................24 
1.c 
Classification of Events ...........................................................................................................25 
i 
Assessing Severity of Adverse Events .................................................................................................... 25 
ii 
Assessing Relationship of Adverse Events ............................................................................................. 25 
iii 
Assessing Expectedness of Adverse Events ............................................................................................ 26 
iv 
Assessing Seriousness of Adverse Events .............................................................................................. 26 
1.d 
Data Collection Procedures for Adverse Events .....................................................................27 
1.e 
Reporting Procedures for Adverse Events ...............................................................................27 
G2 DATA SAFETY AND MONITORING BOARD .........................................................................................27 
H 
STATISTICAL PLAN ........................................................................................................................28 
H1 ANALYSIS PLAN FROM OPTIMUM GRANT .......................................................................................28 
H2 SAMPLE SIZE DETERMINATION AND POWER .....................................................................................30 
H3 INTERIM ANALYSIS ...........................................................................................................................30 
H4 MISSING OUTCOME DATA .................................................................................................................30 
I 
DATA HANDLING AND RECORD KEEPING .............................................................................30 
I1 
CONFIDENTIALITY AND SECURITY ....................................................................................................31 
I2 
TRAINING ..........................................................................................................................................31 
I3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .............................................................................32 
I4 
RECORDS RETENTION .......................................................................................................................32 
J 
STUDY MONITORING, AUDITING, AND INSPECTING ..........................................................32 
J1 
STUDY MONITORING PLAN ...............................................................................................................32 
J2 
AUDITING AND INSPECTING ..............................................................................................................32 
K 
STUDY ADMINISTRATION ...........................................................................................................32 
K1 ORGANIZATION AND PARTICIPATING CENTERS .................................................................................32 
K2 FUNDING SOURCE .............................................................................................................................33 
K3 PARTICIPANT COMPENSATION ..........................................................................................................33 
K4 MILESTONE SCHEDULE .....................................................................................................................33 
K5 HISTORY OF CHANGES TO STUDY PROTOCOL ...................................................................................38 
L 
REFERENCES ...................................................................................................................................40 
 


 
 
 
 
 
 
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A Introduction 
 
A1 Study Abstract 
Background and Significance: One-half or more of older adults fail to remit with antidepressant 
pharmacotherapy. Treatment-resistant depression (TRD) in older adults is highly deleterious, 
because persistence of depression is a leading cause of disability, suicide, dementia, and 
premature mortality. Making it worst is the lack of evidence-supported treatments at a stage in 
life when medications’ benefit vs. risk ratio crucial.  
 
The Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) study 
will provide the evidence that older adults need to get effective treatment that works best for 
them, improving their quality of life while minimizing risks of medications. 
 
Study Aims: The study aims to close the evidence gap on late-life depression in three ways. First, 
we will examine the comparative benefits and risks of antidepressant strategies (augmentation 
and switching) in older adults with TRD. We will focus on the effects on the outcomes that matter 
most to older adults, like well-being, adverse events, and falls. Secondly, we will explore how 
aging changes the balance of benefits vs. risks. With aging comes a decline in brain and systemic 
health that may alter the benefit/risk ratio of antidepressant strategies. Third, we will maximize 
stakeholder engagement to ensure relevancy to providers and patients alike. Armed with the 
knowledge of differential benefits and risks, stakeholders could provide personalized precision 
care that maximizes the benefits of TRD treatment strategies for older adults with minimizing 
risks. 
 
Study Description: We will randomize 1500 adults aged 60+ to 10 weeks of one of three Step 1 
strategies: aripiprazole augmentation, bupropion augmentation, or switch to bupropion. Those 
who do not attain remission in Step 1 will be randomized to 10 weeks of one of two Step 2 
strategies: lithium augmentation or switch to nortriptyline. Those who complete acute treatment 
will be followed in a one-year continuation. This pragmatic RCT will be carried out in real-world 
clinical settings. Primary care and mental health clinical partners will provide treatments, with 
decision support from the study team.  
 
Study population: Participants will be non-demented older adults aged 60+, with equal 
proportions aged 60-70 and 70+, with current major depression that has failed to respond to 2+ 
adequate antidepressant trials. We will recruit across five regions: St. Louis and rural Missouri; 
Los Angeles City and County; Western Pennsylvania; New York City; and Toronto and rural 
Ontario. Two-thirds of the sample will be women and 70% white, 15% black, 10% Latino, and 5% 
other racial groups. 
 
Patients will be identified from clinical networks at each of the five participating centers. Our two 
primary mechanisms of recruitment will be through screening and referrals. We will screen 
through clinical networks using Electronic Medical Records (EMR) and will contact all patients in 
practices aged 60 and older who in the recent past were prescribed or are currently taking 
antidepressants. Referrals will be elicited from practitioners and through in-practice 


 
 
 
 
 
 
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advertisements to patients and their caregivers specifically asking if the doctor, patient, or 
caregiver describes the clinical situation as treatment resistant or difficult to treat.  
 
Primary/secondary outcomes: Psychological well-being is the patient-centered effectiveness 
outcome and remission from depression is the clinician-focused effectiveness outcome. 
Secondary patient-reported outcomes include physical function and social participation. Safety 
will be monitored through serious adverse events as well as falls and fall-related injuries. As well, 
the study will test how aging influences the relative benefits and risks of antidepressants for TRD.  
Additionally, a qualitative study of patient and clinician partners will provide the lived experience 
of TRD and antidepressant strategies. 
 
Analytic methods: Repeated measures ANOVA will test effectiveness of antidepressant strategies 
with respect to the primary patient-centered outcome of psychological well-being, as well as 
other continuous variables. Then, specific time*group contrasts will compare the changes across 
pairs of treatment groups.  Corresponding generalized linear models with a logit link function will 
test effectiveness for reaching remission.  Cox models examining time to event will test safety of 
antidepressant strategies in terms of serious adverse events, falls, and fall-related injuries.  
 
Moderator analyses will examine the effect of aging on changing the relative benefits and risks of 
antidepressants.  We will include the treatment by age group (<70 vs >70) by time interaction to 
the linear models described above to test for both the benefits and risks for the treatment 
alternatives. 
A2 Purpose of the Study Protocol 
This study protocol will serve as the shared working document for the study team to ensure that 
the research is being conducted consistently at all participating sites. Investigators Revisions will 
be made and shared by the Coordinating Site (Washington University). Changes requiring the 
approval of local IRB’s or the funding agency (PCORI) will not be implemented until such 
approval is obtained.  
B Background 
Treatment-resistant depression (TRD) is a major health problem for the growing population of 
older adults. Older adults with persistent depression experience devastating medical 
consequences, place high burdens on caregivers, and suffer high suicide rates.4,5 
 
TRD is the norm, not the exception in older depressed adults, as most fail to remit with standard 
antidepressant pharmacotherapy.6,7 Persistent depression decreases older adults’ quality of life 
more than any other illness.8 Effective antidepressant treatment would address a leading cause 
of disability,9 excess mortality,10  and cognitive decline.11-13 Understanding the risks and benefits 
of antidepressant strategies in older adults could vastly improve the quality of life of seniors and 
save billions of dollars each year in health care costs.23 This public health issue will rapidly grow 
with the aging of the US and world population.24 
 
Yet, in spite of the high stakes for public health, the comparative risk/benefit ratio of 
antidepressants is entirely unstudied in older adults with TRD.  This stands in contrast with 
numerous studies in younger adults.25-29   This evidence gap was highlighted in critical reviews30,31 


 
 
 
 
 
 
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that found a complete lack of evidence in this age group.  The sole exception is our recent 
randomized controlled trial (RCT) of aripiprazole augmentation in older adults.2,32   
 
C Study Objectives 
The study aims to close the evidence gap on late-life depression in three ways: 
C1 Aim 1: Effectiveness 
Examine the comparative benefits and risks of antidepressant strategies (augmentation and 
switching) in older adults with TRD.  
 
Effectiveness outcomes: psychological well-being and remission from depression 
Safety outcomes: serious adverse events, falls, and fall-related injuries 
C2 Aim 2: Effects of Aging 
Explore how age, and age-related variables (medical comorbidity, cognitive problems) change 
the balance of benefits vs. risks.  
C3 Aim 3: Maximize Stakeholder Engagement 
We will maximize stakeholder engagement to ensure relevancy to providers and patients alike.  
C4 Rationale for the Selection of Outcome Measures 
 
OUTCOME 
WHEN AND HOW MEASURED 
RATIONALE 
Psychological well-being is the 
patient-centered effectiveness 
outcome (Hypothesis 1a [H1a]).  
 
Secondary quality of life 
measures are self-reported 
physical function and social 
participation. 
In Acute, beginning and end of 
Step 1 (and Step 2); in 
Continuation months 4, 8, 12. 
Measured by NIH Toolbox* 
(Psychological Well-being) and 
PROMIS* (Physical function, 
Social participation). 
Assessed by independent 
rater**  
Psychological well-being 
encompasses satisfaction, 
happiness, cognitive engagement, 
and meaning/purpose.  It is a 
critical dimension of quality of life, 
recommended by patient 
stakeholders in focus groups as an 
outcome that matters.  
 
Remission is our clinician-
focused effectiveness outcome 
(H1b): reduction of depressive 
symptoms below a threshold 
(MADRS≤10).  This goal of 
treatment is a consensus among 
practitioners.53,54  
In Acute, beginning and end of 
Step 1 (and Step 2); in 
Continuation, months 4, 8, 12 
Assessed by independent 
(blind) rater** via 20-30 
minute phone interview. 
The MADRS measures 10 areas of 
depressive symptoms.  It is a 
standard outcome in 
antidepressant studies.   
Patient stakeholders described this 
assessment as “very important” 
for assessing effectiveness.  
Serious adverse events (SAEs) 
(H2a) 
This safety outcome 
encompasses life threatening 
illness, hospitalization, or need 
of medical care. 
Anytime when a SAE occurs. 
Key measure of antidepressant 
safety in older adults. 


 
 
 
 
 
 
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Falls and fall-related injuries via 
self-report are another safety 
outcome (H2b). 
 
End of Step 1 and Step 2, 
every 4 months in 
continuation. 
Assessed by independent 
rater**   
Patient stakeholders told us that 
fall risk was very important to 
them.  Clinicians and policy-
makers are also concerned about 
fall risk due to antidepressants.   
D Study Design  
D1 Overview or Design Summary 
The study design compares benefits and risks of 3 first-line (simpler to use) strategies: 
augmentation with aripiprazole, augmentation with bupropion, and switch to bupropion; and 2 
second-line (requires more monitoring) strategies: augmentation with lithium and switch to 
nortriptyline. The step-wise design matches real-world care, in which clinicians go from easier to 
more challenging management strategies.   
 
This is a collaborative, multi-site study with five sites: Washington University (Coordinating Site) 
which includes University of Missouri-Columbia, University of Pittsburgh, University of Toronto, 
University of California Los Angeles, and Columbia University. Each site will randomize 300 
eligible participants into Step 1, for a total of 1,500 participants across all sites.  
 
Figure updated after completion of the study to reflect actual sample enrollment numbers.  


 
 
 
 
 
 
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D2 Subject Selection and Withdrawal  
All participants will meet the following eligibility criteria:  
1.a 
Inclusion Criteria (Steps 1 & 2) 
a) Men and women aged 60 and older, with equal proportions aged 60-70 and 70+. 
b) Current Major Depressive Disorder (MDD), single or recurrent, as diagnosed by DSM-
5 criteria. 
c) Failure to respond adequately to two or more antidepressant treatment trials of 
recommended dose and length (approximately 12 weeks). 
d) PHQ-9 score of 10 or higher. 
1.b 
Exclusion Criteria (Steps 1 & 2) 
a) Inability to provide informed consent. 
b) Dementia, as defined by Short Blessed ≥10 and/or clinical evidence of dementia. 
Patients screened out due to possible dementia will be referred to a local Memory Clinic 
or back to their clinician for evaluation to clarify the presence or absence of dementia. 
c) Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, 
schizophreniform disorder, delusional disorder, or current psychotic symptoms. A 
recommendation for psychiatric referral will be made in these cases. 
d) High risk for suicide (e.g. active SI and or current/recent intent or plan) and unable to 
be managed safely in the clinical trial, such as unwilling to be hospitalized). Urgent 
psychiatric referral will be made in these cases. 
e) Contraindication to proposed study medications, as determined by study physician 
including history of intolerance or non-response to proposed medications. 
f) Non-correctable, clinically significant sensory impairment (e.g., cannot hear well 
enough to cooperate with interview). 
g) Unstable medical illness, including delirium, uncontrolled diabetes mellitus, 
hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are 
not under medical management. This will be determined based on information from the 
patient’s personal physician’s and study physician clinical judgement. Referral to the 
patient’s personal physician or to a general practitioner will be made in these cases. 
h) Moderate to severe substance or alcohol use disorder, as determined by study 
physician. Referral to appropriate treatment will be made in these cases.  
i) Seizure disorder. 
j) Parkinson’s Disease 
No exclusion criteria are based on race, ethnicity, or gender. 
 
1.c 
Exclusions to Enter Step 2  
The following conditions are contraindications to Step 2 medications. Participants with them will 
not be eligible for Step 2 participation (but may be considered for Step 1 provided they meet  
criteria outlined in Sections 1.a & 1.b.) 
 
a) QTc prolongation or Wide QRS on EKG 


 
 
 
 
 
 
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b) Active Ischemic Heart Disease as evidenced by angina or requiring treatment (e.g., 
nitrates)  for ischemic attacks.  Patients with history of prior MI, stent, or bypass may be 
included who have had no symptoms of ischemia (e.g., no chest pain) for 2 years.  
c) Acute or chronic renal insufficiency (as indicated by creatinine clearance below 30 
mL/min; suspected if creatinine above 1.5 mg/dL; per PI and/or clinician 
discretion)  
d) Narrow angle glaucoma 
1.d 
Ethical Considerations  
This study will be conducted in compliance with the protocol, United States (US) Food and Drug 
Administration (FDA) regulations, and all other applicable local laws and regulatory 
requirements.  
 
Each study site will seek approval by an institutional review board (IRB) according to regional 
requirements.  The IRB will evaluate the ethical, scientific and medical appropriateness of the 
study.  Further, in preparing and handling electronic case report forms (E-CRFs), the investigator, 
sub-investigator and their staff will take measures to ensure adequate care in protecting 
participant privacy.  To this end, a participant identification number will be used to identify each 
participant. 
 
1.e 
Informed Consent 
All subjects will have the purpose of the study, study interventions and evaluations, and the 
potential risks and benefits of participation explained to them and any questions will be 
answered.  If a subject agrees to participate in this study, the subject will review and sign the 
informed consent form (ICF). 
 
Written informed consent will be obtained from all subjects, themselves, with no proxy consent. 
If requested by subject, we will be prepared to include others (family members, friends, or their 
personal physician-making) in the process of informed consent to . Consent will be documented 
on a written ICF.  The ICF will be approved by the same IRB that approves this protocol.  Each ICF 
will comply with the FDA regulations in Title 21 Code of Federal Regulations (CFR) Part 50 ICH, 
GCP, and local regulatory requirements.   
 
Investigators may discuss study availability and the possibility for entry with a potential subject 
without first obtaining consent and conduct preliminary pre-screening with the patient’s verbal 
assent, following the process described in section F1. 
 
Written Informed consent will be obtained before any study procedures other than pre-
screening are performed. 
 
Once appropriate essential information has been provided and fully explained in layman’s 
language to the subject by the investigator, or a qualified designee, the IRB-approved written 
ICF will be signed and dated by both the subject and the person obtaining consent (i.e., 
investigator or designee).  The subject will receive a copy of the signed informed consent form; 
the original shall be kept on file by the investigator. 


 
 
 
 
 
 
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1.f 
Subject Recruitment Plans and Consent Process 
Study sites will be responsible for developing their site-specific recruitment plans and obtaining 
IRB approval for the plan and all recruitment materials. In most cases, recruitment will be 
facilitated through partnerships with community mental health and primary care clinics. Plans 
for recruitment by referral or via a partial waiver of HIPAA authorization for recruitment 
purposes must be agreed upon by the appropriate community personnel, and approved by the 
local IRB, prior to implementing.  
1.g 
Randomization Method and Blinding 
Randomization of participants will be implemented in REDCap, using a randomized block design 
within clinic and age group using variable block size, stratified by institutional site and age 
strata. 
 
Only assessors of outcome measures will be blinded. Participants, providers, and other research 
staff will not be blinded to participants’ condition. 
 
In this pragmatic design where all levels of adherence are allowed, participants will be 
considered randomized assuming they meet the eligibility requirements at screening (including 
any safety screens as applicable) and they and/or their clinician has been given a randomization 
assignment.  
 
1.h 
Potential Risks  
Study Instruments and measures: The assessments to be conducted as part of this study 
involving mood assessments, neuropsychological testing, and behavioral and functional 
assessments are non-invasive and carry with them no more than minimal risk. The most 
significant risks to the participants related to assessments are those that would follow a breach 
of confidentiality and the disclosure of clinical information. We also include discomfort in the 
potential risks. The instruments to be used in this study are brief and pragmatic and have been 
well-tolerated by older adults in other studies.  
 
Aripiprazole:  The most common side effect of aripiprazole (occur in 25% of people) is akathisia.  
 
Common side effects (occur in 1-25% of people) include restlessness, insomnia, fatigue, blurred 
vision, somnolence, tremor, constipation, sedation, and dizziness. There is a potential that 
aripiprazole may increase the risk of hyperglycemia (increased blood sugar), diabetes, abnormal 
cholesterol or increased triglycerides.  
 
We will monitor patients for these symptoms and require that they have a fasting blood glucose 
and lipid profile obtained prior to start of aripiprazole and as often as clinically necessary. 
 
Neuroleptic malignant syndrome (NMS) has been reported for all atypical antipsychotics, 
including aripiprazole (albeit rarely  -- only 14 cases have been reported, and the aripiprazole 
dose in these was higher than what is used in this study).  Patients who develop this syndrome 
may have high fevers, muscle rigidity, altered mental status, irregular pulse or blood pressure, 
rapid heart rate, excessive sweating, and heart arrhythmias.  
 


 
 
 
 
 
 
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Bupropion: The most frequent (occurs in more than 25% of people) side effects of bupropion 
include agitation, dry mouth, and headache. Common side effects (occurs in 1-25% of people) 
include excessive sweating, dizziness, tremor, constipation, nausea, decreased appetite, weight 
loss, rash, heart pounding, high blood pressure, unsteadiness when walking, confusion, anxiety, 
increased urination, and difficulty sleeping. Seizures may occur in patients receiving bupropion; 
however, at the dose range (max 300mg) and once-daily formulation used in this study, only 2 
cases of seizures have been reported, and our exclusion of individuals with seizure disorders will 
minimize this risk. There is a rare (<1%) risk of mania or hypomania associated with 
antidepressant treatment.  
 
Lithium: Likely side effects (occurs in more than 25% of people) of lithium carbonate include 
shakiness of the hands, drowsiness, headache, increased urination, increased thirst, and dry 
mouth. Common side effects (occurs in 1-25% of people) include weight gain, nausea, vomiting, 
and diarrhea. These are temporary side effects that will usually stop after the body adjusts over 
1-2 weeks. Lithium may commonly slow down the functioning of the thyroid hormone (hormone 
that controls growth and ability to burn energy) and, after years of treatment, it may affects 
(occurs in less than 1% of people) the functioning of the kidneys. In rare cases, lithium 
intoxication may occur with muscular weakness and lack of coordination, confusion, altered 
consciousness.  These risks are less likely at the lower serum levels used in this study. 
 
Nortriptyline: The most frequent side effects of nortriptyline include dry mouth and constipation 
(25-30% of elderly participants in our past studies). Other common (occurs in 1-25% of people) 
side effects include sedation, sweating, dizziness, rapid pulse, heart pounding, blurred vision, 
headache, and hypertension (high blood pressure). There is a rare risk of arrhythmia. There is a 
rare (<1%) risk of mania or hypomania associated with antidepressant treatment. 
 
Potential Risks from Drug Cross-Over: The intent of the study is to move patients onto 
augmentation and switch strategies; therefore, there is some chance that patients will be 
switched to a drug that is either ineffective or that the transition will cause side effects (e.g., 
discontinuation syndrome).  In cases of switch, tapering the previous drug while cross-titrating 
the new drug should minimize any discontinuation risks. 
 
One of our primary aims is to evaluate the safety of these antidepressant pharmacotherapy 
options.  We will closely monitor all participants for any problems (either in low effectiveness, or 
with side effects) and use this information as part of our “decision support” to inform 
participants and their clinicians about treatment steps such as increasing or decreasing the 
medication.  Thus, we believe that participants treated in the proposed protocol will actually be 
safer in than they would in usual care. The potential risks associated with participation 
(including the risk of medications and the risk of receiving an ineffective treatment) are typical 
for antidepressant treatment in clinical care, and these will be clearly described to all potential 
participants as part of the informed consent process.  
 
Suicide:  Suicide is not a risk of the study per se but is a risk of having major depression.  Patients 
who are identified as being acutely suicidal will be excluded from the study. Nevertheless, since 
the rate of completed suicide in the USA remains high (i.e., about twice the rate of homicide) 
and most Americans who commit suicide suffer from depression, all participants eligible to 
participate in this study are statistically at a relatively higher risk for suicide than the general 
population. Participation in the study does not create or increase the risk of completed suicide; 


 
 
 
 
 
 
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most experts believe that one of the most efficient ways to decrease suicidal risk in older 
depressed individuals is to treat their depression. Furthermore, all participants will be formally 
assessed frequently throughout the study. All sites have a 24/7/365 on-call system with geriatric 
psychiatry back-up. If the study personnel identify that a participant has become acutely 
suicidal, this participant will be referred to a mental health professional for further evaluation 
and treatment. This may lead to a clinical intervention that is lifesaving and may not have 
occurred had the participant not been participating in the study. We have included a Suicide 
Risk Management protocol to assess and reduce suicide risk in the manual of procedures as well 
as a Quick Suicide Safety Screening that may be used during phone pre-screening.  
 
Body Composition Measurement (Washington University site only):  
For participants with a pacemaker or a prosthesis that uses any other type of battery-powered 
or electrical power implant, there is a chance that the measurement of body composition could 
cause interference with the device. In order to protect from that risk, participants should not 
take part in the body composition measurement if they have a battery-powered or electrical 
implant. Participants with a history of abnormal heart rhythms will be reviewed by a medical 
doctor to make sure that the body composition measurement will not worsen their condition. 
1.i 
Potential Benefits 
Participants may or may not benefit from being in this study. Changing medication strategies 
may provide relief from symptoms of depression. Results from this study will provide doctors 
and patients with knowledge about the risks and benefits of antidepressant medications for 
older adults, so that they can make informed choices to manage depression. 
1.j 
Early Withdrawal of Subjects  
Participants will be asked to continue in the study for follow-up regardless of their and their 
physician’s adherence to the medication recommendations from the study team. Participants 
who discontinue study medications for tolerability reasons will be asked to complete the 
appropriate Acute Phase End Assessments for their phase of the study (see Section F5). 
Participants who end Step 1 treatment early due to tolerability issues will be invited to proceed 
to Step 2 after completing  Acute Phase End Assessments. 
 
Participants who choose to withdraw from the study early will be asked to complete the 
appropriate final visit for their phase of the study (Step 1 Week 10, Step 2 Week 20, or 
Continuation Month 12).  
 
Withdrawal from the study for any reason, including study completion, will be documented in 
the Electronic Case Report Form. 
Participants’ reasons for withdrawal will be summarily reviewed by each site’s IRB at Continuing 
Review and at DSMB meetings. 
E Medication Strategies and Decisional Support 
1.a 
Description of Decisional Support 
The pragmatic, comparative effectiveness design research participants continue to receive 
ongoing care, management, and prescriptions from their own physicians. The research team will 


 
 
 
 
 
 
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randomly assign participants to the well-established,evidence-based, standard of care 
medication strategy conditions. The research team will assess participants for symptoms and 
tolerability by phone every two weeks during acute treatment. The research team will make a 
recommendation for medication dosing that the treating physician can override or ignore. The 
Manual of Procedures for this study will describe how the study team will communicate the 
randomization assignment and any recommended changes to the treating physician. This 
decision support is greater than is seen in usual clinical care.  Patients highly recommended it, 
and a similar measurement-based approach has worked well in our prior studies in late-life 
depression. 
• 
Dose adjustment is done by the treating clinician with support from researchers:  
o If PHQ-9 score is 6 or greater, and side effects are absent or well-tolerated: 
increase the dose. 
o If PHQ-9 score is 5 or less, or side effects are enough that participant cannot 
tolerate a dose increase: keep dose the same. 
o If side effects are such that participant needs a dose decrease: decrease dose 
back to previous. 
o If side effects are intolerable such that participant needs a medication change: 
end step and move on to the next step (or remove from study if in step 2). 
• 
Clinicians and patients have flexibility: they may decide to exit Step 1 or Step 2 
treatment early (e.g., due to tolerability issues). Clinicians are allowed to coprescribe 
other medications as well.  The Manual of Procedures for this study will contain the 
communication plan for how the treating physician will communicate any changes or 
new medications back to the study team.  
• 
Decision support will also ask participants their study med adherence.  If participants 
have missed doses, brief counselling about adherence, including the importance of 
100% adherence, and solving barriers to adherence, will be provided. 
1.b 
Treatment Group Assignment 
In this step-wise design, participants will be randomized 1:1:1 to a Step 1 medication strategy: 
aripiprazole augmentation, bupropion augmentation, or bupropion switch. Participants whose 
depression has not remitted at the end of Step 1, will be randomized 1:1 to a Step 2 medication 
strategy: lithium augmentation or bupropion switch. All medications  are being used within their 
FDA-indicated population (adults), disease (major depressive episode), dosage, and route of 
administration (PO). 
1.c 
Aripiprazole Augmentation Prescribing Information 
Starting Dose 
2.5 mg 
Maximum Dose:  
15 mg 
Titration:  
Study team will recommend increases 
approximately every two weeks (5, 7.5, 10, 
15) based on symptoms and tolerability.  


 
 
 
 
 
 
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Potential Side Effects:  
-Akathisia, restlessness, insomnia, fatigue, 
blurred vision, somnolence, tremor, 
constipation, sedation, and dizziness.  
-May increase the risk of hyperglycemia, 
diabetes, abnormal cholesterol or increased 
triglycerides. 
-Neuroleptic malignant syndrome (NMS) has 
been reported for all atypical antipsychotics, 
including aripiprazole (albeit rarely).  Patients 
who develop this syndrome may have high 
fevers, muscle rigidity, altered mental status, 
irregular pulse or blood pressure, rapid heart 
rate, excessive sweating, and heart 
arrhythmias.  
 
1.d 
Bupropion Switch and Augmentation Prescribing Information 
Starting Dose 
150 mg 
Maximum Dose:  
450 mg 
Titration:  
Study team will recommend increase to 300 
after approximately two to four weeks based 
on symptoms and tolerability.  
Potential Side Effects:  
-Agitation, dry mouth, and headache.  
-Excessive sweating, dizziness, tremor, 
constipation, nausea, decreased appetite, 
weight loss, rash, heart pounding, high blood 
pressure, unsteadiness when walking, 
confusion, anxiety, increased urination, and 
difficulty sleeping.  
-Seizures may occur in 0.4% of patients 
receiving bupropion.  
- There is a rare (<1%) risk of mania or 
hypomania associated with antidepressant 
treatment. 
1.e 
Lithium Augmentation Prescribing Information 
Starting Dose:  
300 mg QHS 
Maximum Dose:  
1200* mg 
*Study team will adherence and accuracy of 
blood level with patient prior to increasing 
Lithium higher than 600mg  
Titration:  
Check blood level 1 week after initiating. 
adjust dosage linearly to target 0.6 mEq/L. 
Recheck level 1-2 weeks later. Adjust dose as 
needed to keep participant in 0.4-0.8 mEq/L 


 
 
 
 
 
 
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window. Levels outside of this range may be 
acceptable per PI discretion. 
Potential Side Effects:  
-Shakiness of the hands, drowsiness, 
headache, increased urination, increased 
thirst, and dry mouth, weight gain, nausea, 
vomiting, and diarrhea. These are temporary 
side effects that will usually stop after the 
body adjusts over 1-2 weeks.  
-Slowed thyroid functioning   
-After years of treatment, less than 1% of 
people it may have kidney functioning 
affected.  
-In rare cases, lithium intoxication may occur 
with muscular weakness and lack of 
coordination, confusion, altered 
consciousness. 
1.f 
Nortriptyline Switch Prescribing Information  
Starting Dose: 
25 mg 
Maximum Dose:  
150 mg 
Titration:  
Increase by 25 mg approximately every 5-7 
days until reaching target dose of 1mg per kg 
of body weight.  
Measure blood level 5-7 days after starting 
target dose. Adjust dose accordingly, 
targeting therapeutic range of 80-120 ng/ml. 
Levels outside of this range may be 
acceptable per PI discretion.  
Potential Side Effects:  
-Dry mouth and constipation, sedation, 
sweating, dizziness, rapid pulse, heart 
pounding, blurred vision, headache, and 
hypertension.  
-Rare risk of arrhythmia.  
-There is a rare (<1%) risk of mania or 
hypomania associated with antidepressant 
treatment. 
 
1.g 
Safety Labs and Monitoring 
Safety labs will be obtained from participants in accordance with accepted clinical practice 
guidelines described below. Participants and their providers will choose a local laboratory to 
conduct the testing according to their own preferences.    
i 
Recommended baseline labs 
Study team will recommend that each participant’s provider conduct the following laboratory 
testing if such tests have not been conducted approximately within the last 12 months.  


 
 
 
 
 
 
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• 
CBC  
• 
Na*  
• 
K*  
• 
Ca*  
• 
creatinine/BUN* 
• 
 liver function tests*  
• 
TSH 
• 
B12  
• 
ECG (to rule out QTc prolongation for Step 2 participants) 
*Note that Na, K, Ca, creatinine, BUN, & liver function tests may be obtained efficiently using a 
CMP. 
ii 
Recommended labs prior to aripiprazole augmentation 
The following laboratory testing is recommended prior to initiation of aripirazole augmnentation 
if such tests have not been conducted approximately within the last 12 months. 
• 
fasting glucose  
• 
fasting lipid panel 
iii 
Required labs prior to Lithium augmentation 
Participants who are randomized to Lithium augmentation in Step 2 must undergo the following 
laboratory testing prior to initiating lithium treatment. Values obtained at baseline or in the last 
12months are acceptable provided they are within the normal limits.  
• 
creatinine 
• 
Sodium (Na) 
• 
Potassium (K) 
• 
TSH 
iv 
Blood Level testing for Lithium Augmentation 
Blood level testing is necessary for appropriate titration of Lithium (See also Section E1.e.).  
Blood levels will be checked approximately 1 week after initiating, and approximately 1-2 weeks 
following a subsequent dose adjustment.  
v 
Required labs prior to Nortriptyline switch 
Participants who are randomized to Nortriptyline switch in Step 2 must undergo an EKG prior to 
initiating nortriptyline treatment. EKG’s conducted at baseline or in the last 12 months are 
acceptable. Participants whose EKG’s reveal the following contraindications to nortriptlyline will 
be advised not to initiate nortriptyline treatment.   If these conditions appear after starting 
notriptyline, participants will be advised to stop nortriptyline treatment.  
• 
QTc prolongation or wide QRS 
vi 
Blood Level testing for Nortriptyline switch 
Blood level testing is necessary for appropriate titration of Nortriptyline (See also Section E1.f). 
Blood levels will be checked approximately 5-7 days after starting target dose. 


 
 
 
 
 
 
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vii 
Recommended Follow-up Labs for Continuing on aripiprazole 
The following laboratory testing is recommended at Step 1 Week 10, Continuation Month 8, and 
every 6 months thereafter for participants who continue taking aripiprazole.  
• 
fasting glucose  
• 
fasting lipid panel 
Or, alternatively, the following may be collected if preferred by the participant’s provider: 
• 
Random blood glucose 
• 
Lipid panel 
• 
Hemoglobin A1C 
viii 
Recommended Follow-up Labs for Continuing on nortriptyline 
The following laboratory testing is recommended at Step 2 Week 10, Continuation Month 8 or 
12, and yearly thereafter for participants who continue taking nortriptyline.  
 
• 
EKG 
• 
Nortriptyline level 
ix 
Recommended Follow-up Labs for Continuing on lithium 
The following laboratory testing is recommended at Step 2 Week 10, Continuation Month 8, and 
yearly thereafter for participants who continue taking lithium.  
 
• 
Creatinine 
• 
Sodium (Na) 
• 
Potassium (K) 
• 
Calcium 
• 
BUN 
• 
TSH 
• 
Lithium level 
 
 


 
 
 
 
 
 
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• 
Transition from Step 1 to Step 2 
  
Step 2 
Nortriptyline Switch 
Lithium Augmentation 
  
Step 1 
Aripiprazole 
Augmentation  
(ADM + Aripiprazole) 
(1) D/C Aripiprazole 
(2) D/C or taper ADM* 
(3) Start Nortriptyline 
(1) D/C Aripiprazole 
(2) Start Lithium 
Bupropion 
(ADM + Bupropion) 
(1) D/C Bupropion 
(2) D/C or taper ADM  
(3) Start Nortriptyline 
(1) Patient and their clinician 
choose whether to D/C 
Bupropion or D/C or taper as 
ADM 
(2) Start Lithium 
Bupropion 
 
(1) D/C Bupropion 
(2) Start Nortriptyline 
(1) Start Lithium 
D/C: discontinue 
ADM: Antidepressant medication 
* Some ADM  can be D/C’ed (e.g., fluoxetine) and most needs to be tapered either rapidly (e.g., 
sertraline) or slowly (e.g., paroxetine or venlafaxine) 
1.h 
Preparation and Administration of Study Drug  
In this pragmatic, real-world study, physicians will prescribe these standard of care medications 
to study participants, who will procure them in the same manner they obtain their other 
prescriptions. This will include but is not limited to: using health insurance and prescription drug 
benefit programs, retail pharmacies, and clinic pharmacies.  
1.i 
Subject Compliance Monitoring  
Because this is a pragmatic study, all levels of adherence are allowed. Compliance with the 
study-recommended medication and dosing will be assessed at each decision support call using 
the Protocol Adherence Form. Reasons for non-compliance will be documented.  
 
1.j 
Prior and Concomitant Therapy  
Patients randomized to an augmentation strategy will continue their previous antidepressant 
monotherapy. Patients randomized to a switching strategy will be tapered off of their current 
antidepressant medication with guidance from the research doctors prior to initiating acute 
treatment. Research doctors will be available 24/7 via exchange in case of issues.  
 
Co-prescription of other medications by the clinician will be permitted, consistent with the 
pragmatic design.  We will recommend limiting benzodiazepine use to ≤2 mg of lorazepam or 
equivalent each 24 hours as needed. 
 
F Study Procedures  
 


 
 
 
 
 
 
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F1 
Screening for Eligibility 
Potential participants identified through each site’s IRB-approved recruitment plans will be 
screened for eligibility. Staff and PI’s at each site are responsible for verifying that participants at 
their site meet all eligibility criteria before being randomized to acute treatment. We anticipate 
differences between sites in which assessments may be obtained in pre-screening (pre- written 
consent) versus screening (post written consent).  Despite these potential differences, the 
following assessments must be conducted prior to randomization to ensure eligibility (see also 
Section D2 for Inclusion and Exclusion Criteria):  
• 
PHQ-9 
• 
MINI MDE Module 
• 
Screening questions for treatment resistance and medical exclusions  
• 
Short Blessed Test 
• 
ATHF 
• 
CIRS-G  
1.a 
Screening Log 
Each site will use a phone screening script and screening log as approved by their IRB. In the 
event that participants do not currently qualify for the study, but may qualify in the near future, 
research staff will ask the potential participant for permission to keep their contact information 
on file and follow up with them and/or their doctor at a later date.  
 


 
 
 
 
 
 
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F2 
Schedule of Measurements
 
OPTIMUM Revised 03/30/17 (Changes in Yellow)
Pre/ 
Screening Baseline
Done by local sites:
wk0
wk2
wk4
wk6
wk8
Step 
end*
wk0
wk2
wk4
wk6
wk8
Step 
end* month 4 month 8 month 12*
PHQ-9 
X
Sociodemographics   
X
Screening questions for treatment resistance and medical exclusions  
X
Short Blessed Test 
X
Consent  
X
Confirm Inclusion/Exclusion Criteria
X
ATHF 
X
CIRS-G
X
Expectations for Adherence
X
Height
X
Weight
X
X
X
X
X
X
Saliva sample for genetic testing
X
Extra Local MADRS if start of treatment >2weeks since Central MADRS
X
X
MINI Modules A&C (Depressive and Manic Episodes)
X
DAST-10 (if indicated by pre-screen)
X
AUDIT (if indicated by pre-screen)
X
X
X
X
X
X
X
X
X
X
X
Side Effect Assessment
X
X
X
X
X
X
X
X
X
X
X
X**
X**
X**
Adherence  
X
X
X
X
X
X
X
X
X
X
X**
X**
X**
Falls and fall-related injuries
X
X
X
X
X
X
X
X
X
X
X
X**
X**
X**
NIH Toolbox Cognition and Motor batteries -@done if participant able to be seen in person
X
X
X
X
Cognition battery including Attention/exec function (flanker and dimsional change card sort), 
Episodic memory (Picture seq memory), working memory (List sorting), Processing speed 
(pattern comparison). Baseline only: Language (Oral reading recognition) 
Motor battery including Dexterity (pegboard), Strength (using grip dynamometer), Balance, 
gait speed
Psychological well-being (NIH Toolbox self-report measure)
X
X
X
x
x
X
Physical Function (PROMIS)
X
X
X
X
X
X
Social Participation (PROMIS)
X
X
X
X
X
X
AE and SAE collection (collected anytime the event occurs)
Anxiety (PROMIS)
X
Done by central rater pool at WU by phone:
MADRS 
X
X
X
X
X
X
* Typically Week 10; or upon dropout
**Central rater pool will assess side effects, falls, and adherence  during continuation; local sites can do additional decision support calls "as needed" during this time
Step 2 (10 weeks)
Continuation (12 months)
Step 1 (10 weeks)


 
 
 
 
 
 
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F3 
Baseline 
• 
Participant signs (or returns signed) informed consent form; all elements of informed 
consent have been discussed and participants’ questions answered.  
• 
Local Research Team Assessments: (in person if possible; approximately 3 hours)  
o MINI MDD & Bipolar Modules 
o PHQ-9 (If more than 7 days has elapsed since the PHQ-9 was done at pre-screen.) 
o Suicide History, Risk & Protective Factors 
o Baseline Side Effects 
o Expectations for Adherence 
o Behavioral Therapy Assessment 
o Falls & Related Injuries (history) 
o Height and Weight (self-reported) 
o If indicated by pre-screen: DAST-10  
o If indicated by pre-screen: AUDIT 
o NIH Toolbox Psychological Well Being 
o PROMIS Physical Function 
o PROMIS Social Participation 
o PROMIS Anxiety 
o NIH Cognition and Motor Batteries (in person assessments - may be foregone for 
participants living in remote locations) 
o ATHF 
o CIRS-G 
o Medical Conditions and Medication List (study doctor to review before 
randomization) 
o Confirm inclusion/ exclusion criteria are met 
o Randomize participant; provide initial decision support per randomization status to 
participant’s doctor.  
• 
Central Rater  Assessments (by phone; approximately 30 minutes) 
o MADRS 
F4 
 Decision Support Calls 
• 
Every 2 Weeks During Acute Treatment: Step 1 Weeks 2, 4, 6, 8, 10* & Step 2 Weeks 2, 4, 6, 
8, 10* 
• 
Phone Call with Local Research Team (approximately 10 minutes) 
o PHQ-9 
o Spontaneous side effect report  & severity  
o Falls Assessment 
o Adherence 
o Counselling about adherence and management of side effects. 
o AE reports done as needed. 
o Decision support staff contact study MDs when needed (e.g. if confusion about 
whether to increase antidepressant dose). 
o Decision support staff contact participant’s clinical provider with recommendations; 
also will typically tell patient the recommendations. 


 
 
 
 
 
 
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F5 
Acute Phase End Assessments 
• 
Step 1 Week 10, Step 2 Week 10, or upon early withdrawal (if possible) 
o If there is a long delay between the Step 1 Week 10 assessment and the 
initiation of Step 2, the participant may be asked to repeat some or all of the 
Step 1 End assessments.  
• 
*In addition to Decision Support assessments, local research team will conduct the 
following assessments (in person if possible; approximately 1 ½ hour): 
o NIH Toolbox Psychological Well Being (may be conducted via phone or Redcap 
survey) 
o PROMIS Physical Function (may be conducted via phone or Redcap survey) 
o PROMIS Social Participation (may be conducted via phone or Redcap survey) 
o NIH Cognition and Motor Batteries (may be foregone for participants living in 
remote locations) 
o Weight (self-reported) 
• 
Central Rater Assessments (by phone; approximately 30 minutes. WU participants may 
do in person or by phone) 
o MADRS 
F6 
Continuation Assessments 
• 
Months 4, 8, and 12 after completing acute treatment in Step 1 and/or 2 as indicated.  
• 
Participants who relapse in Continuation after Step 1 may be invited to participate in 
Step 2; and then continuation subsequently.  
• 
Local Research Team Assessments (in person if possible; approximately 1½  hour):: 
o NIH Toolbox Psychological Well Being (may be conducted via phone or Redcap 
survey) 
o PROMIS Physical Function (may be conducted via phone or Redcap survey) 
o PROMIS Social Participation 
o Weight 
o NIH Cognition and Motor Batteries (Month 12 only; may be foregone for 
participants living in remote locations) 
• 
Central Rater Assessments (by phone; approximately 30 minutes) 
o MADRS 
o Falls & Related Injuries 
o Spontaneous side effects and severity(discuss with local sites if needed) 
o Adherence 
F7 
Genetic Testing 
The proposed study will be a robust clinical trial platform for translational research, and the 
primary aims of this study, regarding effectiveness and safety of augmentation and switch 
strategies, lend themselves to pharmacogenetic studies. For example, these methods can 
address whether efficacy or tolerability are associated with genetic variability at the medication 
target receptors (producing pharmacodynamic variability at serotonin, norepinephrine, and 
dopamine receptors). 
We will collect DNA from all participants at baseline. As the study approaches completion (or 
after completion), we will select specific hypotheses based on pharmacogenetics advances 
expected during the next 5 years.  Resources such as the Human Genome Center at Washington 


 
 
 
 
 
 
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University or the Centre for Pharmacogenetics in Toronto will provide cutting-edge testing and 
analytical methods leading to precision and patient-centered medicine.  
7.a 
Processing of DNA:  
Saliva samples will be obtained  approximately at baseline for each subject. Each site will ship 
samples (typically in batches) to WU for DNA isolation and long-term storage. 
F8 
Qualitative Interviews 
A subset of randomly selected participants will be asked to participate in a semi-structured 
qualitative phone interview to fulfill Aim 3. These interviews will be conducted by trained 
research staff at the University of Pittsburgh. Interviews will be audio recorded and transcribed. 
They will take approximately 60 minutes. Interviews will assess patient experiences with 
depression, treatment, and the study. Participants may choose whether or not to take part in 
the interview. Those that do take part in the interview may choose to skip any questions they 
would prefer not to answer. Participants who take part in the phone interview will be offered 
additional compensation for their time.  
G Safety and Adverse Events  
1.a 
Safety Monitoring 
Safety will be assessed by AE reporting, assessment of side effects, falls, and falls-related 
injuries, and blood level monitoring for participants taking lithium or nortriptyline. Suicide risk 
will also be assessed and managed.  
 
The primary mechanism for ensuring safety of participants, over and above their usual clinical 
care, is the bi-weekly Decision Support Calls. This will ensure we have contact with participants 
that is much more frequent and structured than routine clinical care.  
 
In addition, we will ask each participant and their physician to notify us of new symptoms, 
illnesses, or other problems.  
1.b 
Definitions of Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a drug under study.  An AE does not necessarily have a causal relationship 
with the study drug.   
The criteria for identifying AEs are: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug under study, whether 
or not considered related to the drug under study 
• 
Any new disease or exacerbation of an existing disease 
• 
Any deterioration in nonprotocol required measurements of a laboratory value or other 
clinical test (e.g., ECG or x ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present 
pretreatment (i.e., baseline) 


 
 
 
 
 
 
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• 
An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, whether prescribed in the 
protocol or not. 
• 
A laboratory result should be considered by the investigator to be an AE if it: 
o Results in the withdrawal of study drug 
o Results in withholding of study drug pending some investigational outcome 
o Results in an intervention, based on medical evaluation (e.g., potassium 
supplement for hypokalemia) 
o Results in any out of range laboratory value that in the investigator’s judgment 
fulfills the definitions of an AE with regard to the subject’s medical profile 
 
All AEs observed during the study will be reported on the e-E-CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the last visit.  Serious AEs will be collected for 30 days after the last 
dose or at the Follow up Visit, whichever comes later. 
 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported as an AE on the E-CRF. 
 
It is the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE.  Medical and scientific judgment should be exercised in 
deciding whether an isolated laboratory abnormality should be classified as an AE. 
 
1.c 
Classification of Events 
Every effort must be made by the investigator to categorize each AE according to its severity and 
its relationship to the study treatment. 
i 
Assessing Severity of Adverse Events  
AEs will be graded on a 3 point scale (i.e., mild, moderate, and severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows: 
 
• 
Mild: 
 
Discomfort noticed, but no disruption of normal daily activity 
• 
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity 
• 
Severe:  
Incapacitating, with inability to work or to perform normal daily activity 
ii 
Assessing Relationship of Adverse Events 
The causal relationship of the study drug to an AE will be assessed as related or unrelated, as 
follows: 
• 
Probably Related: 
There is a reasonable causal relationship between the study 
drug and the AE.  The event responds to dechallenge.  Seeing a recurrence of the AE 
with study medication rechallenge is not required. 
o Example: patient in step 1 is started on bupropion augmentation which is 
increased to 300mg.  They report severe insomnia that reduces their day-time 
functioning (moderate AE).  Bupropion is reduced to 150mg and insomnia is no 


 
 
 
 
 
 
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longer present.  Patient and clinician make a decision not to try higher dose of 
bupropion again. 
• 
Possibly Related: 
There is a reasonable causal relationship between the study 
drug and the AE.   Dechallenge is lacking or unclear. 
o Example: patient in step 2 is switched to nortriptyline.  They report constipation 
which is uncomfortable but does not disrupt their daily activity (mild AE).  They 
are willing to continue the medication at the current dose; no dose reduction is 
made. 
Unrelated: 
• 
Not Likely Related: 
There is a temporal relationship to study drug administration, 
but there is not a reasonable causal relationship between the study drug and the event. 
o Example: patient in step 2 is started on lithium augmentation.  One day after 
taking the first dose, they are driving and are hit by another car, necessitating 
hospitalization (severe and serious AE).  The accident is the fault of the other 
driver. 
iii 
Assessing Expectedness of Adverse Events  
An Unexpected Adverse Event is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information. 
iv 
Assessing Seriousness of Adverse Events 
An Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
• 
Results in death 
• 
Is life-threatening (i.e., the subject was at immediate risk of death from the 
adverse event as it occurred; this does not include an event that, had it occurred in a 
more severe form or was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect in the child of a subject who was exposed 
to the study drug 
 
Other important medical events that may not be immediately life threatening or result in death 
or hospitalization but, when based on appropriate medical judgment, may jeopardize the 
subject or may require intervention to prevent one of the outcomes in the definition of SAE 
listed above should also be considered SAEs.  Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in such situations. 
 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (i.e., there is no untoward medical occurrence) associated with the hospitalization: 
 
• 
Hospitalizations for respite care 
• 
Hospitalization planned before informed consent where the condition requiring 
the hospitalization has not changed post study drug administration 
• 
Hospitalization for routine maintenance of a device (e.g., battery replacement) 
that was in place before study entry 


 
 
 
 
 
 
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1.d 
Data Collection Procedures for Adverse Events 
Participating sites are responsible for gathering and documenting data pertinent to Adverse 
Events occurring at their sites and for collecting Adverse Event information from each treating 
physician, including but not limited to:  
• 
Description of the event, including onset and duration 
• 
Treatment assignment, dose recommendation, and adherence 
• 
Relevant medical and laboratory findings and reports 
• 
Correspondence regarding the event 
• 
Action taken in response to the event 
• 
Classification of the Adverse Event (Severity, Relationship, Expectedness, Seriousness) 
 
All Adverse Events observed during the study will be recorded on the e-CRF.  All Adverse Events 
will be collected from the time of informed consent through the last assessment.  
1.e 
Reporting Procedures for Adverse Events 
• 
Serious Adverse Events: Must be reported to Coordinating Site via e-mail as soon as 
possible, within 24 hours of the occurrence of the event or notification to the 
investigator or research team of the event.  
• 
All other Adverse Events: Report to Coordinating Site promptly via Redcap AE form, 
within 5 working days of the occurrence of the event or notification to the investigator 
or research team of the event.  
• 
Other Reporting Requirements: Adverse Events will be reported per relevant reporting 
criteria and timeframes to DSMB, IRB, FDA, and PCORI as required by each institutional 
policy.  
G2 Data Safety and Monitoring Board 
We will convene a Data Safety and Monitoring Board (DSMB) to examine safety data.  
The DSMB will:  
• 
Meet PCORI’s guidelines for Data Safety and Monitoring Plans.  
• 
Meet approximately every 6 months (more frequently – or perhaps less frequently, per 
DSMB determination) via teleconference. 
• 
Include a psychiatrist, a statistician, and a psychopharmacological expert. DSMB 
members will not be otherwise involved in the conduct of the study.  
• 
Have a charter approved by the DSMB. 
• 
Approve the study protocol, including the DSMP, informed consent template, reporting 
templates for data to be presented to the DSMB, and other materials as requested by 
the DSMB prior to the initiation of study enrollment.  
• 
Monitor the progress of subject recruitment and data acquisition, data confidentiality 
procedures, validity, and integrity of the data, the conduct of the protocol and 
deviations from the protocol, and any untoward or unexpected effects of protocol 
participation which might lather the brisk to benefit ratio of subject participation. 
• 
Take meeting minutes to summarize the topics discussed and list DSMB 
recommendations. Meeting minutes must be signed by the DSMB Chair.  
 
The Coordinating Site will:  
• 
Be responsible for preparing reports for the DSMB.  


 
 
 
 
 
 
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• 
Submit DSMB meeting minutes to PCORI with Interim Progress Reports as laid out in the 
Milestone Schedule.  
• 
Arrange for a summary of DSMB recommendations to be sent to each participating IRB 
at the time of Continuing Review (or earlier if required by local institutions or 
recommended by the DSMB) 
H Statistical Plan  
 
H1 Analysis Plan from OPTIMUM grant 
A priori, specific plans for data analysis correspond to major aims and will be directed by Co-I J. 
Philip Miller, professor of biostatistics at the coordinating site.  
We will follow the intention-to-treat (ITT) principle. In other words, patients who receive co-
prescribed medications stop randomized medication, or switch to a different medication will 
continue to be followed.  To confirm that ITT findings represent the “true” data on effectiveness, 
safety, and tolerability of management strategies, we will conduct a sensitivity analysis that will 
compare ITT to per-protocol findings.  
 
H1a (Psychological Well-Being): We will use a repeated measures 2*2*3 ANOVA with age (60-70, 
>70), time (baseline, end of Active phase of Step 1) by treatment group (3 levels). Specific time* 
treatment group contrasts will compare the changes across pairs of treatment groups. These tests 
will be conducted with a significance level of .05/3. We will include site as a strata in all analyses.63 
For those who proceed to Step 2, analogous repeated measures 2*2*2 ANOVA will be used with 
a significance level of .05 for the time*treatment group comparison.  
 
H1b (remission): Corresponding 2*3 (age by treatment group) generalized linear models with a 
logit link function will be computed for the dichotomous outcome of remission.  
 
In the continuation phase we will explore the long-term effectiveness of antidepressants: 
We will test for preservation of psychological well-being and other quality of life variables, and 
sustained resolution of depressive symptoms, by mixed effects repeated measures models. 
 
We will also test for sustained remission by measuring relapse in each arm. Relapse will be 
defined as meeting DSM 5 criteria for a major depressive episode, as determined by an 
Independent Evaluator who will confirm the diagnosis by conferring with a study investigator.  
We will carry out Cox models examining time to relapse and time to dropout, to examine for 
treatment inferiority (i.e., whether one antidepressant strategy produces poorer long-term 
outcomes).  Based on our prior research we don’t have an empirical basis to posit a specific arm 
as inferior.   Therefore, although these analyses are important to our stakeholders, we describe 
them as exploratory. 
 
We will also examine exploratory hypotheses, such as whether there are baseline covariates 
which will help to significantly enhance the prediction of response to treatments, e.g., gender, 
race, treatment site (primary care vs. specialty clinic), social support, co-treatments. This will 
enhance the precision medicine implications of the study. 
 


 
 
 
 
 
 
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H2: serious adverse events, falls, and fall-related injuries are the safety outcomes. Cox models 
examining time to event (with Anderson & Gill64 extensions for repeated events) will compare 
the treatment arms during both the acute phase and the continuation in terms of serious 
adverse events, falls, and fall-related injuries. 
We will also compute rates of side effects in each arm, as specifically recommended by patient 
stakeholders.  These data are not hypothesis-testing, but they support the patient-centered goal 
of allowing clinicians and patients to know what to expect in terms of side effects from 
treatment.  
H3: Moderator analyses (Heterogeneity of Treatment Effects). 
Confirmatory analysis (HT-1): Effectiveness and safety differences between treatment arms will 
be moderated by age. Specifically, with increasing age effectiveness differences between 
treatment arms will decrease, and safety differences between treatment arms will increase. 
 
Rationale: Our stakeholders demand that we move past the current “one size fits all” paradigm 
of antidepressant prescribing.  Precision treatment would greatly improve older adults’ quality of 
life. 
 
Data analysis plan for moderator testing:  We will include the treatment by age group (<70 vs 
>70) by time interaction to the linear models described above to test for both the benefits and 
risks for the treatment alternatives.  
 
We are well-powered for a confirmatory moderator analysis examining how age modulates the 
differences between treatment arms in comparative benefits and risks, because of our 
recruitment strategy aiming for equally-sized strata of ages (60-70 and >70).  Age will be treated 
as a categorical variable, comparing relative benefits and risks of antidepressants in those aged 
<70 to those aged >70.   
 
Here are some scenarios of the types of treatment modulators by age that we will be able to 
detect with a power > 85% (using SAS’s GLMPOWER): (1) If treatment arm A has superior 
effectiveness over arm B by 2.3 points more than what would be predicted based on age and 
treatment effects on Psychological Well-being for age 60-70 but no difference between arms for 
age >70; (2) If treatment arm A has a superior effectiveness over arm B in terms of 13% higher 
remission rate for age 60-70, but there is no difference between arms for age>70.   
Exploratory moderator analyses based on aging-related brain and systemic health variables: Our 
next step will be to analyze three aging-related variables –impairment in executive cognitive 
function, frailty, and medical complexity –   treated both as continuous variables and categorical 
variables, using the same models as with chronological age. 
 
Finally, we will examine the relative strength of these moderator variables by performing a 
combined moderator test.76,77  This exploratory analysis incorporates all of the age-related 
variables into models of each effectiveness and safety finding from hypothesis-testing.   
 
Notes regarding these Heterogeneity of Treatment Effect (moderator) analyses: We will perform 
statistical contrasts between treatment arms as a function of thee pre-specified moderator 
variables, and we will report all of these prespecified analyses, as well as post-hoc analyses, in 
published reports.  
 


 
 
 
 
 
 
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H2 Sample Size Determination and Power 
Power to detect Effect Size of the benefits and risks of antidepressants: As a conservative 
method for computing the detectable effect size we used simple t-tests for comparing change 
scores between groups. The research on minimally clinically relevant changes for Toolbox or 
PROMIS measures suggests that they are between 2-3 T-score points (personal communication, 
David Cella, PI of PROMIS Statistical Center). The table below shows that we have power > 0.80 
to detect changes smaller than minimally clinically relevant changes (e.g., we can detect changes 
< 2 T-score points).  For proportional outcomes we used the conservative approach of a simple 
comparison between proportions for remission. Difference of 10 percentage points around a 
remission rate of 40%1,2 are generally considered clinically meaningful.  Secondary tests of 
effectiveness will examine changes in other aspects of quality of life: physical function, social 
participation, and changes in depressive symptoms (i.e., MADRS scores). Detectable differences 
for these endpoints are also included in the power table below 
 
We have robust power for detecting clinically significant differences even if we only recruit 400 
in each group: we would still have a power of .9 to detect a difference of 2.0 in Step 1 on our 
primary outcome (Psychological Well-being) and a difference of 13 percentage points on our 
primary clinical outcome (remission rate). 
 
 
Step 1 Effect1 
Step 2 Effect2 
Power 
.8 
.9 
.8 
.9 
Toolbox Psychological Well-being3 
1.6 
1.9 
1.6 
1.8 
PROMIS Physical Function3 
1.6 
1.9 
1.6 
1.8 
PROMIS Social Participation3 
1.6 
1.9 
1.6 
1.8 
Remission4,5 
10.2% 
11.5% 
9.8% 
11.4% 
Serious Adverse Events6,5 
5.0% 
5.9% 
4.8% 
5.8% 
Falls7 
8.8% 
10.0% 
8.5% 
9.9% 
Fall-related injuries8 
5.0% 
5.9% 
4.8% 
5.8% 
MADRS9,5 
1.8 
2.1 
1.8 
2.1 
 
 
H3  Interim Analysis 
No interim analysis is planned.  
 
H4  Missing Outcome Data 
The primary analysis will be intent-to-treat; therefore, all data will be utilized and, as 
appropriate, a data imputation technique will be used for missing outcome data. 
 
I 
Data Handling and Record Keeping  
 
1 n=500 each for 3 groups, p=.05/3 
2 n=400 each for 2 groups, p=.05 
3 Points on T-score; sd=8 beginning and end of 
phase, r=.5 between scores 
4 Difference in proportion remitting, around a 40% 
remitting point 
5 Based on aripiprazole group in 1,2 
6 Increase in proportion experiencing an SAE, 
around a 4% baseline rate 
7 Increase in proportion experiencing a fall, 
around a 20% baseline rate 
8 Increase in proportion experiencing an injurious 
fall, around a 4% baseline rate 
9 Scale point change, sd=9 


 
 
 
 
 
 
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I1 
Confidentiality and Security 
Participant confidentiality and data security will be facilitated with the following tools and 
processes:  
The primary data collection and management tool for this study will be REDCap (Research 
Electronic Data Capture) databases created and maintained by the Data Management team at 
the Coordinating Site.  
REDCap’s features support best practices for data confidentiality and security. REDCap 
(Research Electronic Data Capture) is a secure, web-based application designed to support data 
capture for research studies, providing: • user authentication and role-based security • 
collaborative access to data across academic departments and institutions • intuitive electronic 
case report forms (CRFs) • real-time data validation, integrity checks and other mechanisms for 
ensuring data quality (e.g. double-data entry options) • data attribution and audit capabilities • 
protocol document storage and sharing • central data storage and backups • data export 
functions for common statistical packages • data import functions to facilitate bulk import of 
data from other systems. Data that is imported and/or exported will be kept on a secure 
department network. 
Secure data collection in sites with inconsistent internet connections will be facilitated by using 
the REDCap Mobile App on password-protected tablet devices. The REDCap Mobile App allows 
for secure data transmission (using SSL/HTTPS), secure data storage, secure user authentication, 
and remote lockout capability. Details of the security features for the REDCap Mobile App can 
be located here: https://projectredcap.org/security.pdf 
Washington University Security Architecture: To ensure patient privacy and compliance with 
HIPAA regulations, data is stored behind the university approved, hardware firewalled network. 
Access is context specific to each user and individual collection protocols such that it supports 
both the regulatory guidelines (e.g. HIPAA and patient privacy) and proprietary (intellectual 
property) concerns. 
Hard copy records will be stored in a locked drawer/cabinet in a locked office/suite. The study 
team will treat all subject/patient data used and disclosed in connection with this study in 
accordance with all applicable privacy laws, rules and regulations, including all applicable 
provisions of HIPAA and its implementing regulations. Study records sent to the sponsor will not 
include participant's name to protect patient confidentiality. 
I2 
Training  
The Coordinating Site will ensure that the PI and Study Coordinator at each site have access to 
appropriate training materials in study procedures, assessments, and recordkeeping. The PI 
and/or Study Coordinator at each site are responsible for ensuring and documenting that all 
research team members at their respective sites are trained and supervised appropriately prior 
to conducting any study procedures.  
 
Training of each treating physician will be the responsibility of each site working with the 
treating physician’s patient and will be done according to the training plan outlined in the 
manual of procedures.  


 
 
 
 
 
 
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I3 
Case Report Forms and Source Documents 
This study will utilize REDCap-based electronic Case Report Forms (e-CRF’s) for data capture and 
storage. Source documents, including laboratory values, medical records and physician 
communications will be maintained at each site to verify adherence to protocol, 
inclusion/exclusion criteria, and data accuracy.  
I4 
Records Retention 
 
The investigator will maintain records in accordance with state and federal government 
regulations standards of Good Clinical Practice, and applicable institutional research policies and 
procedures. All electronic and hard copy research records and imaging data are stored for at 
least seven years beyond the close of the study. 
 
J Study Monitoring, Auditing, and Inspecting  
 
J1 
Study Monitoring Plan  
In order to fulfill our ethical, legal, and scientific obligations to conducting this study in a 
detailed and orderly manner, the Coordinating site may visit the other participating sites during 
the study, as well as communicate frequently via telephone and written communications.  
J2 
Auditing and Inspecting  
The Coordinating site may conduct study site audits.  Audits would typically include, but are not 
be limited to, presence of required documents, the informed consent process, and review of 
research records.  Most auditing will be done remotely via review of REDCap records. 
 
Regulatory authorities may inspect the investigator during or after the study.  The investigator 
will cooperate with such inspections and will contact the Coordinating site immediately if such 
an inspection occurs. 
K Study Administration 
 
K1 Organization and Participating Centers 
This is a collaborative, multi-site study with five academic sites: Washington University 
(Coordinating Site), University of Pittsburgh, University of Toronto, University of California Los 
Angeles, and Columbia University. 
 
Ongoing communication and coordination between sites will be facilitated by regular 
conference calls attended by PI’s and appropriate personnel. Records of these conference calls 
will be maintained by the Coordinating Site.  
 


 
 
 
 
 
 
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A Manual of Procedures will be provided to sites and updated as needed to ensure consistent 
conduct of the trial across sites.  
K2 Funding Source  
This project is funded by the Patient Centered Outcomes Research Institute (PCORI).  
K3 Participant Compensation 
Compensation plans for participants will be determined by each study site and approved by 
their respective IRB’s. Compensation plans must adhere to the following guidelines:  
• 
All participants should receive equal compensation for equivalent time and effort..  
• 
The compensation amount should be reasonable for the time and effort of the 
participant. 
• 
Compensation may not be held until completion of all study activities. If there are 
multiple visits or study procedures compensation must be pro-rated for the completion 
of each visit or part of the study. 
• 
Information about compensation must be included in the Consent Document. 
K4  Milestone Schedule 
The overall timetable for the study will follow the milestone schedule agreed upon in the PCORI 
contract. Any barriers or delays to completing milestones per the schedule should be discussed 
with the Coordinating Site, who will bring significant issues to the attention of the PCRI program 
officer as needed.  
 
  
Milestone Name 
Description 
Projected 
Completion 
Date 
A 
Effective Date 
- 
10/1/2016 
B1 
IRB Approval Obtained 
Obtain local IRB approval 
1/1/2017 
B2 
Formation of Stakeholder 
Advisory Board (SAB) 
Finalize the composition of the SAB to include members 
recommended by PCORI. Document the members of the SAB 
including the organization, title, and stakeholder group they 
represent. Deliverable: Complete SAB roster (including the 
organization, title, and stakeholder group they represent).  
1/1/2017 
B3 
In-person Kickoff 
Meeting. Initiate 
implementation and start 
recruitment 
Study startup meeting. Launch study and begin recruitment in some 
practices once approved by DSMB. Kickoff meeting to include 
investigators, research coordinators, and other key partners. Train 
staff and clinicians from each site on the study protocol. 
1/12/17-
1/13/17 
B4 
Stakeholder Advisory 
Board Kickoff Meeting  
Kick off meeting for the Stakeholder Advisory Board. Deliverable: 
Meeting minutes and/or summary of the meeting discussion should 
document the input of the patient/stakeholder members and should 
be submitted with the Interim Progress Report  
1/12/17-
1/13/17 
B5 
Protocol Complete 
Complete the final study protocol and submit to 
fundedpfa@pcori.org and cc the Program Officer and Associate 
2/1/2017 
B6 
Finalize study 
Finalize assessments, materials, study protocol, and statistical 
analysis plan in collaboration with SAB. Submit materials as 
attachment in next Interim Progress Report. Design database and 
implement data entry process. 
2/1/2017 


 
 
 
 
 
 
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B7 
Select and register project 
at appropriate site for the 
study design 
(Clinicaltrials.gov, RoPR, 
or other as approved by 
PCORI before study start 
date) 
Study Identification Number and the Primary Research Completion 
Date must be sent to PCORI.  
3/1/2017 
B8 
IRB approval 
Approval by all sites' IRBs 
4/1/2017 
B9 
DSMB meeting 
Minutes from 1st DSMB meeting. Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
4/1/2017 
B 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
4/1/2017 
C1 
Complete implementation 
Launch study and begin recruitment in all practices. Recruit and 
randomize 125 participants each quarter for 12 quarters (total 
randomized N=1,500; approximately 42 participants recruited per 
month).  
7/1/2017 
C2 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
7/1/2017 
C3 
DSMB meeting 
Minutes from 2nd DSMB meeting. Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
10/1/2017 
C 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
10/1/2017 
D1 
Complete 25% of 
recruitment 
Recruit 375 participants in total (approximately 42 participants 
recruited per month). Document and send to PCORI Program Officer 
and Associate. 
1/1/2018 
D2 
DSMB meeting 
Minutes from 3rd DSMB meeting. Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
4/1/2018 
D3 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
4/1/2018 
D 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
4/1/2018 
E1 
Start follow-up data 
collection 
250  participants finish 4-month acute phase and begin 12-month 
continuation phase (based on 45% remission rate and 8% attrition in 
each of steps 1 and 2).  
7/1/2018 
E2 
Complete 50% of 
recruitment 
Recruit 750 participants in total (approximately 42 participants 
recruited per month).  Document and send to PCORI Program Officer 
and Associate. 
10/1/2018 


 
 
 
 
 
 
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E3 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
10/1/2018 
E4 
Begin semi-structured 
interviews 
Begin semi-structured interviews (goal N=150) 
10/1/2018 
E5 
DSMB meeting 
Minutes from 4th DSMB meeting.  Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
10/1/2018 
E 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
10/1/2018 
F1 
DSMB meeting 
Minutes from 5th DSMB meeting.  Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
4/1/2019 
F2 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
4/1/2019 
F 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
4/1/2019 
G1 
Complete 25% of follow-
up data collection 
225 participants finish 4-month acute phase and begin 12-month 
continuation phase (estimate of 12-month completers = 225, based 
on 45% of participants remitting at each of steps 1 and 2, 8% of 
participants dropping out during each of steps 1 and 2, and additional 
10% dropping out during the 1-year continuation phase). The Interim 
Progress Report should include summary of data collected to date for 
review of patient accrual, patient characteristics and data quality. 
7/1/2019 
G2 
Complete 75% of 
recruitment 
Recruit 1125 participants in total (approximately 42 participants 
recruited per month). Document and send to PCORI Program Officer 
and Associate. 
7/1/2019 
G3 
Complete semi-structured 
interviews 
Complete semi-structured interviews (goal N=150) 
7/1/2019 
G4 
DSMB meeting 
Minutes from 6th DSMB meeting.  Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
10/1/2019 
G5 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. During this meeting, findings 
from semi-structured interviews analyzed and provided to SAB. 
Deliverables: Meeting minutes and/or summary of the meeting 
discussion should document the input of the patient/stakeholder 
members and should be submitted with the Interim Progress Report  
10/1/2019 
G 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
10/1/2019 
H1 
Complete recruitment 
Recruit 1500 participants total (approximately 42 participants 
recruited per month). Document and send to PCORI Program Officer 
and Associate. 
1/1/2020 


 
 
 
 
 
 
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H2 
Complete 50% of follow-
up data collection 
450 participants finish 4-month acute phase and 12-month 
continuation phase (estimate of 12-month completers = 450, based 
on 45% of participants remitting at each of steps 1 and 2, 8% of 
participants dropping out during each of steps 1 and 2, and additional 
10% dropping out during the 1-year continuation phase). The Interim 
Progress Report should include summary of data collected to date for 
review of patient accrual, patient characteristics and data quality. 
4/1/2020 
H3 
DSMB meeting 
Minutes from 7th DSMB meeting.  Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
4/1/2020 
H4 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
4/1/2020 
H 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
4/1/2020 
I1 
Complete acute phase 
All participants finish 4-month acute phase 
10/1/2020 
I2 
DSMB meeting 
Minutes from 8th DSMB meeting.  Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
10/1/2020 
I3 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
10/1/2020 
I 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
10/1/2020 
J1 
Complete 75% of follow-
up data collection 
675 participants finish 4-month acute phase and 12-month 
continuation phase (estimate of 12-month completers = 675, based 
on 45% of participants remitting at each of steps 1 and 2, 8% of 
participants dropping out during each of steps 1 and 2, and additional 
10% dropping out during the 1-year continuation phase). The Interim 
Progress Report should include summary of data collected to date for 
review of patient accrual, patient characteristics and data quality. 
1/1/2021 
J2 
DSMB meeting 
Minutes from 9th DSMB meeting. Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
4/1/2021 
J3 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
4/1/2021 
J 
Report Submission  
Submit Progress Report, Using Interim Progress Report Template 
4/1/2021 


 
 
 
 
 
 
______________________________________________________________________________________ 
OPTIMUM Protocol Version 3.0 2019-03-04 Final Version 
37
K1 
Complete follow-up data 
collection 
All (n=900) participants finish 12-month continuation phase (estimate 
based on 45% of participants remitting at each of steps 1 and 2, 8% of 
participants dropping out during each of steps 1 and 2, and additional 
10% dropping out during the 1-year continuation phase). The Interim 
Progress Report should include summary of data collected to date for 
review of patient accrual, patient characteristics and data quality. 
9/1/2021 
K2 
Primary Research 
Completion Date 
A Primary Research Completion Date must be provided when 
registering the study in Clinicaltrials.gov. For studies that are not 
clinical trials or observational studies registered on ClinicalTrials.gov, 
the Awardee and PCORI shall agree on a primary completion date as a 
milestone that precedes the agreed-upon date to submit a Draft Final 
Research Report.  
9/1/2021 
K3 
Initiate data analyses 
Clean database and set up analytic files 
9/1/2021 
K4 
Complete data analyses 
"Break blind" and run analytic files 
9/1/2021 
K5 
Final DSMB meeting 
Minutes from 10th DSMB meeting.  Review and discuss subject data 
collected to date. In the interim progress report, include any 
significant data & safety monitoring issues that occurred in the 
reporting period.  If there are any serious unanticipated problems 
(e.g., serious adverse event, serious safety issue, or other serious 
problem) relating to the research study, awardee institutions must 
notify PCORI promptly, but no later than 10 days after. 
9/30/2021 
K6 
Stakeholder Advisory 
Board Meeting  
Stakeholder Advisory Board Meeting. Deliverables: Meeting minutes 
and/or summary of the meeting discussion should document the 
input of the patient/stakeholder members and should be submitted 
with the Interim Progress Report  
9/30/2021 
K7 
Dissemination and 
implementation 
Prepare findings for D&I 
9/30/2021 
K8 
Data sharing 
Begin preparation of de-identified final dataset for replication and 
data-sharing. Prepare results for publication in peer-reviewed 
journals and submission of results to clinicaltrials.gov 
9/30/2021 
K 
Final Progress Report 
Submit Final Progress Report, Using Final Progress Report Template 
9/30/2021 
L 
Research Project Period 
End Date 
  
9/30/2021 
M 
Results submitted to 
ClinicalTrials.gov or 
appropriate database. 
Awardee ensures results are submitted to ClinicalTrials.gov or 
appropriate database. For ClinicalTrials.gov, the generated tables are 
a required section in the Draft Final Research Report. 
12/1/2021 
N 
Draft Final Research 
Report Submission 
Submit Draft Final Research Report according to instructions found 
at http://www.pcori.org/awardee-resourcesx 
 
*Draft Final Research Report must be submitted no later than 30 
days from when results are posted to clinicaltrials.gov or other 
applicable website. 
1/1/2022 
O 
Final Research Report 
Upon receipt of written summary, and as applicable, PI will make 
revisions and submit revised Draft Final Research Report for 
acceptance as directed by PCORI.                                                                    
See Description 
P 
Approval / sign off of the 
Lay Abstract 
Sign off must be no later than 90 days beyond the date PCORI 
accepts the final report 
See Description 
Q 
Contract Term Date 
- 
5/31/2022 
R 
Final Expenditure Report 
Submit Final Expenditure Report (See Contract for Instructions) 
90 days from 
Contract Term 
Date 
S 
Notification of 
Publication Acceptance 
See Contract for Instructions 
Within 30 Days 
of Acceptance 
 


 
 
 
 
 
 
______________________________________________________________________________________ 
OPTIMUM Protocol Version 3.0 2019-03-04 Final Version 
38
K5 History of Changes to Study Protocol 
Version number 
and date 
Description of changes 
V2.3: 1/19/17 
Originally approved version of the study protocol.  
V2.4: 3/31/17 
1) Participants who do not qualify for Step 1 due to a contraindication to 
a Step 1 medication, but otherwise meet eligibility criteria, may 
participate and proceed directly to Step 2. 
2) Increase in maximum dose of bupropion from 300 mg to 450 mg to 
be consistent with the FDA approved maximum dose. 
3) Additional baseline assessments. 
4) Assessment of falls at every decision support. 
5) Collection of self-reported weight at baseline, acute phase end, and 
continuation time points. 
6) All participants followed in Continuation, not just remitters. 
7) NIH Cognitive and Motor Batteries assessed at Continuation Month 
12 but not at 4 or 8.  
8) DNA samples collected via saliva sample instead of blood.  
V2.5: 6/26/17 
1) Changes to eligibility criteria. Seizure disorder and Parkinson’s disease 
are exclusions for Step 1 but not for Step 2.  
2) Clarification to Step 2 exclusions indicating that participants may still 
be considered for Step 1 participation even if ineligible for Step 2.  
3) Clarification to lithium augmentation prescribing information that 
levels outside of 0.4 – 0.8 mEq/L window may still be acceptable per 
PI discretion. 
4) Clarification to nortriptyline switch prescribing information that levels 
outside 80-120 ng/ml window may still be acceptable per PI 
discretion. 
5) Removed fasting glucose from (generally) recommended baseline 
labs and added new section for recommended labs prior to 
aripiprazole augmentation including fasting glucose and fasting lipid 
panel.  
V2.6: 10/2/17 
1) Clarified Step 2 exclusion of Acute or chronic renal insufficiency with 
the addition of the following language: as indicated by creatinine 
clearance below 30 mL/min; suspected if creatinine above 1.5 mg/dL; 
per PI and/or clinician discretion. 
V2.7: 10/31/17 
1) Updates to assessment procedures:  
a. If there is a long delay between the Step 1 Week 10 
assessment and the initiation of Step 2, the participant may 
be asked to repeat some or all of the Step 1 End assessments.  
b. Participants who relapse in Continuation after Step 1 may be 
invited to participate in Step 2; and then continuation 
subsequently.  
2) Addition of qualitative interviews for randomly selected subset of 
participants to fulfill Aim 3.  
V2.8: 12/5/17 
1) Narrowed Step 2 exclusion criteria to identify and exclude patients 
with active ischemic heart disease while including patients with 
history but no symptoms for the past 2 years.  


 
 
 
 
 
 
______________________________________________________________________________________ 
OPTIMUM Protocol Version 3.0 2019-03-04 Final Version 
39
V2.9: 3/26/18 
1) Addition of body composition measurement at WU. 
V3.0: 3/4/19 
1) All participants are to begin the study in Step 1. Following their 
participation in Step 1, they will be considered for Step 2 (as in the 
current protocol). However they will not be invited to participate in 
Step 2 without first participating in Step 1. 
a) Accordingly, because direct entry into Step 2 is disallowed, the Step 
1 exclusions of Seizure disorder and Parkinson’s Disease are 
exclusions to the study as a whole. 
2) Increasing the inclusion criteria for the PHQ-9 from 6 to 10 to include 
participants with higher degree of symptom severity. 
3) Recommended schedule for standard of care follow-up labs is being 
standardized in the protocol. 
4) Removal of body composition measurement. This was exploratory 
and is not safety related. 
 
 
 
 


 
 
 
 
 
 
______________________________________________________________________________________ 
OPTIMUM Protocol Version 3.0 2019-03-04 Final Version 
40
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