Conditions: PTSD
Keywords: ketamine Written Exposure Therapy PTSD intervention treatment posttraumatic stress disorder
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
The current pilot project will evaluate the efficacy of adding Written Exposure Therapy (WET) to a course of repeated IV ketamine infusions in improving PTSD symptoms and maintaining symptom improvement in patients with chronic PTSD. WET is a brief, 5-session evidence-based written trauma-focused therapy without in between-session assignments, with demonstrated efficacy and low dropout rates in patients with PTSD. WET will be administered to all eligible participants; the first WET sessions will be interleaved with the last two ketamine infusions to take advantage of a window of increased neuroplasticity potentially induced by repeated ketamine infusions. WET will be administered on different days as the ketamine infusions.

Detailed description:
Current treatments for PTSD do not work for a significant proportion of individuals with PTSD, or work only partially, leaving persistent and disabling residual symptoms. The research team has led the development of ketamine for the treatment of chronic PTSD. After the initial, proof-of-concept randomized controlled trial (RCT) of a single ketamine infusion in individuals with chronic PTSD showed promising results, the study team recently completed the first RCT of repeated intravenous ketamine infusions where individuals with chronic PTSD received a course of six ketamine infusions (vs. active placebo midazolam infusions) and demonstrated a rapid and robust improvement in PTSD symptoms. Median time to loss of response, however, occurred a few weeks following the course of infusions, making it imperative to investigate novel approaches aimed at preventing symptom relapse following ketamine treatment. The study team proposes a proof-of-concept, open-label pilot study to evaluate the efficacy of adding an evidence-based, brief and scalable trauma-focused psychotherapy, Written Exposure Therapy (WET), to a course of ketamine infusions in improving PTSD symptoms and maintaining symptom improvement, in participants with chronic PTSD. To accomplish this aim, the study team will enroll individuals who meet DSM-5 criteria for chronic PTSD. Eligible patients will receive a total of six ketamine infusions and will participate in WET (a total of five sessions). The primary outcome will be change in PTSD symptom severity from baseline to 12 weeks from the start of WET, assessed with the Clinician-Administered PTSD Scale for DSM-5. Additionally, all participants will be assessed weekly until 12 weeks following the start of WET. Thereafter, participants who remain improved will be assessed monthly for up to 24 weeks. The study team will also evaluate whether extinction learning ability -assessed with a computerized extinction learning task- predicts maintenance of ketamine response over time, and will explore potential sociodemographic and clinical predictors of treatment response. If demonstrated to have preliminary efficacy, this novel combined treatment may represent a promising intervention for individuals with chronic PTSD, deserving further study.

Arms:
arm 1: Intravenous Ketamine 0.5 mg/kg and Written Exposure Therapy

Interventions: intervention 1: Ketamine intervention 2: Written Exposure Therapy
Intervention descriptions: intervention 1: Repeated intravenous Ketamine infusions. intervention 2: WET is a brief, 5-session evidence-based written trauma-focused therapy

Protocol document:
Prot_SAP_000.pdf: 
Adding Trauma-focused Psychotherapy To Ketamine Treatment For Chronic PTSD: A 
Pilot Study
NCT04889664
Principal Investigator: Adriana Feder, MD
Document Date: 23 August 2023


 
Adding Trauma-focused Psychotherapy To Ketamine 
Treatment For Chronic PTSD: A Pilot Study
Protocol Number: STUDY-21-00167
National Clinical Trial (NCT) Identified Number:  NCT04889664
Principal Investigator: Adriana Feder, MD
IND Sponsor: Icahn School of Medicine at Mount Sinai (ISMMS)
Funded by: ISMMS
Version Number:  v.2.0
17 June 2023
Summary of Changes from Previous Version:
Affected 
Section(s)
Summary of Revisions Made
Rationale
1.1, 1.2, 1.3, 
3, 4.1, 4.4, 
5.5, 6.1.2, 
6.3, 8.1, 8.2, 
8.3.5, 9.1, 
9.3, 9.4.3
All eligible participants will receive six (6) 
infusions of ketamine and five (5) WET 
sessions, regardless of responder status, and 
will be assessed weekly for 12 weeks 
following the start of WET. After 12 weeks, 
participants who demonstrate ≥ 30% 
improvement at the 12-week assessment will 
be assessed monthly for up to 24 weeks 
following the start of WET or until loss of 
response.
Based on our recent meeting with a panel of 
experts in the field, and following their 
recommendation, we would like to offer all 
6 infusions and 5 WET sessions in order to 
capture more gradual effects of WET and the 
potential effects of Ketamine + WET in both 
responders and non-responders to 
ketamine.
The primary aim of the study remains 
unchanged.
1.3, 8.1, 11
Adding Hood Mysticism Scale and 
Psychological Insight Questionnaires to 
Infusions 1 and 2.
We would like to add these self-report scales 
to the first two infusions to assess 
participant experiences during the ketamine 
infusions.
Effective Date: 8/23/2023
End Date:4/3/2024


 
Table of Contents
STATEMENT OF COMPLIANCE.......................................................................................................................................1
1
PROTOCOL SUMMARY......................................................................................................................................1
1.1
Synopsis..................................................................................................................................................1
1.2
Schema...................................................................................................................................................4
1.3
Schedule of Activities (SoA)....................................................................................................................4
2
INTRODUCTION.................................................................................................................................................6
2.1
Study Rationale ......................................................................................................................................6
2.2
Background ............................................................................................................................................7
2.3
Risk/Benefit Assessment......................................................................................................................11
2.3.1
Known Potential Risks ......................................................................................................11
2.3.2
Known Potential Benefits .................................................................................................12
2.3.3
Assessment of Potential Risks and Benefits .....................................................................12
3
OBJECTIVES AND ENDPOINTS .........................................................................................................................13
4
STUDY DESIGN ................................................................................................................................................15
4.1
Overall Design ......................................................................................................................................15
4.2
Scientific Rationale for Study Design....................................................................................................18
4.3
Justification for Dose............................................................................................................................21
4.4
End of Study Definition ........................................................................................................................21
5
STUDY POPULATION .......................................................................................................................................21
5.1
Inclusion Criteria ..................................................................................................................................21
5.2
Exclusion Criteria..................................................................................................................................22
5.3
Lifestyle Considerations .......................................................................................................................23
5.4
Screen Failures .....................................................................................................................................23
5.5
Strategies for Recruitment and Retention ...........................................................................................24
6
STUDY INTERVENTION ....................................................................................................................................26
6.1
Study Intervention(s) Administration...................................................................................................26
6.1.1
Study Intervention Description.........................................................................................26
6.1.2
Dosing and Administration ...............................................................................................28
6.2
Preparation/Handling/Storage/Accountability ....................................................................................31
6.2.1
Acquisition and accountability..........................................................................................31
6.2.2
Formulation, Appearance, Packaging, and Labeling.........................................................31
6.2.3
Product Storage and Stability ...........................................................................................31
6.2.4
Preparation.......................................................................................................................31
6.3
Measures to Minimize Bias: Randomization and Blinding ...................................................................31
6.4
Study Intervention Compliance............................................................................................................31
6.5
Concomitant Therapy...........................................................................................................................31
6.5.1
Rescue Medicine...............................................................................................................32
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL .............32
7.1
Discontinuation of Study Intervention.................................................................................................32
7.2
Participant Discontinuation/Withdrawal from the Study ....................................................................32
7.3
Lost to Follow-Up .................................................................................................................................33
8
STUDY ASSESSMENTS AND PROCEDURES.......................................................................................................33
8.1
Efficacy Assessments............................................................................................................................33
8.2
Safety and Other Assessments.............................................................................................................39
8.3
Adverse Events and Serious Adverse Events........................................................................................39
8.3.1
Definition of Adverse Events (AE).....................................................................................39
Effective Date: 8/23/2023
End Date:4/3/2024


 
8.3.2
Definition of Serious Adverse Events (SAE) ......................................................................39
8.3.3
Classification of an Adverse Event....................................................................................40
8.3.4
Time Period and Frequency for Event Assessment and Follow-Up..................................41
8.3.5
Adverse Event Reporting ..................................................................................................41
8.3.6
Serious Adverse Event Reporting .....................................................................................42
8.3.7
Reporting Events to Participants ......................................................................................42
8.3.8
Events of Special Interest .................................................................................................42
8.3.9
Reporting of Pregnancy ....................................................................................................42
8.4
Unanticipated Problems.......................................................................................................................43
8.4.1
Definition of Unanticipated Problems (UP) ......................................................................43
8.4.2
Unanticipated Problem Reporting....................................................................................43
8.4.3
Reporting Unanticipated Problems to Participants..........................................................43
9
STATISTICAL CONSIDERATIONS.......................................................................................................................44
9.1
Statistical Hypotheses ..........................................................................................................................44
9.2
Sample Size Determination..................................................................................................................45
9.3
Populations for Analyses......................................................................................................................46
9.4
Statistical Analyses...............................................................................................................................46
9.4.1
General Approach.............................................................................................................46
9.4.2
Analysis of the Primary Efficacy Endpoint(s) ....................................................................47
9.4.3
Analysis of the Secondary Endpoint(s) .............................................................................47
9.4.4
Safety Analyses.................................................................................................................48
9.4.5
Baseline Descriptive Statistics ..........................................................................................48
9.4.6
Planned Interim Analyses .................................................................................................48
9.4.7
Sub-Group Analyses..........................................................................................................48
9.4.8
Tabulation of Individual participant Data.........................................................................48
9.4.9
Exploratory Analyses ........................................................................................................48
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......................................................49
10.1
Regulatory, Ethical, and Study Oversight Considerations ....................................................................49
10.1.1
Informed Consent Process................................................................................................49
10.1.2
Study Discontinuation and Closure...................................................................................49
10.1.3
Confidentiality and Privacy...............................................................................................50
10.1.4
Future Use of Stored Specimens and Data.......................................................................51
10.1.5
Key Roles and Study Governance .....................................................................................51
10.1.6
Safety Oversight................................................................................................................51
10.1.7
Clinical Monitoring ...........................................................................................................53
10.1.8
Quality Assurance and Quality Control.............................................................................54
10.1.9
Data Handling and Record Keeping ..................................................................................54
10.1.10
Protocol Deviations ..........................................................................................................55
10.1.11
Publication and Data Sharing Policy .................................................................................55
10.1.12
Conflict of Interest Policy..................................................................................................55
10.2
Additional Considerations....................................................................................................................56
10.3
Abbreviations .......................................................................................................................................56
10.4
Protocol Amendment History ..............................................................................................................58
11
REFERENCES....................................................................................................................................................59
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
1
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
•
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
PROTOCOL SUMMARY
1.1
SYNOPSIS 
Title:
Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic 
PTSD: A Pilot Study
Study Description:
Current treatments for posttraumatic stress disorder (PTSD) do not work 
for a significant proportion of individuals with PTSD, or work only partially, 
leaving persistent and disabling residual symptoms. Our research team has 
led the development of ketamine for the treatment of chronic PTSD. After 
our initial, proof-of-concept randomized controlled trial (RCT) of a single 
ketamine infusion in individuals with chronic PTSD showed promising 
results, we completed the first RCT of repeated intravenous ketamine 
infusions where individuals with chronic PTSD received a course of six 
ketamine infusions (vs. active placebo midazolam infusions) and 
demonstrated a rapid and robust improvement in PTSD symptoms. The 
median time to loss of response, however, was 27.5 days following the 
course of infusions, making it imperative to investigate novel approaches 
aimed at preventing symptom relapse following ketamine treatment. We 
thus propose a proof-of-concept, open-label pilot study to evaluate the 
efficacy of adding an evidence-based, brief and scalable trauma-focused 
psychotherapy, Written Exposure Therapy (WET), to a course of ketamine 
infusions in maintaining PTSD symptom improvement over time, in 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
2
participants with chronic PTSD.. To accomplish this aim, we will enroll 
individuals who meet DSM-5 criteria for chronic PTSD. 
Eligible patients will receive a total of 6 ketamine infusions and 5 WET 
sessions. The primary outcome will be change in PTSD symptom severity 
assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) 
from baseline (before the first infusion) to 12 weeks from the start of WET. 
All participants will be assessed until week 12 following the start of WET. 
They will complete weekly assessments from baseline until 6 weeks from 
the start of WET, as well as assessments at 12 weeks from the start of 
WET. At other time points between 6 and 12 weeks, participants will be 
assessed weekly, or less frequently as tolerated. 
Although initial response to ketamine (PTSD and co-morbid depressive 
symptom improvement) will be assessed after the first four infusions 
(prior to starting WET), all participants will receive 6 infusions and 5 WET 
sessions regardless of their initial response to ketamine.
Participants will be asked not to make any changes to any concomitant 
treatment (i.e., medication dosages, psychotherapy) during this period.
Thereafter, participants who remain improved at the 12-week time point 
(compared to baseline) will then receive additional monthly assessments 
up to 24 weeks or until loss of this improvement.
We will also evaluate whether extinction learning ability –assessed with a 
computerized extinction learning task– is associated with PTSD symptom 
improvement from baseline to 12 weeks from the start of WET. If 
demonstrated to result in significant and maintained PTSD symptom 
improvement, this novel combined treatment may represent a promising 
intervention for individuals with chronic PTSD, deserving further study.
Objectives:
Primary Objective: To evaluate the efficacy of adding WET to ketamine 
therapy in improving PTSD symptoms from baseline to 12 weeks from the 
start of WET,  in individuals with chronic PTSD . 
Secondary Objectives (exploratory): (1) To evaluate improvement in PTSD 
symptoms from baseline to 6 weeks, and on other measures from baseline 
to 6 weeks, and from baseline to 12 weeks; (2) To evaluate durability of 
PTSD symptom improvement beyond 12 weeks in patients who remain 
improved, up to 24 weeks; (3) To evaluate whether ketamine-induced 
change in extinction learning is associated with improvement in PTSD 
symptoms from baseline to 12 weeks from the start of WET.
Endpoints:
Primary Endpoint: Change in PTSD symptom severity assessed by the 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from baseline to 12 
weeks from the start of WET. 
Secondary (Exploratory) Endpoints: 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
3
- Change in PTSD symptom severity from baseline to 6 weeks from the 
start of WET, assessed by the CAPS-5. 
- Change on other measures, including the Montgomery-Asberg 
Depression Rating Scale (MADRS), Sheehan Disability Scale (SDS), and 
Clinical Global Impression severity and improvement (CGI-S and CGI-I), 
from baseline to 6 weeks, and from baseline to 12 weeks. 
- In participants with maintained PTSD symptom improvement after 12 
weeks, change on the CAPS-5 and other measures, from baseline to 16, 20, 
and  24 weeks. 
- Additionally, change from baseline to 24 hours after the first ketamine 
infusion, at each ketamine infusion day, and 24 hours after the 4th 
infusion, on the Impact of Events Scale (IES-R) and Quick Inventory of 
Depressive Symptomatology – Self-Report (QIDS-SR), both with past-24-
hour recall.
Study Population:
Up to N=15 participants with chronic PTSD will be enrolled in the study. 
Participants will be aged 18-70 years, male or female, with a current 
primary diagnosis of chronic PTSD according to DSM-5 and at least 
moderate current illness severity, as determined by a score of 30 or 
greater on the CAPS-5. Participants will be recruited from the greater New 
York City area.
Phase:
2
Description of 
Sites/Facilities Enrolling 
Participants:
This will be a single-site study, carried out at the Icahn School of Medicine 
at Mount Sinai (ISMMS) in New York City, United States.
Description of Study 
Intervention:
Ketamine: Participants will receive six (6) intravenous ketamine infusions. 
All ketamine infusions will be administered by a study physician 
credentialed for ketamine administration at Mount Sinai, at subanesthetic 
doses of 0.5 mg/kg over 40 minutes at each administration, and a 
frequency of three times per week over two consecutive weeks. 
Participants will also receive 5 WET sessions (the first 2 WET sessions will 
be interleaved with the last 2 infusions, each on a different day).
After four (4) ketamine infusions, participants will begin WET sessions. All 
participants will receive two additional ketamine infusions, interleaved 
with 5 WET sessions.
Written Exposure Therapy (WET): WET consists of 5 sessions, with the 
first session lasting 1 hour and each subsequent session lasting 
approximately 40 minutes. The first session includes psychoeducation 
about common trauma reactions and the treatment rationale, presented 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
4
by the therapist. The participant is then given general instructions for 
completing the trauma narratives and specific instructions for completing 
the first 30-minute narrative during that first session. All WET sessions 
begin with the therapist reading the specific writing instructions, clarifying 
any questions the participant might have, and leaving the instructions with 
the participant for the 30-minute writing session. Writing instructions 
begin with a focus on the details of the trauma and then shift to the 
meaning of the trauma event. After 30 minutes of writing, the therapist 
stops the writing and conducts a 5-10 minute check-in regarding how the 
writing session went for the participant.
Study Duration:
The study is anticipated to take place over 48 months.
Participant Duration:
Participants will be in the study for up to 27 weeks. See schema in section 
1.2 below for a summary.
1.2
SCHEMA
Figure 1. Flow diagram
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
5
1.3
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Screen
ing
Baseli
ne
Ketamine 
Infusions
24 hour 
Follow-
Up Visit
Assessme
nt of 
Response 
to 
Ketamine
WET 
Sessions
Weekly 
Assessmen
t Until 12 
weeks
Monthly 
Assessmen
t Until 
Loss-of-
Response
Day -
28 to 0
Visit 
1a, 
Day 1
Visit 1a-9; 
Days 1, 3, 
5, 8, 11, 12
Visit 1b, 
Day 2  
Visit 5, Day 
9
Visit 6-
12, Days 
10, 12, 
16, 18, 
22
Visits 10, 
13-23, Days 
12, 19, 26…
Visits23-26, 
Days 33…
Informed consent
x
Demographics
x
Medical history
x
SCID-5
x
CAPS-5
x
x
x
x
x
MADRS
x
x
x
x
x
WTAR
x
MoCA
x
IES-R
x
x
x
x
QIDS-SR
x
x 
x
x 
PCL-5
x
x
x
x
x
MOS-5
x
x1
CES
x
x1
PACT
x
x1
CTQ
x
TLEQ
x
SDS
x
x
x
x
x
x
HMS
x2
PIQ
x2
C-SSRS
x
x
x
x
x
CADSS
x
x
BPRS
x
x
YMRS
x
x
Extinction Learning 
Task
x
x
CGI
x
x
x
x
x
x
x
Concomitant 
medication review
x
x
x
x
x
x
x
PRISE
x
x
x
x
x
x
x
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
6
Adverse event 
review and 
evaluation
x
x
x
x
x
x
x
x
Physical exam 
(including height 
and weight)
x
Vital signs
x
x
Weight
x
x
EKG
x
Routine labs
x
Plasma ketamine 
and norketamine 
levels
x3
Urine pregnancy 
test
x
x
Urine drug screen 
(UTOX)
x
x
Ketamine infusion 
(0.5 mg/kg)
x
Written Exposure 
Therapy (WET)
x
Complete Case 
Report Forms 
(CRFs)
x
x
x
x
x
x
x
x
1Visit 14 and 23 only
2 only at Infusions 1 and 2
3 only at Infusion 1
2
INTRODUCTION
2.1
STUDY RATIONALE 
Posttraumatic stress disorder (PTSD) is a chronic and disabling condition. Trauma-focused 
psychotherapies for PTSD have the strongest evidence base. Access to these specialized forms of 
therapy, however, is often limited by geographic, economic, and time-commitment barriers, as well as 
need for extensive therapist training. Additionally, 25-40% of patients drop out of treatment 
prematurely. There is thus a strong need to develop more efficacious and scalable treatments for PTSD. 
Recent evidence from our research group showed efficacy of repeated intravenous (IV) infusions of 
ketamine at sub-anesthetic doses (0.5 mg/kg) in rapidly improving PTSD symptoms in patients with 
chronic PTSD, as well as co-morbid depressive symptoms. However, these effects are time-limited, with 
loss of initial response to ketamine within 2 to 4 weeks following a course of six infusions. Additionally, 
results from pre-clinical studies suggest that ketamine administration might facilitate fear extinction 
learning.
Building on these findings, the current project will evaluate the efficacy of adding Written Exposure 
Therapy (WET) to a course of repeated IV ketamine infusions in improving PTSD symptoms  from pre-
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
7
infusion baseline to 12 weeks from the start of WET, in patients with chronic PTSD. WET is a brief, 5-
session evidence-based written trauma-focused therapy without in between-session assignments, with 
demonstrated efficacy and low dropout rates in patients with PTSD. WET will be administered to 
participants starting after they receive four initial ketamine infusions; the first WET sessions will be 
interleaved with two additional ketamine infusions to take advantage of a window of increased 
neuroplasticity potentially induced by repeated ketamine infusions. WET be administered on different 
days as the ketamine infusions.
2.2
BACKGROUND 
1. SIGNIFICANCE 
Chronic posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder.1,2 There is an urgent 
need for the development of novel treatment interventions for this disabling condition, as currently 
available treatments have limited efficacy.3-5 Our research group has led the development of ketamine 
administration for the treatment of chronic PTSD, demonstrating a rapid and robust improvement in PTSD 
symptoms following a course of six infusions.6-8 Additionally, recent years have seen a rapidly growing 
interest in the potential synergistic effect of ketamine infusions and psychotherapy,9,10 but only open-
label pilot studies have been published to date, including only one in individuals with PTSD (n=10).11-13 Our 
proposed open-label trial is the first of which we are aware to evaluate the efficacy of adding a trauma-
focused psychotherapy, Written Exposure Therapy (WET), to a course of ketamine infusions in maintaining 
ketamine response over time in individuals with chronic PTSD who demonstrate a rapid and clinically 
significant response to initial ketamine infusions. If demonstrated to be efficacious, this novel combined 
treatment may represent a promising intervention worthy of additional study for the broader population 
of individuals with chronic PTSD.
1.A. Chronic PTSD and insufficient efficacy of currently available treatments. Only two medications 
[selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine] are FDA-approved for the 
treatment of PTSD, with two additional medications showing moderate-level efficacy. Only about one 
third of individuals with PTSD achieve remission with SSRIs, with another third showing symptom 
improvement; thus, about two thirds of patients are either treatment non-responders or partial 
responders.3,5,14 Although trauma-focused psychotherapies have the most evidence base for the 
treatment of PTSD, they require extensive therapist training and significant time commitment on the part 
of patients; these therapies are associated with significant rates of non-response and treatment 
dropout.15,16
1.B. Ketamine as an emerging treatment for PTSD. In recent years, clinical trials conducted by our 
research team have led the development of ketamine as a novel treatment for chronic PTSD. Ketamine, a 
noncompetitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, was first FDA-approved as 
an anesthetic and analgesic agent several decades ago.7 Following initial evidence of its efficacy for 
treatment-resistant depression (TRD),17 we conducted the first proof-of-concept RCT of a single IV infusion 
of ketamine in individuals with chronic PTSD (compared to the psychoactive placebo midazolam), showing 
rapid and significantly greater improvement following ketamine administration.6 Ketamine was well-
tolerated in patients with PTSD, with only transient emergence of dissociative symptoms during infusion. 
Continuing our research on ketamine for the treatment of PTSD, we then completed the first RCT of 
repeated IV ketamine infusions for chronic PTSD, compared to repeated midazolam infusions, 
demonstrating significantly greater efficacy of ketamine (67% treatment responders in the ketamine 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
8
group, compared to 20% responders in the midazolam group) following a course of six infusions 
administered over two consecutive weeks.8 This rapid and robust improvement in PTSD symptoms lasted 
for several weeks, with median time to relapse occurring 27.5 days after the full course of infusions, 
making it imperative as the next step to investigate novel approaches aimed at preventing symptom 
relapse following this very promising treatment for PTSD. 
1.C. Neurobiology of PTSD and Ketamine Mechanisms of Action. 
1.C.1. Chronic stress, PTSD, disrupted synaptic connectivity and abnormal glutamatergic transmission. 
Glutamate, the principal excitatory neurotransmitter in the brain, is crucial to learning and memory 
formation via strengthening of synaptic connections, including the formation of trauma memories.18,19 
Pre-clinical studies have demonstrated that chronic stress is associated with atrophy of dendrites and 
synaptic loss in the hippocampus and medial prefrontal cortex (mPFC), resulting in dysfunction of 
glutamatergic transmission.20,21 It has been proposed that recurrent intrusions of trauma memories 
experienced by individuals with chronic PTSD represent a form of chronic stress, in turn associated with 
maintenance and worsening of disrupted synaptic connectivity and abnormalities in glutamatergic 
transmission, increasingly understood as key biological abnormalities underlying the pathophysiology of 
PTSD.22,23 
1.C.2. Fear extinction abnormalities in chronic PTSD. Alterations in fear processing and regulation 
characterize PTSD and are thought to contribute to the persistence of PTSD symptoms.24 Key among these 
alterations is impaired fear extinction learning, assessed by repeatedly presenting a conditioned stimulus 
without the unconditioned stimulus.24 Extinction learning involves learning that certain stimuli previously 
associated with danger or a trauma (e.g., a quiet street) are now safe (e.g., do not signify that an assault 
is imminent). Successful fear extinction involves formation of a new memory of safety, which overlays the 
original fear memory and relies on intact ventromedial prefrontal cortex (vmPFC) function.25 Several 
studies have found fear extinction deficits in individuals with PTSD, in the form of persistent abnormal 
fear during extinction learning or reduced extinction recall upon testing during a subsequent session.26-29 
Deficits in fear extinction have been proposed to underlie a range of PTSD symptoms, including intrusions 
and heightened arousal. 
1.C.3.  Mechanisms underlying the effects of ketamine: Reversal of disrupted synaptic atrophy, 
enhancement of fear extinction learning. Studies in animal models have yielded insights into the 
mechanisms of action of ketamine. In rats first subjected to chronic unpredictable stress for 21 days, a 
single dose of ketamine was shown to reverse, within 24 hours, stress-induced behavioral deficits, 
synaptic atrophy, and pyramidal neuron dysfunction in the prefrontal cortex (PFC).30 In individuals with 
chronic PTSD, ketamine is thought to work by rapidly restoring disrupted synaptic connectivity.22,23 While 
neuroimaging studies examining the effects of ketamine in PTSD have not yet been published, ketamine 
was shown to normalize disrupted functional dysconnectivity between PFC/subcortical regions and the 
rest of the brain in patients with major depressive disorder, 24 hours post-administration.31 Additionally, 
results from animal studies employing fear-conditioning paradigms suggest that ketamine enhances fear 
extinction learning. In one study of fear-conditioned rats, ketamine administration enhanced the effects 
of fear extinction training, resulting in reduced return of fear a week later upon exposure to the original 
fear conditioning context, mediated by mTORC1 signaling in the mPFC.32 In a mouse model of PTSD, 
repeated ketamine administration also enhanced the effects of fear extinction training, resulting in 
reduced relapse of fear associated with increased brain-derived neurotrophic factor (BDNF) in the 
hippocampus and mPFC.33 Findings to date suggest that ketamine might open a window of increased 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
9
neuroplasticity and enhanced fear extinction learning, during which the efficacy of psychotherapeutic 
interventions might be enhanced.7,9,10,22
1.D. Adding Psychotherapy to Ketamine Treatment for PTSD: Potential for Synergistic Effect: As the 
effects of ketamine 
administration 
in 
individuals with PTSD 
(or TRD) are rapid and 
robust, a key next step 
in treatment research 
is to identify strategies 
to maintain this initial 
response to ketamine 
over time. In this 
context, interest in 
leveraging a ketamine-
induced 
temporary 
window of increased 
neuroplasticity 
and 
enhanced learning by 
adding psychotherapy 
to ketamine treatment 
has grown significantly 
in recent years.7,9,10,22 
Open-label pilot studies adding psychotherapy to ketamine treatment have been conducted in patients 
with TRD (cognitive-behavioral therapy, CBT)  and with obsessive-compulsive disorder (exposure-based 
CBT),11,12 and most recently in PTSD (prolonged exposure, PE).13 Exposure-based psychotherapies have the 
most empirical support for the treatment of PTSD.14 A key mechanism thought to underlie these therapies, 
including WET, is fear extinction learning.34-37 Following repeated exposure to traumatic memories in a 
therapeutic context, individuals gradually learn the safety of previously conditioned PTSD symptom 
triggers.36,37 As pre-clinical research suggests that ketamine enhances fear extinction learning, the addition 
of an exposure-based therapy to ketamine treatment might have a synergistic effect, helping maintain 
response to ketamine over time (see Figure 2). An open-label pilot study combining ketamine infusions 
(three infusions, administered weekly) with a course of PE therapy in a small sample (n=10) of veterans 
with chronic PTSD was recently published.13 While results suggest the feasibility of adding an exposure-
based psychotherapy to ketamine treatment, the potential efficacy of this approach in maintaining 
response to ketamine over time needs to be formally studied. Of note, in this pilot study, which employed 
a 10-session traditional Prolonged Exposure (PE), 50% of participants dropped out prior to completing 
therapy.13 In our proposed trial, we anticipate that the selection of WET, a brief and highly tolerable 
exposure-based therapy, will be associated with much lower participant dropout. 
1.E. Written Exposure Therapy (WET) is an evidence-based, brief and scalable exposure-based 
psychotherapy for the treatment of PTSD, co-developed by Co-Investigator Dr. Denise Sloan, and designed 
to be a tolerable and efficient exposure-based treatment for PTSD that does not include between-session 
assignments. WET evolved from a careful and systematic series of studies to identify necessary 
components for successful PTSD treatment.38 The minimal therapist-patient contact, nominal time 
needed to train therapists, and brevity of treatment results in an approach that addresses many of the 
Figure 2: Potential Synergistic Effect of Adding an Exposure-based 
Therapy to Ketamine Treatment for PTSD
Figure 2: Potential Synergistic Effect of Adding an Exposure-based 
Therapy to Ketamine Treatment for PTSD
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
10
challenges identified with implementing other exposure-based psychotherapies for PTSD.38,39 
Fundamental components of WET include a treatment rationale, psychoeducation, and directing 
individuals to write repeatedly about the details of a traumatic stressor linked to their symptoms, with 
particular attention to felt emotions and the meaning of the traumatic event.38 Clinical trials conducted 
by Sloan and colleagues have demonstrated the efficacy of WET in reducing PTSD symptom severity, 
including in a non-inferiority RCT comparing WET to cognitive processing therapy (CPT),40,41 one of the 
therapies with highest evidence base for the treatment of PTSD.42 WET is also highly tolerable and 
associated with very low patient attrition,40,41 and is included among the recommended PTSD treatments 
in the VA/DoD Clinical Practice Guidelines for managing PTSD.14 
1.F. Extinction learning as a potential predictor of PTSD symptom change following repeated ketamine 
+ WET. The collective findings summarized above (and in Figure 2) constitute the scientific rationale for 
evaluating ketamine-induced improvement in extinction learning as a predictor of  response to ketamine 
+ WET (Aim 2). While better extinction learning prior to starting exposure therapy has been hypothesized 
to predict better outcomes, this has rarely been studied, with the exception of two neuroimaging studies 
evaluating extinction learning as a predictor of response to exposure therapy in individuals with public 
speaking anxiety and spider phobia, respectively. Better extinction learning pre-intervention, and neural 
activation during extinction learning, predicted higher post-intervention symptom reduction, assessed in 
the first study two weeks post-intervention.43,44 The authors of the second study conclude that “boosting 
the extinction circuitry may be a target for improving exposure therapy success.”44 We are not aware, 
however, of any published study examining extinction learning as a predictor of response to exposure-
based psychotherapy for PTSD.  
Some studies of exposure-based psychotherapies have investigated whether fear activation, necessary 
for fear extinction to occur, predicts response to psychotherapy. Of particular relevance to the proposed 
study, cardiovascular activation during the first WET session was found to predict PTSD symptom 
improvement, suggesting that fear extinction learning is a mechanism underlying WET.34,35 In other studies 
of exposure-based therapies for PTSD, higher fear activation to trauma reminders prior to starting therapy 
or during the first session –measured by coding participants’ facial fear expression, acoustic startle, skin 
conductance, or heart rate reactivity– predicted great PTSD symptom reduction in response to therapy.45-
47 In particular, higher fear activation was found to predict better response to exposure-based treatment 
specifically in participants receiving D-cycloserine (DCS) as a potential exposure therapy-enhancing 
agent.46 In our proposed study (Aim 2), we will evaluate whether ketamine-induced change in extinction 
learning, assessed with an online Extinction Learning Task48 sensitive to PTSD (see Preliminary Data), 
predicts response to ketamine + WET in individuals with chronic PTSD. 
2.3
RISK/BENEFIT ASSESSMENT  
2.3.1
KNOWN POTENTIAL RISKS 
Risks to privacy and confidentiality: 
As the research study involves collection of protected and sensitive health information, there is a 
potential risk of loss of confidentiality. This risk will be conveyed to subjects as part of informed consent 
and will be minimized by using Standard Operating Procedures at our Depression and Anxiety Center, 
which comply with Health Insurance Portability and Accountability Act rules.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
11
Risks associated with blood draw or insertion of intravenous canula: 
Subjects might feel pain during blood draw or when IV is inserted, and can develop bruising, and rarely, 
infection. The sight of blood or insertion of IV canula may also cause dizziness or brief loss of 
consciousness due to vasovagal response. Therefore, all blood draws will be conducted by trained 
personnel, using aseptic precautions, and in a setting where the subject is resting comfortably and the 
risk of fall is minimized.
Risks associated with psychological questionnaires and assessments: 
Answering questions related to mental health and past experiences may be stressful. Research 
interviews will be interrupted if subjects become distressed or object to answering questions. If in the 
judgment of the PI or study-affiliated psychiatrist, the patient has worsened to such a degree that 
further participation would put the patient at risk, then the subject will be discontinued from the study 
and provided appropriate clinical care.
Risks associated with ketamine infusion: 
Ketamine is an analgesic agent and general anesthetic for human and veterinary use. It also has 
dissociative and psychedelic properties. For that reason, ketamine was categorized as a Schedule III drug 
in the Controlled Substance Act in August 1999. Over the past several decades, ketamine has been 
administered as an anesthetic to several million adults and children and has a very favorable safety 
profile. In addition, it has been used in psychophysiological studies in normal volunteers and patients 
with severe mental disorders including major depressive disorder and PTSD (with similar doses to those 
used in our proposed study) safely for three decades. Furthermore, the s-enantiomer of ketamine was 
approved for use as an adjunctive treatment for major depressive disorder by the Food & Drug 
Administration, and more recently for the treatment of depressive symptoms in individuals with major 
depressive disorder with acute suicidal ideation or behavior, reflecting its favorable risk versus benefit 
profile. Perceptual disturbances may manifest as vivid dreaming, visualization of psychedelic color, 
suspension in space, kaleidoscopic floating, and out-of-body experiences. Some patients report the 
psychic experiences as bizarre or frightening, while others describe them as pleasurable, joyful, or 
fascinating. When such reactions occur, they are usually mild and short-lived, resolving several minutes 
following the end of infusion. Other side effects commonly associated with ketamine include temporary 
increases in blood pressure and/or heart rate which will be monitored closely during, and for 1 hour 
after the end of, the infusions. Use of ketamine may also be associated with nausea. Interruption or 
discontinuation of infusion is usually adequate to resolve these ketamine-associated acute side effects.
Risks associated with WET: 
Although WET may decrease PTSD and related symptoms, we recognize that individuals with PTSD may 
face the risk of symptomatic worsening. Indeed, one concern with exposure to trauma reminders is that 
individuals may acutely feel more anxious, even though exposure and habituation generally decrease 
PTSD symptoms over time. Conducting WET remotely via video telehealth requires special care in 
monitoring potential symptom worsening during sessions. We will take multiple precautions to ensure 
patient safety. 
Financial risks: 
Subjects will not be charged for any study procedures. However, in case they experience an adverse 
effect and seek care, they or their insurance provider will be responsible for this clinical care. Subjects 
will be informed of this risk as part of informed consent process.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
12
2.3.2
KNOWN POTENTIAL BENEFITS 
All study subjects will be informed that there may not be any benefit to them individually as a result of 
taking part in the study. All study subjects will receive without cost an extensive psychiatric and medical 
evaluation, which may be of potential benefit to the subjects. Furthermore, participants may experience 
improvement in symptoms, including PTSD and co-morbid depressive symptoms, with ketamine 
infusions and WET.
2.3.3
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
There are three areas in which safeguards to protect subjects from undue risk require discussion. 
These include the procedures used to obtain informed consent, the procedures used to ensure 
confidentiality of the subjects’ data, and the procedures used to minimize possible risks associated with 
the study procedures. In the consent form, and in discussion with an investigator, subjects are advised 
fully of the procedures to be used, the amount of time required of them, the possible risks and benefits 
of the procedures, their right to refuse participation in the study without prejudice, their right to 
terminate participation at any moment without prejudice, and the name and telephone number of the 
Principal Investigator. In the informed consent form, subjects are told that the information they provide 
and all findings will be kept strictly confidential, with access limited to the research staff and the 
possible exception of state or federal regulatory personnel. Only the PI and the clinical research 
coordinator will have access to the code which links that participant study ID number to protected 
health information. This information will be kept on a password-protected computer on the ISMMS 
campus and backed up on a protected ISMMS server that is maintained by IT personnel and designed to 
house confidential patient information. The electronic data capture system used to collect data for this 
proposed study, REDCap (Research Electronic Data Capture), will collect it in a de-identified fashion, 
using only the subjects’ assigned study ID number (after eligibility is verified). As the study requires 
infusions of ketamine, subjects will be informed that their protected health information may be entered 
in the electronic medical record system that is used by ISMMS (EPIC). Results from this proposed study 
will be published as group data without the use of characteristics that would identify individual subjects. 
We quote information only by number in conference discussions, scientific reports, or publications, in 
order to maintain anonymity.
We have described above the potential risks of the research procedures and the safeguards that will 
be used to minimize risks. These include termination of subjects from research participation if it is 
believed that such participation endangers their welfare. Monitoring procedures are used to evaluate 
potential side effects of treatment or of research procedures. The protocol stipulates an extensive 
medical and psychiatric evaluation of all subjects as a condition for research participation. Subjects are 
monitored throughout the study for potential reactions to psychological assessments, ketamine 
administration, or participation in WET, including treatment-emergent suicidality. Special attention will 
be devoted to monitoring and assessing participant safety during remote video telehealth sessions, 
including monitoring for potential symptom worsening. Any concern about elevated participant risk 
identified by a clinical rater or study therapist is immediately brought to the attention of the PI or 
another study-affiliated psychiatrist, who will evaluate the participant further. As is standard for our 
Center, a physician is on call at all times between clinic visits so that adverse reactions can be evaluated.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
13
Suicidal Ideation and Imminent Harm: Despite treatment, participants may get worse or become 
withdrawn and uncommunicative. In these cases, it is helpful and potentially lifesaving for doctors to 
have access to a family member or friend who can inform them of the subject’s condition. To ensure 
safe participation, it is helpful to ask each subject to designate an emergency contact person. All suicide 
threats are taken seriously. It is important to assess the risk of suicide carefully when working with these 
patients. Due to these reasons, as part of the informed consent process, all participants will be asked to 
identify an emergency contact person, provide their contact information and complete a release of 
information form so that the study team may contact these individuals in case of an emergency.
Many subjects may admit to fleeting thoughts of death or briefly wishing for death; these thoughts 
need to be considered in context of the subject’s overall history, along with a consideration of other risk 
factors for suicide. Study psychiatrists will assess every patient at each visit for suicide risk and potential. 
As is the SOP for our Center, a 24-hr on call psychiatrist (PI or study-affiliated psychiatrist) will be 
designated to cover emergencies. Individuals at such risk will be treated appropriately, including options 
such as increased contact, more frequent clinical visits, or emergency psychiatric hospitalization. Please 
note that subjects who score 4 or more on the past-month suicidal ideation module of the C-SSRS or had 
any suicidal behavior within the past month on the CSSRS at screening will be excluded. Our Center, and 
the PI, have extensive experience working with individuals with elevated risk of suicide and maintaining 
the safety of individual subjects.
Incidental findings: For laboratory tests, all results will be reviewed by the PI or study-affiliated 
psychiatrist, and any incidental finding will be conveyed to the subject with provision for additional 
work-up if needed.
3
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
To evaluate the efficacy of adding 
WET to ketamine therapy in 
improving PTSD symptoms from 
baseline to 12 weeks from the start 
of WET, in individuals with chronic 
PTSD.
Change in PTSD symptom severity, as 
assessed with the Clinician-
Administered PTSD Scale for DSM-5 
(CAPS-5), between baseline and 12 
weeks following the start of WET.
The CAPS-5 is the gold-
standard outcome 
measure in clinical 
trials in patients with 
PTSD. Timing and 
duration of primary 
outcome assessment 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
14
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
were selected based on 
findings from prior 
WET and repeated 
ketamine studies.  
Secondary (Exploratory)
To evaluate longitudinal change in 
PTSD and depressive symptoms 
(and clinical global impression and 
psychosocial functioning) following 
administration of ketamine 
infusions and WET, as well as the 
relationship between change in 
PTSD and depressive symptoms. All 
participants will be followed for 12 
weeks from the start of WET.
To capture any ketamine-related 
rapid changes in PTSD and 
depressive symptoms 
Change in PTSD symptom severity 
from baseline to 6 weeks, using the 
CAPS-5; 
change in PCL-5, MADRS, CGI, and 
SDS from baseline to 6 weeks, and 
from baseline to 12 weeks; 
in patients with maintained PTSD 
symptom improvement after 12 
weeks, change in PTSD symptom 
severity from baseline to 16, 20, and  
24 weeks.
Change in IES-R and QIDS-SR, with 
24-hour recall, from baseline to 24 
hours after the first infusion, at each 
infusion day, and 24 hours after the 
fourth infusion.
The CAPS-5 is the gold-
standard outcome 
measure, and the PCL-5 
is a self-report measure 
commonly used in 
clinical trials for PTSD. 
The MADRS (depressive 
symptoms), CGI 
(clinical global 
impression), and SDS 
(psychosocial 
functioning) are 
commonly used as well.
These scales are 
commonly used in 
clinical trials, including 
in our 2 previous 
clinical trials of 
ketamine for PTSD to 
capture rapid symptom 
improvement.
To evaluate whether ketamine-
induced change in extinction 
learning predicts PTSD symptom 
improvement from baseline to 12 
weeks from start of WET. 
Performance on Extinction Learning 
Task following ketamine infusions.
The computerized 
Extinction Leaning Task 
is sensitive to PTSD. 
Assessment time point 
after four infusions 
(compared to baseline) 
allows for assessment 
of maximal change in 
extinction learning 
prior to adding WET to 
ketamine treatment.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
15
4
STUDY DESIGN 
4.1
OVERALL DESIGN
The main objective of this study is to evaluate the efficacy of adding WET to a course of ketamine 
infusions in improving PTSD symptoms from baseline to 12 weeks from the start of WET, in individuals 
with chronic PTSD (Aim 1). Additional objectives are to evaluate whether ketamine-induced change in 
extinction learning, assessed with an online Extinction Learning Task, predicts PTSD symptom 
improvement (Aim 2) in participants with chronic PTSD. In order to accomplish these objectives, we will 
conduct an open-label trial of ketamine plus WET in individuals with chronic PTSD. Participants will start 
WET after completing the first four ketamine infusions. Participants will receive two additional ketamine 
infusions (for a total of six infusions), interwoven with five WET sessions.  
Eligible participants will receive a total of six ketamine infusions (see Figure 1 and Methodological 
Details below), administered over 2 consecutive weeks,49 and will also begin WET sessions.  The first 2 
WET sessions will be administered interleaved with the last 2 ketamine infusions, on different days. The 
last three sessions of WET will be administered during the week following the end of ketamine infusions.
The clinical trial primary outcome is change in PTSD symptom severity from baseline to 12 weeks from 
the start of WET, measured with the CAPS-550. Secondary outcomes include change in PTSD symptom 
severity from baseline to 6 weeks from the start of WET, and change in other outcome measures from 
baseline to 6 weeks, and baseline to 12 weeks. Patients whose improvement in PTSD symptoms is 
maintained after 12 weeks will complete monthly assessments up to 24 weeks from start of WET. A 
continuous clinical rater will administer the CAPS-5 and the MADRS for the primary and secondary 
outcome assessments.
Methodological Details 
a. Screening Procedures (see 3.1 Schedule of Activities): Individuals will undergo informed consent 
procedures and study screening at the clinical site. If the COVID-19 pandemic remains a concern, these 
procedures will be conducted remotely, via a HIPAA-compliant telehealth platform (e.g., VSee, Doximity, 
HIPAA-Zoom). After signing the informed consent form, participants will complete a structured 
diagnostic interview with the SCID-5,51 the CAPS-5 to determine PTSD symptom severity,50 the MADRS to 
determine depressive symptoms severity,52,53 the Wechsler Test of Adult Reading (WTAR),54 and the 
Montreal Cognitive Assessment test (MoCA).55 Please see 3.1 Schedule of Activities for a complete list 
of scales to be completed by study participants at screening. All subjects will complete forms related to 
demographics, medical history, concomitant medications and treatment, and self-report measures 
including the Childhood Trauma Questionnaire (CTQ),56 Traumatic Life Events Questionnaire (TLEQ),57 
PTSD Checklist for DSM-5 (PCL-5),58 and Sheehan Disability Scale (SDS).59 Participants will also undergo a 
medical evaluation, including medical history; physical examination by a nurse practitioner; 
documentation of height, weight and vital signs; comprehensive blood tests; and urinalysis, urine 
toxicology screen, and urine pregnancy test (in women of childbearing potential). After reviewing all 
information, the PI or other study psychiatrist will meet with each patient to review their psychiatric and 
medical history, and current medications and treatment, answer any questions the patient might have, 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
16
administer the Columbia Suicide Severity Rating Scale (C-SSRS)60 and the CGI-S,61 document 
contraceptive use, and verify patient eligibility for the study. If a participant is taking any exclusionary 
psychotropic medication listed in the exclusion criteria, the prescribing psychiatrist or other prescribing 
physician must taper the participant off the medication, in consultation with the study PI or other study 
psychiatrist, if it is determined that the medication is of no clinical benefit to the individual. 
b. Administration of ketamine infusions: Eligible participants will receive a total of six infusions, 
administered over two consecutive weeks. At each infusion, they will receive 0.5 mg/kg of racemic 
ketamine hydrochloride, and total dose no higher than 60 mg per infusion (regardless of body weight). 
All infusion procedures and monitoring will take place at the Icahn School of Medicine at Mount Sinai 
(ISMMS) Psychiatry Infusion Suite  or Clinical Research Unite (CRU) using the existing Standard Operating 
Procedures that are in place for the administration of ketamine in research studies. 
c. Assessment of response to ketamine: Response to ketamine, assessed 24 hours after the fourth 
infusion, is defined as ≥ 30% reduction in PTSD symptom severity on the CAPS-5, administered to the 
participant by a trained clinical rater, compared to baseline (prior to any infusions). This degree of 
improvement is commonly used in clinical trials in individuals with PTSD to represent clinically significant 
PTSD symptom improvement,62-64 and was also employed in our completed RCT of repeated ketamine 
for PTSD.8
d. WET Sessions: 
WET consists of five sessions, with the first session lasting 1 hour and each subsequent session lasting 
approximately 40 minutes. The first session includes psychoeducation about common trauma reactions 
and the treatment rationale, presented by the therapist. The participant is then given general instructions 
for completing the trauma narratives and specific instructions for completing the first 30-minute narrative 
writing during that first WET session. All WET sessions begin with the therapist reading the specific writing 
instructions, clarifying any questions the participant might have, and leaving the instructions with the 
participant during the 30-minute writing session. Writing instructions begin with a focus on the details of 
the trauma and then shift to the meaning of the trauma event. After 30 minutes of writing, the therapist 
stops the writing and conducts a 5-10 minute check-in regarding how the writing session went for the 
participant.
All participants will be administered WET, beginning after they complete the first four infusions. WET will 
be delivered remotely by therapists to participants in their homes, via a HIPAA-compliant video telehealth 
platform, using methods implemented before the COVID-19 pandemic and further developed during the 
pandemic by study consultant Dr. Denise Sloan, who co-developed the WET intervention.65 Therapists will 
be Master’s- or PhD-level mental health providers, supervised by Dr. Sloan. WET will be delivered over a 
total of two weeks. The first two sessions of WET will be delivered starting after completion of the first 
four ketamine infusions, and interleaved with the last 2  ketamine infusions (each WET session and 
ketamine infusion occurring on one of four different days). The ketamine dose and administration 
protocol will be the same for all six infusions. The last three sessions of WET will be delivered the following 
week, after completion of the six ketamine infusions. Participant narratives will be collected as part of the 
WET sessions, as they are a necessary part of treatment and are used to ensure that the instructions for 
each writing session are followed by the participants. Collection will be completed securely, either by 
uploading a picture of the narratives to the REDCap database, uploading a scanned copy of the narratives, 
or by participants delivering the narratives in person (if there is a planned in-person visit shortly 
thereafter) or by mail. 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
17
e. Assessments and Outcome Measures (please see 3.1 Schedule of Activities for additional details). 
Assessments will be administered weekly starting at baseline, prior to the first infusion.
Primary outcome measure: The Clinician-Administered PTSD Scale (CAPS-5),50 the gold standard measure 
in clinical trials in individuals with PTSD, will be administered weekly by a blinded clinical rater. The primary 
outcome is change in PTSD symptom severity as measured by the CAPS between baseline and 12 weeks 
following the start of WET. All participants will be followed for 12 weeks. Participants who remain 
improved will additionally be followed monthly for 12 to 24 weeks. 
Secondary outcome measures (exploratory): The CAPS-5 will be administered weekly (beginning at 
baseline prior to the first ketamine infusion) until 6 weeks from the start of WET; thereafter, the CAPS-5 
will be administered weekly as tolerated until 12 weeks; all participants will be administered the CAPS-5 
at the 12-week time point. Participants who maintain PTSD symptom improvement after 12 weeks will be 
assessed monthly up to 24 weeks from the start of WET or until loss of improvement, by the blinded 
clinical rater. The PCL-5 and SDS (self-report scales), the MADRS (administered by the blinded clinical 
rater), and the CGI-S and CGI-Improvement scales (administered by a study psychiatrist or clinician) will 
be administered at the same time points until 12 weeks, and then monthly up to 24 weeks or until loss of 
improvement (See 3.1 Schedule of Activities). The Quick Inventory of Depressive Symptomatology-Self-
Report version (QIDS-SR)66 and the Impact of Events Scale-Revised (IES-R),67 both self-report scales, will 
be administered at baseline, 24 hours after the first infusion, at each infusion visit, and on the day of 
response to ketamine assessment, to capture any ketamine-related rapid changes in symptom levels. An 
abbreviated version of the Medical Outcomes Study Social Support Survey (MOS-SSS),68 the Centrality of 
Event Scale (CES),69 and the Perceived Ability to Cope with Trauma Scale (PACT)70 will be administered at 
baseline (prior to any infusions) and again 3 weeks after the first WET session; data from these scales will 
be used for Aim-3 analyses.
Safety Assessments: Participants will be evaluated prior to each infusion by the PI or another study-
affiliated psychiatrist; including review of vital signs, weight/BMI, drug and pregnancy tests, concomitant 
medications and adverse events. Participants will be monitored continuously during all ketamine 
infusions. On infusion days, side effects will be assessed with the Patient-Rated Inventory of Side Effects 
(PRISE) Adverse Event Visit Checklist,71 the Clinician-Administered Dissociative States Scale (CADSS),72 the 
Brief Psychiatric Rating Scale (BPRS) 4 items assessing positive symptoms,73 and the Young Mania Rating 
Scale first item.74  
f. Online Extinction Learning Task (see Figure 7 : The computerized task, administered online, consists of 
three phases: an initial aversive conditioning phase (in context A), extinction learning phase (in context 
A), and further extinction learning (in novel context B) (see Figure 6). Importantly, the conditioned 
stimulus (CS) associated with the aversive loss outcome (US), the CS+, is only partially reinforced 
(P(US|CS+)=1/3), and the transition to extinction (P(US|CS+)=0) is unsignaled. This design maximizes 
uncertainty about whether CS+ trials during extinction should be grouped with unreinforced conditioning 
phase CS+ trials, implying a common cause is responsible for both kinds of observations, or instead that 
the change in contingencies indicates it is likely that a new cause is active in the environment. The 
predictive measure generated from this task for Aim 2 analyses is the difference in discrimination between 
CS+ and CS- across the first six blocks of the task. Further, loss expectancy ratings data from each trial of 
the online extinction task will be analyzed via a computational model of latent cause inference developed 
by Gershman, Niv, and colleagues75,76 (see Data Analysis Strategy). There are two versions of the task (see 
Figure 7 note): one version will be administered prior to any ketamine infusions, and the second version 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
18
after completion of the first four infusions. We will examine whether ketamine-induced improvement in 
extinction learning is associated with improvement in PTSD symptoms from baseline to 12 weeks from 
start of WET.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
Preliminary Data: 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
19
RCT of repeated IV ketamine for PTSD. Following our initial proof-of-concept RCT of single-dose IV 
ketamine infusion in patients with chronic PTSD,6 we completed the first RCT of repeated IV ketamine 
infusions in individuals with chronic PTSD (six infusions over two consecutive weeks), compared to 
repeated IV infusions of the psychoactive placebo midazolam (n=30). Participants’ primary trauma ranged 
from assault to the WTC attacks/recovery work, and PTSD duration averaged 15 years. Results revealed a 
robust, large-magnitude improvement in PTSD symptom severity in the ketamine group from baseline to 
week 2, compared to the midazolam group, assessed with the CAPS-5 (F=5.97, df=2, 55, p=0.0045, 
d=1.13).8 In the ketamine group, the CAPS-5 total score was 11.88 (SE=3.96, p=0.004) points lower 
(d=1.13, 95% CI=0.36-1.91; see Figure 3); 67% of participants were treatment responders, defined as ≥ 
30% improvement from baseline on the CAPS-5, compared with 20% in the midazolam group (2=4.89, 
p=0.03).8 Ketamine infusions were additionally associated with significantly greater improvement in co-
morbid depressive symptoms from baseline to 2 weeks, assessed with the Montgomery-Åsberg 
Depression Rating Scale (MADRS; F=5.68, df=2, 55, p=0.006, d=0.92), and on a global measure of clinical 
improvement, the Clinical Global Impression Severity Scale (CGI-S; F=5.19, df=2, 50, p=0.009). In 
participants who responded to ketamine, median time to loss of response was 27.5 days after the 2-week 
primary outcome assessment day (see Figure 4), motivating the proposed study, investigating a novel 
approach aimed at maintaining symptom improvement over time by adding a brief and scalable exposure-
based psychotherapy to a course of ketamine infusions delivered with the same schedule of six infusions 
over two consecutive weeks, which was associated with rapid and robust symptom improvement in 
individuals with chronic PTSD in our completed RCT.8
Development of Written Exposure Therapy. In NIMH-funded studies, Co-Investigator Dr. Sloan and 
colleagues have demonstrated the efficacy of WET in reducing PTSD symptom severity,39-41 including an 
NIMH-funded RCT (R01MH095737) that demonstrated WET’s non-inferiority to CPT,41 one of the two 
therapies with highest evidence base for the treatment of PTSD (see Figure 5). Of key relevance to the 
proposed RCT, greater physiological activation in response to written exposure during the first session 
was found to significantly predict symptom improvement from WET, suggesting that fear extinction 
learning is a mechanism underlying improvement in PTSD with WET.34,35 If ketamine infusions in 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
20
individuals with chronic PTSD enhance extinction learning, a mechanism thought to underlie WET, the 
addition of WET might result in enhanced PTSD symptom improvement through a synergistic effect.
Online Extinction Learning Task: Study in WTC Workers and Survivors with and without PTSD. Our 
research team developed the online Extinction Learning Task proposed for Aim 2 of this study, led by 
postdoctoral fellow Dr. Agnes Norbury.48 This behavioral extinction learning paradigm consists of three 
phases: (1) initial aversive conditioning phase, in context A; (2) extinction learning phase, also in context 
A; and (3) further extinction learning, in new context B (see Figure 6). Participants are told that they are 
traveling through different zones of a spaceship. In order to power their trip home, they need to escape 
with enough space coins. These coins are carried by helper robots, but some are unreliable. Participants 
are asked to rate (sliding bar), on each trial, how likely they think that particular robot would be to lose 
the coins it is carrying. Task sensitivity to PTSD status: Pilot data were collected for N=48 adults with DSM-
5 criterion A trauma 
exposure to the World 
Trade Center (WTC) 
disaster 
(WTC 
responders 
and 
survivors; mean age 53 
 7.0, N=16 female). 
N=34 
(71%) 
participants currently 
met DSM-5 criteria for 
WTC-related 
PTSD 
(mean 
PCL-5 
total 
score 44.1  8.6), and 
N=14 
(29%) 
participants 
were 
highly resilient to WTC-
related exposures (no 
current 
or 
lifetime 
diagnosis of PTSD or 
other 
DSM-5 
Axis-I 
disorder; mean PCL-5 
total score 1.6  1.7). An earlier version of the online Extinction Learning Task that we propose to use in 
this study was administered to all participants. Behavior on the Extinction Learning Task differed between 
the PTSD and Resilient groups (repeated-measures ANOVA of loss-expectancy ratings with within-subjects 
factors of conditioned stimulus [CS] type, task stage, and clinical group, using Tukey-LSD correction for 
multiple comparisons in follow-up contrasts). Specifically, there was a significant CS x group interaction 
(F1,806=12.6, p<0.001) –driven by a tendency towards higher overall loss prediction ratings for CS- stimuli 
(less discrimination between CS+ and CS- stimuli) in symptomatic individuals (mean difference in CS- rating 
PTSD vs resilient 13.8 [SE 5.7], 95%CI -1.3–28.9, p=0.08; difference in CS+ rating PTSD vs resilient 2.1 [SE 
5.7], p>0.9). Discrimination between CS+ and CS- stimuli across the first six blocks of the task differed 
between the groups [t34=-2.02, p=0.051, mean discrimination (difference in loss expectancy ratings) in the 
PTSD group=20.1, in the Resilient group=35.6 (points on a scale 0-100), Cohen’s d = 0.57. Computational 
latent cause modeling in this study showed that higher PTSD symptom severity, and specifically higher 
Figure 6. Loss expectancy ratings on the extinction task by conditioned 
stimulus (CS) type and task stage, by clinical group (PTSD, Resilient). 
Data is represented separately for WTC-exposed individuals who met criteria 
for WTC-related PTSD (N=34), and resilient individuals who were exposed to 
criterion A trauma during the WTC disaster but never met diagnostic criteria 
for PTSD (N=14). Error bars represent standard error of the mean. CS+, 
CS
(59)
Figure 6. Loss expectancy ratings on the extinction task by conditioned 
stimulus (CS) type and task stage, by clinical group (PTSD, Resilient). 
Data is represented separately for WTC-exposed individuals who met criteria 
for WTC-related PTSD (N=34), and resilient individuals who were exposed to 
criterion A trauma during the WTC disaster but never met diagnostic criteria 
for PTSD (N=14). Error bars represent standard error of the mean. CS+, 
CS
(59)
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
21
severity of intrusion symptoms, was associated with the belief that the same underlying cause explains 
events observed during conditioning and extinction stages of the task.48 
For Aim 2, extinction learning will be measured twice, with two versions of the online Extinction 
Leaning Task: (1) before the first ketamine infusion and (2) after completion of four ketamine infusions 
(pre-WET). Extinction learning will be defined as the difference in discrimination between the aversively 
conditioned (CS+) and safe (CS-) stimuli on the first six blocks of this task. Ketamine-induced change in 
extinction learning will be evaluated as a predictor PTSD symptom improvement from baseline to 12 
weeks from the start of WET. A recently developed computational model75,76 will be employed to 
determine whether differences in discrimination between CS+ and CS- are related to differential 
inferences about the causal structure of the task during learning (i.e., participants’ belief that one vs. 
multiple underlying causes explain observations during progression through the task).48
4.3
JUSTIFICATION FOR DOSE
In this trial, the dose of ketamine administered at each infusion (0.5 mg/kg, administered over 40 
minutes) is the same dose that is administered in most clinical trials of intravenous ketamine for 
treatment-resistant depression (TRD), and the same dose that was administered in our two completed 
clinical trials of intravenous ketamine for chronic PTSD. This dose has shown efficacy and safety for 
these disorders. Additionally, as requested by the FDA for safety reasons, the maximum dose of 
ketamine will be 60 mg at each infusion, regardless of participant body weight. 
Employing the same dose, frequency, and total number of infusions in this open-label clinical trial of 
ketamine + WET will allow us to compare study findings to the findings from our completed clinical trial 
of repeated ketamine infusions for PTSD, which evaluated the efficacy of a repeated course of ketamine 
infusions, without WET. 
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he or she has completed all phases of the 
study shown in the Schedule of Activities (SoA), Section 1.3. For all participants, the earliest end of study 
will be the 12-week follow-up assessment. For participants who remain improved at this 12-week 
assessment, the end of study will be their final follow-up visit (depending on time to loss of this 
improvement). 
5
STUDY POPULATION
5.1
INCLUSION CRITERIA
INCLUSION 
1.
Men or women, 18-70 years of age;
2.
Participants must have a level of understanding sufficient to agree to all tests and 
examinations required by the protocol and must sign a written informed consent document;
3.
Participants must fulfill DSM-5 criteria for current civilian or combat-related PTSD, based on 
clinical assessment by a study psychiatrist and on the CAPS-5, and a past-month total CAPS-
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
22
5 score ≥ 30 at screening – this is done to ensure at least moderate severity and to 
safeguard against high placebo response rates; 
4.
Women must be using a medically accepted reliable means of contraception (if using an oral 
contraceptive medication, they must also be using a barrier contraceptive) or not be of 
childbearing potential (i.e., surgically sterile, postmenopausal for at least one year);
5.
Women of childbearing potential must have a negative pregnancy test at screening and 
prior to each intravenous infusion;
6.
Men who are sexually active with women of childbearing potential must use a medically 
accepted reliable means of contraception and must agree not to donate sperm for a period 
of 90 days after receiving the last dose of ketamine;
7.
Participants must be able to identify a family member, physician, or friend (i.e. someone 
who knows them well) who will participate in a Treatment Contract (and e.g. contact the 
study physician on their behalf in case manic symptoms or suicidal thoughts develop).
5.2
EXCLUSION CRITERIA
EXCLUSION
1.
Women who plan to become pregnant, are pregnant or are breast-feeding (because the 
medical risk of using ketamine during pregnancy and breast-feeding is unknown);
2.
Serious, unstable medical illnesses such as hepatic, renal, gastroenterologic, respiratory, 
cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease, including 
gastro-esophageal reflux disease, obstructive sleep apnea, history of difficulty with airway 
management during previous anesthetics, ischemic heart disease and uncontrolled 
hypertension, and history of severe head injury;
3.
Clinically significant abnormal findings of laboratory parameters, physical examination, or 
ECG;
4.
Renal impairment, as reflected by a BUN >20 mg/dL, and/or creatinin clearance of >1.3 
mg/dL;
5.
Clinically significant uncorrected hypothyroidism or hyperthyroidism, as indicated by a TSH 
value 25% above or below the normal range;
6.
A Body Mass Index (BMI) >40;
7.
Hormonal treatment (e.g., estrogen) started in the 3 months prior to the first infusion day;
8.
History of a neurodevelopmental disorder (e.g., autism, pervasive developmental disorder) ;
9.
History of one or more seizures without a clear and resolved etiology;
10. Lifetime history of bipolar I or II disorder;
11. Presence of psychotic symptoms, or diagnosis of a lifetime psychotic disorder including 
schizophrenia or schizoaffective disorder;
12. Drug or alcohol use disorder within the preceding 3 months;
13. Previous recreational use of ketamine or PCP on more than one occasion, or any 
recreational use of ketamine or PCP within the last two years;
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
23
14. Previous non-response to clinical or research ketamine or esketamine administration;
15. Current diagnosis of bulimia nervosa or anorexia nervosa;
16. Patients judged clinically to be at serious and imminent suicidal or homicidal risk;
17. SBP >165 and DBP >95 at infusion days – higher BP allowed to account for stress or anxiety;
18. Concurrent treatment with opioid medication, or with long-acting or daytime short-acting 
benzodiazepines within two weeks of study start;*
19. Current cognitive impairment, as defined by a score <23 on the Montreal Cognitive 
Assessment (MoCA);
20. Estimated IQ <80;
21. Currently receiving evidence-based psychotherapy for PTSD (e.g., prolonged exposure, 
cognitive processing therapy);
Note: Concurrent treatment with other psychotropic medications (including a short-acting 
benzodiazepine at bedtime only) will be permitted, but dose must be stabilized for at least three months 
before study start.
* Potential participants will not be told to discontinue medication for the purposes of this study if there 
is any evidence that the medication is clinically beneficial. Further, a study physician will not taper a 
potential participant off of a medication; rather, this may only be completed by the prescribing 
physician. This is our policy across all of our studies.
5.3
LIFESTYLE CONSIDERATIONS
During this study, participants are asked to:

Participants will be asked to refrain from eating anything or drinking any non-clear liquids 
starting at midnight the night before each infusion.

Inform the study team of any changes in their medications or psychotherapy regimen.

Refrain from taking short-acting benzodiazepines during daytime.

Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical unit. 
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention or entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of an 
exclusionary concomitant medication, or a recent change in medications or psychotherapy may be 
rescreened. Rescreened participants should be assigned the same participant number as for the initial 
screening.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
24
5.5
STRATEGIES FOR RECRUITMENT AND RETENTION
Planned Recruitment Activities:
The research strategy for the present study calls for the enrollment of N=30 adults with chronic 
posttraumatic stress disorder (PTSD), aged 18-70 years. This enrollment is with the goal of identifying up 
to N=16 participants who are screened, eligible, and go on to receive ketamine infusions and WET. This 
is based on an anticipated screen fail rate of 25% to 50%.This enrollment will take place over the 
proposed 54-month recruitment period. 
The expected enrollment rate of ~1.2 subjects per month who receive ketamine infusions is highly 
feasible based on the current flow of subjects in clinical trials at the Depression and Anxiety Center for 
Discovery and Treatment (DAC) and the demonstrated track record of similar rates in prior studies at 
DAC and recruiting from WTC populations in CDC/NIOSH-funded studies led by PI Dr. Feder. As one of 
the major research and clinical programs at the Department of Psychiatry at the Icahn School of 
Medicine at Mount Sinai (ISMMS), DAC has five full-time faculty members. This includes three 
psychiatrists, two part-time clinical psychologists, two full-time post-doctoral fellows, three full-time 
Masters-level clinical raters, five full-time clinical research coordinators, a database manager, and a 
program administrator. Investigators at DAC have a long track record in successfully recruiting subjects 
and completing studies involving the assessment and treatment of individuals with PTSD.  
Recruitment Procedures:
We will post advertisements on Craigslist, ResearchMatch, Facebook, TrialFacts, BuildClinical and Google 
and will post flyers in the community, and accept referrals from clinicians. Through TrialFacts and 
BuildClinical, we will have targeted advertisements on Google and Facebook.
Potentially eligible participants who express interest in being considered for this clinical trial will 
complete a phone screen interview under the supervision of PI Dr. Feder. The PI will review subject 
enrollment at weekly project meetings with the primary study coordinator and Co-Investigators Drs. Jha 
and Murrough, so that any deviation from the anticipated enrollment schedule will be detected and 
remedied quickly. All outreach and advertising activities will also be reviewed on a weekly basis. 
 
Engagement Strategies for Retention:
The PI will hold weekly project meetings with the study coordinator and Co-Investigators Drs. Jha and 
Murrough to monitor enrollment and ensure that enrolled subjects are completing all study procedures 
as per protocol.
For infrastructure, the Scientific Computing department at ISMMS provides a secure centralized 
electronic data management platform that is HIPAA and FDA-compliant – Research Electronic Data 
Capture (REDCap). For this specific project, we will create databases in REDCap for screening, subject 
tracking, and a study database proper. As subjects complete study visits, the date of each visit will be 
entered in the database. Missed visits will be coded for reason (such as scheduling issues, illness). On a 
weekly basis, the primary research coordinator, who will also serve as data manager, will run a report on 
patient enrollment and study progress for review by the PI. On an ongoing basis, the data manager, PI, 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
25
and Co-Investigators Drs. Murrough and Jha will review the status of patient accrual and retention, as 
well as study case report form completion, to identify and resolve bottlenecks or problem areas that 
arise. Dr. Feder will additionally meet regularly with the study therapists, and work together with Dr. 
Denise Sloan (who will supervise the study therapists) to identify any potential issues related to delivery 
of WET to participants.
Within DAC, the study coordinator will be the participant’s point of contact during the study. Subjects 
will be provided with phone and email contact information for their coordinator, in addition to contact 
information for the PI. When enrolled, participants will provide detailed contact information for 
themselves, their clinical providers (if applicable), and a family member or close friend who is aware of 
the participant’s study participation. At each visit, the study coordinator will “check in” with the 
participant regarding protocol adherence and study satisfaction, in addition to any protocol-specific 
procedures. This system provides an opportunity to detect reasons for non-adherence or early 
discontinuation in a timely fashion and to address any issues, if at all possible. 
Strategies to ensure a diverse, representative sample: 
Since its inception, ISMMS has fostered community partnerships that are mutually beneficial to the 
School and nearby underserved populations. Faculty members have benefited from collaborations with 
underserved and often hard-to-reach populations and front-line clinicians, to recruit for research, 
develop research partnerships and to ensure that community expertise, experiences and priorities 
inform their work. The Centers for Community and Academic Research Partnerships (CCARP) at Mount 
Sinai is facilitating the formation and transformation of these partnerships so that they become the 
catalyst for groundbreaking research that uncovers and addresses important social, environmental, and 
health problems; builds skills among academic and community partners; and improves health of 
communities. 
The ISMMS is part of a large urban medical center, located in the Manhattan borough of New York City, 
and benefits from a large and diverse catchment area. For the proposed clinical trial there are no special 
restrictions with regard to ethnicity or race. It is expected that the study sample will closely approximate 
the racial and ethnic composition of populations residing in the New York City metropolitan area. 
Potential recruitment/enrollment challenges and strategies that can be implemented in the event of 
enrollment shortfalls:
Anticipated barriers include issues with staff workload and scheduling windows. This will be addressed 
by the use of back-up coordinators for the primary study coordinator on the proposed project. 
Furthermore, Co-Investigators Dr. Jha, Dr. Murrough, and Dr. Klein will serve as back-up study physicians 
for the PI, Dr. Feder, within the research team. Back-up team members will allow the team to screen 
and enroll participants and complete study visits within participant’s availability. All study staff involved 
in participant recruitment will be trained by the PI, in collaboration with Director of DAC Dr. Murrough, 
and participant progress and study procedures will be reviewed at weekly project meetings to ensure 
protocol adherence and consistency of procedures across primary and back-up study personnel. 
Anticipated participant-related barriers include appointment scheduling, transportation issues, and 
maintaining contact between study visits. To ensure that participants are able to attend appointments, 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
26
the visit schedule will allow for flexibility. To help address transportation issues, the study team will 
offer patients metro cards and other transportation resources available through DAC, including a car 
service to take participants home on the days of their ketamine infusions. Research staff will discuss 
contact methods with each participant during screening in order to establish multiple methods of 
contact, along with preferred contact methods to maintain contact between appointments. Research 
staff will check voicemail and email daily in order to be able to respond to patient contact. Staff will also 
reach out before each scheduled appointment to ensure participants are able to attend and complete 
visits as scheduled. To ease the burden on participants, we will also administer the five WET sessions 
remotely, via a HIPAA-compliant video telehealth platform.
At the current moment, the COVID-19 pandemic poses a potential barrier to enrollment in this and 
other studies. DAC is working closely with Departmental and Health System leadership to ensure 
optimization of SOPs related to mitigating risks pertaining to COVID-19 infection. Strategies to mitigate 
this barrier include the use of clear and consistent messaging to potential participants regarding safety 
precautions at DAC, including the implementation of thorough and consistent hospital-grade cleaning 
and disinfecting, the use of masks and eye protection by study personnel, the use of masks by 
participants, and social distancing. We are also allowing provisions for remote visits (via HIPAA-
compliant video telehealth platforms) wherever possible, in addition to the WET sessions, which will 
take place remotely.
In the case of slower than anticipated enrollment, PI Dr. Feder and Co-Is Drs. Murrough and Jha will 
review reasons for pre-screen and screen failures during weekly DAC research meetings, and consider 
additional recruitment and outreach methods including additional advertising methods, and additional 
outreach methods to clinicians and centers providing treatment to individuals with chronic PTSD.
6
STUDY INTERVENTION
6.1
STUDY INTERVENTION(S) ADMINISTRATION
6.1.1
STUDY INTERVENTION DESCRIPTION
Ketamine:
Ketamine is widely available as an anesthetic agent under the brand name Ketalar, for use in emergency 
rooms and hospital settings for sedation and analgesia. The typical sub-anesthetic dose in clinical trials 
for patients with TRD or PTSD is 0.5 mg/kg, administered intravenously over 40 minutes.
Relevant to the criteria for an exemption in § 312.2(b), we informally reached out to the Food and Drug
Administration (FDA) via email seeking their advice regarding the IND exemption. We were informed 
that the Division of Psychiatry Products is currently exempting studies with 3 or fewer intravenous 
infusions of subanesthetic doses of ketamine. As our proposed project involves 6 infusions, we will 
proceed with an IND submission. The PI, Dr. Feder, and Co-Is Drs. Murrough and Jha have extensive 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
27
experience in obtaining IND exemptions for ketamine trials. No subject will be enrolled in the proposed 
study until an IND exemption has been granted.
Relevant to the individual criterion for exemption in § 312.2(b) (bolded statements from FDA guidance):
1.
The drug product is lawfully marketed in the United States. We propose to use ketamine that is 
commercially available and will be supplied by our research pharmacy, the Investigational Drug 
Service at the Icahn School of Medicine at Mount Sinai.
2.
The investigation is not intended to be reported to the FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other significant 
change in the labeling of the drug. We do not intent to report the results of our proposed study 
to the FDA as a well-controlled study in support of a new indication, nor do we intend to use it 
to support any other significant change in the labeling of the drug. As mentioned earlier, the 
purpose of this study is to evaluate whether the addition of Written Exposure Therapy to a 
course of ketamine infusions can extend the effect of ketamine on PTSD symptoms in individuals 
with chronic PTSD who respond to ketamine.
3.
The investigation is not intended to support a significant change in the advertising for the 
drug. We do not intend to utilize the data we generate to support any changes in advertising of 
ketamine. As mentioned in the specific aims section, the purpose of this study is to evaluate 
whether the addition of Written Exposure Therapy to a course of ketamine infusions can extend 
the effect of ketamine on PTSD symptoms in individuals with chronic PTSD who respond to 
ketamine.
4.
The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases the acceptability of the risk) 
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)). We intend to use 
ketamine via intravenous route (after diluting it with normal saline for total infusion volume of 
100 mL) in adults with PTSD who are medically stable and have no medical contraindications 
against ketamine administration, three times per week for two weeks (total of 4 or 6 infusions 
over 2 weeks, depending on ketamine response). Previous reports have used repeated infusions 
of ketamine (up to 6) over a two-week period, including our recently completed randomized 
controlled trial of repeated ketamine infusions in patients with chronic PTSD, compared to the 
active placebo midazolam (PI of the proposed study, Dr. Feder, was the PI of that trial, funded in 
part by a NARSAD Independent Investigator Award from the Brain & Behavior Research 
Foundation).
5.
The investigation is conducted in compliance with the requirements for review by an IRB (21 
CFR part 56) and with the requirements for informed consent (21 CFR part 50). We plan to 
enroll subjects after the study is approved by the Institutional Review Board at Mount Sinai and 
after individual subjects have provided informed consent.
6.
The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product). We do not 
intend to promote or commercialize the drug product (ketamine) with this investigation.
Written Exposure Therapy:
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
28
Written Exposure Therapy (WET) is a brief evidence-based treatment for PTSD, developed by our 
collaborator and study consultant Dr. Denise Sloan (Boston University). WET will be administered by 
trained therapists, under the supervision of Dr. Sloan. 
6.1.2
DOSING AND ADMINISTRATION
Ketamine:
The dose of ketamine at each infusion is fixed at 0.5mg/kg mg, and up to 60 mg per infusion (regardless 
of body weight), to be administered intravenously over 40 minutes. Individuals at or above 120 kg will 
receive 60 mg over 40 minutes. Ketamine infusion will be discontinued earlier if necessary due to side 
effects as described below:
1.
Changes in psychiatric symptoms at any time during the study: 
a.
Treatment-emergent mania, hypomania, worsening suicidality or psychosis
2.
Emergent medical symptoms on the infusion days:
a.
Criteria for stopping the infusion:
i.
Any change in mental status resulting in inability to respond to verbal 
stimuli.
ii.
Severe headache, or severe anxiety, or other patient tolerability issues
iii.
SBP >180, DBP >110 on 2 consecutive readings, ~5 min apart
iv.
HR >120 for 5 minutes
v.
RR< 6, SPO2 <90% at any time point
vi.
Should the patient’s vital signs deviate from normal, the clinician may 
temporarily pause the infusion until the vital signs/mental status have 
returned to normal, and subsequently resume the infusion at the same or 
slower rate. Recommended protocol: If 150 ml/h not tolerated, slow to 100 
ml/h; If 100 ml/h not tolerated, slow to 50 ml/h.
b.
During intravenous infusion day and post-administration monitoring period: in the 
event of tachycardia >110 beats per minute, systolic BP>160 mm Hg or diastolic 
BP>100mg Hg that is not resolved by pausing or slowing the rate of infusion, the 
study physician will treat using the following preferred medications;
i.
Esmolol 100-500 mcg/kg IV titrated to reduce the heart rate and systolic BP.
ii.
Nitroglycerin 20-80 mcg IV titrated to reduce the BP to an acceptable range.
iii.
Further therapy with longer acting agents such as metoprolol, esmolol and 
labetalol will be administered if the response to initial therapy is not 
adequate.
c.
If three consecutive vital sign measurements (over 15 minutes) are consistently 
above the HR and BP limits stated above despite therapy, intravenous infusion will 
be discontinued.
d.
If a patient becomes sedated to the point that he/she is unresponsive to verbal 
commands or there is complete or partial airway obstruction, intravenous infusion 
will be discontinued. The patient would then be transferred to the Post Anesthesia 
Care Unit or an intensive care unit bed as necessary for further observation and 
treatment.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
29
e.
In the event that SpO2 < 95% over 5-minute interval, the study physician will have 
the option of inserting a nasal cannula or adjusting the flow rate. If the SpO2 does 
not increase to 95% or greater with intervention, the study will be discontinued and 
further therapy will be administered by the study physician.
f.
 In the event of a respiratory or cardiac arrest, Team 7000 will be called.
Procedures Related to Ketamine Administration:
Ketamine Infusion: All infusion procedures and monitoring will take place at the Psychiatry Infusion 
Suite, Icahn School of Medicine at Mount Sinai (ISMMS), using the existing Standard Operating 
Procedures that are in place for the administration of ketamine in research studies. All eligible 
participants will receive six infusions, administered three times per week over two consecutive weeks. 
At each infusion, participants will receive 0.5 mg/kg racemic ketamine hydrochloride, the same dose 
administered in prior studies of ketamine for the treatment of PTSD 6,49. An indwelling catheter will be 
placed in the antecubital vein of the non-dominant arm, and pulse, blood pressure, digital pulse-
oximetry, and ECG monitoring will be instituted. All physiologic monitoring data will be recorded on a 
standard anesthesia record beginning five minutes prior to ketamine administration. Co-Investigator Dr. 
Jha or another study- affiliated physician with privileges to administer ketamine will be present at the 
Psychiatry Infusion Suite throughout the administration of ketamine so that potential adverse events 
can be evaluated and treated promptly. A medical crash cart is available for emergencies. Dr. Jha or 
another study-affiliated physician will remain available until at least one hour following the termination 
of the study drug infusion or until the patient meets Aldrete criteria (good respiration, O2 saturation, 
consciousness, circulation, and activity) for post- anesthesia care, whichever period is longer. Blood 
samples will be collected from participants during the first infusion for measurement of plasma 
ketamine and norketamine levels.
Assessment of response to ketamine after four initial infusions: Response to ketamine is defined as ≥ 
30% reduction in PTSD symptom severity from baseline (prior to any infusions) determined with the 
CAPS-5, administered to the participant by a trained clinical rater 24 hours following completion of the 
fourth infusion. This degree of improvement is commonly used in clinical trials in individuals with PTSD 
to represent clinically significant improvement,62,64,77 and was also used in our recently completed RCT of 
repeated ketamine for PTSD.49
WET:
Procedures Related to WET Administration:
WET will be delivered using a structured manual to ensure fidelity. Therapists will be trained Master’s- 
or PhD-level licensed mental health providers, supervised by study consultant Dr. Sloan. WET will be 
delivered remotely by therapists to participants in their homes, via a secure HIPAA- compliant video 
telehealth platform, using methods implemented before the COVID-19 pandemic and further developed 
during the pandemic by Dr. Sloan and colleagues.65 WET will be administered over a total of 2 weeks. 
Week 1: The first two sessions of WET will be delivered interleaved with the last two ketamine infusions 
(each WET session and ketamine infusion occurring on a different day, i.e., four different days). The 
ketamine dose and administration protocol will be the same for all six infusions. Week 2: The last three 
sessions of WET will be delivered during the second week post-WET start.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
30
Delivery of WET:
WET will be delivered using a structured manual to ensure treatment fidelity. Therapists will be mental 
health providers at Mount Sinai. We anticipate that there will be between one and three therapists in 
this study, who will be assigned to individual participants for the duration of their participation.
WET consists of 5 sessions, with the first session lasting 1 hour and each subsequent session lasting 
approximately 40 minutes. The first session includes psychoeducation about common trauma reactions 
and the treatment rationale, presented by the therapist. The participant is then given general 
instructions for completing the trauma narratives and specific instructions for completing the first 30-
minute narrative writing session. All WET sessions begin with the therapist reading the specific writing 
instructions, clarifying any questions the participant might have, and leaving the instructions with the 
participant during the 30-minute writing session. Writing instructions begin with a focus on the details 
of the trauma and then shift to the meaning of the trauma event. After 30 minutes of writing, the 
therapist stops the writing and conducts a 5-10 minute check-in regarding how the writing session went 
for the participant.
Training and Supervision of Therapists and Treatment Fidelity:
Following established procedures used clinical trials of WET,40,41 therapists will be trained and supervised 
by Dr. Sloan. Therapists will attend a four-hour WET training workshop led by Dr. Sloan, followed by 
completion of at least two cases of WET supervised by Dr. Sloan that are completed with competency as 
determined by the supervisor. Therapists will be instructed on data collection during sessions and any 
required paperwork related to the proposed study. Treatment fidelity will be closely monitored to 
prevent drift. 
Narratives from WET Sessions:
Participant narratives will be collected as part of the WET sessions, as they are a necessary part of 
treatment and are used to ensure that the instructions for each writing session are followed by the 
participants. Collection will be completed securely, either by uploading a picture of the narratives to the 
REDCap database, uploading a scanned copy of the narratives, or by participants delivering the 
narratives in person or by mail.
Procedures for Transition to Clinical Care at Study Completion:
At the time of initial screening, subjects will be asked to identify if they have a current mental health 
provider. For patients with a current provider, we will ask them to provide the name and contact 
information of this provider. Patients who are not eligible for study participation and do not have a 
current provider will be offered a referral for clinical care if appropriate. For patients who complete the 
study (including outcome assessments), a study clinician (PI or psychiatrist who is covering for the PI) 
will meet with them to discuss the transition of care plan. As part of the study exit visit, the study 
clinician will complete an end-of-study disposition form, which includes a description of the treatment 
plan and the next scheduled follow-up appointment with their provider, if applicable. This will be 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
31
documented in the participant’s chart. For patients who have an established psychiatrist or other 
treatment provider, the study team will work closely to ensure that there is a smooth transition of care 
from the end of the study to their clinical treatment. A study clinician may contact the participant’s 
primary provider for coordination of clinical care. For patients who do not have pre-established care, the 
study team will provide referrals to one of the programs currently serving individuals with PTSD, i.e.,  a 
referral within the Mount Sinai Health System or larger community, based on availability and patient 
preference. At the exit visit, the study team will check in on the status of the disposition plan, and any 
follow-up appointments will be discussed.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
6.2.1
ACQUISITION AND ACCOUNTABILITY
The study drug, ketamine, will be acquired, stored, and tracked by the ISMMS research pharmacy, 
Investigational Drug Services (IDS), in keeping with institutional policies. Full MOPs are available directly 
from IDS.
6.2.2
FORMULATION, APPEARANCE, PACKAGING, AND LABELING
This information will be provided by the ISMMS research pharmacy, IDS.
6.2.3
PRODUCT STORAGE AND STABILITY
This information will be provided by the ISMMS research pharmacy, IDS.
6.2.4
PREPARATION
This information will be provided by the ISMMS research pharmacy, IDS.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
As this is an open-label pilot study, no randomization is required; all eligible participants will receive  six 
ketamine infusions and participate in five WET sessions. No blinding is necessary, as all participants will 
receive the same treatment. 
6.4
STUDY INTERVENTION COMPLIANCE
The primary study monitors, Dr. Feder and Dr. Murrough, will monitor study progress, compliance, and 
safety continuously. The two monitors will meet formally during a weekly lab meeting.  In addition, the 
DSMB (see below) will review the accumulated safety and data information twice a year.
6.5
CONCOMITANT THERAPY
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
32
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements.
6.5.1
RESCUE MEDICINE
The study site will supply the following medications, available emergently through the Psychiatry 
Infusion Suite or Clinical Research Unit or non-emergently through IDS:
o
Naloxone (opioid reversal)
o
Flumazenil (benzodiazepine reversal)
o
Epinephrine, Ephedrine, Phenylephrine
o
Esmolol, Metoprolol, Labetalol, Hydralazine
o
Atropine
o
Albuterol Inhaler
o
Lidocaine, Amiodarone
o
Hydrocortisone, Diphenydramine
o
Aspirin 81mg, Nitroglycerin Tab, Dextrose 25%
o
Ondansteron
  
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1
DISCONTINUATION OF STUDY INTERVENTION
Discontinuation from ketamine or WET does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically significant 
finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE).
The data to be collected at the time of study intervention discontinuation will include the following:

Symptom measures (e.g.,CAPS-5, MADRS, PCL-5, SDS)

Global Clinical Severity and Improvement (CGI-S and CGI-I)

End-Of-Infusion labs

Safety data

Concomitant medications

Follow-up plan 
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Participants are free to withdraw from participation in the study at any time upon request.
An investigator may discontinue or withdraw a participant from the study for the following reasons:
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
33

Pregnancy

Significant study intervention non-compliance 

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant

Disease progression which requires discontinuation of the study intervention

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Participant unable to receive a total of four or six ketamine infusions, or unable to participate in 
WET. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Visit 
Check-list Case Report Form (CRF). Subjects who sign the informed consent form and begin study 
procedures but do not receive the study intervention may be replaced.  Subjects who sign the informed 
consent form, and begin study procedures and receive the study intervention, and subsequently 
withdraw, or are withdrawn or discontinued from the study, will not be replaced.
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he or she fails to return for three scheduled visits and 
is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study visit:

The site will attempt to contact the participant and reschedule the missed visit within one week 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
8
STUDY ASSESSMENTS AND PROCEDURES
8.1
EFFICACY ASSESSMENTS 
Participants in this proposed study will provide the following efficacy data: (A) data from clinician-
administered structured interviews (e.g., structured diagnostic interview with the SCID-5 and CAPS-5, 
clinical evaluation); (B) self-report data (e.g., symptom measures); and (C) behavioral data (online 
Extinction Learning Task). Additionally, participant will provide data on (D) demographics (e.g., age, sex, 
race, education, socioeconomic status); (E) measures of estimated IQ and cognitive functioning; and (F) 
psychiatric history and treatment, including any history of psychiatric hospitalization.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
34
Diagnostic and Assessment Procedures: The diagnostic interviews and clinical ratings will be conducted 
by Master’s- or PhD-level clinical raters well-trained in diagnostic interviews and the clinical rating 
scales, supervised by the PI. Bi-annual inter-rater reliability procedures are conducted at DAC to ensure 
adequate calibration of inter-rater reliability (ICC> 0.90). In the event of staff turnover, new raters must 
achieve this threshold of reliability prior to participation.
The Structured Clinical Interview for DSM-5 (SCID-5) is the most widely used structured diagnostic 
interview to determine psychiatric diagnoses in clinical research settings based on DSM-5 criteria. The 
SCID-5 is organized into diagnostic modules, to assess mood, psychotic, substance use, anxiety, 
obsessive-compulsive and related, eating, and trauma- and stressor-related disorders, and other 
disorders 51. The SCID-5 will be used in this study to determine whether subjects meet DSM-5 criteria for 
PTSD and to assess other co-morbid psychiatric diagnoses, in order to determine study eligibility.
The Clinician Administered PTSD Scale for DSM-5 (CAPS-5) is a structured diagnostic interview and the 
gold standard for assessing the DSM-5 symptoms of PTSD. The scale also assesses social and 
occupational functioning, dissociation symptoms, and the validity of symptom reports. The CAPS-5 uses 
a single 5-point ordinal rating scale to measure symptom severity. Symptom severity ratings combine 
information about symptom frequency and intensity obtained by the interviewer. Psychometric 
properties indicate high criterion and construct validity and high agreement with a self-report measure 
of PTSD.50 The CAPS-5 requires approximately 40 minutes to administer. The CAPS-5 will be 
administered at screening to determine PTSD symptom severity. In addition to meeting DSM-5 criteria 
for PTSD, subjects must also have a total CAPS-5 score ≥30, indicating at least moderate PTSD symptom 
severity, in order to be eligible to participate in this study. The CAPS-5 will also be used to determine 
ketamine responder on non-responder status of participants following the first four ketamine infusions. 
Importantly, participants’ total CAPS-5 severity scores will serve as the primary outcome of interest.
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item instrument used for the 
evaluation of depressive symptoms in adults and for the assessment of any changes to those 
symptoms.52 Each of the 10 items is rated on a scale of 0 to 6, with differing descriptors for each item. 
These individual item scores are added together to form a total score, which can range between 0 and 
60 points. The estimated time to administer this scale is 20 minutes. Inter-rater reliability of the scale is 
high and scores correlate significantly with those of the HAM-D. On the infusion days a modified MADRS 
will be used that will exclude the sleep and appetite items. The MADRS will be used in this study as a 
secondary outcome measure, to assess change in co-morbid depressive symptom levels over time. 
Additionally, the MADRS will be employed to assess severity of co-morbid depressive symptoms as a 
clinical predictor for Aim 3 analyses.
The Montreal Cognitive Assessment (MoCA) is a widely used cognitive screening tool to differentiate 
mild cognitive impairment from cognitive changes associated with health aging.55 A recommended 
cutoff score of 23 will be used to determine eligibility for this study, based on meta-analytic findings 
indicating that the cutoff of 26/30 originally suggested for this measure is associated with a higher 
percentage of false positives, especially among individuals of lower education or older age.78
The Wechsler Test of Adult Reading (WTAR) is a neuropsychological assessment measure used to derive 
a pre-morbid estimate of intelligence, and requires participants to read a list of 50 words.54 The WTAR 
will be administered at study screening to estimate participant IQ. Subjects with estimated IQ < 80 will 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
35
be excluded from the study. Additionally, estimated IQ derived with the WTAR, used in a prior non-
inferiority RCT comparing WET to CPT,41 will be used as a predictor for Aim 3 analyses.
The Childhood Trauma Questionnaire (CTQ) is a widely used, valid and reliable retrospective self-report 
scale to screen for a history of childhood abuse and neglect. It includes a total of 28 items, and yields 
five subscale scores –emotional abuse and neglect, physical abuse and neglect, and sexual abuse–, as 
well as a minimization-denial score.56 In the proposed study, the CTQ will be employed as a trauma 
history predictor for Aim 3 analyses.
The Traumatic Life Events Questionnaire (TLEQ) is a commonly used and rigorously tested self-report 
scale to assess the frequency, severity, and timing of a wide range of traumatic experiences experienced 
across the individual’s lifetime, including childhood and adulthood.57 Lifetime number of traumas, 
trauma type, and timing will be employed as trauma history predictors for Aim 3 analyses.
The PTSD Checklist for DSM-5 (PCL-5) is a widely used 20-item self-report measure to assess the 20 
DSM-5 PTSD symptoms.58 The PCL-5 measure has a Specific version to assess severity of PTSD symptoms 
in relation to a specific trauma. The Specific version of the PCL-5 will be used in this study as an 
additional, secondary outcome measure of PTSD symptom severity.
A 5-item abbreviated version of the Medical Outcomes Study Social Support Survey (MOS-SSS),68 a 
widely used self-report scale assessing perceived social support, including emotional/informational, 
tangible and affectionate support, utilizing a 5-point Likert scale. This scale will be administered at 
baseline (before the first infusion) and again 3 weeks after the addition of WET. This scale will be used 
for exploratory analyses for Aim 3.
The Perceived Ability to Cope with Trauma (PACT)70 is a 20-item self-report scale assessing perceived 
coping abilities following a traumatic event. There are two main subscale scores: Forward-focused 
Coping score, reflecting the respondent’s ability to maintain goals and plans following a traumatic event, 
and Trauma-focused Coping score, reflecting the respondent’s ability to face feelings and cognitions 
relating to a traumatic event. Additionally, a Flexibility score can be calculated to determine the 
respondent’s ability to engage in both forward-focused and trauma-focused coping strategies following 
a traumatic event. This scale will be administered at baseline (before the first infusion) and again 3 
weeks after the addition of WET. This scale will be used for exploratory analyses for Aim 3.
The short-item Centrality of Event Scale (CES)69 is a 7-item scale that measures how central the most 
stressful/traumatic event is to an individual’s identity and life narrative. This scale will be administered 
at baseline (before the first infusion) and again 3 weeks after the addition of WET. This scale will be used 
for exploratory analyses for Aim 3.
The Impact of Event Scale-Revised (IES-R) is one of the most widely used self-report measures of stress 
reactions to traumatic events,67 measuring both intrusion and avoidance. Correlations between IES-R 
subscales and PTSD diagnosis assessed with the CAPS are high (>0.75). Unlike the PCL-5, this scale is able 
to assess changes in PTSD symptoms (intrusion and avoidance) over a 24-hour time period. In this study, 
we will use this measure as a secondary outcome measure to assess for rapid improvement in  PTSD 
symptom severity at 24-hours after the first ketamine infusion, and to assess symptom change at each 
ketamine infusion and on the ketamine response assessment day. 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
36
The Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR) is a commonly used self- 
report scale to assess depressive symptom severity.66 The total score of the QIDS-SR is based on the nine 
criterion symptom domains of major depressive disorder. In this study, we will use this measure as a 
secondary outcome measure to assess for rapid improvement in comorbid depressive symptom severity 
at 24-hours after the first ketamine infusion, and to assess symptom change at each ketamine infusion 
and on the ketamine response assessment day. 
The Hood Mysticism Scale (HMS) is a validated measure of subjective spirituality, tested in multiple 
cultural contexts.79 More recently this scale has been used to capture mystical or spiritual experiences 
during sub-anesthetic ketamine infusions, and there is evidence that these mystical experiences under 
ketamine treatment may mediate treatment response, at least in alcohol use disorder populations.80 In 
this study, we will use the 8-item version of this scale to assess mystical experiences for exploratory 
analyses of mediators of response to ketamine. This scale is administered immediately after the end of 
Infusions 1 and 2, as we expect participants’ experiences to be more intense during the first two infusion 
days.
The Psychological Insight Questionnaire (PIQ) assesses insightful experiences, which may be an 
essential part of psychedelic treatments.81 This newly developed questionnaire assess many aspects of 
psychological insight, including realizations about personality, relationships, emotions, and behaviors, 
with the goal of assessing these experiences in clinical trials of psychedelic medications. This scale will 
be administered at the end of the post-infusion monitoring period on Infusions 1 and 2, as we expect 
participants’ experiences to be more intense during the first two infusion days. 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a comprehensive, semi-structured interview 
measure commonly employed in clinical trials. The C-SSRS measures the full spectrum of suicidality, 
including passive and active suicidal ideation, suicidal intent, and suicidal behaviors.60 All study subjects 
will be assessed for suicidal ideation and behavior by the study PI or other trained member of the study 
team. Both past-month and lifetime versions of the C-SSRS will be administered at study screening. 
Individuals who score a 4 or greater on the past-month suicidal section, or who have engaged in any 
suicidal behavior in the past month, will be excluded and referred promptly for clinical care. Our 
clinicians and staff at the Depress Anxiety Center all undergo formal web-based training on 
administering the C-SSRS, and have extensive experience in its utilization. The Center has established 
SOPs for handling suicidality. For patients who do not show suicidality at the described threshold and 
proceed to participate in this study, the C-SSRS will be administered at each assessment time point (until 
12 weeks, and then monthly up to 24 weeks or until loss of response), to assess for suicidal ideation and 
participant safety throughout the study. Participants with scores of 4 or greater at any point during the 
study will be exited from the study and promptly referred for clinical care.
The Sheehan Disability Scale (SDS) is a brief, 5-item self-report scale that assesses functional 
impairment in domains of work or school, social life, and family life.59 Higher scores on this scale 
represent higher functional impairment. This scale will be administered at screening, and then at each 
assessment time point (weekly until 12 weeks, and then monthly up to 24 weeks or until loss of 
response).
The Clinical Global Impression –Severity and –Improvement scales (CGI-S and CGI-I) are among the 
most widely used brief assessment tools in psychiatry and clinical trials.82 The CGI-S will be administered 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
37
at screening and baseline prior to any infusions, and both the CGI-S and the CGI-I will be administered at 
each assessment time point (weekly until 12 weeks, and then monthly up to 24 weeks or until loss of 
response) by the PI or another study clinician, to determine global severity of psychiatric illness.
The Brief Psychiatric Rating Scale (BPRS) is a clinician-administered assessment used to capture acute 
behavioral changes throughout treatment.73 We will use only the four items assessing positive (+) 
symptoms of psychosis such as conceptual disorganization, hallucinatory behavior, suspiciousness, and 
unusual thought content for this proposed study. The scale will be administered before and after each 
infusion.
The Clinician-Administered Dissociative States Scale (CADSS) is commonly used in ketamine studies, 
and will be administered before and after each infusion to assess the severity of dissociative symptoms 
associated with ketamine administration.72
The Young Mania Rating Scale (YMRS), first item (assessing elevated mood), is commonly used in 
ketamine studies.74 We will administer only the first item of the YMRS before and after each infusion.
 
Online Extinction Learning Task: The computerized task, administered online, consists of three phases: 
an initial aversive conditioning phase (in context A), extinction learning phase (in context A), and further 
Figure 7. Online extinction learning task (updated version). Participants are told that they are traveling through different zones 
of a spaceship, and needed to escape with enough space coins to power their journey home. Unfortunately, the coins need to 
be carried by helper robots, some of whom are unreliable. On each trial, participants encounter a robot and rate how likely they 
think that robot will be to lose coins using a sliding bar (participants are informed that their ratings will not change the outcome 
they observe, but that their predictions should be as accurate as possible in order to aid future space travelers). In a second 
version of the task (identical in structure but with an underwater setting), participants must travel through different parts of the 
ocean, and predict how likely they think different sea creatures they encounter are to keep or lose pearls they must trade for 
their passage.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
38
extinction learning (in novel context B) (see Figure 7). Importantly, the conditioned stimulus (CS) 
associated with the aversive loss outcome (US), the CS+, is only partially reinforced (P(US|CS+)=1/3), and 
the transition to extinction (P(US|CS+)=0) is unsignaled. This design maximizes uncertainty about 
whether CS+ trials during extinction should be grouped with unreinforced conditioning phase CS+ trials, 
implying a common cause is responsible for both kinds of observations, or instead that the change in 
contingencies indicates it is likely that a new cause is active in the environment. The predictive measure 
generated from this task for Aim 2 analyses (PTSD symptom change between baseline and 12 weeks 
from the start of WET) is the difference in discrimination between CS+ and CS- across the first six blocks 
of the task. 
Further, loss expectancy ratings data from each trial of the online extinction task will be analyzed via a 
computational model of latent cause inference developed by Gershman, Niv, and colleagues75,76 (see 
Data Analysis Strategy). There are two versions of the task (see description in Figure 7 note): one version 
will be administered prior to any ketamine infusions, and the second version after completion of the 
first four infusions. We will examine whether improvement in extinction learning from baseline to 
completion of four initial ketamine infusions (prior to starting WET) is associated with PTSD symptom 
improvement from baseline to 12 weeks from the start of WET.
8.2
SAFETY AND OTHER ASSESSMENTS
Participants in this proposed study will provide the following safety data: 
(A) Data related to medical history, physical examination including review of systems, vital signs, 
ECG, routine laboratory tests (comprehensive metabolic panel, complete blood count, thyroid 
function testing) needed to determine eligibility and to monitor safety of participants
(B) Measures to assess for any acute side effects associated with ketamine before and after each 
infusion; potential longer- lasting side effects will be assessed weekly until resolution.
For laboratory tests, all results will be reviewed by the PI or study-affiliated psychiatrist, and any 
incidental finding will be conveyed to the subject with provision for additional work-up if needed.
Plasma ketamine and norketamine levels will be assessed via serial blood draws at the first ketamine 
infusion. Blood will be drawn from a second IV catheter at 30, 60, 90, and 120 minutes from the start of 
the infusion. Samples will be spun down and aliquoted into plasma samples. These samples will then be 
transported to Mount Sinai Clinical Laboratory Services (Sinai Labs) for shipment to an external 
laboratory (LabCorps) for the ketamine and norketamine levels.
The Patient-Rated Inventory of Side Effects (PRISE) Adverse Event Visit Checklist71 is a clinician- 
administered questionnaire used to qualify side effects by identifying and evaluating the tolerability of 
each symptom. This scale will be completed before and after each infusion, and at each assessment time 
point (weekly until 12 weeks, and then monthly up to 24 weeks or until loss of response), by the PI or 
another study psychiatrist.
  
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
39
8.3.1
DEFINITION OF ADVERSE EVENTS (AE)
 All adverse events (AEs), defined as any physical or clinical change or disease experienced by a 
participant at any time during the course of the study, will be recorded in the participant’s research 
records and will be captured in the electronic data capture system. Dr. Feder will be responsible for 
reporting to and following the guidance of any other applicable oversight bodies, including (but not 
limited to) the Institutional Review Board, the Data Safety and Monitoring Board.
8.3.2
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
8.3.3
CLASSIFICATION OF AN ADVERSE EVENT
8.3.3.1
SEVERITY OF EVENT
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity. 
•
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.
8.3.3.2
RELATIONSHIP TO STUDY INTERVENTION
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect. 
•
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
40
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary.
•
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition.
•
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate.
•
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments).
•
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.
8.3.3.3
EXPECTEDNESS 
The PI will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention.
8.3.4
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor.
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution.
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE. 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
41
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode.
Drs. Adriana Feder, James Murrough,  Manish Jha, or Matthew Klein will record all reportable events 
with start dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 
days (for SAEs) after the last day of study participation.  At each study visit, the investigator will inquire 
about the occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information 
until resolution or stabilization.
8.3.5
ADVERSE EVENT REPORTING 
Dr. Feder will be responsible for reporting AEs to and following the guidance of any other applicable 
oversight bodies, including (but not limited to) the Institutional Review Board, the Data Safety and 
Monitoring Board, and the sponsor (the Icahn School of Medicine at Mount Sinai). At six-month intervals 
during the course of the study and again at its completion, the DSMB will be provided with summaries of 
the numbers and rates of adverse events. These reports will include types of events, severity, and 
treatment phase. Data on individual non-serious adverse events is not expected to be needed for this 
review.
Many subjects may admit to fleeting thoughts of death or briefly wishing for death; these thoughts need 
to be considered in context of the subject’s overall history, along with a consideration of other risk 
factors for suicide. The presence of suicidal ideation without intent will therefore not be considered an 
Adverse Event, unless the suicidal ideation has increased in frequency or severity since baseline.
8.3.6
SERIOUS ADVERSE EVENT REPORTING 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the DSMB and ISMMS IRB.
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the DSMB or ISMMS IRB and should be provided as soon as possible.
The study sponsor (ISMMS) will be responsible for notifying the Food and Drug Administration (FDA) of 
any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the sponsor's initial receipt of the information.
8.3.7
REPORTING EVENTS TO PARTICIPANTS 
Both ketamine and WET have been extensively used in clinical trials and clinical practice, thus AEs 
associated with these treatments are known; they are summarized in the study consent form, and are 
reviewed with study participants during administration of study consent procedures. In the event that 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
42
any unexpected AE emerges during the course of the study, this unexpected AE will be added to the 
study consent (through an IRB amendment request), and reviewed with study participants during 
consent procedures.
8.3.8
EVENTS OF SPECIAL INTEREST 
 Not applicable.
8.3.9
REPORTING OF PREGNANCY 
In the event that a participant becomes pregnant while completing the study intervention(s), the 
participant will be exited from the trial after having completed end-of-infusion safety labs. Any 
pregnancies that occur while a subject is active in the protocol and after they have received ketamine 
infusions will be reported to the DSMB, ISMMS IRB, and other agencies (FDA, OHRP) as necessary.
8.4
UNANTICIPATED PROBLEMS
8.4.1
DEFINITION OF UNANTICIPATED PROBLEMS (UP)
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied;
•
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and
•
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized.
8.4.2
 UNANTICIPATED PROBLEM REPORTING 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information:
•
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number;
•
A detailed description of the event, incident, experience, or outcome; 
•
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
•
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP.
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
43
•
UPs that are serious adverse events (SAEs) will be reported to the IRB within 24 hours of the 
investigator becoming aware of the event. 
•
Any other UP will be reported to the IRB within 5 business days of the investigator becoming 
aware of the problem. 
•
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 6 months of the IRB’s receipt of the report of the 
problem from the investigator.
 
8.4.3
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
Unanticipated problems will be added to the study consent form if any are identified (via an IRB 
amendment). Newly enrolled participants will thus be informed about any such problems during 
administration of consent procedures for the study.
9
STATISTICAL CONSIDERATIONS 
9.1
STATISTICAL HYPOTHESES

Primary Efficacy Endpoint(s): 
o
The primary outcome is change in PTSD symptom severity from baseline to 12 weeks 
from the start of WET measured by the Clinician-Administered PTSD Scale for DSM-5 
(CAPS-5) score at 12 weeks from the start of WET minus the CAPS-5 score at baseline. 
The analysis of the primary endpoint for this pilot study will be descriptive and no 
formal hypothesis testing will be conducted.  The mean change in CAPS-5 score and 
corresponding 95% confidence interval will be reported.  

Secondary Efficacy Endpoint(s) (Exploratory):
In this early-phase study, analyses of secondary efficacy outcomes will be considered 
exploratory and hypothesis-generating. Therefore, no formal hypothesis testing will be 
conducted. 
9.2
SAMPLE SIZE DETERMINATION
In this pilot study up to 15 patients will be enrolled.  A sample size of 15 patients will produce a two-
sided 95% confidence interval around the mean change in CAPS-5 at 12 weeks from the start of WET 
with a distance from the mean to the limits that is equal to 0.5 standard deviations.
Precision was calculated using PASS 2019.83
9.3
POPULATIONS FOR ANALYSES
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
44
Analysis datasets will include and Intention-to-treat (ITT) Analysis Dataset (all enrolled patients) and a 
Per-protocol Analysis Dataset (including only participants who completed the study). Additionally, a 
Safety Analysis Dataset and descriptive analyses will include all participants in the study.
9.4
STATISTICAL ANALYSES
9.4.1
GENERAL APPROACH
Continuous variables will be summarized using the following descriptive statistics: number of non-missing 
values, means, standard deviations, medians, interquartile range, maximum, and minimum. Categorical 
variables will be summarized using number of non-missing values, counts and percentages. 
Rates of events will be calculated as the ratio of the total number of events recorded divided by the total 
patient-time. Total patient-time will be calculated by summing the time (in study time units, e.g., days or 
months) that patients were at risk for a specific event from the reference time point until either study exit or 
the end of the time period of interest. Rates and their 95% confidence intervals will be reported.  
Time-to-event variables will be summarized using the Kaplan-Meier method.
For any variable measured at multiple points in time, change since the day prior to starting WET, “pre-
WET” (i.e., the day when response to ketamine is assessed), will be calculated as the difference between 
the value of the variable at a specific point in time (e.g. 12 weeks) minus the value from pre-WET. 
Relative change from pre-WET will be calculated as the value of a parameter at a specific point in time 
minus the pre-WET value of the parameter divided by the pre-WET value of the parameter.  Percent 
change will be calculated as the relative change multiplied by 100.
Should any of the statistical methods proposed prove unsuitable during data analysis, more appropriate 
methods will be used. These include data transformation (for example to a logarithmic scale) to satisfy model 
assumptions such as normally distributed residuals with constant variance, the application of non-parametric 
techniques or the use of a different link function or analytical/modeling technique. The SAP will be updated 
with the methods used and the justification for the change prior to data set and database lock.
9.4.2
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S)
The primary outcome is change in PTSD symptom severity from baseline to 12 weeks from the start of 
WET measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score at 12 weeks from the 
start of WET minus the CAPS-5 score at baseline. The analysis of the primary endpoint for this pilot study 
will be descriptive. The mean change in CAPS-5 score from baseline with corresponding 95% confidence 
interval will be reported.
9.4.3
ANALYSIS OF THE SECONDARY ENDPOINT(S)
o
Secondary Efficacy Outcomes (Exploratory): In this early-phase study, analyses of secondary 
efficacy outcomes will be considered exploratory and hypothesis-generating.  CAPS-5, PCL-5, 
MADRS, CGI and SDS scores will be collected weekly through 6 weeks after the start of WET from all 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
45
eligible participants, and thereafter until 12 weeks (up to weekly, as tolerated, ensuring assessment 
at the 12-week time point for all participants). All participants will be followed naturalistically for 12 
weeks from the start of WET, in order to capture, descriptively, more gradual effects of WET and 
potential effects of the combination of ketamine + WET in all patients. Thereafter, they will be 
collected monthly through week 24 from start of WET or until loss of treatment response, for the 
subgroup of participants who demonstrate improvement on the CAPS-5 at the 12-week assessment. 
Aggregate scores prior to adding WET, during WET, and during the maintenance phase (weeks 3 
onward) will be reported descriptively at each time point using the number observed, mean, 
standard deviation, median, and interquartile range. Individual patient trajectories on these 
measures will be plotted over time to explore treatment response and patterns in maintenance of 
response.  Mean change in CAPS-5 scores from baseline and corresponding 95% confidence 
intervals, as well as the proportion of patients with ≥30% improvement from baseline on the CAPS-5 
will also be reported at each time point. In addition, linear mixed-effects models of these outcomes 
may be fit to compare mean scores over time. Mixed models will test for the inclusion of a random 
intercept for patient and fixed effects for week against a fixed intercept model using a likelihood 
ratio test after comparing each model fit statistic (i.e., Akaike information criterion, AIC) where the 
best fitting model is the model with the lowest corresponding AIC. Once fit is assessed, parameter 
interpretation will commence. 
o
IES-R and QIDS-SR with past-24-hour recall – collected only at baseline, before each ketamine 
infusion, 24 hours after the first infusion, and on the response to ketamine assessment day – will be 
examined descriptively.
The relationship between depressive symptoms and PTSD will be explored to assess whether 
worsening depressive symptoms correlate with worsening PTSD symptoms and whether there is any 
evidence that the worsening of one precedes the other. Scale scores of both measures will be plotted 
over time together to evaluate trends descriptively.  Fixed and mixed effects regression models will also 
be explored to estimate effects and 95% confidence intervals.  
o
Finally, additional analyses might explore differences with a historical comparison group from our 
published repeated IV ketamine study for PTSD (Feder et al 2021).
Aim 2 (Exploratory): To evaluate whether ketamine-induced change in extinction learning predicts 
maintenance of ketamine response over time. We will use regression models to evaluate whether 
ketamine-induced change in extinction learning [improvement in extinction learning between two time 
points: (1) before infusions and (2) after four infusions (prior to starting WET), measured with the 
computerized online Extinction Learning Task, is associated with change in CAPS-5 at 12 weeks after the 
start of WET. A univariable model of ketamine-induced change on the extinction learning measure 
[discrimination between aversively conditioned (CS+) and safe (CS-) stimuli over the first six blocks of the 
task] and changes in CAPS-5 score will be examined. Beta coefficients and 95% confidence intervals will 
be reported. A significant association between greater ketamine-induced improvement in extinction 
learning and improvement in CAPS-5 scores will be considered supportive of Hypothesis 2.
Computational analyses: Loss expectancy ratings data from each trial of the online extinction task will 
be analyzed via a computational model of latent cause inference developed by Gershman, Niv, and 
colleagues.75,76 Importantly, this model has previously been shown to be able to explain individual 
differences in failure of extinction learning in both healthy volunteers and trauma-exposed individuals 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
46
with and without PTSD.75,76 In brief, the model posits that during learning, an individual attempts to infer 
which underlying (latent) cause is responsible for their observations, based on a combination of their 
previous experience and prior beliefs about causal structure of the environment. Prior beliefs about the 
causal complexity of the environment are governed by a single concentration parameter, alpha (α). The 
key model output submitted to further analysis is the likelihood for each participant of a model where α 
was allowed to be > 0 (favoring multiple causes), compared to a model where α=0 (single cause 
responsible for all observations), quantified as a log Bayes Factor (logBF; higher values=greater 
likelihood of a multi-cause model). The analysis will be run in MATLAB,84 using publicly-available code 
associated with Gershman and Niv’s published work.75,76
9.4.4
SAFETY ANALYSES
Side effects measured by the Patient-Rated Inventory of Side Effects (PRISE) will be reported 
descriptively using the number and percentage of patients with each reported side effect.  
Psychotomimetic, dissociative, and manic symptoms experienced on infusion days, measured by the 
Clinician-Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and 
the first item (elevated mood) of the Young Mania Rating Scale (YMRS) will also be reported 
descriptively. The distribution of suicide risk (low, moderate or high) as measured by the Columbia-
Suicide Severity Rating Scale (C-SSRS) will be reported by visit descriptively.  
9.4.5
BASELINE DESCRIPTIVE STATISTICS
Patient demographics and baseline characteristics will be summarized using mean and standard 
deviation or median and interquartile range as appropriate for continuous measures, and number and 
percentage for categorical measures. 
9.4.6
PLANNED INTERIM ANALYSES 
 Not applicable.
9.4.7
SUB-GROUP ANALYSES
Not applicable.
9.4.8
TABULATION OF INDIVIDUAL PARTICIPANT DATA
Not applicable.
9.4.9
EXPLORATORY ANALYSES
Secondary efficacy endpoint analyses and Aim 2 analyses are exploratory (see details above).
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
47
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS
10.1.1 INFORMED CONSENT PROCESS
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written or electronic documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol: HRP-502a, documentation of informed consent.
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION
After completing the screening process at DAC through protocol STUDY-10-00606, potentially eligible 
participants will be invited to participate in a screening visit for this protocol. Informed consent may be 
obtained in person or remotely, using a HIPAA-compliant telehealth platform(e.g., VSee, Doximity, 
HIPAA-Zoom) and the electronic consent survey housed on REDCap. As the proposed study involves 
ketamine infusions, the informed consent will be obtained by either the PI or one of the study-affiliated 
psychiatrists. Consent may be obtained by a clinical research coordinator prior to administering clinical 
rating scales, self-report scales, the extinction learning task, and/or the medical clearance assessment. 
In this case, the PI or study-affiliated psychiatrist will re-review the consent form with the participant 
and will co-sign the form prior to the participant beginning the first study intervention (ketamine 
infusions). Potential participants will be informed about possible alternatives to participating in the 
study. A release of information will be obtained for review of any available historical and clinical data. 
Authorization is also obtained from each subject in the consent document, permitting the research team 
to use, create, or disclose the subject's PHI for research purposes. The nature of the project, procedures, 
relative risks and benefits, and alternatives to participation in the project will be discussed with the 
individual. The individual will be given ample opportunity to ask any questions they might have. 
Following this discussion, the individual will be given a physical or electronic copy of the consent form to 
review at their leisure, and any remaining questions will be answered. If the individual remains 
interested in the project, written or electronic informed consent is obtained, and medical and 
psychiatric screening procedures are undertaken to confirm eligibility. If the individual decides not to 
participate in this study, a staff member provides reasonable and timely assistance in obtaining an 
alternative referral, if so desired. The decision not to participate does not affect eligibility to participate 
in future studies, to receive treatment at Mount Sinai or at any program serving PTSD populations, or to 
receive treatment on a private basis. Subjects will be also be given the opportunity to withdraw from the 
study at any point. The consent process also includes documentation of permission to obtain previous 
medical records, including contact with previous physicians, pharmacies, and family members.
10.1.2 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
48
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, and 
be informed of changes to study visit schedule.
 
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).
10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible. Prior to beginning any study 
procedures conducted remotely via HIPAA-compliant telehealth video platform (e.g., clinical 
assessment, delivery of a WET session), study personnel will first confirm with the participant that 
he/she is situated in a private room at home, with no other persons present in the room, to ensure 
privacy and confidentiality.
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the ISMMS. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by the clinical site and 
by ISMMS research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the ISMMS.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
49
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by 
the National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants.
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
Data collected for this study will be analyzed and stored at the ISMMS. 
Blood samples will be collected for routine clinical labs at screening (medical clearance) and study exit, 
and to measure plasma ketamine and norketamine during the first ketamine infusion. No specimens will 
be stored for future use.
When the study is completed, access to de-identified study data should requested by contacting the PI, 
Dr. Feder.
10.1.5 KEY ROLES AND STUDY GOVERNANCE
Principal Investigator
MSSM Additional Monitor
Adriana Feder, Associate 
Professor of Psychiatry
James Murrough, Assistant 
Professor of Psychiatry
Icahn School of Medicine at 
Mount Sinai 
Icahn School of Medicine at 
Mount Sinai 
1 Gustave L. Levy Place, Box 
1230, New York, NY 10029
1 Gustave L. Levy Place, Box 
1230, New York, NY 10029
212-585-4670
212-585-4640
Adriana.feder@mssm.edu
James.murrough@mssm.edu
10.1.6 SAFETY OVERSIGHT
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
50
Study PI Dr. Feder will monitor potential risks and oversee protection against risks on a regular basis, 
working closely with Co-Is Drs. Jha and Murrough for the duration of the study. The study team will also 
meet weekly as part of the larger weekly group meetings at our Depression and Anxiety Center for 
Discovery and Treatment (DAC) at Mount Sinai, where the proposed study will be conducted. All adverse 
events (AEs), defined as any physical or clinical change or disease experienced by a participant at any 
time during the course of the study, will be recorded in the participant’s research records and will be 
captured in the electronic data capture system. Dr. Feder will be responsible for reporting to and 
following the guidance of any other applicable oversight bodies, including (but not limited to) the 
Institutional Review Board and the Data Safety and Monitoring Board. 
Dr. Feder and the full-time study coordinator will evaluate the progress of the study, including periodic 
assessments of data quality and timeliness, participant recruitment, accrual and retention, participant 
risk versus benefit, and other factors that can affect study outcome.
A Data and Safety Monitoring Board (DSMB) has been established as an independent body to ensure the 
safety of participants and the validity and integrity of study data for all protocols at DAC that involve 
ketamine administration.
Functions of the Data and Safety Monitoring Board (DSMB)
The primary goals of the DSMB are as follows:
1.
To monitor and advise on scientific and ethical issues related to study 
implementation for the protection of human subjects.
2.
To review and approve the protocol and subsequently conduct bi-annual reviews to 
determine whether participant safety has been adequately safeguarded.
3.
To review procedures and decisions regarding the adequate protection of specific 
patients when investigators remove patients from protocol treatment because of 
serious adverse events (SAEs) or clinical deterioration. 
4.
To review progress to see that enrolment and retention goals are being met.
5.
To monitor and advise on ethical issues related to serious adverse events.
6.
To oversee the confidentiality of data, and quality of data collection, management, 
and analysis.
7.
To conduct any interim analysis of study outcome, as well as determining from such 
analyses whether study continuation or discontinuation is warranted. 
 
Membership of the DSMB
The DSMB will be the same DSMB that currently reviews all ongoing ketamine clinical trials conducted 
by investigators at DAC, and will be comprised of the same personnel. The DSMB includes the following 
members: Dan Iosifescu, MD (DSMB Chair, Department of Psychiatry, New York University), Lee Chang, 
MD (Department of Anesthesiology, Baylor College of Medicine), Mark Green, MD (Department of 
Neurology, Icahn School of Medicine at Mount Sinai), Menachem Wiener, MD (Department of 
Anesthesiology, Icahn School of Medicine at Mount Sinai), and Emilia Bagiella (Statistician, Icahn School 
of Medicine at Mount Sinai). The board will review the project’s data and safety on bi-annual basis and 
report their findings to the PI.  Dr. Feder will work with the study research coordinator to convene the 
DSMB within the first three months of the project period.
 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
51
Monitoring of Safety Data by the DSMB
  Safety Reporting to the DSMB.  The DSMB review adverse events (AEs and serious adverse events 
[SAEs]), as well as treatment retention rates and reasons for dropout.
  Serious Adverse Events. Expedited review will occur for all Serious Adverse Events (SAEs) – any fatal 
event, immediately life-threatening event, permanently or substantially disabling event, or any event 
requiring inpatient hospitalization. This also includes any event that a study investigator or the DSMB 
judges to impose a significant hazard, contraindication, side effect, or precaution. Notification by email, 
and fax transmittal of all related study forms shall be made to the DSMB within 2 days of the occurrence 
of any SAE. Additional reporting to the Mount Sinai IRB will be done within 24 hours of the SAE. 
  Non-Serious Adverse Events. At six-month intervals during the course of the study and again at its 
completion, the DSMB will be provided with summaries of the numbers and rates of adverse events. 
These reports will include types of events, severity, and treatment phase. Data on individual non-serious 
adverse events is not expected to be needed for this review.
  Other Safety-Related Reports. At six-monthly intervals throughout the course of the study, the DSMB 
will also receive summary reports of treatment retention and reasons for dropout, by study phase.
  Study Stopping Rules. If at any time during the course of the study, the DSMB judges that risk to 
participants outweighs potential benefits, the DSMB shall have the discretion and responsibility to 
recommend terminating the study.
  DSMB Monitoring of Data Quality. At least half-yearly during the course of the study, the DSMB will 
receive a report on data quality and completeness. At a minimum, this will include an overview of the 
progress of participant recruitment and retention; summary reports describing patient compliance with 
WET; and a summary of the completeness and quality of key data elements needed to characterize 
patients, and their primary and secondary outcomes. These reports will be used by the DSMB to 
evaluate the capacity of the data capture and processing to support scientifically valid analyses. 
  Biannual DSMB Report to the IRB. Biannually during the course of the study the DSMB will prepare a 
summary report of its findings regarding safety and quality based on data received to that point in the 
study. This report will include a summary of all safety findings as well as an assessment of protocol 
compliance and data quality. Any recommendations to improve patient safety, protocol adherence, or 
data quality will be made in the annual DSMB report. A copy of the annual DSMB report will be sent to 
the Mount Sinai IRB along with the annual renewal report. 
10.1.7 CLINICAL MONITORING
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). 
•
On-site monitoring will be conducted by the database manager for the study monthly 
throughout the study, comprehensively reviewing all CRF’s and eCRF’s for completion and 
accuracy. At study close, the database manager will randomly review 10% of cases to verify 
completion and accuracy of all CRF’s and eCRF’s for a given participant. The results of these 
audits will be available within the electronic data capture system, REDCap, and will be 
summarized to the PI.
•
Independent audits will not be conducted.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
52
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the PI for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the PI and Co-I Dr. James Murrough will verify 
that the clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good 
Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all source data/documents and reports for the 
purpose of monitoring and auditing by the ISMMS, and inspection by local and regulatory authorities.
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by the ISMMS. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents.
10.1.9.2 STUDY RECORDS RETENTION 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
53
10.1.10
PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly. 
These practices are consistent with ICH GCP: 
•
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
•
5.1 Quality Assurance and Quality Control, section 5.1.1 
•
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site investigator to use continuous vigilance to identify and record any 
deviations from the IRB-approved protocol. All deviations must be addressed in study source 
documents. Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the MOP.
10.1.11
PUBLICATION AND DATA SHARING POLICY
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations:
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication.
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested by other researchers 10 years after the 
completion of the primary endpoint by contacting Dr. Adriana Feder or Dr. James Murrough.
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data.
10.1.12
CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the ISMMS FCOI Committee has established policies and procedures for 
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
54
all study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest.
10.2 ADDITIONAL CONSIDERATIONS
Not applicable.
10.3 ABBREVIATIONS
AE
Adverse Event
ANCOVA
Analysis of Covariance
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
CMP
Clinical Monitoring Plan
COC
Certificate of Confidentiality
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
DRE
Disease-Related Event
EC
Ethics Committee
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act of 2007
FFR
Federal Financial Report
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
HIPAA
Health Insurance Portability and Accountability Act 
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
IDE
Investigational Device Exemption
IND
Investigational New Drug Application
IRB
Institutional Review Board
ISMMS
Icahn School of Medicine at Mount Sinai
ISO
International Organization for Standardization
ITT
Intention-To-Treat
LSMEANS
Least-squares Means
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Procedures
MSDS
Material Safety Data Sheet
NCT
National Clinical Trial
NIH 
National Institutes of Health
NIH IC
NIH Institute or Center
OHRP
Office for Human Research Protections
PI
Principal Investigator
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
55
PTSD
Posttraumatic Stress Disorder
QA
Quality Assurance
QC
Quality Control
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOC
System Organ Class
SOP
Standard Operating Procedure
WET
Written Exposure Therapy
UP
Unanticipated Problem
US
United States
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
56
10.4 PROTOCOL AMENDMENT HISTORY
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page. 
Version
Date
Description of Change 
Brief Rationale
1.1
3/23/21
Limited maximum dose of ketamine 
to 60 mg per infusion (dose for 
approximately 120 kg body weight)
Safety; requested by FDA
1.2
5/24/21
Removed End of Infusions Medical 
Assessment and changed CAPS-5 
cutoff score from (score ≥ 25) to 
(score ≥ 30).
Undue patient burden; not 
necessary for patient safety
For consistency with prior 
studies, and to capture moderate 
severity PTSD
2.0
6/23/21
All eligible participants will receive 
six (6) infusions of ketamine and five 
(5) WET sessions, regardless of 
responder status, and will be assessed 
weekly for 12 weeks following the 
start of WET. After 12 weeks, 
participants who demonstrate ≥ 30% 
improvement at the 12-week 
assessment will be assessed monthly 
for up to 24 weeks following the start 
of WET or until loss of response.
Adding Hood Mysticism Scale and 
Psychological Insight Questionnaires 
to Infusions 1 and 2.
Based on our recent meeting 
with a panel of experts in the 
field, and following their 
recommendation, we would like 
to offer all 6 infusions and 5 
WET sessions in order to 
capture more gradual effects of 
WET and the potential effects of 
Ketamine + WET in both 
responders and non-responders 
to ketamine. The primary aim of 
the study remains unchanged.
We are adding the scales to 
assess participant experiences 
during the infusions.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
57
11
REFERENCES 
References
1.
Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National 
Comorbidity Survey. Archives of general psychiatry. 1995;52(12):1048-1060.
2.
Schell TL, & Marshall, G. N. . Survey of individuals previously deployed for OEF/OIF. In: T. Tanelian LHJ, ed. 
Invisible wounds of war: Psychological and cognitive injuries, their consequences, and services to assist 
recovyer. Santa Monica, CA: Rand Corporation; 2008:87-115.
3.
Berger W, Mendlowicz MV, Marques-Portella C, et al. Pharmacologic alternatives to antidepressants in 
posttraumatic stress disorder: a systematic review. Progress in neuro-psychopharmacology & biological 
psychiatry. 2009;33(2):169-180.
4.
Defense UDoVAaDo. VA/DoD clinical practice guideline for the management of posttraumatic stress 
disorder and acute stress disorder. June 2017.
5.
Hoskins M, Pearce J, Bethell A, et al. Pharmacotherapy for post-traumatic stress disorder: systematic 
review and meta-analysis. The British journal of psychiatry : the journal of mental science. 2015;206(2):93-
100.
6.
Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic 
posttraumatic stress disorder: a randomized clinical trial. JAMA psychiatry. 2014;71(6):681-688.
7.
Feder A, Rutter SB, Schiller D, Charney DS. The emergence of ketamine as a novel treatment for 
posttraumatic stress disorder. Adv Pharmacol. 2020;89:261-286.
8.
Feder A, Costi S, Rutter SB, et al. A randomized controlled trial of repeated ketamine administration for 
chronic posttraumatic stress disorder. The American journal of psychiatry.2021;178(2),193-202
9.
Wilkinson ST, Holtzheimer PE, Gao S, Kirwin DS, Price RB. Leveraging Neuroplasticity to Enhance Adaptive 
Learning: The Potential for Synergistic Somatic-Behavioral Treatment Combinations to Improve Clinical 
Outcomes in Depression. Biological psychiatry. 2019;85(6):454-465.
10.
Hasler G. Toward specific ways to combine ketamine and psychotherapy in treating depression. CNS 
Spectr. 2020;25(3):445-447.
11.
Rodriguez CI, Wheaton M, Zwerling J, et al. Can exposure-based CBT extend the effects of intravenous 
ketamine in obsessive-compulsive disorder? an open-label trial. The Journal of clinical psychiatry. 
2016;77(3):408-409.
12.
Wilkinson ST, Wright D, Fasula MK, et al. Cognitive Behavior Therapy May Sustain Antidepressant Effects 
of Intravenous Ketamine in Treatment-Resistant Depression. Psychotherapy and psychosomatics. 
2017;86(3):162-167.
13.
Shiroma PR, Thuras P, Wels J, Erbes C, Kehle-Forbes S, Polusny M. A Proof-of-Concept Study of 
Subanesthetic Intravenous Ketamine Combined With Prolonged Exposure Therapy Among Veterans With 
Posttraumatic Stress Disorder. The Journal of clinical psychiatry. 2020;81(6).
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
58
14.
Department of Veterans Affairs DoD. VA/DoD clinical practice guideline for the management of 
posttraumatic stress disorder and acute stress disorder. June 2017.
15.
Steenkamp MM, Litz BT, Hoge CW, Marmar CR. Psychotherapy for Military-Related PTSD: A Review of 
Randomized Clinical Trials. Jama. 2015;314(5):489-500.
16.
Steenkamp MM, Litz BT, Marmar CR. First-line Psychotherapies for Military-Related PTSD. Jama. 2020.
17.
Zarate CA, Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in 
treatment-resistant major depression. Archives of general psychiatry. 2006;63(8):856-864.
18.
Malenka RC, Nicoll RA. Long-term potentiation--a decade of progress? Science (New York, NY). 
1999;285(5435):1870-1874.
19.
Reul JM, Nutt DJ. Glutamate and cortisol--a critical confluence in PTSD? Journal of psychopharmacology 
(Oxford, England). 2008;22(5):469-472.
20.
Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids 
on glutamate transmission. Nat Rev Neurosci. 2011;13(1):22-37.
21.
Radley JJ, Morrison JH. Repeated stress and structural plasticity in the brain. Ageing research reviews. 
2005;4(2):271-287.
22.
Krystal JH, Abdallah CG, Averill LA, et al. Synaptic Loss and the Pathophysiology of PTSD: Implications for 
Ketamine as a Prototype Novel Therapeutic. Current psychiatry reports. 2017;19(10):74.
23.
Averill LA, Purohit P, Averill CL, Boesl MA, Krystal JH, Abdallah CG. Glutamate dysregulation and 
glutamatergic therapeutics for PTSD: Evidence from human studies. Neuroscience letters. 2017;649:147-
155.
24.
Norrholm SD, Jovanovic T. Fear Processing, Psychophysiology, and PTSD. Harvard review of psychiatry. 
2018;26(3):129-141.
25.
Schiller D, Delgado MR. Overlapping neural systems mediating extinction, reversal and regulation of fear. 
Trends Cogn Sci. 2010;14(6):268-276.
26.
Norrholm SD, Jovanovic T, Olin IW, et al. Fear extinction in traumatized civilians with posttraumatic stress 
disorder: relation to symptom severity. Biological psychiatry. 2011;69(6):556-563.
27.
Milad MR, Pitman RK, Ellis CB, et al. Neurobiological basis of failure to recall extinction memory in 
posttraumatic stress disorder. Biological psychiatry. 2009;66(12):1075-1082.
28.
Wessa M, Flor H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from 
second-order conditioning. The American journal of psychiatry. 2007;164(11):1684-1692.
29.
Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK. Presence and acquired origin of reduced recall 
for fear extinction in PTSD: results of a twin study. J Psychiatr Res. 2008;42(7):515-520.
30.
Li N, Liu RJ, Dwyer JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse 
behavioral and synaptic deficits caused by chronic stress exposure. Biological psychiatry. 2011;69(8):754-
761.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
59
31.
Abdallah CG, Averill LA, Collins KA, et al. Ketamine Treatment and Global Brain Connectivity in Major 
Depression. Neuropsychopharmacology : official publication of the American College of 
Neuropsychopharmacology. 2017;42(6):1210-1219.
32.
Girgenti MJ, Ghosal S, LoPresto D, Taylor JR, Duman RS. Ketamine accelerates fear extinction via mTORC1 
signaling. Neurobiology of disease. 2017;100:1-8.
33.
Ju LS, Yang JJ, Lei L, et al. The Combination of Long-term Ketamine and Extinction Training Contributes to 
Fear Erasure by Bdnf Methylation. Frontiers in cellular neuroscience. 2017;11:100.
34.
Sloan DM, Marx BP. A closer examination of the structured written disclosure procedure. Journal of 
consulting and clinical psychology. 2004;72(2):165-175.
35.
Wisco BE, Baker AS, Sloan DM. Mechanisms of Change in Written Exposure Treatment of Posttraumatic 
Stress Disorder. Behavior therapy. 2016;47(1):66-74.
36.
Stojek MM, McSweeney LB, Rauch SAM. Neuroscience Informed Prolonged Exposure Practice: Increasing 
Efficiency and Efficacy Through Mechanisms. Front Behav Neurosci. 2018;12:281.
37.
Helpman L, Marin MF, Papini S, et al. Neural changes in extinction recall following prolonged exposure 
treatment for PTSD: A longitudinal fMRI study. Neuroimage Clin. 2016;12:715-723.
38.
Sloan DM, Marx BP. Written Exposure Therapy for PTSD: A Brief Treatment Approach for Mental Health 
Professionals. Washington, DC: American Psychological Association; 2019.
39.
Thompson-Hollands J, Marx BP, Sloan DM. Brief novel therapies for PTSD: Written Exposure Therapy. Curr 
Treat Options Psychiatry. 2019;6(2):99-106.
40.
Sloan DM, Marx BP, Bovin MJ, Feinstein BA, Gallagher MW. Written exposure as an intervention for PTSD: 
a randomized clinical trial with motor vehicle accident survivors. Behaviour research and therapy. 
2012;50(10):627-635.
41.
Sloan DM, Marx BP, Lee DJ, Resick PA. A Brief Exposure-Based Treatment vs Cognitive Processing Therapy 
for Posttraumatic Stress Disorder: A Randomized Noninferiority Clinical Trial. JAMA psychiatry. 
2018;75(3):233-239.
42.
Resick PA, Monson CM, Chard KM. Cognitive Processing Therapy for PTSD: A Comprehensive Manual. New 
York, NY: The Guilford Press; 2016.
43.
Ball TM, Knapp SE, Paulus MP, Stein MB. Brain activation during fear extinction predicts exposure success. 
Depression and anxiety. 2017;34(3):257-266.
44.
Lange I, Goossens L, Michielse S, et al. Neural responses during extinction learning predict exposure 
therapy outcome in phobia: results from a randomized-controlled trial. Neuropsychopharmacology. 
2020;45(3):534-541.
45.
Foa EB, Riggs DS, Massie ED, Yarczower M. The impact of fear activation and anger on the efficay of 
exposure treatment for posttraumatic stress disorder. Behavior therapy. 1995;26:487-499.
46.
Norrholm SD, Jovanovic T, Gerardi M, et al. Baseline psychophysiological and cortisol reactivity as a 
predictor of PTSD treatment outcome in virtual reality exposure therapy. Behaviour research and therapy. 
2016;82:28-37.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
60
47.
Wangelin BC, Tuerk PW. Taking the Pulse of Prolonged Exposure Therapy: Physiological Reactivity to 
Trauma Imagery as an Objective Measure of Treatment Response. Depression and anxiety. 
2015;32(12):927-934.
48.
Norbury A, Brinkman H, Kowalchyk M, et al. Latent cause inference during extinction learning in trauma-
exposed individuals with and without PTSD. PSyArXiv https://doiorg/1031234/osfio/ybr6f. 2020.
49.
Feder A, Costi S, Rutter SB, et al. A Randomized Controlled Trial of Repeated Ketamine Administration for 
Chronic Posttraumatic Stress Disorder. American Journal of Psychiatry. 2021:appi. ajp. 2020.20050596.
50.
Weathers FW, Bovin MJ, Lee DJ, et al. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): 
Development and initial psychometric evaluation in military veterans. Psychological assessment. 
2018;30(3):383-395.
51.
First MB, Williams JBW, Karg RS, Spitzer RL. User's Guide for the Structured Clinical Interview for DSM-5 
Disorders (SCID-5). Arlington, VA: American Psychiatric Association; 2015.
52.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. The British journal 
of psychiatry : the journal of mental science. 1979;134:382-389.
53.
Williams JB, Kobak KA. Development and reliability of a structured interview guide for the Montgomery 
Asberg Depression Rating Scale (SIGMA). The British journal of psychiatry : the journal of mental science. 
2008;192(1):52-58.
54.
Corporation TP. Wechsler Test of Adult Reading. In. San Antonio, TX: Harcourt Assessment; 2001.
55.
Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening 
tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699.
56.
Bernstein DP, Fink L, Handelsman L, et al. Initial reliability and validity of a new retrospective measure of 
child abuse and neglect. The American journal of psychiatry. 1994;151(8):1132-1136.
57.
Kubany ES, Haynes SN, Leisen MB, et al. Development and preliminary validation of a brief broad-
spectrum measure of trauma exposure: the Traumatic Life Events Questionnaire. Psychological 
assessment. 2000;12(2):210-224.
58.
Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The Posttraumatic Stress Disorder Checklist for 
DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. Journal of traumatic stress. 
2015;28(6):489-498.
59.
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 
1996;11 Suppl 3:89-95.
60.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and 
internal consistency findings from three multisite studies with adolescents and adults. The American 
journal of psychiatry. 2011;168(12):1266-1277.
61.
ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Department of Health, 
Education, and Welfare; 1976.
62.
Villarreal G, Hamner MB, Cañive JM, et al. Efficacy of Quetiapine Monotherapy in Posttraumatic Stress 
Disorder: A Randomized, Placebo-Controlled Trial. The American journal of psychiatry. 2016;173(12):1205-
1212.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
61
63.
Golier JA, Caramanica K, Demaria R, Yehuda R. A Pilot Study of Mifepristone in Combat-Related PTSD. 
Depress Res Treat. 2012;2012:393251.
64.
Markowitz JC, Petkova E, Neria Y, et al. Is Exposure Necessary? A Randomized Clinical Trial of 
Interpersonal Psychotherapy for PTSD. The American journal of psychiatry. 2015;172(5):430-440.
65.
Worley CB, LoSavio ST, Aajmain S, Rosen C, Stirman SW, Sloan DM. Training During a Pandemic: 
Successes, Challenges, and Practical Guidance From a Virtual Facilitated Learning Collaborative Training 
Program for Written Exposure Therapy. Journal of traumatic stress. 2020.
66.
Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology 
(QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with 
chronic major depression. Biological psychiatry. 2003;54(5):573-583.
67.
Weiss DS, & Marmar, C.R. The Impact of Events Scale—Revised. In: Wilson J, Keane, TM, ed. Assessing 
psychological trauma and PTSD. Vol 19.1997:399-411.
68.
Sherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med. 1991;32(6):705-714.
69.
Berntsen D, Rubin DC. The centrality of event scale: a measure of integrating a trauma into one's identity 
and its relation to post-traumatic stress disorder symptoms. Behaviour research and therapy. 
2006;44(2):219-231.
70.
Bonanno GA, Pat-Horenczyk R, Noll J. Coping flexibility and trauma: The Perceived Ability to Cope With 
Trauma (PACT) scale. Psychological Trauma: Theory, Research, Practice, and Policy. 2011;3(2):117-129.
71.
Rush AJ, O'Neill B. Patient-Rated Inventory of Side Effects (PRISE). Dallas, TX: University of Texas 
Southwestern Medical Center; 1999.
72.
Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the Clinician-
Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998;11(1):125-136.
73.
Overall JE, Gorham DR. The brief psychiatric rating scale. Psychological reports. 1962;10(3):799-812.
74.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. The 
British journal of psychiatry : the journal of mental science. 1978;133:429-435.
75.
Gershman SJ, Niv Y. Learning latent structure: carving nature at its joints. Curr Opin Neurobiol. 
2010;20(2):251-256.
76.
Gershman SJ, Niv Y. Exploring a latent cause theory of classical conditioning. Learn Behav. 2012;40(3):255-
268.
77.
Golier JA, Caramanica K, Demaria R, Yehuda R. A Pilot Study of Mifepristone in Combat-Related PTSD. 
Depress Res Treat. 2012;2012:393251-393251.
78.
Carson N, Leach L, Murphy KJ. A re-examination of Montreal Cognitive Assessment (MoCA) cutoff scores. 
Int J Geriatr Psychiatry. 2018;33(2):379-388.
79.
Hood Jr RW. The construction and preliminary validation of a measure of reported mystical experience. 
Journal for the scientific study of religion. 1975:29-41.
Effective Date: 8/23/2023
End Date:4/3/2024


Adding Trauma-focused Psychotherapy to Ketamine Treatment for Chronic PTSD: A Pilot Study
Version 2.0
Protocol STUDY 21-00167
23 June  2021
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
62
80.
Rothberg RL, Azhari N, Haug NA, Dakwar E. Mystical-type experiences occasioned by ketamine mediate its 
impact on at-risk drinking: results from a randomized, controlled trial. Journal of Psychopharmacology. 
2021;35(2):150-158.
81.
Davis AK, Barrett FS, So S, Gukasyan N, Swift TC, Griffiths RR. Development of the Psychological Insight 
Questionnaire among a sample of people who have consumed psilocybin or LSD. Journal of 
Psychopharmacology. 2021;35(4):437-446.
82.
Clinical Global Impression (CGI). In: W. G, ed. ECDEU Assessment Manual for Psychopharmacology. 
Rockville, MD: U.S. Department of Health, Education, and Welfare; 1976.
83.
PASS 2019 Power Analysis and Sample Size Software [computer program]. Kaysville, Utah, USA2019.
84.
MATLAB [computer program]. Natick, Massachusetts, USA2019.
Effective Date: 8/23/2023
End Date:4/3/2024

ICF_001.pdf: 
Adding Trauma-focused Psychotherapy To Ketamine Treatment For Chronic PTSD: A Pilot Study
NCT04889664
Principal Investigator: Adriana Feder, MD
Document Date: 23 August 2023


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 1 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
__________________________
STUDY INFORMATION:
Study Title: Adding Trauma-focused Psychotherapy To Ketamine Treatment For 
Chronic PTSD: A Pilot Study
Study site(s): Icahn School of Medicine at Mount Sinai
Principal Investigator (Head Researcher): Adriana Feder, MD
Physical Address: 1399 Park Avenue, 2nd floor, New York, NY 10029
Mailing Address: One Gustave L Levy Place Box 1230, NY, NY 10029
Phone: 212-585-4670
____________________________
SUMMARY OF THIS RESEARCH STUDY:
This document explains a research study you might be interested in joining.  Participation in the study 
is voluntary. You can agree to join or not. Your decision will not limit your ability to receive care at 
Mount Sinai. You should only agree to take part if you understand the study and if all of your 
questions about the research study are answered. If you do join the study, the research team must 
share any new information with you that may change your mind about taking part.
 
The purpose of this research study is to study new ways to treat post-traumatic stress disorder 
(PTSD). Treatments for PTSD do not work for everyone and it can take time to determine whether a 
person responds to treatment. The purpose of this study is to evaluate the preliminary efficacy of 
adding Written Exposure Therapy (WET) to a course of repeated IV ketamine infusions in improving 
PTSD symptoms and maintaining symptom improvement in patients with chronic PTSD. WET is a 
form of therapy that has helped alleviate symptoms of PTSD. At higher doses, ketamine has been 
used for many years as an anesthetic for medical procedures and at lower doses may be an effective 
treatment in patients with major depression and PTSD. Ketamine given for PTSD is investigational, 
which means that the FDA has not approved the drug for treating this condition. In this study, the 
effects of adding WET to ketamine treatment will be evaluated, to see their combined effect on PTSD 
symptoms and how long this effect lasts.
If you choose to participate, you will be asked to:
•
Complete a medical and psychiatric evaluation for the purposes of screening
•
Receive six (6) repeated intravenous infusions of the study drug (ketamine)
•
Receive five (5) WET sessions from a trained therapist
•
Complete psychiatric tests before and after the infusions, weekly for 12 weeks after your first 
WET session, and then monthly up to 24 weeks after your first WET session
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 2 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
You will be compensated for your time, and there are no costs associated with participating in this 
study.
Your participation is expected to last approximately 27 weeks and involves at least 25 visits, and up to 
30 visits depending on your treatment response. See below for a summary of the study flow:
The main risks to you if you choose to participate are acute ketamine side effects, discomfort from the 
questions asked during assessments, and loss of private information. 
You may also benefit from participation in this research; it is possible that participation in this study 
may temporarily improve your PTSD and/or depressive symptoms. However, longer-lasting benefits 
after completing the study are not necessarily anticipated. It is possible that you might not respond to 
ketamine or WET, and thus not experience any benefit from participating in this research study. Even 
if you do not personally benefit, your participation in this study will help to provide more information 
about the treatment of PTSD. 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 3 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
Instead of participating in this research, your choices may include continuing the standard treatment 
for PTSD, which is determined by your psychiatrist based on your psychiatric symptoms and may 
include medication, psychotherapy, and possibly other treatments. The most common standard 
treatments for PTSD include talk therapy and oral medications such as selective serotonin reuptake 
inhibitors (SSRIs), which are antidepressant medications.
If you are interested in learning more about this study, please continue to read below.
____________________________
STUDY PARTICIPATION: 
You may qualify to take part in this research study because you have experienced a traumatic event 
and may suffer from PTSD.  
Your participation in this research study is expected to last up to 27 weeks (slightly more than 6 months), 
depending on how you respond to the study treatments.
There are up to 20 people expected to take part in this research study at the Icahn School of Medicine 
at Mount Sinai (ISMMS).
Funds for conducting this research study are provided by the Icahn School of Medicine at Mount Sinai.
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.
__________________________
DESCRIPTION OF WHAT IS INVOLVED:
If you agree to take part in this research study, here is what may be involved:
1. Medical and Psychiatric Evaluation (1 or 2 screening visits, total 5-6 hours):
Location: Depression and Anxiety Center at 1399 Park Avenue, New York, NY 10029, Clinical Research 
Unit at 1468 Madison Avenue, or Remotely
On the screening visit(s), you will meet with a psychiatrist and with other members of the research team 
at the Depression and Anxiety Center (DAC).  During this part of the study, the investigator will ask 
detailed questions about your psychiatric and medical history. You will be given questionnaires that will 
involve a series of questions assessing symptoms of PTSD and depression, and a comprehensive 
diagnostic interview will be conducted as part of a full evaluation. In total, this first visit will take 
approximately 3-4 hours to complete. 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 4 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
Also during this screening visit, or when you return to DAC for a second screening visit if necessary 
(usually within a week of the first screening visit), you will complete a medical evaluation. Blood (about 
4 teaspoons; 18 ml) and urine samples will be obtained for various medical tests (blood cell count, liver 
function, thyroid function, others). All subjects will be tested for the presence of drugs of abuse in their 
urine. If any of the test results are positive you will not be able to be a part of this study, but can receive 
other clinical care by your treating psychiatrist. In addition, your blood will be screened for Hepatitis B 
and C, as the presence of these viruses can also make it unsafe for you to participate in the study.  An 
electrocardiogram (ECG), a commonly used machine that records heart electrical activity by placing 
sticky pads on the chest, will also be performed. This procedure takes about 5 minutes, and is 
administered to help identify individuals that have abnormal activity in their heart. 
After you have completed the psychiatric evaluation and medical screening, the study psychiatrist will 
review the results of your medical tests and you will be notified if you continue to qualify for the study. 
Please note that if the research team finds that you not eligible after the medical tests, you will not 
complete the other parts of the study. 
Before enrolling in the study, you will be asked to complete a Treatment Contract. In the Treatment 
Contract you will be asked to identify a doctor, family member or friend who is aware of your participation 
in this research study and who is willing to be a part of your support system. The Treatment Contract 
also outlines coping skills and things you can do when you are feeling depressed or anxious. The study 
psychiatrist may contact the person(s) who have agreed to act as your support system in the case that 
your symptoms worsen during the study or in case there is an emergent medical issue that requires 
immediate contact. You will be given a copy of this Treatment Contract for your records.
You will not qualify to continue in the study if the psychiatric evaluations show that you do not have the 
type of illness that we are studying (PTSD that is moderate or severe) or if you have other psychiatric 
problems that might make it dangerous for your participation. You will also not qualify to continue in the 
study if the medical evaluations or blood tests show that it might be dangerous for you to participate 
because you have medical problems. Finally, you will not qualify to continue in the study if you cannot 
complete the treatment contract. 
Medication Taper
After the screening visit(s), if you are currently taking any medications that cannot be taken during this 
study (this includes for example opioid pain medications), the study psychiatrist, in consultation with 
your private physician, will decide if it is safe and appropriate for you to stop taking these medications. 
The study psychiatrist will discuss with you which medications are not allowed. If you are taking 
medications for your PTSD and/or depression, you will only stop taking these if they are not helping to 
relieve your symptoms and you want to discontinue treatment. Some medications, for example 
antidepressants, can be continued during the study as long as you have been taking these medications 
at the same dose for at least three months before starting the study. Long-acting benzodiazepines (e.g., 
clonazepam, diazepam) may not be taken for two weeks prior to the first infusion, and during the study 
treatment period. Short-acting benzodiazepines (e.g., alprazolam, lorazepam) can be continued if only 
taken at bedtime. If you take any type of benzodiazepine in the daytime, you may not participate in the 
study unless you are able to taper off the medication with your personal physician or psychiatrist.
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 5 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
If it is determined that it is safe and appropriate for you to stop taking any medications that are not 
allowed during the study, then you will begin a period during which you will be gently “tapered off,” or 
taken off these medications. The length of this period will vary depending upon the type and dose of 
medications that you are taking. Your personal physician will monitor your progress throughout the 
medication taper, in consultation with a study psychiatrist. If your personal physician or  psychiatrist 
feels that your condition has significantly worsened without these medications, you will be withdrawn 
from the study and your participation will end. You will receive recommendations about the treatment 
that is decided to be the most appropriate for you from your physician or psychiatrist, in consultation 
with a study psychiatrist.
You will not be able to begin taking a new sleep medication during the study.
Drug-Free Period
Following the medication taper, you will be required to be free of any of the medications that are not 
allowed in this study for a period of 2 weeks.  If you were not taking medication and did not require a 
taper, you will proceed directly to the intravenous infusions described below.
2. Administration of study medication:
If you continue to meet study criteria the morning of the first infusion, you will receive the first intravenous 
infusion of ketamine. Our goal is to have first infusions take place on a Monday, second administrations 
on a Wednesday and the third administration on a Friday. In the event of holiday or scheduling 
difficulties, it is possible that you would receive 2 infusions on consecutive days (i.e., Tuesday, 
Thursday, Friday). You will never receive 3 infusions on 3 consecutive days. You will receive a total of  
6 infusions over a period of 2 weeks, each preceded and followed by clinical assessments, and 5 
sessions of WET beginning the day after the fourth infusion. The total combined treatment will be 
delivered over a period of approximately 3 weeks.  
All infusion procedures and monitoring will take place at the Mount Sinai Clinical Research Unit (CRU) 
or the Psychiatry Infusion Suite. You will arrive at Mount Sinai at 7:30 am on a Monday after an overnight 
fast for solid food and non-clear liquids.  All procedures will be performed in a private, quiet room. 
You will be admitted to the CRU or the Psychiatry Infusion Suite the morning of each study treatment. 
On the morning of each scheduled ketamine infusion, careful monitoring will be started, including 
continuous monitoring of blood pressure, heart rate, and breathing rate. You will also need to provide a 
urine sample as all subjects will be tested for the presence of drugs of abuse in their urine. If you are a 
woman of child-bearing age, your urine will also be tested for pregnancy. One IV line will be placed by 
a registered nurse, and you may receive oxygen through your nose. At 11:00 am you will receive 
intravenous infusion of 0.5mg/kg of ketamine (total dose) over 40 minutes. If you are unable to tolerate 
the infusion, you will be withdrawn from the study and your participation will end.  Immediately and at 
120 minutes following the infusion, you will be repeatedly assessed by means of clinician-administered 
and self-report rating scales. 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 6 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
During the infusion procedure you will be closely monitored by a study physician. You will also be 
monitored for a total of 2 hours afterwards by CRU staff and/or by study staff and a study psychiatrist. 
At 40 minutes and 120 minutes after the start of the intravenous infusion, you will be asked questions 
that check for possible side effects of the drug you are receiving. Also, on the first infusion day only, a 
small amount of blood (1-2 tablespoons) will be collected before the infusion and at 30 minutes, 60 
minutes, 90 minutes, and 120 minutes after the start of the infusion to determine how much ketamine 
or midazolam has entered your blood stream. No tests other than those authorized will be performed 
on the blood sample. After at least a 2-hour monitoring period and a check of vital signs, you will be 
discharged from the CRU or the Psychiatry Infusion Suite. The earliest time that you will be discharged 
is 130 minutes after the start of the infusion (90 minutes after end of infusion), consistent with current 
post-anesthesia clinical practice. You will be asked to have a family member or friend drive you home, 
or accompany you home by taxi or public transportation, or will be offered car service to get home.  You 
will be instructed not to take public transportation on your own on the day of discharge from the CRU 
or the Psychiatry Infusion Suite. If the study psychiatrist identifies the presence of any significant and 
problematic side effects, you may be further monitored until 5:00 pm.  If there is additional need for 
monitoring after 5:00 pm, you will be admitted to the Mount Sinai ED, after which you will be exited from 
the study.  
3. Written Exposure Therapy Sessions:
You will also complete Written Exposure Therapy (WET), which consists of five (5) sessions completed 
over a span of 2 weeks. WET sessions will begin after you have completed the first four ketamine 
infusions. All sessions will be administered by a trained therapist remotely (via telehealth). The first 
session will require one hour of time, and the remaining four sessions will require approximately 40 
minutes per session. During each session, you will be asked to complete a writing exercise related to 
your trauma, for 30 minutes, following instructions provided by the therapist. The first 2 WET sessions 
will be scheduled on days that alternate with your last 2 ketamine infusions, and you will complete the 
last 3 WET sessions over the week following your last infusion.
The written narratives that you provide as part of the WET sessions will be collected by the study team 
and/or study therapist. The narratives are a necessary part of treatment and are used to ensure that 
the instructions for each writing session are followed. We will ask you not to provide your name or 
identifying information on the narratives, and will collect the narratives securely (i.e., uploading a picture 
to the secure REDCap database, uploading a scanned copy to the secure REDCap database, or 
delivering the hard copy of the narratives by mail or in-person).
4.Extinction Learning Task:
This task involves an online game that measures how people learn to change their expectations. The 
game takes about 15 minutes total each time. The game will be played on a computer. This game will 
be completed at screening and again on the day after the fourth ketamine infusion.
5.Follow-Up Assessments:
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 7 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
In addition to the visits for intravenous ketamine infusions, following the first intravenous infusion you 
will be asked to connect with the study team remotely (via telehealth) 24 hours later for a follow-up 
assessment. We will ask you questions about the severity of your PTSD symptoms, mood and anxiety 
level to see if anything has changed since the infusion. 
All individuals who complete the study interventions (six ketamine infusions and WET sessions) will be 
asked to complete weekly assessments for 12 weeks after the first WET session, and then monthly for 
up to 3 additional months. Each of these assessments will require no more than 2 hours of your time, 
and we will ask you questions about the severity of your PTSD symptoms and mood and anxiety level.
Because this research study involves the use of a study drug, a note must be included in your electronic 
medical record that you are taking part in the research. This way, anyone involved in your medical care 
will know that you are a study participant, and they can work to avoid any problems or negative 
outcomes that could arise if they do not know.
Pregnancy
If you can possibly get pregnant, a urine test for pregnancy will be done before you begin the study and 
the pregnancy test will be repeated on the morning of each infusion.
You cannot be included in the study if you are or become pregnant, as the study drug could harm your 
fetus. You also should not be in the study if you are producing milk to feed a child as the study drug 
could harm your baby.
Unless you are at least one year past menopause or have had a successful operation to make 
pregnancy impossible, you should use effective birth control. Unless you are sexually abstinent (not 
having genital sex) the recommended methods of birth control are:

The consistent use of approved hormonal birth control (pill, patches, or rings), 

An intrauterine device (IUD), 

Contraceptive injection (Depo-Provera), 

Double barrier methods (Diaphragm with spermicidal gel or condoms with contraceptive foam), 

Sexual abstinence (no sexual activity), 

Sterilization (a vasectomy, getting tubes tied, or a hysterectomy).
All birth control methods (other than abstinence and sterilization) are only effective if you use them 
properly, start them at least one month before you begin the research study, and continue using them 
throughout the research study and for one month after the research study ends. If you are unsure 
whether the method of birth control you use is approved to use while you are in this study, you should 
ask the Lead Researcher before you begin the study. If you are less than one-year post-menopausal, 
you could still become pregnant. If you or your partner becomes pregnant, or may be pregnant, at any 
time throughout the study you must tell a person from the research team immediately. The team may 
stop the study drug and refer you/your partner to an obstetrician/gynecologist for follow-up. 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 8 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
Should you/your partner become pregnant, whether or not you/your partner have the baby, the people 
funding and overseeing the research may ask for information on the pregnancy, even if you are no 
longer part of the study. You/your partner will be asked for additional written consent to share this 
information if that happens.
Semen/Sperm:
Drugs can be found in semen and alter sperm. Since you are taking part in a study using experimental 
drugs or treatments, it is recommended that 1) you use a condom, 2) you do not get a partner pregnant 
or expose them to semen, and 3) you do not donate semen.  These recommendations apply both while 
you are taking the study drug, and for 3 months after you stop taking the study drug This is because 
levels of the study drug may be present in the sperm and/or semen even after you stop taking the study 
drug.  You are encouraged to tell your female partner(s) and/or their doctor(s) that you are participating 
in this clinical trial.
____________________________
Future Contact: 
The researchers may wish to use your personal contact information to contact you in the future. Do you 
give the researchers permission to contact you in the future to request the collection of  
additional information about you, discuss how your private information, study data and/or samples might 
be used, or discuss possible participation in another research study? 
Please initial your choice: Yes_________ No__________
If “Yes”, please indicate your preferred method of contact: (initial all that apply)
           [  ] Email            [  ] Phone          [  ] Letter             [  ] Text
____________________________
USE OF YOUR DATA AND/OR SAMPLES:
The researchers would like your permission to keep the data collected from you during this study to use 
or share in future studies. You can still be part of the study if you do not allow us to use or share them. 
Please select Yes or No to each of the questions below. To decline all future uses/sharing please select 
‘No’ each time.
(1) Will you allow the researchers to store your data and/or samples to use in future research studies?
Please initial your choice: Yes________ No_________ 
If you select No, please stop here and move to the next section, 'Your Responsibilities If You Take 
Part in This Research' section below."
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 9 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
If yes, please continue to the next question and tell us how your personal information, study data and/or 
samples may be used in future research studies. 
(2) The researchers can store your data and/or samples in one of two ways:
a) Anonymously (no one will know who the data and/or samples came from). If you choose this 
option, you can’t change your mind. So, if you wanted to have your data and/or samples 
destroyed in the future, the team could not do it as they would not know which data and/or 
samples were yours.
b) Linked to your identity (using a code that can show the information came from you personally). 
In this case you could ask for your data and/or samples to be destroyed in the future if you want 
that to happen. 
How would you like your data and/or samples stored? Please initial ONE choice below:
I would like my data and/or samples stored anonymously ______________
I would like my data and/or samples stored with a link to my identity through the use of a code______
(3) Do you give the researchers permission to keep the data and/or samples, so they could use them 
in future studies that are directly related to the purpose of the current study?
Please initial your choice: Yes_________ No____________________
(4) Do you give the researchers permission to keep the data and/or samples indefinitely, so they could 
use them for future studies that are not related to the purpose of the current study (for example a 
different area of research)?   
Please initial your choice: Yes_________ No__________
(4.1) From time to time, researchers outside of medicine and related sciences would like to use data 
and/or samples. This might be in the fields such as anthropology, human origins, mapping human 
migration patterns. Do you give permission for researchers outside the field of medicine to use your 
data and/or samples? 
Please initial your choice: Yes_________ No__________
a.
If the future research in a different area can be done without having to know that the data and/or 
samples came from you personally, that will be done.  
b. If the future research in a different area requires that it is known specifically who the  data and/or 
samples came from, then one of the following will be done:
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 10 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
I.
If you allowed the researchers to contact you in the future, they may be able to contact you to 
explain why your data and/or samples is needed and what will be done with it. Your permission 
will be asked to use your data and/or samples in that research project.
II.
If you do not give permission to be contacted in the future, or if it is found that contacting you is 
not practical (for example, because you have moved), your data and/or samples may still be 
used. The Institutional Review Board (IRB) will be asked for permission to use the data and/or 
samples linked to your identity. The IRB can give permission for researchers to use and share 
identifiable health information without contacting you, but only if it determines that sharing the 
data and/or samples will not be more than minimal risk to you or your privacy. The IRB is a 
committee of doctors and scientists and nonscientists, including people not associated with this 
hospital or medical school, whose job it is to protect people who participate in research.
 
(5) Do you give permission to have your data and/or samples given to other researchers, including 
those at Mount Sinai, other medical or scientific institutions and for-profit companies, for use in research 
within the limits you have chosen above? 
Please initial your choice: Yes_________ No__________
(6) Do you give permission to have portions of your data and/or samples deposited in large public 
databases (repositories) for use in research with the limits you may have chosen above? Please read 
the paragraphs below which explains repositories, then initial your choice:
To do more powerful research, it is helpful for researchers to share data and/or samples from the people 
they study. They do this by putting data and/or samples into a repository. A repository is where 
something is stored safely for a specified period of time. Data and/or samples from one study may be 
stored in a repository along with data and/or samples from other studies. Sample repositories are 
commonly called biobanks, while data repositories are commonly called databases. . Researchers can 
then use the data and/or samples from multiple studies to learn even more about health and disease. 
If you agree to take part in this study, some of your genetic and health information might be placed into 
one or more scientific databases, but they will not share your direct identifiers (for example, name, 
address, date of birth). These databases are maintained by either Icahn School of Medicine at Mount 
Sinai, another institution, the federal government, or private companies. Any researcher who wants to 
do a study using data and/or samples from the repository must apply for permission. There are different 
ways of reviewing such requests. Researchers with an approved study may be able to see and use 
your data, along with that from many other people. Researchers may use your samples for genetic 
sequencing and other experimental testing. Researchers will always have a duty to protect your privacy 
and to keep your information confidential, but there are always risks associated with data and/or sample 
collection and sharing. They are described in more detail in the Risks section. 
____________________________
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH:
If you decide to take part in this research study, you will be responsible for the following things: using 
birth control methods as described in the Description of What’s Involved section, avoiding 
certain medications, and punctual attendance of study visits.
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 11 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
____________________________
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION:
If you agree to take part in this study, you will be paid up to $880 for your time and effort. Your check 
will be initiated following each week of completed study visits. Post-treatment follow-up visits are 
compensated $25 per visit and the total compensation due is contingent on the length of the follow-up 
period. If you are unable to complete the entire study, the payment will be prorated for the part 
you have completed.
Procedure
Reimbursement
Screening:
Screening visit 1 (interview)
$50
Screening visit 2 (medical clearance)
$25
Extinction Learning Task (remote)
$10
Ketamine Infusions and Assessments:
First ketamine infusion day 
$75
24-hour follow up
$10
Second infusion day 
$50
Third infusion day
$50
Fourth infusion day
$50
Ketamine responder Determination Assess.
$35
Start of Therapy Sessions (WET):
Fifth infusion day
$50
Sixth infusion day
$50
Assessments (for 12 weeks, and after that 
depending on your treatment response):
1-week Assessment
$25
2-week Assessment
$25
3-week Assessment
$25
4-week Assessment
$25
5-week Assessment
$25
6-week Assessment
$25
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 12 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
7-week Assessment
$25
8-week Assessment
$25
9-week Assessment
$25
10-week Assessment
$25
11-week Assessment
$25
12-week Assessment
$25
16-week Assessment
$25
20-week Assessment 
$25
24-week Assessment 
$25
Total – up to 12 weeks
$755
Total for participation in all parts of the study, 
if all follow-up visits are needed
$830
It can take up to 6 weeks to prepare and give you a check for study participation. If you do not get a 
check by then, you can first contact the research team. If further assistance is needed, please contact 
Mount Sinai’s Program for the Protection of Human Subjects at (212) 824-8200.
Tax law may require the Mount Sinai Finance Department to report the amount of payment you receive 
from Mount Sinai to the Internal Revenue Service (IRS) or other agencies, as applicable. Generally, this 
happens if you receive payments that equal $600 or more from Mount Sinai in a calendar year.  
You would be responsible for the payment of any tax that may be due.
____________________________
POSSIBLE BENEFITS:
There is a chance this study may benefit you, but this is not guaranteed. Others may benefit from what 
researchers learn from the study. Possible benefits to you include: temporary improvements in your 
PTSD and/or depressive symptoms However, longer-lasting benefits after completing the study are not 
necessarily anticipated. There is no firm evidence that you will respond to ketamine and/or WET and 
thus it is possible that you will not experience any benefit from participating in this research study. Even 
if you do not personally benefit, your participation in this study will help to provide more information 
about the treatment of PTSD. 
____________________________
POSSIBLE RISKS AND DISCOMFORTS:
1.
Physical risks:
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 13 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
Risks of IV insertion and blood draw: The risks IV insertion and of blood draw include pain, 
bruising, and the slight possibility of infection at the place where the needle goes in. Some people feel 
dizzy or may faint during or after a blood draw.
Acute ketamine side effects: Ketamine has been determined to be safe for use as an anesthetic 
agent. Over the past several decades, ketamine has been administered as an anesthetic to several 
million adults and children and has a favorable safety profile overall.  Ketamine may produce mild to 
moderate increases in blood pressure and heart rate, and performance. Additionally, some patients 
report dizziness or nausea. Ketamine may also cause an impairment of supply of blood to the heart in 
patients with underlying coronary artery disease. Five to 30% of subjects who receive ketamine may 
experience changes in their perceptions such as vivid dreaming, temporary visual changes, 
visualization of psychedelic color, feeling of suspension in space, and out-of-body experiences.  Some 
patients report these experiences as bizarre or frightening, while others describe them as pleasurable, 
joyful, or fascinating.  When such reactions occur, they are usually mild and brief. Studies suggest that 
these sensory effects of ketamine are usually short-lasting (less than 60 minutes) and rarely last longer 
than 2 hours. These sensory effects appear more commonly in those with preexisting psychosis 
(schizophrenia), which is why patients with a history of psychosis are excluded from the study.
2.
Psychological risks associated with clinical interviews:
During the clinical interviews, you may become tired or upset about the questions.  If this happens, you 
should tell the interviewer/study personnel and he/she will stop the examination.  Depending upon how 
you feel, you may then 1) take a rest period and resume later, 2) reschedule for a later appointment or 
3) decide not to finish the exam. 
3.
Privacy risks:
Risk of loss of private information; this risk always exists, but there are procedures in place to 
minimize the risk. 
Your name and other information that could directly identify you (such as address, date of birth or social 
security number) will never be placed into a scientific database. However, because your genetic 
information is unique to you, there is a small chance that someone could trace it back to you. The risk 
of this happening is very small, but may grow in the future.  Since the database includes genetic 
information, a break in security may also pose a potential risk to blood relatives as well as yourself. For 
example, it could be used to make it harder for you (or a relative) to get or keep a job or insurance.  If 
your private information was misused it is possible you would also experience other harms, such as 
stress, anxiety, stigmatization, or embarrassment from revealing information about your family 
relationships, ethnic heritage, or health conditions.
The Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
information. This law generally will protect you in the following ways:
•
Health insurance companies and group health plans may not request your genetic information 
that we get from this research.
•
Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums.
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 14 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
•
Employers with 15 or more employees may not use your genetic information that we get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment.
Be aware that this new Federal law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance.
Group Risks - Although your name will not be given to researchers, basic information such as your race, 
ethnic group, and sex may be shared. This information helps researchers learn whether the factors that 
lead to health problems are the same in different groups of people. It is possible that such findings could 
one day help people of the same race, ethnic group, or sex as you. However, they could also be used 
to support harmful stereotypes or discrimination.
4.
Pregnancy risks:
If you are or become pregnant, this research may hurt your baby or your pregnancy in ways that are 
unknown. The unknown risks might be minor or might be major (death) for the pregnancy. You should 
not become pregnant or impregnate a woman while on this research study. Please read the 
acceptable methods of birth control found under the Description of What’s Involved section of this 
document.
5.
Increased risk of suicidal thoughts and actions: 
Antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age 
and younger, especially within the first few months of treatment or when the dose is changed. We do 
not expect this to occur, and in fact ketamine has been shown to reduce suicidal thinking in certain 
patients. However if the following should occur: suicide attempts, worsening depression, thoughts 
about suicide or dying, or other unusual changes in behavior or mood please contact the principal 
investigator immediately. 
___________________________
OTHER OPTIONS TO CONSIDER:
You may decide not to take part in this research study. If you decide not to take part, this will not affect 
the clinical care you receive at Mount Sinai. The choice is totally up to you. Instead of being in this 
research study, your choices may include continuing the standard treatment for PTSD, which is 
determined by your psychiatrist based on your psychiatric symptoms and may include medication, 
psychotherapy and possibly other treatments. The most common standard treatments for PTSD include 
talk therapy and oral medications such as SSRIs like sertraline. The benefits of these treatments are 
that talk therapy has few side effects and therefore limited risk. Also, the benefits of SSRIs like sertraline, 
is that they have been shown to be useful in a wide variety of patients with PTSD, and have been used 
widely, so the side effects are well understood. These options are also available outside of a research 
context.  However, the important risk of these alternatives is the possibly limited and slower effect 
of these standard treatments on the symptoms you are suffering from.  In addition, no matter 
what treatment you receive, you will be exposed to the specific side effects of that treatment.
____________________________
IN CASE OF INJURY DURING THIS RESEARCH STUDY 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 15 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
If you are injured or made sick from taking part in this research study, you will get medical care. 
Generally, it will be billed to you or your insurance.  You will be responsible for all treatment costs not 
covered by your insurance, including deductibles, copayments, and coinsurance. This does not prevent 
you from seeking payment for injury related to malpractice or negligence. You can contact the Lead 
Researcher for more information.
____________________________
ENDING PARTICIPATION IN THE RESEARCH STUDY:
You may stop taking part in this study at any time.  No matter what you choose, your care and benefits 
through Mount Sinai will not be negatively impacted.
If you decide to stop being in the study, please contact the Lead Researcher or the research staff.  
You may also withdraw your permission for the researchers to use and share any of your protected 
information for research, but you must do so in writing to the Lead Researcher at the address on the 
first page. Even if you withdraw your permission, the Lead Researcher may still use the information that 
was already collected if that information is necessary to complete the research study. Your health 
information may still be used or shared after you withdraw your authorization if you have an adverse 
event (a bad effect) from taking part in the research study.
If you decide you don’t want your samples and/or data to be used for research anymore, you can contact 
the researcher and ask to have your samples and/or data removed from future use. If any samples or 
data have already been shared without your identity, it won’t be possible to retrieve them because no 
one will know who you are. Samples and data that have already been used will not be affected by your 
decision. Any samples and/or data that are still linked to your identity by a code the researcher has will 
be withdrawn so that no future sharing of your samples and/or data will take place. If your samples have 
already been deposited in an external repository, the study team will request that your samples be 
removed.
Withdrawal without your consent: The Lead Researcher, the funder or Mount Sinai may stop your 
involvement in this research study at any time without your consent. This may be because the research 
study is being stopped, the instructions of the research team have not been followed, the Lead 
Researcher believes it is in your best interest, or for any other reason. If data and/or samples have been 
stored as part of the research study, they too can be destroyed without your consent.  
____________________________
CONTACT INFORMATION:
If you have any questions, concerns or complaints at any time about this research, or you think the 
research has harmed you, please contact the office of the research team and/or the Lead Researcher 
at phone number 212-585-4670.
If there is an emergency, please call 911 or go to the emergency room. Let the emergency room staff 
know you are in a research study so they can contact the Lead Researcher if needed.
____________________________
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 16 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
DISCLOSURE OF FINANCIAL INTERESTS:
Researchers sometimes get paid for consulting or doing work for companies that produce drugs, 
biologics or medical devices. If you have questions regarding industry relationships, you are 
encouraged to talk to the Lead Researcher or visit our website at http://icahn.mssm.edu/ where Mount 
Sinai publicly discloses the industry relationships of our faculty.   
Dr. Dennis Charney (Dean of Icahn School of Medicine at Mount Sinai) and Dr. Adriana Feder (the 
Principal Investigator on this study) are named co-inventors on a patent application filed by Mount Sinai 
for the use of ketamine as a therapy for post-traumatic stress disorder (PTSD, a type of anxiety 
disorder).  At the current time, the medical school is seeking a licensing agreement with a 
pharmaceutical company in order to develop ketamine as a therapy for PTSD.     
In addition, Dr. Charney is a named co-inventor on several issued U.S. patents, and several pending 
U.S. patent applications filed by the Icahn School of Medicine at Mount Sinai (ISMMS) related to 
pharmacologic therapy for treatment-resistant depression, suicidal ideation and other disorders. ISMMS 
has entered into a licensing agreement with Janssen Pharmaceuticals, Inc. and it has and will receive 
payments from Janssen under the license agreement related to these patents. As a coinventor, Dr. 
Charney is entitled to a portion of the payments received by the ISMMS. Since SPRAVATO 
(esketamine) has received regulatory approval for treatment-resistant depression, ISMMS and Dr. 
Charney as its employee and a co-inventor, will be entitled to additional payments, under the license 
agreement. 
One or more researchers has a financial interest that could be affected by the outcome of this research 
study. 
____________________________
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION:
As part of this study, some of your private and/or protected health information will be obtained, used, 
and shared with your permission. There is a Federal Health Insurance Portability and Accountability Act 
(HIPAA) that makes sure this is done correctly and safely. 
What is protected health information (PHI)? 
PHI is the combination of two things:
1.
PHI contains information that identifies you. It will be used to contact you and link you to your 
health information, like name, date of birth, medical record number, and address.  
2.
PHI also contains health information, including information about your mental and physical 
health from your visits to doctors or hospitals, or from study visits. 
Every time you visit a hospital or your doctor, PHI is created and recorded in your medical record by 
your healthcare providers. In the same way, the PHI created as part of this study will be linked to who 
you are and your medical information. 
What PHI is collected and used in this research study, and might also be shared with others? 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 17 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
As part of this study, the research team at the hospital(s) involved in the research will collect your name, 
address, telephone/fax numbers, dates directly related to you as an individual (birth, admission, 
discharge, date of death, etc.), e-mail addresses, social security number, medical records number.
During the study, the researchers will gather information by: 

Reviewing and/or taking your medical history (includes current and past medications or 
therapies, illnesses, conditions or symptoms, family medical history, allergies, etc.) 

Doing a physical examination that generally also includes blood pressure reading, heart rate, 
breathing rate, and temperature.

Completing the tests, procedures, questionnaires and interviews explained in the description 
section of this consent.

Reviewing narratives and therapist notes from the Written Exposure Therapy sessions 
conducted as part of this study 
Why is your PHI being used?
Researchers need the information that identifies you so they can contact you during the study. They 
need your health information and the results of any tests and procedures being collected as part of this 
study to answer the questions posed in the study. The purpose of the study is discussed earlier in this 
consent form. Before researchers analyze the data, they remove any information that would let others 
know who you are or that you took part in the study. If researchers publish or present study results at 
scientific meetings, lectures, or other events, their presentations would not include any information that 
would let others know who you are, unless you give separate permission to do so.
The Lead Researcher may also use and share the results of these tests and procedures with other 
healthcare providers at Mount Sinai who are involved in your care or treatment. The research team and 
other authorized members of The Mount Sinai Health System (“Mount Sinai”) workforce may use and 
share your information to ensure that the research meets legal, institutional or accreditation 
requirements. For example:

The Mount Sinai Program for the Protection of Human Subjects is responsible for overseeing 
research on human participants and may need to see your information. 

If you receive any payments for taking part in this study, the Mount Sinai Finance Department 
may need your name, address, social security number, payment amount, and related 
information for tax reporting purposes.  

If the research team uncovers abuse, neglect, or reportable diseases, this information may be 
disclosed to appropriate authorities. 
Who, outside Mount Sinai, might receive your PHI?
As part of the study, the Lead Researcher, research team and others in the Mount Sinai workforce may 
disclose your PHI, including the results of the research study tests and procedures, to the following 
people or organizations: (It is possible that there may be changes to the list during this research study; 
you may request an up-to-date list at any time by contacting the Lead Researcher.)
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 18 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
-
The United States Department of Health and Human Services (DHHS) and the Office of 
Human Research Protection (OHRP) (the government organization that is responsible for 
protecting human research participants).
-
Outside laboratory who will be performing laboratory analysis for all the research centers 
involved in this project: LabCorps
-
A Data Safety Monitoring Board or other committee that will monitor the study on an ongoing 
basis for safety.
-
The United States Food and Drug Administration.
In almost all disclosures outside of Mount Sinai, you will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier. Some records and 
information disclosed may be identified with a unique code number. The Lead Researcher will ensure 
that the key to the code will be kept in a locked file or will be securely stored electronically. The code 
will not be used to link the information back to you without your permission, unless the Institutional 
Review Board (IRB) allows it after determining that there would be minimal risk to your privacy. The 
Certificate of Confidentiality obtained from the Department of Health and Human Services will not be 
used to prevent disclosure to local authorities of child abuse and neglect, or harm to self or others. It is 
possible that a sponsor or their representatives, a data coordinating office, a contract research 
organization, may come to inspect your records. Even if those records are identifiable when inspected, 
the information leaving the institution will be stripped of direct identifiers.  Additionally, OHRP, as well 
as the Food and Drug Administration (FDA) will be granted direct access to your medical records for 
verification of the research procedures and data. OHRP and FDA are authorized to remove information 
with identifiers if necessary to complete their task. By signing this document, you are authorizing this 
access. The results of this research may be published. However, your name and other identifying 
information will be kept confidential.
For how long will Mount Sinai be able to use or disclose your PHI? 
Your authorization for use of your PHI for this specific study does not expire.
Will you be able to access your records?
During your participation in this study, you will have access to your medical record and any study 
information that is part of that record. The research team is not required to release research information 
to you that is not part of your medical record.
Do you need to give the researchers permission to obtain, use or share your PHI?
NO! If you decide not to let the research team obtain, use or share your PHI, you should not sign this 
form, and you will not be allowed to volunteer in the research study. If you do not sign, it will not affect 
your treatment, payment, or enrollment in any health plans or affect your eligibility for benefits.
Can you change your mind?
If you decide to stop being in the study, please contact the Lead Researcher or the research staff.
The research team may ask you whether they can continue to collect information from your medical 
record. You will also have to decide if you wish to limit the continued use of the information collected 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 19 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
during the study. Under US privacy laws you may also withdraw your permission for the researchers to 
use and share any of your protected information for research, but you must do so in writing to the Lead 
Researcher at the address on the first page. 
Even if you withdraw your permission, the Lead Researcher may still use the information that was 
already collected, but only to complete this research study. Your health information may still be used or 
shared after you withdraw your authorization if you have an adverse event (a bad effect) from taking 
part in the research study.
If you have not already received it, you will also be given The Hospital’s Notice of Privacy Practices that 
contains more information about how The Hospital uses and discloses your PHI.
It is important for you to understand that once information is disclosed to others outside Mount Sinai, 
the information may be re-disclosed and will no longer be covered by the federal privacy protection 
regulations. However, where possible, Mount Sinai has entered into agreements with those who will 
receive your information to continue to protect your confidentiality.
If researchers are reviewing your medical records or asking questions about your medical history or 
conditions, it is possible that they may learn information related to your HIV status. If that is the case, 
the following information concerns you. If researchers are not reviewing your medical records or asking 
questions about your medical history or conditions, then you may ignore the following section.
_________________________________________________________________________________
Notice Concerning HIV-Related Information 
If you are authorizing the release of HIV-related information, you should be aware that the recipient(s) is 
(are) prohibited from re-disclosing any HIV-related information without your authorization unless permitted 
to do so under federal or state law. You also have a right to request a list of people who may receive or use 
your HIV-related information without authorization. If you experience discrimination because of the release 
or disclosure of HIV-related information, you may contact the New York State Division of Human Rights at 
(888) 392-3644 or the New York City Commission on Human Rights at (212) 306-5070. These agencies are 
responsible for protecting your rights.
_____________________________________________________________________________________
Certificate of Confidentiality: To further protect your privacy, the researchers have obtained a Certificate 
of Confidentiality from the Department of Health and Human Services. This is intended to ensure that 
your identity as a participant in this research study will not have to be disclosed as a result from a 
subpoena, for the purpose of identifying you in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings other than to the FDA or OHRP as identified above.
The research staff will not share any of your personal information, study data and/or samples with 
anyone who is not a member of the research team, including any family members or friends, other than 
those identified above. However, you should know that if it is learned that you or someone else is 
threatened with serious harm, such as a child or an elderly person being abused, the research team 
may notify the appropriate authorities if necessary to protect you or others.  A Certificate of 
Confidentiality does not prevent you or a member of your family from voluntarily releasing information 
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 20 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
about yourself or your involvement in this research. This means that you and your family must also 
actively protect your own privacy. If an insurer or employer learns about your research participation, 
and you agree that they can have your research information, then the researchers may not use the 
Certificate of Confidentiality to keep this information from them.
____________________________
How the Institutional Review Board (IRB) can help you:
This research has been reviewed and approved by an Institutional Review Board (IRB). You may reach 
a representative of the Mount Sinai Program for Protection of Human Subjects at telephone number 
(212) 824-8200 during regular work hours (Monday-Friday, 9am-5pm, excluding holidays) for any of the 
reasons listed below. This office will direct your call to the right person within the Mount Sinai Health 
System:

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You are not comfortable talking to the research team.

You have questions about your rights as a research participant.

You want to get information or provide input about this research.
Effective Date: 8/23/2023
End Date:4/3/2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 21 of 21
Study ID: STUDY-21-00167                   
Form Version Date: 15March2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022
ADULT PARTICIPANT:
Your signature below documents your permission to take part in this research study and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you.
_________________________
_________________________
__________
__________
Signature of Participant
Printed Name of Participant
Date
Time
PERSON EXPLAINING STUDY AND OBTAINING CONSENT:
_________________________
_________________________
__________
__________
Signature of Consent Delegate
Printed Name of Consent Delegate
Date
Time
WITNESS SECTION:
My signature below documents that the information in the consent document and any other written 
information was accurately explained to, and apparently understood by, the participant, and that 
consent was freely given by the participant.
_________________________
_________________________
__________
__________
Signature of Witness
Printed Name of Witness
Date
Time
Effective Date: 8/23/2023
End Date:4/3/2024