Randomized Controlled Trial of Repeated-Dose Intravenous Ketamine for PTSD
Phase: PHASE2
Conditions: Posttraumatic Stress Disorder (PTSD)
Sponsor: Icahn School of Medicine at Mount Sinai

Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
PI: Adriana Feder, MD 
NCT02397889 
Document Date: 1-24-2020

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
1 
 
MSSM Protocol Template 
Instructions: 
1. Prepare a document with the following sections. Note that, depending on the nature of your research, 
certain sections below may not be applicable. Indicate N/A as appropriate, explaining where possible. 
2. For any items described in the sponsor’s protocol, grant application or other source documents 
submitted with the application, you may reference the title and page numbers of these documents rather 
than cutting and pasting into this document. Do NOT refer to any derived documents, such as the 
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3.  If you reference page numbers, attach those pages to this protocol. 
4. When you write a protocol, keep an electronic copy. You will need to modify this copy when making 
changes. 
 
1) Objectives 
 
The objective of the present research protocol, a parallel-arm, double-blind, randomized 
controlled clinical trial, is to test the efficacy of repeated intravenous administration of 
the glutamatergic NMDA receptor antagonist ketamine in providing (1) rapid relief of 
and (2) sustained improvement in core PTSD symptoms and co-morbid depressive 
symptoms in patients with chronic PTSD. The effects of ketamine will be compared with 
those of repeated intravenous administration of the benzodiazepine anesthetic 
midazolam, which mimics some of the acute subjective effects of ketamine but is 
expected to have lesser or less sustained anxiolytic effect, and no sustained 
antidepressant effect.  Patients with chronic PTSD will be randomized to receive 
repeated intravenous administrations of either ketamine or midazolam, administered 3 
times a week over the course of 2 consecutive weeks. 
 
We have completed a randomized, double-blind controlled study of a single dose of IV 
ketamine (compared to a single dose of IV midazolam) for chronic posttraumatic stress 
disorder (PTSD) at the Depression and Anxiety Center (DAC) at Mount Sinai. In that 
study, we found ketamine infusion to be associated with significant and rapid 
improvement in PTSD symptom severity, compared to midazolam, when assessed 24 
hours post-infusion (Feder et al., 2014). Ketamine was also associated with 
improvement in co-morbid depressive symptoms and in overall clinical presentation, 
and was generally well-tolerated without clinically significant persistent dissociative 
symptoms.   

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
2 
 
 
In the past ten years, evidence has emerged showing that sub anesthetic doses of 
ketamine (0.5mg/kg) administered over a 40-minute infusion period can have a fast-
acting antidepressant effect on both treatment-naïve and treatment resistant 
depression (TRD) individuals (Murrough et al., 2013; Fond et al., 2014; McGirr et al., 
2014). We also reported results from an open-label study of IV ketamine administration 
that was conducted at DAC in patients with TRD, which showed a more prolonged 
improvement in depressive symptoms in this population (aan het Rot et al., 2010). Given 
the initial promising findings in patients with chronic PTSD summarized above (Feder et 
al., 2014), as well as our experience and findings with ketamine in patients with TRD 
(Berman et al., 2000; Zarate et al., 2006, aan het Rot et al., 2010; Murrough and 
Charney, 2010; Murrough et al., 2013), it is now imperative to identify strategies for 
effective and practical continuation pharmacotherapy for patients with chronic PTSD.   
 
 
SPECIFIC AIMS 
 
Aim 1: To examine the effect of repeated intravenous administration of ketamine on 
core PTSD symptoms in patients with chronic PTSD. Hypothesis: Repeated intravenous 
administration of ketamine will be effective in (1) rapidly reducing core PTSD symptoms 
and (2) maintaining improvement in core PTSD symptoms, measured over time, 
compared to repeated intravenous administration of midazolam. 
  
Aim 2: To examine the effect of repeated intravenous administration of ketamine on co-
morbid depressive symptoms in patients with chronic PTSD.  Hypothesis: Repeated 
intravenous administration of ketamine will be effective in (1) rapidly reducing co-
morbid depressive symptoms and (2) maintaining improvement in co-morbid depressive 
symptoms, measured over time, compared to repeated intravenous administration of 
midazolam. 
 
Aim 3: To examine the safety and tolerability of this intervention. Hypothesis: Ketamine 
administered via the intravenous route will be well tolerated, with limited side effects 
including short-lived dissociative effects. 
 
Aim 4 (Exploratory): To measure the effects of ketamine on emotion-processing 
networks in the brain, in particular amygdala, insula, ACC and other prefrontal cortex 
(PFC) regions involved in top-down regulation of emotion processing, including the 
ventromedial PFC (vmPFC) and other regions. 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
3 
 
 
2) Background 
PTSD is a debilitating anxiety disorder characterized by intrusive re-experiences of 
traumatic events, avoidance of situations and stimuli that serve as reminders of these 
events, and increased startle and hypervigilance. Patients with PTSD often suffer from 
co-morbid depressive symptoms, and many have significant memory impairments. 
Existing drug treatments are unsuccessful in a majority of patients, especially in those 
with combat-related PTSD.  
 
As summarized above, several studies, including those conducted by our research 
group, have reported rapid improvement in depressive symptoms following a single IV 
infusion of sub-anesthetic doses of ketamine in patients with TRD, including a large 
study comparing ketamine to midazolam (Berman et al., 2003; Zarate et al., 2006; aan 
het et al., 2010; Murrough and Charney, 2010; Murrough et al., 2013).  As mentioned 
above, we have also reported sustained improvement in depressive symptoms following 
repeated administration of IV ketamine in patients with treatment-resistant MDD in an 
open-label trial (aan het Rot et al., 2010), and have recently completed a study of 
intranasal ketamine administration for treatment-resistant MDD, also showing 
significant improvement in depressive symptoms (Lapidus et al., 2014).  Finally, we have 
recently completed a randomized cross-over trial of a single IV infusion of ketamine, 
compared to a single IV infusion of midazolam, in patients with chronic PTSD, 
demonstrating significant rapid improvement in core PTSD symptoms following 
ketamine administration, as well as improvement in co-morbid depressive symptoms 
(Feder et al., 2014).  
 
Thus the effects of ketamine administration on depressive symptoms in patients with 
TRD are well-established, and we have shown more recently that a single IV infusion of 
ketamine significantly improved core PTSD symptoms and co-morbid depressive 
symptoms in our initial, proof-of-concept study in patients with chronic PTSD.  The next 
steps are to: (1) further test the efficacy of ketamine in achieving rapid symptom relief 
in patients with PTSD; (2) test the efficacy of repeated administration of intravenous 
ketamine in maintaining symptom relief in patients with PTSD; and (3) examine the 
safety and tolerability of this intervention in PTSD patients.  
 
In the present study, and consistent with our prior studies, we expect a rapid reduction 
of core PTSD symptoms after the first intravenous infusion of ketamine.  Over the 
course of subsequent administrations (6 total administrations over 2 weeks), we expect 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
4 
 
further and/or sustained reduction in PTSD symptoms, as well as reduction in co-morbid 
depressive symptoms.  We will also examine the tolerability and safety of this 
intervention.  
 
Functional neuroimaging, PTSD and response to ketamine:  
As an exploratory aim, we plan to measure the impact of ketamine on neural emotion 
processing networks.  Functional neuroimaging (functional magnetic resonance imaging 
- fMRI) studies of patients with PTSD have shown altered reactivity in emotion 
processing networks, also involved in fear learning and extinction, including the 
amygdala, insula, vmPFC and dorsal anterior cingulate cortex (dACC), among other 
regions (Pitman et al., 2012). Tasks involving viewing emotional facial expressions (e.g., 
fearful, angry, happy) are well-suited to study amygdala reactivity to negative facial 
expressions compared to neutral or happy expressions, and have been used to study 
predisposition to anxiety, as well as patients with anxiety disorders or PTSD, including 
changes in emotion processing networks pre-/post-treatment interventions (Hariri et al., 
2002, 2005; Fonzo et al., 2010, Shin et al., 2005, Bryant et al., 2008). We plan to employ 
emotion processing tasks to study the effects of ketamine infusion (compared to 
midazolam infusion) in patients with chronic PTSD, by conducting fMRI imaging pre- and 
post-study drug administration. 
 
3) Setting of the Human Research 
All of the human research will be conducted at the Icahn School of Medicine at Mount 
Sinai.  Consent will be obtained at Mt. Sinai premises, prior to a screening interview, 
with only members of the research group present.  These offices are located at the 
Depression and Anxiety Center (DAC) on the second floor of 
, and in the 
Outpatient Psychiatry Department building located at 
, where the 
office for the PI (Dr. Feder) is located, a few blocks from 
.  Drug 
administration, acute monitoring, and initial assessments will be performed in the 
Clinical Research Unit (CRU) on the first floor of the Annenberg building or at the 
Psychiatry Infusion Suite on the 5th floor of the Icahn building. All monitoring and follow-
up assessments will be performed at DAC.  Functional MRI scans will be completed at 
the Translational Molecular Imaging Institute (TMII) in the Hess Center for Science and 
Medicine.  No research will be performed outside of Mt. Sinai. No reference to the 
potential participant’s identity will be made outside of closed quarters. 
4) Resources Available to Conduct the Human Research 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
5 
 
The Icahn School of Medicine at Mount Sinai’s DAC (Director James Murrough, MD, 
Ph.D) actively and regularly recruits patients for clinical trials of interventions for PTSD.  
In addition, several studies with ketamine have been performed by DAC, and current 
DAC investigators have conducted NIMH- and DoD-sponsored clinical trials for PTSD and 
mood disorders. Based on our previous recruitment of patients with PTSD at Mt Sinai, 
we estimate being able to recruit and successfully enroll on average 1 to 1.2 patients per 
month with chronic PTSD over a 36- to 48-month period. 
 
DAC is located on the second floor of 
, which is part of the Mt. Sinai 
Medical Center.  Available space in DAC includes 8 private offices, 2 treatment rooms, 
one examination/phlebotomy room, a neuropsychology room, a conference room, and 
7 cubicles for research assistants and interns, as well as a comfortable waiting area.  The 
clinic has adequate office space for faculty members, research assistants, and post-
doctoral fellows.  Additionally, Dr. Feder, a DAC investigator, has an office located at 
, a few blocks away from 
.  All office space is fully 
equipped with necessary elements for conducting research, including computers using a 
common network, printers, telephones, fax machine, photocopy machines, and 
supplies. 
 
All staff members listed on this protocol have extensive clinical experience, including 5 
psychiatrists, 1 PhD in clinical psychology, 1 LMSW-PhD in neuroscience, and several 
research coordinators.  All listed Mt. Sinai faculty members have extensive research 
experience and are familiar with performing research at Mount Sinai. No research will 
be performed outside Mt. Sinai for this project. All staff participating in this study will be 
fully informed about the protocol and their trial-related duties. A Manual of Procedures 
(MOP) will be designed and accessible to address the general aspects of the study, 
summarizing the inclusion/exclusion criteria, treatment interventions, assessment tools, 
and summary of the procedures.  All staff who screen and evaluate patients will be 
trained on scale administration. 
 
After the protocol is described to the participant and the participant’s questions are 
answered, the participant will be asked to summarize the procedures that he/she will 
undergo and to describe 2 risks involved in the study.  An independent psychiatrist will 
assess the participant to determine whether the study is understood and informed 
consent can be provided.  Only individuals with capacity to consent will participate in 
this study.   
 
 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
6 
 
5) Study Design 
a) Recruitment Methods 
The primary sources of PTSD patients will be self-referrals generated from media 
advertisements. Print advertisements will be placed in local newspapers (i.e., Village 
Voice) and college newspapers (NYU, Hunter College). Online advertisements will 
also be utilized (i.e., Craigslist, Google Search Ad Campaign, Clinical Connection, 
TrialFacts). Through TrialFacts, we will have targeted advertisements on Google and 
Facebook. The study will also use online and print advertisements for Veterans’ 
organizations. Additionally, we will advertise on the radio (including, Pandora or 
Spotify). Participants will also be recruited using paper advertisements, such as 
flyers, which will be posted in designated areas of Mount Sinai and other college 
campuses. Flyers will also be posted in designated boards in community areas 
surrounding Mount Sinai, including, for example, YMCA centers, places of worship 
and domestic violence shelters with approval from the site.  In addition, we plan to 
recruit participants from clinical practices at Mt. Sinai, including the World Trade 
Center (WTC) Health Program (and its Mental Health Treatment Program led by Dr. 
Fatih Ozbay, where the PI, Dr. Feder, is also a staff psychiatrist); Internal Medical 
Associates (IMA); and the Outpatient Psychiatry Department (OPD); referral of 
Veterans by clinicians at the James J. Peters and the Manhattan VA Medical centers, 
as well as Veterans organizations such as Iraq and Afghanistan Veterans of America 
(IAVA); and also anticipate referrals from other clinicians in the Mount Sinai Medical 
Center, other New York City area hospitals affiliated with Mount Sinai, and 
community clinics and programs, who are aware of our clinical and research 
program.  Other sources of recruitment will include outreach at crime victims’ 
treatment programs. 
Potential participants who are current or former patients of study investigators (for 
example, Dr. Feder’s patients at the WTC Mental Health Treatment Program) will 
not be referred directly to the research study.  Instead, they will be asked if they 
would like to participate in the study.  Potential participants will be offered an IRB-
approved study brochure or flyer that will include information about the study and 
the contact information of the PI and research coordinator.  If the participant is 
interested, he or she will contact the study team directly.  Subjects will be 
compensated for the time and inconvenience associated with participation in this 
protocol.  

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
7 
 
 
b) Inclusion and Exclusion 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   –
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. 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). 
As in our completed study of IV ketamine vs. midazolam for PTSD, we are not 
excluding patients with co-morbid MDD (except those with bipolar or psychotic 
depression) because we feel that this will affect the generalizability of our findings. 
Almost 50% of patients with PTSD have this co-morbid diagnosis. Allowing patients 
with histories of co-morbid MDD to participate broadens the inclusion criteria to more 
closely approximate PTSD patients seen in real-world settings. Also, it allows us to 
investigate the antidepressant effect of ketamine in PTSD patients with co-morbid 
MDD. In general, inclusion / exclusion criteria are intended to protect patient welfare 
where, for example, administration of ketamine in the context of standardized 
research would be inadvisable or unsafe (e.g. because of pregnancy, history of allergy 
or other intolerance to study drug, or active suicidality). An additional purpose is to 
limit variability due to demographic and other factors, and to decrease psychiatric co-
morbidities that may affect the clinical phenomenology or treatment response and 
thus obscure findings (e.g. primary diagnosis of bipolar disorder or schizophrenia, co-

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
8 
 
morbid substance use disorder). 
 
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 hypothyroidism or hyperthyroidism, as indicated by a 
TSH value 25% above or below the normal range 
6. A Body Mass Index (BMI) >40; 
7. Patients with uncorrected hypothyroidism or hyperthyroidism; 
8. Hormonal treatment (e.g., estrogen) started in the 3 months prior to the first 
infusion day; 
9. History of autism, mental retardation, pervasive developmental disorders, or 
Tourette’s syndrome; 
10. History of one or more seizures without a clear and resolved etiology; 
11. History of (hypo)mania; 
12. Past or current presence of psychotic symptoms, or diagnosis of a lifetime 
psychotic disorder including schizophrenia or schizoaffective disorder; 
13. Drug or alcohol abuse or dependence within the preceding 3 months; a rather 
narrow time period was chosen, however, in order to allow participation by 
individuals with a history of substance abuse or dependence problems that 
could be secondary to their PTSD, and to more closely approximate patients 
seen in real-world settings; this is the same period of time that we used in our 
recently completed study of IV ketamine for PTSD. 
14. Previous recreational use of ketamine or PCP on more than one occasion; Any 
recreational use of ketamine or PCP within the last two years will be 
exclusionary, even if only taken once. 
15. Current diagnosis of bulimia nervosa or anorexia nervosa; 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
9 
 
16. Diagnosis of schizotypal or antisocial personality disorder (since these are 
known to reduce the possibility of study completion); other Axis II diagnoses 
will be allowed; 
17. Patients judged clinically to be at serious and imminent suicidal or homicidal 
risk. 
18. A blood pressure of one reading over 160/90 or two separate readings over 
140/90 at screen or baseline visits 
19. Patients who report current treatment with a long-acting benzodiazepine 
(e.g., clonazepam, diazepam) or an opioid medication within 2 weeks prior to 
randomization, and patients who take daily morning doses of any type 
benzodiazepine. Note: Patients taking stable doses of antidepressant 
medication or mood stabilizer (such as valproic acid or lithium) for 3 months 
prior to randomization will be allowed. Patients who report current 
treatment with a short-acting benzodiazepine (e.g., alprazolam, lorazepam), 
but not daily in the morning, will be allowed, and will be asked not to take 
their benzodiazepine on the mornings of infusion days.  
20. For subjects who may participate in the MRI portion of the study, 
claustrophobia, any trauma or surgery which may have left magnetic 
material in the body, magnetic implants or pacemakers, and inability to lie 
still for 1 hour or more. 
 
* 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 take a potential patient off of a 
medication; rather, this may only be completed by the prescribing physician. 
This is our policy across all of our studies. 
 
c) Number of Subjects 
We have established our sample size of N = 40 (total number of participants expected 
to complete study procedures) based on considerations of estimated effect size in 
parallel-arm, repeated dose, active control design, and feasibility of subject 
recruitment (please see Data Analysis Plan). Based on our previous recruitment of 
patients with PTSD at Mt. Sinai, we estimate that we will be able to recruit and 
successfully enroll on average 1 to 2 patients per month with chronic PTSD, and an 
average of 1 to 1.2 patients meeting criteria for study drug administration over a 36-
month period. Therefore, within a 48-month study period, we expect to complete 
recruitment, study procedures and data collection.  

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
10 
 
 
In order to achieve our planned study sample size, based on our prior experience, we 
expect that up to N = 80 individuals may sign the study consent form. 
 
Rationale for parallel-arm design and three-week subject participation: 
We considered both parallel-arm and cross-over randomized, controlled study 
designs. We concluded that the parallel-arm design is better suited to test a 
sustained response to continuation dose of IV ketamine in comparison to a control 
condition, given the potential carry-over treatment effects in treatment responders 
in a cross-over study design, and has better likelihood to yield meaningful clinical 
data with a relatively conservative sample size.  This conclusion is based on our 
experience in our recently completed cross-over study of a single IV administration 
of ketamine compared to a single IV administration of midazolam. 
 
Given that ketamine or midazolam will be administered 3 times per week over 2 
weeks, we will employ a parallel-arm design. After 30 study participants have been 
randomized, partially unblinded analyses (drug A, drug B) will be conducted by a 
statistician under the supervision of Dr. Emilia Bagiella, a member of the study 
DSMB, to advise whether to complete the study at that point or continue the study.  
Other study investigators will remain fully blinded, as the partially unblinded data 
will be provided directly to Dr. Bagiella by the research pharmacist, Ivy Cohen, 
Pharm.D.   
 
 
d) Study Timelines 
As detailed in section 5c above, we anticipate that in a 48-month period we will be 
able to enroll all study participants, complete all study procedures/data collection, 
and complete a preliminary data analysis. Subject’s completion of all study related 
procedures depends on the length of the screening period and the necessity of a 
potential washout period.  Completion of the study procedures can range from 4 to 
8 weeks. The length of the follow-up phase is contingent on the patient’s treatment 
response; formal study follow-up visits will end upon the patient’s relapse. The 
patient follow-up phase can last from one week to six months. Patients who 
successfully complete the study double-blind phase (6 infusions) will be offered up to 
three ketamine infusions in an optional open-label extension (open-label phase) if 
their PTSD symptom levels have not improved during the double-blind phase or if 
they experience return of symptoms during the Follow-up phase. These three open-
label infusions will be administered over the course of up to three weeks.  

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
11 
 
 
 
 
e) Study Endpoints 
The primary outcome is  change in PTSD symptom severity measured  
 at 2 weeks after the first infusion, measured with the Clinician-Administered PTSD scale 
(CAPS) for DSM-5 (Blake et al., 1995; Weathers et al., 1993, 2001). 
 
Secondary outcomes include: 
• 24 hours after the first infusion with the Impact of Event Scale - Revised (IES-
R) (Weiss and Marmar, 1996). 
• Change in PTSD symptom severity at 1 and 2 weeks after the first infusion, 
measured with the CAPS for DSM-5. 
• PTSD symptom severity measured at each drug infusion day with the IES-R 
• Depressive symptom severity measured with the Quick Inventory of 
Depressive Symptomatology - Self-Report (QIDS-SR) and the Montgomery 
Asberg Depression Rating Scale (MADRS) 24 hours after the first drug 
administration, with the QIDS-SR at each drug infusion day, and the MADRS 
at 1 and 2 weeks after the first drug infusion day. 
• Treatment-emergent side effects will be measured with the Patient-Rated 
Inventory of Side Effects (PRISE) at each study session (drug infusion day). 
• Functional impairment will be assessed with the Sheehan Disability Scale. 
• Additionally, resilience, psychological growth and life satisfaction will be 
measured with the Connor-Davidson Resilience Scale (CD-RISC), the Purpose 
                     Up to 4 weeks
2 weeks, 3 administrations/week*
Up to 6 months
 
PTSD 
Subjects
N~40
Randomization:
50:50
Screening and 
Medicine Washout
Intravenous Ketamine (0.5 mg/kg)
Midazolam (0.045 mg/kg)
Double-blind
Post Study Treatment 
Follow Up
Posttreatment
*fMRI scans pre and post fourth
administration only

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
12 
 
in Life Scale, the abbreviated Medical Outcomes Study (MOS) Social Support 
Survey, the Posttraumatic Growth Inventory (PTGI) and the Quality of Life 
Enjoyment and Satisfaction Questionnaire (Q-LES-Q). 
 
 
f) Procedures Involved in the Human Research 
The primary objective of this study is to determine the efficacy of repeated 
administration of intravenous ketamine in achieving rapid improvement in PTSD 
symptoms and maintaining this improvement over time in patients with chronic 
PTSD.   
Screening and Washout Period:  
After receiving complete disclosure about the research and opportunity to fully 
review the consent form, potential participants will be given the opportunity to ask 
questions. If they choose to take part in the study, then they will be asked to sign 
the written informed consent form.  Medical and psychiatric history and response to 
previous treatments will be obtained by a study investigator, and the diagnosis of 
PTSD will be made using the CAPS for DSM-5 (Blake et al., 1995; Weathers et al., 
1993, 2001)  The presence of any co-morbid diagnoses will be ascertained with the 
SCID-P for DMS-5 (First et al., 2001).  
At screening, participants will also be administered a battery of cognitive tests to 
quantify cognitive function at baseline, including tests of processing speed, attention, 
working memory, learning, and executive function (reasoning and problem solving). 
All patients will have a physical examination and specific laboratory tests as outlined 
in 5). These tests will include: a physical examination, electrocardiogram (ECG), 
supine and standing vital signs, complete blood cell counts, hepatitis B and C screen, 
electrolytes, thyroid function tests, fasting blood sugars and chemistries, liver 
function tests, urinalysis and toxicology screening. A pregnancy test will be 
performed in premenopausal women. After Screening (which generally takes 2-3 
visits), participants are expected to meet all inclusion and not meet any of the 
exclusion criteria listed above. 
 
Patients who are taking allowed psychotropic medications at Screening (e.g., 
antidepressant medications) at stable doses for 3 months prior to enrolling in the 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
13 
 
study (without changes, including adding or stopping any such medication) will be 
considered for participation and will be allowed to continue taking these 
medications.  If they qualify for study participation, we will request their permission 
for a study psychiatrist to contact their prescribing physician for coordinating 
purposes.  The subject’s treating physician will oversee the tapering process, if a 
washout period is necessary. We will also ask that they do not make any changes in 
dosage of these medications, or start or stop any medication for emotional or 
psychiatric symptoms, for the duration of the study.  If it becomes necessary to 
change, adjust or stop their psychiatric medication while in this study, we will ask 
that the participant inform the study PI, Dr. Feder, and this will end the participant’s 
involvement in the study.   
 
If at Screening patients are taking psychotropic medication that is not allowed in the 
study (e.g., an opioid medication), they must be drug-free for a minimum of 2 weeks 
prior to Visit 1 (the first IV ketamine or midazolam infusion). Patients who are 
benefiting from medications that are not permitted in the study will not be tapered 
off such medications and will be excluded from the study.  Patients who experience 
withdrawal symptoms from the medication taper may have this drug-free period 
extended. The monitoring of the tapering or “washout” of psychotropic medications 
will be conducted by the patient’s prescribing physician, with consultation from the 
study physician investigators. Study physician investigators will actively participate in 
this process only if a patient no longer has an active treatment relationship with 
her/his prescribing physician. 
 
Participants who qualify and agree to participate in the MRI portion of the study will 
undergo their first MRI scan at the end of the screening and washout period, the 
week prior to their first study drug administration. 
 
Study drug infusion days: 
Following medical and psychiatric screening, and if required a washout period of 2 
weeks from medications that are not permitted in the study (exclusion criteria), 
eligible patients will be randomized to ketamine or midazolam treatment. Patients 
who continue to meet symptomatic threshold of severity within 24 hours prior to 
the first infusion, based on the CAPS, will receive the first IV infusion of 0.5mg/kg of 
racemic ketamine hydrochloride with an infusion pump over a period of 40 minutes 
(or IV midazolam (0.045mg/kg with an infusion pump over 40 minutes)). First 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
14 
 
infusions will always take place on a Monday, unless there is a holiday or scheduling 
difficulties that would significantly delay the patient’s participation, in which case it 
will be administered the following day. 
 
After the first infusion of IV ketamine or midazolam, treatment will consist of 5 
additional IV ketamine/midazolam infusions conducted on Wednesday, Friday; 
Monday, Wednesday, and Friday, each preceded and followed by clinical 
assessments. Participants who tolerate study drug infusion without significant side 
effects will continue to receive the same maximum total dose. Participants will not 
receive infusions 3 days in a row. 
 
• The primary outcome measure is the change in PTSD symptom severity 
measured at 2 weeks after the first infusion, measured with the CAPS for 
DSM-5. 
• Secondary outcome measures include the IES-R, QIDS-SR, CGI-S and CGI-I, 
administered at visits 1b (24 hours after the first IN administration), 2, 3, 
4, 5, 6 (end of week 2), as well as the MADRS, administered at the end of 
weeks 1 and 2. Additionally, the MADRS will also be administered at 24 
hours after the first IV infusion. 
• Additional secondary outcome measures will include the Connor-
Davidson Resilience Scale (CD-RISC), the Purpose in Life Scale, the 
abbreviated Medical Outcomes Study (MOS) Social Support Survey, the 
Posttraumatic Growth Inventory (PTGI) and the Quality of Life Enjoyment 
and Satisfaction Questionnaire (Q-LES-Q), administered at the end of 
weeks 1 and 2 (in addition to baseline). 
 
Neuroimaging: 
Patients randomized to receiving IV ketamine or midazolam, who provide written 
consent for the MRI portion of the study, will undergo (1) a baseline MRI scan the 
week prior to the first IV drug infusion, and (2) a second MRI scan approximately one 
week after the first IV drug infusion.   
Scanning Session: We will escort subjects to the Translational Molecular Imaging 
Institute (TMII) at the Hess Center for Science and Medicine, and ask them to change 
into a medical gown. Subsequently, an MRI technician will orient and situate 
patients inside the Siemens MAGNETOM Skyra 3.0 Tesla scanner. The MRI scanner is 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
15 
 
without contrast.  The MRI portion is optional; subjects will be given this choice 
during the consent process. Throughout the procedure, participants will remain in 
contact with an investigator via a microphone and intercom system.  
We will record three types of data: functional, structural, and diffusion tensor 
images. Functional images offer information about changes in blood flow in the 
brain, a proxy for neuronal activity. Structural images reveal the anatomy of the 
brain. Diffusion tensor images allow us to probe the integrity of the white matter 
tracts that connect distant brain regions to one another. During functional imaging, 
participants will view stimuli consisting of facial expressions of emotion (e.g., fearful, 
happy) and will press buttons while in the scanner in response to task instructions.  
The primary endpoint of the MRI portion of the study will be the degree of change 
observed in emotion-processing networks as a function of ketamine treatment. 
After the functional imaging task, we will collect seven additional minutes of 
functional data. We will instruct participants to keep their eyes open, and to fixate 
on a small white cross at the center of the scanner computer screen. Next, we will 
allow participants to close their eyes for twelve minutes while we capture images of 
their brain structure. The final scan will last seven minutes, recording diffusion 
tensor data. Total time in the scanner will be approximately 60 minutes. 
 
Visit 1a: First IV Ketamine or Midazolam Infusion 
 
All intravenous infusion procedures and monitoring will take place at the Mount 
Sinai CRU or the Psychiatry Infusion Suite. Patients will have all procedures 
performed in a private, quiet room. Initial assessments are performed by the same 
continuous rater (CR-1) who performed the initial Screening assessment. The CAPS 
will be administered within 24 hours prior to the first infusion to determine that the 
participant remains eligible for drug infusion. 
 
A urine toxicology and, for women, pregnancy screen will be performed. In the 
mornings of treatment days, initial assessments will include the IES-R, QIDS-SR16, 
HAM-A, Brief Psychiatric Rating Scale (BPRS), Clinician-Administered Dissociative 
States Scale (CADSS), Sheehan Disability Scale (SDS), Clinical Global Impression scale 
(CGI), Visual Analogue Scale (VAS), and Profile of Mood States (POMS). At visit 1a 
(and selected visits listed below), assessments will additionally include the TOP-8, 
MADRS and CAPS. 
 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
16 
 
Patients will arrive at the CRU on a Monday after an overnight fast for solid food and 
non-clear liquids.  An indwelling catheter will be placed in the antecubital vein of the 
nondominant 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 infusion. At 
9:00 am each patient will receive an intravenous infusion of 0.5mg/kg of ketamine 
or 0.045mg/kg midazolam over a period of 40 min.  Immediately and at 120 minutes 
following the infusion, patients will be repeatedly assessed by means of clinician-
administered and self-report rating scales, including scales to assess side effects.  
Mood and symptom ratings during and following the administration will be 
conducted by a separate rater (CR-2). Inter-rater reliability is established for all 
outcome measures prior to study. Blood will be collected and serum frozen for later 
testing of ketamine and midazolam levels. 
 
A study physician with privileges to administer ketamine will be present at the 
infusion throughout the administration of ketamine or midazolam so that 
potential adverse events can be evaluated and treated promptly, and a medical 
cart is available for emergencies. The study physician will remain in the 
continuous presence of the patient following the termination of the ketamine or 
midazolam infusion or until the patient meets Aldrete criteria (good respiration, 
O2 saturation, consciousness, circulation, and activity) for post-anesthesia care, 
whichever period is longer. After the acute post-infusion period and attainment of 
sufficient recovery as assessed by the study physician, the patient will be given lunch 
and will be monitored for two hours from the time of the intravenous infusion. Once 
the patient has completed the study self-reports and clinical ratings scheduled to 
begin at +120 minutes, a study physician will evaluate the patient to determine 
whether he/she can be discharged safely. The earliest time that a patient will be 
discharged is at +130 minutes (130 minutes after infusion start, i.e., 90 minutes after 
infusion end), consistent with current clinical practice for patients post-anesthesia. 
All patients will be asked to have a family member or friend drive them home, or 
accompany them home by taxi or public transportation, or will be offered car service 
to get home.  Patients will be instructed not to take public transportation on his/her 
own on the day of discharge from the CRU or Psychiatry Infusion Suite.  If the study 
psychiatrist identifies the presence of any significant psychotomimetic or other 
problematic side effects, the patient will be kept longer until he/she is ready to be 
discharged (e.g., awake and alert), as determined by the study physician..  If there is 
additional need for monitoring after 5:00 pm, the patient will be admitted to the 
Mount Sinai ED, after which he/she will be exited from the study.   

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
17 
 
 
Visit 1b (24 Hours Post First Ketamine or Midazolam Infusion) 
 
Patients will come to DAC (1399 Park).  They will be assessed by the same rater who 
conducted the ratings prior to IV infusion (CR-1), and will complete all assessment 
scales administered at Visit 1a, with the exception of the CAPS, which will be 
administered weekly.  
 
Participants who participate in the MRI portion of the study will undergo their 
second MRI scan during this visit. Patients will also repeat the cognitive testing 
battery performed at baseline. 
 
Visit 2 (48 Hours Post First Ketamine or Midazolam Infusion) 
 
On Visit 2, patients will go to the CRU for their 2nd IV drug infusion.  Initial 
assessments will include the IES-R, QIDS-SR16, HAM-A, Brief Psychiatric Rating Scale 
(BPRS), Clinician-Administered Dissociative States Scale (CADSS), Sheehan Disability 
Scale (SDS), Clinical Global Impression scale (CGI), Visual Analogue Scale (VAS), and 
Profile of Mood States (POMS). 
 
Participants in this study will receive ketamine or midazolam under blinded 
conditions. Procedures to be followed at the CRU before, during, and after each 
infusion will be identical to those used during Visit 1a. Clinical ratings prior to each 
IV infusion will be obtained by the same rater who evaluated the patient prior to the 
first IV infusion (CR-1). Ratings conducted on IV infusion days during and after IV 
ketamine or midazolam infusion will be administered by the same rater who 
administers ratings on all study days after IV ketamine or midazolam infusion (CR-2).  
It is expected that no significant psychotomimetic side effects will occur, such that 
patients can be discharged at 130 minutes post-infusion. As described above, 
patients will be assessed by a study psychiatrist at 130 post-infusion to determine if 
they can be discharged safely.  Prior to discharge, all patients will be asked to have a 
family member or friend drive them home, or accompany them in a taxi or public 
transportation, or will be offered a car service to get home.   
 
Visits 3-6  
Since Visits 1a and 2 will take place on a Monday and Wednesday, respectively, 
Visits 3-6 will take place on the following Friday; Monday, Wednesday, and Friday. In 
the event of a Monday holiday, IV infusion of ketamine or midazolam will each take 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
18 
 
place one day later.  
 
Procedures to be followed at the CRU or the Psychiatry Infusion Suite before, during, 
and after each infusion will be identical to those used during Visit 1a.  Clinical ratings 
will continue to be obtained by the same raters who evaluated patients prior to IV 
infusion (CR-1) and following IV infusion (CR-2), respectively. If, at any point during 
treatment patients do exhibit significant psychotomimetic side effects during IV 
infusion, resulting in need for additional monitoring beyond 5:00 pm on the day of 
infusion, they will be exited from the study following additional observation at the 
Mt Sinai ED. 
 
In addition to the rating instruments and scales mentioned above, rater CR1 will 
administer the CAPS once a week (prior to the first IV infusion, and 1 and 2 weeks 
after the first IV infusion, usually on Mondays unless there is a holiday or scheduling 
difficulties that would significantly delay the patient’s participation, in which case it 
will be administered the following day). 
 
At Visit 4b, approximately one week after their first infusions, participants who 
participate in the MRI portion of the study will undergo their second MRI scan 
during this visit. 
 
At Visit 7 (2 weeks after first drug infusion), patients will again be administered the 
battery of cognitive tests to assess any potential changes in cognitive function 
compared to baseline.  
 
Visit 7 (After all Ketamine or Midazolam infusions are completed) 
Laboratory testing will be repeated three days after the conclusion of ketamine or 
midazolam treatment.  
 
Patients will be assessed with the TOP-8, CAPS and the MADRS by the same rater 
who performed these assessments at Visit 1a prior to the first IV infusion (CR-1). 
Patients will also be assessed by a study physician with CGI-I and CGI-S scales, and 
will be asked to complete the IES-R, QIDS-SR16, the POMS and the VAS.  
 
During this visit (2 weeks after first drug infusion), patients will again be 
administered the battery of cognitive tests, to assess any changes in cognitive 
function compared to baseline.  
 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
19 
 
Visits 8-11 (Weekly Follow-Ups) 
Patients will be assessed with the CAPS and MADRS by the same rater who 
performed these assessments at Visit 1a prior to the first IV infusion, and with CGI-I 
and CGI-S scales by a study physician. Patients will also complete the IES-R, QIDS-
SR16, the POMS and the VAS.  
 
Visits 12-16 (Monthly Follow-Ups)  
Patients will be assessed with the CAPS and MADRS by the same rater who 
performed the assessments on the morning of Visit 1aVisit 1a (CR-1), and with CGI-I 
and CGI-S scales by a study physician. Patients will also complete the IES-R, QIDS-
SR16, the POMS, and VAS.  
 
Visits 17-19 (Optional Open Label Phase)  
Patients will be offered up to three open-label ketamine infusions. These infusions 
will occur over the course of up to three weeks. The same assessments indicated 
above will be completed on these infusion days. 
 
Description of measures and summary table:  
 
Both clinician-administered and validated self-report instruments are used, with the aim 
of measuring baseline symptomatology as well as drug actions on (1) the overall severity 
of the disorder, (2) the core symptoms of PTSD, and (3) depressed mood. Below is a 
description of the instruments used. 
 
The Structured Clinical Interview for DSM-5 Axis I Disorders, Patient Edition (SCID-P) is a 
semi-structured interview that provides probe questions as well as follow-up questions 
to be asked by the clinician to assist in diagnosis (First et al 2002).  The new version 
modified for DSM-5 is available from the authors (First, M.).  It includes an overview to 
obtain information about demographics, work, chief complaint, history of present 
illness, past history, treatment history, and current functioning. The main body of SCID-
P includes 9 modules that are designed to diagnose 51 mental illnesses in all.  
 
The Clinician-Administered PTSD Scale (CAPS) is a structured clinical interview designed 
to assess the essential features of PTSD as defined by the DSM5 (Blake et al., 1995; 
Weathers et al., 1993, 2001).  We will use the new version modified for DSM-5.  The 
CAPS can be used to provide categorical ratings of diagnostic status as well as a 
quantitative index of symptom severity. Both frequency and intensity scores are derived 
for each individual symptom. The CAPS total score is based on an individual’s response 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
20 
 
to the 17 items that assess the frequency and intensity of current PTSD symptoms. 
Subscales of the CAPS will be utilized to assess specific symptom clusters. Our research 
group has extensive experience using the CAPS from ongoing PTSD studies. 
 
The Treatment Outcome PTSD Scale (TOP-8) is a brief interviewer-administered scale 
designed specifically for the assessment of commonly occurring signs and symptoms of 
PTSD that are subject to change in response to treatment (Davidson et al., 1997). The 
TOP-8 is comprised of eight items, each measured on a scale of 0–4, with defined 
anchors given for each item. The items are representative of the three core features of 
PTSD with a maximum possible score of 32. 
 
The Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) is a widely used 
observational rating measure of anxiety severity. The scale consists of 14 items. Each 
item is rated on a scale of 0 to 4. This scale will be administered to assess the severity of 
anxiety and its improvement during the course of treatment. The HAM-A total score is 
the sum of the 14 items and the score ranges from 0 to 56. (Hamilton, 1959)  
 
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 (Montgomery and Asberg, 1979). 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 Brief Psychiatric Rating Scale (BPRS) is used to assess acute behavioral changes 
during the administrations (Overall and Gorham, 1962). Four key BPRS items for the 
positive (+) symptoms of psychosis will be used: conceptual disorganization, 
hallucinatory behavior, suspiciousness, and unusual thought content. Three items 
representing the negative (-) symptoms of psychosis will also be used: blunted affect, 
emotional withdrawal, and motor retardation. 
 
The Young Mania Rating Scale, item 1 (YMRS-1) will be used to assess mood elevation 
on the infusion days (Young et al., 1978). 
 
The Clinician-Administered Dissociative States Scale (CADSS) is used to measure 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
21 
 
dissociative effects during the administrations (Bremner et al., 1998). The scale includes 
19 questions and 8 observer ratings scored from 0 (not at all) to 4 (extremely). The 
CADSS measures impairment in body perception, environmental perception, time 
perception, memory impairment, and feelings of unreality. 
 
The Patient Rated Inventory of Side Effects (PRISE) is a patient self-report measure used 
to identify and evaluate the tolerability of side effect symptom. This scale is a 7 item 
assessment of the side effects in the following symptom areas; gastrointestinal, heart, 
skin, nervous system, eyes/ears, genital/urinary, sleep, sexual functioning, and other. 
Each domain has multiple symptoms and for each domain the patient rates whether 
these symptoms are tolerable or distressing. The administration time is less than 5 
minutes. 
 
The Clinical Global Impression (CGI) scale assesses treatment response in psychiatric 
patients. The administration time is 2 minutes. This scale consists of three items: 
Severity of Illness (item 1); Global Improvement (item 2); and Efficacy Index (item 3). 
Item 1 is rated on a seven-point scale (1 = normal, 7 = among the most extremely ill 
patients) as is item 2 (1 = very much improved, 7 = very much worse). Each includes an 
additional response of “not assessed.” Item 3 is rated on a four-point scale (from “none” 
to “outweighs therapeutic effect”). Only items 1 (CGI-Severity or CGI-S) and 2 (CGI-
Improvement or CGI-I) will be used. 
 
The Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner Oquendo et al., 2007) is a 
comprehensive, semi-structured interview measure that uniquely measures the full 
spectrum of suicidality including passive and active suicidal ideation, suicidal intent as 
well as suicidal behaviors. 
The Impact of Event Scale-Revised (IES-R) is one of the most widely used self-report 
measures of stress reactions to traumatic events (Weiss and Marmar, 1996). It measures 
both intrusion and avoidance. A 2002 review that evaluated its psychometric properties 
revealed high internal consistencies for both subscales (intrusion: mean α = 0.86; 
avoidance: mean α = 0.82), adequate test-retest reliability for intervals of >1 year, and 
good internal and external validity. Correlations between IES subscales and PTSD 
diagnosis assessed with the CAPS are high (>0.75). The IES is considered particularly 
useful as a measure of the intrusive and avoidant processes that mediate between the 
experience of trauma and subsequent adjustment (Sundin and Horowitz, 2002). The 
total score can range from 0 to 75. 
 
The Posttraumatic Stress Disorder Checklist (PCL-5) is a 20-item self-report measure 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
22 
 
reflecting DSM-5 symptoms of PTSD. The PCL-5 measures symptoms in response to 
stressful situations (Blake et al., 1995; Weathers et al., 1993, 2001). 
 
The Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) is a 16-item 
self-rated instrument designed to assess the severity of depressive symptoms present in 
the past seven days (Rush et al. 2003). The 16 items cover the nine symptom domains of 
major depression, and are rated on a scale of 0-3. Total score ranges from 0 to 27, with 
ranges of 0-5 (normal), 6-10 (mild), 11-15 (moderate), 16-20 (moderate to severe), and 
21+ (severe). 
 
The Childhood Trauma Questionnaire (CTQ) is a 28-item self-report instrument that 
assesses childhood trauma in the following areas: physical, sexual and emotional abuse 
and physical and emotional neglect (Bernstein and Fink, 1998). Each item is rated on a 
scale of 1 (never true) to 5 (very often true). The 5 subscales are then totaled, with 
scores ranging from 5-25 for each traumatic category.  
 
Traumatic Life Events Questionnaire (TLEQ) The TLEQ is a 23-item self-report measure of 
22 types of potentially traumatic events including natural disasters, exposure to 
warfare, robbery involving a weapon, physical abuse and being stalked. 
 
Visual Analogue Scales (VAS) are used to assess subjective state changes (Bond and 
Lader, 1974). They are 100-mm horizontal lines marked proportionately to the 
perceived intensity of the subjective experience (0=not at all, to 10=extremely) for the 
following states: anxious, depressed, drowsy, high, hungry, and nauseous. 
 
The Sheehan Disability Scale (SDS) is the most frequently used self-report disability 
measure. It has demonstrated sensitivity to impairment and changes as a result of 
treatment across a wide range of psychiatric disorders. The SDS asks only about current 
levels of impairment, providing no indication of whether the person has done better or 
worse in the past, thus making it a reasonable short-term outcome measure that is un-
confounded by historical impressions. The dependent variable is the total score, which 
is based on the sum of three 10-point items (work, social life, and family life), with 
higher scores reflecting greater disability (Sheehan et al., 1996). 
 
The Connor-Davidson Resilience Scale (CD-RISC) (Connor & Davidson, 2003) is a 25-item 
self-report scale, each rated on a 5-point scale (0-4), with higher scores reflecting 
greater resilience. 
 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
23 
 
LOT-R (Life Orientation Test-Revised) (Scheier, M. F., Carver, C. S., & Bridges, M. W. 
(1994).) This 10-point self-report scale was developed to assess individual differences in 
generalized optimism versus pessimism. 
 
The Medical Outcomes Study (MOS) Social Support Survey (Sherbourne & Stewart, 
1991) is a 19-item self-report measure designed to assess levels of functional social 
support. The MOS-SS has two subscales (emotional and instrumental social support) to 
identify potential social support deficits. 
 
The Purpose in Life test - Short Form (PIL-SF) (Schulenberg et al 2010) is a brief, 4-item 
form of the 20-item Purpose in Life test (ref).  This scale asks respondents to report to 
what extent they have achieved their goals in life, and to what extent they perceive 
their life to be meaningful or purposeful.  
 
The Posttraumatic Growth Inventory (PTGI)-Short Version (Cann et. al, 2010) is a 10-
item shortened version of the PTGI self-report questionnaire (ref).  It asks respondents 
to rate the extent to which they have changed as the result of experiencing a highly 
stressful life event. Items span positive changes in five domains: relating to others, new 
possibilities, personal strength, spiritual change, and appreciation of life. 
 
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (Endicott, Nee, 
Harrison & Blumenthal, 1993) is a self-report scale measuring the degree of enjoyment 
and satisfaction experienced by subjects in various areas of daily functioning. The 
summary scores are reliable and valid measures of these dimensions in a group of 
depressed subjects. 
 
The Wechsler Abbreviated Scale of Intelligence 2-Subtest (WASI-2) is a reliable brief 
measure of IQ for 6 to 89 year-olds that takes 15 minutes to complete and includes 
Vocabulary (an estimate of verbal fluid abilities) and Matrix Reasoning (an estimate of 
nonverbal fluid abilities) (Donders and Axelrod, 2002). It is extensively used in clinical, 
educational, and research settings. Average reliability coefficient is 0.96 and test-retest 
reliability is 0.88. 
 
The Profile Of Mood States –Bipolar Version (POMS - Bi) scale measures moods and 
feelings primarily in clinical rather than nonclinical settings. It can help to determine an 
individual's psychiatric status for therapy, or be used to compare mood profiles 
associated with various personality disorders. It is also a useful instrument in identifying 
the effects of drug treatments (O’Halloran et al., 2004). 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
24 
 
 
The Beck Scale for Suicide Ideation (BSS) (Beck , Kovacs et al., 1979) is a 21-item self or 
clinician-administered instrumentation used to measure the current intensity of 
patients’ specific attitudes, behaviors and plans to commit suicide. The BSS consists of 5 
screening items. Three items assess the desire to live or to die and two items assess the 
desire to attempt suicide. If the subject reports any passive or active suicidal ideation 
the additional 14 items are administered. 
 
The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning 
Questionnaire (CPFQ) (Fava et al, 2009): This is a brief (7-item), validated self-report 
inventory to assess rates of significant cognitive symptoms such as memory, attention 
and executive function difficulties. 
 
The Snaith-Hamilton Pleasure Scale (SHAPS) (Leventhal, A.M., et al., 2006) This 14-item, 
self-report was developed for the assessment of hedonic capacity. The inability to 
experience pleasure, anhedonia, is recognized as a hallmark symptom of depression. 
 
The Perceived Stress Scale (Cohen, S et al., 1983). A 10-item self-report scale that was 
developed to measure the degree to which situations in one’s life are appraised as 
stressful. 
 
The State-Trait Anxiety Inventory (STAI) (Spielberger 1985) is a self-report instrument 
that differentiates between the temporary condition of state anxiety and the 
longstanding quality of trait anxiety. With a fifth grade reading level, the STAI is suitable 
for individuals who are 15 years old and older. 
g) Specimen Banking  
Blood samples for assessment of plasma ketamine, norketamine, midazolam, and α-
hydroxy-midazolam levels will be obtained 30, 60 minutes, 90 minutes, and 120 minutes 
after the start of the first infusion only. Blood will be drawn from a heplock contralateral 
to the administration IV. Plasma ketamine and norketamine levels, and plasma 
midazolam and α-hydroxy-midazolam levels will be assayed using validated liquid 
chromatography procedures.  Blood samples will be stored in a freezer at the CRU with 
appropriate labeling.  The specimen will be stored until the end of the study or for 
interim analysis. They will be accessed only by study personnel. The information 
provided with the specimen include randomization number of the participant, visit 
number, type of sample and project identification information. 
 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
25 
 
 
h) Data Management and Confidentiality 
All data collected will be kept confidential and used for research purposes only. Each 
participant will be assigned a coded identifier that will be used to associate stored data 
with each participant. Questionnaires, forms, and results of medical and laboratory tests 
will not have identifiers that can be linked to the participant other than the coded 
identifier. Diagnostic interviewers will only enter coded identifiers on their notes and 
forms. The only forms that will contain the participants’ names and identifying 
information will be the consent forms, which will be stored in a locked file in the principal 
investigator’s locked office. The list associating participants’ names with coded identifiers 
will be maintained separately from the data and in a locked file. No participant’s 
identifying data will be published. All electronic records will be kept confidential to the 
extent permitted by law, stored in a file (including the linking file) on an electronically 
secure database in the Department of Psychiatry at MSSM maintained by Sinai’s IT 
department. This database is password protected and only study personnel will be given 
the password. The results will be gathered with a coded identifier.  We will keep a master 
log that will allow us to interpret the results by matching them with clinical data.  
 
Data will be stored in a cabinet that is in a locked room.  The cabinet is secured with a 
lock, and only the PI and his associates have access to that computer.  Data will be 
stored by the participant’s coded identifier only. 
 
Access to this information will be limited to Drs. Adriana Feder, James Murrough, 
Andrew Perez, and Dan Iosifescu, as well as members of their research group, namely 
study clinicians and research coordinators. 
 
Data Analysis Plan: 
 
Partially unblinded sequential data analyses (“drug A/drug B”) will be conducted each 
time 5 additional participants complete study procedures, under the supervision of Dr. 
Michael Parides, who will receive partially unblinded data from the research pharmacist.  
All other study investigators will remain fully blinded. Based on findings from this data 
analysis, if response to one drug is superior to response to the other drug, the 
randomization ratio will switch from 50%-50% to 60%-40% favoring the drug with 
superior effect. 
 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
26 
 
The primary outcome is planned to evaluate the short-term effects of repeated 
intravenous infusions of ketamine compared to the active control (midazolam).  A 
paired two-sample t-test will be used to compare mean CAPS scores in the two 
treatment groups at 2 weeks after the first study drug administration.  
 
For the IES-R, one of the secondary outcome measures for this study, based on data 
from a recent study of a single infusion (Feder et al., 2014), a decrease of 30 (sd=10) 
from baseline of 45 is expected in the ketamine arm, and a decrease of 25 (sd=10) is 
expected in the midazolam arm. A paired t-test was chosen in order to determine 
whether IES-R scores improved compared to baseline and whether the change was 
different between treatment groups. A sample size of 40 will provide 89% power 
assuming a Type I error rate of 0.05.  
 
To assess longer-term effects of repeated study drug administrations, mean CAPS scores 
at 7 days after the initial administration will be compared using a paired two-sample t-
test. If the difference between ketamine and midazolam is statistically significant at 7 
days, mean CAPS scores at baseline and at 28 days after the initial infusion will be 
compared between groups using a paired two-sample t-test. This sequential testing, or 
gatekeeping, strategy is used to preserve Type I error and increase power. In the single 
infusion study (Feder et al., 2014), a decrease of 27 (sd =20) in CAPS score at 7 days was 
seen in the ketamine arm compared to a decrease of 13 (sd = 18) in the midazolam arm. 
Assuming a sample size of 40, these conservative estimates would provide 96% power 
assuming a Type I error rate of 0.025 (using the Bonferroni adjustment to hold the 
family-wise error rate at 0.05). 
 
Neuroimaging data analyses: We will preprocess imaging data using SPM8 and Neuroelf 
as follows (in order): realignment of functional images, co-registration of functional and 
structural images, normalization to MNI template, and three-dimensional smoothing 
with a 6 mm kernel. Inferential statistical analysis will use the general linear model 
(GLM) as implemented in Neuroelf. Bilateral anatomical ROIs will be created of the 
amygdala and insula, as well as vmPFC and dACC.  Exploratory whole-brain analyses will 
additionally be conducted to examine group differences in contrasts of interest using 
paired t-tests and simple regression analyses in Neuroelf, with a threshold of p < 0.05, 
cluster-level corrected for multiple comparisons across the whole brain. 
 
 
i) Provisions to Monitor the Data to Ensure the Safety of subjects 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
27 
 
Part I: Elements of a Data and Safety Monitoring Plan 
1. List the name(s) of the individual(s) at MSSM who will be responsible for data and 
safety monitoring of this study. For each individual, indicate their role, name, title, and 
department information. The Principal Investigator may be the only monitor of a study.  
 
If the qualifications of an individual to serve as a monitor are not contained in the PPHS 
application, they must be added to the DSMP either as a narrative description or as a 
CV. 
 
MSSM Principal Monitor: 
Check One:   PI:
  Team Member: 
 
Independent:
 
Last Name: Feder 
First Name: Adriana  
Academic Title: Associate Professor 
Department: Psychiatry 
Mailing Address: 1 Gustave L. Levy Place, Box 1230 
New York, NY 10029   
Phone: 212-659-9145   
Fax: 212-659-9291 
E-mail: adriana.feder@mssm.edu 
 
MSSM Additional Monitor: 
Check One: PI: 
 Team Member: 
 Independent: 
 
Last Name: Murrough 
First Name: James 
Academic Title: Assistant Professor 
Department: Psychiatry  
Mailing Address: 1 Gustave L. Levy Place, Box 1230  
New York, NY 10029 
Phone: 212-585-4640 
Fax: 212-241-3354 
E-mail: james.murrough@mssm.edu 
 
 
2. Justify your choice of principal monitor in terms of the assessed risk to the research 
subject‘s health and wellbeing. In high risk studies when the principal monitor is 
independent of the study staff, indicate the individual’s credentials, relationship to the 
PI, and the rationale for selection. 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
28 
 
 
Drs. Feder and Murrough have extensive experience in the conduct of clinical trials 
studying the effects of ketamine in patients with PTSD and TRD at ISMMS.   
 
3. List the specific items that will be monitored for safety (e.g., adverse events, subject 
compliance with the protocol, drop outs, etc.). 
 
Both the recruitment process and the informed consent process will be monitored 
by independent monitors who are not affiliated with the research team. Adverse events, 
subject compliance with the protocol, side effects and dropouts will also be closely 
monitored. 
 
4. Indicate the frequency at which accumulated safety and data information (items 
listed in number 3 above and interim analysis of efficacy outcomes) will be reviewed by 
the monitor(s) or the Data Monitoring Committee (DMC). Although this information 
must be reviewed at least annually, the higher the study risks, the more frequently 
reviews must be scheduled. 
 
The primary study monitors, Dr. Feder and Dr. Murrough, will monitor study 
progress 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. 
 
5. Where applicable, describe rules which will guide interruption or alteration of the 
study design. 
 
Medical Criteria for discontinuation are as follows: 
1. Changes in psychiatric symptoms at any time during the study: 
Treatment emergent mania, hypomania, worsening suicidality or psychosis 
2. Emergent medical symptoms on the infusion days: 
a. 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, 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. 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
29 
 
iii. Further therapy with longer acting agents such as metoprolol, 
esmolol and labetolol will be administered if the response to 
initial therapy is not adequate. 
b. 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. 
c. 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. If either of 
these problems occurs, the study physician will open the sealed 
envelope with the drug identity and treat the patient accordingly. 
Midazolam sedation would be reversed by using flumazenil. 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. 
d. In the event that SpO2 < 95% over 5-minute interval, the study 
physician will have the option of adjusting the nasal cannula position 
or 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. 
 
6. Where applicable, indicate dose selection procedures that will be used to minimize 
toxicity.  
 
The dose of ketamine is fixed at 0.5mg/kg mg and that of midazolam is fixed at 
0.045mg/kg, to be given over 40 min.  As above, ketamine or midazolam infusion will be 
discontinued earlier if necessary due to side effects. 
 
7. List any specialized grading system that will be used to evaluate adverse events (e.g., 
National Cancer Institute Common Toxicity Criteria). 
 
The study physician will be present at the CRU or Psychiatry Infusion Suite 
throughout the infusions so that potential adverse events can be evaluated and treated 
promptly. The study physician will remain until at least one hour following the 
termination of the administration or until the patient meets Aldrete criteria (good 
respiration, oxygen saturation, consciousness, circulation and activity). The following 
clinical endpoints of hypnosis will be obtained: Ramsay Sedation Scale Score, loss of 
eyelash reflex, inhabitation of nasal-body movement response and/or sneezing, 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
30 
 
nystagmus and salivation. The PI will report any serious adverse events, verbally and in 
writing, to the Mount Sinai IRB within 48 hours. 
 
8. Describe procedures that will be used to assure data accuracy and completeness. 
 
There will be one project coordinator who will coordinate the database. Two 
volunteer research assistants will enter and verify data. To help avoid errors in data 
entry, limits will be set for each scale (on Excel), only allowing the range of values 
possible for that specific scale to be entered in those data cells. Furthermore, the total 
of each scale will be calculated by Excel equations to ensure accuracy.  
 
9. Should a temporary or permanent suspension of your study occur, in addition to the 
PPHS, to whom (NIH, FDA, sponsor, IRB) will you report the occurrence?  
 
 
This will be reported to the funding agency (we are currently applying for 
funding). 
 
 
Part II. Data Monitoring Committee/Data Safety Monitoring Board (DMC/DSMB) 
 
The DSMB includes the following members:, Lawrence Price MD (Department of 
Psychiatry, Brown University, named by ISMMS chair of psychiatry, Dr. Wayne 
Goodman) and Yaakov Beilin MD (Department of Anesthesiology, ISMMS).  Currently, a 
new chair of the DSMB committee is being selected to replace Dr. Larry Siever, the 
previous chair.  A final determination has not been made. This is the same DSMB that 
currently reviews all ongoing ketamine clinical trials conducted by investigators at DAC.  
The board will review the project’s data and safety on bi-annual basis and report their 
findings to the PI.  DSMB reports will also be made available to the Mt. Sinai PPHS.  The 
DSMB will ensure the safety of study participants and the integrity of the data collection 
in the projects. To achieve this goal, the DSMB will perform an ongoing evaluation of the 
safety of patients participating in the clinical trial. This includes monitoring adverse 
events and overall clinical outcomes in the studies. Through this process, the board will 
evaluate the need for study termination and/or modification of study criteria for 
inclusion, exclusion, or discontinuation.  In addition, the DSMB will be responsible for 
the evaluation of the adherence to written protocols regarding the protection of human 
subjects and the assurance of identity protection as specified in the Data Sharing 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
31 
 
Section. The DSMB will expeditiously review all serious adverse events and perform 
ongoing scheduled reviews of non-serious adverse events and study dropouts. 
 
j) Withdrawal of Subjects 
Patients will be withdrawn from the double-blind treatment period if, in the 
investigator’s opinion, there is a safety risk to the patient or a chance that the patient 
may deliberately injure him- or herself or others. In the event that a subject is 
discontinued from the study early and/or following completion of the study, the patient 
will continue to receive standard psychiatric care as determined by the treating 
psychiatrist. 
 
However, the Principal Investigator for the research may still use the information that 
was already collected if that information is necessary to complete the study. Subject’s 
health information may still be used or shared after withdrawal in cases where the 
subjects develop side effects. 
 
 
6) Risks to Subjects 
General research procedures: Research interviews will be interrupted if individuals 
become distressed or object to answering questions. If in the clinician’s judgment a 
patient has worsened to such a degree that further participation would put him or her at 
risk, he or she will be discontinued from the study. 
 
At any point during the study patients will be told to immediately inform their research 
physician if they develop a worsening of depressive symptoms, symptoms of mania, or 
active suicidal plans. Patients will also be encouraged to identify someone who knows 
them well to contact the research physician on their behalf in case manic symptoms or 
suicidal thoughts develop. We have included safety measures such as discontinuation of 
the study drug and transition to standard clinical treatment should patients worsen to a 
sufficient degree. These precautions are likely to be highly effective in minimizing risks.  
 
Infusions and post-infusion days: Patients will be closely monitored by the study 
physician, study psychiatrist, and nursing staff at the Infusion Suite or CRU. Assessments 
will be administered repeatedly during immediately and 120 minutes following 
intravenous infusion to ensure that symptoms, including any potential psychotomimetic 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
32 
 
symptoms do not worsen. A physician will be on-call during off hours.  
 
Risks of IV catheterization and minimization of this risk: The risks of venipuncture include 
pain, bruising, and to a lesser degree, the risk of infection at the injection site, dizziness 
or syncope during or after the blood draw. To limit risk, these procedures will be 
performed by staff members who are experienced in venipuncture, using sterile 
technique. 
 
Risks associated with clinical interview and scale administration, and minimization of 
these risks:  During the clinical interviews, patients may express fatigue, frustration, or 
anxiety in response to the questions.  In these situations, the interview will be stopped 
and depending on the situation, the patient may then 1) take a rest period and resume 
later, 2) be rescheduled for a later appointment, or 3) decide to terminate the exam. 
There always exists the potential for loss of private information; however, there are 
procedures in place to minimize this risk. 
 
Pertaining to participants who complete the MRI portion of the study, the fMRI 
procedure is very safe and exposes the study subjects to minimal risk or discomfort.  The 
MRI scanning involves the subject placing their head in a tube and some subjects may 
experience a feeling of claustrophobia while in the scanner. However, a study 
investigator will be present for all scanning sessions in case of any unexpected 
complications. In addition, the participant will remain in verbal contact with a study 
investigator (via intercom) throughout the procedure so that they may communicate 
immediately any problems, or express a desire to terminate the scan at any time. 
 
Follow-ups: Patients will be closely monitored by a physician at regular appointments 3 
times per week for the first 2 weeks, i.e., during the period of intravenous infusions and 
one more visit after infusions are completed.  Post-study, patients will be followed weekly 
for one month or until relapse, defined by CAPS administration, and thereafter monthly 
for up to 6 months from randomization or until relapse (defined by CAPS administration).  
In addition, a psychiatrist knowledgeable of the study will be on-call during off hours. 
Patients will be informed that if their clinical condition deteriorates during the study, they 
may be hospitalized. Individuals may be hospitalized if they exhibit worsening of their 
symptoms, including becoming suicidal.  In this case or if participants discontinue 
treatment they will receive standard short-term clinical treatment as long as they remain 
on a voluntary basis.  However, if they do not remain on a voluntary basis, then they may 
be transferred to a local hospital for further treatment.  If individuals are hospitalized 
elsewhere, ISMMS will not cover the costs associated with that hospitalization. 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
33 
 
 
Patients will be told to immediately inform their research physician if they develop 
suicidal ideation or symptoms of mania, or a worsening of depressive, anxiety or PTSD 
symptoms. They will also be encouraged to identify someone who knows them well to 
contact the research physician on their behalf in the event suicidal thoughts or manic 
symptoms develop.  As an additional safeguard, we will utilize in this study a treatment 
contract, and will only include patients who are able to identify a family 
member/physician/friend who agrees to participate in this contract.  We have 
successfully used similar treatment contracts in other studies at DAC. 
 
Acute Ketamine Side Effects: Ketamine is a general anesthetic for human and veterinary 
use with a good safety profile. Over the past several decades, ketamine has been 
administered as an anesthetic to millions of adults and children. In addition, it has been 
used for years in psychophysiological studies in normal volunteers and patients with 
severe mental disorders, including several studies conducted by our research group (with 
doses similar to those in this study). Although ketamine’s anesthetic effects include 
respiratory changes, we will use sub-anesthetic doses of ketamine with which these 
changes can be prevented or minimized. We have not observed any clinically significant 
respiratory changes in our previous ketamine administration studies. 
 
The reported incidence of perceptual disturbances varies from less than 5% to 69%). 
Perceptual disturbances can 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-limited.  Studies by our research group and others suggest that the effects 
of ketamine administration on these symptoms are usually short-lasting (less than 60 
minutes) and rarely last longer than 2 hours. The perceptual disturbances appear more 
commonly in those with preexisting psychosis (schizophrenia), which is why those 
patients with a history of psychosis are excluded.  
 
Patients will be closely monitored by the study physician, study psychiatrist, and the 
nursing staff at the CRU or Infusion Suite. Assessments will be administered immediately 
and 120 minutes following infusion to ensure that symptoms, including any potential 
psychotomimetic symptoms do not worsen. A physician will be on-call during off hours. 
 
Acute Midazolam Side Effects: Side effects associated with midazolam, especially at the 
sub-anesthetic dose given, are expected to be mild. Midazolam has good cardiovascular 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
34 
 
stability, and induces only a transient and mild respiratory depression in comparison with 
other benzodiazepines. Midazolam produces a short-duration anterograde amnesia that 
is not likely to last beyond 30-60 minutes following the infusion. 
 
 
7) Provisions for Research Related Injury 
Medical and psychiatric resources will be available during and acutely following drug 
administration and subjects will be actively monitored during this period. In general, if 
subjects are injured or made sick from taking part in this research study, medical care will 
be provided. Generally this medical care will be billed to the health care insurance. 
However, Mount Sinai may be responsible for the costs of any research-related injury. 
Mount Sinai agrees to pay for those subjects without health insurance and financially 
vulnerable in case an emergency or injury related to the research occurs. 
 
Patients will be told to immediately inform their research physician if they develop 
suicidal ideation, or a worsening of anxiety, depressive or PTSD symptoms. They will also 
be encouraged to identify someone who knows them well to contact the research 
physician on their behalf in the event suicidal thoughts.  
 
Patients will also be provided with contact information for the study psychiatrist. 
 
8) Potential Benefits to Subjects 
The risks of this study are reasonable in relation to the anticipated benefits to the 
patient and his/ her environment (remission or improvement of PTSD symptoms). No 
other direct benefits result from study participation. All participants will receive, 
without cost, an extensive psychiatric and medical evaluation. All participants will 
receive reimbursement of travel expenses and some compensation for their time and 
participation. 
 
9) Provisions to Protect the Privacy Interests of Subjects 
Research coordinators will call participants from previous research studies to see if they 
are interested in participating in this research study. Only those participants who 
consented to be contacted will be reached out to. Those conducting phone screens will 
introduce themselves, the clinic and talk briefly about the study. The questions go from 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
35 
 
more general questions to more specific. Only if the participant is comfortable will 
he/she answer more specific questions about his/her history and symptoms.  
 
Participants are also told that answering all questions is voluntary and if anything were 
to make him/her feel uncomfortable they would not have to answer the questions. If a 
participant has any special need (e.g., only seeing a female study doctor, etc) 
arrangements will be made for the individual as much as possible. After assessments 
and interviews, participants are given the opportunity to express any concerns about 
how they feel post-follow-up, etc. All study assessments will be conducted in a private 
room. Patients will assured that all information shared with study personnel is 
confidential and protected by MSH policy and HIPPA. 
 
 
 
10) 
Economic Impact on Subjects 
No costs shall be incurred by participants for their participation in the study. In the event 
of an injury resulting from the research study, the facilities of Mount Sinai Hospital and 
professional attention will be made available to patients.  
 
11) 
Payment to Subjects  
Procedure 
Reimbursement 
Screening visit 1 (interview) 
$50 
Screening visit 2 (medical clearance) 
$25 
First administration day  
$75 
24-hour follow up 
$50 
Second administration day  
$50 
Third administration day 
$50 
Fourth administration day 
$75 
Fifth administration day 
$50 
Sixth administration day 
$50 
Study Exit Visit 
$75 
First Follow up 
$25 
Second Follow up 
$25 
Third Follow up 
$25 
Fourth Follow up 
$25 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
36 
 
Fifth Follow up 
$25 
Sixth Follow up 
$25 
Seventh Follow up 
$25 
Eighth Follow up 
$25 
Ninth Follow up 
$25 
MRI Scanning (x 2) 
$100 per scan 
Total for participation in all parts of the study, if 
all eight follow-up visits are needed 
$975 
Reimbursements will be made by check and will be requested on each visit day. Checks 
are requested through the Mount Sinai finance department and typically take 2-3 weeks 
to process; patients have the option of having their checks mailed directly to them or to 
pick them up in the office. Payment is not contingent on completing the study. 
 
12) 
Consent Process 
Informed consent will be obtained prior to screening in DAC, located on ISMMS premises, 
in a closed office with only members of the research group present. These offices are 
located at DAC on the 2nd floor of 1399 Park Avenue.  No reference to the potential 
participant’s identity will be made outside of closed quarters. The study team is following 
“SOP HRP-090 Informed Consent Process for Research.” Prior to obtaining consent, a brief 
study synopsis will be presented and the following options will be presented to the 
patient by a member of the study personnel: 1) the option to hear detailed information 
about the study at that time, 2) the option to take a copy of the consent form home with 
them and to contact study personnel if they are interested, and 3) the option to decline 
participation or hearing more about the study. We will clearly state that participation in 
the research study is completely voluntary and only one of several options to consider. 
We will also tell the patient that his/her decision about whether or not to participate does 
not impact clinical care or their relationship with treatment providers. This consent 
process should allow adequate time for subjects to make an educated and autonomous 
decision. In compliance with ICH Good Clinical Practice guidelines, the consent process 
will be documented.  
 
After the protocol is described to the participant and the participant’s questions are 
answered, the participant will be asked to summarize the procedures that he/she will 
undergo and to describe two risks involved in the study.  A capacity assessment will also 
be conducted by an independent psychiatrist to determine whether the participant has 
understood and informed consent can be provided.  Only individuals who are assessed 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
37 
 
to have the capacity to consent will participate in this study. Additionally, this study will 
only enroll English speaking participants. This study will not enroll non-English speaking 
subjects due to a lack of available validated instruments in other languages and a lack of 
bilingual study staff and clinicians to communicate with participants and administer 
clinical research interviews or rating scales. 
13) 
Process to Document Consent in Writing 
Individuals will be required to sign an informed consent form if they are interested in 
participating in this research study. An investigator or research coordinator listed under 
assurances will also sign the consent form. A copy will be given to the research 
participant and the original will be stored in their patient file in a locked cabinet in a 
locked room. 
 
Additionally, a capacity assessment will also be conducted by an independent 
psychiatrist to determine whether the participant has understood and informed consent 
can be provided. Only individuals who are assessed to have the capacity to consent will 
participate in the study. An independent capacity assessment form will be signed by this 
psychiatrist if he/she grants capacity to the patient to participate in this study. 
 
 
14) 
Vulnerable Populations 
 
Include 
Exclude 
Vulnerable Population Type 
 
x 
Adults unable to consent 
 
x 
Individuals who are not yet adults (e.g. infants, children, teenagers) 
 
x 
Wards of the State (e.g. foster children) 
 
x 
Pregnant women 
 
x 
Prisoners 
 
Individuals who are economically or educationally disadvantaged persons. In the Mount 
Sinai catchment area we expect to enroll individuals who are economically or 
educationally disadvantaged. Additional efforts will ensure that these persons 
understand all of the proposed research. These efforts would include: (1) not 
preferentially enrolling vulnerable patients; (2) providing a consent document and all 
other information to subjects in terms they can fully understand; (3) not exerting any 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
38 
 
overt of covert coercion; (4) offering payment amounts that are not considered to be 
coercive.  
 
15) 
Control of Drugs or Devices 
Ketamine and midazolam will both be stored at the ISMMS pharmacy. 
 
16) 
Multi-Site Human Research (Coordinating Center) 
N/A 
 
17) 
Community-Based Participatory Research 
N/A 
 
18) 
Sharing of Results with Subjects 
Subjects can be provided with a copy of their medical work up (labs, ECG, etc) upon 
written request to the PI.  After analysis of data, outcomes and results may be shared 
with participants upon request. 
 
19) 
IRB Review History 
N/A 
 
 
 
 

 
Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
39 
 
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Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
40 
 
 
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Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
41 
 
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Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
42 
 
 
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Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
43 
 
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Protocol Title: 
Randomized Controlled Trial of Repeated-Dose Intravenous 
Ketamine for PTSD 
Principal Investigator 
Name/Contact Info:  
Adriana Feder, MD 
adriana.feder@mssm.edu; x89145 
Primary Contact 
Name/Contact Info 
Sarah B. Rutter 
sarah.rutter@mssm.edu, x54634 
Date Revised: 
January 24th, 2020 
Study Number: 
HSM 14-00843, GCO 15-0265 and 14-1781 
 
44 
 
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