Clinical trial NCT02727998
Conditions: Posttraumatic Stress Disorder
Keywords: PTSD
Sponsor: Yale University
Start date: 2015-12-01; Completion date: 2021-11-28
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to combine a single infusion of Ketamine with 7-days of trauma focus psychotherapy to relieve post traumatic stress disorder (PTSD) symptoms more effectively. This treatment has the potential to produce a significant therapeutic effect that otherwise would take months to occur.

Detailed description:
Based on the current research findings on the therapeutic effectiveness of trauma focus psychotherapy and of ketamine, combining the two treatments may yield a promising new rapid 7-day treatment for PTSD. As PTSD symptoms' structure is comprised of several unique clusters which include re-experiencing, avoidance, numbing/depression and hypervigilance the investigators hypothesize that by combining Ketamine with prolonged exposure (PE) the investigators can address these symptoms clusters more effectively. This treatment has the potential to produce a significant therapeutic effect that otherwise would take months to occur by tapping on the enhanced neuroplasticity and the antidepressant effect of ketamine (which lasts between 24hrs to 7 days), to promote rapid changes in learning and memory using prolonged exposure therapy within this unique "window of opportunity".

During the first visit participants will undergo a clinical interview to establish a PTSD diagnosis and other eligibility criteria. If found eligible participants will be invited to take part in this 7-day rapid treatment trial for PTSD.

On the first therapy visits, participants will be educated about the psychological treatment that will be provided and the potential benefit of ketamine to enhance the psychotherapy outcomes.

On the second day of the study, participants will receive an infusion of ketamine or placebo and will undergo a magnetic resonance imaging (MRI) scan and will receive the second psychotherapy session.

On days 3-6 participants will attend a 60-90 minutes psychotherapy session to address their PTSD symptoms.

Day 7 will include another MRI scan and the last psychotherapy session.

Participants will be asked to come back for a follow up evaluation of their PTSD symptoms 30 and 90 days post discharge.

Arms: arm 1: After the reactivation of the scripted memories during PE on day 2, the ketamine infusion procedure will begin inside the MRI. A physician will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady state ketamine infusion of 0.50 mg/kg/hour. The infusion will continue for 40 minutes. arm 2: After the reactivation of the scripted memories during PE on day 2, the midazolam infusion procedure will begin inside the MRI. A physician will oversee and administer the Midazolam infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following midazolam infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady midazolam infusions at a rate 0.045 mg/kg for 40 minutes.
Interventions: intervention 1: Ketamine intervention 2: Midazolam
Intervention descriptions: intervention 1: Prolonged exposure therapy combined with a single infusion of 0.50 mg/kg/hour for 40 min on day 2. intervention 2: Prolonged exposure therapy combined with a single infusion of 0.045 mg/kg/hour for 40 min on day 2.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
NCT02727998  
Intensive 7-day Treatment for PTSD Combining 
Ketamine With Exposure Therapy 
08FEB2021 


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Version 17.0, 08FEB2021 
 
 
YALE UNIVERSITY 
 
                                  HUMAN INVESTIGATION COMMITTEE 
 
                                     Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2015-1)  
 
SECTION I: ADMINISTRATIVE INFORMATION 
 
Title of Research Project: Combining neurobiology and new learning: Ketamine and Prolonged exposure: A 
potential rapid treatment for PTSD 
Principal Investigator: Ilan Harpaz-Rotem 
 
Yale Academic Appointment: Associate Professor 
 
Department: Psychiatry  
Campus Address:  300 George St. New Haven, CT 06511 
 
Campus Phone: 2039374760 
Fax:  
Pager:  
E-mail: ilan.harpaz-
rotem@yale.edu 
Protocol Correspondent Name & Address (if different than PI): 
Kristin DeFrancesco, 2 CSS, Suite 401, New Haven, CT 06519 (through initial approval) 
 
Charles Gordon, 950 Campbell Ave, West Haven, CT 06516-2770 (after initial approval) 
Campus Phone:  
Kristin : 203-785-3852 
Charles : 203-932-5711 
Fax:  
E-mail:  
kristin.defrancesco@yale.edu 
charles.gordon@yale.edu 
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable): 
 
Campus Phone:  
Fax:  
E-mail:  
Business Manager: 
Campus Phone : 
Fax : 
E-mail 
 
Investigator Interests: 
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA 
 
Yale Academic Appointment: 
 
Campus Address:  
 
Campus Phone:  
Fax:  
Pager:  
E-mail:  


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degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.  
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI  
  Yes  
X  No  
 
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol? 
  Yes  
X  No  
 
 
 
If yes to either question above, list names of the investigator or responsible person: 
 
 
 
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form:  http://www.yale.edu/coi/   
 
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol. 
 
SECTION II: GENERAL INFORMATION 
 
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply: 
  
a. Internal Location[s] of the Study: 
 Magnetic Resonance Research Center  
 
 Yale University PET Center 
     (MR-TAC)    
 
 
 
 
 YCCI/Church Street Research Unit (CSRU) 
 Yale Cancer Center/Clinical Trials Office (CTO)    
 YCCI/Hospital Research Unit (HRU) 
 Yale Cancer Center/Smilow 
 
 
 YCCI/Keck Laboratories 
 Yale-New Haven Hospital  
 
 
 Yale-New Haven Hospital—Saint Raphael Campus 
 Cancer Data Repository/Tumor Registry 
 Specify Other Yale Location: 300 George St. (Decision Neuroscience Lab)  
 
 
 
 


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b. External Location[s]: 
 APT Foundation, Inc. 
 
 
 
 Haskins Laboratories 
 Connecticut Mental Health Center 
 
 John B. Pierce Laboratory, Inc. 
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven 
 
 Other Locations, Specify:  
 
 
 International Research Site  
(Specify location(s)): 
 
 
c. Additional Required Documents (check all that apply): 
 N/A 
*YCCI-Scientific and Safety Committee (YCCI-SSC)  
Approval Date:  
*Pediatric Protocol Review Committee (PPRC) 
 
Approval Date:  
*YCC Protocol Review Committee (YRC-PRC) 
 
Approval Date: 
 
*Dept. of Veterans Affairs, West Haven VA HSS 
 
Approval Date:  
*Radioactive Drug Research Committee (RDRC) 
 
Approval Date:  
 YNHH-Radiation Safety Committee (YNHH-RSC) 
 
Approval Date:  
 Magnetic Resonance Research Center PRC (MRRC-PRC) 
Approval Date: 8/26/2015 
 YSM/YNHH Cancer Data Repository (CaDR)  
 
Approval Date:  
 Dept. of Lab Medicine request for services or specimens form 
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found 
at  http://radiology.yale.edu/research/ClinTrials.aspx) 
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements. 
 
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.  
 
The anticipated duration of the project is 5 years.  
 
3. Research Type/Phase: (Check all that apply) 
a. Study Type 
   
 Single Center Study 
   
 Multi-Center Study 
Does the Yale PI serve as the PI of the multi-site study? Yes 
 
No 
 
  
 Coordinating Center/Data Management 
  
 Other:  
 
 
b. Study Phase 
 N/A 
    
 Pilot  
 Phase I 
 Phase II 
 Phase III 
 Phase IV 
    
 Other (Specify)  
 
 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following can 
be found  in the instructions section 4c: 
 Clinical Research: Patient-Oriented 
   
 
 Clinical Research: Outcomes and  


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 Clinical Research: Epidemiologic and Behavioral  
                 Health Services 
 Translational Research #1 (“Bench-to-Bedside”)      
 Interdisciplinary Research 
 Translational Research #2 (“Bedside-to-Community”)  
 Community-Based Research 
 
 
5.   Is this study a clinical trial? Yes 
 
No 
 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events” 
  
If yes, where is it registered? 
  
 
Clinical Trials.gov registry 
  
  
 
Other (Specify)  
 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE. 
 
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used. 
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx 
or  contact YCCI at 203.785.3482) 
 
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)?  
Yes 
 No
 
 
 
7. Will this study have a billable service? A billable service is defined as any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either Yale-
New Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The service 
may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include 
x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. 
There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects.  
 
Yes 
 No
 
 If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu 


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8.. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes _X_ No __ If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III. 
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? Yes.  
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?  No 
  
c. Will a novel approach using existing equipment be applied?  No 
  
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol. 
 
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or  mid-level 
practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet 
the criteria, please telephone the Physician Services Department at 203-688-2615. By signing 
this protocol as a PI, you attest that you and any co-investigator who may have patient contact 
has a medical staff appointment and appropriate clinical privileges at YNHH. 
 
 
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING 
 
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply. 
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).   
 
 
PI  
Title of Grant 
Name of Funding Source  
Funding 
Funding Mechanism 
 
Ilan Harpaz-
Rotem 
Combining 
neurobiology and 
new learning. 
Ketamine and 
Prolonged exposure: 
A potential rapid 
treatment for PTSD 
Clinical Neuroscience 
Division, National Center 
for PTSD 
 
 
Yale School of Medicine, 
Department of 
Psychiatry  
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
  Other 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 


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  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
  Other 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 
 
 
 
 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
  Other 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify:  
 
 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided. 
 
Send IRB Review Fee Invoice To: 
 
Name: 
 
Company: 
Address: 
  
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol.  See NOTE below. 
 
 Listed in IRES IRB 


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Department Chair’s Assurance Statement 
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 


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sponsoring company, patents, licensure) associated with this research project? 
 Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
 No 
 
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No 
 
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately. 
 
   _John Krystal MD___________________________ 
 
 
 
 
 
 
 
   Chair Name (PRINT) and Signature   
     
 
 
  
 
Date 
 
   _Psychiatry________________________________ 
   Department 
 
 
YNHH Human Subjects Protection Administrator Assurance Statement 
Required when the study is conducted solely at YNHH by YNHH health care providers. 
 
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that: 
▪ I have read a copy of the protocol and approve it being conducted at YNHH. 
▪ I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest. 
▪ The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project. 
 
  ______________________________________ 
 
 
 
 
 
 
 
 
    YNHH HSPA Name (PRINT) and Signature         
 
 
Date 
 
 
SECTION V: RESEARCH PLAN 
 
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.  
 
Aim 1: To examine the feasibility to recruit, randomize, retain, and assess participants in a one-week 
exposure therapy combined with single dose ketamine infusion or a series of two ketamine infusions. 
Aim 2: To demonstrate the beneficial effects of combining low dose ketamine (0.5 mg/kg or 0.2mg/kg 
infused over 40 min) and intensive prolonged exposure (PE) therapy on PTSD symptoms as assessed 
by structured interviews and behavioral ratings in the OIF/OEF/OND population.  
Aim 3: To assess changes in the brain’s functional connectivity and hyper-reactivity in the “mood” 
and “memory” network which include: the amygdala, striatum, insula, anterior cingulate cortex, 


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hippocampus and prefrontal cortex in pre and post treatment task listening to the trauma 
narrative/neutral narrative/and a significant non-traumatic memory narrative pre and post treatment.  
Aim 4: To demonstrate the ability of ketamine treatment to restore structural connectivity by using 
diffusion weighted imaging (DTI) and global probabilistic tractography with anatomical priors, we 
will estimate the cingulum fractional anisotropy (FA) at baseline, and post treatment. 
 
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data. 
 
 
 
Prolonged Exposure therapy (PE) is based upon the Emotional Processing Theory of 
PTSD, which emphasizes the critical importance of mentally processing traumatic memories 
in order to alleviate PTSD symptoms (Foa, Hembree, & Rothbaum, 2007). The content of the 
therapy itself emerged from exposure therapy, which has long been used to help anxious 
clients confront fear and anxiety-producing stimuli in a non-threatening environment. PE 
utilizes psychoeducation about anxiety and its treatment and breathing exercises to provide 
clients with some immediate anxiety-reducing skills (Foa, Rothbaum, Riggs, & Murdock, 
1991). Among the techniques employed in PE, imaginal and in vivo exposure constitute the 
core of the therapy. Imaginal exposure asks clients to audibly recount a traumatic event while 
mentally visualizing the experience, and is typically repeated during therapy sessions. In vivo 
exposure involves the client repeatedly confronting avoided environments or stimuli in real 
life, and is often assigned as homework (Foa & Rothbaum, 1998). Imaginal exposure 
enhances memory reconsolidation of the traumatic memories, leading to reduction of re-
experiencing symptoms, while in vivo exposure reduces avoidant behavior and exaggerated 
startle responses. By assisting the client to not engage in avoidance behavior during these 
exposures, the maladaptive associations between feared stimuli, avoidance behavior, and 
psychological relief become weakened as new, positive associations are forged. The client 
learns that memories of their trauma are not identical to the trauma itself, and as this occurs 
the ability of environmental, cognitive, and behavioral reminders of trauma to elicit a fear 
response is diminished.  
 
 
PE is widely considered to be an efficacious and effective treatment for chronic PTSD 
(Eftekhari, Stines, & Zoellner, 2006; Foa et al., 1991; Foa et al., 2005). However, the therapy 
has limitations: it is traditionally administered on a weekly basis over a period of 3 or more 
months. Naturalistic studies suggest that more than 60% drop out of therapy before receiving 
appropriate dose to experience a significant symptoms reduction (Harpaz-Rotem & 
Rosenheck, 2011). Since PTSD is often exacerbated over time, faster treatment may also 
prevent the escalation of minor affective disturbances into chronic anxiety and depression 
symptoms, particularly when delivered temporally close to a traumatic event. A recent 
investigation of a novel, intensive form of PE delivered over 7 consecutive days found that 
PSTD clients were able to achieve outcomes comparable to traditional PE in a fraction of the 
time (Ehlers et al., 2014). Even among those receiving this intensive brief treatment, however, 
about 47% of clients did not demonstrate significant improvement as measured by the 
Clinician Administered PTSD Scale. Augmenting PE with pharmacotherapy has been 
suggested as a promising solution to address treatment-resistant PTSD (Eftekhari, Stines, & 
Zoellner, 2006). Case studies report that significant additional improvements have been 
observed made when PE was supplemented with SSRIs (Marshall, Carcamo, Blanco, & 


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Liebowitz, 2003) and with sertraline (Otto et al., 2004). However, rates of nonresponse to 
these pharmacological approaches remain high, indicating a tremendous need to test novel 
pharmacological approaches to PTSD. 
 
 
 
 
The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has been shown to 
have rapid-acting effects on treatment-resistant depression. Following a single 0.5mg/kg 
subanesthetic infusion of ketamine, numerous studies report antidepressant effects among 
43%-90% of clients which present within 4 hours post-infusion and persist for 7-28 days 
(Ibrahim et al., 2012; Phelps, Brutsche, Moral, Luckenbaugh, Manji, & Zarate, 2009; aan het 
Rot et al., 2008; Zarate et al., 2006). Initial investigation of ketamine as a fast-acting treatment 
for PTSD has been met with positive empirical support: a randomized control trial found 
greater PTSD symptom reduction and lengthier symptom alleviation following a single 
infusion of ketamine compared to the active placebo midazolam (Feder et al., 2014).  
 
 
 
Based on the current research findings on the therapeutic effectiveness of trauma focus 
psychotherapy and of ketamine, combining the two treatments may yield a promising new 
rapid 7-day treatment for PTSD. As PTSD symptoms’ structure is comprised of several 
unique clusters which include re-experiencing, avoidance, numbing/depression and 
hypervigilance we hypothesize that by combining Ketamine with PE we can address these 
symptoms clusters more effectively.  This treatment has the potential to produce a significant 
therapeutic effect that otherwise would take months to occur by tapping on the enhanced 
neuroplasticity and the antidepressant effect of ketamine (which lasts between 24hrs to 7 
days), to promote rapid changes in learning and memory using prolonged exposure therapy 
within this unique “window of opportunity”.  
 
 
 
We will also use 3T MRI scanner to assess biomarkers of structural connectivity (using 
DTI) and fMRI for biomarkers of functional connectivity and hyper-reactivity to trauma 
reminders. DTI has been used to study PTSD, where connectivity deficits have been described 
in cortico-limbic structures that do not appear to be dependent upon a diagnosis of traumatic 
brain injury (Admon et al., 2013). PTSD is also associated with differences in activation or in 
functional connectivity in the amygdala, striatum, insula, anterior cingulate cortex, 
hippocampus and prefrontal cortex (Shin, L. & Liberzon, I., 2010). It was found that ketamine 
enhances functional connectivity at rest, but reduces working memory task-related activation 
and connectivity and the functional antagonism between the executive and default mode 
networks (Driesen N. et al., 2013). We propose to evaluate functional connectivity using f-
MRI in the current study to test the following hypotheses: 1) Alterations in functional 
connectivity (hyperconnectivity of amygdala-insula-cingulate and reduced DLPFC-amygdala 
connectivity prior to treatment, will predict treatment response; and 2) Ketamine will 
normalize these changes to better understand this type of functional relationship between the 
PFC and amygdala. It is also important to link the connectivity changes in humans to 
alterations in brain activation during trauma cue exposure.  Thus, we will also use personal 
trauma narratives during fMRI scans (from the PE) to assess level of brain activation during 
trauma reminders. Prior studies in PTSD have suggested that patterns of cortico-limbic 
functional connectivity are associated with circuit reactivity to traumatic reminders and 
anticipation of negative stimuli (Fonzo et al., 2010).  


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Using a biomarker-informed, double blind placebo-controlled design, the present proposal 
aims to examine the efficacy of a single dose or series of two doses of ketamine infusion, as 
compared to midazolam, that will be combined with an intensive one week PE, in producing a 
rapid and sustained reduction in PTSD symptomatology in veterans. In addition, we propose 
use of state-of-the-art neuroimaging assessments at baseline and at the end of treatment trial to 
gain insight into the neurobiology of PTSD and the neural mechanisms dictating treatment 
response or resistance.   
References 
Admon, R. et al. (2013). Stress-induced reduction in hippocampal volume and connectivity with 
 
the ventromedial prefrontal cortex are related to maladaptive responses to stressful 
 
military service. Hum Brain Map, 34, 2808-16. 
Driesen N. et al. (2013). Relationship of resting brain hyperconnectivity and schizophrenia-like 
 
symptoms produced by the NMDA receptor antagonist ketamine in humans. Molecular 
 
Psychiatry, 18, 1199-204 
Ehlers, A., Hackmann, A., Grey, N., Wild, J., Liness, S., Albert, I.…Clark, D. (2014). A 
 
randomized control trial of 7-day intensive and standard weekly cognitive therapy for 
 
PTSD and emotion-focused supportive therapy. American Journal of Psychiatry, 171(3), 
 
294-304. 
Eftekhari, A., Stines, L., & Zoellner, L. (2006). Do you need to talk about it? Prolonged 
 
Exposure for the treatment of chronic PTSD. The Behavior Analyst Today, 7(1), 70-83. 
Feder, A., Parides, M., Murrough, J., Perez, A., Morgan, J., Saxena, S…. Charney, D. (2014). 
 
 Efficacy of intravenous ketamine for treatment of chronic PTSD. JAMA Psychiatry, 
 
71(6), 681-688. 
Foa, E., Hembree, E., & Rothbaum, B. (2007). Prolonged exposure therapy for PTSD: 
 
Emotional processing of traumatic experiences, Therapist Guide. New York: Oxford 
 
University Press.  
Foa E., Hembree E., Cahill S., Rauch S., Riggs D., Feeny N., & Yadin E. (2005). Randomized 
 
trial of prolonged exposure for posttraumatic stress disorder with and without cognitive 
 
restructuring: Outcome at academic and community clinics. Journal of Consulting and 
 
Clinical Psychology, 73(5), 953–964. 
 
Foa, E. & Rothbaum, B. (1998). Treating the trauma of rape: Cognitive-behavioral therapy for 
 
PTSD.  New York: Guilford Press. 
 
Foa E., Rothbaum B., Riggs D., & Murdock T. (1991). Treatment of posttraumatic stress  
 
disorder in rape victims: A comparison between cognitive-behavioral procedures and 
 
counseling. Journal of Consulting and Clinical Psychology, 59, 715–723. 
 
Fonzo, G.. et al. (2010). Exaggerated and disconnected insular-amygdalar blood oxygenation 
 
level-dependent response to threat-related emotional faces in women with intimate-
 
partner violence posttraumatic stress disorder. Biological Psychiatry, 68, 433-41  


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Harpaz-Rotem, I. & Rosenheck, R. (2011). Serving the one who served: Retention of newly 
 
returning veterans from Iraq and Afghanistan in mental health treatment. Psychiatric 
 
Services, 62, 22-27 
 
Ibrahim, L., DiazGranados, N., Franco-Chaves, J., Brutsche, N., Henter, I., Kronstein, 
 
P….Zarate, C. Jr. (2012) Course of improvement in depressive symptoms to a single 
 
intravenous infusion of ketamine vs add-on riluzole: Results from a 4-week, double-
 
blind, placebo-controlled study. Neuropsychopharmacology, 37, 1526–1533. 
 
 
Marshall, R., Carcamo, J., Blanco, C., & Liebowitz, M. (2003). Trauma-focused psychotherapy 
 
after a trial of medication for chronic PTSD: Pilot observations. American Journal of 
 
Psychotherapy, 57, 374–383. 
 
Otto, M., Hinton, D., Korbly, N., Chea, A., Ba, P., Gershuny, B., & Pollack, M. (2003). 
 
Treatment of pharmacotherapy-refractory posttraumatic stress disorder among 
 
Cambodian refugees: a pilot study, of combination treatment with cognitive-behavior 
 
therapy vs sertraline alone. Behaviour Research and Therapy, 41(11), 1271–1276. 
 
Phelps, L., Brutsche, N., Moral, J., Luckenbaugh, D., Manji, H., & Zarate, C. Jr. (2009). Family 
 
 history of alcohol dependence and initial antidepressant response to an N-methyl-D-
 
aspartate antagonist. Biological Psychiatry 65, 181–184. 
aan het Rot, M., Collins, K., Murrough, J., Perez, A., Reich, D., Charney, D., & Matthew, S. 
 
(2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant 
 
depression. Biological Psychiatry, 67, 139–145. 
Shin, L. & Liberzon, I. (2010). The neurocircuitry of fear, stress, and anxiety disorders. 
 
Neuropsychopharmacology, 35, 169-91  
Zarate, C., Jr. , Singh J., Carlson P., Brutsche N., Ameli R., Luckenbaugh D., Charney D., & 
 
Manji H. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-
 
resistant major depression. Archives of General Psychiatry 63, 856-864. 
 
 
 
 
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and 
include any flowcharts of visits specifying their individual times and lengths. Describe the 
setting in which the research will take place. 
 
Participants: Participants will be physically healthy adult males and females meeting the 
diagnostic criteria for PTSD, as well as the inclusion and exclusion criteria specific in the 
human subjects section. 
 


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Procedures: Potential subjects will be referred to the present study via the National 
Center for PTSD screening protocol (HSS# IHR009) which was approved by the West 
Haven VA IRB. Participants will be first interviewed over the phone to obtain information 
related to their eligibility, including a medical records review if available. As per the 
screening protocol, qualifying participants will then schedule an appointment to determine 
that they meet all of the inclusion and exclusion criteria. The initial psychological 
screening may take place remotely or in -person, as has been approved by the West Haven 
VA IRB. During their first screening appointment participants will complete:  
 
Screening Measures: 
Assessments that will be used during the psychological evaluation are listed below. 
 
Psychological Evaluation:  
 
1. Alcohol and Consumption Habits: This is a brief measure that documents alcohol, 
caffeine, and nicotine habits.  
2. Brief TBI Screen: The Brief Traumatic Brain Injury Screen, also called the DVBIC TBI 
Screening Tool, is a 3-item instrument used to evaluate the presence of head injury and 
related symptomatology.  
3. Mini-Mental State Examination (MMSE): The MMSE measures the severity and 
progression of cognitive impairment, including functions such as registration, attention 
and calculation, recall, language, ability to follow simple commands and orientation. 
4. Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a brief clinician 
administered and standardized measure that uniquely assesses essential information about 
suicide behavior, ideation, lethality and severity, and distinguishes between suicidal 
occurrences and non-suicidal self-injury.  
5. Early Trauma Inventory (ETI-SR): The ETI-SR is a self-report instrument to assess 
childhood trauma and includes physical, emotional and sexual abuse as well as general 
traumas.  
6. Life Events Checklist (LEC): The LEC is a self-report instrument that measures reports of 
traumatic life events.  
7. Massachusetts General Hospital Antidepressant Treatment History Questionnaire (MGH-
ATRQ)-This is a self-rated questionnaire used to determine treatment resistance in major 
depressive disorder.  
8. Penn State Worry Questionnaire (PSWQ): The PSWQ is a self-report questionnaire to 
assess for ‘worry’ symptoms that are typical of generalized anxiety.  
9. Pittsburgh Sleep Quality Index (PSQI): The PSQI is a self-report questionnaire to assess 
sleep quality and sleep disturbance.  
10. PTSD Checklist (PCL): The PCL is used to measure PTSD symptoms and is a self-report 
questionnaire that has high reliability.  
11. Quick Inventory of Depressive Symptoms – Self-Report (QIDS-SR): The QIDS-SR is a 
patient-rated depression instrument.  
12. Socio-demographic/General Information: At intake, demographic data and medical 
history will be assessed with interviews and self-report forms that provide data on age, 
race, socioeconomic status, marital status, educational and occupational levels, and 


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significant medical history.  These are adapted from previous diagnostic and clinical 
studies at this center.  
13. Structured Clinical Interview for DSM (SCID): The SCID is the gold standard instrument 
for establishing a DSM diagnosis. It is a structured, clinician administered interview 
which aim to establish both current and lifetime psychiatric diagnoses record for each 
study participant.   
Medical Assessments (conducted in-person only): 
1. Physical exam by a licensed physician, or Advanced Practice Registered Nurses 
(APRN’s).  
2. Routine laboratory studies including a complete blood count (CBC) w/ differential, a 
comprehensive metabolic panel (e.g., BUN/creatinine, glucose, sodium, potassium, 
chloride, carbon dioxide, calcium, AST, ALT, fT4, TSH, bilirubin, total protein, VDRL, 
vitamin B12, folate, etc.), HCG, CRP, ESR, a complete lipid panel and electrolytes in 
addition to urinalysis and urine toxicology screen. Additional tests will be requested as 
clinically indicated.  
3. Urine toxicology screens will be performed at the screening appointment and will be 
administered more frequently if the clinician or research staff becomes concerned about 
possible illicit drug use.  Patients will be informed of random urine drug screens.  
4. An EKG will be performed.  
5. Pregnancy Tests- female subjects will have a blood sample drawn for a pregnancy test.  
6. MRI safety form 
 
If upon completion of these measures interested participants qualify for the current study, 
a member of the research team will be notified and contact the participant to schedule an 
initial visit for this Yale preformed study. Data from the screening protocol will be 
collected only after the participant has given a signature of informed consent to be 
involved in the current study. 
 
Study Design: This is a biomarker-informed, double blind, active placebo-controlled 
design. The participants will be randomized based on a randomization table that will be 
available solely to the Yale Investigational Drug Service. Subjects will be stratified by 
gender and age. Participants will undergo 7 consecutive visits, and two follow-up visits.  
 
 
 
 
 
 
 
 
 
 
 
 


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 Figure 2. Summary of Study Procedures for 2-infusion group 
Figure 1. Summary of Study Procedures for Single-infusion 
group 
Visit 0
•SCR Protocol
Visit 1
•4 hours
•Clinical Assessment (PE session)
•Trauma Scripts and Avoidance Behaviors
Visit 2
•6 hours
•PE session
•MRI w/ trauma scripts
•Ketamine/ midazolam infusion
Visit 3
•90 mins
•PE Session 
Visit 4
•90 mins
•PE session
Visit 5
•90 mins 
•PE session
Visit 6
•90 mins
•PE session 
Visit 7
•3 hours
•PE Session, Clinical exit interview 
•MRI/ trauma scripts
30 days
Visit 8
•3 hours
•Clinical assessment
•MRI with trauma scripts
60 days
Visit 9
•3 hours
•Clinical assessment
•MRI w/ trauma scripts
Visit 0
•SCR Protocol
Visit 1
•4 hours
•Clinical Assessment (PE session)
•Trauma Scripts and Avoidance Behaviors
Visit 2
•6 hours
•PE session
•MRI w/ trauma scripts
•Ketamine/ midazolam infusion 
Visit 3
•90 mins
•PE Session 
Visit 4
•4 hours
•PE session
•Ketamine/ midazolam infusion 
Visit 5
•90 mins 
•PE session
Visit 6
•90 mins
•PE session
Visit 7
•3 hours
•PE Session, Clinical exit interview 
•MRI/ trauma scripts
30 days
Visit 8
•3 hours
•Clinical assessment
•MRI with trauma scripts
60 days
Visit 9
•3 hours
•Clinical assessment
•MRI w/ trauma scripts


Page 16 of 46 
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Visit 1: At the initial visit the participant will first receive the fully informed consent 
process.  Study procedures, risks, benefits, and withdrawal procedures will be explained 
and any questions will be answered by the appropriate study personnel. The subject will 
then be asked sign a consent form if they choose to participate. A trained clinician will 
administer the Clinical-Administered PTSD Scale for DSM-V (CAPS-5) to ensure that 
participants meet the diagnostic criteria for inclusion. At this time participants will also 
complete the State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI). 
The initial clinical assessment may take place remotely using Zoom, if it is not feasible for 
an in-person session to occur due to physical distance or risk of infection from COVID-19. 
 
Eligible participants will be asked to describe specific life events: one traumatic, one sad, 
and one neutral.  
Afterwards they will be asked to circle at least 3 physiological responses and to complete 
the Impact of Events Scale as it pertained to the experience they just described. Scripting 
of trauma memories is a reliable means for eliciting psychophysiological responses in 
PTSD that are prognostically predictive. The script development session may be 
conducted remotely for participants unable to attend an in-person session due to distance 
of COVID-19 related concerns. At this visit, participants may be asked to wear a portable 
physiotracking watch to record their GSR and Heart rate during trauma recall (E4 
Wristband, Empatica Inc.) 
We will examine those responses before and after ketamine infusion and PE therapy in 
order to establish the relationship between combined treatment with ketamine and 
intensive PE and objective measures of PTSD symptomatology.  
 
After the session has ended, research staff will compose a written script for each 
experience incorporating 3 physiological responses—the script is portrayed in the 2nd 
person and present tense. The script is normally 30s-60s in length when read aloud and is 
narrated onto an audio file for use in later visits. 
 
Eligible participants will be assigned to either one or two infusions of the investigative 
drug (ketamine) or the active placebo. Subjects assigned to receive one infusion will be 
randomized to receive either the standard (0.5mg/kg) or lowered (0.2mg/kg) dose.   Thus 
the 5-arm design will include the following groups (1) PE + 0.5mg/kg single-infusion 
ketamine (2) PE + 0.2mg/kg single-infusion ketamine (3) PE + single-infusion of 
midazolam (4) PE + two 0.5mg/kg infusion ketamine and (5) PE + two-infusions of 
midazolam.  
 
The first PE session will then occur. The focus of this session will be evaluation of 
traumatic life events, and the identification of 3-5 avoidance behaviors. These behaviors 
will serve as the focus of in vivo exposure exercises.  
 
Visit 2: 
The second visit will consist of (1) a PE session (2) MRI with trauma scripts and (3) 
infusion with ketamine or midazolam.  
 


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Participants will report to the TAC Center approximately 1 and a half hours before the 
scheduled scan time. They will meet the study PE therapist who will deliver the first PE 
therapy session in the exam room which is mainly psychoeducational, and will provide the 
participant with information about PTSD and the therapeutic process. This session will 
take about 30 min.   
 
 
All subjects will be asked not to drink or eat the night before the scan and to drink 
plenty of fluids during the day before the scan.  They will be given clear juice when they 
first arrive. Next, a YCCI nurse will place two IV lines: one for infusing saline or 
ketamine and another for blood samples. If we are unable to place two lines, we will run 
the protocol with one line and not draw blood samples, if necessary.  
 
 
Participants will be scanned in one of the 3T Siemens Trio scanners, using a 64-channel 
receiver array head coil. After completing the MRI safety checklist, participants will have 
electrodes attached to measure Galvanic Skin Response (GSR) and heart rate. Participants 
will then be positioned in the scanner. Baseline GSR/ECG will first be measured while 
participants are listening to a 5-minute relaxation recording. Next, high-resolution, T1-
weighted anatomical images will be collected for each subject using an MPRAGE 
sequence (TR=2.5 s, TE=3.93 ms, TI=900 ms, flip angle=80, 176 sagittal slices, 1x1x1 
mm, 256x256 matrix in a 256 mm FOV).  Functional data will then be collected using the 
MRRC multiband sequence (multiband factor=4, TR=1s, TE=30 ms, 60 near axial slices, 
2x2x2 mm, 110x110 matrix in a 220x220 mm FOV) and local shimming to the field of 
view.  During the first functional scan, headphones will play each of the participant’s 
scripts from visit 1. The presentation order of the scripts (trauma, sad, neutral) will be 
randomized. Before listening to the script the participant will be instructed to remember 
the experience as vividly as possible while it plays (script listening). Each script (neutral, 
sad and trauma memory) will be played 3 times. Between scripts there will be 30-second 
periods of relaxation. In a second functional scan subjects will be asked to lie still with 
their eyes open (resting-state scan). An Eyelink eyetracker mounted in the MR machine 
will measure pupillometry during the scan. Finally, Diffusion tensor images (DTI) will be 
acquired, using the MRRC multiband sequence (multiband factor=4, 64 noncollinear 
directions with b-value = 1000 sec/mm2, plus an acquisition without diffusion weighting; 
TR = 2200 msec; TE = 84 msec; in-plane resolution: 2x2mm2 and 64 two-millimeter 
slices without gap). 
 
 
Infusion Procedure 
 
After the reactivation of the scripted memories will end, the ketamine/ midazolam infusion 
procedure will begin. The ketamine/midazolam infusion will occur inside the scanner at 
the MRRC. 
 
Participants will be reminded that they are free to end the infusion at any time if they 
experience significant discomfort. A physician who is trained and has significant 
experience with both ketamine and infusion studies will oversee and administer the 
ketamine infusions. A nurse will accompany the subject throughout the study sessions, 
from the insertion of bilateral cannula for drug infusion and blood sampling, to the 
recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart 


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rate and blood pressure will be closely monitored (approximately every 5 minutes). 
Participants in the single-infusion condition will receive a steady state ketamine infusion 
of 0.50 mg/kg or 0.2mg/kg. Participants in the two-infusion condition will receive a steady 
state ketamine infusion of 0.50 mg/kg. Midazolam infusions will take place over a similar 
time course at a rate 0.045 mg/kg, except for individuals aged over 60 who will receive 
0.032 mg/kg over the same time course. The infusion will continue for 40 minutes. If the 
heart rate goes higher than 100 or the subject reports being lightheaded or dizzy, they will 
be medically evaluated as to whether they can safely continue the protocol.  Participants 
will then undergo a full psychiatric interview, allowing us to rate, in detail, with standard 
psychiatric rating scales the nature and severity of any changes in their thoughts, emotions 
and perceptions that the infusion has induced.  They will also rate their level of sedation, 
before, during and after scan. 
 
Blood samples (7 cc each) will be taken 3 times equally spaced apart during the 
midazolam and ketamine infusions.  These will be used to assess plasma ketamine levels. 
The samples will be stored at -80 degrees Celsius in the YCCI.  Pulse, blood pressure, 
respiration, and oxygen saturation will be assessed before the ketamine and saline 
infusions and approximately every five minutes thereafter.   After the ketamine infusion is 
finished, the subject will be placed at a recovery room to rest and the examiner will 
provide time for participants to discuss their experiences, have questions answered, and be 
observed for any untoward effects. However, the patient will not be informed of when 
they received ketamine.  Intravenous catheters will be removed once the study doctor has 
determined that the patient is stable and sufficiently recovered from the effects of the 
ketamine.  Participants will receive a light meal. To assure patient safety, they will not be 
discharged until they have modified Aldrete’s score of 7 and no symptoms of orthostatic 
hypotension.  In the period between the end of infusion and discharge, participant vital 
signs will be assessed approximately every 15 minutes. Participants will be counseled not 
to drive for 24 hours. They will be accompanied by a designated adult of their choice to 
take them to their residency or if they prefer will be placed in a Taxi by one of the study 
staff personnel to ensure their safe ride home.   
 
Ketamine Experience Interview 
Participants’ experiences of the ketamine/midazolam infusion will be rated using standard 
psychiatric interview questionnaires including the Brief Psychiatric Rating Scale (BPRS), 
PANSS, the Paranoia inventory questionnaire (PIQ), the Clinician Administered 
Dissociative States Scale (CADSS) and the Rating Scale for Psychotic Symptoms (RSPS). 
 
PE Session 
After participants have recovered from the infusion, they will meet with the PE therapist 
for approximately 90 mins. Participants will receive PE therapy from a standardized 
manual delivered by a Dr, Harpaz-Rotem or any other trained clinician from the study 
team. The content of therapy will progress from basic psychoeducation to individualized 
imaginal exposure to the traumatic event and in vivo exposure to the situation the 
participants listed in session 1 that he wishes no longer to avoid and are safe. Participants 
will be asked to wear a portable GSR device while in the PE therapy sessions. In addition, 
the study therapist will assign homework exercises to complement the skills practiced in 


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session. PE is considered to be the most effective psychotherapy for PTSD and was tested 
in more than 50 clinical trials. 
 
The total length of the second visit is 6 hours. 
 
Visits 3-6:  
Participants will report to the Decision Neuroscience Lab on the 8th floor of 300 George 
St. on days 3—6 of the study. The length of these sessions will be 90 minutes.  
 
Participants who receive 2-infusions will also receive ketamine or midazolam infusions on 
day 4 of the experiment. For these participants, all the same infusions procedures 
described above (for infusion #1) will be repeated. The infusion will take place either 
inside the MRI machine at the MRRC. Participants will be monitored until the effects of 
ketamine have worn off, and study staff will ensure that either a taxi is provided, or a 
subject-designated adult driver will transport the participant home.  
 
Visit 7: 
A final session of PE therapy will be given. After this, participants will walk to TAC for a 
post-treatment MRI and fMRI. Procedures for the scan will match those of Visit 2. The 
trauma scripts will again be presented through headphones while the participant is 
undergoing scanning. No Ketamine/midazolam infusion will be given following the 
presentation of the scripts. Participants will complete the following end of treatment 
measures: PCL, BDI, STAI, C-SSRS and PSQI. Total visit time including MRI – 3 hours. 
Based on the final assessment, participants will be then be discharged from the clinical 
trial by the PI, as all treatment procedures have concluded.    
 
Follow-up visits (Visits 8 & 9) to monitor potential long-term study benefits: 
Participants will be asked to return to TAC approximately 30 days and 90 days after Visit 
7 to assess the long-term psychiatric effects of the intervention. The study clinician will 
evaluate the mental health of the participant and ensure that no negative sequelae of the 
ketamine infusion persist. Participants will complete the PCL, BDI, STAI, C-SSRS and 
PSQI at this time. Following clinical assessment, participants will undergo MRI and fMRI 
while the original scripts are played through headphones. Procedures for the scan will be 
identical to those listed previously; no infusion will be given. The total length of time for 
each follow-up visit is 3 hours. If participants are unable to attend the follow-up scan 
sessions, the study clinician will conduct the ketamine follow-up evaluation via telephone. 
Additionally, the PCL, BDI, STAI, C-SSRS, and PSQI will be collected over telephone if 
the participant cannot attend the follow-up scans.  
 
 
4. Genetic Testing    N/A 
 
A. Describe 
i. the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned 


Page 20 of 46 
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ii. the plan for the collection of material or the conditions under which material will 
be received 
iii. the types of information about the donor/individual contributors that will be 
entered into a database 
iv. the methods to uphold confidentiality 
 
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects? 
C. Is widespread sharing of materials planned? 
D. When and under what conditions will materials be stripped of all identifiers? 
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials? 
i. How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)? 
 
F. Describe the provisions for protection of participant privacy 
G. Describe the methods for the security of storage and sharing of materials  
 
 
5. Subject Population: Provide a detailed description of the types of human subjects who will be 
recruited into this study. 
 
 
For the current study, 120 participants (ages 21-70) meeting the diagnostic criteria for PTSD 
are needed to investigate the therapeutic potential of PE combined with ketamine infusion. 
An extensive medical and psychiatric assessment will be conducted to exclude subjects who 
are at increased risk. 
 
 
Females of childbearing potential will be eligible, and appropriate safeguards will be 
 
instituted, e.g. serum pregnancy test and reproductive counseling, to prevent pregnant 
 
patients from enrolling or subjects conceiving, respectively, during this investigation. 
 
 
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement. 
 
 Children 
 
 
 Healthy  
 
Fetal material, placenta, or dead fetus 
 Non-English Speaking 
 Prisoners  
 Economically disadvantaged persons 
 Decisionally Impaired 
 Employees  
 Pregnant women and/or fetuses 
 Yale Students  
 
Females of childbearing potential 
 
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements) 
 


Page 21 of 46 
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7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or   
exclusion? 
 
Inclusion Criteria: 
• Male or female between the ages of 21-70 years. This age range was chosen to fit with prior 
samples in which no adverse effects of ketamine have been observed. Adults in the 18-20 
ranges have been eliminated because previous experience indicates that they often lack the 
maturity to participate effectively in similar protocols. Females will be included if they are 
not pregnant and agreed to utilize a medically accepted birth control method (to include 
oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine 
device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at 
least 1 year, or surgically sterile. 
• 
Must not have a medical/neurological problem or use medication that would render 
ketamine unsafe by history or medical evaluation. 
• 
Diagnosis of PTSD with a score of 25 or higher (i.e. severe PTSD) on the Clinician-
Administered PTSD Scale (CAPS-5) at screening. 
• 
Subjects on FDA-approved antidepressant, trazodone, atypical neuroleptic, prazosin, or 
clonidine may enter the study if they have been on a stable treatment, as determined by the 
study clinician, for at least 4 weeks prior to randomization. Following randomization, small 
changes to doses may be allowable at the PI’s discretion.  
• 
Able to provide written informed consent. 
• 
Able to read and write English. 
Exclusion Criteria: 
• Patients with a diagnostic history of  borderline personality disorder, obsessive compulsive 
disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic 
features as determined by the Structured Clinical Interview for DSM (SCID) (First, et al. 
2010); dementia or suspicion thereof, are excluded. Patients with history of bipolar disorder 
will be included only if they have not experienced a manic or hypomanic episode in the 30 
days prior to enrollment.  Other DSM Axis I disorders are permitted as long as they are not 
considered primary disorders.  
• Patients with a history of antidepressant-induced hypomania or mania as determined by 
open-ended psychiatric interview. 
• 
Current, ongoing serious suicidal risk as assessed by evaluating investigator or by scoring 
5 or more on item-10 of the MADRS. 
• 
Moderate severity or greater Substance Use Disorder (excepting Alcohol Use Disorder) 
during the 3 months prior to randomization, as determined by the SCID. Alcohol Use 
Disorder may be allowed based on the judgment of study physician/APRN/clinician that 
patients can remain sober for all study visits.  
• 
Subjects on a prohibited medication (see Table 1). Patients will not be taken off medication 
for the purpose of this study.  
• 
History of traumatic brain injury (TBI) with loss of consciousness for more than 24 hours 
or posttraumatic amnesia for more than 7 days may be considered if the trauma occurred 
more than 1 year ago, and no more than minimal symptoms have persisted over the past 
year. 


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• 
Positive pregnancy test at screening or prior to any study drug infusion. 
• 
Breathalyzer showing an alcohol level > 0% at screening, or at the discretion of the 
investigator, prior to any study drug infusion. 
• 
Resting blood pressure lower than 90/60 or higher than 150/90, or resting heart rate lower 
than 45/min or higher than 100/min. 
• Any significant history of serious medical or neurological illness. 
• Any signs of major medical or neurological illness on examination or as a result of ECG 
screening or laboratory studies. 
• Abnormality on physical examination.  A subject with a clinical abnormality may be 
included only if the study physician considers the abnormality will not introduce additional 
risk factors and will not interfere with the study procedure. 
• A positive pre-study (screening) urine drug screen or, at the study physician’s discretion on 
any drug screens given before the scans. 
• Pregnant or lactating women or a positive urine pregnancy test for women of child-bearing 
potential at screening or prior to any imaging day. 
• Any history indicating learning disability, mental retardation, or attention deficit disorder. 
• Known sensitivity to ketamine. 
• Body circumference of 52 inches or greater. 
• Body weight of 250 pounds or greater. 
• History of claustrophobia. 
• Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign 
bodies in vulnerable positions as assessed by a standard pre-MRI screening questionnaire. 
• Donation of blood in excess of 500 mL within 56 days prior to dosing. 
• History of sensitivity to heparin or heparin-induced thrombocytopenia. 
 
 
 
Table 1. 
Concomitant Treatments that are prohibited 
Use 
category 
Type of medication 
Details 
Prohibited 
MAOIs 
4-weeks off medication prior to 
randomization is required. 
 
Memantine 
4-weeks off medication prior to 
randomization is required. 
 
 
 
 
Long Acting Benzodiazepines: 
Chlordiazepoxide, Diazepam, 
Flurazepam 
 
 
2-weeks off medication prior to 
randomization is required. 
 
 
• 
Notes: As above, individuals who have used any of the prohibited medications within the 
“weeks off” time period will not be eligible for the study. Use of sedatives, hypnotics, 
benzodiazepines, sedating antihistamines or other psychotropic medications are not 
permitted within 8 hours of treatment sessions; except – at the discretion of the 
investigator – for medications that will result in discontinuation/withdrawal symptoms or 
that may alter the risk benefit ratio. 


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• . 
 
 
8. How will eligibility be determined, and by whom?  
 
Eligibility will be determined by the PI and/or the study physicians. Additionally, participants 
recruited from local clinics will have eligibility determination made by the PIs listed in the 
research staff section. Eligibility determinations will be made using the listed inclusion and 
exclusion criteria.  
 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
 
Ketamine administration 
Ketamine is a dissociative anesthetic that has been used clinically since the late 1960s (Domino, 
Chodoff, & Corssen, 1965).  Despite extensive experience, there is no clear and compelling 
evidence of long-term toxicity associated with ketamine administration in medically supervised 
settings (Perry et al., 2007a; Schorn & Witwam, 1980).  However, there are acute medical and 
neuropsychiatric sequelae that deserve special consideration.  The ketamine doses employed in 
the Healthy group have been specifically selected to produce mild to moderate behavioral 
effects without significant sedation.  At these doses, ketamine produces a transient alteration of 
consciousness including altered sensory processing and thought processes.  Initially, subjects 
frequently feel “drunk” and giddiness is common.  As blood levels increase, blood pressure and 
heart rate increase moderately.  This increase is transient and not considered clinically 
significant.  Subjects report differences in complex problem solving evident on frontal lobe and 
delayed memory tasks, some subjects may report a narrowing of their concentration, feeling 
distant from surroundings, and enhanced perception of some sensory stimuli.  Subjects 
sometimes report blurred vision and nystagmus.  Alterations in the perception of time, body 
boundaries, and illusions occur.  Subjects may experience visual distortions, altered perception 
of orientation in space, and inability to control thought processes.  Subjects may report feeling 
quite distanced from their surroundings, describe altered awareness of their bodies, and they 
may close their eyes.  During this period, they are still oriented to time and place.  They can 
complete ratings scales testing memory without impairment, their rate of finger tapping is 
unchanged and the latency of their response on continuous performance tasks of attention is not 
increased.  However, some individuals feel that they cannot control the experience and find it 
frightening.  Some subjects may experience heightened PTSD reactions.  Additionally, vivid 
dreams and poor sleep quality after infusion of ketamine have also been reported, although 
dream content was not necessarily unusual and alterations in sleep were not reported on 
subsequent nights. 
The doses used in this protocol produce blood levels that are 1/6 to 1/3 of those produced 
clinically when ketamine is used as an anesthetic. Short-term safety data showed that adverse 
events in response to ketamine infusion have been mild and transient, with no evidence of any 
clinically significant or persistent adverse effects 109.  Adverse events included nausea and 


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vomiting, sedation, anxiety, hypotension, insomnia and nightmares and transient pain in the 
infusion arm. 
Phlebotomy  
We may need to draw additional blood for the routine laboratory testing. Inserting a needle into 
a vein is safe when done by professionals under clean conditions. Sometimes a bruise will occur 
at the puncture site and on rare occasions a blood clot or an infection may form in the vein. If 
this occurs, appropriate treatment will be instituted immediately. 
Risks associated with blood loss are minimal. Less than 200 cc will be drawn, and this 
represents 40% of a 500-cc blood donation.  
Psychiatric Evaluation and Clinical Assessments 
These are all non-invasive, should add no risk, and have been used without difficulty or adverse 
events in our previous studies with a similar population.  The major disadvantage is the time 
taken to complete them.  Our past experience with these measures indicates that they are 
acceptable to patients.  Only subjects' code numbers will be recorded on the forms themselves 
to protect confidentiality. 
Magnetic Resonance Imaging (MRI) 
Magnetic resonance (MR) is a technique that uses magnetism and radio waves to take pictures 
and measure chemicals of various parts of the body. The United States Food and Drug 
Administration (FDA) has set guidelines for magnet strength and exposure to radio waves, and 
we will carefully observe those guidelines.  
Some people may feel uncomfortable or anxious.  As previously noted, some subjects may 
experience heightened PTSD reactions while in the scanner.  If this happens, the subject may 
ask to stop the study at any time, and we will take them out of the MR scanner. On rare 
occasions, some people might feel dizzy, get an upset stomach, have a metallic taste or feel 
tingling sensations or muscle twitches. These sensations usually go away quickly but subjects 
will be encouraged to tell the research staff if they have them.  
There are some risks with an MR study for certain people. If the subject has a pacemaker or 
some metal objects inside their body, they may not be in this study. 
Another risk is the possibility of metal objects being pulled into the magnet and hitting the 
subject. This MR study is for research purposes only and is not in any way a clinical 
examination. The scans performed in this study are not designed to find abnormalities. The 
primary investigator, the lab, the MR technologist, and the Magnetic Resonance Research 
Center are not qualified to interpret the MR scans and are not responsible for providing a 
diagnostic evaluation of the images. If a worrisome finding is seen on a scan, a radiologist or 
another physician will be asked to review the relevant images. Based on his or her 
recommendation (if any), the primary investigator or consulting physician will contact the 


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subject, inform them of the finding, and recommend that they seek medical advice as a 
precautionary measure. The decision for additional examination or treatment would lie solely 
with the subject and their physician. The investigators, the consulting physician, the Magnetic 
Resonance Research Center, and Yale University are not responsible for any examination or 
treatment that subjects receive based on these findings. The images that will be collected in 
this study are not a clinical MR exam and for that reason, they will not be made available for 
diagnostic purposes. 
Portable Physiotracker 
It is possible that some individuals experience skin irritation as a result of wearing the portable 
physiotracker device. In such cases subjects will be advised to discontinue wearing the device.  
 
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized. 
 
 
Recruitment and Informed Consent 
 Prior to enrollment, subjects will have face-to-face or virtual interviews with one of the 
investigators where the nature of the project, the risks, the benefits, and the alternatives to 
participation in the project will be discussed with the subject and, if necessary, the subject's 
family. A focused history will be taken, and a checklist of hazards will be reviewed with the 
subject. If, following these discussions, the subject continues to be interested in the project, 
informed written consent will be obtained on the consent form approved by the Yale University 
Human Investigation Committee (HIC). Thereafter, the project investigators assume clinical 
responsibility for the care of the subject.  
 
General risk-minimizing strategies:  
1. Effective screening to exclude subjects who would be placed at a greater risk. This includes 
a comprehensive psychiatric and medical evaluation, physical examination, and the screening 
studies. Trained staff, under the supervision of the PI, will conduct all screening procedures.  
2. The investigator or a designated person will explain the benefits and risks of participation 
in the study to each subject. Subjects will be asked to verbalize their understanding of all 
aspects of the consent, including risks, benefit and alternatives. The voluntary nature of 
research studies is always emphasized.  
3. To reduce the risk of metal objects being pulled into the magnet and hitting the subject we 
will require that all people involved with the study remove all metal from their clothing and all 
metal objects from their pockets. We will also ask all people involved with the study to walk 
through a detector designed to detect metal objects. No metal will be allowed to be brought 
into the magnet room at any time. Once the subject is in the magnet, the door to the room will 
be closed so that no one from outside accidentally goes near the magnet.  


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Each subject will fill in the MR safety sheet prior to participation in the fMRI study. We will 
stress to subjects that we want them to read and answer the questions very carefully and to tell 
us any information they think might be important.  
All research staff that might accompany the subject into the magnet room will undergo annual 
MR safety training and will also fill out the MR safety sheet each year.  
The subject will be watched closely throughout the MR study. Subjects will be monitored by 
an MR operator in respect to all aspects pertaining to the MR scan, and the research team that 
is comprised of a physician, a nurse, and a research scientist. Subjects may ask to stop the study 
at any time and we will take them out of the scanner. 
4. All subject information will be kept confidential and only members of the investigative team 
with appropriate IRB/HIC and HIPAA training will have access to the study data. Data will be 
maintained and secured in locked file cabinets or password protected electronic media. A 
numbering code will be used to assign a unique identifier to each subject.  
5. A Data and Safety Monitoring Plan is described below. 
All personnel are trained in an established procedure for terminating the infusion and dealing 
with emergency. There will be an M.D. present at all times who will be able to perform 
immediate resuscitation in the unlikely event it is needed. 
 
Subject Monitoring and Emergency Procedures 
An experienced clinical research team will closely monitor the subjects. All of the information 
obtained from subjects participating in this study will be coded by numbers and kept in locked 
files in the research unit to ensure confidentiality. One member of the two to three-person team 
will watch the subjects while in the magnet room. Visual and verbal contact will be maintained 
throughout the infusion. Subjects who become claustrophobic in the magnet will be removed 
immediately from the magnet room. Subjects who experience distress during the infusion for 
any reason, including seizures, loss of consciousness or pain will have the infusion terminated 
immediately. All team members will be thoroughly familiar with the established emergency 
plan.  If immediate resuscitation is needed the physician present during the study will perform 
this procedure.  
 
Anxiousness 
If a subject is anxious and expresses a desire to end the infusion then the study will be 
immediately terminated. 
 
Irritation 
If there is irritation due to IV blood sampling, the physician present during the study will 
examine the subject, and the study will be terminated if the subject is in pain. If skin irritation 
is caused by the portable physiotracker, its use will be discontinued.  


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Effects of ketamine 
Before participating, healthy subjects undergo careful psychiatric and medical evaluation.  A 
research nurse, study physician and research scientist will be present in the MRRC magnet 
suite at all times during test sessions to provide support and consistent “reality testing” for 
individuals experiencing confusion or transient psychosis.  If a subject report that symptoms 
cannot be tolerated, the ketamine infusion will be stopped immediately. 
Subjects will be observed for at least 4 hours after the termination of testing, and if intolerable 
physical or behavioral symptoms persist, subjects will be admitted to the Clinical Neuroscience 
Research Unit at the Connecticut Mental Health Center for further observation and overnight 
if necessary.  Participants will be informed that they may not drive or operate machinery for 
24 hours after end of test day procedures, and study staff will ensure that they are picked up 
by a responsible adult or safely reach their home on alternate transportation.  Subjects will be 
provided a number to call to reach an on-call research psychiatrist (24 hours/day) should 
unpleasant effects occur after subjects have left the testing facility.  Medication effects will be 
reviewed and “debriefed” with subjects following each test day by a study clinician.  If 
necessary, subjects will be administered oral diazepam to reduce residual symptoms and their 
participation in the study will be terminated if necessary.  Such subjects will be monitored as 
found appropriate by the study physicians. 
We are also taking a number of precautions to help reduce the chance of having an unpleasant 
response to ketamine or to reduce the severity of any lingering medication effects.  These 
precautions include: 
1) A research clinician and research nurse and research scientist will be present throughout 
the study, at all times, to offer support and to help clarify the progress of the test day in 
case the medication causes feelings of confusion.   
2) Medications are available (Valium) to relieve distress related to the behavioral effects 
of ketamine. 
3) We will ask the subject to remain in the recovery room for several hours after the 
behavioral effects of ketamine should have worn off. 
4) We will review the test day with the subject to deal with your feelings and reactions to 
each test day before you leave. 
5) We will ask the subject to contact us at any time if any unpleasant effects occur. 
6) We will ask the subject not to engage in demanding work in the day following the test 
sessions and we will work with the subject to schedule your test days accordingly. 
7) If the subject has any lingering medication effects, such as sedation, we will terminate 
the remaining test days and work with him/her until these side effects have resolved. 
8) If the subject develops psychiatric symptoms, we may admit him/her to the hospital.  
This may be involuntary if he/her are in danger of harming yourself or others. 
9) We will also contact the subject at 24 hours, one week, and one month after the last 
infusion for safety reasons 
If inpatient psychiatric admission is clinically indicated, subjects may be admitted to the 
inpatient Clinical Neuroscience Research Unit (CNRU) at Connecticut Mental Health Center 


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(CMHC) for closer supervision free of charge.  Subjects will then be discharged with 
appropriate follow-up care when their proximal safety risk is minimal. 
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24. 
a. 
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study?  
We have assessed the proposed study as one of moderate risk. We do not view the 
risks associated with ketamine as minimal. We do not view the risks associated with 
the combined use of ketamine and 13C-MRS imaging as minimal. Given the now 
established safety and validity of the current research of ketamine in our prior work, 
we do not view the proposed study as high risk. However, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since 
it is not possible to predict with certainty the absolute risk in any given individual or 
in advance of first-hand experience with the proposed study methods. 
b. 
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?  
 
Not Applicable 
 
c. 
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are   
 available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for 
i. Minimal risk 
ii. Greater than minimal 
 
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures /design by one of the study physicians together 
with the principal-investigator, Ilan Harpaz-Rotem, Ph.D., according to the 
following categories: 
a.) Definite: Adverse event is clearly related to investigational 
procedures(s)/agent(s). 
b.) Probable: Adverse event is likely related to investigational 
procedures(s)/agent(s). 
c.) Possible: Adverse event may be related to investigational 
procedures(s)/agent(s). 
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
e.) Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s). 
 
 Plan for Grading Adverse Events: 
The following scale will be used in grading the severity of adverse events noted 
during the study: 


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1. Mild adverse event 
2. Moderate adverse event 
3. Severe 
 
Plan for Determining Seriousness of Adverse Events:  
Serious Adverse Events: 
In addition to grading the adverse event, one of the study physicians together with 
the PI will determine whether the adverse event meets the criteria for a Serious 
Adverse Event (SAE). An adverse event is considered serious if it: 
- 
is life-threatening 
- 
results in in-patient hospitalization or prolongation of existing hospitalization 
- 
results in persistent or significant disability or incapacity 
- 
results in a congenital anomaly or birth defect OR 
- 
results in death  
- 
based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition 
- 
 adversely affects the risk/benefit ratio of the study 
 
An adverse event may be graded as severe but still not meet the criteria for a 
Serious Adverse Event. Similarly, an adverse event may be graded as moderate but 
still meet the criteria for an SAE. It is important for the PI to consider the grade of 
the event as well as its “seriousness” when determining whether reporting to the 
HIC or HSC is necessary. 
 
Plan for reporting serious and unanticipated and related adverse events, 
anticipated adverse events occurring at a greater frequency than expected, 
and other unanticipated problems involving risks to subjects or others to the 
HIC  
 
The investigator will report the following types of adverse events to the HIC:  
a) serious and unanticipated and possibly, probably or definitely related events; 
b) anticipated adverse events occurring with a greater frequency than expected;  
c) other unanticipated problems involving risks to subjects or others. 
These adverse events or unanticipated problems involving risks to subjects or 
others will be reported to the HIC or HSC within 48 hours of it becoming known 
to the investigator, using the appropriate forms found on the website. 
 
Plan for reporting adverse events to co-investigators on the study, funding 
and regulatory agencies 
 
For the current study, the following individuals, funding, and/or regulatory 
agencies will be notified: 
□ All Co-Investigators listed on the protocol. 
□ National Institutes of Health 


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One of the study physicians together with the principal investigator, will conduct a 
review of all adverse events upon completion of every study subject. The principal 
investigator will evaluate the frequency and severity of the adverse events and 
determine if modifications to the protocol or consent form are required. 
 
d. For multi-site studies for which the Yale PI serves as the lead investigator:  N/A 
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed? 
ii. What provisions are in place for management of interim results? 
iii. What will the multi-site process be for protocol modifications? 
 
12. Statistical Considerations: Describe the statistical analyses that support the study design.  
 
A mixed effects regression model will reveal a significant group by time interaction, with rapid reduction 
in PTSD symptoms in the ketamine group compared to midazolam. 
 
 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES 
 
 
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section. 
 
A.  DRUGS, BIOLOGICS and RADIOTRACERS 
 
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s)  
biologic(s) or radiotracer(s) being used? Identify whether FDA approval has been granted and for what 
indication(s).  
 
Ketamine has U.S. Food and Drug Administration (USFDA) approval as the only anesthetic for 
diagnostic and surgical procedures that do not require skeletal muscle relaxation.  Ketamine is also 
indicated for anesthesia induction prior to the administration of other general anesthetic agents or 
to augment low potency anesthetics such as nitrous oxide. 
Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.  
It also has U.S. Food and Drug Administration (USFDA) approval for the acute treatment of 
intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive 
seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years 
of age and older.  
 
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:   
a. What is the Investigational New Drug (IND) number assigned by the FDA? 
 
Not Applicable  
 


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b. Who holds the IND?  
 
Not Applicable 
 
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: ________N/A_______ 
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check if 
appropriate)_________N/A____ 
 
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for radioisotopes 
used in the PET Center, PET Center personnel may complete this step) 
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete the 
application and attach a copy to this submission.      
 
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and 
 an exemption is being sought, review the following categories and complete the category that applies 
 (and delete the inapplicable categories): 
 
Exempt Category 1 
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes: 
 
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
     of a new indication for use or to be used to support any other significant change in the labeling for 
     the drug.  
 Yes  
 No 
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
      the intention of the investigation is NOT to support a significant change in the advertising for the 
      product. 
 Yes  
 No 
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations 
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)    
      associated with the use of the drug product. 
 Yes  
 No 
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)    
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56). 
 Yes  
 No 
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
 Yes  
 No 
 
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption) 
 
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or 
more of the following (check all that apply): 
 Blood grouping serum 
 Reagent red blood cells  
 Anti-human globulin 
 
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the 


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diagnosis made by another, medically established, diagnostic product or procedure; and 
 
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160. 
 
Exempt Category 3 
 
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60 
 
Exempt Category 4 
 
 A clinical investigation involving use of a placebo if the investigation does not otherwise require 
submission of an IND. 
 
 
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models.  
Ketamine has been administered to over 10,000 patients and reported in greater than 100 individual 
research investigations, including many (as previously cited) from our department.  Ketamine has 
a wide margin of safety and is typically provided in doses of 1-4.5 mg/kg IV over 1 minute as a 
sole anesthetic agent.  In the majority of psychiatric investigations in depressed subjects to date, 
ketamine has been administered at subanesthetic doses (typically 0.5mg/kg infused over 40 
minutes). In healthy subjects, the typical subanesthetic doses used are about 0.23 mg/kg bolus of 
over 1 minute followed by 0.58 mg/kg/hour infusion (e.g. Refs (Anand et al., 2000; D'Souza, Singh, 
Elander, Carbuto, Pittman, de Haes, et al., 2012; Gunduz-Bruce et al., 2011; Krystal et al., 1999; 
Krystal et al., 1998; Krystal et al., 2005). Extensive experience suggests that ketamine 
administration is not associated with long-term toxicity.  The doses of ketamine administered 
produce blood levels 1/3 - 1/6 those associated with blood levels achieved when ketamine is used 
as a primary surgical anesthetic. Since 1989, studies at our department administered ketamine on 
over 800 occasions to over 300 subjects. Our group has extensive experience using ketamine in 
psychiatric research. 
In addition to the recently found rapid-acting antidepressant effect, ketamine has been extensively 
used in human research as a model of psychosis owing to its acute psychotomimetic and cognitive 
adverse effects (Kantrowitz & Javitt, 2010). In healthy volunteers, subanesthetic doses of ketamine 
induce transient perceptual disturbances, dissociative experiences, cognitive dysfunction, affective 
changes, thought disorder, and mild physical symptoms (Bubenikova-Valesova, Horacek, Vrajova, 
& Hoschl, 2008). These studies showed dose-dependent effects with increased symptoms at higher 
doses (Krystal et al., 1994b; Newcomer et al., 1999; Oye, Paulsen, & Maurset, 1992). However, the 
symptoms were transient, starting within minutes of ketamine infusion and lasting up to 2 hours 
(Krystal et al., 1994b). Recently, Perry and colleagues at Yale reviewed a dataset of 450 healthy 
subjects who collectively received a total of 833 ketamine infusions in a medically supervised 
setting as part of laboratory studies (Perry et al., 2007a). This report noticed no evidence of serious 


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adverse events, residual sequelae, or sensitization. Only 2% of subjects experienced non-serious 
adverse reactions. These emerging side effects resolved by the end of the test day in all subjects, 
except for one participant who experienced symptoms for 4 days (Perry et al., 2007a). 
 
 
3.  Source:  a) Identify the source of the drug or biologic to be used.  
 
  
 
 
 
Ketamine and midazolam will be acquired from the research pharmacy of either the 
Connecticut Mental Health Center (CMHC) or YNHH IDS 
 
  
 
 
  
b) Is the drug provided free of charge to subjects? 
 Yes  
 No 
  
If yes, by whom? 
 
 Drugs will be administered during Day 2 for all participants, and also on Day 4 for those 
in the 2-infusion groups. A physician and a nurse from the research team will administer 
the drug as described in the methods.  
 
 
 
4.  Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and pyrogenicity.  
 
Check applicable Investigational Drug Service utilized: 
     
   YNHH IDS                                                                      
   Yale Cancer Center  
     
   CMHC Pharmacy                                                          
  West Haven VA 
     
   PET Center                                                       
    None       
     
    Other:  
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.   
   
 
5.  Use of Placebo: 
 Not applicable to this research project 
 
If use of a placebo is planned, provide a justification which addresses the following: 
a. Describe the safety and efficacy of other available therapies. If there are no other 
available therapies, state this. 
 
An active placebo will be used for this trial.  There are no alternative pharmacotherapies to 
midazolam. The midazolam will generate some level of sedation so that participants would not 
know if they were in the treatment group (Ketamine) or the placebo. It has a rapid onset of 
action, high effectiveness, and low toxicity level. The alternative is to not take the drug. 
 
 
b.   State the maximum total length of time a participant may receive placebo while on the study. 
 
Infusion with ketamine or midazolam will occur once during the study for those in the 
single-infusion groups, and 2 times for those in the two-infusion groups. Each infusion 
will occur over a period of about 45 minutes. 
 
 
c.   Address the greatest potential harm that may come to a participant as a result of receiving     


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       placebo.  
 
  
Midazolam is a benzodiazepine that may result in side effects including drowsiness,  
  
confusion, amnesia, ataxia, and hang-over like symptoms. However, midazolam is  
  
typically safe and effective for most individuals when infused at the rates specified for the 
  
current study (Riss, Colyd, Gates, & Collins, 2008).  
 
 
d.   Describe the procedures that are in place to safeguard participants receiving placebo.  
 
 
  
Participants will be supervised at all times during infusion with midazolam by a trained  
  
doctor and nurse practitioner experienced in infusion procedures. As described in the  
  
Minimizing Risk section, several precautions are in placed to ensure participant safety,  
  
including: 
 
- 
Consistent “reality testing” for individuals experiencing confusion or transient 
psychosis.   
- 
If a subject report that symptoms cannot be tolerated, the infusion will be 
stopped immediately. 
- 
Subjects will be observed for at least an hour after infusion ends and will be 
admitted to the Clinical Neuroscience Research Unit at the Connecticut Mental 
Health Center for further observation if necessary. 
- 
Participants will be informed that they may not drive or operate machinery for 
24 hours after end of test day procedures, and study staff will ensure that they 
are picked up by a responsible adult or safely reach their home on alternate 
transportation.  
- 
Subjects will be provided a number to call to reach an on-call research 
psychiatrist (24 hours/day) should unpleasant effects occur after subjects have 
left the testing facility.   
- 
If necessary, subjects will be administered oral diazepam to reduce residual 
symptoms and their participation in the study will be terminated if necessary.   
 
 
6. Use of Controlled Substances: 
 
Will this research project involve the use of controlled substances in human subjects? 
 
 Yes  
 No  See HIC Application Instructions to view controlled substance listings.  
 
 
If yes, is the use of the controlled substance considered: 
 
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant. 
 
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical studies 
or other non-therapeutic purposes. See Instructions for further information. 
 
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project 


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Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended? 
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access.  
 
 
 
 No    If no, explain why this is acceptable. 
 
  
Ketamine/ midazolam will be administered to participants during the study, followed  
  
by an intensive dose of psychotherapy. Ketamine is predicted to enhance the learning that 
  
takes place during psychotherapy, but is not currently indicated as a long-term  
 
  
pharmacotherapy.  
 
 B.  DEVICES 
 
2.      Are there any investigational devices used or investigational procedures performed at Yale-
New Haven Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and 
Vascular Center)?  ☐Yes   ☒No    If Yes, please be aware of the following requirements: 
 
a.       A YNHH New Product/Trial Request Form must be completed via EPIC: Pull down the Tools 
tab in the EPIC Banner, Click on Lawson, Click on “Add new” under the New 
Technology Request Summary and fill out the forms requested including the “Initial 
Request Form,” “Clinical Evidence Summary, “ and attach any other pertinent 
documents. Then select “save and submit” to submit your request; and 
 
b. Your request must be reviewed and approved in writing by the appropriate YNHH 
committee before patients/subjects may be scheduled to receive the investigational device or 
investigational procedure. 
 
 
2. What is the name of the device to be studied in this protocol? 
 
Has this device been FDA approved? 
 Yes  
 No 
If yes, state for what indication. 
 
 
3. Background Information: Provide a description of previous human use, known risks, and 
any other factors that might influence risks. If this is the first time this device is being used in 
humans, include relevant data on animal models.  
 
 
4. Source:  
a) Identify the source of the device to be used.  
 
b) Is the device provided free of charge to subjects? 
 Yes  
 No 
 
5. What is the PI’s assessment of risk level (significant or non-significant) associated with the 
use of the device?  


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 Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents 
impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant.    
 
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA. 
 
What is the IDE number assigned by the FDA?  
 
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B 
(non-experimental/investigational)? 
 
Who holds the IDE? 
 
 Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the   
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants.  Note that if the HIC concurs with this determination, an IDE is 
not required. 
 
6.  Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and there 
also are exemptions to the requirement for an IDE.  See the criteria in the HIC Application 
Instructions, Section VI.B.4 at 
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructions5-
25-11.pdf to determine if these pertain to this study. 
 
  
 Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions 
are met, copy and paste the completed relevant section from the Instructions into this application. 
 
 
7.   Investigational device accountability: 
a. State how the PI, or named designee, ensures that an investigational device is used only in 
accordance with the research protocol approved by the HIC, and maintains control of the 
investigational device as follows: 
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES  
 
1. Targeted Enrollment: Give the number of subjects: 
a.   targeted for enrollment at Yale for this protocol: 120 
b.    If this is a multi-site study, give the total number of subjects targeted across all sites___  
 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used. 
 
 Flyers 
 
 
 
 
 Internet/Web Postings 
 
 
 Radio 


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 Posters  
 
 
 
 Mass E-mail Solicitation  
 
 Telephone 
 Letter 
 
 
 
  
 Departmental/Center Website 
 
 Television 
 Medical Record Review  
 
 Departmental/Center Research Boards 
 Newspaper 
 Departmental/Center Newsletters 
 Web-Based Clinical Trial Registries 
 
  YCCI Recruitment database 
 
 Clinicaltrials.gov Registry (do not send materials to HIC) 
 Other (describe):  
 
3.  Recruitment Procedures:  
a. Describe how potential subjects will be identified. 
Subjects will be recruited by flyers, public advertisements (newspaper, radio, internet 
posting) by word of mouth, clinician referral, contact with community service groups 
and clinics (VA PTSD clinics-West Haven and the Newington mental health clinic, 
CMHC, Yale Depression Research Program, the Yale Psychiatric Research Hospital, 
and the YCCI recruitment database). We may also utilize the National Center for PTSD 
newsletter to advertise the study and the trial will be registered at Clinical Trials.gov. 
Subjects will be identified by their response to advertisements and/or internal recruiting.  
 
b. Describe how potential subjects are contacted.  
 
The subjects will be asked to call us if they are interested in participating in the research 
study. There will not be any web based questionnaires utilized for pre-screening subjects 
in this study. 
 
c. Who is recruiting potential subjects?  
 
All listed member of the research team and the NCPTSD screening protocol staff may 
recruit potential participants. The aforementioned clinics may also refer potentially 
eligible clients to the study. 
 
 
4. Screening Procedures 
a. Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office? 
 Yes  
 No 
b.  If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.  
 
HEALTH INFORMATION TO BE COLLECTED: 
Current psychiatric treatment 
Current medications 
Allergies 
 
 
HIPAA identifiers:  
 Names  
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 


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more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000.  
  Telephone numbers 
 Fax numbers  
 E-mail addresses 
 Social Security numbers  
 Medical record numbers 
 Health plan beneficiary numbers  
 Account numbers  
  All elements of dates for dates related to an individual, including: birth date, admission date, discharge date, date of death, 
all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages and elements may be 
aggregated into a single category of age 90 or older  
 Certificate/license numbers  
 Vehicle identifiers and serial numbers, including license plate numbers  
 Device identifiers and serial numbers  
 Web Universal Resource Locators (URLs)  
 Internet Protocol (IP) address numbers  
 Biometric identifiers, including finger and voice prints  
 Full face photographic images and any comparable images  
 Any other unique identifying numbers, characteristics, or codes  
 
 
5. Assessment of Current Health Provider Relationship for HIPAA Consideration: 
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?  
 Yes, all subjects 
 Yes, some of the subjects 
 No 
 
If yes, describe the nature of this relationship. 
 
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of a 
phone or email screen, you must request a HIPAA waiver for recruitment purposes.) 
 
Choose one:  
☐ For entire study  
☒ For recruitment purposes only  
☐ For inclusion of non-English speaking subject if short form is being used 
 
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data; 
 
Initial screening procedures occurring over the phone with subjects does not allow for signed 
authorization to occur.  However, potential subjects will be told that their information will be 
recorded during the call to determine if they are eligible to participate in the study.  Subjects will 
be verbally asked if they agree to this process and if they are, the screening will occur. The initial 
clinical interview session may take place over Zoom if it is not feasible for subjects to attend an 
in-person session due to physical distance or risk of infection due to COVID-19. 


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ii. If requesting a waiver of signed authorization, describe why it would be impracticable 
to obtain the subject’s signed authorization for use/disclosure of this data; 
 
In order to determine if a subject is eligible to come into the clinic for a screening 
visit, we conduct phone screens. We ask their permission to record data and tell them 
that everything we write down is confidential and will be kept in a locked cabinet. 
Therefore, due to prescreening on the phone, we cannot get their signed authorization.  
We can only get their verbal authorization. 
 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB. 
 
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer. 
 
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided: 
 
  
 Compound Consent and Authorization form 
 
  
 HIPAA Research Authorization Form 
 
 
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.  
 Listed in IRES IRB 
 
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be 
obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.  
 
If an individual appears to meet enrollment criteria and is interested in participating, a face-to-
face interview, or Zoom or telephone call is conducted at by one of the project investigators. A 
written authorization form is obtained from each subject, permitting the research team to use, 
create, or disclose the subject's PHI for research purposes. The nature of the project, procedures, 
relative risks and benefits, and alternatives to participation in the project are discussed with the 
individual. Following this discussion, the individual is given a copy of the consent form to review 
at their leisure, and any questions are answered. When it is not feasible for written consent to be 
obtained in person due to physical distance or threat of infection due to COVID-19, a consent will 
be emailed from a Yale account to the subject, who will then sign and return the document. 


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If the individual remains interested in the project, written informed consent is obtained, and medical 
and psychiatric screening procedures are undertaken to confirm eligibility. A copy of the consent 
form is provided to all participants. 
If the individual decides not to participate in this study, the decision not to participate does not 
affect eligibility to participate in future studies, to receive treatment at YNNH, YCCI, CMHC, the 
VACHS, or to receive treatment on a private basis from a referring clinician. 
 
 
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.  
After trained and knowledgeable research personnel explain all aspects of the research protocol 
with a consent form at hand, the potential subject will be asked to communicate a reciprocal 
understanding of the protocol.  This “say back” method has demonstrated reliability among 
educators in ascertaining degree of comprehension. 
 
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.  
 
 Research personnel capable of determining consent will conduct this process with the most up-
 to-date copies of the Yale informed consent documentations at hand.  
 
 
12. Non-English-Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use.  
  
 
 Not applicable as non-English speaking subjects will not be enrolled. 
 
 
12(a) As a limited alternative to the above requirement, will you use the short form* for 
consenting process if you unexpectedly encounter a non-English speaking individual interested in 
study participation and the translation of the long form is not possible prior to intended 
enrollment?  
YES ☐  NO ☒ 
 
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time a 
subject speaking that language is to be enrolled. 
 
Several translated short form templates are found on our website 
at:  http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short 


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form is not available on our website, then the translated short form needs to be submitted to the 
IRB office for approval via amendment prior to enrolling the subject. Please review the guidance 
and presentation on use of the short form available on the HRPP website. 
 
If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above.  
 
 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, or 
a waiver of signed consent for this study, complete the appropriate section below.   
 
 Not Requesting a consent waiver  
 
 Requesting a waiver of signed consent 
       
 Requesting a full waiver of consent 
    
 
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is collected, 
information in this section must match Section VII, Question 6) 
 Requesting a waiver of signed consent for Recruitment/Screening only  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 
c. Does the research activity pose greater than minimal risk?  
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity   
 No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
 Requesting a waiver of signed consent for the Entire Study (Note that an information sheet 
may be required.) 
 
  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 


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c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
  
 B. Full waiver of consent: (No consent from subjects will be obtained for the activity.)  
 Requesting a waiver of consent for Recruitment/Screening only  
a. Does the research activity pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is collected, 
information here must match Section VII, question 6.) 
 
  
 
If requesting a full waiver of consent, please address the following: 
 
 
  
a. Does the research pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted.   
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS 
 
    Confidentiality & Security of Data: 
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?    
 
Names 
 
Home addresses 
 
Telephone Numbers 
 
Email addresses 
 
All elements of dates for dates related to an individual, including: birth date, 
 
admission date, discharge date, date of death, all ages over 89 and all elements of dates 
 
(including year) indicative of such age, except that such ages and elements may be 
 
aggregated into a single category of age 90 or older 
        
b.    How will the research data be collected, recorded and stored?  


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Research personnel will collect research data via direct interview after potential subjects 
sign release of information for available informants.  This data will be recorded in both 
written and/or electronic formats, and all confidential PHI will be quoted by number and 
stored in locked and secured files to ensure confidentiality 
 
All confidential protected health information (PHI) obtained from screened and enrolled 
research subjects will be assigned a number and stored in locked and secured clinic 
repository to ensure confidentiality.  This data will only be made available to the 
investigators and other research personnel, the National Institutes of Mental Health 
(NIMH) and Yale’s HIC.  Additional confidentiality measures follow the procedures and 
policies of CMHC and Yale. 
 
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard    
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other 
d.    What methods and procedures will be used to safeguard the confidentiality and security of     
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study? 
Do all portable devices contain encryption software? 
 Yes   
 No 
 
All written confidential PHI will be quoted by number and stored in locked and secured 
 
locations at both sites to ensure confidentiality.  All electronic PHI/PI resources will be 
 
encrypted and password-protected to preclude access by non-research personnel. 
 
         If no, see http://hipaa.yale.edu/guidance/policy.html 
  
e. What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured. 
 
All electronic PHI (ePHI) will continue to be encrypted and password-protected after 
 
subject participation.  Both written and ePHI will be destroyed 10 years after the protocol 
 
is completed. 
f.   Who will have access to the protected health information (such as the research sponsor, the 
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data)  
 
All research personnel listed on this protocol and Yale HIC will have access to written and 
ePHI and study data throughout and after the completion of the study until the data is destroyed at 
the discretion of the primary investigators.  The Brain and Behavior Research Foundation, the 
funding source for this study, will also have access to subjects’ PHI. 
 
g.   If appropriate, has a Certificate of Confidentiality been obtained?  Yes 
 
.  


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h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported.  
 
 
 
SECTION IX: POTENTIAL BENEFITS 
 
 
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)  
 
 
 
The present study may benefit participants directly via infusion with ketamine followed by 
an intensive form of PE therapy. The combined treatment with ketamine and PE is 
predicted to help participants by reducing PTSD symptoms such as hyperarousal, re-
experiencing trauma, and maladaptive avoidance behaviors. Results from the current study 
may provide clinicians with a novel evidence-based intervention option for treatment-
resistant PTSD.  
 
 
The relative risks and inconveniences associated with participation in this study, including 
ketamine administration, are balanced by the potential benefits to participants and society 
at large.  
 
 
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 
 
1.     Alternatives: What other alternatives are available to the study subjects outside of the research? 
 
 
 
Not to participate  
 
2.  
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.  
 
 
 
 
Compensation for study procedures will break down as follows:  
 
 
 
Single-Infusion Group: 
 
 
 
Screening Clinic (Visit 0) …………..$50.00 for psychological assessment;  
 
 
 
 
 
 
 
          $50.00 for medical assessment 
Visit 2 (first MRI)..…………….………...$50.00  
Visit 2 (1st infusion)……………………….$100.00 
Visit 7 (second MRI)…………….………...$150.00  
Visit 8 (one month follow-up)..……………..$200.00  
Visit 9 (3-month follow-up).…………………..$250.00  
Total .…………………………………..……… $850.00 


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Two-Infusion Group:  
 
 
 
Screening Clinic (Visit 0) …………..$50.00 for psychological assessment;  
 
 
 
 
 
     
 
        $50.00 for medical assessment 
Visit 2 (first MRI)..…………….………...$50.00  
Visit 2 (1st infusion)……………………….$100.00 
Visit 4 (2nd infusion)………………………$100.00 
Visit 7 (second MRI)…………….………...$150.00  
Visit 8 (one month follow-up)..……………..$200.00  
Visit 9 (3-month follow-up).…………………..$250.00  
Total .…………………………………..……… $950.00 
 
 
Subjects will receive payment for the screening procedures from the VA Screening protocol. 
Subjects will receive payments for Visits 2 -9 either by cash or via a Bank of America pre-paid 
debit card.  The subject’s name, address, and telephone number will be shared with Bank of 
America for ePayments. After the second payment milestone (second study visit) subjects will 
receive a card in the mail which will need to be activated over the phone.  Subsequent milestones 
payments will occur after Visit 8 and again after Visit 9 and will automatically add additional 
funds to the subject’s card.  
 
 
 
At the principal investigator’s discretion, only reasonable expenses, such as transportation 
costs to and from study locations will also be covered by the National Center for PTSD or by 
Yale Department of Psychiatry paying subjects with cash at the end of each study visit. Should 
any participants require local accommodations, a hotel room in New Haven will be provided by 
the National Center for PTSD or by Yale Department of Psychiatry. If too much time passes 
between the screening visit and first scan, it may be necessary for subjects to repeat the 
psychological interview, medical evaluation, or both. Subjects will be paid $50 for completing a 
repeat psychological screening session, and $50 for completing a repeat medical evaluation. If 
subjects come to the session but are unable to take part in the scheduled scans due to MRI 
downtime or scheduling error, a $50 show-up fee will be offered. 
 
3. 
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.   
 
 
 
All services and evaluations are provided free of charge.  
 
4. 
In Case of Injury: This section is required for any research involving more than minimal risk. 
 
a.     Will medical treatment be available if research-related injury occurs? Yes 
 
b.     Where and from whom may treatment be obtained? From the PI or an appropriate referral 
 
c.     Are there any limits to the treatment being provided? Only that is limited by the subject 
ability to pay for the costs of the care provided 
 
d.     Who will pay for this treatment? The subject and/or the subject’s insurance 


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e.     How will the medical treatment be accessed by subjects? Via the PI, the Connecticut Mental 
Health Center (CMHC), or emergency room visit 
 
 
 Medical treatment will be offered to the subjects for any physical injuries that they 
receive as a result of participating in this research.  However, the subject or his/her 
insurance company is responsible for the cost.  As required by Federal regulations, all 
subjects will be told that if they are physically injured, no additional financial 
compensation is available.