Clinical trial NCT04260607
Conditions: Suicide Suicide Threat Depression Severe
Keywords: ketamine
Sponsor: Naval Medical Center Camp Lejeune
Start date: 2020-01-14; Completion date: 2022-02-16
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Current treatment for acutely suicidal patients are limited to hospitalization, psychotherapy, electro-convulsant therapy, or a combination of the aforementioned. However, this has added to the national boarding problem. Long term pharmacologic treatment for suicidal behaviors and mood stabilization has been studied in specific populations. In these populations, the decreases in suicidal ideation results from stabilization of the underlying psychiatric illness. Ketamine is most commonly used as an anesthetic with analgesic properties. It has been used off-label for pain management, procedural sedation, status epilepticus, and treatment resistant depression. It has been safely administered intravenously and well tolerated for chronic Post Traumatic Stress Disorder. It increases norepinephrine, dopamine, and serotonin through adrenergic neuron stimulation and prevention of catecholamine uptake. There is a strong corollary between stress and the development of depression and suicidal behaviors. It is proposed that the use of low dose intravenous ketamine may have benefit on the suicidal ideation of patients presenting to the Emergency Department.

Detailed description:
There is a strong corollary between stress and the development of depression and suicidal behaviors. The neurobiological mediators of stress are primarily controlled by the noradrenergic and corticotropin-releasing factor (CRF) median eminence systems. Furthermore, stress directly and indirectly, through the Hypothalamic Pituitary Axis, activates the Locus Coeruleus (LC), which is the primary producer of NE in the central nervous system (CNS). Directly, glutaminergic neurons send excitatory signals to the LC via interaction with N-Methyl-D-Aspartate (NMDA) receptors NMDA antagonists, such as ketamine, can dampen the glutaminergic system, which has been implicated during states of depression and low moods.

The neurobiological commonality between multiple psychiatric disorders and depression, suicide, and attempted suicide is a decrease in serotonergic activity. It has been shown that patients who died of suicide, have decreased serotonin transporter in the ventromedial prefrontal cortex and anterior cingulate, which are areas that control decision making or willful action. The prefrontal cortex is important for inhibitory behavioral control. A potential treatment modality of ketamine, is that it produces activation of this region.35 The anterior cingulate cortex has been shown to be associated with impulsive aggression compared to control. Clinical studies have shown that low CSF 5-HIAA, metabolite in serotonin system, has been implicated and positively correlated to aggression scores and impulsivity. This is interesting because, suicides in the military are thought to have an impulsivity component, triggered by one or more major life stressors.

Another region associated with suicide is the infralimbic cortex. A recent study, based on neuroimaging techniques, demonstrated that glucose metabolism in this region was associated with SI at baseline, and decreases in SI was observed after ketamine infusion. This is the same region target by deep brain stimulation, for depression treatment. Additionally, the infralimbic cortex has been implicated in behavioral flexibility. Implicating that ketamine's anti-suicidal properties may stem from its ability to promoting cognitive flexibility. Most likely due to its ability to increase brain-derived neurotrophic factor (BDNF), which is a major contributor to neuronal plasticity. BDNF also plays key roles in synaptic and long-term potentiation, which may counteract the decreased levels in Mood Disorder (MDD) patients. Furthermore, ketamine infusion has been shown to change sleep slow wave activity. This biomarker is functionally related to increased synaptic strengthening and cortical synchronization. These factors, combined, may be implicated in not only ketamine's antidepressant effects and counteraction of decreased synaptic plasticity seen mood disorders, but also its ability to have week long lasting effects.

This information leads us to hypothesize that treatment of acutely suicidal patients with ketamine would: 1) decrease suicidal ideationto a clinically significant degree, and 2) the effect of ketamine will be seen for as long as one-week post administration.

To the best of our knowledge, this study does not duplicate any ongoing work. Instead, it would strengthen power to past studies and current work. There are four clinical trials investigating ketamine's effect on SI. One has an unknown status. There are two that are investigating ketamine in relationship to psychiatric standard of care, whereas this study is investigating its effects against a saline placebo. Finally, the last clinical trial is investigating the Neurobiology of Suicide. Their phase 2 component, which utilizes a similar protocol, uses ketamine as a tool to identify potential biomarkers for suicide. Furthermore, this study differs from Janssen Research \& Development's clinical trial in administration route and study design. Their study focuses on using ketamine through intranasal administration. Their primary outcomes are the long-term safety and efficacy, and the design of their study is an open label multicenter trial.

This research does not duplicate any prior work. To date, there is only one study, from Iran, that evaluates the effectiveness of ketamine in high risk patients, or those that present as acutely suicidal to the ED. This was a single blinded trial that utilized 0.2mg/kg infused over one minute. The study indicated significant decrease in their measurement outcomes. However, they concluded that ketamine is not a good choice for treatment because it did not meet their cut off values. Their results might have been influenced by the rapid infusion over one minute, which differs from our study as well as the vast majority of the literature. We believe the slower 40-minute infusion is necessary for optimal results, as the larger dosage has produced more clinically meaningful results in prior studies, and the slower infusion produced less negative side effects. They chose the minimal dose shown to diminish SI41 200 ng/ml (0.2 mg/kg), which provokes lateral nystagmus.35 This protocol utilizes a higher dose, 0.5 mg/kg, which is the ED50 for narcosis. Our study is medically relevant because dosage effects on SI have not been studied. Comparison of our studies may address questions regarding the optimal dose and infusion rate.

The BSSI will measure the severity of SI. It is based on the interviewer rated version of the original Scale for Suicidal Ideation (SSI), which is one of the few document suicide assessment tools with predictive validity for suicide completion. The internal reliability, test and retest validity, as well as invariance over time has been demonstrated for the BSS. Furthermore, the first five items of the BSSI are a common clinical screening for the presence of suicidal thoughts. For these reasons, the BSSI was chosen as our primary outcomes measure. Two studies have indicated that the cut off between high and low risk is a BSS ≥ 2. A recent investigation has determined BSSI ≥ 6 is predictive of future suicide attempts. These two values will serve in our analysis.

The Montgomery- Åsberg Depression Rating Scale (MADRS) is a widely known 10 item clinician administered measure of depression severity. Since it's development in the late 1970s, it has become more popular than the gold standard, Hamilton rating scale for Depression (HAM-D). It is considered to be more sensitive to change, just as effective, and simpler to use clinically. However, the reliability depends on good interrater agreement. Difficulties in clinical trial to show signal detection for known effective drugs have implicated clinician administered measurement as a possible source of error. To avoid poor interrater reliability, rater bias, and variable interview quality, this trial will utilize the self-administered version of the MADRS-S. This has 9 items and a total score ranging from 0 to 27.50 The scoring of MADRS-S has shown to be similar to that of physician scoring.

The emotional pain of the suicidal patient requires empathetic care that may not always be possible with the time pressures, volume, and pragmatic nature of the ED environment. A pharmacologic intervention with rapid effects to decrease SI would play a vital role in improving the standard of care for this vulnerable population.

Arms: arm 1: single dose IV Ketamine (Ketalar) 0.5mg/kg in 100ml Normal Saline infused over 40 minutes arm 2: 100ml Normal Saline infused over 40 minutes
Interventions: intervention 1: Ketamine Hydrochloride intervention 2: Normal saline
Intervention descriptions: intervention 1: Experimental Procedure

1. Baseline evaluation of suicidal severity (BSSI) \& degree of depressive symptoms (MADRS-S) will be evaluated through self-administered questionnaires.
2. The experimental and placebo arms will receive a single dose of IV ketamine, 0.5 mg/kg in 100 cc NS or 100 cc of NS infused over 40 minutes.
3. Post ketamine re-evaluation of outcome measures at four and twenty-four hours will determine clinical effectiveness of ketamine intervention
4. Inspection of admission and transfer time provides time measurement for LOS. This secondary measure is needed to determine efficiency of intervention.
5. Post ketamine re-evaluation of outcome measure at one-week post infusion will elucidate ketamine's durability of effect. intervention 2: Experimental Procedure

1. Baseline evaluation of suicidal severity (BSSI) \& degree of depressive symptoms (MADRS-S) will be evaluated through self-administered questionnaires.
2. The placebo arms will receive a single dose of 100 cc of NS infused over 40 minutes.
3. Post Placebo infusion re-evaluation of outcome measures at four and twenty-four hours
4. Inspection of admission and transfer time provides time measurement for LOS. This secondary measure is needed to determine efficiency of intervention.
5. Post Normal Saline re-evaluation of outcome measure at one-week post infusion.

Protocol documents:
ICF_001.pdf: 
CIP# NMCCL. 
PI: Butler, D.O. 
Page 1 of 
ICF Version 7 – 10 JUN 2021
NAVAL MEDICAL CENTER CAMP LEJEUNE 
CAMP LEJEUNE, NC 28547
CONSENT BY A SUBJECT FOR VOLUNTARY PARTICIPATION IN A CLINICAL INVESTIGATION
at Naval Medical Center Camp Lejeune
PARTICIPANT ID # 
DATE: _ _ /_ _ _/_ _ _ _
           DD  MMM  Y Y Y Y
Key Information for
Impact of Ketamine on Acutely Suicidal Patients in the Emergency Department
You are being asked to decide if you want to volunteer for a research study about investigating the clinical 
effectiveness of ketamine as a medication treatment for the acutely suicidal patient in the Emergency Department. 
You can decide if you want to participate. You can ask questions about how being in the study will affect you. If you 
decide to be in the study you will be asked to sign the consent form after a researcher goes over it with you.
What is the study about and how long will it last?
In this study, we hope to learn whether or not treating a patient with suicidal thoughts with a medication called 
ketamine can effectively, safely, and rapidly reduce or get rid of those thoughts. Your participation in the research 
will last up to a week after discharge from the hospital.
What will you be asked to do?
While you are participating in this study you will be answering 2 self-questionnaires about suicidality at four different 
time periods. You will be randomly assigned to receive either the study medication (ketamine) or a placebo (saline) 
given by IV infusion over 40 minutes.
What are key reasons you may not want to volunteer in this study?
You may experience uncomfortable thoughts or feelings if you are treated with the study medication, ketamine, similar 
to a reaction to a bad dream.
What benefits may be expected by volunteering in the study?
You may not experience any direct benefit by volunteering in this study, but it will help us determine if ketamine can 
effectively, safely, and rapidly reduce or get rid of suicidal thoughts.
Do you have to agree to be in the study?
If you decide to participate in the study it should be because you really want to volunteer. You will not lose any 
services, benefits, or rights you would normally have if you decide not to volunteer. Military rank is of no consideration 
when you are deciding whether or not to participate in this study.
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021


CIP# NMCCL. 
PI: Butler, D.O. 
Page 2 of 
ICF Version 7 – 10 JUN 2021
Please read this form carefully. Take time to ask the study doctor or study staff as many questions about the 
study as you would like. If there are any words or information that you do not understand, the study doctor or 
study staff will explain them to you. Reading this form and talking to the study doctor or study staff may help you 
decide whether to take part or not. Before you take part in the research study, you must sign the end of this 
form.
1.
Study Title:
You have been asked to voluntarily participate in a research study entitled Impact of Ketamine on 
Acutely Suicidal Patients in the Emergency Department,” being conducted at the Naval Medical Center 
Camp Lejeune by medical researchers from the Emergency Department.
2.
Why Is This Study Being Done?
The purpose of this study is to investigate the clinical effectiveness of ketamine as a medication 
treatment for the acutely suicidal patient in the ED.
3.
Why Are You Being Asked to Take Part?
You are being asked to take part in this study because you expressed suicidal thoughts and have been 
determined by the mental health provider to require admission to the psychiatric ward.
This study includes only those people who voluntarily choose to take part. Please take your time to 
make your decision and feel free to ask any questions that you might have.
4.
Screening Process to Qualify for Participation in This Study
Certain information must be collected, and you must be accepted for admission to psychiatric inpatient 
services before the researcher can confirm that you meet the qualifications to become a subject in this 
study. This is called the “Screening Process”. Tests, such as blood, urine, or EKG may have been 
collected as a part of your regular medical care, although not necessarily. Females of child-bearing 
potential will receive a urine pregnancy test.
5.
What Is Involved in This Study?
If you choose to take part in this study, you will be given two self-questionnaires to assess your degree 
of depression and suicidality.
Then, you will be randomly assigned into one of two groups. It is like flipping a coin. Neither you, your 
doctor, nor the investigator, will be able to choose the group to which you are assigned, and you will not 
find out which group you were in at the end of the study unless there was a safety concern during your 
participation.
•
Group 1 - will be given the treatment
o
0.5mg/kg ketamine, mixed in 100cc of Normal Saline, and infused over 40 minutes 
intravenously (i.e through an IV)
•
Group 2 - will be given a placebo.
o
100cc of Normal Saline infused over 40 minutes intravenously
If you take part in this study, you will have the following tests and procedures, independent of 
standard medical care:
•
2 self-questionnaires about suicidality given before the infusion, at 4 (+/- 1) hours after infusion, 
and at 24-36 hours after the infusion.
•
I.V. Placement for the administration of the treatment or placebo.
•
A follow-up phone call at 7-8 days post-discharge with a study team member. You will be asked 
to complete the same two questionnaires.
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021


CIP# NMCCL. 
PI: Butler, D.O. 
Page 3 of 
ICF Version 7 – 10 JUN 2021
Prior studies have shown that slow infusion of IV ketamine has anti-depressant and anti-suicidal effects. 
The experimental procedure being tested in this study is if 0.5mg/kg ketamine, mixed in 100cc of 
Normal Saline, and infused over 40 minutes intravenously will provide a clinically effective decrease in 
suicidal ideation.
The following are routine procedures that will be done if you decide to participate in this study:
•
IV
•
Medication infusion
The following procedures are part of regular medical care that may be done even if you do not join the 
study:
•
Blood Draw
•
History and Physical
6.
How Many People Will Take Part in This Study?
A total number of 62 subjects are expected to participate in this study.
7.
How Long Will You Be in This Study?
Your participation in this research project will be for a period of the duration of your admission plus 1- 
week post-discharge. However, it will take only 1-2 hours total hour of your time, completing 
questionnaires and responding to emails.
You may stop participating in this study at any time. However, if you decide to stop participating, we 
encourage you to talk to the researcher and your regular healthcare provider first.
8.
When Should You Not Take Part?
In order to participate in this study, you must be active duty military, military dependent, or retiree.
If you have any of the following conditions listed below, you are not eligible to take part in this study:
•
Less than 18 years old or greater than 89 years old
•
Have a personal or family history of schizophrenia or schizoaffective disorder
•
Currently pregnant or nursing
•
Currently intoxicated
•
Have previously participated in this study
9.
What Are the Risks of The Study?
The risks and side effects related to the medication, ketamine, we are studying include:
Likely:
•
Strange dreams or disturbances in visual and auditory perception, mood, body image, and time. 
You may experience feelings of floating, conscious dreams, or hallucinations. These symptoms will 
peak at 40 minutes and resolve within 120 minutes. To prevent emotional discomfort from vivid 
dreams, the researcher will discuss pre-conditioning, which is when you are encouraged to think of 
a pleasant place for your dream to occur. This process will decrease the discomfort.
Moderate:
•
Increased salivation
•
Nausea and vomiting
•
Anxiety or paranoia
•
Hallucinations
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021


CIP# NMCCL. 
PI: Butler, D.O. 
Page 4 of 
ICF Version 7 – 10 JUN 2021
Rare:
•
Reducing or stopping breathing, sense of choking, low blood pressure or low heart rate.
While on the study, you are at risk for these side effects. You should discuss them with the investigator 
and your regular healthcare provider. Other medications may be given to make the side effects less 
serious and make you more comfortable. Many side effects go away shortly after the interventions or 
medications are stopped, but in rare cases the side effects can be serious, long lasting or permanent.
Reproductive risks: Because the medications in this study can affect an unborn baby, you cannot 
participate in this study if pregnant. You should not breastfeed your baby for 24 hours after being given 
the medication while on this study. Please ask about counseling and other information about preventing 
pregnancy.
There also may be other side effects that are unknown, and we cannot predict.
For more information about risks and side effects, ask the Principal Investigator, Dr. Nathan Butler or the 
Research Coordinator, Ms. Catherine Christian.
10.
Are There Benefits to Taking Part in This Study?
If you agree to take part in this study, there may or may not be direct benefit to you. Although it is 
possible you will feel a decrease in suicidal ideation, there is no guarantee that you will personally 
benefit from taking part in this study. We hope the information learned from this study will benefit other 
people with suicidal ideation in the future.
11.
Are There Alternatives to This Study?
You may choose to not participate. You will then receive standard medical treatment that may or may 
not include any one of the procedure(s) or treatment(s) that are part of the planned research study.
12.
What About Confidentiality?
We plan to hold all health information in strict confidence, but we cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Authorized personnel 
from (the Institutional Review Board, Department of the Navy, Department of Defense, FDA) may have 
access to your research file for authorized purposes, including verification that your rights have been 
safeguarded.
A description of this clinical trial will be available on http://www.ClinicalTrials.govas required by U.S. Law. 
This web site will not include information that can identify you. At most, the Web site will include a 
summary of results. You can search this Web site at any time.
There is a possibility that identifiers (like your name or date of birth) might be removed from your 
identifiable private information or identifiable biospecimens and the information or biospecimens could 
be used for future research studies or distributed to another investigator for future research studies 
without additional informed consent from you or your legally authorized representative.
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021


CIP# NMCCL. 
PI: Butler, D.O. 
Page 5 of 
ICF Version 7 – 10 JUN 2021
Privacy Act Statement
In accordance with the Privacy Act of 1974 (Public Law 93-579), this notice informs you of the purpose of this form 
and how it will be used. Please read it carefully.
1. Authority. Public Law 104-191; E.O. 9397 (SSAN); DoD 6025.18-R.
2. Purpose. Medical research information will be collected to enhance basic medical knowledge or to develop 
tests, procedures, and equipment to improve the diagnosis, treatment, or prevention of illness, injury, or 
functional impairment. This form is to provide the Naval Medical Center Camp Lejeune/TRICARE Health Plan 
with a means to request the use and/or disclosure of your protected health information.
3. Use. To any third party or the individual upon authorization for the disclosure from the individual for: personal 
use; insurance; continued medical care; school; legal; retirement/separation; or other reasons.
4. Disclosure. Voluntary. Failure to sign the authorization form will result in the non-release of the protected 
health information. This form will not be used for the authorization to disclose alcohol or drug abuse patient 
information from medical records or for authorization to disclose information from records of an alcohol or 
drug abuse treatment program. In addition, any use as an authorization to use or disclose psychotherapy 
notes may not be combined with another authorization except one to use or disclose psychotherapy notes.
HIPAA: Release Authorization
a. You have the right to revoke this authorization at any time. Your revocation must be in writing and 
provided to the facility where the research is being conducted. You are aware that if you later revoke this 
authorization, the research facility may have used and/or disclosed your protected information on the 
basis of this authorization.
b. If you authorize your protected health information to be disclosed to someone who is not required to 
comply with federal privacy protection regulations, then such information may be re-disclosed and would
no longer be protected.
c. You have a right to inspect and receive a copy of your own protected health information to be used or 
disclosed, in accordance with the requirements of the federal privacy protection regulations found in the
Privacy Act and 45 CFR 164.524.
d. The Military Health System (which includes the TRICARE Health Plan) may not condition your treatment in 
MTFs/DTFs, payment by the TRICARE Health Plan, enrollment in the TRICARE Health Plan or eligibility for 
TRICARE Health Plan benefits on failure to obtain this authorization. (i.e. The MHS may not alter, deny, or 
make your legal entitlement to benefits a condition of your participation in this study or your decision to 
provide consent to use your protected health information).
By signing this consent, you are authorizing NMC Camp Lejeune to obtain and release the information as described 
in this consent form. You have the right to refuse to sign this permission form.
5. Disclosure. All information contained in this Consent Statement or derived from the medical research study 
described herein will be retained permanently at Naval Medical Center Camp Lejeune and salient portions thereof 
may be entered into your health record. You voluntarily agree to its disclosure to agencies or individuals identified 
in the preceding paragraph. You have been informed that failure to agree to such disclosure may negate the 
purposes for which the research study was conducted.
13.
What If You Get Injured?
If you suffer any injury as a result of your participation in this study, medical treatment is available at 
Naval Medical Center Camp Lejeune. All medical care (including medical treatment for injuries related to 
this study and medical care unrelated to this study) will be evaluated and provided in keeping with the 
benefits to which you are entitled under applicable regulations.
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021


CIP# NMCCL. 
PI: Butler, D.O. 
Page 6 of 
ICF Version 7 – 10 JUN 2021
14.
Will You Get Paid for Participation?
You will not be compensated for your participation in this study. All treatments related to this study will 
be provided in accordance with applicable regulations.
15.
What Are Your Rights as A Participant?
Your participation in this project is voluntary and your refusal to participate will involve no penalty or loss 
of benefits to which you are otherwise entitled under applicable regulations. If you are currently in the 
military, this study does not involve rank structure or chain of command; you are free to decline if you do 
not want to participate. If you choose to participate, you are free to ask questions or withdraw from the 
project at any time without prejudice to your future care. Any new significant findings developed during 
the course of the research, which may affect your willingness to participate further, will be explained to 
you. Please notify Dr. Nathan Butler at (910) 548-1272 or Catherine Christian at 
catherine.c.christian2.ctr@mail.mil or (910) 459-0760. 
If you withdraw, you will no longer receive study drugs or treatments that are part of the study, unless 
these are also part of your normal drugs or treatments. Your withdrawal will involve no loss of benefits to 
which you are otherwise entitled. If you withdraw from this study, your data will be included in the data 
analysis for this project.
16.
Can Your Participation in This Study Be Terminated?
The investigator may terminate your participation in this project for the following reasons:
•
If your provider determines that any point that you are not eligible for the study.
•
If you wish to be terminated from the study.
17.
Who Can You Call If You Have Questions or Concerns About This Study?
If you have any questions regarding this research project, you may contact the Principal Investigator, Dr. 
Nathan Butler at (910) 548-1272 or by email at  nathan.h.butler.mil@mail.mil or the study coordinator, 
Catherine Christian at Catherine.c.christian2.ctr@mail.mil  or (910) 459-0760.
If you feel you have suffered an injury as a result your participation in this research project or if you have 
any questions regarding your rights as a research subject at Naval Medical Center Camp Lejeune, you 
can contact the Research Administration Officer at (910) 450-3460, the Chair, Institutional Review Board 
at Naval Medical Center Camp Lejeune at (910) 450-4048, or the Head, Clinical Investigation 
Department at (910) 450-3460.
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021


CIP# NMCCL. 
PI: Butler, D.O. 
Page 7 of 
ICF Version 7 – 10 JUN 2021
SIGNATURES
Investigators must use the following steps in order to orient the potential subject to the purpose of the research and 
why they might wish to participate:
•
Step One: The Investigator must explain the study to the potential subject verbally, providing all pertinent 
information (purpose, procedures, risks, benefits, alternatives to participation, etc.), and must allow the potential 
subject ample opportunity to ask questions.
•
Step Two: Following this verbal explanation, the potential subject should be provided with a written consent form 
and afforded sufficient time to consider whether or not to participate in the research. "Sufficient time" can range 
from hours to days, depending on how long it reasonably takes to evaluate the procedures, risks, potential 
benefits, and alternative treatments.
•
Step Three: After allowing the potential subject time to read the consent form, the Investigator should meet with 
the potential subject and answer any additional questions he or she may have.
PARTICIPANT STATEMENT
By signing below, you are indicating that you were given enough time to read this study consent form, all of your 
questions about this research project were adequately answered and a copy of this consent form was given to you for 
future reference. Most importantly, by signing this consent form, you are indicating that you voluntarily agree to 
participate in this research study.
Participant’s Signature
Date
(DD/MMM/YY)
Typed/Printed Name
Sponsor's Status
PARTICIPANT CONTACT INFORMATION
Home Phone: (
)
-
Cell Phone:
(
)
-
Email Address:  
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021


CIP# NMCCL. 
PI: Butler, D.O. 
Page 8 of 
ICF Version 7 – 10 JUN 2021
INVESTIGATOR STATEMENT
You have explained to the above individual the nature and purpose of the study, the potential benefits and possible 
risks associated with the study, and the alternatives to participation in this study. You have answered any questions 
that were raised. You have explained the above to the subject on the date stated on this consent form. Consent was 
obtained prior to participation in the study.
Investigator performing consent process and obtaining written signature.
Investigator or Coordinator’s
Signature
Date 
(DD/MMM/YY)
Typed/Printed Name
Grade or Rank
WITNESS STATEMENT
I confirm that the research study was thoroughly explained to the subject by the investigator or coordinator. The 
consent form was reviewed with the subject and the subject’s questions were answered. The subject appeared 
to have understood the information.
Witness’ Signature
Date 
(DD/MMM/YY)
Typed/Printed Name
Grade or Rank
iMedRIS Data Corporation
IRB NUMBER: NMCCL.2018.0011
IRB APPROVAL DATE: 07/08/2021
IRB EXPIRATION DATE: 11/18/2021

Prot_SAP_002.pdf: 
Cover Page 
NMCCL.2018.0011 
31Jan2024 
“Impact of Ketamine on the Acutely Suicidal Patients in the Emergency Department” 


2/1/24, 7:47 AM
iRIS: Protocol Application
https://eirb.csd.disa.mil/System_Help_Win.jsp?s=101010101
1/36   
 EIRB Protocol Template (Version 1.7)
1.0
General Information
*Please enter the full title of your study:
Impact of Ketamine on the Acutely Suicidal Patients in the Emergency Department  
*Please enter the Protocol Number you would like to use to reference the protocol:
NMCCL.2018.0011
* This field allows you to enter an abbreviated version of the Protocol Title to quickly identify this
protocol.  
Is this a multi-site study (i.e. Each site has their own Principal Investigator)?
No  
Does this protocol involve the use of animals?
Yes
No  
2.0
Add Site(s)
2.1 List sites associated with this study:
Primary
Dept?
Department Name
Navy - Naval Medical Center Camp Lejeune (NMCCL) 
3.0
Assign project personnel access to the project
3.1 *Please add a Principal Investigator for the study: 
Butler, Nathan Henry, DO, MBA
Select if applicable
Student
Site Chair
Resident
Fellow 
3.2 If applicable, please select the Research Staff personnel: 
A) Additional Investigators
Jolicoeur, Amy N, BSN  
Associate Investigator


2/1/24, 7:47 AM
iRIS: Protocol Application
https://eirb.csd.disa.mil/System_Help_Win.jsp?s=101010101
2/36
B) Research Support Staff
BURTON, SARAH BETH 
  Team Member
CHRISTIAN, CATHERINE Catlett 
  Research Coordinator
Cisneros, Kylee Joelene, MSN 
  Monitor
Nottingham, Kole KONNER DEAN 
  Team Member
3.3 *Please add a Protocol Contact:
 
CHRISTIAN, CATHERINE Catlett 
The Protocol Contact(s) will receive all important system notifications along with the Principal
Investigator. (i.e. The protocol contact(s) are typically either the Protocol Coordinator or the Principal
Investigator themselves).
3.4 If applicable, please select the Designated Site Approval(s):
 
Add the name of the individual authorized to approve and sign off on this protocol from your Site
(e.g. the Site Chair).
4.0
Project Information
4.1   * Has another IRB/HRPP reviewed this study or will another IRB/HRPP be reviewing this study? If Yes,
answer the questions according to the IRB/HRPP Determination.
  Yes   
  No
IRB Name
Review Date
Determination
No records have been added
4.2   * Is this a research study or a Compassionate Use/Emergency Use/HUD project?
 Yes   
 No
4.3   What type of research is this?
Biomedical Research
Clinical trial (FDA regulated)
Behavioral Research
Educational Research
Psychosocial Research
Oral History
Other
4.4   Are you conducting this project in pursuit of a personal degree?


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  Yes   
  No
4.6   * Is this human subjects research? (As defined by 32 CFR 219)    Human subject means a living
individual about whom an investigator (whether professional or student) conducting research: 
   (i) Obtains information or biospecimens through intervention or interaction with the individual, and
uses, studies, or analyzes the information or biospecimens; or 
  (ii) Obtains, uses, studies, analyzes or generates identifiable private information or identifiable
biospecimens.  
 Yes   
 No
4.7   * Do you believe this human subjects research is exempt from IRB review?
  Yes   
  No
5.0
Personnel Details
5.1   List any Research Team members without EIRB access that are not previously entered in the protocol:
No records have been added
5.2  
Will you have a Research Monitor for this study?
Yes 
No 
N/A 
Research Monitor Qualifications
Ensure the individual has expertise consistent with the nature of risk(s) identified within your study
and is independent of the team conducting the research.
Research Monitor Role:
The protocol for Impact of Ketamine on the Acutely Suicidal Patients in the Emergency
Department will be considered “greater than minimal.” For this reason, the below stated individual
has been appointed as research monitor.
 
A research monitor has the expertise commensurate with the nature of risk(s) identified within the
research protocol and must be independent of the investigative team. For this investigation, the
research monitor will
serve concurrently as the ombudsperson if there is a misalignment in wishes between the subject
and their LAR. The Human Subjects Protections Unit (HSPU) team member who is monitoring the
informed consent process will complete a capacity assessment.
 
To appropriately act as research monitor, the monitor may discuss the research protocol with the
investigators, interview study subjects, and consult with others outside of the project about the
research.
 
Duties
The research monitor will perform oversight functions. This will encompass the following duties: 
1. Observation of recruitment, enrollment, and consenting.
2. Monitor the study intervention and interaction between investigators and subjects.


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3. Examine monitoring plans and reports and review data matching, collection, and data
analysis procedures.
 
Authorities
In the event a problem is identified, the monitor will have the authority to stop a research
protocol, remove individual subjects from a study, and take whatever steps are necessary to
protect the safety and well-being of subjects until the IRB can assess the monitor’s report.
The monitor is required to promptly report her medical monitoring and oversight monitoring
observations and findings to the IRB or other designated official
If applicable, you may nominate an individual to serve as the Research Monitor:
Kylee Joelene Cisneros, MSN
6.0
Data/Specimens
6.1   Does the study involve the use of existing data or specimens only (no interaction with human subjects)?
  Yes   
  No
7.0
Funding and Disclosures
7.1   Source of Funding:
Funding Source
Funding Type
Amount
No records have been added
Total amount of funding:
7.2   Do you or any other Investigator(s) have a disclosure of a personal interest or financial nature
significant with sponsor(s), product(s), instrument(s) and/or company(ies) involved in this study?
  Yes   
  No
If Yes, complete and attach Conflict of Interest forms for all key personnel
8.0
Study Locations
8.1   Is this a collaborative or multi-site study? (e.g., are there any other institutions involved?)
  Yes   
  No
8.2   Study Facilities and Locations:
Institution
Site Name
Site Role
FWA or DoD
Assurance
Number
Assurance
Expiration
Date
Is there an
agreement?
IRB
Reviewing
for Site
Selected Users


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No records have been added
Other:
Other
Institution
Site
Site Role
FWA or DoD
Assurance
Number
FWA or DoD
Expiration
Date
Is there an
agreement?
IRB Reviewing
for Site
No records have been added
8.3   Are there international sites?
Attach international approval documents, if applicable, when prompted. Note: Ensure local research
context has been considered
  Yes   
  No
8.4   Is this an OCONUS (Outside Continental United States) study?
  Yes   
  No
Select  the area of responsibility:
Have you obtained permission from that area of responsibility? (This is a requirement prior to study
approval)
  Yes   
  No
9.0
Study Details
9.1   Key Words:
Provide up to 5 key words that identify the broad topic(s) of your study
Suicidal Ideation
Ketamine
Infusion
Emergency Department
Military
9.2   Background and Significance:
Include a literature review that describes in detail the rationale for conducting the study. Include
descriptions of any preliminary studies and findings that led to the development of the protocol. 
The background section should clearly support the choice of study variables and explain the basis
for the research questions and/or study hypotheses.  This section establishes the relevance of the
study and explains the applicability of its findings
Suicide is the 10th leading cause of death in the United States.1 Worldwide, it is the 17th leading
cause of death, taking 800,000 lives each year.10 Suicide is a serious public health problem with a
complex and multidimensional etiology. The risk of suicide increases with age, as well as having a
history prior attempts, a history of psychiatric disorders,1 and with military service11. Furthermore,
SI is increased after the first month of starting an antidepressant.12 As of 2010, suicide is the 2nd
leading cause of death among military personnel.2 Interestingly, most active members who
committed suicide were never deployed. The Armed Forces Health Surveillance Center (AFHSC)
reported the demographic who committed tended to be white, male, and active component
members.2 This is similar to the general population who present to the ED with SI, who tend to be
male, and between 18-64 years old.3 Soldiers with a history of behavioral health disorders have a
higher suicide rate. Overall, there is an acute increase in suicide and suicide rates in military


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members. 2 Despite increased number of medications and therapy modalities in psychiatry, the rate
of suicide remains constant.9
 
Although the Navy has a lower suicide rate compared to other branches, this study is relevant to the
Navy because it addresses a vital public concern which affects the lives and families of their service
members. Also, Navy medicine takes care of any member or dependent of any branch of the
military, not just sailors. There is a general lack of validated and effective intervention to prevent
suicide in not only the military, but also the civilian population. 2
 
Over the last three-decades, Emergency Medicine (EM) has seen a 12% annual average increase in
the number of visits due to attempted suicide.3, 4 This profound increase has forced many ED staff
members to be the first point of contact for acute mental health care.4 Although mental health and
substance dependence diagnoses increases an individual’s risk for suicide, 37% of those who did not
have these comorbidities visited the ED within a year of death from suicide.13 The ED has been
identified as a vital component of suicide risk identification, support, and management.14 However,
after discharge from the ED, as many as 70% of civilian patients do not attend their first outpatient
appointments.15 This observed behavior follows from the idea that SI is associated with cognitive
rigidity.16 Suicidal patients may not be mentally or emotionally motivated towards the safety
planning17, patient education17, or efforts directed towards saving their life. The days immediately
after discharge from the ED or psychiatric unit are a high-risk period17, and this elevated risk can
last as long as a month.14 
 
“Boarding” of psychiatric patients is an enormous and growing problem due to limited capacity for
inpatient psychiatric care. Boarding is the practice of holding the patient in the ED while waiting for
an open inpatient mental health bed. Studies cite an average of a seven hour wait for a bed
following the decision to admit, which is extended if transfer to an outside facility is required.6-8
The boarding of psychiatric patients is 3.2 times longer than non-psychiatric ED patients.  For each
psychiatric patient awaiting inpatient care, there is a loss of 2.2 ED bed turnovers, which equates to
$2,250 loss in payments and delay in care.  This “healthcare system quality failure,” is evidenced by
an increased morbidity and mortality in not only the psychiatric, but other patients in need of
emergent attention. The quick paced, busy, and chaotic environment of the ED can exacerbate
psychological stress.18 This can negatively affect the psychiatric patient because leaving prior to
screening and treatment increases the risk of self-harm and suicide.19 Furthermore, a lack of
prospectively validated screening tools and scarcity of qualified professionals, especially during off
hours, contribute to this phenomenon. 20
 
Current treatment for the acutely suicidal patients are limited to hospitalization, psychotherapy,
ECT, or a combination of the aforementioned.5 However, as previously discussed, this has added to
the national boarding problem. Long term pharmacologic treatment for suicidal behaviors and mood
stabilization has been studied in specific populations. In these populations, the decreases in suicidal
ideation results from stabilization of the underlying psychiatric illness. For example, Lithium has
been used in mood disorders and Clozapine in schizophrenic patients.20 In those with mood
disorders, cognitive behavioral therapy (CBT) and dialectical behavioral therapy (DBT) have shown
to decrease deaths and rate of attempts long term.22,23
 
Irrespective of this psychiatric disease, suicidal thoughts alone represent a huge morbidity, and
approximately 5.6% of the US population suffers from this. There are no drugs indicated for the
treatment of immediate suicide risk.9 There exists initial support for the safety and tolerability of
ketamine as an intervention for SI.9 Various recent studies have shown ketamine, at low doses, to
have a rapid transient antidepressant and anti-suicidal effects. This off-label use has a B level of
Evidence.25 Due to the urgent need for effective therapy, the FDA granted IV esKetamine, a form of
ketamine, “Breakthrough therapy” status in both 2013 and 2016 to expedite its development in the
treatment of those with major depressive disorder. Results of Phase three data demonstrate
ketamine’s ability to reduce depressive symptoms. To date, outcomes of ketamine’s utility in
addressing immediate risk of suicide is unknown.9
 
Historically, Ketamine is most commonly used as an anesthetic with analgesic properties. Recently,
it has been used off-label for pain management, procedural sedation, status epilepticus, and
treatment resistant depression. 25 Furthermore, it has been demonstrated that a single dose of IV
ketamine is a safe and generally well-tolerated intervention for patients with chronic PTSD. 26
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is most commonly metabolized to
Norketamine, which shows up in the blood within two to three minutes, and peaks at 30 minutes.28
In addition to NMDA receptors, Ketamine, also, binds to the opioid, monoaminergic, cholinergic,
nicotinic, and muscarinic receptors. By stimulating adrenergic neurons and preventing
catecholamine uptake, through the monoaminergic system, it increases norepinephrine (NE),
dopamine, and serotonin. An increase in theses neurotransmitters (NT) is similar to the effects of
anti-depressants. In continuation, these NT are central players in the serotonergic system,
noradrenergic system, and the hypothalamic-pituitary-adrenal (HPA) axes, which all have been
identified as abnormal in suicide and attempted suicide individuals.30
 
There is a strong corollary between stress and the development of depression and suicidal
behaviors.30,31 The neurobiological mediators of stress are primarily controlled by the
noradrenergic and corticotropin-releasing factor (CRF) median eminence systems. Furthermore,
stress directly and indirectly, through the HPA axis, activates the Locus Coeruleus (LC), which is the
primary producer of NE in the central nervous system (CNS). Directly, glutaminergic neurons send


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excitatory signals to the LC via interaction with NMDA receptors 32 NMDA antagonists, such as
ketamine, can dampen the glutaminergic system, which has been implicated during states of
depression and low moods. 33
 
The neurobiological commonality between multiple psychiatric disorders and depression, suicide,
and attempted suicide is a decrease in serotonergic activity.34 It has been shown that patients who
died of suicide, have decreased serotonin transporter in the ventromedial prefrontal cortex and
anterior cingulate, which are areas that control decision making or willful action. The prefrontal
cortex is important for inhibitory behavioral control. A potential treatment modality of ketamine, is
that it produces activation of this region.35 The anterior cingulate cortex has been shown to be
associated with impulsive aggression compared to control.  Clinical studies have shown that low CSF
5-HIAA, metabolite in serotonin system, has been implicated and positively correlated to aggression
scores and impulsivity.30 This is interesting because, suicides in the military are thought to have an
impulsivity component, triggered by one or more major life stressors. 2
 
            Another region associated with suicide is the infralimbic cortex. A recent study, based on
neuroimaging techniques, demonstrated that glucose metabolism in this region was associated with
SI at baseline, and decreases in SI was observed after ketamine infusion.  This is the same region
target by deep brain stimulation, for depression treatment. Additionally, the infralimbic cortex has
been implicated in behavioral flexibility. Implicating that ketamine’s anti-suicidal properties may
stem from its ability to promoting cognitive flexibility.33 Most likely due to its ability to increase
brain-derived neurotrophic factor (BDNF), which is a major contributor to neuronal plasticity. BDNF
also plays key roles in synaptic and long-term potentiation, which may counteract the decreased
levels in MDD patients.36 Furthermore, ketamine infusion has been shown to change sleep slow
wave activity.37 This biomarker is functionally related to increased synaptic strengthening and
cortical synchronization.34 These factors, combined, may be implicated in not only ketamine’s
antidepressant effects and counteraction of decreased synaptic plasticity seen mood disorders,36
but also its ability to have week long lasting effects.24
 
This information leads us to hypothesize that treatment of acutely suicidal patients with ketamine
would: 1) decrease SI to a clinically significant degree, and 2) the effect of ketamine will be seen for
as long as one-week post administration.
 
To the best of our knowledge, this study does not duplicate any ongoing work. Instead, it would
strengthen power to past studies and current work. There are four clinical trials investigating
ketamine’s effect on SI. One has an unknown status. There are two that are investigating ketamine
in relationship to psychiatric standard of care, whereas this study is investigating its effects against
a saline placebo. Finally, the last clinical trial is investigating the Neurobiology of Suicide.  Their
phase 2 component, which utilizes a similar protocol, uses ketamine as a tool to identify potential
biomarkers for suicide.39 Furthermore, this study differs from Janssen Research & Development’s
clinical trial in administration route and study design. Their study focuses on using ketamine
through intranasal administration. Their primary outcomes are the long-term safety and efficacy,
and the design of their study is an open label multicenter trial.9
 
This research does not duplicate any prior work. To date, there is only one study, from Iran, that
evaluates the effectiveness of ketamine in high risk patients, or those that present as acutely
suicidal to the ED. This was a single blinded trial that utilized 0.2mg/kg infused over one minute.
 The study indicated significant decrease in their measurement outcomes. However, they concluded
that ketamine is not a good choice for treatment because it did not meet their cut off values. Their
results might have been influenced by the rapid infusion over one minute, which differs from our
study as well as the vast majority of the literature. We believe the slower 40-minute infusion is
necessary for optimal results, as the larger dosage has produced more clinically meaningful results
in prior studies, and the slower infusion produced less negative side effects.41 They chose the
minimal dose shown to diminish SI41 200 ng/ml (0.2 mg/kg), which provokes lateral nystagmus.35
This protocol utilizes a higher dose, 0.5 mg/kg, which is the ED50 for narcosis. Our study is
medically relevant because dosage effects on SI have not been studied. Comparison of our studies
may address questions regarding the optimal dose and infusion rate.
 
The BSSI will measure the severity of SI. It is based on the interviewer rated version of the original
Scale for Suicidal Ideation (SSI), which is one of the few document suicide assessment tools with
predictive validity for suicide completion.42 The internal reliability, test and retest validity, as well as
invariance over time has been demonstrated for the BSS. 43, 45Furthermore, the first five items of
the BSSI are a common clinical screening for the presence of suicidal thoughts.40 For these
reasons, the BSSI was chosen as our primary outcomes measure. Two studies have indicated that
the cut off between high and low risk is a BSS ≥ 2.43, 45 A recent investigation has determined
BSSI ≥ 6 is predictive of future suicide attempts. 53 These two values will serve in our analysis.
 
            The Montgomery– Åsberg Depression Rating Scale (MADRS) is a widely known 10 item
clinician administered measure of depression severity.46 Since it’s development in the late 1970s, it
has become more popular than the gold standard, Hamilton rating scale for Depression (HAM-D).  It
is considered to be more sensitive to change, just as effective, and simpler to use clinically.47
However, the reliability depends on good interrater agreement.48 Difficulties in clinical trial to show
signal detection for known effective drugs have implicated clinician administered measurement as a
possible source of error. To avoid poor interrater reliability, rater bias, and variable interview
quality,48 this trial will utilize the self-administered version of the MADRS-S.49 This has 9 items and


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a total score ranging from 0 to 27.50 The scoring of MADRS-S has shown to be similar to that of
physician scoring.51
 
The emotional pain of the suicidal patient requires empathetic care52 that may not always be
possible with the time pressures, volume, and pragmatic nature of the ED environment. A
pharmacologic intervention with rapid effects to decrease SI would play a vital role in improving the
standard of care for this vulnerable population.53
 
 
 
9.3  
Objectives/Specific Aims/Research Questions:
Describe the purpose and objective(s) of the study, specific aims, and/or research
questions/hypotheses
Suicide is a leading cause of death worldwide.1 In the United States, this national problem has
profound effects in not only the civilian, but also the military population.2 Over the last few
decades, the Emergency Department (ED) has seen an increase in visits due to attempted
suicide.3,4 Current treatment for the acutely suicidal patients are limited to hospitalization,
psychotherapy, ECT, or a combination of the aforementioned.5 However, this adds to the national
problem of boarding psychiatric patients. In the ED, this poses a danger and adds to the complexity
revolving around management of the suicidal patient.6-8  Despite increased number of medications
and therapy modalities in psychiatry, the rate of suicide remains constant.9 A growing body of
research has implicated ketamine’s antidepressant and anti-suicidal properties.9 So much so that,
the FDA has granted Janssen’s esKetamine, a derivative, breakthrough drug status for treatment
resistant depression. However, there is still no drug indicated for the treatment of immediate suicide
risk
 
Problem statement: There is a general lack of validated and effective pharmacologic interventions
for the treatment of suicide in not only in the military, but also the civilian population. To date,
outcomes of ketamine’s utility in addressing immediate risk of suicide is unknown.9 Rapid acting
pharmacologic intervention for the acutely suicidal patient, although necessary, suffers from a lack
of critical studies.
 
Primary outcome:
Specific aim 1: The objective of this investigation is to identify the clinical
effectiveness of sub-dissociative dose IV Ketamine as an adjunctive treatment for
the acutely suicidal patient in the ED.
Hypothesis 1: There will be a clinically significant decrease in suicidal ideation
(SI) in those treated with Ketamine after 24 hours.
 
Secondary outcomes:
Specific aim 2: Determine if this protocol for ketamine holds its effectiveness
over time post infusion.
Hypothesis 2: The effects of ketamine can last up to a week post infusion.
 
Primary outcome measures of SI will be through self-administered Beck Scale for Suicidal Ideation
(BSS or BSSI or SSI). The self-administered version of Montgomery– Åsberg Depression Rating
Scale (MADRS) will be used to measures degree of concomitant depression symptoms. These
patient-level data will serve as baseline comparatives. Subjects shall be randomized by the
pharmacy and designated to either ketamine treated or saline placebo arm, with both the treating
nurse and physician blinded. The experimental arm shall receive 0.5 mg/kg IV ketamine infusion
over 40 minutes. To test for effectiveness within groups, we will measure outcomes at two different
time points, 4 and 24 hours post infusion. To evaluate effectiveness between groups we will
compare results between treatment and placebo arms. To test for specific aim 2, and to maximize
response rate, a phone call will be made, one week after the initial questionnaire was done.
9.4   Study Design:
Describe study design in one to two sentences (e.g., prospective, use of existing
records/data/specimens, observational, cross-sectional, interventional, randomized, placebo-
controlled, cohort, etc.). Specify the phase – Phase I, II, III, or IV – for FDA-regulated
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This study is designed as an RCT with two arms, Experimental vs. Placebo. Table 1 shows a
detailed description of both arms. This will be a triple masked study. The patient, healthcare
providers, and outcomes assessor will be blinded.
                  Table 1: Description of Experimental Arms
 
Arm
Intervention/Treatment
Experimental:
Ketamine
 
Drug: Ketamine (Ketalar)
Single dose IV ketamine, 0.5 mg/kg in 100 cc Normal Saline,
infused over 40 minutes
Other Name: N-methyl-D-aspartate (NMDA) glutamate
receptor antagonist
Placebo: Saline
Drug: Normal Saline (NS)
100 cc infused over 40 minutes
9.5   Target Population:
Describe the population to whom the study findings will be generalized
 
Suicidal behavior is complex and affects all age groups, with the highest prevalence in those that
are middle aged (45-54 years old). With this said it is the 4th leading cause of death in those 35 to
44 years old. <35 years old it is the second leading cause of death.1 Therefore, the selected subject
population reflects any adult that could present to the ED. Children and adolescents (< 18 years
old) are excluded to mitigate the variabilities their developing brain would introduce into the study.
9.6   Benefit to the DoD:
State how this study will impact or be of benefit to the Department of Defense
 
Suicide is an enormous burden on the active duty service member’s operational readiness, as it has
the potential to permanently take the member out of the fight.  The rippling effects, of this
individual action, not only affects moral of that sailor or marine’s unit, but it also has profound
impacts on the friends, coworkers, and, most importantly, their family. This study has the potential
to provide additional intervention treatment literature.
10.0
Study Procedures, Data Management, and Privacy
10.1   Study Procedures:
Describe step-by-step how the study will be conducted from beginning to end
RESEARCH DESIGN/METHODS/SUBJECT JUSTIFICATION
 
General Approach
This study will be conducted in the ED. The investigative team will notify the ED that this research is
underway. Emergency Department staff will be given an informational brief regarding the nature,
purpose and scope of the research protocol. The brief will be distributed digitally via email, and will
be discussed in staff meetings and huddles to reach 100% of staff. Healthcare personnel who wish
to participate will be given a script and check list for exclusion criteria. If a physician feels that a
patient may be eligible for participation he/she can refer the patient to the research team for
additional evaluation and approach regarding the research study” The role of this individual is only
for recruitment purposes and will not be involved in any other activities of the protocol or informed
of patient information pertaining to the research. 
 
Participants will be adults, whom are 18 years or older, military personnel or civilians eligible for
care in the military treatment facility. This study aims to test for a clinically significant decrease in
SI in the acutely suicidal patient. Repeat measures over time will be conducted at two subsequent


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time points. To determine week long lasting effects of treatment, a third repeat measure will be
conducted. All time point collections will be done for both arms.
 
 The trial is designed as a double-blinded Randomized Control Trial (RCT) with two arms,
Experimental vs. Placebo.  This trial will mask patients, health providers, and outcome assessors to
avoid ascertainment bias; the only unblinded participants will be the pharmacy, which will not affect
the blinding, because at our institution they do not decide on patient disposition. This study design
is not only necessary to demonstrate the effectiveness as a treatment for the acutely suicidal
patient, but also to validate and add power to studies supporting anti-suicidal properties of
ketamine. Outcomes will be measured by Psychometric testing (BSSI & MADRS-S). With the
exception of the aforementioned experimental procedure, which will be done prior to transfer to
inpatient units, both arms will then be treated in accordance to usual management for suicidal
patients, which for both arms includes inpatient admission, therapy, and possible initiation of
antidepressants.
 
Suicidal patients, subjectively identified by clinician, upon admission to the ED will be medically
cleared by the EM physician, and then meet with the mental health liaison to be screened for
admission to the psychiatric department, per normal standard of care. Study investigators will not
be available around the clock, but when available will begin the pre-screening method for this
investigation. The treating physician will pre-screen them for inclusion and exclusion criteria per an
IRB approved check list (Appendix D: Criteria Checklist).
 
The patient will be approached for informed consent in accordance to with 21 CRF 50. They will be
provided with a written document that embodies the elements of the informed consent. The consent
will be presented orally to the subject with a witness. Once presented the subject will be given a
reasonable time to review the contents and inquire information. Upon signing of the form, a copy
shall be given to them.
 
Once consent is obtained, they will be presented with a paper form to complete the BSSI and
MADRS-S. These measures will serve as baseline severity of suicidal wishes and plans, and degree
of depression symptoms. Questionnaires will be stored in locked drawer's in the locked office the
Division Officers in the Emergency Department, the Inpatient Mental Health ward, or the study
coordinator.
 
Once the patient is deemed medically cleared by the treating physician, the study treatment will be
ordered by an ED provider, per the randomization schedule, and administered by an ED nurse
(Please see below for more detailed methodology).  Those in the experimental arm will be treated
with 0.5 mg/kg IV infusion of ketamine over 40 minutes. Those in the control arm will be treated
with 100 cc Saline infusion over 40 minutes. (Table 1) Since there are no pharmaceutical treatment
specific for acute suicide, it is in accordance to the Declaration of Helsinki (DOH) to utilize a saline
placebo control. Vitals will be checked every 5 minutes during infusion. Questionnaires will be
repeated at four time points for both arms, once in the ED before drug administration, one at 4
(+/-1) hours post-infusion, whether in the ED or the psychiatric unit, another 24-36 hours after the
infusion in the inpatient psychiatric unit, and lastly one-week (+1 day) post treatment by phone
call.
 
Research Objective
 
The primary objective of this investigation is to identify utility of Ketamine as a clinically effective
and efficient adjunctive treatment modality for the acutely suicidal patient in the ED setting.
Secondary objective is to investigate prospectively if the anti-suicidal effects are able to have lasting
effect up to one week within the vulnerable period post discharge. 
 
Detail How Many Groups or Arms are in the Study and what each Receives
 
 This study is designed as an RCT with two arms, Experimental vs. Placebo. Table 1 shows a
detailed description of both arms. This will be a triple masked study. The patient, healthcare
providers, and outcomes assessor will be blinded.
 
            Table 1: Description of Experimental Arms
Arm
Intervention/Treatment
Experimental:
Ketamine
 
Drug: Ketamine (Ketalar)
Single dose IV ketamine, 0.5 mg/kg in 100 cc Normal Saline,
infused over 40 minutes
Other Name: N-methyl-D-aspartate (NMDA) glutamate
receptor antagonist
Placebo: Saline
Drug: Normal Saline (NS)
100 cc infused over 40 minutes


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Randomization Procedures
 
Randomization will be done through permuted block randomization and stratified for history of
mood disorder (e.g., major depression, bipolar disorder, dysthymia). Due to the small size of this
study, block randomization will ensure an equal number of treatment and controls.52
Randomization can lead to unbalanced groups with respect to prognostic factor.52 Because 60% of
those who commit suicide have a mood disorder, this study will be stratified by this prognostic
factor.52 This computer-generated list,54 will provide a subject identifier. This list of subject
identifier and procedure status will serve secondarily as an audit trail
 
Methods and Materials
 
All procedures in the management of the acutely suicidal patient will be in accordance with the
standard of care, which includes a focused history and physical by an Emergency Medicine
physician. Figure 1 demonstrates the flow of investigational procedures. The EM provider shall
medically screen the patient and include appropriate ancillary studies. For example, if a patient is
altered, intoxicated, sick-appearing, or exhibiting a clinical toxidrome, standard labs, EKG, or
imaging will be ordered per standard of care.  All female patients will have a urine HCG
documented. Then, screening for admission to the psychiatric department will be done by the
mental health liaison. This standard procedure will serve secondarily as the pre-screening method
for this investigation. This will minimize duplication of work.
 
Once the patient is deemed “to be admitted to the psychiatric unit,” the physician will check the
Electronic Medical Records (EMR) for inclusion and exclusion criteria. If a patient’s current
medication has a possible interaction with ketamine, the ordering provider will consider consulting
with the inpatient pharmacist about possible contraindications, which will be documented in the
chart. Once screened as a potential subject for the study, the patient will be approached for
consent. Consent explaining the research protocols, benefits, and risks will be obtained once by a
member of the investigative team. Consent will be obtained from a clinically sober intervention-
eligible patient, who is accepted to inpatient psychiatry. It will be obtained while in the ED. Subjects
will consent on an individual basis. Consent will be documented on a standardized consent form
approved by the IRB. Any female patient will undergo a pregnancy test to verify eligibility.
 
Once the patient is enrolled, the physician will calculate the dosage based on actual weight70,71
and place the order in the electronic medical record. The emergency department nurse assigned to
the care of the patient will fax the order to the pharmacy. At this point, the pharmacy will follow the
randomization instruction and schedule, and undergo three safety checks per pharmacy protocol.
(Appendix D: Randomization List & Instructions.) The medication will be treated as a controlled
substance and will require a nurse or clinician to pick it up from the inpatient pharmacy. 
 
To attain a psychometric baseline, the patient will complete the BSSI and MADRS, on paper forms.
After completion of baseline, the clinician will administer a single dose of IV ketamine, per
experimental protocol procedure. The specific dose and route of administration were selected based
on average dosage and administration from meta-analysis studies.5,41 A bolus of ketamine was
another common route of administration. However, there is no statistical significance between this
and the one selected.51 This study will not require any wash out periods or concomitant dosing
regimens. This dosage and infusion regimen is not considered sedation.
 
During ketamine infusion, vitals will be checked q5min with serial pulse and blood pressure
measurements, and patient will have continuous pulse oximetry (Pox), with all vitals connected to
monitors at the nurse’s and doctor’s stations. In addition, an attendant will be present at all times
as per suicidal patient protocol. Treatment will be stopped if pulse or systolic blood pressure
increases > 25% of baseline, respiratory rate is sustained at < 7, Pox decreases below 92%, or if
severe psychomimetic effects or agitation present.57
 
If treatment is stopped before completion for any reason, the patient will be dropped from the
study, and their symptoms will be treated as per usual protocol of the physician. For instance, for
severe psychomimetic effects and agitation, benzodiazepines such as midazolam could be
considered. If a negative side effect occurs and treatment is stopped, it will be reported to the
research monitor immediately.
 
Post assessment psychometric testing will be repeated at three time points for both arms. The first
time point will be 4 hours post treatment, which is the standard time to evaluate acute response to
ketamine.51 This may be collected in the ED or in the Psychiatric Unit. Subsequent questionnaires
will be completed either in the ED or in the Psychiatric Unit. ED nurses giving report to the
Psychiatric Unit will indicate that the patient is enrolled in the study, and give the time of
administration of the study intervention and will indicate when the next questionnaire should be
completed. Based on the literature, 24 hours post treatment, our second time point is when half of
patients treated with a single dose of IV ketamine have shown reduction in SI.24
 
Finally, patients will perform psychometric tests, ideally, one-week post infusion. They will be called
at their phone number on file. The follow up BSSI will be administered by a study evaluator.58
Forms will be filled out, placed in trial mailbox, data transferred onto spreadsheet.


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Potential difficulties:
1. Continuation/Concomitant use of psychotropics influence the same neurotransmitter as
ketamine, making it difficult to discern direct effects of ketamine.
2. Heterogeneity of patients, enhances generality, but reduces confidence in any conclusions
drawn.
3. Difficulty lie inherently in treating those with mood instability and difficult-to-treat patients. 
a.) Those with mood disorders (BD & MDD) may metabolize ketamine differently59
Potential limitations
1. Sample size
2. Need for replication
3. Placebo effect
4. Enrollment is only available when eligible study personnel are present
5. Depression is a placebo-responsive illness.60 Because suicide risk varies with the nature of
depressive or mood disorder,61 the placebo effect is uncertain. Increased placebo effect
increases variance and poor signal detection.
6. Lack of translational studies, especially in neurobiology of suicide.
7. SI measures suicide risk. However, it does not measure other psychological constructs
associated with increased suicidal risk, such as hopelessness.61
8. Lack of variety of outcome measure limits the study.
9. There is no established clinical biomarker predictor of ketamine.62
 
Figure 1: Flow of Experimental procedure
Experimental Procedure
1. Baseline evaluation of suicidal severity (BSSI) & degree of depressive symptoms (MADRS-S)
will be evaluated through self-administered questionnaires.
2. The experimental and placebo arms will receive a single dose of IV ketamine, 0.5 mg/kg in
100 cc NS or 100 cc of NS infused over 40 minutes.
3. Post ketamine re-evaluation of outcome measures at four and twenty-four hours will
determine clinical effectiveness of ketamine intervention
4. Inspection of admission and transfer time provides time measurement for LOS. This
secondary measure is needed to determine efficiency of intervention.
5. Post ketamine re-evaluation of outcome measure at one-week post infusion will elucidate
ketamine’s durability of effect.
Table 2: Description of activities at time points during the study
 
Study Visit 1
Baseline (t0)
Study Visit
1
4 hours (t1)
Study Visit 1
24 hours (t2)
Study Visit 2
1 week (t3)


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Eligibility review and
confirmation
X
 
 
 
Education regarding
research & Informed
Consent signed
X
 
 
 
History & Physical
X
 
 
 
Randomization
X
 
 
 
Dispense study drug
X
 
 
 
IV Ketamine
X
 
 
 
Vital Signs & ADR*
monitored
X
X
X
 
Review adverse events
X
X
X
 
Psychometric testing
X
X
X
X
*ADR: Adverse drug reaction
 
 
 
10.2   Data Collection:
Describe all the data variables, information to be collected, the source of the data, and how the
data will be operationally measured.
Research Material to Be Collected
1. The protocol requires patients to submit the following data:
1. Phone number and email
2. To measure SI severity, Self-administered BSSI (Appendix D: Sample BSSI)
3. Level of depression shall be measured by the self-administered version of
Montgomery-Åsberg Depression scale (MADRS-S). (Appendix D: MADRS-S)
2. The following information are obtained per standard of care, and will be collected through
chart review:
1. Medical history
1. Psychiatric history
2. Current and or Previous Diagnoses
3. Current/recent antidepressant medication
4. Current psychotropic medications
2. Time stamps (admission & transfer)
3. The following additional information will be collected
1. Class: military or civilian
2. Number of previous suicide attempts
3. History of self-harm
4. Recent use of antidepressants
5. Any applicable ancillary studies such as labs or imaging modalities
6. Appendix D: Sample Data Collection Sheet
4. Identifier will be maintained in a spreadsheet that correlates subject identifier number and
subject name. This will exist in privileged shared folder that only Investigators have
permission to access. Data sheets will be coded such that only subject identifier numbers will
exist on them.
5. Waiver of Authorization for the Use of PHI will not be necessary because request for access
of medical history for research purposes is a component of the consent document. A
separate authorization for the use of email in the one week follow up will also be requested
at the time of consent.
Data Collection Tools
1. Pearson’s BSSI paper form
2. MADRS-SI paper form
3. EMR for chart review
4. Excel for data sheets
 


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10.3   At any point in the study, will you request, use, or access health information in any form, including
verbal, hard copy and electronic?
 Yes   
 No
10.4   Review the definitions below and respond to the following two questions.  If you are not sure of the
answers, email DHA.PrivacyBoard@mail.mil for assistance.   The Military Health System (MHS) is
defined as all DoD health plans and DoD health care providers that are organized under the
management authority of, or in the case of covered individual providers, assigned to or employed by,
the Defense Health Agency (DHA), the Army, the Navy, or the Air Force   MHS workforce members are
employees, volunteers, trainees, and other persons whose conduct, in the performance of work for the
MHS, is under the direct control of the MHS, whether or not they are paid by the MHS.   MHS business
associates are persons or entities that provide a service to the MHS and require protected health
information (PHI) to provide the service.
Are you an MHS workforce member?
Yes, I am an MHS workforce member 
No, I am not an MHS workforce member 
Are you an MHS business associate?
Yes, I am an MHS business associate 
No, I am not an MHS business associate 
10.5   Have you consulted with an MHS data expert to determine the data elements required for your study?
Consulting with a data expert often saves time later in the compliance process because the data
expert can advise on the data available in the numerous MHS information systems, the quality of
that data and the methods for encrypting and collapsing data.  To schedule a consult with an MHS
data expert, send an email to: (DHA.PrivacyBoard@mail.mil)
Yes, then complete the questions below according to the data consult 
No, then complete the questions below according to the best of your knowledge 
10.6   Indicate how you will request data from the MHS.  Select all that apply.
Talking with MHS health care providers or MHS health plans about specific research participants
Obtaining MHS hard copy records specific to research participants
Obtaining data from an MHS information system(s)
10.7   If you are obtaining data from an MHS information system(s), indicate whether you plan to receive a
data extract or whether you plan to access an MHS information system directly to create a data set.
A data extract is when the MHS or a contractor provides the data set directly to the researcher. 
When receiving a data set through data extract, the researcher may indicate whether the data
elements should be provided as is, encrypted or collapsed.  In contrast to a data extract, access to
an information system means that the researcher may directly access an MHS information system
and create a data set for the research study
Data Extract
Access
10.8   Do you intend to request de-identified data from the MHS in your research study? 
There are different two methods for de-identifying data pursuant to HIPAA:
1) Safe Harbor Method: Removing all of the identifiers listed in Table 1 below, provided that the
researcher does not have actual knowledge that the remaining data can be used alone or in
combination with other information to identify the individual who is the subject of the information


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2) Statistical Method: An expert, with appropriate knowledge of and experience with generally
accepted statistical and scientific principles and methods for rendering information not individually
identifiable, determines that the data is not individually identifiable
  Yes   
  No
10.9   Indicate the MHS information system(s) from which you will seek to obtain data
If you do not know which system(s) contains the data elements you need, refer to the Guide for
DoD Researchers on Using MHS Data or request guidance from an MHS data expert at:
DHA.PrivacyBoard@mail.mil.
 
Below is a list of commonly used MHS systems. If the system from which you seek to obtain data is
not listed below, list the name of the system in the “Other MHS Systems” category below
PHI Systems:
MHS Information System
Requesting Data
:
AHLTA
:
Yes
:
ESSENTRIS
:
Yes
PII-Only Systems:
MHS Information System
Requesting Data
De-Identified Data & Other Systems:
Information System
Requesting Data
Other MHS System (May include PII and/or
PHI)
List other system here:
T-SYSTEMS
:
Yes
10.10   Do you intend to merge or otherwise associate the requested data with data from any sources outside
of the MHS, including other DoD systems that are not part of the MHS?
Yes, will merge data  
No, will not merge data 
10.11   Indicate the data elements about research participants or relatives, employers, or household members
of the research participants that you will request from MHS hard copies or from MHS information
systems.
If you will merge data, also indicate non-MHS data elements about research participants or relatives,
employers, or household members of the research participants that you will have access to in any
form or medium.
Data Element(s)
MHS
Non-MHS Systems
MHS Hard Copies
1. Names
2. Postal address
with only town, city,
state and zip code


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3. Postal address
with all geographic
subdivisions smaller
than a state,
including street
address, city, county,
precinct, zip code
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
Census: 1) the
geographic unit
formed by combining
all zip codes with the
same three initial
digits contains 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
4. Dates including all
elements (except
year) directly related
to an individual,
including birth date,
admission date,
discharge date, and
date of death
5. Ages over 89 and
all elements of dates
(including year)
indicative of such
age, unless you will
only request a single
category of “age 90
or older”
6. Telephone
numbers
7. Fax numbers
8. Electronic mail
addresses
9. Social Security
numbers (SSNs)
10. Medical record
numbers


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11. Health plan
beneficiary numbers
12. Account numbers
13. Certificate/license
numbers
14. Vehicle identifiers
and serial numbers,
including license
plate numbers
15. Device identifiers
and serial numbers
16. Web Universal
Resource Locators
(URLs)
17. Internet Protocol
(IP) address numbers
18. Biometric
identifiers, including
finger and voice
prints
19. Full-face
photographic images
and any comparable
images
20. Any other unique
identifying number,
characteristic, or
code (Diagnosis,
DEERS ID, EDI-PI,
Rank)
If you are obtaining SSNs, provide a justification as to why and explain why a substitute cannot be
used
10.12   Do you believe it is possible for the MHS data to become identifiable because of triangulation, a small
cell size, or any unique data element(s)?
Triangulation means using different data elements that are not themselves identifiable but that
when combined can be used to identify an individual. For example, triangulation would use rank
and race together to determine the identity of an individual with a particular health condition.
 
Small cell size means that there is only a small number of eligible individuals that satisfy the
category description. Guidance for acceptable cell size is available from the Centers for Medicare
and Medicaid Services. For example, the rank category of four star generals with a particular


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diagnosis may be less than 30, so the rank category may need to be expanded to include lower
ranks.
 
A unique data element includes any unique features that are not explicitly enumerated in the
categories of data in rows 1 – 20 of the table above (in Section 10.10), but that could be used to
identify an individual. Unique data elements include characteristics that are not themselves
identifying, such as the rank of general or admiral, or a race or gender, but within the context of
other information could be identifiable.
Yes, I believe there is a reasonable possibility the MHS data will become identifiable 
No, I believe there is no reasonable possibility the MHS data will become identifiable 
10.13   Have you completed and uploaded an appropriate HIPAA document ( i.e. HIPAA Authorization will be
obtained or Waiver/alteration of HIPAA Authorization is being requested)?
Yes 
No 
N/A 
10.14   Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for this
Study:
Include in this section the plan for acquiring data (both electronic and hard copy), access during the
study, data/specimen storage and length of time stored, shipment/transmission, and the plan for
storage and final disposition at the conclusion of the study. Describe any data agreements in place
for accessing data within and/or outside of your institution (e.g., Data Sharing Agreement, Data
Use Agreement, Business Agreements, etc.)
Protection and Security of Data and Identifying Information
1. Handling of paper questionnaires will be as follows:
1. Questionnaires will be placed in trial mailbox.
2. They will be kept in a locked box in a locked office, until they can be scanned into a
secure digital folder.
2. Digital protection:
1. Data will be stored in accordance to Navy HRPO policy and data storage policies
2. Password protection: Each patient will be assigned a subject identifier during
randomization. This file will be password protected. 
1. The data will remain on a study team member's computer which is only
accessible with a CAC card. 
3. De-Identification: Only subject identifiers will be used in psychometric testing.
Additionally, as shown in Figure 2, the subject identifier will be the only means to
connect to various data related to the subject. The Subject identifier will be stored
separate from all de-identified information.
4. Separation of data: Data collection sheets will be separated into different files, as
shown in Table 3.
 
Figure 2: Subject Identifier connection to other data sheets for a participant
 
Table 3: Security Management breakdown of Data Collection Sheets
Spreadsheet
Contents
Who has access?
Security
Subject
Identifier key
Subject identifier code & Patient
name
NMCCL Investigators
Password
protected
Demographics Email, gender, DOB, age, number of
previous attempted suicide, history
of self-harm, psychiatric history,
Only Investigators
Separate file


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recent antidepressant use, current
psychotropic medication,
classification (military/civilian)
LOS
Time of admission & transfer
Only Investigators
Separate file
BSSI
BSSI results
Only Investigators
Separate file
MADRS
MADRS results
Only Investigators
Separate File
 
 
(6)        Disposition of Data and Identifying Information at End of Project
 
Specified data will be stored digitally in accordance to Navy regulation. All other
documents will be disposed per Navy Instruction at the conclusion of the storage
period. In accordance to DHHS protection of human subject’s regulation, IRB
activities and records will be maintained in digitally secure location for at least
three years (45 CFR 46.115(b)).  In accordance to HIPAA requirements, data that
fall under this regulation will be stored for at least six years.
 
10.15   Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for
Future Research:
If the study involves collecting, storing, or banking human specimens, data, or documents (either
by the Investigator or through an established repository) for FUTURE research, address. How the
specimens/data will be used, where and how data/specimens will be stored (including shipping
procedures, storage plan, etc.), whether and how consent will be obtained, procedures that will
fulfill subjects’ request as stated in the consent, whether subjects may withdraw their
data/specimens from storage, whether and how subjects may be recontacted for future research
and given the option to decline, whether there will be genetic testing on the specimens, who will
have access to the data/specimens, and the linkage, the length of time that data/specimens will be
stored and conditions under which data/specimens will be destroyed.
n/a
11.0
Statistical/Data Analysis Plan
11.1   Statistical Considerations:
List the statistical methods to be used to address the primary and secondary objectives, specific
aims, and/or research hypotheses.  Explain how missing data and outliers will be handled in the
analysis.  The analysis plan should be consistent with the study objectives.  Include any sub-group
analyses (e.g., gender or age group).  Specify statistical methods and variables for each analysis. 
Describe how confounding variables will be controlled in the data analysis
STATISTICAL ANALYSIS
All data analysis will be carried out using SPSS ® Version 25. Tableau Desktop 2018.1 will be used
to augment the creation of graphs. See 3.7.C for power calculation and sample size derivation. If
subjects do not complete a baseline, they will not be incorporated in the analysis. A recent clinical
study validated that an average of four items from the SSI, with a cut-off of ≥ 2, is sufficient in
classifying patients as high risk vs. low risk.61 Therefore, any patient who does not complete at
least four items on the SSI during each of the post administration time points will be excluded from
the study. Missing data will be excluded from analysis as long as the degree of freedom permits.
 The type of data analysis will be in accordance to the Test plan, Table 6. Each arm of the trial will
be considered a “group.” Appendix D: Sample Data Collection Sheet describes demographic data
points as well as measurement scale of each of the below variables. Stratification factors will be
accounted for as a covariate in multivariant models.54
 
11.2   Sample Size:
62


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11.3   Total number of subjects requested (including records and specimens):
62
11.4   If you are recruiting by study arm, please identify the arms of the study and how many subjects will be
enrolled in each arm
Experimental arm (Ketamine) - 31 subjects
Placebo arm (saline) - 31 subjects
11.5   Please provide a justification for your sample size
Number of Subjects and Justification
 
This trial aims to have a minimum of 62 individuals. N calculation was done using R's built
in statistical power pack.63 (Appendix D: N Calculation) Significance level and power used were the
standard 0.05 and 0.8 respectively. Prior studies showed very large effect sizes. Their Cohen's d
within groups and between groups were 1.23 and 1.45 respectively.38 The power of a study
depends on effect size as well as sample size. Because their effect size is sufficiently large, they are
able to detect differences from even a small sample.
 When using this effect size, N calculations resulted in 8.5 to 11.4 individuals, which
correlates to 17 to 22.8 individuals. However, the design of our study varies from past studies, in
that we include a broader patient population. Instead of simply at individuals diagnosed with a
mood disorder.
Based on suggested Cohen's d values, in order to have a large effect size in the T-test and
ANOVA tests, N should be 25.5. In order to determine large correlations, N needs to be at least
28.2. This correlates to 52 to 56 subjects. Applying an estimated 10% subject dropout rate, the
estimated number of subjects needed for the study is 62. Full effect and sample size breakdown are
shown in Table 4.
 
Table 4: Effect and Sample Size Breakdown 
Test
Effect size
N
Two sample T-Test
Large (d =0.8)
25.5
Two sample T-Test
Medium (d = 0.5)
63.7
Two sample T-Test
Average within groups (d=1.23)
11.4
Two sample T-Test
Average between groups (d=1.45)
8.5
ANOVA
Large (f = 0.4)
25.5
ANOVA
Medium (f = 0.25)
63.7
 
 A Linear model will be used for analysis of repeat measures if sample size reach
74 subjects.  This model accounts for uneven spacing in repeated measures,
accounts for random effects, will provide a greater flexibility in analysis.64 The
ability of this analysis is limited by the degree of freedom, which is influenced by
the sample size. R separates the F test into two variables representing the degree
of freedom of the model and error, which are the numerator and the denominators
in the F test. In this test, the numerator (u) is the number of observations, and is
equal to p -1, where p is the number of predictors (sex, age, etc.…). The
denominator (v) is the degree of freedom of the error and is equal to n - p, where
n is the number of observations, or, in our case, subjects.64 Sample Calculation 1
was used to determine n need to power a model that would take into account
three to five predictors. (Table 5)
 
Sample Calculation 1:
u = p - 1 → u +1 = p
v = n - p → v + p = n
To solve for n:
v + u +1 = n
Table 5: N needed to power Linear model with a large effect size (f2 =
0.35)
Numerator (u)
Denominator (v)
n
2n


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5
37
43
86
4
34
37
74
3
31
35
70
11.6   Data Analysis Plan: Complete description: Background, Objectives, Design, Step by Step how the project
is going to be done, Data analysis plan:
Table 6: Test Plan of Data Analysis
Question to be answered
Type of
Analysis
Independent
(x)
Dependent
(y)
Relationship
Is there a difference effect of ketamine in
those who are high suicide vs. high
depressed?
McNemar test
High Suicide
High
depressed
Within
Is there a difference in the placebo between
the same two groups?
McNemar test
High Suicide
group
High Suicide
group
Within
Is there any difference between ketamine vs.
placebo on BSSI & MADRS?
One-way
MANOVA
Group
BSSI; MADRS
Between
Is there a difference in SI between Ketamine
vs placebo
2 Independent
sample t test
Group
BSSI @T4
Between
Is there a difference in depression between
Ketamine vs placebo
2 independent
sample t test
Group
MADRS @ T4
Between
Is there a difference in effect from placebo
when accounting for covariates?
 
MANCOVA
Fixed factor:
Group
 
Covariates:
Demographics
BSSI, MADRS
 
@ T4
Between
Is there a difference in effect from ketamine @
the different time points?
 
Mixed model
 
Or
 
Repeated
measure ANOVA
Fixed factor:
Group
 
 
BSSI
Within &
between
Is there a difference in group at the different
time points, when MADRS is a covariate?
Mixed model
Fixed factor:
Group
Covariates:
MADRS
BSSI
Within &
between
Is there a difference in group at the different
time points, when MADRS, and demographics
are considered? *
Mixed model
Fixed factor:
Group
 
Covariates:
MADRS,
demographics
BSSI
Within &
between
*This case requires a larger sample size.
 
 
12.0
Participant Information
12.1   Subject Population:


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Participants will be adults, whom are 18 years or older, military personnel or civilians eligible for
care in the military treatment facility.
 
 
12.2   Age Range:
Check all the boxes that apply. if the age range of potential subjects (specimens, records) does not
match the range(s) selected, please specify in the text box.
0-17
18-24
25-34
35-44
45-54
55-64
65-74
75+
12.3   Gender:
Male
Female
Other
12.4   Special categories, check all that apply
Minors /Children
Students
Employees - Civilian
Employees - Contractor
Resident/trainee
Cadets /Midshipmen
Active Duty Military Personnel
Wounded Warriors
Economically Disadvantaged Persons
Educationally Disadvantaged Persons
Physically Challenged (Physical challenges include visual and/or auditory impairment)
Persons with Impaired Decisional Capacity
Prisoners
Pregnant Women, Fetuses, and Neonates
Non-English Speakers
International Research involving Foreign Nationals - Headquarters Review is necessary
You must also consider the requirements of DoDI 3216.02, paragraph 7.e. 
You must also consider the requirements of DoDI 3216.02, Enclosure 3, paragraphs 7.e. and 12.
You must also consider the requirements of DoDI 3216.02, Enclosure 3, paragraph 7.e.
Depending on your intended subjects’ status, you may also need to consider the requirements of
DoDI 3216.02, Enclosure 3, paragraph 7.e.


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You must also consider the requirements of 32 CFR 219.111(b).
You must also consider the requirements of 32 CFR 219.111(b).
12.5   Inclusion Criteria:
Order
Number
Criteria
1 
Subject Inclusion and Selection Criteria
 
1. Patient demographics will consist of Active, Reserve, or retired military
personnel or their dependents.
Subjects must meet the following inclusion criteria:
2. Adult (18 to 89 years old)
3. Present with active SI
4. Deemed to being admitted to inpatient psychiatric unit
 
12.6   Exclusion Criteria:
Order
Number
Criteria
1 
Subject Exclusion
1. Age < 18 years old or > 89 years old
2. Currently presenting with psychosis as determined by mental health
consultant
3. Have a history of Cognitive disorder that would impair understanding of
consent
4. Have a personal/family history of Schizophrenia
5. Currently pregnant or nursing
6. Serious and unstable medical condition/problems
7. Inability to medically clear
8. Non-English Speakers
9. Civilian Humanitarians
10. Have previously enrolled in this study
 
 
 
13.0
Recruitment and Consent
13.1   Please describe the recruitment process, including how subjects will be identified and selected for the
study.    
        Subject Recruiting Methods
 
The method for subject recruitment is demonstrated in Figure 1. Explicitly they are
as follows:
1. Patient Identification/Pre-screening
1. Clinician will subjectively identify patients who present to the ED that express SI
2. Clinician or nurse reviews EMR for documented inclusion/exclusion criteria
3. Clinician will medically clear patient
2. Screening: The mental health liaison interviews patient, and along with the on-call mental
health provider, determines whether or not patient requires inpatient psychiatric
hospitalization.


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3. Screen positive: Eligible patients, who are being hospitalized on inpatient psychiatry, are
approached for consent. If intoxicated on presentation, they are approached when clinically
sober.
4. Consent is obtained:
1. Patient will complete BSSI & MADRS-S
2. Treatment is administered per protocol
3. Vitals and ADR are monitored
5. Potential medication contraindications will be indentified by treating physician, and a
pharmacy consult will be obtained at the physician’s discretion
 
13.2   Compensation for Participation:
 
Subjects enrolled in the study will not be compensated monetarily.
13.3   Please describe the pre-screening process. If no pre-screening, enter Not Applicable in the text editor
All procedures in the management of the acutely suicidal patient will be in accordance with the
standard of care, which includes a focused history and physical by an Emergency Medicine
physician. Figure 1 demonstrates the flow of investigational procedures. The EM provider shall
medically screen the patient and include appropriate ancillary studies. For example, if a patient is
altered, intoxicated, sick-appearing, or exhibiting a clinical toxidrome, standard labs, EKG, or
imaging will be ordered per standard of care. All female patients will have a urine HCG documented.
Then, screening for admission to the psychiatric department will be done by the mental health
liaison. This standard procedure will serve secondarily as the pre-screening method for this
investigation. This will minimize duplication of work.
 
 
13.4   Consent Process:   Revised Common Rule, Section 219.116:  General requirements for informed
consent, whether written or oral, are set forth in this paragraph and apply to consent obtained in
accordance with the requirements set forth in paragraphs (b) through (d) of this section. Broad consent
may be obtained in lieu of informed consent obtained in accordance with paragraphs (b) and (c) of this
section only with respect to the storage, maintenance, and secondary research uses of identifiable
private information and identifiable biospecimens.
Are you requesting a waiver or alteration of informed consent?
  Yes   
  No
Please explain the consent process:
Informed Consent Procedures
Research team members will review study procedures, potential risks and benefits of the study. 
Informed consent procedures will be conducted in private offices or exam rooms located in the ED.
In accordance to 32 CRF 219, under no circumstances will the supervisors or commanding officers
to the potential subject allowed to be present during the consent process. This is to ensure the
avoidance of undue influence or coercion that may stem from the nature of the superior-subordinate
relationship.
 
The patient will be approached for informed consent in accordance to with 21 CRF 50. They will be
provided with a written document that embodies the elements of the informed consent. The consent
will be presented orally to the subject with a witness. Once presented the subject will be given a
reasonable time to review the contents and inquire information. All questions will be answered by
the investigator obtaining consent. If consent is granted, the subject and the investigator will sign
the consent form. A copy of the informed consent document will be given to the subject, and the
original will be retained by the study investigator. This consent form will not be tied to any medical
or data records. Consent forms will be maintained in a research specific locked drawer located in an
investigator's/coordinator's office and only accessible by study the primary investigator, associate
investigators or coordinator.  The locked consent will be check by the P.I. or A.I. weekly.
 
In accordance with North Carolina State Law, if subjects are unable to consent for themselves due
to emergent situations or impaired status, a LAR will be approached for consent. In the context of
this study, subjects in these circumstances will be excluded from recruitment. If they are clinically
intoxicated, consent will not be sought until they are clinically sober. Decisionally impaired subjects
will not be approached for consent.


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Vulnerable Populations
 
Due to the fact investigations take place in the ED, vulnerable populations that will recruited are
persons in an emergency situation presents with situational cognitive vulnerabilities. Protections for
this process have been put in place during the selection, and informed consent process.
Furthermore, the selection of an interdepartmental research monitor will ensure the utmost care of
this vulnerable population.
 
Under the Common Rule, DoDI 3216.02 military members are not considered a vulnerable
population. However, due to the nature of hierarchical social structure they are more susceptible
than the general population. Protections for this population will be in place during the consent
process, and have been added to the consent verbiage.
 
 
13.5   DoDI 3216.02 requires an ombudsman to be present during recruitment briefings when research
involves greater than minimal risk and recruitment of Service members occurs in a group setting. If
applicable, you may nominate an individual to serve as the ombudsman.
N/A 
Propose ombudsman 
13.6   Withdrawal from Study Participation:
Explain the process for withdrawal and specify whether or not the subjects will be given the
opportunity to withdraw their data their data/specimens in the event they wish to withdraw from
the study
Per Informed Consent Form:
 
"If you choose to participate, you are free to ask questions or withdraw from the project at any time
without prejudice to your future care. Any new significant findings developed during the course of
the research, which may affect your willingness to participate further, will be explained to you.
Please notify Dr. Christine DeForest at 910-450-4840, Catherine Christian at
catherine.c.christian2.ctr@mail.mil or Andrea Brzuska at 910-449-1141 to ensure an orderly
termination process.
 
If you withdraw, you will no longer receive study drugs or treatments that are part of the study,
unless these are also part of your normal drugs or treatments. Your withdrawal will involve no loss
of benefits to which you are otherwise entitled. If you withdraw from this study, your data will be
included in the data analysis for this project."
14.0
Risks and Benefits
14.1  
Risks of Harm:
Identify all research-related risks of harm to which the subject will be exposed for each research
procedure or intervention as a result of participation in this study.  Consider the risks of breach of
confidentiality, psychological, legal, social, and economic risks as well as physical risks.  Do not
describe risks from standard care procedures; only describe risks from procedures done for
research purposes
List and Document Risks
The overall risk of an adverse event while using ketamine is very low, and
easily manageable. Low dose IV ketamine can cause:
1. Transient Psychedelic effects  – disturbances in visual and auditory perception, mood, body
image, and time.
2. Hemodynamic changes – increase in blood pressure and heart rate


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3. Psychotomimetic effects – mimicking the symptoms of psychosis, including delusions and
delerium
4. Narcosis
5. Hypersalivation
6. Nausea and vomiting
7. Anxiety and Paranoia
Respiratory depression, apnea, laryngospasm, hypotension, bradycardia, myocardial
infarction, central diabetes insipidus, anaphylaxis, increased intraocular pressure,
increased intracranial pressure, porphyria and death.
 
(2)        Justification of Risks
 
Ketamine holds a high degree of safety. In a review that describes over 70,000
patients only a single cardiorespiratory event of lasting significance was reported.
Fully dissociative patients maintain their pharyngeal reflexes.66
 
Risk
Justification & Mitigation
Transient Psychedelic effects
are disturbances in visual and
auditory perception, mood, body
image, and time. Patient may
experience feelings of floating,
conscious dreams, or
hallucinations.35 These effects
occur between 50 and 200 ng/ml
with more severe effects at higher
doses. 34
Dissociative symptoms are
transient and will peak at 40
minutes and resolve within 120
minutes. 26
 
To mitigate psychiatric
discomfort, pre-induction
coaching will be provided. This is
where the patient will be
informed that they may have
vivid dreams. 66
 
Signs of psychiatric discomfort
will be managed with titratable
sedatives (eg, midazolam) on an
as needed basis.
Hemodynamic changes are
extremely rare with ketamine use,
especially with such a slow infusion.
Will be monitored hourly. Mild
increases in heart rate can be
mitigated by sympatholytic
agents.
 
Treatment will be stopped if
pulse or systolic blood pressure
increases > 25% of baseline,
respiratory rate is sustained at <
7, or if severe psychomimetic
effects or agitation present.
Psychotomimetic effects33
Can be mitigated through slow
infusion or concomitant use of
benzodiazepines if needed
clinically.24
Narcosis (absence of verbal
response) 33 at 0.5 mg/kg. This
phenomenon is more likely with a
quicker infusion.
This will be lessened or negated
by mixing the dosage of
medication in 100cc of NS and
infusing slowly over 40 minutes.
Hypersalivation. Less likely at this
concentration and with slow
infusion.
This side effect can be addressed
with concomitant use of
glycopyrrolate if clinically
indicated. 24
Nausea and vomiting. Less likely
at this concentration and with slow
infusion. Generally, occur after
emergence from dissociative state.
66
 This side effect can be
addressed with use of
ondansetron if clinically
indicated. 68
Psychopathological symptoms65
such as difficulties in abstract
thinking, lack of spontaneity, and
decrease flow of conversation. This
phenomenon is more likely with a
quicker infusion.
This will be lessened or negated
by mixing the dosage of
medication in 100cc of Normal
Saline and infusing slowly over
40 minutes.
Anxiety and Paranoia65 can
present at 500 ng/ml. This
phenomenon is more likely with a
quicker infusion.
This side effect can be addressed
with use of a benzodiazepine if
clinically indicated.


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Acute Delirium can present at
high doses or too fast
administration of low doses (5 to 10
mg) 65
This will be mitigated by the low
dosage used in this investigation
coupled with the slower infusion
rate of 40 minutes and can be
treated with a benzodiazepine if
clinically indicated.
Transient respiratory
depression & Apnea. Extremely
Rare occurrence may occur with
rapid delivery or concomitant use of
midazolam.66
This will be mitigated through
appropriate weight-based
dosing, slow infusion, careful
monitoring of those on
concomitant midazolam.66
Other extremely rare, serious
adverse events have been
reported:
laryngospasm, hypotension,
bradycardia, myocardial
infarction, and death.
 
 Mitigation of these events will
be through continuous
hemodynamic monitoring
including pulse oximetry.66
 
For full list of possible adverse drug reactions see Patient Drug Handout in Appendix D.
 
14.2  
Measures to Minimize Risks of Harm (Precautions, safeguards):
For each research procedure or intervention, describe all measures to minimize and/or eliminate
risk of harms to subjects and study personnel
Minimization of Risks
 
In general, slow infusion of low-dose ketamine has been shown to significantly reduce reporting of
moderate to greater side effects, specifically hallucination s and feelings of unreality.67 We will be
excluding those patients most vulnerable to adverse events, such as those with a history of
psychosis, schizophrenia, or schizoaffective disorder. Because Ketamine is pregnancy category B,
they will be excluded from the study. Patients will also be excluded medically at the discretion of the
treating physician or if they are being involuntarily admitted. Vital sign monitoring every 5 minutes
will ensure adverse drug reactions are addressed promptly.
 
Although the dose used should not induce emergence reaction, it should be noted that transition to
conscious perception can be terrifying, and severe emergence reaction can be a traumatic
experience. This effect will be inherently mitigated through the low dosage used. Furthermore, pre-
induction coaching, slow infusion, and PRN administration of midazolam strategy will be used to
mitigate this potential adverse side effect.66
 
14.3  
Confidentiality Protections (for research records, data and/or specimens):
Describe in detail the plan to maintain confidentiality of the research data, specimens, and records
throughout the study and at its conclusion (e.g., destruction, long term storage, or banking).
Explain the plan for securing the data (e.g., use of passwords, encryption, secure servers, firewalls,
and other appropriate methods). If data will be shared electronically with other team
members/collaborators outside the institution, describe the method of transmission and safeguards
to maintain confidentiality. Explain whether this study may collect information that State or Federal
law requires to be reported to other officials or ethically requires action, e.g., child or spouse abuse
Protection and Security of Data and Identifying Information
1. Handling of paper questionnaires will be as follows:
1. Questionnaires will be placed in trial mailbox.
2. They will be kept in a locked box in a locked office, until they can be scanned into a
secure digital folder.


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2. Digital protection:
1. Data will be stored in accordance to Navy HRPO policy and data storage policies
2. Password protection: Each patient will be assigned a subject identifier during
randomization. This file will be password protected. 
1. The data will remain on a study team member's computer which is only
accessible with a CAC card. 
3. De-Identification: Only subject identifiers will be used in psychometric testing.
Additionally, as shown in Figure 2, the subject identifier will be the only means to
connect to various data related to the subject. The Subject identifier will be stored
separate from all de-identified information.
4. Separation of data: Data collection sheets will be separated into different files, as
shown in Table 3.
 
Figure 2: Subject Identifier connection to other data sheets for a participant
 
Table 3: Security Management breakdown of Data Collection Sheets
Spreadsheet
Contents
Who has access?
Security
Subject
Identifier key
Subject identifier code & Patient
name
NMCCL Investigators
Password
protected
Demographics
Email, gender, DOB, age, number of
previous attempted suicide, history
of self-harm, psychiatric history,
recent antidepressant use, current
psychotropic medication,
classification (military/civilian)
Only Investigators
Separate file
LOS
Time of admission & transfer
Only Investigators
Separate file
BSSI
BSSI results
Only Investigators
Separate file
MADRS
MADRS results
Only Investigators
Separate File
 
 
(6)        Disposition of Data and Identifying Information at End of Project
 
Specified data will be stored digitally in accordance to Navy regulation. All other
documents will be disposed per Navy Instruction at the conclusion of the storage
period. In accordance to DHHS protection of human subject’s regulation, IRB
activities and records will be maintained in digitally secure location for at least
three years (45 CFR 46.115(b)).  In accordance to HIPAA requirements, data that
fall under this regulation will be stored for at least six years.
14.4  
Potential Benefits:
Describe any real and potential benefits of the research to the subject and any potential benefits to
a specific community or society
If the individuals in the research are considered experimental subjects (per 10 USC 980), and they
cannot provide their own consent, the protocol must describe the intent to directly benefit all
subjects
Benefits
 
1. It is possible that subjects may not receive any benefit from participation especially those in the
placebo arm. However, it is likely they will experience a small degree of benefit from the placebo
effect. 


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2. Subjects in the experimental arm have the potential to experience a decrease in SI, and LOS in
the ED. Thus, improving their quality of care. The experimental protocol may have a positive impact
on their mental state post discharge. Thereby decreasing their risk for repeat attempts.
3. Subjects enrolled in the study will not be compensated monetarily.
 
14.5  
Privacy for Subjects:
Describe the measures to protect subject’s privacy during recruitment, the consent process, and all
research activities, etc.
Informed consent procedures will be conducted in private offices or exam rooms located in the ED.
In accordance to 32 CRF 219, under no circumstances will the supervisors or commanding officers
to the potential subject allowed to be present during the consent process. This is to ensure the
avoidance of undue influence or coercion that may stem from the nature of the superior-subordinate
relationship.
 
A copy of the informed consent document will be given to the subject, and the original will be
retained by the study investigator. This consent form will not be tied to any medical or data records.
Consent forms will be maintained in a research specific locked drawer located in an
investigator's/coordinator's office and only accessible by the study primary investigator, associate
investigators, or coordinator.  The locked consent will be check by the P.I. or A.I. weekly.
14.6  
Incidental or Unexpected Findings:
Describe the plan to address incidental findings and unexpected findings about individuals from
screening to the end of the subject’s participation in the research. In cases where the subject could
possibly benefit medically or otherwise from the information, state whether or not the results of
screening, research participation, research tests, etc., will be shared with subjects or their primary
care provider. State whether the researcher is obligated or mandated to report results to
appropriate military or civilian authorities and explain the potential impact on the subject
 
In the case of incidental findings, it will be at the discretion of the PI whether or not to inform the
subjects of these findings.
15.0
Study Monitoring
15.1   Your study requires either Data and Safety Monitoring Plan (DSMP) or a Data and Safety Monitoring
Board (DSMB).
DSMP 
DSMB 
Both 
Not Applicable 
16.0
Reportable Events


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16.1   Reportable Events: Consult with the research office at your institution to ensure requirements are met.
Describe plans for reporting unexpected adverse events and unanticipated problems. Address how
unexpected adverse events will be identified, who will report, how often adverse events and
unanticipated problems will be reviewed to determine if any changes to the protocol or consent form
are needed and the scale that will be used to grade the severity of the adverse event. 
Consult with the research office at your institution to ensure requirements are met
 
• Describe plans for reporting expected adverse events. Identify what the expected adverse events
will be for this study, describe the likelihood (frequency, severity, reversibility, short-term
management and any long-term implications of each expected event)
 
• Describe plans for reporting unexpected adverse events and unanticipated problems. Address how
unexpected adverse events will be identified, who will report, how often adverse events and
unanticipated problems will be reviewed to determine if any changes to the research protocol or
consent form are needed and the scale that will be used to grade the severity of the adverse event
ADVERSE EVENT MANAGEMENT AND REPORTING
Unanticipated problems involving risk to subject or others, serious and unexpected adverse
experiences related to participation in the study and all subject deaths will be promptly reported in
accordance with the requirements of the Naval Medical Center Camp Lejeune Institutional Review
Board. The local site PI and/or overall study PI will report all serious adverse events (SAE) occurring
among enrolled subjects to the NMCCL IRB within 24 hours of the discovery of the adverse event.
The PI will submit an internal adverse event report memorandum to the IRB. Unexpected (but not
serious) adverse events occurring among enrolled subjects which, in the opinion of the local site PI
or overall study PI, are possibly related to participation in the protocol, will be reported by the local
site PI and/or overall study PI within 24 hours to the IRB using this same procedure. A summary of
all adverse events will be submitted along with the annual continuing review report.
 
Serious adverse events will be addressed through standard emergency resuscitative care (Table 5)
will be rendered. The IRB will be notified within 24 hours of any case of serious adverse events.
 
Table 5: Rapid overview for the management of ketamine intoxication69
Clinical presentation
Impaired consciousness is the most common presentation, although ketamine intoxication may cause
a range of central neurologic symptoms, from mild agitation to hallucinations; mild tachycardia and
hypertension often occur
Massive overdose can cause coma or apnea
Laryngospasm and heavy salivation may infrequently occur during intravenous use, even with
standard doses; laryngospasm is rare but occurs most often in infants
Vertical or rotatory nystagmus may occur
Diagnostic testing
Diagnosis of ketamine intoxication is based on history and clinical evidence; no readily available
definitive laboratory test exists
Obtain fingerstick glucose, acetaminophen and salicylate concentrations, electrocardiogram, and
pregnancy test in women of childbearing age
Management
Secure airway, breathing, and circulation
Laryngospasm and respiratory depression
Generally, resolve with noninvasive support (e.g., bag-mask ventilation; oxygen); endotracheal
intubation is rarely required
Salivation that compromises respirations or interferes with procedures
Treat with glycopyrrolate (5 mcg/kg, may be repeated once after five minutes)
Psychomotor agitation
Treat with benzodiazepines (e.g., intravenous doses of diazepam 0.1 mg/kg or in adults 5 to
10 mg, or lorazepam 0.05 mg/kg or in adults 1 to 2 mg) until the desired level of sedation is
achieved
Butyrophenones (e.g., haloperidol, droperidol) and other antipsychotic agents should not be
used to treat agitation
Disposition


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Patients with uncomplicated ketamine toxicity may be observed and discharged when symptoms
have resolved
 
17.0
Equipment/non-FDA Regulated Devices
17.1   Does the study involve the use of any unique non-medical devices/equipment?
  Yes   
  No
18.0
FDA-Regulated Products
18.1   Will any drugs, dietary supplements, biologics, or devices be utilized in this study?
Drugs
Dietary Supplements
Biologics
Devices
N/A
18.2   Drugs, Dietary Supplements and Biologics/Vaccines details:
Are drug(s) in this research being used in accordance to the approved labeling?
Are drug(s) in this research being used in a manner other than its approved labeling?
Enter Dietary Supplements and Biologics/Vaccines in the Drug Information table. Complete all
relevant fields in the table (“Protocol Drug Details” screen). If the question is not relevant, leave
the question blank and/or do not change the default selection.
View
Details
Drug Name
FDA Approved
A new drug or a
new use of
approved drug:
IND Number
Trade Drug
Name: ketamine
Generic Drug
Name:
Investigational
Drug Name:
Yes 
No 
 
Trade Drug Name:
ketamine 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the
manufacturer or source of
investigational drug/biologic:
Mylar Institutional LLC, Rockford, IL  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new use
of an already approved drug
No  
Is an IND necessary
No  
IND Number
 


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Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is
not required, Please provide a
rationale for exemption:
I. It is not intended to be reported to FDA in support of a new
indication for use or to support any other significant change
in the labeling for the drug; RESPONSE: It will not be
reported to the FDA for a new indication or to change labeling
ii.it is not intended to support a significant change in the
advertising for the product; RESPONSE: we do not intend to
change the advertising for the product. iii.it does not involve
a route of administration or dosage level, use in a subject
population, or other factor that significantly increases the
risks (or decreases the acceptability of the risks) associated
with the use of the drug product; RESPONSE: it will not
significantly affect dosing or risks of using medication iv.it is
conducted in compliance with the requirements for IRB
review and informed consent [21 CFR parts 56 and 50,
respectively]; RESPONSE: it has been reviewed by an IRB
and informed consent will be obtained v.it is conducted in
compliance with the requirements concerning the promotion
and sale of drugs [21 CFR 312.7]; and RESPONSE: will be
conducted in compliance with 21 CFR 312.7 vi.it does not
intend to invoke 21 CFR 50.24. RESPONSE: does not intend
to invoke 21 CFR 50.24  
Are you currently using this IND
in another research project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
0.5mg/kg in 100 cc normal saline  
Frequency:
single IV infusion over 40 minutes  
Route of administration:
IV  
Will the investigational
pharmacy be dispensing?
No  
If the source is not a FDA
licensed facility, provide details
regarding the purity, quality,
stability and sterility of the
investigational drug/biologic:
NMCCL pharmacy  
Identify who will be preparing
the investigational drug/biologic
for administration and describe
in detail how it will be prepared:
Pharmacy staff  
Indication(s) under
Investigation:
suicidal ideation  
Where will the drug be stored
NMCCL pharmacy  
Drug Storage Restrictions
(including temperature, etc.):
Stored according to NMCCL pharmacy standards  
Administration Instructions:
standard administration  
Possible Untoward Effects, Their
Symptoms & Treatment:
see protocol sections regarding risks  
Potential or Actual Antidotes for
Excessive or Adverse Drug
Effect:
see protocol for adverse reaction treatment  
Contraindications and
Interactions, If Known:
see protocol for contraindications  
Investigators Authorized to
Prescribe:
Clinicians with ED priveledges  
18.4   Reporting Requirements for FDA-regulated research under IND and IDE:


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Describe the process for complying with FDA regulatory requirements for adverse event reporting
and adverse device effects reporting to the sponsor
18.5   Sponsor (organization/institution/company):
N/A
If applicable, provide sponsor contact information:
19.0
Research Registration Requirements
19.1   ClinicalTrials.gov Registration:
Registration is not required 
Registration pending 
Registration complete 
“NCT” number:
NCT04260607
19.2   Defense Technical Information Center Registration (Optional):
Registration is not required 
Registration pending 
Registration complete 
20.0
References and Glossary
20.1   References:
      BIBLIOGRAPHY FOR BACKGROUND SECTION AND RESEARCH PLAN
1. Violence Prevention [Internet]. Centers for Disease Control and Prevention, National Center
for Injury Prevention and Control, 2018 [cited 2018 July 1]. Available from:
http://www.cdc.gov/injury.
2. Armed Forces Health Surveillance C. Deaths by suicide while on active duty, active and
reserve components, U.S. Armed Forces, 1998-2011. 2012 [cited 2018 May 21]. MSMR
[Internet]. 19(6):7–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22779434.
3. Owens PL, Fingar KR, Heslin KC, Mutter R, Booth CL. Emergency Department Visits Related
to Suicidal Ideation, 2006–2013. 2017. HCUP Statistical Brief #220. Available from:
https://www.hcup-us.ahrq.gov/reports/statbriefs/sb220-Suicidal-Ideation-ED-Visits.pdf
4. Ting SA, Sullivan AF, Boudreaux ED, Miller I, Camargo CA. Trends in US emergency
department visits for attempted suicide and self-inflicted injury, 1993-2008. 2012. Gen Hosp
Psychiatry. 34(5):557–65. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428496/pdf/nihms367860.pdf.
5. Reinstatler L, Youssef NA. Ketamine as a Potential Treatment for Suicidal Ideation: A
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20.2   Abbreviations and Acronyms: