Conditions: Pain Postoperative Depression
Keywords: perioperative period pain gastric bypass
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 90
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, two-arm parallel, single-center study. One hundred subjects (50 in each arm) will be enrolled. Subjects, between the ages 18 and 65, undergoing laparoscopic gastric bypass or sleeve gastrectomy will be recruited and consented during the preadmission visit prior to surgery.

Detailed description:
This is a randomized, double-blind, placebo-controlled, two-arm parallel, single-center study. One hundred subjects (50 in each arm) will be enrolled. Subjects, between the ages 18 and 65, undergoing laparoscopic gastric bypass or sleeve gastrectomy will be recruited and consented during the preadmission visit prior to surgery. Eligible subjects will be randomized to one of the two treatment group in a 1:1 ratio to receive either IV ketamine (0.4mg/kg) or matching placebo. Both men and women will be recruited, and there is no limitation as to racial and ethnic origin. In the PACU, patients will receive either 0.4mg/kg IV ketamine or placebo. All patients will also receive standard post-anesthetic monitoring and care, as well as routine care after transfer out of the PACU. Patients are followed until the date of discharge, and endpoints (see below) are collected from patient reports as well as from medical charts. During their hospital stay (and once after their discharge from the hospital), patients will fill out five questionnaires which provide estimates of their postoperative pain control, mood and function, and quality of postsurgical recovery. An additional component of the study, which is entirely optional, is to obtain patient serum samples (about two teaspoons) in the operating room and 15 minutes and 4 hours after ketamine infusion. The investigators will use these samples to assess levels of IL-1, IL-6, TNF-α, and BDNF, which are markers for pain. In addition, with patient consent, the investigators will also store serum samples for future research use to measure other cytokines and neurotrophic factors and molecular markers associated with pain and depression.

Arms:
arm 1: saline infusion arm 2: ketamine (0.4mg/kg)

Interventions: intervention 1: Ketamine intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: 0.4mg/kg infusion intervention 2: 0.4mg/kg infusion

Protocol document:
Prot_SAP_000.pdf: 
March 20, 2017 
 
Page 1 
 
 
 
Randomized, double-blind, placebo controlled study on the effect of a single postoperative 
administration of low dose ketamine after gastric bypass and gastrectomy surgeries 
 
Primary Investigator: Jing Wang, M.D. Ph.D. 
 
New York University Langone Medical Center, Department of Anesthesiology 
 
Study Number: S13-00719 
 
Background 
 
Bariatric surgeries for the treatment of obesity and type II diabetes represent one of the most 
common abdominal operations, with over 300,000 cases performed in 2011.1 Postoperative care 
is a critical component for outcome from these procedures. Optimal postoperative pain 
management, however, can be difficult to achieve. While many incisions are small, a significant 
proportion of patients who undergo bypass or sleeve gastrectomy still stay in the hospital for 
more than two to three days, and patients can suffer from a combination of incisional and 
visceral pain. Pain control currently is achieved through a combination of opioids, 
Acetaminophen, and NSAIDs. Opioids are the most powerful analgesic in this group. Opioids, 
however, are well known to cause sedation and respiratory depression, which can significantly 
impact respiratory status of bariatric patients, many of whom already suffer from respiratory 
compromise due to obesity and obstructive sleep apnea. NSAIDs, meanwhile, may increase the 
rate of bleeding complications. Thus, additional analgesics are needed to achieve optimal pain 
control. 
 
A key component of postoperative pain experience is depressed mood, which further complicates 
functional recovery.2,3 Bariatric patients, in particular, have a high co-morbidity of depression, 
which can be worsened by postoperative pain.4-6 Optimal pain control, on the other hand, has 
been shown to improve patient satisfaction, elevate mood, and allow early participation in 
physical rehabilitation such as early mobility, all of which contribute to better surgical outcome. 
Studies are needed, however, to examine additional postoperative measures that can enhance 
functional recovery in bariatric patients. 
 
Ketamine is a well-known analgesic that has been frequently used pre-, intra-, and post-
operatively. The analgesic property of ketamine is dose dependent, but it is generally believed to 
be short lived, as the medication is metabolized within an hour.7 Although ketamine has been 
shown in animal studies to block central sensitization to mediate long-acting analgesia,8 this 
remains to be proven in clinical practices.9 Low dose ketamine (<0.5mg/kg/hr) is used routinely 
and safely for inpatient pain management10 and outpatient management of certain chronic 
neuropathic pain conditions such as complex regional pain syndrome.11 
 
Meanwhile, in the last ten years or so, a number of studies have provided exciting evidence that 
ketamine has rapid-onset antidepressant effects that may last up to seven days.12-14,15,16 Several 
mechanisms have been proposed to explain this mood elevating effect of ketamine including 
increased glutamate transmission17,18 and increased brain derived neurotrophic factor 
expression.19 Animal studies have confirmed that ketamine, given as an analgesic, has rapid and 


March 20, 2017 
 
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enduring mood elevating effects in postoperative pain states.20 Despite its wide use in the 
postoperative setting as an analgesic, however, few clinical studies have examined the effect of 
ketamine on mood and functional status in the postoperative patients. Currently, there is only one 
study on peri-operative use of ketamine in bariatric patients,21 which showed that pre-inductive 
use of ketamine leads to early extubation and decreased total use of opioids. No study, in 
contrast, has examined the effects on mood and functional recovery with the use of ketamine 
postoperatively for pain control. 
 
A number of pro- and anti-inflammatory cytokines (interleukin IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, and 
tissue necrosis factor, TNF-α) have been linked with stress and mood regulation.22 Some of these 
cytokines, particularly IL-1, IL-6 and TNF-α, have also been implicated in pain states as well. In addition, 
reduced serum levels of brain derived neurotrophic factor (BDNF) have been described to correlate with 
pain as well as depressed mood, and ketamine has been hypothesized to increase BDNF levels.23 
However, there has been limited study in postoperative pain on the involvement of cytokines and 
neurotrophic factors as potential markers for assessing pain and predicting analgesia. 
 
Study Rationale 
 
Ketamine, given for postoperative pain control, can be hypothesized to have long lasting 
analgesic effects as well as effects on improving mood and function in the postoperative period. 
Ketamine can be administered as a single dose in the post-anesthetic care unit (PACU), where 
patients are closely monitored for potential side effects.  We hypothesize that postoperative use 
of ketamine should lead to improvement in pain indices including visual analog scale (VAS), a 
decrease in opioid requirement, mood improvements as measured by psychometric indices, and 
finally improvements in functional measures including early mobility and faster discharge from 
the hospital. In addition, we will assess serum levels of IL-1, 6, TNF-α, and BDNF to see if 
alterations in levels of cytokines and neurotrophic factors occur with postoperative pain and how 
ketamine treatment may influence the levels of these biomarkers. 
 
Study Objective 
 
Specific aim 1: examine the effect of a single, subanesthetic dose (0.4mg/kg) of ketamine vs. 
saline control on mood and postoperative function in patients who have undergone gastric 
bypass and sleeve gastrectomies. 
 
Pain relief and changes in postoperative mood and function will be assessed using both patient 
report, in the forms of a series of questionnaires, and medical chart review. The questionnaires 
we use will be Beck Depression Inventory (BDI), Visual Analog Scale (VAS), McGill’s short 
form, QoR-15 form and the Montgomery-Asberg Depression Rating Scale (MADRS). Please see 
below for a detailed discussion of these forms. In addition, from the chart review we will monitor 
length of stay during hospitalization, opioid usage per hour during the PACU stay before and 
after ketamine infusion, total opioid usage per day throughout the hospital stay, time to out of 
bed to chair, and spirometry use after ketamine infusion. 
 
Specific aim 2: examine the effect of a single, subanesthetic dose (0.4mg/kg) of ketamine vs. 
saline control on inflammatory cytokines and neurotrophic factors in the postoperative period. 
 


March 20, 2017 
 
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We will examine the effect of ketamine on proinflammatory markers and neurotrophic factors 
known to be linked with pain. We will examine levels of interleukin factor 1 and 6 (IL-1, IL-6), 
TNF-α, and BDNF. This aim will provide potential mechanism of action for ketamine. 
 
Overall study design and plan 
 
This is a randomized, double-blind, placebo-controlled, two-arm parallel, single-center study. 
One hundred subjects (50 in each arm) will be enrolled. Subjects, between the ages 18 and 65, 
undergoing laparoscopic gastric bypass or sleeve gastrectomy under general anesthesia will be 
screened for eligibility to participate in the study. Subjects will be screened, recruited and 
consented during the preadmission visit prior to surgery. Eligible subjects will be randomized to 
one of the two treatment group in a 1:1 ratio to receive either IV ketamine (0.4mg/kg) or 
matching placebo. Both men and women will be recruited, and there is no limitation as to racial 
and ethnic origin. 
 
Participation in the study will not alter the patient’s surgical or anesthetic are, post-anesthetic 
care, or care on the floor. In the PACU, patients, if deemed medically stable by the study 
physician, will receive either 0.4mg/kg IV ketamine or placebo. All patients will also receive 
standard post-anesthetic monitoring and care, as well as routine care after transfer out of the 
PACU. There is no restriction on the use of other analgesics throughout the hospital stay. 
Patients are followed until the date of discharge, and endpoints (see below) are collected from 
patient reports as well as from medical charts. During their hospital stay (and once after their 
discharge from the hospital), patients will fill out five questionnaires which provide estimates of 
their postoperative pain control, mood and function, and quality of postsurgical recovery. 
 
Patients will be randomized using a block randomization code for assigning 100 subjects to two 
groups. In Excel we generated 100 random numbers. In the next column we inserted multiple 
copies of the sequence PCPC where p= “placebo” and c = “control”, forming 25 blocks. Then we 
sorted the random numbers in each 4 subject block, including the assignment letters (P, C) in the 
sort. The remaining list of Ps and Cs is the randomization.  
 
To check the balance, we then did running counts of the cumulative repeats of “p” and “c” and 
“p – c”. The tally for each totaled 50 and the two groups were always within 2 counts of being 
perfectly balanced, which met our goal. The list can be extended at will to accommodate 
screening failures. 
 
Randomization lists will be sent to the pharmacy who will then be able to distribute the study 
drug/placebo as patients are enrolled and undergoing surgery, and the remainder of the study 
staff will be blinded. 
 
An additional component of the study, which is entirely optional, is to obtain patient serum 
samples (about two teaspoons) in the operating room and 15 minutes and 4 hours after ketamine 
infusion. We will use these samples to assess levels of IL-1, IL-6, TNF-α, and BDNF, which are 
markers for pain. In addition, with patient consent, we will also store serum samples for future 
research use to measure other cytokines and neurotrophic factors and molecular markers 
associated with pain and depression. 


March 20, 2017 
 
Page 4 
 
 
 
 
Study site: Tisch Hospital  
 
Outcome measures 
 
Primary outcome measure: scores on the following questionnaires: 1) The Beck Depression 
Inventory (BDI); 2) Visual Analog Scale (VAS) score; 3) McGill’s short form; 4) QoR-15 form; 
and 5) Montgomery-Asberg Depression Rating Scale (MADRS). The BDI and MADRS provide 
assessments for mood and function, VAS and McGill’s assess pain, and QoR-15 assesses 
patient’s overall satisfaction with postoperative recovery. 
 
After consent is achieved in the pre-admission clinic prior to surgery, patients will be asked to 
fill out BDI, MADRS and QoR-15 forms to establish baseline scores. The BDI, MADRS will be 
filled out on postoperative days (POD) 0 after the infusion of ketamine, and BDI, MADRS and 
QoR-15 forms will be repeated on POD1, 2 and 7. McGill’s short form will be filled out prior to 
discharge from the PACU and on POD 1, 2 and 7. VAS will be filled prior to PACU discharge, 
and every day while patient is in the hospital and on POD 7. VAS is a routine part of hospital 
care and will be administered daily whether a patient is enrolled in the study or not. If a patient 
has been discharged prior to POD2 or 7 (patients typically are discharged on POD2 or 3 in our 
practice), then a member of the study team will contact the patient by telephone to fill out these 
questionnaires. 
 
Secondary outcome measures: 1) length of stay during hospitalization; 2) opioid usage per hour 
during the PACU stay before and after ketamine infusion; 3) opioid usage per day throughout the 
hospital stay; 4) time to out of bed to chair (OOB); 5) spirometry use 4 hours after the 
termination of ketamine infusion; 5) anti-emetic use in the PACU. 
 
Length of stay, opioid usage, and anti-emetic use will be recorded from electronic medical chart. 
Patient will be asked to record and report the time to OOB. Spirometry use will be assessed by a 
study team member to determine whether the patient is meeting the goal set by the surgical team 
4 hours after ketamine infusion. 
 
Exploratory secondary outcome measures: changes in serum levels of IL-1, IL6, TNF-α, and 
BDNF, which will be collected at baseline (in the OR preoperatively), and 15 min and 4 hours 
after the termination of ketamine infusion. 
 
Study population 
 
Inclusion criteria: 
1. Adults, >18 years, <65 years, who will undergo gastric bypass or sleeve gastrectomy. 
2. Subject is non-lactating and is either: 
a. Not of childbearing potential; or 
b. Of childbearing potential but is not pregnant at time of baseline as determined by pre-
operative pregnancy testing. 
3. Subject is ASA physical status 1, 2, or 3. 
4. Subject who is deemed medically stable 


March 20, 2017 
 
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Exclusion criteria: 
1. <18 years of age; >65 years of age 
2. Pregnant or breastfeeding 
3. Does not speak or understand English (the study forms used are copy-right in English) 
4. Cognitively impairment (by history) or clinical signs of altered mental status  
5. History of misuse or abuse of ketamine 
6. History of chest pain or chest pain in the PACU 
7. Use of a medication that interferes with metabolism of ketamine within the last 24 hours 
8. A diagnosis of schizophrenia and/ or a history of chronic antipsychotic medication use 
9. History of head trauma 
10. History of intracranial mass or hemorrhage 
11. History of stroke 
12. History of cardiac arrhythmia  
13. Subject for whom ketamine is contraindicated 
14. Unwillingness to give informed consent according to HIC guidelines 
 
Entry into Study  
 
Flyers will be designed and posted in the bariatric clinic as well as the pre-admissions testing 
(PAT) clinic to inform patients about this study. Patients will be recruited from the bariatric 
clinic during their visit with the pre-surgical clinic visit with their surgeons, from the PAT during 
their preadmission visit, or from the holding area on the day of surgery. Researchers will hold a 
general discussion with interested patients regarding the study. The patient may have family 
included, if he/she prefers. We will be approaching all subjects (male and female) who are 
undergoing laparoscopic gastric bypass or sleeve gastrectomy. 
 
Pre-Study Screening 
 
Potential subjects will have an initial pre-study screening, conducted by a member of the 
research team, to determine eligibility for the study. Potential subjects who are non-English 
speaking will be automatically excluded, because the questionnaires are copyrighted in English 
only. Subjects who do not have the capacity to consent will not be recruited. All other subjects 
will be recruited. For any patient who might be illiterate, consents will be read to him or her and 
witnessed by available staff or family member. 
 
Informed Consent 
 
Eligible patients will be assessed for capacity to give informed consent by a study team member. 
Medical clearance/status/stability will be addressed by members of the research team. Eligible 
patients will be invited to participate in the study. A verbal explanation of the study will be given 
followed by a written consent form. Study staff members are experienced at consenting patients 
for anesthesiology studies, and they include physicians as well as research associates. 
 
 
 


March 20, 2017 
 
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Intervention Administration 
 
Ketamine bolus doses of 0.4 mg/kg (by ideal body weight) will be prepared and stored by the 
Pharmacy staff at Tisch Hospital and will be delivered to the PACU on an on-call basis when 
required for a study subject. The study drug will be administered in accordance to best practices. 
Ketamine will be given via intravenous infusion through an IV line established in the PACU. All 
patients will have an IV line in the PACU as per standard postoperative care protocol after 
bariatric surgery. If necessary, an additional IV line will be placed by the study team for the 
infusion of the study drug. The study drug or control will be administered over <60 minutes. The 
dose for ketamine will be fixed at 0.4 mg/kg (ideal body weight). The staff administering the 
infusion will have no knowledge whether the agent is drug or saline control. The patient will be 
monitored in the PACU according to the standard PACU protocol. In addition, the patient will be 
monitored for any potential side effects of the medication, which include hypertension, 
tachycardia, nystagmus, perceptual disturbances, confusion, sedation, euphoria, dysphoria, and 
dizziness. These side effects are uncommon, and a majority of these side effects are expected to 
resolve shortly after infusion.13 Side effects will be documented and treated if necessary as per 
standard PACU protocol. 
 
Study drug storage 
The Pharmacy at Tisch Hospital will randomize and prepare samples (study medication or saline 
control). Study medications and placebo will be kept by the Pharmacy staff at Tisch Hospital 
until use. 
 


March 20, 2017 
 
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Main Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit I: Signing consent, doing questionnaires. 
Visit II: Drug Infusion in the PACU. 
Visit III: –Questionnaires before discharge from 
PACU 
Visit IV: Spirometer, in hospital room. 
Visit V Post-Op Day 1, questionnaires. 
Visit VII (may be done by telephone): POD 7, 
questionnaires. 
Visit VI (may be done by telephone): POD 2, 
questionnaires. 


March 20, 2017 
 
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Pharmacologic profile of study drug 
 
Ketamine [(+/-)-2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone] is a white, crystalline 
powder or clear liquid. It is a schedule III substance and is classified as a dissociative anesthetic. 
Ketamine is available as a racemic mixture with the S-(+)- isomer being more potent than the R-
(-)- isomer. It is commercially supplied as the hydrochloride salt in 0.5 mg/mL and 5 mg/mL 
ketamine base equivalents. Clinically, it is commonly used as an anesthetic induction agent for 
diagnostic and surgical procedures prior to the administration of general anesthetics. It is also 
used as a low dose infusion for analgesia. For induction of 5-10 minutes surgical anesthesia, a 
dose of 1.0-4.5 mg/kg is intravenously administered; 6.5-13 mg/kg is given intramuscularly for 
12-25 minutes of surgical anesthesia. As an analgesic, it is infused at a rate of 0.1 - 0.5 mg/kg/hr, 
with or without a loading dose. 
 
The risks for ketamine are well studied. In general, ketamine is a well-tolerated medication. 
However, the following risks have been reported. 
 
Pharmacokinetics: Bioavailability following an intramuscular dose is 93%, intranasal dose 25-
50%, and oral dose 20±7%. Ketamine is rapidly distributed into brain and other highly perfused 
tissues, and is 12% bound in plasma. The plasma half-life is 2.3 ± 0.5 hours. Oral administration 
produces lower peak concentrations of ketamine, but increased amounts of the metabolites 
norketamine and dehydronorketamine. Ketamine and its metabolites undergo hydroxylation and 
conjugation. Norketamine produces effects similar to those of ketamine. There are no significant 
differences between the pharmacokinetic properties of the S-(+) and R-(-)-isomers. 
 
Pharmacodynamics: Analgesia, anesthetic and sympathomimetic effects of ketamine are 
mediated by different sites of action. Non-competitive NMDA receptor antagonism is associated 
with the analgesic effects; opiate receptors may contribute to analgesia and dysphoric reactions; 
and sympathomimetic properties may result from enhanced central and peripheral 
monoaminergic transmission. Ketamine blocks dopamine uptake and therefore elevates synaptic 
dopamine levels. Inhibition of central and peripheral cholinergic transmission could contribute to 
induction of the anesthetic state. 
 
Molecular Interaction / Receptor Chemistry: Cytochrome P450 3A4 is the principal enzyme 
responsible for ketamine N-demethylation to norketamine, with minor contributions from 
CYP2B6 and CYP2C9 isoforms. Potential inhibitors of these isoenzymes could decrease the rate 
of ketamine elimination if administered concurrently, while potential inducers could increase the 
rate of elimination  
 
Psychological Effects: Decreased awareness of general environment, sedation, dream-like state, 
vivid dreams, feelings of invulnerability, increased distractibility, disorientation, and subjects are 
generally uncommunicative. Hallucinations, impaired thought processes, delirium, out-of-body 
experiences, and changes in perception about body, surroundings, time and sounds can occur at 
higher doses. Delirium and hallucinations can be experienced after awakening from full 
anesthetic doses of ketamine. 
 


March 20, 2017 
 
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Physiological: Anesthesia, cataplexy, immobility, tachycardia, increased blood pressure, 
nystagmus, hypersalivation, increased urinary output, profound insensitivity to pain, amnesia, 
slurred speech, and lack of coordination. 
 
Cardiovascular: Cardiovascular side effects have included elevated blood pressure and pulse 
rate following administration of ketamine alone. However, hypotension and bradycardia have 
been observed. Arrhythmia has also been reported. 
 
Respiratory: Respiratory side effects have included stimulated respiration, although severe 
depression of respiration or apnea may occur following rapid intravenous administration of 
ketamine. Laryngospasms and other forms of airway obstruction have occurred during ketamine 
anesthesia. 
 
Ocular: Ocular side effects have included diplopia, nystagmus, and a slight elevation in 
intraocular pressure. 
 
Oral: Hypersalivation can occur but is rare. 
 
Gastrointestinal: Gastrointestinal side effects have included anorexia, nausea, and vomiting. 
 
Musculoskeletal: Musculoskeletal side effects have included enhanced skeletal muscle tone 
manifested by tonic and clinic movements sometimes resembling seizures. 
 
Local: Local side effects have included pain and exanthema at the injection site. 
 
Dermatologic: Dermatologic side effects have included transient erythema and/or morbilliform 
rash. 
 
Psychiatric: Psychiatric side effects have included anxiety, euphoria, dysphoria, illusions, 
hallucinations, flashbacks, blunted affect, catatonia and psychotic episodes. 
 
Neurologic: Impaired attention/memory/judgment, disorientation, delirium, diplopia, blurred 
vision. 
 
Urinary: Increased urinary output; rarely cystitis. 
 
Duration of Effects: Onset of effects is within seconds if smoked, 1-5 minutes if injected, 5-10 
minutes if snorted and 15-20 minutes if orally administered. Effects generally last 30-45 minutes 
if injected, 45-60 minutes if snorted, and 1-2 hours following oral ingestion. 
 
Tolerance, Dependence and Withdrawal Effects: In long-term exposure, high tolerance, drug 
craving, and flashbacks are described. Little evidence of a physiological withdrawal syndrome 
unless abrupt discontinuation in chronic users. 
 
Drug Interactions: Lorazepam may decrease ketamine-associated emotional distress but does not 
decrease cognitive or behavioral effects of ketamine. Acute administration of diazepam increases 


March 20, 2017 
 
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10 
 
 
 
the half-life of ketamine. Lamotrigine significantly decreases ketamine-induced perceptual 
abnormalities, but increases the mood elevating effects. Haloperidol may decrease impairment 
by ketamine in executive control functions, but does not affect psychosis, perceptual changes, 
negative schizophrenic-like symptoms, or euphoria. Alfentanil is additive to ketamine in 
decreasing pain and increasing cognitive impairment. Physostigmine and 4-aminopyridine can 
antagonize some pharmacodynamic effects of ketamine. 
 
Absolute contraindications to IV ketamine are age <3 months and schizophrenia. Relative 
contraindications include increased ICP, glaucoma, or acute globe injury. Caution is suggested in 
patients with cardiovascular illness, porphyria, or thyroid disorder. 
 
Human subject 
 
This study will be carried out under the guidelines of the New York University School of 
Medicine, Institutional Review Board (IRB), the NYU-HHC CTSI, and in accordance with the 
Guide for the Care and the Use of Laboratory Subjects as adopted and promulgated by the US 
National Institutes of Health. 
 
Protection of Human Subjects: Patients who will undergo bariatric surgery who meet entry 
criteria will be presented the option of enrolling in proposed studies. If they decide to participate, 
they will be asked to provide written informed consent prior to participation in this study. They 
will review an IRB-approved research consent with study personnel. This consent form will 
describe the purpose of the study and how long it will last, the procedures to be used, any 
expected discomfort or inconvenience, the expected risks and benefits, alternative treatment 
plans, use of research results, and any special circumstances. The consent form will be read and 
signed in the presence of a member of the research team. Study subjects will be given the 
opportunity to ask questions at the time of signing consent and throughout the course of the 
study. They will also be informed of their rights as study participants, that they are free to choose 
not to participate and can withdraw at any time. A copy of the consent will be given to all study 
participants. If they have questions or concerns at a later time, they may use the phone numbers 
listed on the consent form to contact the investigator or other study associates. 
 
Institutional Review Boards: The principal investigator will ensure that a duly constituted 
Institutional Review Board (IRB) complying with all Federal regulations will review all 
protocols and informed consent forms. The investigator will promptly report to the IRB all 
changes in research activity and all serious adverse events or unanticipated problems involving 
risks to human subjects or others. No changes will be made to protocols without IRB approval, 
except where necessary to eliminate immediate hazards to human subjects. If an emergency 
change is necessary, the IRB will be notified within 24 working hours. The NYU School of 
Medicine IRB operates under OHRP Federal-Wide Assurance of compliance number 
FWA00004952. 
 
Patient Confidentiality: To maintain patient confidentiality, all laboratory specimens, evaluation 
forms, reports and other records will be identified by a coded number only, and HIPAA 
guidelines will be followed. Clinical information will not be released without the written 
permission of the patient, except as necessary for monitoring by the NYU IRB. Subjects will be 


March 20, 2017 
 
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11 
 
 
 
informed of these exceptions in the informed consent document 
 
The research material obtained from human subjects in this proposed study is to be collected 
solely for research purposes. It will include the following: 
a. Research information obtained by medical history, research questionnaires and patient 
interviews. 
b. Clinical information obtained from chart review of the subject’s hospital records to help in 
clarifying diagnostic and concurrent treatment information. 
c. Serum levels of inflammatory cytokines and neurotrophic factors will be obtained three 
times during the course of study. 
d. Pregnancy: Subjects currently pregnant will not be eligible for study participation. Female 
subjects of child bearing age must agree to use acceptable contraception throughout the 
study. As these subjects are inpatients admitted for surgery, there is minimal likelihood that 
they should be pregnant or become pregnant during our study. 
 
Confidentiality and Study Assessments: To safeguard confidentiality, all information will be 
stored on locked files which can be accessed only by members of the research staff for this 
project. No names or other identifying information will be used in publications which stem from 
this research. The study data will be stored in a locked drawer within a locked office space at 
NYU School of Medicine and The Alexandria Center. Only study staff will have access to the 
study data. All electronic data will be accessible only to authorized personnel. 
 
Risk/benefit Ratio of the Study: The risks involved in this study are justified by the anticipated 
benefits. There is a potential benefit gained to study subjects for better postoperative analgesia, 
mood elevation as well as faster recovery from surgery. In addition, there is benefit in society for 
better understanding of the postoperative analgesic and mood elevating strategies. The risks for 
engaging in this procedure are primarily related to brief acute ketamine effects as addressed 
above. 
 
Costs to the subject: Patients will not receive payment for participation in the study. The cost of 
ketamine and its preparation will be paid by research funds from the PI of the study and the 
Department of Anesthesiology. 
 
Statistical Analysis 
 
Sample Size Justification: Previous studies on the antidepressant effects of ketamine on 
depressed patients typically yield a mean difference in psychometric measures of 40%, with a 
standard deviation of roughly 40% as well. Power analysis yields n = 50 patients in each arm. 
This will allow for us to detect a true difference in the mean value of our outcome variable of + 
22.5% with a probability (power) of 0.8. The type I error probability associated with this test of 
the null hypothesis that the population means of the ketamine versus control groups are equal is 
0.05. 
 
Statistical Analysis: For this study, descriptive statistics will be performed for all data and 
subgroups as needed: 
1) Outcome tests (see above), N (%) for each category, showing absolute values, absolute 


March 20, 2017 
 
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12 
 
 
 
and percent differences, stratified by treatment etc. 
2) Demographics showing continuous parameters (age, height, weight, etc.) as mean + SD; 
categorical parameters, as N (%); all also stratified by treatment. 
 
Analysis of variance (ANOVA) test with repeated measures will be performed to determine 
within-patient effects (time) and between patient effects (treatment) on outcome measures. 
Pearson correlation will be used to assess relationships between continuous variables, and 
Spearman’s Rho will be used for ranked data. For non-normally distributed, the Kruskall-Wallis 
test will be used for global significance, and Mann Whitney for subsequent pairwise 
comparisons. 
 
Exploratory analysis will fit continuous (VAS score, length of stay in the hospital) and 
categorical (ordinal outcome data) to a Logistic Regression model which predicts the treatment 
bivariate (IV ketamine or placebo). 
 
Interim Data analysis: An interim data analysis will be performed after a total of 50 patients 
have completed the study. An analysis of primary and secondary endpoints will be analyzed, and 
if the primary endpoints are met, we will opt to terminate the study. 
 
DATA SAFETY AND MONITORING PLAN 
 
Timeline 
1) Estimated start date: Sept 1, 2013 
2) Estimated time for start-up: 2 months 
3) Time allotted for enrollment: 2 years 
4) Estimated study end date: August 30, 2015 
 
Data acquisition and management 
 
The research material obtained from human subjects in this proposed study will be collected 
solely for research purposes. It will be as follows: 
a. Clinical information obtained by medical history, questionnaires and interviews. 
b. Clinical information obtained from chart review of the subjects’ hospital records 
c. Serum samples will be obtained. 
 
All research data will be collected in Case Report Forms (CRFs). Clinical safety data, routine 
labs, screening information, informed consent, and progress notes will also be collected in 
Source Documents. 
 
Data Entry: CRFs of all research data will be entered into assessment specific data entry forms 
with macro programming to organize repeated measures into table format. Data and results from 
laboratory tests will be entered by study staff directly from the CRFs into secure computer 
designated for Dr. Wang at NYU-Tisch Hospital. The data are then stored using a secure 
password. The computer used for this study will be password protected and kept locked in a 
locked office in the Anesthesia office. Only designated study staff will have access to patient 
data and these include: the PI of the study Dr. Wang, the Research Coordinator and the Research 


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Assistant. Hard paper copies of the laboratory results, if necessary, will be stored in a secured 
area in Dr. Wang’s office in Alexandria Center for Life Sciences. Though the information 
collected in this study may be published, no patient will be identified by name or other personal 
information. 
 
Adverse events will include events reported by the subject and thought to be associated with the 
research. Unanticipated problems and adverse events will be gathered by study investigators. 
Adverse events will be evaluated throughout the hospital stay. Any serious adverse effects will 
be reported to the IRB according to regulatory requirements. 
 
Quality Assurance: Source Documentation and CRF’s collected for the first 5 participants will 
be reviewed by the PI, Dr. Wang, following completion of testing with each participant. Study 
procedure consistency, data entry accuracy and completeness, and normative range of values will 
be checked. Where applicable, consistency between Source Document and CRF will be 
evaluated. Thereafter, source documentation and CRF’s for 1 out of every 5 participants will be 
selected randomly and reviewed in a similar manner. If an error or errors are discovered, 
corrective action will be taken to remedy particular errors when discovered. 
 
Sample Size Justification: Previous studies on the antidepressant effects of ketamine on 
depressed patients typically yield a mean difference in psychometric measures of 40%, with a 
standard deviation of roughly 40% as well. Power analysis yields n = 50 patients in each arm. 
This will allow for us to detect a true difference in the mean value of our outcome variable of + 
22.5% with a probability (power) of 0.8. The type I error probability associated with this test of 
the null hypothesis that the population means of the ketamine versus control groups are equal is 
0.05. 
 
Statistical Analysis 
For this study, descriptive statistics will be performed for all data and subgroups as needed: 
1) Outcome tests (see above), N (%) for each category, showing absolute values, absolute 
and percent differences, stratified by treatment etc. 
2) Demographics showing continuous parameters (age, height, weight, etc.) as mean + SD; 
categorical parameters, as N (%); all also stratified by treatment. 
 
Analysis of variance (ANOVA) test with repeated measures will be performed to determine 
within-patient effects (time) and between patient effects (treatment) on outcome measures. 
Pearson correlation will be used to assess relationships between continuous variables, and 
Spearman’s Rho will be used for ranked data. For non-normally distributed data, the Kruskall-
Wallis test will be used for global significance and Mann Whitney for subsequent pairwise 
comparisons. 
 
Exploratory analysis will fit continuous (VAS score, length of stay in the hospital) and 
categorical (ordinal outcome data) to a Logistic Regression model which predicts the treatment 
bivariate (IV ketamine or placebo). 
 
Interim Data analysis 
An interim data analysis will be performed after a total of 50 patients have completed the study. 


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An analysis of primary and secondary endpoints will be analyzed, and if the primary endpoints 
are met, we will opt to terminate the study. 
 
Data Safety and Monitoring Board (DSMB) 
In addition to the PI, Dr. Wang, an independent patient safety DSMB panel will also review 
study documents and safety data on a routine basis. This board will meet once every three 
months, and more frequently as needed. In addition, the board will meet with study coordinator 
and assistant after a total of 50 patients have completed the study to perform an interim analysis. 
This board will include the additional following members from the department of 
anesthesiology. 
1. Dr. Lisa Doan 
2. Dr. Fahad Khan 
 
None of these DSMB panel members has any conflict of interest with this study protocol. 
 
Study safety assurance 
 
Confidentiality and Study Assessments: To safeguard against the loss of confidentiality, all 
information will be stored on locked files which can be accessed only by members of the 
research staff for this project. No names or other identifying information will be used in 
publications which stem from this research. Subjects will be informed of these exceptions in the 
informed consent document. 
 
Reporting of Adverse Events (AEs): The DSMB Panel will report a study summary and updates 
on the clinical safety documentation and assessments, as well as the primary outcome measures. 
Baseline demographics, recruitment rates and reasons of ineligibility, as well as study retention 
rates, will be summarized. An update of regulatory status and any protocol amendments will be 
provided. A summary of adverse events (AEs) and serious adverse events (SAEs) that have 
occurred will be provided. 
 
An AE is defined as any reaction, side effect, or untoward event that occurs during the course of 
the clinical trial, whether or not the event is considered medication-related or clinically 
significant. A new illness, symptom, sign, or worsening of a pre-existing condition or 
abnormality is considered an AE. Stable chronic conditions, such as arthritis, which are present 
(and documented) prior to clinical trial entry and do not worsen are not considered AEs. AEs 
will be recorded on the AE Form. The AE Form is also used to record follow-up information for 
unresolved events. Each month, a study investigator and/or study clinician (physician, nurse, or 
physician’s assistant) will review the AE Form completed for the previous month for any events 
that were reported as continuing, and provide corrective action as needed. Per the IRB of the 
NYUSOM policies, only those adverse events that are unexpected and related to the study drug, 
and those events that are harmful, will be submitted to the IRB within five days. All other events 
will be reviewed by the DSMB. 
 


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All adverse events will be collected – whether they are related to study drug or not, and 
submitted to the IRB or not. Events will be collected by speaking to the patients as well as 
through the medical record. Data will be kept up to date by patient, and investigator will be 
notified when something comes up. 
 
The study coordinators will be in charge for the initial monitoring. All data collected by the 
coordinators, will be reviewed by the PI. In cases where the PI feels there needs to be further 
review, he will do so. In addition, all data will be formally assessed every three months. The 
study coordinators will inform the PI immediately when there is any serious adverse event, 
whether or not it needs to be submitted to the IRB. Unexpected adverse events and harmful 
events related to the study drug will be reported to the IRB, will be within five days.  
 
Any event that is considered serious and attributable to the study drug will be immediately 
submitted to the IRB and the PI. The investigator will assess any events that are related and 
serious and decide whether or not to continue with this study. 
 
The IRB will be kept apprised of all serious events.  
 
Reporting of Serious Adverse Events (SAE): The study clinician will classify each AE as serious 
or non-serious and will follow all appropriate reporting procedures. Serious adverse events 
(SAEs) are defined as any fatal event, any immediately life-threatening event, any permanent or 
substantially disabling event, any event that requires or prolongs inpatient hospitalization, any 
congenital anomaly, or any event that requires intervention in order to prevent permanent 
impairment/damage. An unexpected SAE is one that is not described with respect to nature, 
severity, or frequency in the current PDR (2007) description for ketamine. The study clinician 
will assess all SAEs prior to submitting reports to the appropriate IRB. Any SAE (including 
death) due to any cause, which occurs during the course of this investigation, whether or not 
related to the investigational medication, will be reported within 24-hours by written notification 
to the IRB, accompanied by a faxed copy of the initial SAE CRF to the Institutional Review 
Board (IRB). 
 
Role of the Institutional Review Boards (IRB): The principal investigator will ensure that a duly 
constituted IRB complying with all Federal regulations will review all protocols and informed 
consent forms. The investigator will promptly report to the IRB all amendments in research 
activity and all SAEs and/or unanticipated problems involving risks to human subjects or others. 
No changes will be made to protocols without IRB approval, except where necessary to 
eliminate immediate hazards to human subjects. If an emergency change is necessary, the IRB 
will be notified within 24 working hours. The NYU School of Medicine IRB operates under 
Federal Wide Assurance (FWA) number: 00004952. 


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