Clinical trial NCT03146806
Conditions: Cancer Pain
Keywords: Cancer pain Anesthesiology Opiates Intranasal ketamine
Sponsor: Emory University
Start date: 2017-07-25; Completion date: 2020-04-22
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to determine the safety, feasibility, and utility of intranasal (NAS) ketamine in persistent uncontrolled cancer related pain. In this prospective clinical trial the researchers will investigate the use of NAS ketamine in patients with pain related to cancer or cancer treatment. The researchers plan to enroll at least 25 patients meeting inclusion/exclusion criteria, to achieve a minimum of 10 patients who complete the study. Participants will be recruited from the supportive oncology clinic, oncology clinics, the pain clinic and Acute Pain Service at Emory. Participants will be asked to return to the Phase I unit of the Winship Cancer Building C for a total of 5 study visits, each two to five days apart. During these visits participants will complete questionnaires, have blood samples drawn and will have study medication administered to them in escalating doses. For safety monitoring participants will be contacted by telephone 14 days after the last dose of medication administered.

Detailed description:
There are about 11.9 million Americans affected with cancer. 53% of patients with cancer experience pain at all stages of cancer. These patients often require high doses of opioids with uncontrolled pain that makes them too sedated to effectively participate in day-to-day activities and have a good quality of life. Depression often co-exists with cancer pain due to the nature of the disease. The researchers are searching for improved therapies for chronic cancer pain and ketamine with its novel mechanism of action may be a promising solution.

Ketamine is an FDA approved anesthetic with the ability to effect memory loss, pain relief and sedation. Safety and efficacy of ketamine as an anesthetic and analgesic agent is well documented. Low doses of ketamine have minimal adverse impact on circulatory or breathing functions but can reduce pain. Research has shown that ketamine is effective in controlling breakthrough pain and reducing depression in a randomized double blind controlled trial. There is limited data regarding the use of ketamine for pain management in cancer.

One of the challenges with ketamine is the route of administration, most commonly given intravenously (IV) or intramuscularly (IM). It has also been given by mouth and rectally, but absorption is very poor. Intranasal (NAS) administration may be a promising method of delivery and can be ordered by a physician from a compounding pharmacy. From other research the investigators expect absorption to be higher than oral or rectal administration and this method of delivery as needle-free is a patient-friendly route of administration.

The main purpose of this study is to determine the safety, feasibility, and utility of intranasal (NAS) ketamine in persistent uncontrolled cancer related pain. In this prospective clinical trial the researchers will investigate the use of NAS ketamine in patients with pain related to cancer or cancer treatment. The researchers plan to enroll at least 15 patients meeting inclusion/exclusion criteria, to achieve a minimum of 10 patients who complete the study. Participants will be recruited from the oncology clinic, pain clinic and Acute Pain Service at Emory. Participants will be asked to return to the Phase I unit of the Winship Cancer Building C for a total of 5 study visits, each two to five days apart. During these visits participants will complete questionnaires, have blood samples drawn and will have study medication administered to them in escalating doses. For safety monitoring participants will be contacted by telephone 14 days after the last dose of medication administered.

Data obtained from this study will help determine if ketamine provides a reduction of pain using the Numeric Pain Rating Scale and a reduction in the use of opioid consumption and other rescue medications. Additionally the researchers will study the bioavailability, pharmacodynamics and pharmacokinetics of ketamine and the safety profile of NAS ketamine.

Arms: arm 1: Study participants who are receiving intranasal ketamine treatments.
Interventions: intervention 1: Intranasal ketamine
Intervention descriptions: intervention 1: 10mg of intranasal ketamine will be given to make sure that the study patients are able to tolerate a small dose of NAS ketamine.

On the second visit, 10 mg of IV ketamine will be given to help establish bioavailability of NAS ketamine, with patients serving as their own controls.

On the third and fourth visit, higher doses of ketamine, 30 mg and 50 mg respectively, will be given.

All doses of ketamine will be administered by an anesthesia research nurse.

Protocol documents:
Prot_SAP_000.pdf: 
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Safety of Intranasal Ketamine for Reducing Uncontrolled 
Cancer Related Pain 
 
Winship EU3238-16 
IND 133570 
NCT Number: NCT03146806 
 
 
Principal Investigator  
Vinita Singh, MD  
Assistant Professor, Department of Anesthesia  
 
  
Protocol Version Date: 02/01/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
A. SIGNIFICANCE……………………………………………………………………………....3 
A.1   Background……………………………………………………………………………...4 
A.2   Pharmacokinetics………………………………………………………………………..5 
A.3   Preliminary Data………………………………………………………………………...6 
 
B. INNOVATION………………………………………………………………………………..7 
Objectives……………………………………………………………………………………..7 
 
C. APPROACH…………………………………………………………………………………..9 
C.1   Study design and methods……………………………………………………………….9 
C.2   Methods………………………………………………………………………………….9 
        TABLE of Assessments………………………………………………………………….11 
         Dose Finding…………………………………………………………………………….12 
         Pharmacokinetics………………………………………………………………………..12 
         Patient Reported Outcomes……………………………………………………………...13 
C.3   Monitoring and Documentation……………………………………………………….....14 
             C.4   Potential Risks…………………………………………………………………………....15 
             C.5   Management of specific side effects……………………………………………………..16 
             C.6   Benefits…………………………………………………………………………………...17 
             C.7   Participant Selection……………………………………………………………………...17 
             C.8   Inclusion Criterion………………………………………………………………………..18 
             C.9   Exclusion Criterion……………………………………………………………………….18 
             C.10 Informed Consent Process………………………………………………………………..20 
             C.11 Compensation for time and effort………………………………………………………...20 
             C.12 Statistical Analysis………………………………………………………………………..20 
             C.13 Data and Safety Monitoring and Reporting……………………………………………....21 
                          Confidentiality………………………………………………………………………....24 
C.14 Potential Pitfalls…………………………………………………………………………..24 
 
D. REFERENCES/BIBLIOGRAPHY…………………………………………………………….24 
 
APPENDIX I: Assessment scales under in the study 
A. Numerical Pain rating scale………………………………………………………………..29 
B. SERSDA (Side effects Rating Scale for Dissociative Anesthetics)……………………….29 
C. ECOG (Eastern Cooperative Oncology Group) Performance Status……………………...29 
D. ESAS (Edmonton Symptom Assessment System) Score………………………………….30 
E. RASS (Richmond Agitation-Sedation Scale) Scale to Assess Sedation…………………..31 
F. CAM-ICU ( Confusion Assessment Method for the Intensive Care Unit) scale to assess  
for delirium………………………………………………………………………………...32 
G. PHQ-9 (Patient Health Questionnaire)…………………………………………………….33 
H. MADRS (Montgomery-Asberg Depressions Scale) Questionnaire……………………….34 
I. PROMIS Questionnaire……………………………………………………………………35 
J. Pain Diary………………………………………………………………………………….36 
APPENDIX II 
A. Summary sheets from NMS Labs………………………………………………………….37 
B. Ketamine package insert…………………………………………………………………...38 


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C. Ketamine Safety Data Sheet, Hospira……………………………………………………...39 
D. Cytochrome P450 3A4 and 3A5 Known Drug Interaction Chart………………………….40 
 
A. SIGNIFICANCE: 
 There are about 11.9 million Americans affected with cancer; of these, 53% of patients with cancer 
experience pain at all stages of cancer. The number rises to 58 to 69% in those with advanced cancer 1.  
Depression often co-exists with cancer pain. Patients with cancer pain often require high dosages of 
opioids that make them too sedated to effectively participate in day-to-day activities and have a good 
quality of life. Occasionally, even after high dose opioids their pain remains uncontrolled in the setting of 
opioid tolerance or opioid unresponsive pain. An epidemiological study revealed that 10 to 15% of these 
patients fail to achieve acceptable pain relief with opiates alone or in combination with conventional 
adjuvant analgesics 5-7. Opioid medications are associated with numerous side effects such as: 1) Most 
commonly- constipation, sedation, nausea and vomiting, respiratory depression, urinary retention, and 
pruritus. 8-11, 2) Tolerance, causes loss of treatment effectiveness forcing the increase of dosage, which 
simultaneously entails a greater risk for ADRs 12 , 3) Increased pain sensitivity, also known as 
hyperalgesia, can appear during opioid treatment, despite increasing dosage of opioids or steady state of 
disease13, 4) Immunosuppression leading to significant infections has been demonstrated for opioids in 
experimental studies 14, 5) Hypogonadism caused by the central suppression of hypothalamic secretion of 
gonadotropin releasing hormone 15 6) Hyperglycemia by decreasing the insulin secretion through the 
sympathetic nervous system 16  and 7) “Stress cardiomyopathy”, also known as Takotsubo 
cardiomyopathy (transient left ventricular dysfunction, usually triggered by intense emotional or physical 
stress), could appear when withdrawing opioid 17.  
 
The need to identify and evaluate new evidence-based interventions, including pharmacologic agents, to 
address cancer pain is a priority for the NIH as well as global public health agencies. The NIH Pain 
Consortium was established in 1996 to enhance pain research and promote collaboration among 
investigators across the NIH. Currently, the research interests of 21 NIH Institutes, Centers, and Offices 
are represented in the Consortium. In 2011, the Institute of Medicine (IOM) released its landmark report, 
Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research, 
which outlines the state of the science of pain prevention, care, training, and research, and provides a guide 
intended to transform pain care in the United States. NIH, in response, set forth a program of research 
funding for all conditions, including cancer, for which pain is a prominent component. The Cochrane Pain, 
Palliative and Supportive Care Group has urged the generation of evidence for effective, well-tolerated 


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pain interventions. Despite these efforts, the understanding and treatment of cancer pain remains 
inadequate.  
 
A1. Background: 
 In the search for improved therapies for chronic cancer pain, medications with novel mechanisms of action 
have been sought. One such promising pharmacologic approach is ketamine.  
 
Ketamine is an FDA approved anesthetic with amnesic, analgesic, dissociative, and sedative properties. It 
is unique among anesthetic agents in that it does not depress cardiovascular and respiratory systems.  
Ketamine is a noncompetitive, antagonist of N-methyl-D-aspartate (NMDA) receptors that blocks the 
NMDA channel in the open state by binding to the phencyclidine (PCP) site located within the lumen of 
the channel. Antagonism of NMDA receptors produces antinociception of persistent or neuropathic pain 
in animal models and analgesia in pain states in humans. The NMDA receptor is believed to play a role in 
the development of opioid tolerance and ketamine has been shown in a rat model to prevent fentanyl-
induced hyperalgesia and subsequent acute morphine tolerance 18. Ketamine also interacts at a number of 
other receptor sites to block pain. Some of these sites include voltage-sensitive calcium channels, 
depression of sodium channels, modulation of cholinergic neurotransmission, and inhibition of uptake of 
serotonin and norepinephrine. Ketamine also interacts with kappa and mu opioid receptors; however, in 
humans, naloxone, an opioid antagonist, does not antagonize the analgesic effects of ketamine. Safety and 
efficacy of ketamine as an anesthetic and analgesic agent is well documented 2-4. Ketamine is not labeled 
by the FDA as an analgesic agent. Low (subanesthestic) doses of ketamine have minimal adverse impact 
upon cardiovascular or respiratory function but produce analgesia and modulate central sensitization, 
hyperalgesia, and opioid tolerance. Cancer pain, especially in end stages, can be very complicated and is 
mediated by a variety of pathways: visceral, nociceptive, neuropathic and central. If ketamine can be 
utilized for pain in end stage cancer patients, this could provide them with superior analgesia and better 
quality of life, without the risk of significant respiratory depression associated with opioid medications.  
 
One of the challenges that we face with ketamine is the route of administration. The most common route 
is intravascular or intramuscular. Although it has been given orally and rectally, the bioavailability of 
ketamine when given via these routes is limited to 20-30%. Intranasal (NAS) administration represents a 
promising route because of:   
1) Potential method of ketamine maintenance therapy as an outpatient;   
2) Ease of access as a needle-free, patient-friendly route of administration;  
3) Higher bioavailability compared to oral route due to absence of hepatic first    
                          pass effect; and   


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4) Large surface area, uniform temperature, high permeability and extensive  
vascularity of the nasal mucosa facilitate rapid systemic absorption of intranasal 
administered drugs [19]. 
 
Intranasal ketamine has been shown to be effective in controlling breakthrough pain in a double blind 
randomized control trial (DBRCT) performed by Carr in 2003, as well as help with depression in a DBRCT 
by Lapidus in 2014 20,21. Both studies were NIH funded. The Carr study was a DBRCT in 20 patients with 
breakthrough pain and noted pain relief within 10 min, lasting up to 60 minutes with 10-50 mg of intranasal 
ketamine (2.65 point average decrease on NPRS scale). The pain scores were only recorded until 60 
minutes after the drug administration and the patients were allowed to determine the dose themselves, 
without precise description for this in the study. Lapidus study was performed in 20 patients with major 
depression and noted significant improvement in depressive symptoms (7.6 point average decrease on 
MADRS scale) in 44% of patients at 24hrs with 50mg of intranasal ketamine. There are limited data 
regarding the use of ketamine as an adjuvant to opioids for the management of cancer pain22. We seek to 
obtain preliminary data on safety, feasibility, and utility of this novel technique for the treatment of 
uncontrolled cancer pain. Ketamine is a scheduled III medication. Intranasal ketamine can be ordered by 
a physician from a compounding pharmacy.   
  
A2.  Pharmacokinetics:  
Ketamine has a rapid onset and relatively short duration when administered as a single intravenous dose.  
Onset of action for intravenous dose is 30 seconds; distribution half-life 10 minutes; elimination half-life 
2-3 hours. Oral bioavailability is poor (20-25%) possibly due to the hepatic first pass effect/GI tract effect. 
Ketamine undergoes rapid demethylation to norketamine via cytochrome P450 (CYP) conversion, with 
CYP3A4 being the principle pathway, with minor and clinically insignificant contributions from CYP2B6 
and CYP2C9. 50 Bioavailability of intranasal ketamine was found to be 50% in children aged 2-9 year old 
in a study done by Malinkovsky et al. in 1996 2.  However this study was done in children and the subjects 
did not serve as their own controls. In a study by Yanagihara et al. in 2002 the bioavailability of intranasal 
ketamine was found to be 45%. In this study the subjects served as their own controls, however, the number 
of subjects was limited to 3. The time for maximum concentration after intranasal ketamine administration 
was found to be 22.5(+- 9.6) min for ketamine and 120(+- 52) min for its metabolite norketamine. The T1/2 
β (elimination half-life) of IV ketamine is reported to be 126.8(+-47.4) min by Yanagihara et al 23.  
Elimination half-life of intranasal ketamine has not been reported. Ketamine has high lipid solubility and 
crosses the blood-brain barrier quickly, and exhibits high hepatic clearance and a large volume of 
distribution.  It undergoes extensive hepatic metabolism by the cytochrome P-450 system to form the 


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active metabolite, norketamine.   Norketamine is one-third to one-fifth as potent as Ketamine.  
Norketamine is eventually conjugated to form more inactive metabolites that are excreted by the kidneys.     
 
A3. Preliminary Data: 
To date, we have collected data on two cases of cancer patients to whom ketamine was delivered 
palliatively for pain unresponsive to usual interventions:  
 
Case 1.  A 38 year old female with squamous cell cancer of the tongue with bone and lung metastases and 
cord compression had back/spinal pain rated as 9-10/10 on NPRS. Increasing opioid medications 
paradoxically increased her pain, representing opioid-induced hyperalgesia. She had failed 
antineuropathic medications and was admitted for the neurological symptoms secondary to cord 
compression. Intravenous ketamine was initiated. On day 1, her pain score reduced to 8-10/10 and on day 
2 went to 4-7/10. On day 2 she was switched to intranasal ketamine (10 mg BID), so it could be continued 
after discharge at home. On day 3, her pain score decreased to 2-6/10, and she was slowly titrated to 20 
mg BID. Her pain score reduced further to 0-7/10 on day 5, however, she developed complications from 
her primary disease and could not be discharged. Throughout her stay she received intranasal ketamine 
without reported side effects except for one episode of bloody mucus discharge after blowing her nose 
when she first started.   
 
Case 2. A 74 year old female with multiple myeloma in remission had developed severe peripheral 
neuropathy and chronic diarrhea secondary to adverse effects of multiple myeloma therapy. She had 
multiple osseous lesions in pelvis and right femur s/p radiation therapy. However, she complained of pain 
in her right sacrum radiating to the front of her groin. Although she had full motor strength, she remained 
bedridden secondary to pain and peripheral neuropathy causing imbalance. She had failed multiple 
medications including opioids and interventions such as steroid injections. She remained on morphine 
extended release, and was started on ketamine IV while in the hospital and appeared to respond, although 
she still reported high pain scores. When ketamine was stopped, she went into a pain crisis again. The 
decision was thus made to continue NAS ketamine 10mg BID at home. She tolerated this dose and did 
not report any side effects. She maintained good pain control and required no further pain related hospital 
visits.  Based on these limited preliminary data, a formal clinical pharmacology and efficacy study is 
indicated to evaluate intranasal ketamine in cancer-related pain.  
   
 
 


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B. INNOVATION:  
Although ketamine has been used as an adjunct to opioid medication for pain, there is no data on intranasal 
ketamine for cancer-related pain. If studied extensively, this could potentially provide physicians with a 
simple option and unique adjunct to treat pain. Ketamine could also modulate central sensitization and 
hyperalgesia which are some of the mechanisms involved in development of chronic pain. This could 
potentially help decrease the severity of pain in general. Depression often coexists with cancer, and 
intranasal ketamine has the potential to improve depressive symptoms when used chronically. 
   
Intravenous ketamine is used by pain physicians to control pain not responding to opioid medications in 
the hospital setting. However, it is not continued as an outpatient therapy as absorption of oral ketamine 
is limited to 25%. Intranasal ketamine, if feasible, will provide clinicians with an option to continue 
ketamine chronically. There is also lack of long term studies regarding use of ketamine for pain. Future 
long term studies with intranasal ketamine for pain control can be designed based on data obtained from 
the current proposed study.  
 
 The route of administration can be limited in terminally ill patients as many suffer from nausea and 
vomiting (limiting the oral route) and have dehydration making it difficult to find veins for intravenous 
route. A study, focusing on the effects of chemotherapy on Chemotherapy Induced Nausea Vomiting 
(CINV), and the effect of CINV on daily life found that 36% of all patients reported emesis and 60% 
reported nausea. Intranasal route is underutilized for medication administration, especially pain 
medications in cancer patients. If successful, this study will open new horizons of medication delivery and 
pain control in this population.  
  
Objectives   
Overall Goal: To determine the safety, feasibility, and utility of intranasal (NAS) ketamine in 
persistent uncontrolled cancer related pain.  
Specific Aims:  
Primary Outcomes 
1. To conduct a clinical trial of NAS ketamine in a sample of patients with cancer related pain.  
1a. To measure pharmacokinetics of NAS ketamine through analysis of ketamine and its 
metabolite norketamine to determine pharmacokinetic variables including peak concentration 
after each dose and route (Cmax), time to peak concentration (tmax), total area under-the-
concentration-time curve (AUC0-t), half-life (t1/2), and clearance (Cl). 


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2. To evaluate (pharmacodynamic) effects of NAS ketamine on Patient Reported Outcomes 
(PROs), such as pain scores, side effects, depression, health-related quality of life, and 
functional status.   
2a. To assess PROs as measured by the Numerical Pain Rating Score (NPRS), Side Effect 
Rating Scale for Dissociative Anesthetics (SERSDA), Montgomery Asberg Depression Rating 
Scale (MADRS), and Edmonton Symptom Assessment (ESAS), Eastern Cooperative 
Oncology Group (ECOG) and Patient-Reported Outcomes Measurement Information System 
(PROMIS) scales.   
Secondary Outcomes 
3. To determine opioid sparing effect of NAS ketamine.   
3a. To document use of rescue medications prior to and during the study 
3b. To evaluate total opioid consumption prior to and during the study.  
 
If intranasal ketamine can be utilized for pain control in cancer patients, this could provide them with 
superior analgesia and better quality of life, without the risk of significant respiratory depression associated 
with opioid medications. We seek to obtain preliminary data via a clinical trial addressing safety, 
feasibility, and utility of this novel technique for the treatment of persistent uncontrolled cancer pain. 
These findings would be an important initial step towards testing the effectiveness of intranasal ketamine 
as a non-opioid medication for cancer pain used as potential maintenance outpatient therapy. These initial 
findings would be applied to a subsequent trial to determine the effectiveness and associated toxicities of 
ketamine in a larger sample of cancer patients, and address the compelling need to identify new, successful 
management therapies for cancer pain.  
 
 
 
 
 
 
 
 


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intranasal doses of ketamine at 10 mg, 30 mg and 50 mg 28. Therefore, for study purposes 10mg, 30 mg and 
50mg of intranasal ketamine will be administered. Each visit will be two to seven days apart to avoid any 
accumulation of study doses.  Subjects will be recruited at the supportive oncology clinic, oncology clinics, 
the pain clinic and Acute Pain Service at Emory. Subjects may be identified and contacted via telephone 
with information about the study prior to their next clinic appointment in order to allow time for them to 
consider the study. After informed consent has been obtained, study eligibility will be confirmed (see Table 
of Assessments). An appointment will be made for the Phase I Unit at Winship. A family member/friend 
must transport the patient home following drug administration, as driving for 24 hours post drug 
administration is discouraged. Written informed consent will be obtained prior to performance of study 
procedures, either while recruiting prior to study visit one or during the first study visit, prior to beginning 
the study. Subjects must meet all study eligibility criteria on Visit 1 prior to study treatment. Patients will 
be asked to return to the Phase 1 Unit for a total of 5 study visits. All study visits to the clinic will take 
place within six weeks or less. A telephone call visit will occur 14 days after the last dose of medication 
administered to follow any ongoing adverse events that occurred during the study period. If there are no 
ongoing adverse events at the end of visit five, the subject’s participation will end at that time. Subjects 
may be reconsented if withdrawn early, at the discretion of the investigator, provided all eligibility 
requirements are met.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Assessments 
Assessments 
Screening  
Visit One 
Visit Two 
Visit Three 
Visit Four 
Visit Five 
Telephone Call 
Review 
of 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Med Hx/Demographics 
X 
 
 
 
 
 
 
Hemoglobin (if none within 
3 months of Visit One) 
 
X 
 
 
 
 
 
Urine pregnancy test-within 
one week of planned Visit 
(women of child bearing 
potential) 
 
X 
X 
X 
X 
X 
 
PHQ9 Depression Screening 
X 
X1 
 
 
 
 
 
Completion 
of 
PROMIS 
Questionnaire 
 
X 
 
 
 
X 
 
ECOG score 
 
X 
X 
X 
X 
X 
 
ESAS  
 
X 
X 
X 
X 
X 
 
MADRS2,3 
 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
 
IV access 
 
X 
X4 
X 
X 
 
 
Study 
Medication 
Administration 
 
X 
X 
X 
X 
 
 
Vital Signs(HR5, BP, RR, 
Pulse Oximetry6) 
 
X7 
X7 
X7 
X7 
X8 
 
Blood Samples (PK) 
 
X9 
X9,10 
X9,10 
X9,10 
X10 
 
Hepatic Function test 
 
X 
 
 
 
X 
 
Urinalysis 
 
X 
 
 
 
X 
 
Pain Scores (NPRS) 
 
X7 
X7 
X7 
X7 
X8 
 
RASS scale 
 
X11 
X11 
X11 
X11 
X8 
 
CAM ICU Scale for RASS 
score between +4 to -3 
 
X 
X 
X 
X 
X 
 
SERSDA scale 
 
X11 
X11 
X11 
X11 
X8 
 
Olfactory assessment- pre 
and post drug 
 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X12 
Rescue 
medication 
use 
details 
 
X 
X 
X 
X 
X 
 
Pain Diary13 
 
X 
X 
X 
X 
X 
 
Opioid Pill Count 
 
X 
X 
X 
X 
X 
 
1If not previously recorded during screening visit or within 3 months of planned visit one and no history of depression 
2If screened positive for depression, questionnaire to be administered before medication given 
3Questionnaire to be repeated between 180 and 240 minutes after medication given 
4Two IV’s needed Visit two: one for study medication, one for blood draw 
5 Monitoring will occur continuously for a minimum of 30 minutes post drug administration 
6Pulse oximetry monitoring will occur continuously for a minimum of 30 minutes post drug administration 
7To be recorded at baseline, 5, 10, 15, 30 (+/- 5), 45(+/- 5), 60 (+/- 5), 120(+/- 15), 180(+/- 15) and 240(+/- 15) minutes 
after medication administration 
8On arrival for study visit 


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9Samples will be obtained at 2, 30(+/-5), 60(+/-5) and 240(+/- 15) min after medication administration on visits 1 
through 4.  
10Baseline samples will be drawn on visits 2 to 5 
11Assess at baseline, 30(+/-5), 60(+/-5), and 240 (+/- 15) minutes after medication administration 
12  Ongoing adverse events will be followed by a telephone call 14 days after the last day of study medication 
administration, plus or minus one day. 
13Patient to record data throughout study enrollment, collected at final visit 
 
Dose Finding. Escalating dosages of intranasal ketamine will be given during the study in order 
to find optimal analgesic dose without significant side effects. On the first study visit, after 
obtaining written informed consent, 10mg of intranasal ketamine will be given to make sure that 
the study patients are able to tolerate a small dose of NAS ketamine. On the second visit, 10 mg 
of IV ketamine will be given to help establish bioavailability of NAS ketamine, with patients 
serving as their own controls. On the third and fourth visit, higher doses of ketamine, 30 mg and 
50 mg respectively, will be given, if the patients did not have severe adverse events with the 
smaller dosage. Licensed study personnel delegated to do so, will administer ketamine. The 
intranasal ketamine will be administered as follows: 1) Ensure mucosal atomization device 
(MAD) is primed and the appropriate dose loaded into the syringe. 2) Have patient sit in chair and 
clear sinuses using a tissue if needed. 3) Tilt the patient’s head back. 4) Insert MAD into nostril 
and aim directly posterior, level with the floor of the nare, and slightly lateral. 5) Administer 
0.1mL (10mg). 6) Have patient keep his head tilted back for 5 minutes, if tolerable, to ensure that 
the medication does not run out of nares. Make a note if medication is visibly noted to run out of 
nares or if patient reports feeling of medication trickling down his throat. 7) If more than 0.1mL 
(10mg) needs to be delivered, repeat steps 3-5 in the contralateral nare, alternating until the full 
dose is delivered. Ensure 30 seconds have passed before re-administration into the same nare. 
Patients may continue to take their usual pain medication as needed. Since most of the oral 
immediate release opioid medications peak between 30 to 90 minutes, ketamine will be given at 
least 120 minutes after the last dose of immediate release opioid medication so the reduction in 
pain score is not confounded with the results of immediate release opioid medications. Pain scores 
will be recorded on NPRS prior to and at 5, 10, 15, 30, 45, 60, 120, and 180 and 240 minutes after 
administration of test medication. NPRS is the most responsive tool to document pain intensity 
when compared to Visual Analogue Scale (VAS) and Visual Rating Scale (VRS) for measuring 
pain, 29 showing higher compliance rates, better responsiveness, ease of use, and good applicability 
relative to VAS/VRS30. In general, improvements of pain severity</=1.5 points on NPRS could 
be seen as clinically irrelevant 31-34.  Above that value, the cutoff point for “clinical relevance” 
depends on patients’ baseline pain severity, and ranges from 2.4 to 5.3 33-35. Higher baseline scores 
require larger raw changes to represent clinically important differences 36.  


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Concomitant Opioid medications: As the study subjects will have uncontrolled pain it is likely 
that they might be on opioid medications during the study. Georgia prescription monitoring 
database will be searched by the investigators and an opioid pill count will be done at each visit to 
monitor opioid intake during the study.   
Pharmacokinetics. Blood samples will be drawn at 2, 30, 60 and 240 minutes. Baseline blood 
samples will be drawn on visits 2 through 5. The specimen requirements for lab testing are 3 ml 
serum or plasma in EDTA containing vacuum tubes. We will draw 6 ml of blood per sample to 
allow for adequate serum/plasma sample. The total blood drawn during one visit would be 24 to 30 
mL. Samples will be promptly centrifuged and serum or plasma will be separated into a plastic 
cryovial and frozen. The plastic containers will be preservative free. All samples will be sent within 
3 months to National Medical Services. The samples are valid for 7 months at -20°C, 30 days when 
refrigerated or stored at room temperature. Samples will be destroyed immediately after analysis. 
A gas chromatography with mass spectrometry (GC/MS) analysis of the samples will be done for 
concentrations of ketamine and its metabolite, norketamine. Plasma concentration-time curves for 
ketamine and norketamine will be generated for each subject and compared within subjects for the 
variables of route and dose, with IV administration serving as the basis for comparison. 
Additional Labs: Liver function test (LFT) and urinalysis (UA) will be done on visits 1 and 5. 
 
Patient Reported Outcomes. Patients will maintain a pain diary(Appendix I-J) for the entire 
study period up until the 5th and final study visit and record how often they took their usual 
breakthrough medication during the trial.  
At home, patients will log pain scores 3 times a day. 10 item PROMIS questionnaire will be filled 
out at first (baseline) and fifth (final) study visit to assess global health. Participants will fill out a 
PHQ-9 scale during the screening visit or the first study visit. PHQ-9 scale ranges from 0 to 27 and 
can be used for screening of depression. Patients who are on antidepressants or score more than 4 
on PHQ-9 scale will be assessed for depression during the study. Depression will be assessed on 
the MADRS on each visit. (See appendix 1 F) This is a 10 item questionnaire designed to be 
particularly sensitive to treatment effects37. Higher MADRS score indicates more severe 
depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Participants 
who screen positive for depression and are not on any treatment for depression, will be offered a 
psychiatry consult as a part of their routine healthcare, if interested. Performance status will be 
assessed on ECOG grading at baseline and throughout the study, which ranges from 0 to 5, where 
0 is fully active and 5 is dead. ESAS will be used to assess 9 common symptoms (pain, tiredness, 


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nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath) experienced 
by cancer patients. Each symptom is rated from 0 to 10 on a numerical scale; with 0 meaning that 
the symptom is absent and 10 that it is the worst possible severity. Patient’s study participation will 
end with the 5th and final study visit. Patients will be followed up in the pain or supportive oncology 
clinic for their routine care for pain management. They will be followed up more frequently if 
needed. Patients who benefit from intranasal ketamine would be offered this medication as an 
outpatient. The dosage and regimen will be decided on a case by case basis by the treating 
physician.   
  
C.3 Monitoring and Documentation: (See appendix 1 for all scales)  
 
The following assessments will be documented in patient research study record:  
1. Height and weight at the first study visit  
2. Pain intensity on NPRS prior to and at 5, 10, 15, 30, 45, 60, 120, 180 and 240 minutes 
after medication is given  
3. Vital signs including heart rate, blood pressure, respiratory rate and pulse oximetry at 
baseline, and 5, 10, 15, 30, 45, 60, 120, 180 and 240 minutes.  Vital signs and pulse 
oximetry will be monitored continuously for a minimum of 30 minutes post drug 
administration. More frequent vital signs if they are unstable  
4. ECOG and ESAS score at baseline on each visit  
5. Sedation level on RASS scale prior to and at 30, 60 and 240 minutes after medication is 
given  
6. If RASS score is between +4 to -3 then sedation/delirium assessment on CAM scale will 
be done prior to and at 30, 60 and 240 minutes after medication is given   
7. Side effects on SERSDA scale prior to and at 30, 60 and 240 minutes after medication is 
given  
8. An olfactory assessment will be performed pre and post study drug administration to 
determine if the study medication has impacted the sense of smell. 
9. Rescue medication taken; if taken, was it taken at the usual interval or longer  
10. Patient response to intervention if anything besides change in NPRS is reported  
11. Patient and family education regarding maintaining pain diary and reviewing discharge 
instructions, including when to call study coordinator or report to emergency department  
12. PROMIS functional scale on the first and last day of the study  
13. Any change in health status during the duration of study  
14. Opioid medication pill count at the beginning of each visit 
15. Only for visits 1, 3, and 4: If the patient reports symptoms of a significant upper 
respiratory tract infection (e.g. rhinorrhea, congestion), the study visit will be canceled 
and re-scheduled at a later date. 


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16. If changes in sense of smell are noted, a study investigator will be notified, and additional 
olfactory assessments will be performed, with the frequency and amount of assessments 
at the discretion of the investigator. 
17. The frequency of the assessments may be increased at the discretion of the investigator. 
  
The study nurse will notify the attending physician if any of the following occur:  
1. Baseline HR >100 or BP>160/100 or pain score  </=3 on NPRS who will make the 
decision of whether or not to proceed with the study visit or cancel based on the 
inclusion/exclusion criterion  
2. After the study medication is given, vital signs change more than 20% from baseline; 
HR<50 or >110, SBP<90 or >180, DBP<30 or >100, RR<8 or >24 or SaO2<90; Any side 
effects or unexpected results  
3. Sedation on RASS scale between -1 and -5 at any time  
4. Positive for delirium on CAM scale at any time  
5. Presence of any possible side effects from the study drug administration 
 
Patients will be deemed eligible for discharge after the 240 minute assessment if they meet the 
following: 
             
• 
Vital signs are within 10% of baseline values 
• 
RASS score is between +1 and -1 
•    Side effects as noted on the SERSDA scale are valued as 2 or less, or no more than 1 
point greater than their baseline value. Investigator must be notified if value is greater 
than 2. 
 
Should the patient not meet these criteria at the end of the 240 minute assessments, the study 
nurse will contact the research physician for further evaluation and assessment.  
 
C.4 Potential Risks   
 
Adverse effects are dose related. No serious side effects have been reported with intranasal ketamine 
doses of up to 50 mg.   
 
Common side effects of ketamine: Include sedation, somnolence, sensory illusions, dissociative feelings, 
blurred vision, anorexia, abdominal pain 38, 39, feeling of insobriety 40, 41, and dream disturbances 42. Dose-
dependent side effects include hallucinations, agitation, nightmares, dizziness, and nausea 43. At higher 
doses, side effects may include delirium, impaired motor function, amnesia, anxiety, panic attacks, mania, 
insomnia, and elevated blood pressure 43. Rarely, hepatic failure43 has been reported in participants with 


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underlying liver disease prior to ketamine administration. Additionally, chronic administration of 
ketamine has been associated with ulcerative or hemorrhagic cystitis, which usually resolves with 
cessation of ketamine administration 43. However this was reported in ketamine abusers and dosage being 
used for this study are very low. Additionally, a LFT and UA will be done the day of or up to 24 hours 
before both visits 1 and 5 to monitor for rare side effects. If obtained as standard of care within this time 
frame, these will not need to be repeated for the study. Benzodiazepines and neuroleptics have been used 
to successfully minimize psychotomimetic effects, such as psychosis or delirium, when ketamine is used 
for the treatment of pain 44, 45.  
  
C.5 Management of specific side effects  
 
Side effects unique to intranasal route: Include transient change in taste, rhinorrhea and nasal passage 
irritation. If the patient reports that these changes to be persistent beyond the date of administration of 
study drug and are moderate to severe in intensity, then a formal ENT consult will be sought.  
Cardiovascular effects: Potential effects include: increases in heart rate, systemic arterial pressure, 
systemic vascular resistance, pulmonary artery pressure, and pulmonary vascular resistance.  In the 
absence of autonomic control, ketamine has direct myocardial depressant effect, usually overridden by 
central response.  If >20% variation from baseline is noted in heart rate or blood pressure, study MD will 
be notified. Risk assessment will be done by the MD and appropriate medications will be given as 
deemed necessary. Patient will be admitted to inpatient medical oncology service for 23 hours 
observation if at the end of study visit a >20% variation persists despite treatment; HR >120; 
hypertensive urgency/emergence occurs. Hypertensive urgency is defined at SBP>180 or DBP>110. In 
hypertensive emergency signs or symptoms of end organ damage are noted such as blurry vision, 
headache, and chest pain.  
Central nervous system effects: Include- tremors, increased intracranial pressure, floating sensation, 
hallucinations (auditory and visual), delirium, vivid dreams or illusions, confusion, restlessness, 
disorientation, dysphoria, dizziness, and sedation.  After discontinuation of ketamine, recurrent illusions 
(flashbacks) can occur.  Ketamine can lower the seizure threshold, especially in patients on aminophylline. 
Benzodiazepines such as midazolam 0.5 mg to 5 mg IV or lorazepam 0.5 mg to 5 mg IV or diazepam 0.5 
mg to 10 mg IV or oral, etc. may be given to mitigate CNS side effects at the discretion of the study MD. 
Admission for 23 hours observation to the inpatient medical oncology service will be considered if at the 
end of a study visit either excessive sedation is noted or RASS score between -3 and -5 or if any severe 
psychological manifestations exist.  
Gastrointestinal system effects: Include nausea, vomiting and increased salivation (due to increased 
salivary and tracheobronchial mucous gland secretions).  Nausea and/or vomiting will be treated with 


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ondansetron 4 to 8 mg IV or PO depending upon severity. Diphenhydramine 6.25 to 25mg IV may be 
given, if no relief from ondansetron or if ondansetron is contraindicated. For increased salivation, not well 
tolerated by the patient, glycopyrollate 0.2mg IV may be given if deemed necessary by the study MD. 
Admit if unable to tolerate oral liquid at the end of visit.  
Respiratory effects: Respiratory depression is rare (ventilator response to CO2 is maintained).  Upper 
airway skeletal muscle tone is maintained; upper airway reflexes remain relatively intact.  Respiratory 
depression can occur when ketamine is given in conjunction with other agents (e.g. opioids) or when given 
in large doses or rapid infusions. Treatment may include: decrease/stop opioids and other sedating 
medications. If respiratory depression (RR < 10/min, O2 sat < 90%) persists at the end of the study visit, 
the study MD will be notified and potential admission will be considered, the patient’s will be admitted 
for 23 hour observation with the inpatient oncology service.  
Ocular effects: Nystagmus (especially vertical nystagmus), diplopia, blurred vision and slight elevation 
in intraocular pressure are possible. If this happens at the end of the study visit, the study MD will 
evaluate for safeness for discharge vs 23 hrs observation.   
Musculoskeletal effects: There is a possibility of increased skeletal tone or tonic-clonic movements. The 
study MD notified if this happens. This will be monitored and treated appropriately. Short acting 
benzodiazepines like IV midazolam may be considered.  
Allergic reaction: Ketamine does not evoke histamine release; and, rarely, if ever causes allergic reaction. If 
an allergic reaction is suspected then the reaction will be treated based on the severity, with steroids and 
antihistamine allergic agents.    
  
 
C.6 Benefits:  
The patient may benefit from improved pain control and improved mood or depression control by 
participating in this research study.  
 
C.7 Participant selection:  
A sample size of 7 from a population of 20 (in the study done by Carr et al.) achieves 91% power to detect 
a NPRS difference of -2.7 between the null hypothesis mean of 0.0 and the alternative hypothesis mean of 
2.7 with an estimated standard deviation of 1.9 and with a significance level (alpha) of 0.05000 using a two-
sided Wilcoxon test assuming that the actual distribution is normal.  
We need a sample size of 7 patients based on statistical analysis observed in the study done by Carr. We will 
include 10 patients to account for the possibility that the observed pain reduction in the current study may 
be different than the study done by Carr, as in this study patients were given ketamine for breakthrough pain, 


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as opposed to for baseline pain. We will enroll up to 25 patients in the study to account for potential dropouts. 
If a higher dropout rate is observed, then we will enroll more patients until we have at least 10 patients who 
complete the entire study.  
Subject Replacement 
Any subject who does not complete the IV dosing and at least one intranasal dose will be replaced and 
followed for safety as needed and/or via telephone call at 14 days. 
Enrolled subjects who discontinue early will be replaced.  
If a subject misses more than one treatment visit during the study period, the subject will be withdrawn and 
replaced to achieve a minimum of 10 subjects who are maximally treated with study medication (4 study 
visits). 
The patients should meet the following inclusion and exclusion criteria.  
 
C.8 Inclusion Criteria:  Patients will be eligible to participate if they are:  
 
1. Male and female subjects at least 18 years of age 
2. Patients with uncontrolled pain related to cancer or cancer treatment. Uncontrolled pain 
will be defined as 46,47  
i. pain which persists for more than 7 days and is rated >/=4 on NPRS  
ii. use of breakthrough medication more than 4 times in 24 hours or being 
treated with oral morphine equivalent of 50 mg/d or more   
 
3. Patients who are48 able to follow-up in person during the trial  
4. Patient on stable analgesic regimen for >7 days without escalation during study period 
with rescue or immediate release medication every 3 hours or longer  
5. Patients who are willing and able to maintain a daily pain diary   
6. Patients who are able to understand written and verbal English  
7. Patient weight >/= 50 kg  
  
C.9 Exclusion Criteria: Patients will be excluded from the study if they have any of the 
following:  
 
1. Transportation issues interfering with return study visits   
2. Patients with high disposition of laryngospasm or apnea  
3. Presence of severe cardiac disease  


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4. Presence of conditions where significant elevations in blood pressure would be a serious 
hazard.  
5. Stage 2 hypertension or greater (systolic blood pressure > 160 and/or diastolic blood 
pressure >100)  
6.  Baseline tachycardia, HR >100  
7. History of seizures, elevated ICP or CSF obstructive states(e.g. severe head injury, 
central congenital or mass lesions)  
8. Conditions that may increase intraocular pressure (e.g. glaucoma, acute globe injury)  
9. History of uncontrolled depression or other psychiatric comorbidity with psychosis  
10. History of liver disease  
11. History of interstitial cystitis 
12. History of nasal or sinus anomalies or dysfunction e.g. allergic or infectious rhinitis.  
13. Patients with lesions to the nasal mucosa 
14. Pregnant women, nursing mothers and women of childbearing potential not using 
contraception known to be highly effective. Highly effective contraception  methods 
include combination of any two of the following:  
i. Use of oral, injected or implanted hormonal methods of contraception 
or;  
ii. Placement of an intrauterine device (IUD) or intrauterine system (IUS);   
iii. Barrier methods of contraception: condom or occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal 
suppository;  
iv. Total abstinence;  
v. Male/female sterilization.  
15. Illicit substance abuse within the past 6 months  
16. Documented history of medication abuse/misuse (e.g.  Unsanctioned dose escalation, 
broken opioid agreement etc.) 
17. Clinical requirement for medications that are concurrent inducers or strong inhibitors of 
CYP3A4. CYP3A4 substrates are allowed. (Appendix II-D) 
18. Porphyria (possibility of triggering a porphyric reaction)  
19. Severe active anemia ( a hemoglobin< 8 documented by labs drawn within 3 months of 
first study treatment)  
20. History of difficult intravenous access  
21. Intractable vomiting  


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C.10 
Informed Consent Process: 
Informed consent will be obtained by a research team member delegated to do so by the PI, prior to 
conducting any research procedures. This process will include a discussion of risks and benefits, as well 
as answering patient questions. If patients are able to provide their own medical history, they will be 
deemed capable of providing informed consent for research participation. The process will be free of 
coercion. Study patients will be paid a small amount to reimburse for travel expenses for each visit 
completed. They can withdraw at any time without penalty to their ongoing care.  
  
C.11 
Compensation for time and effort:  
A compensation of $50 per visit will occur with each patient for each completed visit to reimburse for 
travel expenses to and from the institution.  
  
C.12 
Statistical analysis:   
 
Study results will be analyzed as below to achieve the study objectives:  
 
1. Determine pharmacokinetics of intranasal ketamine.  
Concentrations of ketamine and its metabolite norketamine will be analyzed to determine 
pharmacokinetic characteristics such as bioavailability, peak effect and elimination.  
2. Determine pharmacodynamics of intranasal ketamine in terms of Patient Reported 
Outcomes  
i. Pain scores on NPRS will be analyzed by Wilcoxon signed-rank test as 
the study sample size is too small to be analyzed by paired –t test. 
Generalized Linear Model will be used to model any time trend for pain 
score change and to test if the trend is significant.  
ii. T-test will be used to compare any changes in depression severity on 
MADRS.  
iii. Chi-square test will be used to test presence/absence of any side effects. 
Wilcoxon signed rank test will be used to assess the severity of all the 
side effects (including SERSDA), if needed.   
iv. Paired T-test will be used to asses any changes in functional status on 
PROMIS scale.   
v. T-test will be used to compare any changes in ESAS and ECOG.  
3. Determine PK-PD relationships of NAS ketamine delivered 


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Timing, degree and duration of change in pain scores will be compared 
with individual and group pharmacokinetic parameters to assess 
potential relationships between measures of exposure (Cmax, and AUC0-
t) and pain relief. Multivariate modeling including patient-specific data 
(age, sex, weight, BMI, morphine equivalents) will be performed using 
initial PK parameters and goodness of fit analyses for compartmental 
model selection. If applicable, data from vital sign measurement 
changes will also be used as comparison with pharmacokinetic data. 
4. Determine opioid sparing effect of intranasal ketamine.   
i. Chi-square test will be used to compare frequency of rescue medication 
use.  
ii. T-test will be used to compare total opioid consumption.  
 
 
C.13 Data and Safety Monitoring and Reporting Plan:   
 
1. This study will be followed by the Winship Cancer Institute Data Safety Monitoring Committee 
(DSMC) for local review and confirmation of proper study execution and safety measures. Initial study 
monitoring will occur within 6 months from the date of the first subject accrued, with 2 of the first 5 
subjects reviewed. Therefore, subsequent monitoring will occur in six month intervals if any subjects 
were accrued. The population continuing to receive intervention will be monitored as determined by 
the DSMC. At minimum, 10% of subjects accrued since previous monitoring will be reviewed. An 
additional subject (or subjects) may be selected based on previously noted monitoring deficiencies or 
at DSMC discretion.  Continued monitoring will occur in six month intervals for the population 
continuing to receive intervention as determined by the DSMC. 
 
The DSMC will review pertinent aspects of the study conduct including patient safety, protocol 
compliance, data collection, and efficacy. The PI or designee will be responsible for notifying the 
DSMC of patient accrual and status updates within two months of the planned review. 
 
2. Procedures to assure data integrity and protocol adherence:  
a) A monthly meeting of investigators, clinical research coordinators and regulatory personnel 
will be held to review the clinical data. 
b) Adverse event reporting will utilize the Common Terminology Criteria for Adverse Events  
CTCAE) version 5.0. The grading scale for these adverse events is as follows:   
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 


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Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL) 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4 Life-threatening consequences; urgent intervention indicated 
Grade 5 Death related to AE. 
c) 
A serious adverse event (SAE) is an AE or suspected adverse drug reaction that fulfills one 
of the following: 
• 
results in death  
• 
is immediately life-threatening (life-threatening in the definition of SAE refers to an 
event in which the subject was at immediate risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more 
severe). 
• 
requires in-subject hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability or incapacity 
• 
is a congenital anomaly or birth defect 
• 
is an important medical event: important medical event in the definition of “serious 
refers to those events which may not be immediately life-threatening, or result in 
death, or hospitalization, but from medical and scientific judgment may jeopardize the 
subject and/or may require medical or surgical intervention to prevent one of the other 
outcome listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization. Development of cancer or drug 
dependency or drug abuse will normally be considered serious by this criterion. 
d) Study progress in terms of enrollment and activity of current patients will be reviewed during 
the monthly meeting of the investigators, clinical research coordinators and regulatory 
personnel. The PI may increase the frequency of this meeting if necessary.  
e) 
Study specific training of all study personnel, including management of potential adverse 
events, will occur prior to initiating study enrollment using the final approved protocol and 
study specific standard operating procedure document. Training of the Phase I staff will be 
conducted by the team clinical research coordinator prior to study enrollment. Completion 
of training will be documented on a study training log and stored in the regulatory binder. 
Investigators will complete CITI training as well as any additional training required by the 
Emory Office for Clinical Research. 


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3. Clinical monitoring will occur as previously described (Study Methods).  
 
4. As the  IND sponsor-investigator,  unexpected fatal or life threatening suspected adverse reactions 
will be reported using the Medwatch FDA form 3500A via FedEx to the FDA no later than 7 calendar 
days after the initial receipt of information (21CFR 312.32(C)(2)).  Additionally, serious, unexpected 
suspected adverse reactions and a clinically important increase in the rate of a serious suspected 
adverse reaction will be reported to no later than 15 calendar days after determining the information 
qualifies for reporting (21 CFR 312.32 (C) (1)) in paper format using FDA form 3500A. Finally, an 
annual progress report will be provided within 60 days of the anniversary date that the IND became 
active , January 20, 2017, (21 CFR 312.33). 
 
5. Patient data will be evaluated by the PI on an ongoing basis during the study visits to observe for any 
trends in adverse effects of the study treatment, to ensure continued subject safety and to ensure the 
scientific validity of the trial. Adverse events (AE) will be recorded. An adverse event is defined as 
any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product or study treatment and that does not necessarily have a causal relationship 
with this administration.  An AE can therefore be any unfavorable and unintended sign (including 
any abnormal laboratory findings), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) product. 
Adverse events will be captured from the time of the first study drug administration through the fifth 
study visit. Ongoing adverse events at the fifth visit will be followed with a telephone call visit 14 
days (plus or minus 1 day) after the last medication administration. AEs will be reported to the PI by 
Emory email or telephone. All adverse events will be documented in an AE log. The reporting 
policy of the Emory IRB will be followed.  
  
6. The study will be stopped after a hospitalization that is related to study drug administration for a formal 
review by the PI and the DSMC. When a hospitalization related to study drug administration occurs, 
the study will be put on hold. The PI or delegated person will communicate the event details to the 
DSMC for their review and determination of approval to continue the study. The study will be ended 
if there is more than one hospitalization related to the study drug administration.  
 
7. The Emory University School of Medicine Department of Anesthesiology will conduct this study 
according to national rules, regulations and guidelines governing human clinical research. In addition, 


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procedures cited by the US Code of Federal Regulations (Title 21) will be followed as these apply to 
the principles of Good Clinical Practice and approval by the Emory University Institutional Review 
Board (IRB).   
 
 
Confidentiality: The privacy of the research subjects will be ensured through the standard procedures for 
securing research data. All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and regulations, will not be made publicly available.  Subjects will be 
identified by a study number. If the results of the study are published, the subject’s identity will remain 
confidential.  
  
C.14 Potential Pitfalls:  
 
Lack of blinding/Lack of placebo arm. There is enough evidence to support an analgesic effect of 
ketamine. Since the study is being conducted in cancer pain patients and involves blood draws and 
transport, a placebo arm is considered to be unethical in these circumstances. The possibility exists that 
ketamine might have long term effects beyond its duration of action and the pain scores might be 
significantly lower than the compared to at the beginning of the study. In this case change in pain score 
may not be significant during the later study visits. However, overall this would be a good effect for 
pain control and can future studies can be designed to account for this effect. As cancer pain can be 
evolving and changing, the decision was made to finish all the study visits in the least possible duration of 
time, as possible.  Once feasibility and safety is established with this study, the aim of future studies will 
be allow patients to take this medication at home for maintenance. Lack of standard opioid regimen 
among patients could be problematic in terms of comparison of outcomes.  
 
 
E. REFERENCES/BIBLIOGRAPHY 
  
1. van den Beuken-van Everdingen, M. H. et al. Prevalence of pain in patients with cancer: 
a systematic review of the past 40 years. Ann Oncol 18, 1437-1449, 
doi:10.1093/annonc/mdm056 (2007).  
 
2. Malinovsky. Ketamine and norketamine plasma concentrations after i.v., nasal and 
rectal administration in children. Br J Anaesth.  , 77(72):203-207 (1996 Aug;).  
 
3. Reich, D. L. & Silvay, G. Ketamine: an update on the first twenty-five years of clinical 
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Appendix I: Assessment scales used in the study (click on files G, H, and I to open the files).  
A. 
Numerical pain rating scale. 
 
B. 
SERSDA –Side Effects Rating Scale for Dissociative Anesthetics[20, 40] 
Side effects 
Severity of side effects scale 
Fatigue 
0, no change  
Dizziness 
1, weak  
Nausea 
2, modest  
Headache 
3, bothersome   
Feeling of unreality 
4, very bothersome 
Changes in hearing 
 
Changes in vision 
 
Mood change 
 
Generalized discomfort 
 
Hallucination 
 
 
 
C. 
ECOG score 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 


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5 
Dead 
 
 
  
D. ESAS score - Edmonton Symptom Assessment System  
Please circle the number that best describes how you feel NOW:  
No Pain                  0 1 2 3 4 5 6 7 8 9 10 Worst Possible Pain  
  
No Tiredness            0 1 2 3 4 5 6 7 8 9 10 Worst Possible Tiredness  
(Tiredness = lack of energy)  
  
No Drowsiness          0 1 2 3 4 5 6 7 8 9 10 Worst Possible Drowsiness  
(Drowsiness = feeling sleepy)  
  
No Nausea              0 1 2 3 4 5 6 7 8 9 10 Worst Possible Nausea  
  
No Lack of Appetite 0 1 2 3 4 5 6 7 8 9 10 Worst Possible Lack of Appetite  
  
No Shortness of Breath 0 1 2 3 4 5 6 7 8 9 10 Worst Possible Shortness of Breath  
  
No Depression            0 1 2 3 4 5 6 7 8 9 10 Worst Possible Depression  
(Depression = feeling sad)  
  
No Anxiety                0 1 2 3 4 5 6 7 8 9 10 Worst Possible Anxiety  
(Anxiety = feeling nervous)  
  
Best Wellbeing     0 1 2 3 4 5 6 7 8 9 10 Worst Possible Wellbeing  
(Wellbeing = how you feel overall)  
  
No __________       0 1 2 3 4 5 6 7 8 9 10 Worst possible __________  
Other Problem (for example constipation)  
 
 
 
 
 
 


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E. RASS Scale to Assess Sedation.-PDF file.   
 
   
  
 
 
 
 
 
 
 


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F. CAM scale to assess for delirium if RASS score is between +4 to -3. –PDF file.   
 
 
 
  
  
  
  
 
 
 
 
  
 
 


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G. PHQ-9 questionnaire.-PDF file.  


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H. MADRS questionnaire to be filled out based on clinical interview during the study.-PDF file  
 
I. 
PROMIS questionnaire.  


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J. Weekly Pain Diary 
 


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Appendix II: Ketamine related information (click on files A, B, and C to open the files) 
$ Test summary sheets from NMS labs where ketamine and its metabolites will be measured.  

Lab testing ketamine.xps
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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B.  Ketamine product insert. –PDF file 
 


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C.  Ketamine 500mg/5ml multidose vial safety data sheet from manufacturer, Hospira.-PDF   file.  
 


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D. -Cytochrome P450 3A4 and 3A5 Known Drug Interaction Chart 
CYP3A4 and CYP3A5 Substrates 
CYP3A4 and CYP3A5 Inhibitors 
ANTIHISTAMINES 
NEUROPSYCHIATRIC 
STRONG INHIBITORS 
astemizole 
alprazolam 
clarithromycin 
chlorpheniramine 
diazepam 
 indinavir 
ANTIMETRIC 
midazolam 
itraconazole 
aprepitant 
triazolam 
ketoconazole 
ondansetron 
haloperidol 
nefazodone 
ANESTHESIA/PAIN 
aripiprazole 
ritonavir 
cafergot 
buspirone 
saquinavir 
codeine-N-demethylation 
carbamazepine 
suboxone 
fentanyl 
pimozide 
telithromycin 
levolevomethadyl acetate (LAAM)  
quetiapine 
INTERMEDIATE STRENGTH INHIBITORS 
lidocaine,   
risperidone 
aprepitant 
methadone 
trazodone 
erythromycin 
ANTIBIOTIC/ANTIVIRAL 
zaleplon 
fluconazole 
alfentanil 
ziprasidone 
grapefruit juice 
boceprevir 
zolpidem 
verapamil 
clarithromycin 
ONCOLOGY 
diltiazem 
efavirenz 
docetaxel 
WEAK INHIBITORS 
erythromycin (not CYP3A5),  
gleevec 
cimetidine 
indinavir 
irinotecan 
OTHER POSSIBLE INHIBITORS 
nelfinavir 
paclitaxel 
amiodarone 
nevirapine 
romidepsin 
boceprevir 
quinine 
sorafenib 
chloramphenicol 
ritonavir 
sunitinib 
ciprofloxacin 
saquinavir 
torisel 
delaviridine 
telaprevir 
vemurafenib 
diethyl-dithiocarbamate 
telithromycin. 
vincristine 
fluvoxamine 
CARDIOVASCULAR 
PULMONARY 
gestodene 
amlodipine 
salmeterol 
imatinib 
cilostazol 
sildenafil  
mibefradil 
diltiazem 
STEROID 
mifepristone 
eplerenone 
dexamethasone 
norfloxacin 
lercanidipine 
estradiol 
norfluoxetine 
nifedipine 
hydrocortisone 
starfruit 
nisoldipine 
progesterone 
telaprevir 
nitrendipine 
testosterone 
voriconazole 
propranolol 
OTHER 
 
quinidine (not CYP3A5) 
cocaine 
 
verapamil 
dapsone 
 
HMG COA REDUCTASE INHIBITORS 
dextromethorphan 
 
atorvastatin 
finasteride 
 
lovastatin 
simvastatin 
IMMUNE MODULATORS 
cyclosporine 
sirolimus 
tacrolimus 
nateglinide 
 


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CYP3A4 and CYP3A5 Inducers 
barbiturates 
carbamazepine 
efavirenz 
glucocorticoids 
modafinil 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifabutin 
St. John's Wort 
troglitazone