Clinical trial NCT02459964
Conditions: Advanced Cancers Pain
Keywords: Advanced Cancers Pain Fentanyl nasal spray Hydromorphone hydrochloride Phone call Numeric Rating Scale NRS
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-09-14; Completion date: 2020-06-21
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to compare fentanyl nasal spray with a standard drug given by vein (hydromorphone hydrochloride) to help reduce pain related to cancer in patients coming to the emergency department.

Detailed description:
Study Groups and Drug Administration:

If participant agrees to take part in this study, they will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. This is done because no one knows if one study group is better, the same, or worse than the other group. Participant will have an equal chance of being in either group:

* If participant is in Group 1, they will receive the fentanyl nasal spray. The study staff will help participant use the nasal spray.
* If participant is in Group 2, the emergency center nurse will give them the hydromorphone hydrochloride by vein.

Study Procedures:

Participant will stay in the emergency department for at least 4 hours and will be monitored after receiving fentanyl or hydromorphone hydrochloride. During this time, participant will be asked about their pain and any side effects they may be having every 15 minutes for 2 hours and then every 30 minutes for another 2 hours. The study staff will also monitor participant's vital signs, and ask them a few more questions at the end of the study.

Length of Study Participation:

Although participant will stay in the emergency department for at least 4 hours, the average length of stay for participants with severe pain is about 9 hours. When participant is discharged from the emergency department or admitted to the hospital, their active participation in the study is over.

Follow-Up Phone Call:

About 24 hours after patient's active participation is over, the study nurse will call them to ask if they had any other side effects since taking part in the study. The phone call should last about 5 minutes. If participant is still an inpatient at the hospital, the study nurse may visit them and ask them these questions in person.

This is an investigational study. Hydromorphone hydrochloride is FDA approved and commercially available for the treatment of pain. Fentanyl nasal spray is FDA approved and commercially available for the treatment of pain. Its use to help with cancer pain in the emergency department is investigational.

Up to 84 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Fentanyl nasal spray 100 mcg delivered at time 0 (defined as the time when intranasal Fentanyl spray is administered) with a rescue dose allowed at time 0.5 hour (h).

Study nurse to call patient 24 hours after participation to ask about side effects since taking part in the study. arm 2: Hydromorphone hydrochloride 1.5 mg pushed intravenously (IV) at time 0 (defined as the time of completion of opioid IV push) with a rescue dose allowed at time 0.5 hour (h).

Study nurse to call patient 24 hours after participation to ask about side effects since taking part in the study.
Interventions: intervention 1: Fentanyl Nasal Spray intervention 2: Hydromorphone Hydrochloride intervention 3: Phone Call
Intervention descriptions: intervention 1: Fentanyl nasal spray 100 mcg delivered at time 0 (defined as the time when intranasal Fentanyl spray is administered) with a rescue dose allowed at time 0.5 hour (h) intervention 2: Hydromorphone hydrochloride 1.5 mg pushed intravenously (IV) at time 0 (defined as the time of completion of opioid IV push) with a rescue dose allowed at time 0.5 hour (h). intervention 3: Study nurse to call patient 24 hours after participation to ask about side effects since taking part in the study. The phone call should last about 5 minutes.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
A randomized trial to compare fentanyl nasal spray with 
intravenous opioids to treat severe pain in cancer patients in the 
emergency department setting. 
2015-0086 
 
Core Protocol Information 
Short Title  
Compare fentanyl nasal spray with intravenous opioids to treat severe pain 
Study Chair:  
Sai-Ching J. Yeung 
Additional Contact: Cristina Gonzales 
Denise M. Langabeer 
Srinivas R. Banala 
Additional Memo 
Recipients: 
OPR groups to be copied on all memos: 
Department: 
Emergency Medicine 
Phone: 
713-745-9911 
Unit: 
1468 
Full Title:  
A randomized trial to compare fentanyl nasal spray with intravenous opioids to treat severe 
pain in cancer patients in the emergency department setting. 
Protocol Type: 
Standard Protocol 
Protocol Phase: 
N/A 
Version Status: 
Activated 03/21/2016 
Version: 
06 
Document Status: 
Saved as "Final" 
Submitted by: 
Srinivas R. Banala--3/21/2016 11:40:00 AM 
OPR Action: 
Accepted by: Inar Y. Graur -- 3/21/2016 12:59:12 PM 
Which Committee will review this protocol? 
 
The Clinical Research Committee - (CRC) 
Protocol Body 
 
 
 
 


2 
 
Title:  A randomized trial to compare fentanyl nasal spray with intravenous opioids to treat 
severe pain in cancer patients in the emergency department setting. 
Study Chair:  
Sai-Ching Jim Yeung 
 
Study Co-Chair  
 
Knox Todd 
 
1.  
Objectives 
 
The primary objective of this project is to test the non-inferiority of fentanyl nasal spray versus 
intravenous opioids in the change in pain intensity at one hour, starting from the time of drug 
delivery, in adults with cancer presenting to the ED with severe pain. 
 
Secondary Objectives:   
1. To compare the change in pain intensity [measured using an 11-point (0 to 10) Numeric 
Rating Scale (NRS)] at one hour after randomization in the fentanyl nasal spray arm to 
that in the intravenous opioid arm among adults with cancer presenting to the Emergency 
Department (ED) with severe pain (NRS≥7). 
2. To monitor the safety and side effects of fentanyl nasal spray and intravenous opioids in 
adults with cancer presenting to the ED with severe pain. 
3. To estimate the time from randomization to IV establishment in adults with cancer 
presenting to the ED with severe pain. 
 
Exploratory Objectives: 
1. To compare the time to maximal pain relief of fentanyl nasal spray and intravenous 
opioids in adults with cancer presenting to the ED with severe pain. 
2. To compare the summed pain intensity difference of fentanyl nasal spray and intravenous 
opioids in adults with cancer presenting to the ED with severe pain. 
 
2.  
Background 
It is estimated that approximately 30 to 50% of patients undergoing antineoplastic therapy and 75 
to 90% of patients with advanced cancer have chronic pain severe enough to warrant opioid 
therapy (Kanner, 1996; Vainio A, 1996; WHO, 1996).  In 18 studies reporting pain severity 
among cancer patients, one-third of patients rated pain as moderate to severe (Everdingen, 2007).   
Unfortunately, many of these patients are under-treated.   Recent studies performed both in Italy 
and in Europe demonstrated that pain was present in all phases of the cancer spectrum and was 
not adequately treated in a large number of patients, ranging from 56% to 82% (Constantini, 
2009; Breivik, 2009). 
 
Acute breakthrough cancer pain is commonly caused by diagnostic or therapeutic interventions 
such as surgery (e.g., pneumonectomy for lung cancer).  Chronic cancer pain is more associated 
with cancer itself or to antineoplastic therapy. Most patients with chronic cancer pain will also 
experience periodic flare ups of pain, or “breakthrough pain” (Fine, 2003).  The recognition of 
breakthrough pain as a significant problem among cancer patients in the midst of their long-term 
opioid therapy has supported the use of “rescue doses”.   The rescue dose is often a short-acting 


3 
 
opioid administered during the midst of cancer breakthrough pain (Portenoy, 2009). All patients 
who are receiving slow-release opioids should also have access to immediate-release opioids that 
can be used for breakthrough pain (Bruera, 2003).  
 
Pain is one of the leading reasons for seeking care in the ED (Cordell, 2002), yet it is often 
undertreated in the ED setting because of inadequate assessment and treatment or fears of 
addiction (Rupp, 2004).  In addition, there are few well-designed clinical studies of analgesic 
therapy in the ED setting (Todd, 2004).     
Two recently published reports conclude that pain management practices in emergency 
departments have much room for improvement. The term, “oligoanalgesia”, has been coined to 
describe the underutilization of analgesics in the emergency room setting.  Ritsema et al. (2007) 
reported a study of national scope examining the quality of emergency department pain 
management for long-bone fractures. According to the report only 50% of subjects received a 
dose of an opioid analgesic for pain relief.  Similarly, Todd et al. (2007) reported a multicenter 
emergency department study in which median pain intensity upon arrival was rated as severe, or 
at least 8 out of 10, on an 11-point scale (from 0 to 10).  Only 60% of subjects received any 
analgesic, with half of those treated receiving an opioid or opioid/NSAID, and even then after a 
median delay of 90 minutes for administration. They ascribe these results to overcrowded 
facilities and physicians focusing more on the cause of the symptoms than treating the pain. A 
paper by Fry and Holdgate (2002) suggests that there could be greater use of nurse-initiated 
analgesic administration under physician-directed protocol to improve the standards and quality 
of care. One could speculate that improved treatment of acute pain will reduce the incidence of 
“central sensitization” from post-traumatic injury pain, and subsequent transition of an acute pain 
incident into a chronic pain condition, with all the morbidity and dysfunction subsequent to this 
outcome. 
 
Intravenous hydromorphone titration (the “1+1” protocol) is a well-accepted ED analgesic 
regiment to allow safe analgesia to patients presenting with severe pain. The regimen involves 
administering 1 mg of hydromorphone intravenously, followed by an additional 1 mg if 
requested by the patient.  The efficacy of the “1+1” hydromorphone patient-driven protocol has 
been found both clinical and statistically superior to usual care of ED patients with acute severe 
pain. (Chang, 2011)   
 
One barrier to delivering effective ED analgesia for severe pain using this method is that it 
requires assembling the materials for intravenous (IV) administration.  Particularly if this is the 
only reason to establish IV access, other routes of analgesic administration would be useful.  
Kendall et al. (2001) addressed this problem by conducting a study of nasal diamorphine (the 
chemical cousin of hydromorphone) as compared to intramuscular morphine in children and 
teenagers with long-bone fractures.  The study demonstrated rapid onset of pain relief that was 
superior to intramuscular morphine and that subjects much preferred the nasal spray to an 
injection.  They concluded that there was no longer a need to administer intramuscular morphine 
given this data.   
 
Gahir and Ransom (2006) have developed an integrated care pathway involving intranasal 
diamorphine for pediatric analgesia in an accident and emergency department.  The standard of 
care protocol for use of intranasal diamorphine provided clear directions for nursing staff to 


4 
 
intervene quickly with the nasal spray analgesic.  Borland et al. (2007) has also reported a study 
of intranasal fentanyl compared to IV morphine using a double-dummy design in long-bone 
fracture subjects presenting to the emergency department.  They report that nasal fentanyl and IV 
morphine at standard doses provide equivalent rates and depths of analgesia.  They conclude that 
nasal fentanyl administration may be preferred since there are no inherent delays with drug 
delivery preparation and administration and consequently nursing staff are able to “reduce time 
to analgesia”. 
 
The sum of experience from these studies is that there remains a significant unmet medical 
need to provide prompt analgesia in emergency departments.  Creative clinical scientists have 
attempted to use drug delivery, and specifically nasal drug delivery, to address the issues of 
time to drug administration and to analgesia. More importantly, in the Emergency Department 
(ED) setting, the ease of analgesic administration and time to pain relief are of primary concern. 
Because intranasal delivery does not require establishment of intravenous access, intranasal 
fentanyl spray may potentially provide pain relief more rapidly than intravenous opioids. We 
propose to compare fentanyl nasal spray (Lazanda) to intravenous opioids in terms of how well 
pain relief can be achieved among ED patients of a comprehensive cancer center who present 
with severe pain.     
 
 
3 
Rationale for Agent Selection 
Lazanda (fentanyl) nasal spray has been approved by the FDA (July 2011) for the management 
of breakthrough pain in adult cancer patients.  The drug has been approved for persistent cancer 
pain among patients already receiving and tolerant to opioid therapy.  Intranasal fentanyl 
provides a new approach to managing the acute severe pain that many patients with cancer 
experience.   
 
Advantages to an intranasal mode of fentanyl administration include a rapid onset of action, a 
noninvasive route of administration, high bioavailability with avoidance of hepatic first-pass 
metabolism and high patient acceptability.  As compared to other rapid acting forms of fentanyl 
(oral transmucosal or buccal fentanyl) intranasal fentanyl may be used in the patients with 
radiation-induced xerostomia (dry mouth).  In addition, a recent meta-analysis reports that 
intranasal fentanyl has a faster onset of action than oral transmucosal fentanyl citrate, buccal 
fentanyl tablets, or oral morphine (Vissers, 2010).  
 
4.  
Study Drug Information 
Description 
Lazanda (fentanyl) nasal spray is a liquid formulation of fentanyl citrate intended for intranasal 
transmucosal administration.  The product consists of a clear, colorless, aqueous solution of 
fentanyl citrate in a glass multidose container to which is attached a metered-dose nasal spray 
pump with a visual and audible spray counter.  Each actuation is designed to deliver a spray of 
100 mcL of solution containing 100 mcg fentanyl base.  This enables doses of 100 mcg to be 
administered using a single spray into one nostril (1 spray).   
 
Active ingredient: Fentanyl citrate, USP is N-(l-phenethyl-4-piperidyl) propionanilide citrate 
(1:1).  Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 


5 
 
816:1).  Fentanyl citrate is sparingly soluble in water (1:40).  The molecular weight of the free 
base and citrate salt are 336.5 and 528.6, respectively.  The pKa is 8.4. 
 
Lazanda is available in 2 strengths of nasal spray: 100 mcg fentanyl (yellow label) and 400 mcg 
fentanyl (violet label).  The strength is expressed as the amount of fentanyl free base per spray, 
e.g., the 100 mcg strength provides 100 mcg of fentanyl free base per 100 mcL spray.  
 
Inactive ingredients: mannitol, pectin, phenylethyl alcohol, propylparaben, sucrose, water. 
Sodium hydroxide and/or hydrochloric acid are added if required for pH adjustment. 
 
Mechanism of Action  
Fentanyl is a pure opioid agonist whose principal therapeutic action is analgesia. Other members 
of the class known as opioid agonists include substances such as morphine, oxycodone, 
hydromorphone, codeine, and hydrocodone. 
 
Pharmacokinetics  
Absorption:  
In a study that compared the relative bioavailability of Lazanda and an oral transmucosal 
fentanyl citrate product, the bioavailability of fentanyl from Lazanda was approximately 20% 
higher.  Fentanyl is absorbed from the nasal mucosa following intranasal administration of 
Lazanda, with median Tmax values ranging from 15-21 min after administration of a single dose. 
Cmax and AUC values for fentanyl following administration of Lazanda increase linearly over 
the 100- to 800-mcg dose range. 
Distribution:  
Fentanyl is highly lipophilic.  The plasma protein binding of fentanyl is 80% to 85%.  The main 
binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to 
some extent.  The mean volume of distribution at steady state (Vss) was 4 L/kg. 
Metabolism:  
The metabolic pathways following intranasal administration of Lazanda have not been 
characterized in clinical studies.  The progressive decline of fentanyl plasma concentrations 
results from the uptake of fentanyl in the tissues and biotransformation in the liver.  Fentanyl is 
metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 
isoform.  In animal studies, norfentanyl was not found to be pharmacologically active. 
Elimination:  
The disposition of fentanyl following intranasal administration of Lazanda has not been 
characterized in a mass balance study.  Fentanyl is primarily (more than 90%) eliminated by 
biotransformation to N-dealkylated and hydroxylated inactive metabolites.  Less than 7% of the 
administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged 
in the feces.  The metabolites are mainly excreted in the urine, while fecal excretion is less 
important.  The total plasma clearance of fentanyl following intravenous administration is 
approximately 42 L/h. 
 
Adverse Reactions 
Clinical Studies Experience  
Because clinical trials are conducted under widely varying conditions, adverse event rates 
observed in the clinical trials of a drug product cannot be directly compared to rates in the 


6 
 
clinical trials of another drug and may not reflect the rates observed in practice.  The safety of 
Lazanda has been evaluated in a total of 523 opioid-tolerant patients with breakthrough cancer 
pain.  The average duration of therapy in patients in the long-term study was 73 days, with 153 
patients being treated for over 3 months.  Patients continuing into the open-label extension 
period of the safety study have been treated for up to 26 months.  The most commonly observed 
adverse events seen with Lazanda are typical of opioid side effects, such as nausea, constipation, 
somnolence, and headache. 
 
5 
Eligibility Criteria 
The specific patient population to be studied is the patients presenting to the emergency center 
for treatment of severe pain in the context of cancer-related pain.     
 
Inclusion Criteria: 
1. Cancer patients with severe pain (i.e., ≥7 on NRS, see Table 1) already on opioid therapy 
for one week or longer, at least 60 mg of oral morphine/day, 25 mcg of transdermal 
fentanyl/hour, 30 mg of oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral 
oxymorphone/day, or an equianalgesic dose of another opioid. 
2. Ability to give informed consent before any trial-related activities (Trial-related activities 
are any procedure that would not have been performed during normal management of the 
subject.) 
3. Ability and willingness to communicate the intensity of pain using NRS at the frequency 
dictated by the protocol 
 
Exclusion Criteria: 
1. Patients with a history of chronic active hepatitis, cirrhosis or hepatic encephalopathy 
2. Inability to give informed consent 
3. Known or suspected hypersensitivity or intolerance to fentanyl or hydromorphone or 
excipients in the study medications  
4. Patients with sinusitis, obstruction of nasal passages, nasopharyngeal cancer, paranasal 
sinus malignancies, or any conditions in the nasopharyngeal anatomical area that may 
affect the absorption of fentanyl nasal spray. 
5. Females who are pregnant, breast-feeding or intending to become pregnant 
6. Females of child-bearing potential, who are not using adequate contraceptive measures 
(including condoms, birth control pills, intrauterine devices, contraceptive implants, or 
other US FDA-approved contraceptives) 
7. Previous participation in randomization in this trial  
8. Has taken oral immediate release opioids within 4 hours prior to arrival. 
 
Table 1. Numeric Rating Scale (NRS) 
Rating 
Pain Level 
0 
No Pain 
1 – 3 
Mild Pain (nagging, annoying, interfering little with ADLs) 


7 
 
4 – 6 
Moderate Pain (interferes significantly with ADLs) 
7 – 10 Severe Pain (disabling; unable to perform ADLs) 
*ADLs – Activities of daily living 
6 
Patient Recruitment and Informed Consent 
When a cancer patient presents to the ED for treatment of severe pain, we will assess their 
severity of pain using an 11-point (0 to 10) NRS (Table 1) at triage.  At the ED, eligible cancer 
patients will be approached for informed consent to participate in this study in the Triage Area 
immediately after ascertainment of the complaint of severe pain. If the NRS score is 7 or higher, 
the research nurse will conduct a brief screening physical examination (including vital signs and 
nasal exam), and review their medical history for eligibility (Figure A).  If we determine that the 
patient is eligible for the study, the research nurse will initiate a formal, informed consent 
process, discussing the risks, benefits, and study procedures with the patient, and answer any 
questions the patient has to the best of his/her ability.  The patient will be given his/her own 
personal copy of the written, informed consent document.  This process will be conducted while 
the patient is waiting for room assignment in the ED. 
 
7 
Treatment Plan (Figure A) 
 


8 
 
Figure A: Schematic diagram of the study design.  The primary objective of this project is to 
test the non-inferiority of fentanyl nasal spray versus intravenous opioids in the change in pain 
intensity at one hour, starting from the time of drug delivery (time 0). The patient will be 
evaluated by the responsible ED physician with physical examination, serum chemistries, and 
other diagnostic evaluations as appropriate according to current standard practice. After signing 
the informed consent, the research nurse will log on to a clinical research administration website 
[http://www.oncologyresearch.org/ows-doc/index.htm (CORe)] and randomize the patient to the 
study arms.  The time of randomization will be time stamped by the randomization software. The 
physician order for the study medication or the IV opioid will be signed by the ED physician. 
 
Baseline Measures 
The following baseline evaluations will be performed on consented subjects prior to study drug 
administration: vital signs, oxygen saturation, Ramsay Sedation Scale (Table 2) (Ramsay, 197). 
The baseline pain intensity will be rated using NRS, and a blood sample will be drawn for 
standard of care laboratory investigation of the cause of pain or exacerbation of pain.  
Intervention: 
Intervention Arm:  
A Lazanda dose [100 mcg] at time 0 (defined as the time when intranasal 
Lazanda spray is administered) with a rescue dose allowed at time 0.5 
hour (h). 
Control Arm:  
An equipotent opioid dose [hydromorphone 1.5 mg pushed intravenously 
(IV)] at time 0 (defined as the time of completion of opioid IV push) with 
a rescue dose allowed at time 0.5 hour (h).  
 
For subjects with pain NRS > 4 who desire additional analgesics at thirty minutes after Time 0 
(i.e., Time 30 minutes), a second dose of medication will be administered as in the table above.  
Subjects with excessive sedation (Ramsay Sedation Scale < 4) will not receive analgesics at 
Time 30 minutes.  
 
After another 90 minutes (i.e., Time 120 minutes), for patients with unrelieved pain (NRS >6 and 
Ramsay Sedation Scale <4), the patient may receive supplemental IV bolus doses of opioid as 
clinically indicated and ordered by the treating physician. 
 
Table 2. Ramsey Sedation Scale 
 
Wakeful State 
Scale 
Description 
If Awake 
 
Ramsey 1 
Anxious, agitated, restless 
Ramsey 2 
Cooperative, oriented, tranquil 
Ramsey 3 
Responsive to commands only 
If Asleep 
 
Ramsey 4 
Brisk response to light glabellar tap or loud auditory stimulus 
Ramsey 5 
Sluggish response to light glabellar tap or loud auditory stimulus 
Ramsey 6 
No response to light glabellar tap or loud auditory stimulus 
 
10 
Evaluation during Study 


9 
 
We will perform measurements described in this section for 4 hours after initiation of the drug 
intervention while the patient is in the ED.  The average length of stay for patients presenting 
with severe pain to our ED is currently 9 hours.  
 
Pain Measurements: Pain measurement by NRS will be obtained at the time of randomization, 
time of treatment initiation, and every 15 min from administration of the first dose of pain 
medication up to Time 120 min and then every 30 min from Time 120 min to Time 240 min.  At 
60 min after randomization, one additional NRS rating will be obtained.  
 
Primary Outcome Measure:  
The primary outcome measure is the non-inferiority of fentanyl nasal spray versus IV opioids in 
the treatment-wise response starting from the time of drug delivery. The decrease in pain level 
between treatment initiation and one hour after will be compared between intranasal fentanyl and 
an analgesic equivalent dose of intravenous opioid.  
 
Secondary outcome measures:   
For secondary objective 1, we will compare the decrease in pain level between randomization 
and one hour after randomization between intranasal fentanyl and an analgesic equivalent dose 
of intravenous opioid.  
 
For secondary objective 2, we will monitor the safety and side effects of fentanyl nasal spray and 
intravenous opioid. Safety evaluation will include vital signs, oxygen saturation and respiratory 
rate. Blood pressure, heart rate, oxygen saturation and respiratory rate will be monitored for 
abnormalities. Adverse reactions of nausea and vomiting and neuropsychiatric adverse effects 
will be monitored. Sedation will be measured by Richmond Agitation Sedation Scale (RASS). 
The side effects rating scale for dissociative anesthetics (SERSDA) will be assessed at the end of 
the study period.   
 
For secondary objective 3, we will estimate the time from randomization to IV establishment in 
adults with cancer presenting to the ED with severe pain. 
 
Exploratory measures: 
Time to maximal pain relief and Summed Pain Intensity Difference (SPID) (Davies et al., 2011) 
will be derived using NRS data for the 4-hour period for additional exploratory analyses. Time to 
maximal pain relief is defined as the time duration from Time 0 to the first occurrence of the 
lowest NRS in a subject.  Pain intensity difference (PID) at a time point is defined as the NRS at 
Time 0 minus the NRS at that time point.  The PID over the 4-hour study period will be 
integrated as the SPID using the trapezoidal method to calculate the area under the curve.  
 
11 
Adverse Events Recording 
11.1. Adverse Events Monitoring: 
Adverse event monitoring and reporting will begin after patients receive the study drug or IV 
hydromorphone and will continue to be recorded through discharge from the study.  Patients will 
be instructed to report all unusual events during the study.  All adverse events and corresponding 
treatment will be recorded in the case report forms and summarized in the final clinical study 
report.  Any ongoing adverse events will be followed up by phone if the patient is discharged 


10 
 
from the hospital or by patient visit if the patient is hospitalized, within 24 hours after study 
completion. 
 
Intranasal fentanyl is generally well tolerated with the most common side effects consisting of 
nausea, vomiting, headache, and sedation (side effects common to all opioids). 
 
Unexpected Adverse Drug Event 
All external adverse events/safety reports received from the sponsor will be submitted to the IRB 
through the Office of Protocol Research as described for the “External Adverse Event Report” 
located under section 1 of the OPR Forms Manual.  
 
Adherence to MDA Policy and Procedure for Reporting of Serious Adverse Events.  
This study will follow the MDA policy and procedures for reporting of adverse and serious 
adverse events. All adverse events and serious adverse events will be documented and available 
for review if desired. Criteria for reporting of events before routine review will be determined 
based on established institutional guidelines. 
 
12 
Criteria for Evaluation and Endpoint Determination 
Measurements 
NRS measures will be obtained at triage, randomization, time 0 (initiation of drug intervention) 
and every 15 minutes for 120 minutes and then every 30 minutes from time 2 to 4 hours, and at 
60 min after randomization.    
 
Vital signs, oxygen saturation and respiratory rate will be recorded at each time point of NRS 
measurement.  
Adverse reactions of nausea and vomiting and neuropsychiatric adverse effects will be 
monitored.  
Sedation will be measured by Richmond Agitation Sedation Scale (RASS) (Table 3) at Time 1 h 
(i.e., one hour after initiation of drug delivery).  RASS is a scale used to grade the sedation or 
agitation level of a patient in a clinical setting (Sessler et al., 2002). 
Table 3: Richmond Agitation Sedation Scale 
Points 
Classification 
Description 
4 
Combative 
Overtly combative or violent; immediate danger to staff 
3 
Very agitated 
Pulls on or removes tube(s) or catheter(s) or has aggressive 
behavior toward staff 
2 
Agitated 
Frequent nonpurposeful movement or patient–ventilator 
dyssynchrony 
1 
Restless 
Anxious or apprehensive but movements not aggressive or 
vigorous 
0 
Alert and calm 
 
-1 
Drowsy 
Not fully alert, but has sustained (more than 10 seconds) 
awakening, with eye contact, to voice 


11 
 
-2 
Light sedation 
Briefly (less than 10 seconds) awakens with eye contact to voice 
-3 
Moderate 
sedation 
Any movement (but no eye contact) to voice 
-4 
Deep sedation 
No response to voice, but any movement to physical stimulation 
-5 
Unarousable 
No response to voice or physical stimulation 
 
The side effects rating scale for dissociative anesthetics (SERSDA) (Table 4; Eide et al., 1994) 
will be assessed at time 4h.  
Table 4. Side effects rating scale for dissociative anesthetics  
 
Severity Scale: 0, no change; 1, weak; 2, modest; 3, 
bothersome; 4, very bothersome 
Side Effects 
Severity 
Fatigue 
 
Dizziness 
 
Headache 
 
Feeling of unrealitiy 
 
Changes in hearing 
 
Changes in vision 
 
Mood change 
 
Generalized discomfort 
 
Hallucination 
 
SERSDA score = 
Sum of the Severity Scores of the above side effects 
 
Study Variables 
PROCEDURE-WISE ANALGESIC EFFICACY: The change in pain level between 
randomization and one hour after randomization will be compared between the intranasal 
fentanyl arm and the intravenous opioid arm. The power calculations are based on this primary 
efficacy variable. 
TREATMENT-WISE ANALGESIC EFFICACY: Starting from the time of initiation of drug 
administration, the change in pain level after one hour will be compared between intranasal 
fentanyl arm and intravenous opioid arm. 
 
TOLERABILITY: Tolerability to common adverse effects such as nausea and vomiting 
will be monitored. Neuropsychiatric adverse effects will be assessed by RASS and SERSDA. 
RASS score will be obtained at Time 1 h. SERSDA will be assessed after the final pain rating.  
SAFETY: Blood pressure, heart rate, oxygen saturation and respiratory rate and adverse 
reactions will be monitored. Reports of adverse events will be collected spontaneously and in 
response to nondirected questioning.  Investigators will ask how long the adverse effect lasted 
and categorize these events by seriousness (mild, moderate, or severe) and relationship to 
treatment (not related, doubtful, possible, probably, or very likely). 
EMERGENCY CARE PROCESS CHARACTERIZATION: The time to IV 
establishment of adults with cancer presenting to the ED with severe pain after randomization 
will be estimated. Patients in both arms will have IV access. This time can be estimated using all 


12 
 
the study participants. The time to IV establishment can also be compared between the 2 study 
arms to check for bias in work flow in this open label study. 
 
13 
Data and Protocol Management 
All data from this study will be entered into a secured (password protected) database.  Hard copy 
records of the consent and copies of the survey instruments will be stored securely and 
maintained by the study staff.   Patient identifiers will be handled in a HIPAA-compliant manner.  
Confidentiality will be protected by identifying all medical information by the study with patient 
accession numbers, rather than storage by patient name or medical record number.     
 
14 
Criteria for Removal from Study 
 
  Since only one dose of Lazanda with one rescue dose in 30 min will be administered, 
patients with adverse reactions or side effects will not be removed from the study.  The adverse 
reactions or side effects will be managed medically according to standard care. 
 
15 
Statistical Considerations 
Sample Size Calculations 
This is a two-arm study enrolling 84 cancer patients who present to the emergency department 
with severe pain (NRS pain score ≥ 7). Consented participants will be equally randomized to 
receive fentanyl nasal spray or IV hydromorphone for pain treatment. MD Anderson’s Clinical 
Oncology Research System (CORe) will be used to register participants and randomize 
participants to the study treatment arms. 
 
The primary objective of the study is to examine the important secondary objective of testing the 
non-inferiority of nasal fentanyl relative to IV hydromorphone. At one hour after treatment 
initiation (rather than randomization) the change in NRS pain ratings for each group are assumed 
to be equal. We will have 80% power to detect non-inferiority of fentanyl nasal spray versus IV 
hydromorphone using a one-sided two-sample t-test, with a margin of equivalence of 0.9 and a 
significance level of 0.05 (Hintz, 2004). This sample size will also give us acceptable power to 
compare the two treatment groups on the pain intensity change from randomization (baseline) to 
one hour after randomization. Based on data presented in a meta-analysis of buccal and 
sublingual administration of fentanyl by Jandhyala et al. (2013), we estimate that the NRS pain 
intensity decrease from baseline will be 3.4 (SD 1.86) in the intranasal fentanyl arm at one hour 
after randomization. Although we are administering fentanyl using the nasal spray in the current 
study, the speed of absorption through the nasal mucosal should be similar to the speed of 
absorption through buccal or sublingual mucosa. Assuming that IV hydromorphone works at a 
speed similar to that of transmucosal fentanyl and that there is an average delay of 30 minutes 
from randomization to IV administration of hydromorphone, the expected NRS pain intensity 
decrease from baseline in the IV hydromorphone arm is 2.4 (SD 1.40) at one hour after 
randomization. A t-test with a 0.05 two-sided significance level will have 80% power to detect a 
1-point difference in pain intensity decrease reported by the fentanyl group versus the IV 
hydromorphone group when the sample size is 84 (42 per group) using unequal variances by 
treatment group (Jandhyala et al., 2013).  With an accrual rate of 8 participants per month, the 
expected enrollment duration is 10.5 months. Early withdrawal from the study is expected to be 
minimal and to be 5% at most. No adjustments to sample size will be made based on attrition. 
 


13 
 
Statistical Analysis 
All participants randomized in the study (intention-to-treat population) will be included in the 
primary endpoint analysis. Should a participant withdraw from the study before the 1-hour NRS 
pain assessment, the NRS value used in the analysis will be the last value carried forward. In 
addition, we will conduct a sensitivity analysis that includes only participants with a 1-hour post 
randomization NRS pain rating (per-protocol population). Study dropout rates will be reported 
by treatment arm. 
 
The mean change in pain intensity from treatment initiation until one hour after treatment 
initiation will be compared between the two arms. Non-inferiority will be evaluated by testing 
whether the lower bound of the 90% CI for difference in pain change scores is greater than -0.9, 
the margin of equivalence. Specifically, the mean change in NRS pain scores (assessed on an 11-
point Likert scale with 0 = no pain and 10 = worst pain) from treatment initiation to one hour 
post-initiation will be calculated for both groups. The group difference in pain change scores 
(mean pain change in the fentanyl group minus that in the IV hydropmorphone group) and the 
associated two-sided 95% CI for the difference will be estimated. Non-inferiority of nasal 
fentanyl over IV hydromorphone will be concluded if the lower bound of the 90% CI around the 
estimated difference in pain score change lies above -0.9 points. This analysis will be in the 
intention-to-treat population but will be repeated in the per protocol population for sensitivity 
analysis. Both sets of results will be considered for evaluating the study objective.  
 
The secondary efficacy endpoint is the change in NRS pain scores from randomization to one 
hour after randomization, which will be summarized using mean, standard deviation, minimum, 
median and maximum values. A two-sample t-test will be used to assess group difference in pain 
score change. In addition, analysis of covariance will be used to determine whether significant 
differences exist between the nasal fentanyl and IV hydromorphone groups in pain intensity 
scores at one hour post randomization with treatment group (fentanyl vs. IV hydromorphone) 
and baseline pain intensity included as independent variables. Models will be constructed to 
adjust for relevant baseline demographic and clinical factors, such as age, treatment dose, and 
disease type. Additional exploratory analyses will include time to maximal pain relief as well as 
summed pain intensity ratings for the entire observation period calculated as the sum of time-
weighted pain intensity scores. Group differences in the summed pain intensity will be assessed 
using the area under the curve derived using the trapezoidal rule (Cappelleri et al., 2009). 
 
Because study treatments are FDA approved for treatment of breakthrough pain in cancer 
patients, no formal safety monitoring rule will be established; however, all side effects and 
adverse events will be monitored continuously by the principle investigator. To address the 
secondary objective #2, the safety analysis will include data summaries of treatment side effects 
and adverse events by study group. Side effects will be tallied and reported by number and 
percent for the worst reported severity. Laboratory values and clinical measures will be 
summarized by treatment group using simple descriptive statistics, such as mean change from 
baseline value to the 4 hours after treatment initiation or end of treatment, whichever occurs first. 
In addition, any delayed side effects that occur during the first 24 hours will be reported. This 
randomized trial will be monitored by the MD Anderson Data Safety Monitoring Board. 
 


14 
 
For secondary objective # 3, we will calculate the mean and corresponding 95% confidence 
interval for time from randomization to establishment of the IV. Each of the 84 study patients 
will be included, because it is standard institutional procedure for all patients admitted for pain to 
the ED to receive an IV. A sample size of 84 produces a 95% confidence interval equal to the 
sample mean plus or minus 0.217 when the estimated standard deviation is 1.00. Analyses will 
be performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). P values 
<0.05 will be considered statistical significant. 
 
 
16 
Data Safety Monitoring Board 
This randomized trial will be monitored by the MD Anderson Data Safety Monitoring Board 
(MDACC DSMB). 
 
 
17 
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17 
 
 
Department of Emergency Medicine Protocol Prioritization List
Emergency Medicine
Study Type
Enrollment Site
Protocol No.
Study Chair
Disease Category
Priority
Title
Enrollment 
Funded
Status
Interventional
Emergency Center
2012-0982
Knox Todd, MD
Emergency 
Medicine-Pain
1
A randomized controlled double-
blind trial of fentanyl nasal spray 
(Lazanda) plus hydropmorphone 
demand PCA versus placebo 
nasal spray plus hydromorphone 
demand PCA for treatment of 
breakthrough cancer pain in the 
emergency department
3/60
Yes 
Active
Interventional
Other
2011-0079
Knox Todd, MD
Emergency 
Medicine-Pain
1
HIP-STAT
--
Yes 
Approved
Interventional
Other
2013-0560
Adam Miller, MD
Emergency 
Medicine-
Pulmonary 
Embolism
1
Do Retrievable Inferior Vena 
Cava Filters Reduce the Risk of 
Death or Experiencing a New 
Pulmonary Embolism in Patients 
with a Pulmonary Embolism?   A 
Prospective Multicenter 
Randomized Trial
0/3200
Pending
Approved
Study Type
Enrollment Site
Protocol No.
Study Chair
Disease Category
Priority
Title
Enrollment 
Funded
Status
Observational
Emergency Center
2012-0122
Knox Todd, MD
Emergency 
Medicine-Pain
1
Management of Chronic Pain in 
the Emergency Department
223/285
Yes
Active
Observational
Emergency Center
2012-0640
Ahmed Elsayem, 
MD
Emergency 
Medicine-Palliative 
Care
2
Delirium in the ED
231/500
Yes
Active
Observational/Lab
Other
2012-0642
Cielito Reyes-
Gibby, DrPH
Emergency 
Medicine-Pain
1
Neuropathic Pain in Head and 
Neck Cancer
24/1200
Yes
Active
Observational
Other
2012-1035
Cielito Reyes-
Gibby, DrPH
Emergency 
Medicine-Pain
2
Pain in Survivors of Head and 
Neck Cancer
145/500
No
Active
Observational
Other
Lab10-0985
Sai-Ching J. Yeung, 
MD
Emergency 
Medicine
3
Case-Control Study of metabolic 
syndrome and breast cancer in 
Puerto Rico
94/346
Yes
Active
Study Type
Enrollment Site
Protocol No.
Study Chair
Disease Category
Priority
Title
Enrollment 
Funded
Status
Lab-Based
Emergency Center
Lab06-0616
Sai-Ching J. Yeung, 
MD
Emergency 
Medicine
1
Generation of cell lines from 
tumor cells in bodily fluids
4/60
No
Active
Study Type
Enrollment Site
Protocol No.
Study Chair
Disease Category
Priority
Title
Enrollment 
Funded
Status
Retrospective Chart Review Other
DR09-0635
Katy Toale/Terry 
Rice, MD
Emergency 
Medicine
1
Implementation of a 
standardized sepsis order set
No
Active
Retrospective Chart Review Other
DR08-0066
Sai-Ching J. Yeung, 
MD
Emergency 
Medicine
1
A retrospective chart review of 
patients with oncologic 
emergencies
20,000
No
Active
Retrospective Chart Review Other
PA12-0378
Sai-Ching J. Yeung, 
MD
Emergency 
Medicine
1
A retrospective chart review of 
the effects of metabolism in 
cancer
80,000
No
Active
Retrospective Chart Review Other
PA13-0163
Sai-Ching J. Yeung, 
MD
Emergency 
Medicine
1
Association between body 
composition and docetaxel-
induced toxicity in male prostate 
cancer patients receiving single 
agent docetaxel therapy
1,200
No
Active
Retrospective Chart Review Other
PA13-0331
Knox Todd, MD
Emergency 
Medicine
1
Emergency Departments Visits 
among Cancer Patients in Harris 
County, TX
No
Active
Retrospective Chart Review Other
PA11-1022
Sai-Ching J. Yeung, 
MD
Emergency 
Medicine
1
Evaluation of Fibroblast Growth 
Factors as Circulating Markers of 
Prognosis and Response to 
Therapy in Breast Cancer Patients
No
Active
Retrospective Chart Review Other
PA13-0666
Sai-Ching J. Yeung, 
MD
Emergency 
Medicine
1
Non-Coding RNA and cytokines in 
sepsis and cancer
249
No
Active