Conditions: Moderate-to-severe Acute Pain
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 320
Healthy volunteers: no

Brief summary:
Study to evaluate the overall performance of the Zalviso System™ (sufentanil sublingual tablet system) 15 mcg

Detailed description:
320 adult postoperative in-patients, who met all study entry requirements, and were expected to require opioid analgesia for at least 24 hours, and up to 72 hours, after surgery were enrolled. Patients used the Zalviso™ (sufentanil sublingual tablet system) 15 mcg to self-administer a tablet of study drug as needed for pain. The System was evaluated for usability and functionality for up to 72 hours.

Arms:
arm 1: Zalviso™(sufentanil sublingual tablet system) 15 mcg

Interventions: intervention 1: Zalviso™ 15 mcg
Intervention descriptions: intervention 1: Zalviso™ (sufentanil sublingual tablet system) 15 mcg. Tablets to be self-administered by the patient as needed for pain, no more than every 20 minutes, for 24 hours and up to 72 hours

Protocol document:
ICF_001.pdf: 
 
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SUBJECT INFORMED CONSENT FORM AND HIPAA AUTHORIZATION 
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TITLE: 
A Multicenter, Open-Label Trial to Evaluate the Overall 
4 
Performance of the Zalviso System (sufentanil sublingual 
5 
tablet system) 15 mcg 
6 
 
7 
PROTOCOL #: 
IAP312 
8 
WIRB® Protocol #20152518 
9 
 
10 
SPONSOR:  
AcelRx Pharmaceuticals, Inc. 
11 
 
12 
INVESTIGATOR: 
Name 
13 
Address 
14 
City, State  Zip 
15 
Country 
16 
 
17 
STUDY-RELATED 
18 
PHONE NUMBER(S): 
Name 
19 
Number (24-hour number required) 
20 
 
21 
 
22 
PURPOSE OF THIS SUBJECT INFORMED CONSENT FORM 
23 
This Subject Informed Consent Form may contain words you do not understand.  
24 
Please ask the study doctor or the study staff to explain any words or procedures that 
25 
you do not clearly understand. 
26 
 
27 
You have been asked to take part in this research study because you have elected to 
28 
have surgery (for example, hip or knee replacement, or abdominal surgery).  Before you 
29 
decide to take part, it is important for you to know why the research study is being done 
30 
and what it will involve. 
31 
 
32 
The purpose of this form is to give you information about the research study.  If you 
33 
decide that you would like to take part in the study, you will be asked to sign this form.  
34 
By signing this form, you are giving your permission to take part in the study (if you 
35 
qualify) and become a study subject (or participant).  This form describes the purpose, 
36 
procedures, benefits, risks, discomforts and precautions of the research study.  Take 
37 
time to read the following information carefully and discuss it if you wish with a friend, 
38 
with relatives and/or with your personal doctor (that is, general practitioner or primary 
39 
care physician).  You should take part in the study only if you want to do so.  You may 
40 
refuse to take part or withdraw from this study at any time without penalty or loss of 
41 
benefits to which you are otherwise entitled.  Ask as many questions as needed.  You 
42 
should not sign this form if you have any questions that have not been answered to your 
43 
satisfaction. 
44 
 
45 
INTRODUCTION 
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This study is evaluating an experimental delivery system, the Zalviso System (sufentanil 
1 
sublingual tablet system), that is available at your bedside to allow you to deliver a very 
2 
small tablet of study drug (sufentanil, an opioid pain reliever) for the potential treatment 
3 
of post-operative pain when you need it.  Most doctors treat patients with post-operative 
4 
pain using opioid pain medications (such as morphine) given intravenously (IV) on an 
5 
“as needed” basis, or by using an IV patient-controlled analgesia (pain relief) device 
6 
(machine) to deliver on-demand patient-controlled pain relief called an IV PCA. 
7 
 
8 
The goal of the Zalviso is to decrease the amount of pain that you may experience as a 
9 
result of your surgery with a non-invasive way to give pain medication. 
10 
 
11 
The drug being evaluated in this study, sufentanil, has already been approved by the 
12 
U.S. Food and Drug Administration (FDA) for IV anaesthetic and analgesic use during 
13 
operative procedures.  It has not yet been approved for sublingual (under the tongue) 
14 
use, and its use in this study is “experimental.” 
15 
 
16 
This study is open-label, which means you and the study doctor know that you are 
17 
taking study drug (sufentanil) during the entire study.  All subjects in this study will 
18 
receive medication to treat their post-operative pain. 
19 
 
20 
AcelRx Pharmaceuticals, the sponsor, is paying the study doctor and the study site for 
21 
conducting this study. 
22 
 
23 
THE PURPOSE OF THE STUDY 
24 
The purpose of this study is to measure the safety and effectiveness of the Zalviso 
25 
System and how satisfied patients are with the Zalviso System for treatment of 
26 
moderate-to-severe acute post-operative pain. 
27 
 
28 
DURATION OF THE STUDY 
29 
Approximately 13315 subjects will be enrolled in this study at approximately 10 different 
30 
hospitals in the United States.  Your time in this study will include one screening visit up 
31 
to 30 days before your surgery and then participation for at least 24 hours, and up to 
32 
72 hours, from the time that you begin taking the study drug. 
33 
 
34 
In the sections below, information is presented on how subjects will be chosen to enter 
35 
this study, how the study will be performed, what the potential risks and benefits of 
36 
taking part in the study may be, and other information about this research study. 
37 
 
38 
SELECTION OF SUBJECTS 
39 
To take part in the study, you must: 
40 
 
41 
 Be at least 18 years of age. 
42 
 Be scheduled to undergo surgery (for example upper or lower abdominal surgery, 
43 
hip or knee replacement). 
44 
 Have a negative pregnancy test if you are a female of childbearing potential. 
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 Be using an effective method of birth control from the screening visit through the end 
1 
of the study if you are a female subject of childbearing potential.  Acceptable 
2 
methods of birth control include oral or transdermal contraceptives, condom, 
3 
spermicidal foam, intrauterine device (IUD), progestin implant or injection, 
4 
abstinence, vaginal ring, or sterilization of partner.  If you use a hormonal form of 
5 
birth control, you must also use a barrier method, from the time of your screening 
6 
visit through 30 days after your participation in the study ends. 
7 
 Be willing and able to understand the study procedures, be able to use the Zalviso 
8 
System, be able to use the pain scales and record your pain scores, and talk with 
9 
the study personnel.  You will be shown the Zalviso System and be allowed to 
10 
handle it during your screening visit. 
11 
 
12 
The study doctor or medical staff will discuss the other requirements that you must meet 
13 
in order to be able to enroll into the study and can answer any questions you may have 
14 
related to these criteria. 
15 
 
16 
Even if you meet all of the requirements at screening, due to safety concerns you may 
17 
not get the study drug if any of the following occur after your operation: 
18 
 
19 
 Your breathing rate is less than 8 breaths per minute or greater than 24 breaths 
20 
per minute. 
21 
 The oxygen level in your blood that cannot be maintained at 95% or greater with 
22 
or without the use of supplemental oxygen. 
23 
 You are not able to answer questions and follow instructions. 
24 
 You have vomiting that is not responding to treatment. 
25 
 
26 
STUDY PROCEDURES 
27 
 
28 
Overview 
29 
As part of this study, you will receive study drug for at least 24 hours, and up to 72 hours, 
30 
following your surgery.  All subjects will receive study drug (sufentanil) to treat their pain.  
31 
Additional IV morphine administered by a nurse is available if you have pain when you 
32 
try to get up and walk or when you start other therapy after your operation.  As a subject 
33 
in this study, you will complete a screening visit before your scheduled surgery, and have 
34 
a minimum of 24 hours in the study dosing period.  You may choose to continue to take 
35 
the study drug for another 48 hours for a total of 72 hours. 
36 
 
37 
Screening Visit 
38 
The screening visit will be completed within 30 days prior to your scheduled surgery.  
39 
You will be told why you are being asked to take part and what you will need to do to be 
40 
in the study.  You will be able to have the screening tests done after the study has been 
41 
discussed with you in detail.  During your screening visit, the following procedures will 
42 
be done: 
43 
 
44 
 Review, sign and date this consent form (this must be done before any other 
45 
study-related procedures) 
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 Evaluation for study entry criteria 
1 
 Medical history and physical exam 
2 
 A urine sample will be obtained for drugs of abuse screening, and a pregnancy 
3 
test for women of childbearing potential.  A blood sample may be used for the 
4 
pregnancy test. 
5 
 Training on the Zalviso System 
6 
 
7 
Inpatient Admission (Study Day 1) 
8 
After the screening visit, if you qualify to take part in the study, you will be eligible for the 
9 
treatment phase of the study. 
10 
 
11 
While you are in the pre-operative area, the study staff will also re-instruct you on the 
12 
definitions associated with a 0-10 pain scale and how to use the Zalviso System. 
13 
 
14 
If you are a woman of childbearing potential, you will provide urine for a pregnancy test. 
15 
 
16 
After your operation, you will be taken to the PACU (Post-Anesthesia Care Unit), where 
17 
you will begin to recover from the surgery and anaesthesia.  You must be awake and 
18 
able to respond to questions and instructions to continue on the study. 
19 
 
20 
You may receive morphine, fentanyl, or hydromorphone as your IV opioid pain 
21 
medication to control your pain immediately after surgery in the PACU.  During your 
22 
stay in the PACU, your pain must be adequately treated with these IV medications in 
23 
order to continue on the study.  You will begin the study drug once you have left the 
24 
PACU or are ready to leave the PACU. 
25 
 
26 
You will self-administer study drug by using the Zalviso System. 
27 
 
28 
To self-administer a tablet of study drug under your tongue, you will take the cap off the 
29 
Zalviso System, place the dispenser tip under your tongue, press the dose button, and 
30 
wait for the dosing sounds to stop before removing the dispenser tip from your mouth. 
31 
 
32 
You will need to let the tablet dissolve under your tongue and not crush, chew or 
33 
swallow the tablet.  You also will not be able to eat or drink anything for 10 minutes after 
34 
you have placed the tablet under your tongue.  You should also minimize talking for 
35 
10 minutes after taking a tablet.  These directions apply for all the study drug tablets you 
36 
take. 
37 
 
38 
You will self-record on paper your pain intensity score prior to administering the first 
39 
dose, and then self-record pain intensity and pain relief scores at the following times 
40 
after you get the first dose:  15 minutes, 30 minutes, 45 minutes, 60 minutes, 
41 
120 minutes, and then every 2 hours through the first 12-hour study period, and every 
42 
4 hours from 12 to 72 hours.  The study staff may wake you up if you are asleep when it 
43 
is time to record your pain and pain relief scores.  Within the first 30 minutes after you 
44 
receive the first dose of the study drug, you will be allowed to receive a dose of IV pain 
45 
medication (2 mg morphine) if needed to keep you comfortable. 
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1 
You will be able to self-administer study drug each time you need it, but you will need to 
2 
wait at least 20 minutes in between doses when using the Zalviso System.  This is 
3 
because the Zalviso System is factory programmed to only deliver a tablet every 
4 
20 minutes to make sure you do not take too much study drug. 
5 
 
6 
If you feel after the first dose of study drug that you are not satisfied with your level of 
7 
pain relief, or at any time during the study if you are having pain due to walking or the 
8 
start of therapy for your operation, you may request additional IV pain medication 
9 
(morphine 2 mg).  If your pain is unmanageable or you are too uncomfortable, you may 
10 
withdraw from the study and receive other pain treatment that will be decided by your 
11 
doctor. 
12 
 
13 
You will be able to receive Tylenol® during the study period if you have a headache or 
14 
fever during the study.  You will be able to receive other non-opioid medications for pain 
15 
control that your doctor prescribes for you. 
16 
 
17 
Your vital signs (heart rate, blood pressure, breathing rate and oxygen saturation 
18 
[amount of oxygen in the blood]) will be measured at the start of the study period.  Heart 
19 
rate and blood pressure will be measured after the first dose of sufentanil on the 
20 
following schedule: every 15 minutes for an hour, then 120 minutes after first dose, then 
21 
every 2 hours through first 12 hours, then every 4 hours throughout the rest of the 
22 
study). 
23 
 
24 
Your breathing rate may be checked at additional times as needed per the judgment of 
25 
the study staff, but at least every 30 minutes through the first 24 hours, then every 
26 
2 hours through the rest of the study.  Oxygen saturation will be measured continuously 
27 
by an instrument that fits over your finger, which is called pulse oximetry.  If your 
28 
breathing rate is too low, or there is not enough oxygen in your blood, or you are too 
29 
sedated, these symptoms will be managed, and you may be withdrawn from the study. 
30 
 
31 
You will be asked to report any side effects that you may experience during the study. 
32 
 
33 
End of Study/Early Withdraw 
34 
 
35 
At the end of the study, whether you complete the 24-hour study period, the 72-hour 
36 
study period, or come off of the study early, you will be asked to give a global 
37 
assessment of the study drug’s effectiveness on a 4-point scale where 1 = poor, 2 = fair, 
38 
3 = good, and 4 = excellent.  You will also be asked to answer a short questionnaire on 
39 
the use of the Zalviso System. 
40 
 
41 
POSSIBLE RISKS, INCONVENIENCES AND DISCOMFORTS 
42 
 
43 
The most common side effects related to the study medication reported by patients in 
44 
previous AcelRx studies were nausea, vomiting, oxygen saturation decreased (low level of 
45 
oxygen in your blood), pruritus (feeling itchy), dizziness, constipation, headache, insomnia 
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(unable to sleep or stay asleep), hypotension (low blood pressure), and confusional state 
1 
(feeling confused). 
2 
 
3 
Due to the possible severe side effect of low level of oxygen in your blood due to a 
4 
decrease in your breathing rate, your blood oxygen levels are monitored continuously in 
5 
this study and your breathing rate is measured 02at least every 30 minutes for the first 24 
6 
hours13, then every 2 hours through the rest of the study. 
7 
 
8 
Per the package insert for the sufentanil, adverse events (AEs) in clinical trials that were 
9 
considered to be probably related to sufentanil and that occurred in more than 1 in 100 
10 
patients (1%): 
11 
 
12 
 Cardiovascular:  slow heart rate*, elevated blood pressure*, low blood pressure* 
13 
 Musculoskeletal:  stiffening of the chest wall (difficulty taking a deep breath)* 
14 
 Central Nervous System (CNS):  feeling sleepy* 
15 
 Dermatological:  feeling itchy (25%) 
16 
 Gastrointestinal:  nausea*, vomiting* 
17 
(* = reported incidence of 3% to 9%) 
18 
 
19 
Side effects considered to be probably related to sufentanil and occurring in less than or 
20 
equal to 1 out of 100 patients (1%) were: 
21 
 
22 
 Body as a whole: severe allergic reaction. Severe allergic reactions can be life-
23 
threatening. 
24 
 Cardiovascular: fast or irregular heart beat*, heartbeat stopping 
25 
 CNS: chills* 
26 
 Dermatological: redness of the skin* 
27 
 Musculoskeletal: stiffening of the neck or arms or leg muscles 
28 
 Respiratory: stopping of breathing*, wheezing*, slowed breathing* 
29 
 Miscellaneous: intraoperative muscle movement* 
30 
(* = reported incidence of 3 in 1000 to 1 in 100 patients; italics indicate that the side 
31 
effect was reported in postmarketing surveillance, but not seen in clinical trials). 
32 
 
33 
Opioids can interact with certain medicines that increase the effects of serotonin, a chemical in 
34 
the brain.  The medicines include antidepressants and migraine medicines, and the interaction 
35 
causes a serious central nervous system reaction called serotonin syndrome.  If you are taking an 
36 
opioid along with a serotonergic medicine, you should seek medical attention immediately if you 
37 
develop symptoms such as agitation; hallucinations; rapid heart rate; fever; excessive sweating; 
38 
shivering or shaking; muscle twitching or stiffness; trouble with coordination; and/or nausea, 
39 
vomiting, or diarrhea.  Symptoms generally start within several hours to a few days of taking an 
40 
opioid with another medicine that increases the effects of serotonin in the brain, but symptoms 
41 
may occur later, particularly after a dose increase. 
42 
 
43 
Taking opioids may lead to a rare, but serious condition called adrenal insufficiency in which the 
44 
adrenal glands do not produce adequate amounts of the steroid hormone, cortisol, particularly 
45 
during stressful conditions.  Seek medical attention if you experience symptoms of adrenal 
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insufficiency such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low 
1 
blood pressure. 
2 
 
3 
 
4 
Interaction with other medications 
5 
The effects of the study drug may change when taken with other drugs, so it is very 
6 
important to tell the study staff about any drugs (prescribed by a doctor or over the 
7 
counter) that you take. 
8 
While not reported during any AcelRx studies of sublingual sufentanil tablets, recently, it has 
9 
been determined that opioids combined with drugs that increase brain serotonin concentrations 
10 
(such as certain antidepressants and migraine medications), on occasion, can produce serotonin 
11 
syndrome (with symptoms that include agitation, hallucinations, rapid heart rate, fever, muscle 
12 
twitching and incoordination, nausea, vomiting and/or diarrhea).   
13 
 
14 
 
15 
Other risks 
16 
Answering questionnaires frequently throughout your stay in the hospital may interfere 
17 
with your rest or sleep. 
18 
 
19 
By taking part in this study, you may not be able to take part in other research studies 
20 
for a period of 30 days. 
21 
 
22 
There may be other risks that are currently not known. 
23 
 
24 
REPRODUCTION (PREGNANCY) RISKS 
25 
Women who are pregnant or breastfeeding cannot be in this study; therefore, a 
26 
pregnancy test will be done on admission to the hospital.  If the pregnancy test is positive, 
27 
you cannot be in this study. 
28 
 
29 
Women of childbearing potential must use a medically acceptable method of birth control.  
30 
Acceptable methods include: oral or transdermal contraceptives, condoms, spermicidal 
31 
foam, IUD, progestin implants or injections, abstinence, vaginal ring, or sterilization of 
32 
partner.  If you use a hormonal form of birth control, you must also use a barrier method.  
33 
These methods must be used during this study and for 30 days after the last dose of the 
34 
study drug.  The Zalviso System has not been tested during pregnancy and may pose 
35 
risks to an unborn child that are currently unforeseeable.  You should not become 
36 
pregnant until 30 days after your last dose of study drug. 
37 
 
38 
NEW INFORMATION 
39 
During the course of the study, you will be informed of any new findings that may affect 
40 
your willingness to continue taking part in this study.  You may contact the study doctor 
41 
at any time after your taking part ends to find out if any new information about this study 
42 
has become available. 
43 
 
44 
POTENTIAL BENEFITS 
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If the study drug is effective, you may benefit by having a reduction in your post-
1 
operative pain level following surgery.  It is possible that you may not personally benefit 
2 
from taking part in this study.  However, by taking part in this study, you may contribute 
3 
new information that may benefit patients in the future. 
4 
 
5 
PAYMENT FOR TAKING PART 
6 
There is no payment for taking part in this study. 
7 
 
8 
[OR] For your taking part in this study, you will be paid $[Amount] for each completed 
9 
visit. 
10 
 
11 
COST FOR TAKING PART IN THIS STUDY 
12 
There will be no cost to you for study drug, clinic visits, examinations or laboratory and 
13 
test procedures that are part of this study.  Medical costs of other treatment outside this 
14 
study are your responsibility and will be charged to you or your health insurance 
15 
company or local health agency. 
16 
 
17 
ALTERNATIVE TREATMENTS 
18 
You do not have to be in this study to receive pain treatment.  If you decide not to take 
19 
part in this study, you have other treatment choices that will be described to you by your 
20 
doctor, such as other opioids such as fentanyl, morphine, or hydromorphone, given on 
21 
demand through an IV.  You are urged to discuss these treatments with your primary 
22 
physician to learn if these drugs might benefit you. 
23 
 
24 
CONFIDENTIALITY 
25 
The personal medical information collected from you during this study will be kept 
26 
confidential (private) to the extent required by law.  If you agree to take part in the study, 
27 
your medical information will be collected and recorded by the study doctor and study 
28 
staff.  You will be identified by a subject number, assigned to you as part of the study, 
29 
on data collection forms and laboratory results.  Your name or any other data that may 
30 
identify you will not be used in any reports or publications resulting from this study.  
31 
Because of the research goals of this study, however, your medical information cannot 
32 
be kept completely confidential.  By consenting to take part, your medical records, 
33 
including personal information that may identify you, may be reviewed and/or copied by: 
34 
 
35 
 the study doctor and his/her staff; 
36 
 staff of the hospital or clinic where you are being treated; 
37 
 staff or agents/designees of the study sponsor, AcelRx Pharmaceuticals, Inc.; 
38 
 the FDA (the U.S. drug agency), State Regulatory Agencies, and/or other 
39 
medicine control agencies in other countries; and 
40 
 the Institutional Review Board that reviewed this protocol 
41 
 
42 
The above listed parties will be able to review and/or copy your medical information only 
43 
in connection with carrying out obligations relating to this study, to ensure that the study 
44 
is being carried out correctly, to review the results of the study, or for regulatory 
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purposes, or research purposes.  Because of the need to disclose information to these 
1 
parties, absolute confidentiality cannot be guaranteed. 
2 
 
3 
Your personal identifiers (for example, name, address, health insurance carrier) will be 
4 
kept by your study doctor in a secure place with access to the information restricted. 
5 
 
6 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
7 
required by U.S. Law.  This Web site will not include information that can identify you.  
8 
At most, the Web site will include a summary of the results.  You can search this Web 
9 
site at any time. 
10 
 
11 
You will have the right to withdraw your consent to take part in the study at any time.  If 
12 
you withdraw from the study, no new information will be collected from you and added to 
13 
the existing data or database.  However, the study sponsor may still use information 
14 
about you that was shared with the study sponsor before you withdrew your consent.  If 
15 
you withdraw your consent, you cannot continue to take part in the study, but 
16 
there will be no penalty or loss of benefits to which you are otherwise entitled. 
17 
 
18 
COMPENSATION FOR INJURIES 
19 
If you become injured during this study and your injury is a direct result of the study drug 
20 
given to you in this study according to the study directions, treatment for the injury will be 
21 
made available through the study doctor and the clinic or hospital.  The sponsor, AcelRx 
22 
Pharmaceuticals, Inc., will pay the costs of this treatment to the extent that such treatment 
23 
is not paid by your medical insurance or by third-party or governmental programs.  For 
24 
this to happen, the injury, in the opinion of the study doctor and AcelRx Pharmaceuticals, 
25 
Inc., must be confirmed to have been directly caused by the proper use of the study drug 
26 
in accordance with the study directions.  No other financial compensation will be provided 
27 
from the sponsor.  If you would like further information about compensation for research-
28 
related injuries, please ask your study doctor. 
29 
 
30 
LEGAL RIGHTS 
31 
Your taking part in this study does not affect your right to seek legal assistance for any 
32 
injury alleged to have been suffered as a direct result of administration of the study 
33 
drug.  By signing this consent form, you have not waived any of your legal rights. 
34 
 
35 
VOLUNTARY WITHDRAWAL FROM THE STUDY 
36 
Your decision to take part in this research study is completely voluntary.  Your medical 
37 
care will not be affected if you decide not to take part.  There will not be any penalty or 
38 
loss of benefits to you if you decide not to take part. 
39 
 
40 
In addition, you may withdraw from the study at any time.  If you decide to withdraw 
41 
from the research study, there will be no penalty or loss of benefits to you.  Before 
42 
withdrawing from this study, notify your study doctor that you wish to withdraw.  This 
43 
notice will allow your study doctor to inform you if there are any potential medical risks 
44 
of withdrawal.  Information collected from you prior to withdrawal will be used in the 
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study.  The study doctor will tell you about new information that may affect your health, 
1 
welfare, or willingness to stay in this study. 
2 
 
3 
INVOLUNTARY WITHDRAWAL FROM THE STUDY 
4 
The U.S. Food and Drug Administration (FDA), the study doctor, the Institutional Review 
5 
Board, or the sponsor, AcelRx Pharmaceuticals, Inc., may stop your taking part in this 
6 
study with or without your consent at any time.  The reasons for study termination may 
7 
include, but not be limited to: 
8 
 
9 
 You fail to follow the study procedures outlined above; 
10 
 You experience a serious side effect which requires your discontinuation from the 
11 
study for safety reasons; 
12 
 The study doctor or sponsor decides that continuing the study would be harmful to 
13 
you; 
14 
 You have a change in your condition which requires medications/procedures not 
15 
allowed in this study; 
16 
 You have a positive pregnancy or drugs of abuse (that is inconsistent with your 
17 
medical history) test; and/or 
18 
 The study is terminated by the FDA, the Institutional Review Board, or the sponsor. 
19 
 
20 
QUESTIONS ABOUT THE STUDY OR YOUR RIGHTS AS A RESEARCH SUBJECT 
21 
For questions, concerns or complaints concerning the research, or if you feel you are 
22 
developing side effects from the study dosing, contact: 
23 
 
24 
Principal Investigator Name: 
[Name] 
25 
 
26 
Daytime telephone number(s): [Number] 
27 
 
28 
24-hour contact number(s): 
[Number] 
29 
 
30 
If for any reason you suffer a serious event that requires hospitalization or requires that 
31 
you take additional medication, you should inform the doctor treating you that you are 
32 
taking part in a research study and give the study doctor’s telephone number. 
33 
 
34 
If you have any questions about your rights as a research subject, concerns or 
35 
complaints about the research, or want to discuss a problem, get information or offer 
36 
input, you may contact the Western Institutional Review Board at 1019 39th Avenue SE 
37 
Suite 120, Puyallup, Washington 98374-2115, 1-800-562-4789 (toll free) or 360-252-
38 
2500, E-mail: Help@wirb.com.  An Institutional Review Board is a group of scientific and 
39 
non-scientific individuals who perform the initial and ongoing ethical review of the 
40 
research study with the study subject’s rights and welfare in mind.  If you have study-
41 
related comments, complaints or concerns, you should first contact the study 
42 
investigator.  Please call the Institutional Review Board if you want to talk to someone 
43 
other than the study investigator or have difficulty reaching the study investigator. 
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WIRB will not be able to answer some study-specific questions, such as questions 
1 
about appointment times.  However, you may contact WIRB if the research staff cannot 
2 
be reached or if you wish to talk to someone other than the research staff. 
3 
 
4 
SUBJECT’S STATEMENT OF CONSENT 
5 
 
6 
A Multicenter, Open-Label Trial to Evaluate the Overall Performance of the Zalviso 
7 
System (sufentanil sublingual tablet system) 15 mcg 
8 
 
9 
I voluntarily give my informed consent to take part in this research study (IAP312).  I 
10 
may decide not to take part or to withdraw from the study at any time without penalty or 
11 
loss of benefits or treatment to which I am entitled.  If I choose to leave the study before 
12 
the end of the study period, I will notify the study doctor and he/she will explain the best 
13 
way for me to discontinue. 
14 
 
15 
I have been given sufficient opportunity to consider the information related to the Zalviso 
16 
System and the study, as well as to discuss my participation in the study with others 
17 
and to decide whether or not to take part in this study.  I have read this information, 
18 
which is printed in English.  This is a language that I read and understand.  I have been 
19 
told that my information will be uniquely numbered to prevent direct identification and 
20 
that this information will be processed in line with the requirements of the regulatory 
21 
authorities.  The site staff has explained the information and procedures involved in the 
22 
study and I have had the opportunity to ask questions, which have been answered to 
23 
my satisfaction.  I have been told that I do not give up any of my legal rights by signing 
24 
this form.  My signature certifies that I agree to take part in this study and I agree to the 
25 
use and disclosure of my medical information as stated in this consent form.  I will 
26 
receive a signed and dated copy of this consent form to keep for my own information 
27 
throughout the study. 
28 
 
29 
 
30 
 
 
31 
Printed Name of Subject 
32 
 
33 
 
34 
 
 
 
 
35 
Signature of Subject 
Date 
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37 
I certify that the information provided was given in a language that was understandable 
38 
to the subject. 
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Printed Name of Person Conducting Informed Consent Discussion 
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Signature of Person Conducting Informed Consent Discussion Date 
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2 
 
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[Printed Name of Witness 
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6 
 
7 
 
 
 
 
8 
Signature of Witness 
Date] 
9 
[**FOR VA SITES ONLY**] 
10 
 
11 
HIPAA AUTHORIZATION 
12 
 
13 
The United States government has issued a privacy rule to protect the privacy rights of 
14 
patients.  This rule was issued under a law called the Health Insurance Portability and 
15 
Accountability Act of 1996 (HIPAA).  The Privacy Rule is designed to protect the 
16 
confidentiality of your personal health information.  The document you are reading, called 
17 
an “Authorization,” describes your rights and explains how your health information will be 
18 
used and disclosed (shared). 
19 
 
20 
As part of the above referenced study, medical information about you will be collected 
21 
and analyzed.  This medical information may include (but is not limited to): 
22 
 
23 
 Information obtained from procedures performed to determine whether you can 
24 
take part in the study, including a medical history, physical examination, urine 
25 
drug test and urine pregnancy test. 
26 
 Information that is created or collected from you during the study, including all 
27 
tests performed during the study. 
28 
 Information contained in your medical records related to your medical history and 
29 
treatment. 
30 
 
31 
By signing this document, you authorize the study doctor and staff to use this 
32 
information in conducting the study, and to provide access to and copies of this 
33 
information to the study sponsor or to others working with the sponsor to monitor the 
34 
progress of the study, analyze the study data, and for regulatory and research 
35 
purposes.  Access to this information is necessary for the sponsor to check that the 
36 
study is being done correctly, and to collect and analyze data about the safety and 
37 
effectiveness of the study drug.  Regulatory authorities, such as the U.S. Food and Drug 
38 
Administration (FDA) and the Institutional Review Board may also review or copy your 
39 
information to make sure that the study is done properly, to review the results of the 
40 
study, to decide whether to approve the use of the Zalviso System, or for other 
41 
purposes required by law.  By signing this form, you are agreeing to these uses of your 
42 
medical information identified in this form. 
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This Authorization to use or disclose the information as described above does not end 
1 
when the study ends.  In signing this form, you agree to the use and disclosure of this 
2 
information for the purposes described above at any time in the future. 
3 
 
4 
You agree that, while the study is still in progress, you may not be given access to 
5 
medical information about you that is related to the study.  While a request for access to 
6 
medical information can be denied, the study doctor and staff will not automatically deny 
7 
a request, but will consider whether it is medically appropriate under the circumstances 
8 
to allow access.  Your agreement that you may be denied access to your study-related 
9 
medical information during the study will not be used to deny you access to that 
10 
information after the study is completed at all locations and study results are analyzed. 
11 
 
12 
If at any time before, during or after the study, you have any questions about the use or 
13 
disclosure of your study-related information, we ask that you contact the study doctor at 
14 
the phone numbers listed on the first page of this document. 
15 
 
16 
You may choose to withdraw this Authorization at any time, but you must notify the 
17 
study doctor in writing.  Send your written withdrawal notice to the following address: 
18 
 
19 
[Contact name and address] 
20 
 
21 
If you withdraw from the study and withdraw your approval to share your medical 
22 
information, no new information will be collected for study purposes unless the 
23 
information concerns an adverse event (a bad effect) related to the study.  If an adverse 
24 
event occurs, your entire medical record may be reviewed.  All information that has 
25 
already been collected for study purposes, and any new information about an adverse 
26 
event related to the study, will be sent to the sponsor and may continue to be reviewed 
27 
and/or copied by the parties listed in this Authorization. 
28 
 
29 
You should know that once information is disclosed under this Authorization to someone 
30 
who is not a health care provider, the information is no longer protected by the federal 
31 
privacy rules called the “HIPAA privacy regulations,” and could be disclosed to others by 
32 
the recipient. 
33 
 
34 
This Authorization does not have an expiration date.  If you do not withdraw this 
35 
Authorization in writing, it will remain in effect indefinitely.  [***will expire December 31, 
36 
2050, unless you withdraw it in writing before then.  (FOR WA SITES, DE, IL, IN, CA, 
37 
WI)***]  Your study doctor will keep this Authorization for at least 6 years. 
38 
 
39 
You may decide not to sign this document, or you may change your mind and decide to 
40 
withdraw your approval to share your medical information in writing at any time.  
41 
However, you can only take part in the study if you authorize the use and disclosure of 
42 
the information as described above.  If you decide not to sign this document, you will not 
43 
be enrolled in the study.  If you sign this document and decide later to change your mind 
44 
and withdraw your approval to share your medical information, you will be withdrawn 
45 
from the study at that time.  Information collected up to the time you withdraw your 
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approval will continue to be used as study data if it is scientifically appropriate to do so.  
1 
Your decision to withdraw your Authorization or not to take part will not involve any 
2 
penalty or loss of access to treatment or other benefits to which you are entitled. 
3 
 
4 
AUTHORIZATION 
5 
I authorize the release of my medical records and personal health information related to 
6 
this study to the sponsor and its representatives, the Institutional Review Board, the 
7 
FDA, and other regulatory agencies as described above.  I have been told that I will 
8 
receive a signed and dated copy of this Authorization for my records. 
9 
 
10 
 
11 
 
 
12 
Printed Name of Subject 
13 
 
14 
 
15 
 
 
 
 
16 
Signature of Subject 
Date 
17 
 
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Printed Name of Person Obtaining Authorization 
21 
 
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Signature of Person Obtaining Authorization 
Date 
25 

Prot_002.pdf: 
AcelRx Pharmaceuticals 
1 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
A Multicenter, Open-Label Trial to Evaluate the Overall 
Performance of the Zalviso System (sufentanil sublingual 
tablet system) 15 mcg 
 
Protocol No. IAP312 
 
 
 
 
 
 
 
 
 
AcelRx Pharmaceuticals, Inc. 
351 Galveston Drive 
Redwood CityCA94063 
Phone: 650-216-3500 
 
 
 
Original Protocol Date: 14 October 2015 
Amendment #1: 13 January 2016 
 
IND #75,051 
 
 
 
 
This document and its contents are the property of AcelRx Pharmaceuticals, Inc. and 
are confidential.  Unauthorized copying or use is prohibited. 


AcelRx Pharmaceuticals 
2 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
STUDY APPROVALS 
A Multicenter, Open-Label Trial to Evaluate the Overall Performance of the 
Zalviso System (sufentanil sublingual tablet system) 15 mcg 
IAP312 
 
 
Sponsor Approval: 
 
Signature:    
 
 
 
 
 
         Date:      
Name:  
Pamela Palmer, M.D., Ph.D. 
Title:  
Chief Medical Officer 
 
Signature:    
 
 
 
 
 
         Date:      
Name:  
Mark Evashenk 
Title:  
VP Clinical Operations 
 
Signature:    
 
 
 
 
 
         Date:      
Name:  
Yu-Kun Chiang, Ph.D. 
Title:  
AcelRx Pharmaceuticals Statistical Consultant 
 
Signature:    
 
 
 
 
 
         Date:      
Name:  
Kim Gaumer 
Title:  
VP, Regulatory Affairs& Quality Assurance 
 
 
Investigator Agreement: 
I have read Protocol IAP312 Amendment #1 “A Multicenter, Open-Label Trial to 
Evaluate the Overall Performance of the Zalviso System (sufentanil sublingual tablet 
system) 15 mcg” dated 13 January 2016 and agree to conduct the study in accordance 
with it. 
 
 
Signature:    
 
 
 
 
 
         Date:      
 
Print Name: __________________________________ 
 


AcelRx Pharmaceuticals 
3 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
SYNOPSIS 
Title: A Multicenter, Open-Label Trial to Evaluate the Overall Performance of the 
Zalviso System (sufentanil sublingual tablet system) 15 mcg 
Sponsor:  AcelRx Pharmaceuticals, Inc. 
Investigational Product:  sufentanil sublingual tablet system, 15 mcg 
Active Ingredient:  sufentanil citrate 
Investigators: Multicenter 
Country: USA 
Protocol No.:  IAP312 
Clinical Phase: 3 
Patients:  Up to 330 adult postoperative in-patients who are expected to require opioid 
analgesia for at least 24 hours, and up to 72 hours, after surgery will be enrolled in 
order to ensure at least 315 patients will receive study drug and provide Zalviso 
(sufentanil sublingual tablet system) 15 mcg performance data for analysis. 
Study Objectives:  
The objectives of this study are:   
 
Assess device dispense failure rate with the modified Zalviso System design 
 
Assess impact of System error 302 mitigations on overall System usability 
 
Assess the incidence of misplaced tablets and drug accountability while patients 
were using the Zalviso System 
 
Evaluate patient and nurse usability of, and satisfaction with, the Zalviso System 
to treat moderate-to-severe postoperative pain 
 
Evaluate the efficacy and safety of the Zalviso System to treat moderate-to-severe 
postoperative pain 
Trial Design:  The study is a multicenter, open-label trial for 24 hours, and up to 72 
hours, in patients 18 years and older who are undergoing surgery and are expected to 
require opioid analgesia for at least 24 hours.  Patients who meet all inclusion and 
exclusion criteria at screening and following surgery will receive the Zalviso System. 
 
Non-opioid analgesics may be used at any time along with the Zalviso System in a 
multimodal approach to the treatment of the patient’s postoperative pain. However, 
supplemental opioid medication (2 mg IV morphine) will only be allowed in the first 
30 minutes after the first on-demand dose of study drug has been administered if 
necessary to keep a patient comfortable.  Otherwise, supplemental opioid medication 
(2 mg IV morphine, no more frequently than hourly) is allowed only for pain due to 
ambulation or with the initiation of passive range of motion therapy throughout the 
remainder of the study.  A pain intensity and pain relief score should be obtained prior 
to each administration of supplemental opioid medication. 
 
Overall device performance and usability of the Zalviso System will be assessed by: 
proportion of patients with system-generated (device) errors and other failures of the 
device to function properly, number of patients with misplaced tablets (tablets 
inadvertently dispensed or dosed outside of the mouth), as well as the number of 
misplaced tablets, as assessed by study staff checks every 2 hours, and the Patient 
Usability Questionnaire (PUQ). Usability will also be assessed using the Nurse 
Usability Questionnaire (NUQ) which will be completed by study staff after they have 
experience with 5 or more patients or at the end of the study at the site. 


AcelRx Pharmaceuticals 
4 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
 
Pain intensity will be self-recorded by the patient prior to first dose of study drug and 
then pain relief and pain intensity will be recorded by the patient at the following time 
points after the first on-demand dose of study drug:  ¼ [15 min], ½  [30 min], ¾ [45 
min], 1, 2, 4, 6, 8, 10,  and 12 hours, then every 4  hours at 16, 20, 24, 28, 32, 36, 40, 
44, 48, 52, 56, 60, 64, 68, and 72 hours. During the study period, all PI, PR, and the 
patient global assessment (PGA) scores will be self-recorded by the patient in a 
source document provided by investigator’s staff per the study schema.  The study 
staff must not record the patient’s PI, PR, or global scores for the patient.   
 
Satisfaction with analgesia will be assessed by:  patient global assessment (PGA) and 
healthcare professional global assessment (HPGA) of the method of pain control on a 
four point scale where 1 = poor, 2 =  fair, 3 = good,  and 4 = excellent, patient reports 
of pain intensity on an 11-point numerical rating scale (NRS), where 0 = no pain, and 
10 = worst possible pain, a five-point pain relief scale (0 = no relief, 1 = a little relief, 2 
= moderate relief, 3 = a lot of relief, 4 = complete relief), and percentage of patients 
dropping out of the study due to inadequate analgesia.  Also, the total number of doses 
of study drug administered will be recorded and average hourly use will be calculated 
from the dosing information.  Use of supplemental opioid medication will also be 
recorded. 
 
Patients displaying any one of the following:  
 
 oxygen saturation levels that cannot be maintained at 95% or greater with or 
without the use of supplemental oxygen  
 respiratory rate less than 8 bpm  
 excessive sedation  
 
will not be allowed to have access to study drug or supplemental opioid medication 
until these vital signs have improved.  Sites must document improvement of these 
vital signs in the source and eCRF. 
 
If the oxygen saturation is below 95% with supplemental oxygen, even if no other vital 
sign is abnormal and the patient does not improve following 2 arousal and vital sign 
checks 3 minutes apart, then the patient should be removed from the study.   
 
If the respiratory rate is low (below 8 bpm but oxygen saturation is greater than or 
equal to 95% and no excessive sedation is present) or if excessive sedation exists 
(respiration and oxygenation are above limits), and each adverse event does not 
improve within 20 minutes under supervision with every 3 minute arousal and vital 
sign checks after discontinuing access to study drug, the patient should be removed 
from the study.  If these two adverse events (low respiratory rate and excessive 
sedation) should occur simultaneously, then the more conservative withdrawal criteria 
should be followed:  the patient should be removed from the study if after two arousal 
and vital sign checks 3 minutes apart, these symptoms do not improve. 
 


AcelRx Pharmaceuticals 
5 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
All vital signs measured to manage oxygen desaturation and decreased 
respiratory rate must be recorded in the source and eCRF. 
 
Heart rate and blood pressure will be recorded prior to administration of the first dose 
of study drug, and then when pain intensity and pain relief assessments are recorded  at 
the following time points after the first on-demand dose:  ¼ [15 min], ½  [30 min], ¾ 
[45 min], 1, 2, 4, 6, 8, 10,  and 12 hours, then every 4  hours at 16, 20, 24, 28, 32, 36, 
40, 44, 48, 52, 56, 60, 64, 68, and 72 hours.  These assessments may be collected up to 
5 minutes before scheduled time to allow for the PI and PR assessments to be made at 
the scheduled time. 
 
During the first 24 hours after the first dose of study drug, respiratory rate and oxygen 
saturation will be recorded prior to the first dose of study drug, then 15, 30, 45, and 60 
minutes after the first dose of study drug, and then every 30 minutes.  After 24 hours, 
respiratory rate and oxygen saturation will be recorded every 2 hours. These 
assessments may be collected up to 5 minutes before scheduled time to allow for the PI 
and PR assessments to be made at the scheduled time. 
 
Safety will be monitored via periodic measurement of vital signs, continuous 
monitoring of oxygen saturation, assessment of adverse events (AEs), and the use of 
concomitant medications. 
Inclusion Criteria at Screening: 
1. Male or female patients who are 18 years of age or older.  
2. Patients who are scheduled to undergo surgery under general or spinal anesthesia 
that does not include intrathecal opioids during the operation. 
3. Patients classified as American Society of Anesthesiologists (ASA) class I - III 
(Appendix I). 
4. Female patients of childbearing potential must be using an effective method of 
birth control at the time of screening visit and for 30 days following the end of the 
study period.  Acceptable methods of birth control include oral or transdermal 
contraceptives, condom, spermicidal foam, intrauterine device (IUD), progestin 
implant or injection, abstinence, vaginal ring, or sterilization of partner.  The reason 
for non-child bearing potential, such as bilateral tubal ligation, bilateral 
oophorectomy, hysterectomy, or postmenopausal for > 1 year, must be specified.  
Patients using hormonal forms of contraception must also be willing to use a 
barrier method of contraception from screening through 30 days following the 
study period. 
5. Post-surgical patients who have been admitted to the PACU, and are expected to 
have acute pain requiring opioids for 24 – 72 hours after surgery. 
6. Patients who have the manual dexterity to handle the Zalviso System and are able 
to follow directions for use. 
7. Patients who are willing and capable of understanding and cooperating with the 
requirements of the study. 
8. Patients able to understand and communicate in English. 
9. Patients who have provided written informed consent and signed the IRB approved 
consent form. 


AcelRx Pharmaceuticals 
6 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
 
Exclusion Criteria at Screening 
1. Patients who have taken an opioid for more than 30 consecutive days, at a daily 
dose of 15 mg or more of morphine (or equivalent), within the past 3 months prior 
to surgery (e.g. more than 3 doses per day of Vicodin®, Norco®, Lortab® with 5 mg 
hydrocodone per tablet). 
2. Patients with a positive drug of abuse urine screen unless the positive test result is 
consistent with a prescribed medication 
3. Patients with a history of opioid dependence within two years before the start of the 
study, defined as meeting the DSM-IV-TR™ Criteria for Substance Dependence 
specified in Appendix II. 
4. Patients who have used any illicit drugs of abuse within five years before the start 
of the study. 
5. Patients who have abused any prescription medication or alcohol within one year 
before the start of the study. 
6. Patients with an allergy or hypersensitivity to opioids. 
7. Patients who are currently taking monoamine oxidase inhibitors (MAOIs) or have 
taken MAOIs within 14 days of the first dose of study drug. 
8. Patients with current sleep apnea that has been documented by a sleep laboratory 
study or are on home continuous positive airway pressure (CPAP). 
9. Female patients who are pregnant (positive pregnancy test at screening or after 
hospital admission), breastfeeding or planning to breastfeed within 30 days of the 
last dose of the study drug. 
10. Patients with a medical condition that, in the Investigator’s opinion, could 
adversely impact the patient’s participation or safety, conduct of the study, or 
interfere with the pain assessments, including chronic pain or active infection. 
11. Patients who have cancer and are receiving radiation/chemotherapy and are 
expecting to receive radiation/chemotherapy within 72 hours after surgery. 
12. Patients who require an additional scheduled surgical procedure within 72 hours of 
the surgery. 
13. Patients who are expected to have postoperative analgesia supplied by a long-
acting or continuous regional technique (e.g., spinal opioids or continuous nerve 
block). 
14. Patients who received surgical premedication with long-acting opioid analgesics. 
15. Patients who are receiving oxygen therapy at the time of screening. 
16. Patients who have participated in a clinical trial of an investigational drug or device 
within 30 days of screening visit or is scheduled to receive an investigational 
product while participating in this study. 
 
Exclusion Criteria Post-Surgery: 
1. Patients who are not awake, not breathing spontaneously or have a respiratory rate 
that is less than 8 breaths per minute or greater than 24 breaths per minute. 
2. Patients with arterial oxygen saturation by pulse oximetry (SpO2) that cannot be 
maintained at 95% or greater with or without supplemental oxygen.  
3. Patients not able to answer questions and follow commands. 
4. Patients who are vomiting and not responsive to standard treatment. 


AcelRx Pharmaceuticals 
7 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
5. Patients who have any deviation from the surgical or anesthetic protocols as 
specified in Section 6.1.2.1 of the protocol 
Efficacy Variables and Parameters are:  
 Proportion of patients who experienced at least one system-generated error 
based on the Controller data while using the Zalviso System 
 Proportion of patients, if any, with tablet dispensed but not requested 
 Proportion of patients, if any, with tablet dispensed when the Zalviso System is 
in lockout 
 Proportion of patients with misplaced tablet(s) 
 Number of misplaced tablets (i.e., tablet found outside the patient’s mouth) 
 Proportion of patients who experienced either a system-generated error or a 
misplaced tablet (i.e. a dispense failure) 
 Assessment of the number of Zalviso System notifications to the nurse to 
retrain patient to not pull down on Controller while dosing (i.e., mitigation of 
Error 302) 
 Proportion of patients who rate the Patient Global Assessment (PGA) of 
method of pain control over 24, 48 and 72 hours as “good” or “excellent” 
 Proportion of patients who responded in each category of the PGA 
 Proportion of Healthcare Professionals who rate the Global Assessment 
(HPGA) of method of pain control over 24, 48 and 72 hours as “good” or 
“excellent” 
 Proportion of Healthcare Professionals who responded in each category of the 
HPGA 
 Proportion of patients who terminate from the study due to inadequate 
analgesia over the 24-hour, 48-hour and 72-hour study period 
 Time-weighted summed pain intensity difference (SPID) over the 24-hour 
study period (SPID24), over the 48-hour study period (SPID48), and over the 
72-hour study period (SPID72) 
 Total pain relief (TOTPAR) over the 24-hour study period (TOTPAR24), over 
the 48-hour study period (TOTPAR48) and over the 72-hour study period 
(TOTPAR72) 
 Pain intensity (PI) at each evaluation time point 
 Pain intensity difference (PID) at each evaluation time point 
 Pain relief (PR) at each evaluation time point  
 Patient Usability Questionnaire (PUQ) 
 Nurse Usability Questionnaire (NUQ) 
 Total number of study drug doses used over 24, 48, and 72-hour study period, 
average hourly use, and average inter-dosing interval. 
 Total amount of supplemental morphine utilized  
Safety Variables:  Safety assessments will include the assessment of adverse events, 
vital signs (blood pressure, heart rate, and respiratory rate), oxygen saturation, and the 
use of concomitant medications. 
Determination of Sample Size:  This is a multicenter, open-label, single treatment 
clinical study designed to evaluate the overall functionality of the Zalviso System 
(sufentanil sublingual tablet system) 15 mcg for the treatment of acute moderate-to-


AcelRx Pharmaceuticals 
8 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
severe postoperative pain.  A sample size of approximately 330 patients is planned for 
this study in order to have at least 315 patients receive study drug and have available 
efficacy data for data analysis.   
 
A sample size of 315 patients will have 90% power to demonstrate that the device 
dispense failure rate is non-inferior to a target of 2%.  This failure rate is the proportion 
of patients who experienced at least one of following events: (1) a system-generated 
error, (2) a tablet dispensed but not requested, or (3) a tablet dispensed when the 
Zalviso System is in lockout.  All events listed above will be obtained from the 
Controller patient usage data. 
 
This is based on the criteria that the upper limit of a 90% confidence interval (CI) of 
the device dispense failure rate is not worse than 5%.  This calculation is based on the 
exact binomial test of one-sample proportion for a one-sided case against a 2% target 
proportion with a delta of 3%, and a one-sided significance level of =0.05. This 
sample size was generated from the SAS procedure PROC POWER for one-sample 
proportion. Exact power computations are based on the binomial distribution and 
computing formulas provided by Johnson and Kotz (1970). Assuming a 5% non-
evaluable rate, a sample size of 330 patients is planned for this study.     
Statistical Analysis:  The main analysis of the efficacy variables will include the 
intent-to-treat (ITT) population.  The ITT population includes enrolled patients who 
received study drug.  Demographics and baseline characteristics will be summarized by 
sex group for all enrolled patients and ITT population.  Data will be pooled for all 
study centers for the descriptive summary of baseline data.  No formal hypothesis 
testing will be performed for baseline data. 
 
The data from all study centers will be pooled for the analysis of efficacy data.  Both 
continuous and categorical efficacy variables will be summarized descriptively. A 
point estimate of the device dispense failure rate and its 90% confidence interval based 
on the exact binomial test will be constructed.  For the analysis of the dichotomous 
outcome data, a point estimate and its 90% confidence interval based on the exact 
binomial test will be constructed.   
 
All patients who received at least one dose of study drug will be included in the 
summaries of safety data. An AE thesaurus, the Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to map each AE verbatim term to lowest level term, 
preferred term, and System Organ Class for summary purposes. Adverse events 
occurring while patients are on study drug until 12 hours after the last dose will be 
summarized.  Other safety data, such as premature terminations, vital signs (blood 
pressure, heart rate, and respiratory rate), oxygen saturation, and the use of 
concomitant medications will be tabulated.  
Vital signs taken at baseline and follow-up time points will be summarized.  Patients 
who had baseline data and at least one follow-up data will be included in the summary 
of vital signs by sex group. The descriptive summary statistics will be presented.  A 


AcelRx Pharmaceuticals 
9 
Protocol IAP312 Amendment #1 
CONFIDENTIAL 
paired t-test will be used for the test of mean change from baseline to follow-up time 
points within each group. 
 


AcelRx Pharmaceuticals 
IAP312 Amendment #1 
CONFIIDNTIAL 
 
10 
 
Study Schema – Screening 
 
 
Procedures 
Screening 
(within 30 
days of 
surgery) 
Patient Informed Consent 
 
Inclusion and Exclusion Criteria 
 
Medical History 
 
Vital Signs 
 
Physical Exam 
 
Urine Drug Abuse Screen 
 
Urine Pregnancy Test 
 


AcelRx Pharmaceuticals 
IAP312 Amendment #1 
CONFIIDNTIAL 
 
11 
 
Study Schema– Randomization and Study Treatment 
 
                                                 
A Record prior to first dose and at ¼ [15 min], ½  [30 min], ¾ [45 min], 1, 2, 4, 6, 8, 10,  and 12 hours after 1st on-demand dose, then every 4  hours at 16, 20, and 24 hours after 1st on-demand dose. 
BRecord every 4 hours at 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72 hours after the 1st on-demand dose. 
CRecord prior to first dose and at 15, 30, 45, 60 minutes after 1st on-demand dose and then every 30 minutes after 1st on-demand dose through 24 hours. 
D Record every 2 hours at 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, and 72 hours after the 1st on-demand dose. 
ECheck for and record any misplaced tablets every 2 hours after 1st on-demand dose. 
F The PGA and HPGA will be completed at 24 hours, 48 hours and 72 hours. If the patient withdraws prior to 24 hours, the global assessments should be administered at the time of early termination. 
G Each patient will complete an Usability Questionnaire at the end of his/her participation in the study and prior to completing the PGA; the study staff at each site will complete the Usability 
Questionnaire after he/she has completed 5 patients on the study or at the time the study is completed at the site. 
 
Procedures 
 
Hospital 
Admission 
 
Post-Surgery 
0 - 24 hr 
Treatment 
Period 
24 - 48 hr 
Treatment 
Period 
48 – 72 hr 
Treatment 
Period 
Study 
Completion or 
Early 
Termination 
Urine pregnancy test 
 
 
 
 
 
 
Confirm Patient Continue to Meet Entrance Criteria 
 
 
 
 
 
 
Baseline Pain Intensity (just prior to 1st dose) 
 
 
 
 
 
 
Dosing (record date/time 1st and last dose) 
 
 
 
 
 
 
Continued Zalviso Dosing 
 
 
 
 
 
 
Blood Pressure and Heart Rate 
 
 
A 
B 
B 
 
Respiratory Rate and Oxygen Saturation 
 
 
C 
D 
D 
 
Pain Intensity and Pain Relief Assessments 
 
 
A 
B 
B 
 
Record Number of Doses from Controller 
 
 
A 
B 
B 
 
Check for Misplaced Tablets 
 
 
E 
 E 
E 
 
Patient and Healthcare Professional Global Assessments 
 
 
F 
F 
F 
 
Patient and Nurse  Usability Questionnaire 
 
 
 
 
 
G 
System-Generated Errors 
 
 
 
 
 
 
Study Drug Accountability 
 
 
 
 
 
 
Record Concomitant Meds 
 
 
 
 
 
 
Record AEs 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
TITLE PAGE .....................................................................................................................1 
STUDY APPROVALS...................................................................................................... 2 
SYNOPSIS ......................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................... 12 
1 
INTRODUCTION............................................................................................... 17 
1.1 
Background ..................................................................................................................... 17 
1.2 
Previous Human Experience with Sufentanil Sublingual Tablets (ARX-F01) ......... 18 
2 
STUDY OBJECTIVES ....................................................................................... 21 
3 
STUDY DESIGN ................................................................................................. 21 
3.1 
Study Overview............................................................................................................... 21 
3.2 
Dose and Administration ............................................................................................... 21 
3.3 
Blinding and Randomization ......................................................................................... 22 
3.4 
Discussion of Study Design, Including the Choice of Control Groups ...................... 22 
3.5 
Duration of Study ........................................................................................................... 22 
4 
SELECTION OF PATIENTS ............................................................................ 22 
4.1 
Inclusion Criteria at Screening ..................................................................................... 22 
4.2 
Exclusion Criteria at Screening .................................................................................... 23 
4.3 
Exclusion Criteria Post-Surgery ................................................................................... 23 
4.4 
Withdrawal Criteria ....................................................................................................... 24 
5 
TREATMENTS................................................................................................... 25 
5.1 
Identification and Description ....................................................................................... 25 
5.1.1 
Sufentanil Tablets .............................................................................................................25 
5.1.2 
Zalviso System ..................................................................................................................25 
5.2 
Storage and Dispensing of Drug .................................................................................... 28 
5.3 
Treatment Administration ............................................................................................. 29 
5.4 
Managing Suspected Zalviso System Errors and Failures ......................................... 29 
5.5 
Drug Accountability ....................................................................................................... 30 
5.6 
Emergency Anaphylactic or Overdose Procedures, Dose Modification .................... 30 
5.7 
Prior and Concomitant Medications ............................................................................ 31 
5.7.1 
Prior and Concomitant Medications .................................................................................31 
5.7.2 
Supplemental Medications ................................................................................................31 
6 
STUDY VISIT PROCEDURES......................................................................... 32 
6.1 
Measurements and Evaluations by Visit ...................................................................... 32 


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6.1.1 
Screening Visit ..................................................................................................................32 
6.1.2 
Inpatient Admission (Study Day 1) ..................................................................................32 
6.1.3 
Study Period ......................................................................................................................33 
6.1.4 
End of Study .....................................................................................................................36 
6.2 
Appropriateness of Measurements ............................................................................... 36 
7 
ASSESSMENT OF EFFICACY ........................................................................ 37 
7.1 
Efficacy Variables ........................................................................................................... 37 
8 
ASSESSMENT OF SAFETY ............................................................................. 38 
8.1 
Safety Variables .............................................................................................................. 38 
8.1.1 
Physical Examination/Vital Signs .....................................................................................38 
8.1.2 
Laboratory Parameters ......................................................................................................38 
8.1.3 
Adverse Events .................................................................................................................38 
9 
STATISTICAL METHODS AND DATA ANALYSIS ................................... 40 
9.1 
Determination of Sample Size ....................................................................................... 40 
9.2 
Tests of Hypothesis and Significance Levels ................................................................ 41 
9.3 
Randomization and Blinding of the Treatment Assignment ...................................... 41 
9.4 
Baseline Comparability .................................................................................................. 41 
9.5 
Analysis of Efficacy Data ............................................................................................... 41 
9.5.1 
Efficacy Variables and Parameters ...................................................................................41 
9.5.2 
Analysis Population and Handling of Dropouts ................................................................42 
9.5.3 
Definition of Baseline Measurements ...............................................................................42 
9.5.4 
Methods for the Analysis of Device Dispense Failure Rate .............................................43 
9.5.5 
Pooling of Investigators ....................................................................................................43 
9.5.6 
Methods for the Analysis of Categorical Efficacy Variables ............................................43 
9.5.7 
Methods for the Analysis of Continuous Efficacy Variables ............................................43 
9.6 
Analysis of Safety Data .................................................................................................. 44 
10 
STUDY MANAGEMENT .................................................................................. 44 
10.1 
Regulatory and Ethical Considerations........................................................................ 44 
10.1.1 
Regulatory Guidelines ..................................................................................................44 
10.1.2 
Institutional Review Board ..........................................................................................44 
10.1.3 
Informed Consent .........................................................................................................44 
10.1.4 
Study Documentation ...................................................................................................45 
10.2 
Withdrawals .................................................................................................................... 45 
10.3 
Study Or Study Site Termination ................................................................................. 45 
10.4 
Study Monitoring ........................................................................................................... 45 
10.5 
Data Quality Assurance ................................................................................................. 46 
10.6 
Access to Records ........................................................................................................... 46 
10.7 
Retention of Records ...................................................................................................... 46 
11 
Publications ......................................................................................................... 46 
12 
REFERENCES .................................................................................................... 47 
 


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LIST OF APPENDICES 
 
APPENDIX I: 
American Society of Anesthesiologist Physical Status 
Clarification…………………………………………………… 
 
48 
APPENDIX II: 
DSM IV Alcohol and Drug Substance Dependence and 
Abuse…………………………………………………………... 
 
49 
APPENDIX 
III: 
Patient and Healthcare Professional Global Assessment of 
Method of Pain Control………………………………………... 
 
51 
APPENDIX 
IV: 
Patient Usability Questionnaire……………………………. 
52 
APPENDIX V: 
Nurse Usability Questionnaire…………………………….. 
53 
APPENDIX 
VI: 
Sufenta® Package Insert……………………………………….. 
54 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
ASA 
American Society of Anesthesiologists 
AUC0-inf  
area under the analyte concentration-time curve extrapolated to 
infinity 
BMI 
body mass index (BMI=weight (kg)/[height(m)]2 
BOCF 
baseline observation carried forward 
BPM 
breaths per minute 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CRC 
clinical research center 
CPAP 
continuous positive airway pressure 
CRF 
case report form 
CV 
coefficient of variation 
ED50 
effective dose in 50% of population 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GRAS 
generally recognized as safe 
HCP 
healthcare professional 
HPGA 
Healthcare Professional Global Assessment 
HP-IFU 
Healthcare Professional – Instructions for Use 
HIPAA 
Health Insurance Portability and Accountability Act 
hr 
hour 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IR 
immediate release 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IWRS 
Interactive Web Response System 
kg 
kilogram 
LD50 
lethal dose in 50% of population 
LOCF 
last observation carried forward 
LS 
least squares   


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Abbreviation 
Definition 
MAOI 
monoamine oxidase inhibitor 
mcg 
microgram 
mcL 
microliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
NRS 
numerical rating scale  
PACU 
post-anesthesia care unit 
PCA 
patient-controlled analgesia 
pg 
pictogram 
PGA 
Patient Global Assessment 
PI 
pain intensity 
PID 
pain intensity difference 
PK 
pharmacokinetics 
PR 
pain relief 
PRM 
passive range-of-motion 
RASS 
Richmond Agitation Sedation Scale 
RCT 
randomized controlled trial 
RFID 
radio-frequency identification 
SAE 
serious adverse event 
SAS® 
Statistical Analysis System 
SPID 
summed pain intensity difference 
SpO2 
arterial oxygen saturation by pulse oximetry  
t 1/2 
half-life 
Tmax 
time to maximum plasma concentration 
TOTPAR 
total pain relief 
WOCF 
worst observation carried forward 


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1 
INTRODUCTION 
1.1 
Background 
AcelRx Pharmaceuticals, Inc. (hereafter AcelRx) is developing Zalviso (sufentanil 
sublingual tablet system) for the indication of management of moderate-to-severe acute 
pain in adult patients during hospitalization.  In spite of the wide use and advantages of  
intravenous patient-controlled analgesia (IV PCA), its inherent complexity associated 
with ordering, dispensing, set-up, programming, and administration have resulted in 
many analgesia related postoperative medication errors (Grass, 2005; Hankin et al., 2007; 
Hicks et al., 2008a; 2008b; and Meissner et al., 2009).  Errors utilizing IV PCA have 
been reported across all phases of the medication-use process, but human factors, such as 
programming or administering the wrong dose, are among the most common and serious 
type of errors.  Among the human factors, the operator errors (81% involving pump 
programming errors) are the most concerning since they account for the majority of 
errors that cause harm to patients. Approximately 5% of operator errors reported in the 
MAUDE database (FDA mandatory device-error-reporting database) resulted in patient 
deaths (Hankin et al, 2007). 
Although it is difficult to conclusively determine the incidence rate for IV PCA-related 
events due to significant under-reporting, recent analysis of MEDMARX (USP voluntary 
medication errors reporting database) and MAUDE databases has estimated the annual 
IV PCA error rates as 424 IV PCA-related errors per 10,000 people within the United 
States (Meissner et al., 2009). Assuming that approximately 13 million patients are 
requiring IV PCA therapy annually, it can be estimated that more than 500,000 patients 
are exposed to IV PCA errors every year and about 50,000 patients are harmed because 
of these errors (Meissner et al., 2009).  
The non-invasive (sublingual), pre-programmed, single-dose strength Zalviso System 
addresses many of the limitations of the current IV PCA systems by reducing 
programming errors, IV catheter complications and inappropriate use of basal infusions.  
The Zalviso System is comprised of a disposable bar-coded Cartridge filled with a stack 
of 40 sufentanil tablets 15 mcg (approximately 2 day supply based on usage), a 
disposable Dispenser and a reusable, rechargeable Controller. The Zalviso System is 
designed so that with each actuation by the patient, a single sufentanil tablet will be 
dispensed sublingually with a manufacturer pre-programmed 20-minute lock-out to avoid 
overdosing.  Furthermore, the Zalviso System has additional safety features of 1) a secure 
access system comprised of an adhesive patient identification Thumb Tag which uses 
radio-frequency identification (RFID), 2) an Authorized Access Card with RFID for the 
healthcare professional (HCP) and 3) a security tether. 
 


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Advantages of Sufentanil 
Sufentanil, a synthetic opioid analgesic, is characterized by a high selectivity and affinity 
for mu opiate receptors.  Sufentanil is an optimal opioid to use in the treatment of acute 
in-hospital pain, such as postoperative pain.  Published studies demonstrate that 
sufentanil produces significantly less respiratory depressive effects relative to its 
analgesic effects than other opioids (Clark et al., 1987; Ved et al., 1989; Bailey et al., 
1990; Conti et al., 2004).  This evidence fits well with preclinical data demonstrating that 
the therapeutic index of sufentanil (lethal dose in 50% of animals/effective dose in 50% 
of animals; LD50/ED50 = 25,000) is significantly higher than most clinically used opioids, 
such as fentanyl (LD50/ED50 = 300) and morphine (LD50/ED50 = 70) (Mather, 1983). 
Sufentanil, as opposed to morphine and meperidine, has no active metabolites, therefore 
reduced renal clearance in the elderly or in patients with active renal disease will not 
affect dosing in these populations to any significant extent. Pharmacokinetic studies of 
intravenous sufentanil have demonstrated no clinically significant differences based on 
age (Matteo et al., 1990), liver or kidney function (Fyman et al., 1988, Chauvin et al., 
1989).  Although one study has demonstrated moderate increases in elimination half-life 
and volume of distribution in obese patients, plasma clearance and other pharmacokinetic 
(PK) measurements of time and extent exposure to drug were unchanged in this 
population (Schwartz et al., 1991).  
Sufentanil Sublingual Tablets 
AcelRx has developed the sufentanil tablet using GRAS (generally recognized as safe) 
excipients.  The sufentanil tablet has been designed in a disc-shaped form with a flattened 
face in order to provide increased surface area for adhesion and drug elution.   By virtue 
of its very small size, the sufentanil tablet can comfortably adhere to the sublingual 
mucosa within seconds after administration and provoke minimal taste or saliva response 
which minimizes amount of swallowed drug. 
1.2 
Previous Human Experience with Sufentanil Sublingual Tablets (ARX-F01) 
To date, AcelRx has conducted seven Phase 1 studies, three Phase 2 studies, and three 
Phase 3 studies to support the clinical development of Zalviso.  Two of the Phase 1 
studies (ARX-C-002 and MPS101) were primarily performed for a separate clinical 
development program.  Studies ARX-C-002 and MPS101 included a single-dose 
treatment of a sufentanil tablet in unblocked subjects (subjects not pretreated with the 
opioid antagonist naltrexone).  A Phase 1 study to support registration of a higher dose 
strength SST (30 mcg) was conducted and included administration of SST 15 mcg. 
Phase 1 Study Results 
In the Phase 1 studies, a range of doses (2.5 to 80 mcg) were studied and each treatment 
arm resulted in either a single tablet administered or up to 40 tablets (one every 20 
minutes) administered.  The definitive PK studies evaluated only a 15 mcg dose. 


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 Administration of a single sublingual sufentanil tablet 15 mcg demonstrated high 
bioavailability, blunted Cmax, and 15-fold longer plasma context-sensitive half-time 
(time from Cmax to 50% of Cmax; CST½) compared to dose equivalent IV 
administration. The CST½ was 0.14 hrs for IV sufentanil and 2.5 hrs for sublingual 
sufentanil. 
 Relative to IV administration, bioavailability of the sufentanil tablet 15 mcg 
sublingually was 59%.  Bioavailability of buccal placement of the sufentanil tablet 
was higher at 78%, and oral (swallowed) was much lower at 9%. 
 The buccal route of administration resulted in a similar PK profile compared with 
sublingual administration. 
 The Cmax from a single-dose of the sufentanil tablet 15 mcg was 33 pg/mL (%CV = 
35%), the overall Cmax from 40 doses administered every 20 minutes over 13.3 hours 
was 265 pg/mL (%CV = 28%), and the Cmax following the 40th dose was240 pg/mL 
(%CV = 29%).  
 Ketoconazole, a potent CYP3A4 inhibitor, can increase the systemic exposure to the 
sufentanil tablet, showing a higher AUC0-inf value. However, the peak plasma 
concentration, Cmax, and CST½ of the sufentanil tablet were not impacted to any 
clinically meaningful degree. The variable redosing interval of the sufentanil tablet 
should compensate for any increased AUC caused by concomitant administration of 
CYP3A4 inhibitors. 
 Clearance of sufentanil was reduced in older subjects (61 to 80 years) compared to 
younger subjects (18 to 60 years). The differences were not clinically meaningful. 
 
Across the Phase 1 studies, the incidence of AEs considered treatment-emergent ranged 
up to 91.7%. The highest incidence of AEs occurred in Study ARX-F01-01, a legacy 
study in naltrexone-blocked subjects with sufentanil doses ranging up to 80 mcg. In the 
other studies, the rate of AEs ranged up to approximately 50%. In Study ARX-F01-01 
and other studies in naltrexone-blocked subjects (Studies IAP101, IAP102, and IAP104), 
it was not possible to fully distinguish whether the naltrexone or the sufentanil 
formulation being tested was likely to have caused a particular AE. In Study IAP101, 
which was a multiple-dose study unlike the other studies in naltrexone-blocked subjects, 
40 consecutive sufentanil tablet 15 mcg doses were administered at 20-minute intervals, 
and AEs were experienced by 18 of 39 (46.2%) subjects. 
In studies in non-naltrexone-blocked subjects (Studies MPS101, ARX-C-002, and ARX-
C-006), the rates of AEs in subjects receiving sublingual tablet formulations containing 
sufentanil 15 mcg ranged from 0 of 12 subjects to 4 of 12 subjects (33.3%) experiencing 
AEs. In some patients the sublingual tablet treatments included triazolam. Across all 
Phase 1 studies, there were no SAEs or deaths and only 1 AE (mild nausea) leading to 
discontinuation. 
Dose-Ranging Phase 2 Studies 
AcelRx conducted 3 Phase 2 studies which provide supporting efficacy and safety data. 
These include 2 placebo-controlled, double-blind 12-hour studies and 1 uncontrolled, 
open-label 12-hour study conducted in patients who had undergone open abdominal 


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surgery or knee replacement. Study ARX-C-004 used a prototype version of the delivery 
device. 
Phase 3 Study Results 
In the Phase 3 studies (IAP309, IAP310 and IAP311), Zalviso was evaluated for efficacy 
and safety.  The tablet was self-administered by the patient as needed for pain relief.  The 
device had a pre-programmed 20-minute lockout between doses. In these studies, a 
placebo tablet was also administered using the Zalviso System. The active-comparator 
treatment evaluated in study IAP309 was IV PCA morphine, 1 mg as needed, with a 6-
minute lockout.  
 
In each of the 2 placebo-controlled Phase 3 studies (IAP310 and IAP311), the Zalviso 
System demonstrated superiority over placebo for the primary endpoint, time-weighted 
SPID48.  Supporting the SPID48 results, key secondary endpoint results (total pain relief, 
drop out due to inadequate analgesia, proportion of patients using rescue medication, and 
patient global assessment (PGA) and healthcare professional global assessment (HPGA)) 
were also superior to placebo.  The Zalviso System demonstrated efficacy that was rapid 
in onset and durable over time.  The result of the open-label, active-comparator trial 
showed that Zalviso was superior to IV PCA morphine for the measure of “success” 
(patient rating of good or excellent for method of pain control over the 48-study period).  
Patients had the option to remain in the study past the 48-hour treatment period, up to 72 
hours. 
 
The most common AEs were generally consistent across studies and were consistent with 
opioid treatment and the postsurgical setting in Phase 2 and 3 studies. In the Phase 3, 
placebo-controlled studies, the most common AEs (experienced by > 5% of patients) 
with Zalviso treatment were nausea (46.9%), pyrexia (17.7%), vomiting (11.7%), 
headache (8.6%), oxygen saturation decreased (7.7%), pruritus (6.8%), hypotension 
(5.6%), dizziness (5.4%), and anemia, constipation, and anemia postoperative (each 
5.1%). Of these, 3 common AEs occurred significantly more frequently with Zalviso 
compared with placebo: nausea (46.9% vs. 36.4%, p = 0.026), vomiting (11.7% vs. 6.2%, 
p = 0.049), and pruritus (6.8% vs. 0%, p < 0.001). The following 3 AEs showed nearly 
significant differences between Zalviso and placebo: pyrexia (17.7% vs. 11.1%, p = 
0.058), oxygen saturation decreased (7.7% vs. 3.1%, p = 0.058), and dizziness (5.4% vs. 
1.9%, p = 0.073).  These AEs showing significant or nearly significant differences from 
placebo are consistent with expected AEs of opioid treatment. No other common AEs 
showed significant differences from the placebo System. 
 
Across all 3 Phase 3 studies, including the open-label Study IAP309 which incorporated 
an IV PCA MS treatment group, the rates of common AEs with Zalviso were generally 
similar to or lower than the rates of AEs in the IV PCA morphine group. Comparing AEs 
experienced by > 5% of patients with the Zalviso to AEs in the IV PCA morphine, rates 
of pyrexia, oxygen saturation decreased, anemia, constipation, pruritus, hypotension, 
anemia postoperative, and hypoalbuminemia were at least somewhat greater with the IV 
PCA morphine. Rates of nausea and vomiting were similar, and rates of headache and 
dizziness were somewhat greater (by approximately 2%) with Zalviso. 


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2 
STUDY OBJECTIVES 
The study objectives are:   
 
Assess device dispense failure rate with the modified Zalviso System design 
 
Assess impact of System error 302 mitigations on overall System usability 
 
Assess the incidence of misplaced tablets and drug accountability while patients 
were using the Zalviso System 
 
Evaluate patient and nurse usability of, and satisfaction with, the Zalviso System to 
treat moderate-to-severe postoperative pain 
 
Evaluate the efficacy and safety of the Zalviso System to treat moderate-to-severe 
postoperative pain 
3 
STUDY DESIGN 
3.1 
Study Overview 
The study is a multicenter, open-label trial for at least 24 hours and up to 72 hours in 
patients 18 years and older who are undergoing surgery and are expected to require 
systemic opioid analgesia for at least 24 hours after surgery to treat moderate-to-severe 
pain. 
Patients who meet all inclusion and exclusion criteria at screening and following surgery, 
and transfer to the post-anesthesia care unit (PACU), will be treated with Zalviso System 
with a 20-minute re-dosing interval (lock-out). 
Analgesic efficacy will be assessed by patient global assessment of method of pain 
control on a four-point scale where 1 = poor, 2 = fair, 3 = good, and 4= excellent, patient 
reports of pain intensity on an 11-point numerical rating scale (NRS), where 0 = no pain, 
and 10 = worst possible pain, a five-point pain relief scale (0= no relief, 1 = a little relief, 
2 = moderate relief, 3 = a lot of relief, 4 = complete relief), percentage of patients 
dropping out of the study due to inadequate analgesia, and patient usability questionnaire.   
Safety will be monitored via periodic measurement of vital signs and continuous 
monitoring of oxygen saturation, as well as assessment of AEs and the use of 
concomitant medications. 
3.2 
Dose and Administration 
Patients will receive treatment with the Zalviso System for the duration of the study 
period. 
Patients may have ice chips or swish with water if his/her mouth feels very dry prior to 
receipt of any dose of study drug. Patients will be instructed that the tablets must be 
allowed to dissolve under the tongue and may not be crushed, chewed, or swallowed.  
Expected time for erosion after administration is 6 to 8 minutes.  Patients should not eat 
or drink, and should minimize talking for ten minutes after a tablet has been self-
administered. 


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Administration of the first dose of study drug will start the study period.  Additional 
doses may be self-administered by the patient but at least 20 minutes must lapse between 
doses as controlled by the Zalviso System’s manufacturer pre-programmed 20-minute 
lock-out. 
3.3 
Blinding and Randomization 
This is an open-label single treatment study.  There is no randomization in this study.  All 
patients will receive treatment using the Zalviso System. 
3.4 
Discussion of Study Design, Including the Choice of Control Groups 
This is an open-label, non-controlled study.  Validated instruments will be used to assess 
pain intensity, pain relief, and global assessment during the study. 
3.5 
Duration of Study 
After screening, patients may have up to 30 days to begin receiving treatment with study 
drug.  The duration of study treatment administration is at least 24 hours but may extend 
to 72 hours.  The entire study is expected to last approximately nine months from the first 
patient screened through the last patient’s study procedure. 
4 
SELECTION OF PATIENTS 
4.1 
Inclusion Criteria at Screening 
 
1. Male or female patients who are 18 years of age or older.  
2. Patients who are scheduled to undergo surgery under general or spinal anesthesia 
that does not include intrathecal opioids during the operation. 
3. Patients classified as American Society of Anesthesiologists (ASA) class I - III 
(Appendix I). 
4. Female patients of childbearing potential must be using an effective method of 
birth control at the time of screening visit and for 30 days following the end of the 
study period.  Acceptable methods of birth control include oral or transdermal 
contraceptives, condom, spermicidal foam, intrauterine device (IUD), progestin 
implant or injection, abstinence, vaginal ring, or sterilization of partner.  The 
reason for non-child bearing potential, such as bilateral tubal ligation, bilateral 
oophorectomy, hysterectomy, or postmenopausal for > 1 year, must be specified.  
Patients using hormonal forms of contraception must also be willing to use a 
barrier method of contraception from screening through 30 days following the 
study period. 
5. Post-surgical patients who have been admitted to the PACU, and are expected to 
have acute pain requiring opioids for 24 – 72 hours after surgery. 
6. Patients who have the manual dexterity to handle the Zalviso System and are able 
to follow directions for use. 
7. Patients who are willing and capable of understanding and cooperating with the 
requirements of the study. 
8. Patients able to understand and communicate in English. 


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9. Patients who have provided written informed consent and signed the IRB 
approved consent form. 
 
4.2 
Exclusion Criteria at Screening 
1. Patients who have taken an opioid for more than 30 consecutive days, at a daily 
dose of 15 mg or more of morphine (or equivalent), within the past 3 months prior 
to surgery (e.g. more than 3 doses per day of Vicodin®, Norco®, Lortab® with 5 
mg hydrocodone per tablet). 
2. Patients with a positive drug of abuse urine screen unless the positive test result is 
consistent with a prescribed medication. 
3. Patients with a history of opioid dependence within two years before the start of 
the study, defined as meeting the DSM-IV-TR™ Criteria for Substance 
Dependence specified in Appendix II. 
4. Patients who have used any illicit drugs of abuse within five years before the start 
of the study. 
5. Patients who have abused any prescription medication or alcohol within one year 
before the start of the study. 
6. Patients with an allergy or hypersensitivity to opioids. 
7. Patients who are currently taking monoamine oxidase inhibitors (MAOIs) or have 
taken MAOIs within 14 days of the first dose of study drug. 
8. Patients with current sleep apnea that has been documented by a sleep laboratory 
study or are on home continuous positive airway pressure (CPAP). 
9. Female patients who are pregnant (positive pregnancy test at screening or after 
hospital admission), breastfeeding or planning to breastfeed within 30 days of the 
last dose of the study drug. 
10. Patients with a medical condition that, in the Investigator’s opinion, could 
adversely impact the patient’s participation or safety, conduct of the study, or 
interfere with the pain assessments, including chronic pain or active infection. 
11. Patients who have cancer and are receiving radiation/chemotherapy and are 
expecting to receive radiation/chemotherapy within 72 hours after surgery. 
12. Patients who require an additional scheduled surgical procedure within 72 hours 
of the surgery. 
13. Patients who are expected to have postoperative analgesia supplied by a long-
acting or continuous regional technique (e.g., spinal opioids or continuous nerve 
block). 
14. Patients who received surgical premedication with long-acting opioid analgesics. 
15. Patients who are receiving oxygen therapy at the time of screening. 
16. Patients who have participated in a clinical trial of an investigational drug or 
device within 30 days of screening visit or is scheduled to receive an 
investigational product while participating in this study. 
 
4.3 
Exclusion Criteria Post-Surgery 
1. Patients who are not awake, not breathing spontaneously or have a respiratory rate 
that is less than 8 breaths per minute or greater than 24 breaths per minute. 


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2. Patients with arterial oxygen saturation by pulse oximetry (SpO2) that cannot be 
maintained at 95% or greater with or without supplemental oxygen.  
3. Patients not able to answer questions and follow commands. 
4. Patients who are vomiting and not responsive to standard treatment. 
5. Patients who have any deviation from the surgical or anesthetic protocols as 
specified in section 6.1.2.1 of the protocol. 
 
4.4 
Withdrawal Criteria 
Patients will be informed that they are free to withdraw from the study at any time.  The 
Investigator, the Investigator in consultation with the Medical Monitor, or the Medical 
Monitor may exercise his or her medical judgment to terminate a patient’s participation 
in the study if it is in the best interest of the patient. 
Patients displaying any one of the following:  
 oxygen saturation levels that cannot be maintained at 95% or greater with or 
without the use of supplemental oxygen  
 respiratory rate less than 8 bpm  
 excessive sedation  
 
will not be allowed to have access to study drug or supplemental opioids until these vital 
signs have improved.   Sites must document improvement of these vital signs in the 
eCRF. 
 
If the oxygen saturation is below 95%, even if no other vital sign is abnormal and the 
patient does not improve following supplemental oxygen and two arousal and vital sign 
checks 3 minutes apart, then the patient should be removed from the study.   
 
If the respiratory rate is low (below 8 bpm but oxygen saturation is greater than or equal 
to 95% and no excessive sedation is present) or if excessive sedation exists (respiration 
and oxygenation are above limits), and each adverse event does not improve within 20 
minutes under supervision with every 3 minute arousal and vital sign checks after 
discontinuing access to study drug, the patient should be removed from the study.  If 
these two adverse events (low respiratory rate and excessive sedation) should occur 
simultaneously, then the more conservative withdrawal criteria should be followed:  the 
patient should be removed from the study if after two arousal and vital sign checks 3 
minutes apart, these symptoms do not improve.   
All vital signs measured to manage oxygen desaturation and decreased respiratory 
rate must be recorded in the source and eCRF. 
 
At any time the investigator can remove a patient from the study for any adverse event, 
regardless of the above guidance, if deemed necessary for patient safety. 
 
AcelRx also reserves the right to terminate the study at any time.  All data normally 
collected at completion of the study must be collected either at the time of the patient’s 
early termination, or before the scheduled study closeout visit. 


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A termination case report form (CRF) page should be completed for every patient who 
received study drug, whether or not the patient completed the study.  The reason for any 
early discontinuation from the study should be indicated on this form.  The primary reason 
for a premature withdrawal should be selected from the following standard categories of 
early termination: 
 
Adverse Event:  Clinical or laboratory events occurred that in the medical judgment of the 
investigator for the best interest of the patient are grounds for discontinuation.  This 
includes serious and non-serious AEs regardless of relation to study drug. 
Death:  The patient died. 
Withdrawal of Consent:  The patient desired to withdraw from further participation in the 
study in the absence of a medical need to withdraw determined by the investigator.  If the 
patient gave a reason for this desire, this should be recorded on the CRF. 
Protocol Violation:  The patient's findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (e.g., drug noncompliance, failure 
to return for defined number of visits).  The violation necessitated premature termination 
from the study. 
Lack of efficacy:  The patient was discontinued from the study due to lack of response. 
Lost to Follow-Up:  The patient stopped coming for visits and study personnel were 
unable to contact the patient. 
Other:  The patient was terminated for a reason other than those listed above.  The 
Investigator must specify the reason. 
Separate CRF entries will document whether each patient completed all doses of study 
drug, or if not, the reason a patient terminated study drug early. 
5 
TREATMENTS 
5.1 
Identification and Description 
5.1.1 
Sufentanil Tablets 
The sufentanil tablet is an orange-colored tablet with a volume of approximately 7 mcL 
with dimensions of approximately 3 mm in diameter and 0.85 mm in thickness.  Each 
sufentanil tablet contains 15 mcg of sufentanil base corresponding to 22.5 mcg of 
sufentanil citrate.  All excipients are inactive and are generally recognized as safe 
(GRAS) status. 
5.1.2 
Zalviso System 
The Zalviso System is a handheld, patient-controlled device designed for sublingual, self-
administration of sufentanil tablets by patients requiring postoperative opioid analgesia in 


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the hospital setting.  The Zalviso System also provides the following general 
functionality: 
 Single-patient identification to ensure that only the intended patient may use the 
System 
 Manufacturer pre-programmed lockout interval to ensure that patient cannot 
exceed prescribed dose 
 Recorded dosing and use history, to assist HCPs in keeping accurate patient 
medical records 
 Error monitoring and safety features to monitor and control tablet dispensing, to 
control access to the drug cartridge, and to mitigate diversion 
The Zalviso System houses an internal electro-mechanical system that singulates and 
delivers a tablet to the sublingual space. Furthermore, the System contains electronics 
that detect the successful singulation of a tablet, provide a means to track use data, 
provide a simple user interface that displays the System status and dosing information, 
and utilize a non-contact identification reader for identifying the proper patient (adhesive 
patient ID Thumb Tag with RFID).  
Controlled access is required to limit use of the Zalviso System to the HCP when 
performing setup, take down, patient linking, or un-tethering. Authorized controlled 
access for patient identification and dosing is also required for medication delivery. 
Access is restricted in order to mitigate theft of the Zalviso System (tethering), identify 
the patient for dosing, mitigate drug diversion, and to identify the HCP. 
 


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The Zalviso System is comprised of three main components as follows: 
 A reusable Controller that houses the electro-mechanical elements of the PCA 
System and the power source (rechargeable battery) 
Front Side / Nurse Side 
 
 
 
Back Side / Patient Side 
 
 
 
 
 
 


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 A pre-filled drug Cartridge containing 40 tablets and a green plastic priming cap 
 
 A single-patient use Dispenser that contacts the sublingual space of the patient 
and directs placement of the tablets.  Included with the Dispenser is a cap to cover 
the tip when not in use. 
 
 
 
Ancillary Components: 
 A Tether to lock the PCA System to the bedside, along with a holster for ease of 
bedside storage in between dosing 
 Secure access system comprised of an adhesive patient ID Thumb Tag with RFID 
to limit dosing to only the patient, plus Authorized Access Card with RFID that 
will be used only by the HCP or study monitor to setup, takedown, and to interact 
with the System 
All components are supplied non-sterile in separate packages. 
5.2 
Storage and Dispensing of Drug 
The drug cartridges will be stored in the controlled access of the facility pharmacy to 
ensure adequate controls for a Drug Enforcement Agency (DEA) Schedule II narcotic 


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substance or to the required governing agency standard.  Drug cartridges must be stored 
at room temperature (15°C - 30°C) until time of dispensing. 
When a post-surgery patient is transferred to the PACU and meets all criteria for start of 
dosing, study staff will prepare a Zalviso System for the patient’s use. 
The pouched cartridge will be taken from inventory and labeled with the patient 
identification.  The tear-off section of the two-part label affixed to the pouch will be 
removed and placed in the inventory records and the date and time of dispensing will be 
recorded.  The pouch containing the cartridge labeled with the patient identification will 
be dispensed to the qualified study staff from the pharmacy.  When additional pouched 
cartridges are needed by a patient, the study staff will follow the same process.  If a 
patient uses three drug cartridges and needs an additional drug cartridge, the dispenser 
must be replaced prior to use of the fourth drug cartridge. 
5.3 
Treatment Administration 
Study drug will be self-administered only when a patient needs treatment for his/her pain. 
There is a manufacturer pre-programmed 20-minute lock-out to prevent overdosing. 
The tablets must be allowed to dissolve under the tongue and should not be crushed, 
chewed, or swallowed. Patients should not eat or drink, and should minimize talking for 
10 minutes after a tablet has been self-administered, although ice chips may be used to 
avoid excessively dry mouths in patients during the study period. 
5.4 
Managing Suspected Zalviso System Errors and Failures 
Refer to the Healthcare Professional-Instructions for Use (HP-IFU) for complete 
information on Zalviso System alarm, error and notification messages (HP-IFU to be sent 
under separate cover). 
 
If during patient use an error message is displayed on the controller screen (e.g., Error 
301, Error 302, etc), the error displayed will be recorded in the source record and on the 
suspected technical failure e-CRF.  Per the Zalviso System design, if a system error 
occurs, the Zalviso System will no longer dispense tablets and must be discontinued.  The 
patient will be discontinued from the study and alternate form of postoperative analgesia 
per standard practice at the site should be instituted. 
 
If either the patient or the investigator’s staff observes that the Zalviso System may not 
be operating properly during patient use, but there are no notification or error messages 
displayed on the Zalviso System Controller screen, the Zalviso System will be evaluated 
for the presence of a technical failure in accordance with the procedures detailed in the 
Zalviso System HP-IFU.  If the Zalviso System is suspected of having a technical failure, 
the System must be discontinued, the patient discontinued from the study and an alternate 
form of postoperative analgesia per standard practice at the site should be instituted.  In 
the event any Zalviso System is judged to have a suspected technical failure, the Zalviso 
System will be sent to AcelRx for evaluation and may not be used further until a review 
by AcelRx is complete and the System is approved for further use.  Suspected technical 


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failures must be documented in the source and the eCRF.    
If a misplaced tablet (i.e. any tablet inadvertently dispensed or found outside of the 
patient’s mouth) is found by a patient or study staff, this must be documented in the 
source record and eCRF.  The tablet must be stored securely until CII study drug 
accountability is conducted.  The study staff should document who found the tablet, when 
and where the tablet was found, and query the patient to determine the likely cause of the 
misplaced tablet. 
5.5 
Drug Accountability 
The Investigator, dispensing pharmacist, and nursing staff will be responsible for 
maintaining the medication accountability log, which will contain inventory records 
acknowledging receipt of study drug, and dispensing records tracking distribution of 
medication to patients.  All used and unused cartridges will be kept at the site until study 
completion.  At study closeout, the Investigator will be required to reconcile all received, 
dispensed, used, and unused drug cartridges, and return to AcelRx, or its designee for 
destruction as per instructions from AcelRx. Unused Zalviso System supplies will be 
handled according to directions from AcelRx. 
When a patient is discontinued or a replacement Drug Cartridge is needed, the number of 
tablets remaining in the used Drug Cartridge as displayed on the Zalviso System display 
screen will be recorded in the source records.  Appropriate source records will be sent to 
AcelRx or designee along with the used and unused Drug Cartridges for tablet 
accountability.  AcelRx or designee will count the number of tablets remaining in each 
used Drug Cartridge using the HP-IFU manual method and compared to the site’s source 
records.  Any discrepancies will be investigated. 
 
5.6 
Emergency Anaphylactic or Overdose Procedures, Dose Modification 
Emergency medical treatment for anaphylaxis including the use of epinephrine, 
antihistamine, and/or corticosteroid therapy should be immediately available during the 
administration of Zalviso.  The most serious effect of overdose is respiratory depression.  
Intravenous administration of an opioid antagonist such as naloxone, titrated to effect, 
should be employed as a specific antidote to manage respiratory depression.  
Administration of an opioid antagonist should not preclude more immediate 
countermeasures. In the event of overdosage, oxygen should be administered and 
ventilation assisted or controlled as indicated for hypoventilation or apnea. A patent 
airway must be maintained, and a nasopharyngeal, oral airway, or endotracheal tube may 
be indicated. Other supportive measures such as intravenous fluids and vasopressors for 
the treatment of hypotension may be employed. 
There is no provision for dosage strength modification, although the frequency of dosing 
is determined by the patient (within the constraints of the manufacturer pre-programmed 
20-minute lockout).  


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5.7 
Prior and Concomitant Medications 
5.7.1 
Prior and Concomitant Medications 
Patients may continue the scheduled use of their regular medications throughout the 
study.  Patients are to be dosed only with the Zalviso System during the study period for 
opioid analgesia, with the exception of the supplemental opioid medication as described 
in Section 5.7.2.  Non-opioid analgesics are allowed prior to and throughout the study 
period to be consistent with the current multimodal standard of care.  Deep venous 
thrombosis prophylaxis, as per local best practice, is permitted postoperatively.   
Patients may receive prophylactic anti-emetics based on assessment of risks for 
postoperative nausea and vomiting and investigator’s judgment.  Postoperative anti-
emetics for symptomatic treatment are also allowed. 
The use of any concomitant medications from 30 days prior to the first dose of study drug 
through the completion of the study, or changes in the dose or dosing frequency of 
medications used prior to the study start will be documented in the CRF.  All appropriate 
information (e.g. trade name, formulation, dosage, dates and times (24-hour clock of 
beginning and end), reason for use) of concomitant medications, therapies, and medical 
procedures will be reported in the CRF. Any change to concomitant therapy will be noted 
in the CRF.  This includes concomitant medications taken for the treatment of AEs. 
Patients will receive full supportive care for the treatment of AEs. Treatment will be at 
the discretion of the Investigator, but initially will follow these guidelines: 
 Oxygen saturation, respiratory rate or excessive sedation adverse events will 
be managed with discontinuation of the study drug and, if necessary, with 
resuscitative measures. (See Section 4.4 Withdrawal Criteria) 
 Pruritus will be treated with appropriate therapy. 
 Nausea and vomiting will be treated with appropriate anti-emetic therapy. 
 Shivering may be treated with meperidine in the PACU. 
5.7.2 
Supplemental Medications 
Patients may be treated with standard non-opioid analgesics as per the site’s standard 
multimodal analgesia regimens (with the exception of continuous nerve blocks such as a 
continuous femoral block or a continuous epidural block).  However, supplemental 
opioid medication (2 mg IV morphine) will only be allowed in the first 30 minutes after 
the first on-demand dose of study drug has been administered if necessary to keep a 
patient comfortable or for pain due to ambulation or with the initiation of passive range 
of motion (PRM) therapy throughout the remainder of the study.  A pain intensity and 
pain relief score should be obtained prior to each administration of supplemental opioid 
medication. 


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Supplemental opioid medication should be delivered as a slow IV push by a HCP.  
Patients cannot receive a dose of supplemental opioid medication more than once 
every 60 minutes.  If patients continue to have pain that is not controlled by the use of 
study drug, supplemental opioid medication, and other allowable non-opioid analgesics, 
then the patient should be discontinued from the study and an alternate form of 
postoperative analgesia per standard practice at the site should be instituted. 
6 
STUDY VISIT PROCEDURES 
6.1 
Measurements and Evaluations by Visit 
6.1.1 
Screening Visit 
After obtaining written informed consent, patients will be instructed as to the nature of 
the study and the reason they are being asked to participate. Screening assessments will 
be performed after the informed consent form has been signed. The scheduled date of 
surgery will be verified to ensure that the first dose of study drug occurs within the 30-
day window from screening.   
Patients will provide a full medical and medication history and will have a physical 
examination including vital signs, height and weight, and an examination of the oral 
mucosa.  A drug of abuse screen (urine) will be conducted.  A positive result for any drug 
must be consistent with the patient’s reported medical history and prescription drug use. 
Female patients of child bearing potential will have a pregnancy test.  Patients will 
receive instruction and training on use of the Zalviso System and their ability to handle 
the Zalviso System will be assessed.  Zalviso System demonstrators will be available for 
patient training and assessment of their ability to use the device.  Patients will receive 
training on completion of the rating scales.  Inclusion and exclusion criteria will be 
reviewed. 
6.1.2 
Inpatient Admission (Study Day 1) 
Study staff will verify admission and surgery schedule the day before the scheduled 
procedure and notify the Pharmacy that a potential patient may be enrolled into the study.  
Female patients of child bearing potential will have a urine pregnancy test.  Patients who 
continue to meet all eligibility requirements for study enrollment are eligible to be dosed 
as long as none of the Exclusion Criteria following surgery (Section 4.3) apply. 
6.1.2.1 Anesthetic, Surgical and Postoperative Care Protocols 
 
 
A) Anesthetic Care 
The patient may be administered general anesthesia or spinal anesthesia that does not 
include spinal opioids during the operation.  Intra-operative analgesia will be provided 
using intravenous fentanyl, morphine or hydromorphone as deemed appropriate by the 
anesthesiologist. Surgeons must document any deviation from the pre-operative surgical 
plan.  Long-acting oral opioids are not allowed prior to surgery, during, after surgery, or 
during the study period. 


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Non-opioid analgesic drugs may be administered prior to surgery, during, after surgery, 
and during the study period. 
B) Surgical Care 
Any surgery expected to result in moderate-to-severe acute pain, requiring the treatment 
of systemic opioids for at least 24 hours after surgery, is permitted. 
C) Postoperative Care 
Following surgery, patients will be admitted to the PACU, where they will recover from 
anesthesia and vital signs will be stabilized if necessary.  Patients must be awake and 
breathing spontaneously, with a respiratory rate of 8 to 24 breaths per minute, arterial 
oxygen saturation by pulse oximetry (SpO2) of at least 95% with or without supplemental 
oxygen, able to answer questions and to follow commands before they can be treated 
with study drug.  A patient must begin using study drug within 8 hours of completion of 
surgery.  If the patient does not meet entrance criteria within this 8 hour time limit, the 
patient will be documented as a screen failure. 
Patients will be titrated to comfort (a pain intensity score of <5) in the PACU utilizing 
intravenous fentanyl, morphine, or hydromorphone, if needed, per local best practice.   
When the patient has been discharged from the PACU (or is ready for discharge from the 
PACU) the patient must report a pain score of >4 and request medication for pain in order 
for the study drug treatment to begin.  These pain scores collected just prior to the first 
dose of study drug will be self-recorded by the patient in a source document provided 
by investigator’s staff per the study schema.  The study staff must not record the 
patient’s PI, PR, or global scores for the patient.   
6.1.3 
Study Period 
The study period consists of a minimum of 24 hours and may extend up to 72 hours.  
There could be a situation where the patient is reporting pain scores that would allow 
initiation of the study, but study drug is not yet available from the Pharmacy.  In order to 
keep patients comfortable, opioids (fentanyl, morphine or hydromorphone) may be 
administered intravenously, as per standard practice, prior to the start of the study.  If a 
patient receives IV pain medication in this manner, he/she must still report a pain score of 
above 4 just prior to administration of the first dose of study drug.   
The investigator’s staff will monitor patient safety and oversee collection of efficacy data 
points during the study.  The patient will be given the Zalviso System and be re-
instructed on how to use the Zalviso System.  Patient re-education on use of the Zalviso 
System by the study staff will be based on use of the GUI training screens on the Zalviso 
System, the instructions in the HP-IFU document, and the Patient Reference Sheet.  The 
Patient Reference Sheet will be given to the patient with the instruction for the patient to 
use it as needed. 


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The study period starts with the self-administration of the first dose of study drug.  A 
member of the research study staff must observe the patient self-administer their first 
dose and document correct dosing in the source record and eCRF.  If the study staff 
member observes any incorrect behavior, the patient will be re-educated and the study 
staff member will document this additional training. 
If during the study treatment period, the study staff believes the patient does not possess 
the cognitive ability or manual dexterity to properly use the Zalviso System, alternate 
analgesic therapy should be considered.  
The following must be communicated to the patient during training on use of the Zalviso 
System: 
 Keep the Cap on the Dispenser and the Zalviso System in Holster when not in use 
 Remove the Cap and keep the Zalviso System upright when ready to self-
administer a dose 
 Place the Dispenser Tip under the tongue but do not touch the Dose Button before 
the Tip is under the tongue 
 During dosing, do not pull down on the Controller or apply any upward pressure 
on the Dispenser Tip with the mouth or teeth 
 Keep the Dispenser Tip in the mouth until they hear the dose tone and feel/hear 
the motor stop 
 If the patient cannot take a dose, the Zalviso System’s blue and green lights are 
continuously flashing and the Zalviso System is beeping, call the study staff 
 If the patient notices a misplaced tablet, call the study staff 
The criteria for the study period to begin are: 
 the patient has been discharged from the PACU (or is ready for discharge) 
 the patient has reported a pain score of >4 just prior to the first dose of study drug 
(baseline pain intensity) 
 the patient has requested medication for pain 
Patients should not eat or drink and should minimize talking for 10 minutes after a tablet 
has been self-administered.  Ice chips may be used to avoid excessively dry mouths in 
patients during the study period.  Additional doses will be self-administered by the 
patient as needed to maintain analgesia. 


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During the study period all pain intensity, pain relief, and global assessment scores will 
be self-recorded by the patient in a source document provided by investigator’s staff per 
the study schema.  The patient and study staff will complete a PGA and HPGA, 
respectively, 24 hours, 48 hours and 72 hours after the first dose of study drug.  If the 
patient discontinues before 24 hours, the PGA and HPGA assessments will be completed 
by the patient and study staff at the time of early termination. 
During the study treatment period, the study staff will check for any misplaced tablets 
every 2 hours starting with the 1st on-demand dose.  This would include checking the 
Zalviso System cap, within the patient’s bed and linens, and on the hospital room floor.  
If a misplaced tablet is found, the study staff will document in the source and eCRF 
including the details of when and where found, and query the patient to determine the 
likely cause of the misplaced tablet.  The patient will be retrained on proper dosing 
technique. 
The study staff will record the date and time of the first and last doses of study drug taken 
during the study period from the Controller’s detailed history log. 
Should a patient use all 40 tablets and require additional analgesia within the study 
period, an additional drug cartridge will be provided. 
If a patient is asleep at the time of a protocol-specified pain rating or vital signs 
assessment, the patient will be allowed to sleep, but the study staff will record the 
respiratory rate and oxygen saturation.  A patient will not be allowed to sleep through 2 
consecutive assessments. 
Sleeping patients will be observed for signs of opioid overdose, such as bradypnea and 
airway obstruction.  If a patient does not appear to have signs of opioid overdose the 
patient will be allowed to continue to sleep. 
If a patient is unable to obtain satisfactory analgesia using the study drug, other allowable 
medications, and supplemental opioid medication allowed in the protocol-specified 
dosing regimen, he/she should be withdrawn from the study.  Pain management, as 
deemed appropriate by the Investigator, will be provided. 
Passive range-of-motion therapy is permitted starting 12 hours after the first dose of 
study drug. 
Safety Assessments 
The patient will be monitored continuously by a study staff member for the first hour 
following the first dose of study drug. 
Heart rate and blood pressure will be recorded prior to administration of the first dose of 
study drug, and when pain intensity and pain relief assessments are made i.e. 15, 30, and 
45 minutes, and 1, 2, 4, 6, 8, 10, and 12 hours after the first on-demand dose.  Blood 
pressure and heart rate will then be measured every four hours during the 12 to 72 hour 


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study period.  During the first 24 hours of treatment, respiratory rate and oxygen 
saturation will be recorded prior to the first dose of study drug, 15,30, 45, and 60 minutes 
after the first dose of study drug, and then every 30 minutes.  During the 24 to 72 hour 
study period, the respiratory rate and oxygen saturation will be recorded every 2 hours.  
When vital signs are to be measured at the same time as PI and PR scores, the vital sign 
measurements may be taken up to 5 minutes before the scheduled time, in order for PI 
and PR scores to be self-recorded by patient at the scheduled time. 
The Investigator or the Medical Monitor may exercise his/her judgment to terminate a 
patient’s participation in the study due to clinically significant changes in any clinical 
parameter. 
Patients will be instructed to report any AEs they experience throughout the duration of 
the study.  Reported AEs and any concomitant medications administered during the study 
period will be recorded in the CRF.  SAEs that occur within 30 days of the last dose of 
study drug will be reported. 
6.1.4 
End of Study 
Patients will be considered completers if they complete the study for a minimum of 24 
hours.  Patients who are withdrawn from the study for any reason prior to 24 hours will 
be considered early terminations. 
At the time the patient discontinues from the study or a Drug Cartridge is changed, the 
number of tablets remaining in the Drug Cartridge as displayed on the Zalviso System 
display screen will be recorded in the source records. 
The Patient Usability Questionnaire (Appendix IV) will be completed at the end of the 
study or at the time of early discontinuation. The Patient Usability Questionnaire will be 
completed before the patient completes the PGA (Appendix III). 
Study staff will complete the Nurse Usability Questionnaire (Appendix V) when they 
have interacted with 5 patients, or when enrollment is completed at the study site.  The 
study staff will download the controller data after its use by each patient using the data 
transfer cable and download utility software provided by AcelRx.  The data files will then 
be transferred per AcelRx instructions. 
6.2 
Appropriateness of Measurements 
Global evaluations are recognized as important indicators of efficacy based on a patient’s 
perception of effect.  Patient ratings of pain intensity on an 11-point numerical rating 
scale (0=no pain, 10=worst possible pain), and pain relief on a 5-point numerical rating 
scale (0=no relief, 1=a little relief, 2=moderate relief, 3=a lot of relief, and 4=complete 
relief) are commonly used and validated measures of the effect of a treatment for pain. 
The following questions regarding pain intensity and pain relief will be asked of the 
patient at the protocol-specified time points: 


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“On a scale of 0 to 10, 0 being no pain and 10 being worst possible pain, how would you 
rate your current level of pain intensity?” 
“How would you rate your current level of pain relief on a scale of 0 to 4 with 0 being no 
relief and 4 being complete relief?”  
The Patient and Nurse Usability Questionnaires are not validated. 
7 
ASSESSMENT OF EFFICACY 
7.1 
Efficacy Variables 
Efficacy variables include: 
 Proportion of patients who experienced at least one system-generated error based 
on the Controller data while using the Zalviso System 
 Proportion of patients, if any, with tablet dispensed but not requested 
 Proportion of patients, if any, with tablet dispensed when the Zalviso System is in 
lockout 
 Proportion of patients with misplaced tablet(s) 
 Number of misplaced tablets (i.e., tablet found outside the patient’s mouth) 
 Proportion of patients who experienced either a system-generated error or a 
misplaced tablet (i.e. a dispense failure) 
 Assessment of the number of Zalviso System notifications to the nurse to retrain 
patient to not pull down on Controller while dosing (i.e., mitigation of Error 302) 
 Proportion of patients who rate the Patient Global Assessment (PGA) of method 
of pain control over 24, 48 and 72 hours as “good” or “excellent” 
 Proportion of patients who responded in each category of the PGA 
 Proportion of Healthcare Professionals who rate the Global Assessment (HPGA) 
of method of pain control over 24, 48 and 72 hours as “good” or “excellent” 
 Proportion of Healthcare Professionals who responded in each category of the 
HPGA 
 Proportion of patients who terminate from the study due to inadequate analgesia 
over the 24-hour, 48-hour and 72-hour study period 
 Time-weighted summed pain intensity difference (SPID) over the 24-hour study 
period (SPID24), over the 48-hour study period (SPID48), and over the 72-hour 
study period (SPID72) 
 Total pain relief (TOTPAR) over the 24-hour study period (TOTPAR24), over the 
48-hour study period (TOTPAR48) and over the 72-hour study period 
(TOTPAR72) 
 Pain intensity (PI) at each evaluation time point 
 Pain intensity difference (PID) at each evaluation time point 
 Pain relief (PR) at each evaluation time point  
 Patient Usability Questionnaire (PUQ) 
 Nurse Usability Questionnaire (NUQ) 
 Total number of study drug doses used over 24, 48, and 72-hour study period, 
average hourly use, and average inter-dosing interval. 


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 Total amount of supplemental morphine utilized 
8 
ASSESSMENT OF SAFETY 
8.1 
Safety Variables 
Safety assessments will include the assessment of adverse events, vital signs (blood 
pressure, heart rate and respiratory rate), oxygen saturation, and the use of concomitant 
medications. 
8.1.1 
Physical Examination/Vital Signs 
The physical examination will include examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, oral mucosa, heart, lungs, abdomen, lymph 
nodes, extremities, and nervous system.  Height and weight will be measured. 
Vital signs will include respiratory rate, radial pulse rate, and systolic and diastolic blood 
pressures.  The patient may be sitting, semi-recumbent or lying down.  Recordings are to 
be made after the patient has been in the same position for 5 minutes or more and the 
position will be recorded.  Heart rate will be measured over 30 seconds and respiratory 
rate will be measured over 1 minute. 
Respiratory rate and other vital signs may be checked at additional times on an ad hoc 
basis per the judgment of the study staff.  Oxygen saturation (SpO2) will be measured 
continuously by pulse oximetry but will only be recorded at the time points when 
respiratory rates are measured and recorded. 
8.1.2 
Laboratory Parameters 
A urine drug of abuse screen (barbiturates, benzodiazepines, cocaine, marijuana, 
phencyclidine, and opiates) will be performed at screening.  A test for pregnancy will be 
done at screening and after admission to the hospital for women who are of childbearing 
potential. 
8.1.3 
Adverse Events 
An adverse event is any illness, sign, laboratory value or symptom which appears or 
worsens during the clinical trial, regardless of causal relationship to the investigational 
drug.  AEs that occur from the first dose of study drug and for 12 hours after the last dose 
of study drug will be documented on the AE CRF.  The Investigator will assess the AE 
severity and relationship of the AE to study drug.  The Investigator will treat the patient 
as medically required until the AE either resolves or becomes medically stable.  
Treatments and medications required to treat AEs will be recorded on the appropriate 
pages of the CRFs. 
8.1.3.1 Adverse Event Severity is Defined as Follows: 
Mild:  The event may be noticeable to the patient, but does not influence the patient’s 
daily activities.  The event usually does not require special treatment. 


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Moderate:  The event may result in slight discomfort for the patient and performance of 
the patient’s daily activities may be influenced.  The event may require intervention. 
Severe:  The event may result in severe discomfort for the patient and usually interferes 
with the patient’s daily activities.  The patient may not be able to continue in the study 
and treatment or other intervention is usually needed. 
8.1.3.2 Adverse Event Relationship to Study Drug is Defined as Follows: 
Probably related: Study drug administration and AE occurrence are reasonably related in 
time; AND, the AE is more likely explained by exposure to study drug than by other 
mechanisms. 
Possibly related:  Study drug administration and AE occurrence are reasonably related in 
time; AND, AE is explained equally well by causes other than study drug. 
Not related:  AE is obviously explained by another cause; OR, the time of occurrence of 
AE is not reasonably related to administration of the study drug. 
8.1.3.3 Serious Adverse Events 
Serious, life-threatening, and unexpected AEs will be identified and handled in 
accordance with the guidelines specified in the US Code of Federal Regulations (CFR). 
A serious adverse event (SAE) is defined as any event that is fatal or life-threatening, 
permanently or substantially disabling or incapacitating (causing a substantial disruption 
of a person’s ability to conduct normal life functions), prolongs hospitalization, a 
congenital anomaly, or an important medical event.  Important medical events are defined 
as events that may not result in death, be life threatening, or prolongs hospitalization but, 
based on appropriate medical judgment, may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in the definition of 
an SAE.    
A life-threatening AE is one that, in the view of the Investigator, places the patient at 
immediate risk of death from the reaction as it occurred. 
An unexpected AE is any event, for which the specificity or severity is not consistent 
with the AE profile in the current package insert for Sufenta (Appendix VI) or the 
Zalviso System Investigator Brochure. 
All SAEs, regardless of cause(s) or relationship to study drug, must be reported 
immediately to AcelRx or designee.  Additional contact numbers and AE/SAE reporting 
instructions will be provided to each site in a separate document.   
The name of the Medical Monitor and contact information will be provided to each study 
site. 
The Investigator must report via phone or fax an SAE within 24 hours of learning of the 
event.  The investigator must complete the Serious Adverse Event Report Form and 


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submit it along with other relevant pages of the CRF within 1 working day to AcelRx or 
its designee.  The Investigator will also compile with urgent priority other relevant 
documentation (e.g., copies of test results, hospital discharge summary, autopsy 
report, etc.) and send this information to AcelRx or its designee.  All SAEs will also be 
reported on the AE page of the CRF, and concomitant medications administered in 
association with the SAE will be documented on the Concomitant Medication page of the 
CRF. 
Regulatory agencies and all participating Investigators will be notified in writing of any 
SAE that is both associated with the use of the study drug and unexpected within 15 
calendar days from when the SAE was reported to AcelRx or safety designee.  Safety 
reporting shall also include events described in the scientific literature.  Regulatory 
agencies will be notified by telephone or fax within 7 calendar days of any unexpected 
fatal or life-threatening AE associated with the use of the study drug. 
AEs and SAEs that occur during the study treatment period will be documented.  Any 
SAEs reported during the 30 days after the last dose of study drug will be reported and 
captured in the CRF. 
9 
STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Determination of Sample Size 
This is a multicenter, open-label, single treatment clinical study designed to evaluate the 
overall functionality of the Zalviso System (sufentanil sublingual tablet system) 15 mcg 
for the treatment of acute moderate-to-severe postoperative pain. A sample size of 
approximately 330 patients is planned for this study in order to have at least 315 patients 
receive study drug and have available efficacy data for data analysis.  
A sample size of 315 patients will have 90% power to demonstrate that the device 
dispense failure rate is non-inferior to a target of 2%.  This failure rate is the proportion 
of patients who experienced at least one of following events: (1) a system-generated 
error, (2) a tablet dispensed but not requested, or (3) a tablet dispensed when the Zalviso 
System is in lockout.  All events listed above will be obtained from the Controller patient 
usage data.   
This is based on the criteria that the upper limit of a 90% confidence interval (CI) of the 
device dispense failure rate is not worse than 5%.  This calculation is based on the exact 
binomial test of one-sample proportion for a one-sided case against a 2% target 
proportion with a delta of 3%, and a one-sided significance level of =0.05. This sample 
size was generated from the SAS procedure PROC POWER for one-sample proportion. 
Exact power computations are based on the binomial distribution and computing 
formulas provided by Johnson and Kotz (1970). Assuming a 5% non-evaluable rate, a 
sample size of 330 patients is planned for this study.    


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9.2 
Tests of Hypothesis and Significance Levels 
Both continuous and categorical efficacy variables will be summarized descriptively. A 
point estimate of the device dispense failure rate and its 90% confidence interval based 
on the exact binomial test will be constructed.   
9.3 
Randomization and Blinding of the Treatment Assignment 
This is an open-label single treatment study.  There is no randomization of patients or 
blinding of treatment.  Patients who meet the eligibility requirements will be enrolled into 
this study sequentially within each study center to receive study treatment. 
9.4 
Baseline Comparability 
Demographics and baseline characteristics will be summarized by sex group for all 
enrolled patients and all patients received study drug.  Data will be pooled for all study 
centers for the descriptive summary of baseline data.  No formal hypothesis testing will 
be performed for baseline data. 
9.5 
Analysis of Efficacy Data 
Sections related to the analysis of efficacy data are specified below by topic. 
9.5.1 
Efficacy Variables and Parameters 
The efficacy variables and parameters are: 
1. Proportion of patients who experienced at least one system-generated error based 
on the Controller data while using the Zalviso System 
2. Proportion of patients, if any, with tablet dispensed but not requested  
3. Proportion of patients, if any, with tablet dispensed when the Zalviso System is in 
lockout 
4. Proportion of patients with misplaced tablet(s) 
5. Number of misplaced tablets (i.e., tablet found outside the patient’s mouth) 
6. Proportion of patients who experienced either a system-generated error or a 
misplaced tablet (i.e. a dispense failure) 
7. Assessment of the number of Zalviso System notifications to the nurse to retrain 
patient to not pull down on Controller while dosing (i.e., mitigation of Error 302) 
8. Proportion of patients who rate the Patient Global Assessment (PGA) of method 
of pain control over 24, 48 and 72 hours as “good” or “excellent” 
9. Proportion of patients who responded in each category of the PGA 
10. Proportion of Healthcare Professionals who rate the Global Assessment (HPGA) 
of method of pain control over 24, 48 and 72 hours as “good” or “excellent” 
11. Proportion of Healthcare Professionals who responded in each category of the 
HPGA 
12. Proportion of patients who terminate from the study due to inadequate analgesia 
over the 24-hour, 48-hour and 72-hour study period 
13. Time-weighted summed pain intensity difference (SPID) over the 24-hour study 
period (SPID24), over the 48-hour study period (SPID48), and over the 72-hour 
study period (SPID72) 


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14. Total pain relief (TOTPAR) over the 24-hour study period (TOTPAR24), over the 
48-hour study period (TOTPAR48) and over the 72-hour study period 
(TOTPAR72) 
15. Pain intensity (PI) at each evaluation time point 
16. Pain intensity difference (PID) at each evaluation time point 
17. Pain relief (PR) at each evaluation time point  
18. Patient Usability Questionnaire (PUQ) 
19. Nurse Usability Questionnaire (NUQ) 
20. Total number of study drug doses used over 24, 48, and 72-hour study period, 
average hourly use, and average inter-dosing interval. 
21. Total amount of supplemental morphine utilized 
 
9.5.2 
Analysis Population and Handling of Dropouts 
The main analysis of the efficacy variables will include the intent-to-treat (ITT) 
population.  The ITT population includes enrolled patients who received study drug.     
For patients missing PI or PR data, the following methods will be applied to impute the 
missing data at evaluation time points for the duration of study period: 
(1) Missing data will be first imputed on a patient-by-patient basis by linear interpolation 
method between two observed pain scale values. 
(2) Data occurring after a patient terminated from study or did not provide any follow-up 
data after last available data prior to the end of study period, the pain scale values at 
follow-up time points post-termination up to the end of the study period will be 
imputed on a patient-by-patient basis as described below. 
The last observation carried forward (LOCF) method will be used to impute any 
remaining missing data points after termination due to reasons other than adverse event 
up to the end of the study period. For patients who prematurely terminated from the study 
due to adverse event, the worst observation carried forward (WOCF) method will be used 
to impute the remaining missing data points up to the end of the study period. The worst 
PID is the smaller number between number zero and the last PID obtained prior to 
termination. The worst PR is number zero. 
For patients who used any supplemental opioid during the study period, the last observed 
pain intensity prior to using each dose of supplemental opioid will be carried throughout 
a follow-up 1-hour time interval. Any pain intensity collected within 1 hour after the start 
of any supplemental opioid will be excluded from the calculation of the time-weighted 
SPID24. This same imputation method will also be used to calculate the efficacy 
endpoints derived from pain assessment data. 
9.5.3 
Definition of Baseline Measurements 
Baseline measurements are those taken prior to the start of study drug administration.   


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9.5.4 
Methods for the Analysis of Device Dispense Failure Rate  
For the analysis of the device dispense failure rate, a point estimate of the device dispense 
failure rate and its 90% confidence interval based on the exact binomial test will be 
constructed.  Patients from all study centers will be pooled for the descriptive summary 
of these efficacy data by sex group.  
9.5.5 
Pooling of Investigators 
The data from all study centers will be pooled for the analysis of efficacy data.  
9.5.6 
Methods for the Analysis of Categorical Efficacy Variables 
For the analysis of the dichotomous outcome data, a point estimate and its 90% 
confidence interval based on the exact binomial test will be constructed.  Patients from all 
study centers will be pooled for the descriptive summary of the efficacy data by sex 
group. 
9.5.7 
Methods for the Analysis of Continuous Efficacy Variables 
The method used to derive the efficacy endpoint time-weighted summed pain intensity 
difference (SPID) over the study period is described in this section. Pain intensity will be 
measured using an 11-point NRS with 0 (no pain) and 10 (worst possible pain).  
Patients will provide the pain intensity (PI) and pain relief (PR) measures at baseline and 
at each evaluation time point after the initiation of the first on-demand dose of study 
drug:  ¼ [15 min], ½  [30 min], ¾ [45 min], 1, 2, 4, 6, 8, 10,  and 12 hours, then every 4  
hours at 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72 hours. 
The PID at each evaluation time point after the initiation of the first dose is the difference 
in pain intensity at the specific evaluation time point and baseline pain intensity [PID 
(evaluation time after the first dose) = pain intensity (baseline) – pain intensity 
(evaluation time after the first dose)]. The time-weighted SPID24 is the time-weighted 
summed PID over the 24-hour study period.  
Time-weighted SPID24 = ∑ [T(i) – T(i-1)] x PID(i), 
Where : T(0) = Time 0 (baseline), T(i) is the scheduled or unscheduled 
assessment time, and PID(i) is the PID score at time i for i=0 to 24 hours 
Other time-weighted SPID, SPID48 and SPID72 will be derived similarly. TOTPAR over 
follow-up evaluation time periods (e.g., TOTPAR24, TOTPAR48, and TOTPAR72, etc.) 
will be derived from the PR data collected during the study using similar formula 
described above.   
For the analysis of the continuous efficacy data, a point estimate and its 90% confidence 
interval will be constructed.  Patients from all study centers will be pooled for the 
descriptive summary of the efficacy data by sex group  


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9.6 
Analysis of Safety Data 
All patients who received at least one dose of study drug will be included in the 
summaries of safety data. An AE thesaurus, the Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to map each AE verbatim term to lowest level term, 
preferred term, and System Organ Class for summary purposes. Adverse events occurring 
while patients are on study drug until 12 hours after the last dose will be summarized.  
Other safety data, such as premature terminations, vital signs (blood pressure, heart rate, 
and respiratory rate), oxygen saturation, and the use of concomitant medications will be 
tabulated.  
Vital signs taken at baseline and follow-up time points will be summarized.  Patients who 
had baseline data and at least one follow-up data will be included in the summary of vital 
signs by sex group. The descriptive summary statistics will be presented.  A paired t-test 
will be used for the test of mean change from baseline to follow-up time points within 
each group. 
10 STUDY MANAGEMENT 
10.1 Regulatory and Ethical Considerations 
10.1.1 
Regulatory Guidelines 
The Investigator agrees to conduct the study in accordance with the protocol, ICH 
guidelines on Good Clinical Practice (GCP), and national, state, and local laws of the 
pertinent regulatory authorities. 
10.1.2 
Institutional Review Board 
The protocol, informed consent form (ICF), investigator’s brochure, patient information, 
recruiting materials, subject compensation program (if any) must be approved in writing 
by an Institutional Review Board (IRB) before the study can be initiated at a site. 
If the protocol is amended, AcelRx or the Investigator must obtain IRB for approval prior 
to implementation of the amendment.  The Investigator must report promptly to the IRB 
all changes in the research activity and all unanticipated problems involving risk to 
human subjects or others, including all SAEs that have resulted in an expedited safety 
reporting. 
The Investigator is responsible for obtaining continued review of the clinical study as 
specified by the IRB but at least annually. 
10.1.3 
Informed Consent 
Each patient must provide written informed consent before any study-related procedures 
are started.  It is the responsibility of the Investigator or designated staff member(s) to 
give a copy of the ICF to each potential patient and to be available to answer any 
questions the patient may have about the nature of the study and his or her participation 
in it.  The individual responsible for explaining the consent form to the patient must 
witness the patient’s signature on the form.  It is the responsibility of the Investigator to 


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provide a copy of the IRB-approved consent form to the Sponsor (or designee) prior to 
the start of the study.  If a protocol amendment substantially alters a study design or 
increases the potential risk to the patient, the consent form must be revised and submitted 
to the IRB(s) for review and approval prior to implementation.  The revised consent must 
be used to obtain consent from patients currently in the study if they are affected by the 
amendment and from new patients prior to their enrollment in the study. 
All enrolling patients are required to sign an IRB-approved Health Insurance Portability 
and Accountability Act of 1996 (HIPAA) authorization document. 
10.1.4 
Study Documentation 
The protocol and any amendments signed and dated by the investigator, the completed 
financial disclosure form, and signed and dated statement of the investigator (e.g. Form 
FDA 1572), if applicable, and all other essential documents specified by ICH GCP will 
be provided to AcelRx or designee prior to initiation of the study at the investigational 
center. 
Adequate source documentation will be maintained by the investigator and may be 
recorded on paper or directly into an electronic system.  At a minimum this 
documentation will verify subject identification, eligibility, proper informed consent, visit 
dates, adherence to study procedures, reporting of safety and efficacy parameters, study 
drug dispensing, and study completion. 
Source data may be recorded on paper or directly into an electronic system.  A list of data 
directly entered into an electronic data capture system will be maintained. 
Data should be entered into the CRF within 3 days of a patient completing the study.  
Queries should be resolved within 5 days of being issued. 
10.2 Withdrawals 
Individual patients might voluntarily drop from the study without completing all 
assessments.  In such cases, the Investigator will document the specific reason for the 
incomplete information (e.g., withdrawal of consent) on the appropriate page of the CRF. 
10.3 Study Or Study Site Termination 
AcelRx may suspend or stop the study at all centers or at specific study centers due to 
(but are not limited to) the discovery of an unexpected, serious, or unacceptable risk to 
the patients enrolled in the study, a decision on the part of AcelRx to suspend or 
discontinue development of the product, failure of the Investigator to enroll patients into 
the study at an acceptable rate, failure of the Investigator to comply with regulatory 
authority or ICH Guidelines, or submission of knowingly false information. 
10.4 Study Monitoring 
AcelRx or designee will assign monitors who will perform on site monitoring as 
frequently as necessary and in accordance with ICH GCP. 


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Source documents and CRFs will be reviewed at monitoring visits and any findings will 
be discussed with the investigational staff.   AcelRx expects that at monitoring visits 
study documents and staff will be available and a suitable space will be provided for 
review of the study documents.  The monitor will meet with the investigator on a regular 
basis to provide feedback on the conduct of the study. 
10.5 Data Quality Assurance 
Study auditing, data entry, verification and validation, and subsequent analysis will be 
performed by AcelRx, or its designees, in accordance with GCPs and established 
Standard Operating Procedures. 
10.6 Access to Records 
The study may be subject to audit by AcelRx, its designee, or by regulatory authorities.  
If such an audit occurs, the Investigator must agree to allow access to required patient 
records.  The Investigator should notify AcelRx promptly of regulatory authority audits 
that are scheduled, and must forward copies of any findings or audit reports to AcelRx 
promptly. 
By signing this protocol, the Investigator grants permission to personnel from AcelRx, its 
representatives, and appropriate regulatory authorities for on-site monitoring and review 
of all appropriate study documentation, as well as on-site review of the procedures 
employed in data collection, where clinically appropriate. 
10.7 Retention of Records 
The Investigator must arrange for retention of study records at the site for 2 years after 
the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period, however, if required by 
the applicable regulatory requirements or by agreement with AcelRx.  It is the 
responsibility of AcelRx to inform the Investigator/Institution as to when these 
documents no longer need to be retained.  The Investigator should take measures to 
prevent any accidental or premature destruction of these documents. 
11 Publications 
All information related to this study is considered confidential information belonging to 
AcelRx.  Data on the use of the study drug and results of all clinical and laboratory 
studies are considered private and confidential.  None of the details, results, or other 
information for this study shall be published or made known to a third party without 
written consent from AcelRx, except for disclosure to regulatory agencies if required by 
law. 
 


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12 REFERENCES 
Bailey PL, Streisand JB, East KA, East TD, Isern S, Hansen TW, Posthuma EFM, 
Rozendaal FW, Pace NL, Stanley TH. Differences in magnitude and duration of opioid-
induced respiratory depression and analgesia with fentanyl and sufentanil.AnesthAnalg 
1990, 70:8-15. 
Chauvin M, Ferrier C, Haberer JP, Spielvogel  C, Lebrault C, Levron JC, Duvaldestin P. 
Sufentanil pharmacokinetics in patients with cirrhosis. AnesthAnalg 1989, 68:1-4. 
Clark N, Meuleman T, Liu W, Zwanikken P, Pace N, Stanley T. Comparison of 
sufentanil-N2O and fentanyl- N2O in patients without cardiac disease undergoing general 
surgery. Anesthesiology 1987, 66: 130-135. 
Conti G, Arcangeli A, Antonelli M, Cavaliere F, Costa R, Simeoni F, Proietti R. Sedation 
with sufentanil in patients receiving pressure support ventilation has no effects on 
respiration: a pilot study. Can J Anesth 2004, 51:494-499. 
Fyman PN, Reynolds JR, Moser DF, Avitable M, Casthely PA, Butt K.  
Pharmacokinetics of sufentanil in patients undergoing renal transplantation. Can J 
Anaesth 1988, 35:312-315. 
Grass JA. Patient-controlled analgesia.AnesthAnalg 2005, 101:S44-S61. 
Hankin C, Schein J, Clark J, Panchal S.Adverse events involving intravenous patient-
controlled analgesia.Am J Health-Syst Pharm 2007, 64:1492-1499. 
Hicks RW, Sikirica V, Nelson W, Schein JR, Cousins DD.Medication errors involving 
patient-controlled analgesia.Am J Health-Syst Pharm2008(a), 65:429–440. 
 
Hicks R, Heath M, Sikirica V, Nelson W, Schein J. Medication errors involving patient-
controlled analgesia. The Joint Commission Journal on Quality and Patient Safety 
2008(b), 34:734-742. 
Johnson, NL, and Kotz, S. (1970). Distributions in Statistics: Continuous Univariate 
Distributions, Volume I, Wiley, New York 
Mather L. Clinical pharmacokinetics of fentanyl and its newer derivatives. 
ClinPharmacokin 1983, 8:422-426. 
Matteo RS, Schwartz AE, Ornstein E, Young WL, Chang W. Pharmacokinetics of 
sufentanil in the elderly surgical patient. Can J Anaesth 1990, 37:852-856. 
Meissner B, Nelson W, Hicks R, Sikirica V, Gagne J, Schein J.  The rate and costs 
attributable to intravenous patient-controlled analgesia errors. Hosp Pharm 2009, 44:312-
324. 
SAS Release 9.1.  SAS Institute Inc., Cary, North Carolina, 2004. 


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Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ.Pharmacokinetics of 
sufentanil in obese patients.AnesthAnalg 1991, 73:790-793. 
 
Ved SA, Dubois M, Carron H, Lea D.  Sufentanil and alfentanil pattern of consumption 
during patient-controlled analgesia: a comparison with morphine. Clin J Pain 1989, 
5(suppl 1):S63-S70. 
 


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APPENDIX I 
American Society of Anesthesiologists Physical Status Classification 
System 
 
I  
 
Normal healthy patient 
 
II 
Patient with mild systemic disease; no functional limitation–eg, smoker 
with well-controlled hypertension 
 
III  
Patient with severe systemic disease; definite functional impairment–eg, 
diabetes and angina with relatively stable disease, but requiring therapy  
 
IV 
Patient with severe systemic disease that is a constant threat to life–eg, 
diabetes and angina and congestive heart failure; patientswith dyspnea on 
mild exertion and chest pain  
 
V 
Unstable moribund patient who is not expected to survive 24 hours with or 
without the operation  
 
VI 
 
Brain-dead patient whose organs are removed for donation to another  
 
E 
Emergency operation of any type, which is added to any of the above six 
categories, as in ASA II E  
 


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APPENDIX II 
DSM-IV Criteria for Substance Dependence 
A maladaptive pattern of substance use leading to clinically significant impairment or 
distress, as manifested by three (or more) of the following, occurring at any time in the 
same twelve-month period: 
1. 
tolerance, as defined by either of the following: 
 
a. a need for markedly increased amounts of the substance to achieve 
intoxication or desired effect 
 
b. markedly diminished effect with continued use of the same amount of the 
substance 
2. 
withdrawal, as manifested by either of the following: 
 
a. the characteristic withdrawal syndrome for the substance (see specific 
withdrawal syndromes in the DSM-IV) 
 b. the same substance (or closely related) substance is taken to relieve or 
avoid withdrawal symptoms 
3. 
the substance is often taken in larger amounts or over a longer period than was 
intended 
4. 
there is a persistent desire or unsuccessful efforts to cut down or control 
substance use 
5. 
a great deal of time is spent in activities necessary to get the substance, use the 
substance, or recover from its effects 
6. 
important social, occupational, or recreational activities are given up or 
reduced because of substance use 
7. 
the substance is continued despite knowledge of having a persistent or 
recurrent physical or psychological problem that is likely to have been caused 
or exacerbated by the substance 
 
NOTE: In an individual who denies dependence, substance dependence is assumed if 
there is evidence of a mental or physical disorder or condition that is usually a 
complication of prolonged substance use, e.g., DTs, cirrhosis, alcoholic neuropathy, 
esophageal varices from alcohol use, needle marks or abscesses from substance use. 
 
*Based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-
IV Criteria for Substance Dependence) 


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APPENDIX II (continued) 
DSM-IV Criteria for Substance Abuse 
 
A maladaptive pattern of substance use leading to clinically significant impairment or 
distress, as manifested by one (or more) of the following, occurring at any time in the 
same 12-month period: 
 (1)  recurrent substance use resulting in a failure to fulfill major role obligations at 
work, school, or home (e.g., repeated absences or poor work performance 
related to substance use; substance related absences, suspensions, or 
expulsions from school; neglect of children or household) 
 (2)  recurrent substance use in situations in which it is physically hazardous (e.g., 
driving an automobile or operating a machine when impaired by substance-
related disorderly conduct) 
 (3)  recurrent substance-related legal problems (e.g., arrests for substance-related 
disorderly conduct) 
 (4)  continued substance use despite having persistent or recurrent social or 
interpersonal problems caused or exacerbated by the effects of the substance 
(e.g., arguments with spouse about consequences of intoxication, physical 
fights) 
 
NOTE: If a subject does not meet any of the above criteria, alcohol abuse will be 
assumed if the patient is consistently drinking more than 28 units of alcoholic beverages 
per week or female subjects who drink more than 21 units per week. 1 unit is defined as 
½ pint of beer, 1 glass of wine or 1 measure of spirits. 
 
* Based on Diagnostic and Statistical manual of Mental Disorders, Fourth Edition (DSM-
IV Criteria for Substance Abuse) 


Acel R x P har mace uticals  
I A P 3 1 2 A me n d me nt # 1 
C O N FI D E N TI A L  
5 2  
A P P E N DI X  III 
P atie nt Gl o b al Assess me nt  
T he f oll o wi n g q u esti o n will be a ns were d b y t he patie nt 2 4 h o urs after t he first o n -de ma n d 
d ose:  
“ Over all, h o w w o ul d y o u r ate t he met h o d of p ai n c o ntr ol d uri n g t he l ast 2 4 h o urs ? ”  
 
T he f oll o wi n g q u esti o n will be a ns were d b y t he patie nt 4 8 h o urs after t he first o n -de ma n d 
d ose:  
“ Over all, h o w w o ul d y o u r ate t he met h o d of p ai n c o ntr ol d uri n g t he l ast 4 8 h o urs ? ”  
 
T he f oll o wi n g q u esti o n will be a ns were d b y t he patie nt 7 2 h o urs after t he f irst o n-de ma n d 
d ose:  
“ Over all, h o w w o ul d y o u r ate t he met h o d of p ai n c o ntr ol d uri n g t he l ast 7 2 h o urs ? ”  
  P o or ( 1)  
 
  Fair ( 2)  
 
  G o o d ( 3)  
 
  E x celle nt ( 4)  
 
He alt hc are Pr ofessi o n al Gl o b al Assess me nt  
 
T he f oll o wi n g q u esti o n will be a ns were d b y t he H P  2 4 h o urs after t he first o n -de ma n d 
d ose:  
“ Over all, h o w w o ul d y o u r ate t he met h o d of p ai n c o ntr ol d uri n g t he l ast 2 4 h o urs ? ”  
 
T he f oll o wi n g q u esti o n will be a ns were d b y t he H P  4 8 h o urs after t he first o n -de ma n d 
d ose:  
“ Over all, h o w w o ul d y o u r ate t he met h o d of p ai n c o ntr ol d uri n g t he l ast 4 8 h o urs ? ”  
 
T he f oll o wi n g q u esti o n will be a ns were d b y t he H P  7 2 h o urs after t he first o n -de ma n d 
d ose:  
“ Over all, h o w w o ul d y o u r ate t he met h o d of p ai n c o ntr ol d uri n g t he l ast 7 2 h o urs ? ”  
  P o or ( 1)  
 
  Fair ( 2)  
 
  G o o d ( 3)  
 
  E x celle nt ( 4) 


AcelRx Pharmaceuticals 
IAP312 Amendment #1 
CONFIENTIAL 
53 
APPENDIX IV 
Patient Usability Questionnaire 
 
How would you rate your experience with Zalviso regarding: 
 
 
 
 
 
 
 
Disagree 
Somewhat 
Disagree 
Somewhat 
Agree 
Agree 
I thought Zalviso was easy to use 
 
 
 
 
I had confidence in my ability to 
dose with Zalviso 
 
 
 
 
Zalviso consistently worked as I 
expected it to  
 
 
 
 
I did not understand how to use 
Zalviso 
 
 
 
 
I knew what to do if I dropped a 
tablet 
 
 
 
 
The use of Zalviso was not fully 
explained to me 
 
 
 
 
I would request to use Zalviso 
after my next surgery 
 
 
 
 


AcelRx Pharmaceuticals 
IAP312 Amendment #1 
CONFIDENTIAL 
54 
APPENDIX V 
Nurse Usability Questionnaire 
 
How would you rate your experience with Zalviso regarding: 
 
 
 
 
 
 
 
Disagree 
Somewhat 
Disagree 
Somewhat 
Agree 
Agree 
I thought Zalviso was easy to set-up 
 
 
 
 
I had confidence in my ability to set-
up Zalviso 
 
 
 
 
I did not spend much time having to 
trouble-shoot Zalviso during patient 
use 
 
 
 
 
Dropped tablets were disposed and 
accounted for appropriately and did 
not become a risk to the patient or 
others 
 
 
 
 
I found Zalviso time-consuming to 
set-up 
 
 
 
 
The Zalviso set-up instructions were 
not clear to me 
 
 
 
 
I would recommend Zalviso for the 
treatment of moderate to severe pain 
after surgery 
 
 
 
 


AcelRx Pharmaceuticals 
 
IAP312 Amendment #1 
CONFIDENTIAL 
 
 
 
55 
APPENDIX VI:  Sufenta Package Insert 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AcelRx Pharmaceuticals 
 
IAP312 Amendment #1 
CONFIDENTIAL 
 
 
 
56 
 
 
 
 
 

SAP_000.pdf: 
Protocol No. IAP312: FINAL REPORT 
Statistical Analysis Plan 
 
IAP312\STATDOC\PLAN\IAP312 Final SAP(061017) 
 
AcelRx Pharmaceuticals, Inc. 
 
PROTOCOL No. IAP312 
 
 
A Multicenter, Open-Label Trial to Evaluate the Overall Performance of the Zalviso 
System (sufentanil sublingual tablet system) 15 mcg 
 
Statistical Analysis Plan 
for 
Final Data Analysis 
 
(Final Version, 6/10/2017) 
 
 
 
 
 
 
Prepared by:  _______________________________ 
___________________ 
 
Yu-Kun Chiang, PhD 
 
 
Date 
 
Statistical Consultant to AcelRx 
 
 
 
AcelRx: 
Approved by: _______________________________ 
___________________ 
 
Pamela Palmer, M.D., Ph.D. 
 
Date 
 
Chief Medical Officer 
 
 
 


Protocol No. IAP312: FINAL REPORT 
Statistical Analysis Plan 
 
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i
TABLE OF CONTENTS 
 
 
Page 
1 
Introduction   .................................................................................................................1 
2 
Statistical Methods .......................................................................................................1 
2.1 
Determination of Sample Size .......................................................................................1 
2.2 
Data Processing and Management .................................................................................1 
2.3 
Performance of Statistical Data Analysis  .....................................................................1 
2.4 
Protocol Deviations and Special Cases ..........................................................................2 
2.5 
Test of Hypothesis and Significance Levels ..................................................................2 
2.6 
Randomization and Blinding of Treatment Assignment ...............................................2 
2.7 
Patient Enrollment and Disposition ...............................................................................2 
2.8 
Premature Termination from the Study  ........................................................................2 
2.9 
Baseline Comparability ..................................................................................................2 
2.10 
Analysis of Efficacy Data ..............................................................................................2 
2.10.1  
Efficacy Variables  .............................................................................................2 
2.10.2  
Analysis Population and Handling of Dropouts ................................................3 
2.10.3  
Definition of Baseline Measurements  ...............................................................4 
2.10.4  
Methods for the Analysis of Device Dispense Failure Rate  .............................4 
2.10.5  
Pooling of Investigators .....................................................................................5 
2.10.6  
Methods for the Analysis of Categorical Efficacy Variables  ...........................5 
2.10.7  
Methods for the Analysis of Continuous Efficacy Variables  ...........................5 
2.11 
Analysis of Safety Data .................................................................................................6 
2.11.1  
Extent of Exposure to Study Drug  ....................................................................6 
2.11.2  
Adverse Events  .................................................................................................6 
2.11.3  
Death Reports and Serious Adverse Events  ......................................................6 
2.11.4  
Adverse Events Causing Premature Discontinuation of Study Drug  ...............6 
2.11.5  
Summary of Adverse Events by Severity and Relationship to Study Drug  .....7 
2.11.6  
Subgroup Summary of Adverse Events  ............................................................7 
2.11.7  
Pregnancy Test Results ......................................................................................7 
2.11.8  
Vital Signs  .........................................................................................................7 
2.11.9  
Physical Examination Data  ...............................................................................7 
2.11.10 
Concomitant Medications ..................................................................................7 
2.12  Handling of Partial Dates and Partial Times  .................................................................8 
2.13  The Presentation of Data Listings  .................................................................................8 
2.14  Computer Software  ......................................................................................................9 
 
 References ...................................................................................................................9 
 


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Table A-1 
Evaluation Time Points with Evaluation Windows Used for the Summary of 
Global Assessment Data by Evaluation Time Point ........................................10 
Table A-2 
Scheduled Evaluation Time Points with Evaluation Windows Used for the 
Summary of Pain Assessment Data, Blood Pressures, and Heart Rates by 
Evaluation Time Point .....................................................................................11 
Table A-3 
Scheduled Evaluation Time Points with Evaluation Windows Used for the 
Summary of Respiratory Rates and Oxygen Saturation Data by Evaluation 
Time Point ........................................................................................................13 
 
 


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1 
Introduction  
This is a multicenter, open-label, single treatment clinical study designed to 
evaluate the overall functionality of the Zalviso System (sufentanil sublingual 
tablet system) 15 mcg for the treatment of acute moderate-to-severe postoperative 
pain.   
The study was designed to demonstrate that the device dispense failure rate is 
non-inferior to a target of 2%.  This is based on the criteria that the upper limit of 
a 90% confidence interval (CI) of the device dispense failure rate is not worse 
than 5%.  
The statistical issues regarding the conduct and analysis of this study are 
described briefly in the following sections. 
2 
Statistical Methods 
  
2.1 
Determination of Sample Size 
A sample size of approximately 330 patients is planned for this study in order to 
have at least 315 patients receive study drug and have available efficacy data for 
data analysis.  
A sample size of 315 patients will have 90% power to demonstrate that the device 
dispense failure rate is non-inferior to a target of 2%.  This failure rate is the 
proportion of patients who experienced at least one of following events: (1) a 
system-generated error, (2) a tablet dispensed but not requested, or (3) a tablet 
dispensed when the Zalviso System is in lockout.  All events listed above will be 
obtained from the Controller patient usage data. 
This is based on the criteria that the upper limit of a 90% confidence interval (CI) 
of the device dispense failure rate is not worse than 5%.  This calculation is based 
on the exact binomial test of one-sample proportion for a one-sided case against a 
2% target proportion with a delta of 3%, and a one-sided significance level of 
=0.05. This sample size was generated from the SAS procedure PROC POWER 
for one-sample proportion. Exact power computations are based on the binomial 
distribution and computing formulas provided by Johnson and Kotz (1970). 
Assuming a 5% non-evaluable rate, a sample size of 330 patients is planned for 
this study. 
2.2 
Data Processing and Management 
All data management activities including the Case Report Form (CRF) data entry, 
query generation, query resolution and data base maintenance, were performed by 
the Data Management Department of PRA Health Sciences. 
2.3 
Performance of Statistical Data Analysis 
The statistical data analysis will be performed by Essence Sciences Inc.  


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2.4 
Protocol Deviations and Special Cases 
Enrolled patients who deviate from the study protocol will be listed in Appendix 
16.2.  Protocol deviations at entry and deviations related to the efficacy 
measurements during the study will be identified.  
2.5 
Test of Hypothesis and Significance Levels 
Both continuous and categorical efficacy variables will be summarized 
descriptively. A point estimate of the device dispense failure rate and its 90% 
exact Clopper-Pearson confidence interval will be constructed. The statistical tests 
for the analysis of other efficacy variables and safety data will be performed at the 
 = 0.05 significance level.  All tests will be two-sided. 
2.6 
Randomization and Blinding of the Treatment Assignment 
This is an open-label single treatment study.  There is no randomization of 
patients or blinding of treatment.  Patients who meet the eligibility requirements 
will be enrolled into this study sequentially within each study center to receive 
study treatment. 
2.7 
Patient Enrollment and Disposition 
Post-text Table 14.1.1 summarizes the number of patients enrolled in this study by 
surgery type within each investigator’s site.  Post-text Table 14.1.2 defines the 
patient population used for the efficacy and safety data analysis. 
2.8 
Premature Termination from the Study   
Patients who prematurely terminate from the study will be summarized according 
to the reason for termination.  Each unique reason will be determined by the 
investigator.   
Patients who prematurely terminated from the study and reasons for not entering 
next time period will be summarized in Post-text Tables 14.1.3 to 14.1.7. 
2.9 
Baseline Comparability 
Demographics and baseline characteristics will be summarized for all enrolled 
patients in Post-text Table 14.1.8.  Data will be pooled for all study centers for the 
descriptive summary of baseline data.  No formal hypothesis testing will be 
performed for baseline data. Similar summaries will be performed for the safety 
population separately in Post-text Table 14.1.9. 
2.10 
Analysis of Efficacy Data 
Sections related to the analysis of efficacy data are specified below by topic. 
2.10.1 
Efficacy Variables 
The efficacy variables and parameters are: 


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(1) 
Proportion of patients who experienced at least one system-generated error 
based on the Controller data while using the Zalviso System 
(2) 
Proportion of patients, if any, with tablet dispensed but not requested  
(3) 
Proportion of patients, if any, with tablet dispensed when the Zalviso 
System is in lockout 
(4) 
Proportion of patients with misplaced tablet(s) 
(5) 
Number of misplaced tablets (i.e., tablet found outside the patient’s 
mouth) 
(6) 
Proportion of patients who experienced either a system-generated error or 
a misplaced tablet (i.e. a dispense failure) 
(7) 
Assessment of the number of Zalviso System notifications to the nurse to 
retrain patient to not pull down on Controller while dosing (i.e., mitigation 
of Error 302) 
(8) 
Proportion of patients who rate the Patient Global Assessment (PGA) of 
method of pain control over 24, 48 and 72 hours as “good” or “excellent” 
(9) 
Proportion of patients who responded in each category of the PGA 
(10) 
Proportion of Healthcare Professionals who rate the Global Assessment 
(HPGA) of method of pain control over 24, 48 and 72 hours as “good” or 
“excellent” 
(11) 
Proportion of Healthcare Professionals who responded in each category of 
the HPGA 
(12) 
Proportion of patients who terminate from the study due to inadequate 
analgesia over the 24-hour, 48-hour and 72-hour study period 
(13) 
Time to terminate from the study due to inadequate analgesia 
(14) 
Time-weighted summed pain intensity difference (SPID) over the 24-hour 
study period (SPID24), over the 48-hour study period (SPID48), and over 
the 72-hour study period (SPID72) 
(15) 
SPID up to each evaluation time point 
(16) 
Total pain relief (TOTPAR) over the 24-hour study period (TOTPAR24), 
over the 48-hour study period (TOTPAR48) and over the 72-hour study 
period (TOTPAR72) 
(17) 
TOTPAR up to each evaluation time point 
(18) 
Pain intensity (PI) at each evaluation time point 
(19) 
Pain intensity difference (PID) at each evaluation time point 
(20) 
Pain relief (PR) at each evaluation time point  
(21) 
Patient Usability Questionnaire (PUQ) 
(22) 
Nurse Usability Questionnaire (NUQ) 


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(23) 
Total number of study drug doses used over 24, 48, and 72-hour study 
period, average hourly use, and average inter-dosing interval. 
(24) 
Total amount of supplemental morphine utilized 
2.10.2 
Analysis Population and Handling of Dropouts 
All enrolled patients are those who are enrolled and receive the study treatment.  
The main analysis of efficacy endpoints includes all enrolled patients.  
For patients missing PI or PR data, the following methods will be applied to 
impute the missing data at evaluation time points for the duration of study period: 
(1) 
Missing data will be first imputed on a patient-by-patient basis by linear 
interpolation method between two observed pain scale values. 
(2) 
Data occurring after a patient terminated from study or did not provide any 
follow-up data after last available data prior to the end of study period, the 
pain scale values at follow-up time points post-termination up to the end 
of the study period will be imputed on a patient-by-patient basis as 
described below. 
The last observation carried forward (LOCF) method will be used to impute any 
remaining missing data points after termination due to reasons other than adverse 
event up to the end of the study period. For patients who prematurely terminate 
from the study due to adverse event, the worst observation carried forward 
(WOCF) method will be used to impute the remaining missing data points up to 
the end of the study period. The worst PID is the smaller number between number 
zero and the last PID obtained prior to termination. The worst PR is number zero. 
For patients who use any supplemental opioid during the study period, the last 
observed pain intensity prior to using each dose of supplemental opioid will be 
carried throughout a follow-up 1-hour time interval. Any pain intensity collected 
within 1 hour after the start of any supplemental opioid will be excluded from the 
calculation of the time-weighted SPID. This same imputation method will also be 
used to calculate the efficacy endpoints derived from pain assessment data. 
2.10.3 
Definition of Baseline Measurements 
Baseline measurements are those taken prior to the start of study drug 
administration.   
2.10.4 
Methods for the Analysis of Device Dispense Failure Rate 
For the analysis of the device dispense failure rate, a point estimate of the device 
dispense failure rate and its 90% exact Clopper-Pearson confidence interval will 
be constructed.  Patients from all study centers will be pooled for the descriptive 
summary of these efficacy data. 


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Results generated from the analysis of these dichotomous efficacy endpoints 
derived from the device performance data and misplaced tablets will be presented 
in Post-text Tables 14.2.1 to 14.2.7.  
2.10.5 
Pooling of Investigators 
The data collected from all study centers will be pooled for the analysis of 
efficacy data.  
2.10.6 
Methods for the Analysis of Categorical Efficacy Variables  
For the analysis of the dichotomous outcome data, a point estimate and its 95% 
confidence interval will be constructed.  Patients from all study centers will be 
pooled for the descriptive summary of the efficacy data. 
Results generated from the analysis of these categorical efficacy variables will be 
presented in Post-text Tables 14.2.8 to 14.2.18.  
2.10.7 
Methods for the Analysis of Continuous Efficacy Variables  
The method used to derive the efficacy endpoint time-weighted summed pain 
intensity difference (SPID) over the study period is described in this section. Pain 
intensity will be measured using an 11-point NRS with 0 (no pain) and 10 (worst 
possible pain). 
Patients will provide the pain intensity (PI) and pain relief (PR) measures at 
baseline and at each evaluation time point after the initiation of the first on-
demand dose of study drug:  ¼ [15 min], ½  [30 min], ¾ [45 min], 1, 2, 4, 6, 8, 
10,  and 12 hours, then every 4  hours at 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 
60, 64, 68, and 72 hours. 
The PID at each evaluation time point after the initiation of the first dose is the 
difference in pain intensity at the specific evaluation time point and baseline pain 
intensity [PID (evaluation time after the first dose) = pain intensity (baseline) – 
pain intensity (evaluation time after the first dose)]. The time-weighted SPID24 is 
the time-weighted summed PID over the 24-hour study period.  
Time-weighted SPID24 = ∑ [T(i) – T(i-1)] x PID(i), 
Where : T(0) = Time 0 (baseline), T(i) is the scheduled or unscheduled 
assessment time, and PID(i) is the PID score at time i for i=0 to 24 hours 
Other time-weighted SPID, SPID48 and SPID72 will be derived similarly. 
TOTPAR over follow-up evaluation time periods (e.g., TOTPAR24, TOTPAR48, 
and TOTPAR72, etc.) will be derived from the PR data collected during the study 
using similar formula described above.   


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For the analysis of the continuous efficacy data, a point estimate and its 95% 
confidence interval will be constructed.  Patients from all study centers will be 
pooled for the descriptive summary of the efficacy data 
2.11 
Analysis of Safety Data 
The safety data collected in this study include: 
(1) 
Adverse events(AEs) 
(2) 
Pregnancy test results 
(3) 
Vital signs   
(4) 
Physical examination data 
(5) 
Suspected technical failures 
(6) 
Concomitant medications 
 
All enrolled patients who receive at least one dose of study drug will be included 
in the analyses and summaries of safety data.   
2.11.1 
Extent of Exposure to Study Drug 
The length of exposure to study drug will be summarized in Post-text Table 
14.3.1. 
2.11.2 
Adverse Events 
Adverse events occurring while patients were on study medication during the 
treatment period or within 12 hours after the discontinuation of study medication 
will be summarized in Post-text Table 14.3.2.  All incidences of AEs will be 
summarized in Post-text Table 14.3.3.  The MedDRA (Medical Dictionary for 
Regulatory Activities) V11.0 thesaurus will be used to map the AE verbatim to 
lowest level term (LLT), preferred term (PT) and System Organ Class (SOC) for 
summary purposes.  Adverse event data including the AE verbatim term and the 
associated AE thesaurus preferred term will be provided in the patient data 
listings.  
The most frequent AEs (e.g., those in at least 1% of all treated patients) will be 
summarized in Post-text Table 14.3.4. 
2.11.3 
Death Reports and Serious Adverse Events 
Death that occurred during the study will be listed and discussed.  Serious adverse 
events will be summarized in Post-text Table 14.3.5.   
2.11.4 
Adverse Events Causing Premature Discontinuation of Study Drug 
Adverse events causing premature discontinuation of study drug will be 
summarized in Post-text Table 14.3.6.     


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2.11.5 
Summary of Adverse Events by Severity and Relationship to Study Drug 
Adverse events will be summarized by severity and relationship to study drug 
(related or not related) in Post-text Table 14.3.7.  Related AEs are those AEs 
possibly or probably related to study drug.  Adverse events will be summarized by 
maximum severity in Post-text Table 14.3.8 and summarized by closest 
relationship to the study drug in Post-text Table 14.3.9.  Adverse events related to 
the study drug, severe adverse events, and severe adverse events related to the 
study drug will be summarized by treatment groups in Post-text Table 14.3.10 and 
14.3.12 respectively.  3.6.     
2.11.6 
Subgroup Summary of Adverse Events 
Adverse events will be summarized by age group (< 65 years and ≥ 65 years), sex 
group (male and female), race group (Caucasian and Non-Caucasian), and body 
mass index group (< 30 kg/m2 and ≥ 30 kg/m2) in Post-text Table 14.3.13 and 
14.3.16 respectively. A two-sided Fisher’s exact test will be used for the 
comparison among subgroups.   
2.11.7 
Pregnancy Test Results 
Pregnancy test results will be listed in the Appendix. 
2.11.8 
Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rates, and oxygen 
saturation data, taken at baseline and follow-up time points will be summarized in 
Post-text Tables 14.3.17 to 14.3.21.  Patients who had baseline data and at least 
one follow-up data will be included in this analysis.  The descriptive summary 
statistics will be presented.  A paired t-test will be used for the test of mean 
change from baseline to follow-up time points within each group.   
The lowest oxygen saturation value will be identified for each patient.  Two 
dichotomous variables will be defined based on this lowest observed value at two 
cut-off levels of 93% and 95% of oxygen saturation.  These lowest oxygen 
saturation variables will be summarized. The results of these summaries will be 
presented in Post-text Table 14.3.22.  
2.11.9 
Physical Examination Data 
The physical examination data will be listed in the Appendix. 
2.11.10 
Concomitant Medications 
Concomitant medications used during the study will be summarized in Post-text 
Table 14.3.23.  Medications discontinued before the enrollment date will be 


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excluded from the summary.  The World Health Organization (WHO) Drug 
Dictionary (WHO-DD, 01DEC2015 version) will be used to map the medication 
name to the Anatomical Therapeutic Chemical (ATC) classification codes for 
summary purpose.   
If a medication is mapped to more than one ATC-code, a unique ATC-code will 
be selected based on the condition treated.  The concomitant medications will be 
summarized by the medication category, medication class, and medication 
subgroup based on the ATC-codes.  The medication category will be determined 
by the first character of the ATC-code.  The medication class will be determined 
by the first three characters of the ATC-code.  The medication subgroup will be 
determined by all the characters (maximum five characters) of the ATC-code.  
2.12 
Handling of Partial Dates and Partial Times 
Complete date and time values were required for certain date fields on the CRFs 
(e.g., assessment date and time, dosing date and time, etc.).  However, partial date 
values may have been acceptable for selected date fields on the CRFs (e.g., start 
dates of concomitant medications or adverse events prior to entry).  In order to 
calculate the duration of events, the following assumptions were applied to 
estimate the complete date and time values for the partial event start date and time 
values: 
(1) 
If only the “time” value was missing, the first minute (00:01) of the day 
was used. 
(2) 
If only the “day” value was missing, the first day of the month was used. 
(3) 
If only the “month” value was missing, January was used. 
(4) 
If both “day” and “month” values were missing, January first was used. 
The “year” value of the date field was required for all cases.  The estimated event 
date/time should not be later than the available event stop date/time for a given 
event.  
For those adverse events with partial AE stop date/time and stopped prior to the 
study termination, the following assumptions were applied to estimate the 
complete date values:  
(1) 
If only the “time” value was missing, the last minute (23:59) of the day 
was used. 
(2) 
If only the “day” value was missing, the last day of the month was used. 
(3) 
If only the “month” value was missing, December was used. 
(4) 
If both “day” and “month” values are missing, December 31st was used. 
If the estimated AE stop date/time based on the assumptions listed above was 
later than the study termination date, the partial AE stop date/time was estimated 
from the study termination date/time. 
2.13 
The Presentation of Data Listing 
In addition to the summary Tables presenting the summarized data, individual 


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patient response data for the efficacy analysis will be presented in Appendix 16.2. 
These by-patient data listings present the measurements that will be used in 
supporting the summary Tables.  Other by-patient data listings of baseline 
characteristics and safety measurements will also be presented in Appendix 16.2. 
2.14 
Computer Software 
All data analyses will be performed using SAS for Windows, Release 9.12. 
 
References 
1. 
Johnson, N. L. and Kotz, S. (1970), Distributions in Statistics: Continuous Univariate 
Distributions — 1, New York: John Wiley & Sons. 
2. 
SAS Release 9.1.  SAS Institute Inc., Cary, North Carolina, 2004. 
 


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Table A-1 Evaluation Time Points with Evaluation Windows Used 
for the Summary of Global Assessment Data by Evaluation Time Point 
 
 
Evaluation 
Time Point 
Evaluation 
Time Point 
Number 
Minutes from 
Baseline to 
Target Time 
 
Evaluation Window 
(Minute) 
Baseline 
0 
1 
-14 
- 
1 
2 hours 
1 
121 
2 
- 
181 
4 hours 
2 
241 
182 
- 
361 
8 hours 
3 
481 
362 
- 
721 
16 hours 
4 
961 
722 
- 
1201 
24 hours 
5 
1441 
1202 
- 
1681 
32 hours 
6 
1921 
1682 
- 
2161 
40 hours 
7 
2401 
2162 
- 
2641 
48 hours 
8 
2881 
2642 
- 
3121 
56 hours 
9 
3361 
3122 
- 
3601 
64 hours 
10 
3841 
3602 
- 
4081 
72 hours 
11 
4321 
4082 
- 
4561 
80 hours 
12 
4801 
4562 
- 
5041 
Interim 
x.x 
 
 
--- 
 
Note:  Unscheduled evaluation time points and time points for premature 
termination are considered as regularly scheduled time points.  The time 
point closest to the target time will be used to determine the evaluation 
time-specific measurement.  If there are two measures that obtained at the 
same time distance away from the target time for the same evaluation time 
point number, the one prior to the target time will be used in the summary.  
Measures that do not fall within the evaluation windows will be considered 
as interim data and assigned a decimal evaluation time point number 
between two evaluation time point numbers in integers (e.g., 2.1 or 3.9). 
 
 
 


Protocol No. IAP312: FINAL REPORT 
Statistical Analysis Plan 
 
IAP312\STATDOC\PLAN\IAP312 Final SAP(061017) 
 
 11
Table A-2 Scheduled Evaluation Time Points with Evaluation Windows Used 
for the Summary of Pain Assessment Data, Blood Pressures, and Heart Rates by 
Evaluation Time Point 
 
 
Evaluation 
Time Point 
Evaluation 
Time Point 
Number 
Minutes from 
Baseline to 
Target Time 
 
Evaluation Window 
(Minute) 
Screening 
-1 
-15 
 
 -15 
 
Baseline 
0 
1 
-14 
- 
1 
15 minutes 
1 
16 
2 
- 
23 
30 minutes 
2 
31 
24 
- 
38 
45 minutes 
3 
46 
39 
- 
53 
1 hour 
4 
61 
54 
- 
91 
2 hours 
5 
121 
92 
- 
181 
4 hours 
6 
241 
182 
- 
301 
6 hours 
7 
361 
302 
- 
421 
8 hours 
8 
481 
422 
- 
541 
10 hours 
9 
601 
542 
- 
661 
12 hours 
10 
721 
662 
- 
841 
16 hours 
11 
961 
842 
- 
1081 
20 hours 
12 
1201 
1082 
- 
1321 
24 hours 
13 
1441 
1322 
- 
1561 
28 hours 
14 
1681 
1562 
- 
1801 
32 hours 
15 
1921 
1802 
- 
2041 
36 hours 
16 
2161 
2042 
- 
2281 
40 hours 
17 
2401 
2282 
- 
2521 
44 hours 
18 
2641 
2522 
- 
2761 
48 hours 
19 
2881 
2762 
- 
3001 
52 hours 
20 
3121 
3002 
- 
3241 
56 hours 
21 
3361 
3242 
- 
3481 
60 hours 
22 
3601 
3482 
- 
3721 
64 hours 
23 
3841 
3722 
- 
3961 


Protocol No. IAP312: FINAL REPORT 
Statistical Analysis Plan 
 
IAP312\STATDOC\PLAN\IAP312 Final SAP(061017) 
 
 12
68 hours 
24 
4081 
3962 
- 
4201 
72 hours 
25 
4321 
4202 
- 
4441 
76 hours 
26 
4561 
4442 
- 
4681 
Interim 
x.x 
 
 
--- 
 
Note:  Unscheduled evaluation time points and time points for premature 
termination are considered as regularly scheduled time points.  The time 
point closest to the target time will be used to determine the evaluation 
time-specific measurement.  If there are two measures that obtained at the 
same time distance away from the target time for the same evaluation time 
point number, the one prior to the target time will be used in the summary.  
Measures that do not fall within the evaluation windows will be considered 
as interim data and assigned a decimal evaluation time point number 
between two evaluation time point numbers in integers (e.g., 2.1 or 3.9). 
 
 
 


Protocol No. IAP312: FINAL REPORT 
Statistical Analysis Plan 
 
IAP312\STATDOC\PLAN\IAP312 Final SAP(061017) 
 
 13
Table A-3 Scheduled Evaluation Time Points with Evaluation Windows Used 
for the Summary of Respiratory Rates and Oxygen Saturation Data by Evaluation 
Time Point 
 
 
Evaluation 
Time Point 
Evaluation 
Time Point 
Number 
Minutes from 
Baseline to 
Target Time 
 
Evaluation Window 
(Minute) 
Screening 
-1 
-15 
 
 -15 
 
Baseline 
0 
1 
-14 
- 
1 
15 minutes 
1 
16 
2 
- 
23 
30 minutes 
2 
31 
24 
- 
38 
45 minutes 
3 
46 
39 
- 
53 
1 hour 
4 
61 
54 
- 
76 
1.5 hours 
5 
91 
77 
- 
106 
2 hours 
6 
121 
107 
- 
136 
2.5 hours 
7 
151 
137 
- 
166 
3 hours 
8 
181 
167 
- 
196 
3.5 hours 
9 
211 
197 
- 
226 
4 hours 
10 
241 
227 
- 
256 
4.5 hours 
11 
271 
257 
- 
286 
5 hours 
12 
301 
287 
- 
316 
5.5 hours 
13 
331 
317 
- 
346 
6 hours 
14 
361 
347 
- 
376 
6.5 hours 
15 
391 
377 
- 
406 
7 hours 
16 
421 
407 
- 
436 
7.5 hours 
17 
451 
437 
- 
466 
8 hours 
18 
481 
467 
- 
496 
8.5 hours 
19 
511 
497 
- 
526 
9 hours 
20 
541 
527 
- 
556 
9.5 hours 
21 
571 
557 
- 
586 
10 hours 
22 
601 
587 
- 
616 
10.5 hours 
23 
631 
617 
- 
646 


Protocol No. IAP312: FINAL REPORT 
Statistical Analysis Plan 
 
IAP312\STATDOC\PLAN\IAP312 Final SAP(061017) 
 
 14
11 hours 
24 
661 
647 
- 
676 
11.5 hours 
25 
691 
677 
- 
706 
12 hours 
26 
721 
707 
- 
736 
12.5 hours 
27 
751 
737 
- 
766 
13 hours 
28 
781 
767 
- 
796 
13.5 hours 
29 
811 
797 
- 
826 
14 hours 
30 
841 
827 
- 
856 
14.5 hours 
31 
871 
857 
- 
886 
15 hours 
32 
901 
887 
- 
916 
15.5 hours 
33 
931 
917 
- 
946 
16 hours 
34 
961 
947 
- 
976 
16.5 hours 
35 
991 
977 
- 
1006 
17 hours 
36 
1021 
1007 
- 
1036 
17.5 hours 
37 
1051 
1037 
- 
1066 
18 hours 
38 
1081 
1067 
- 
1096 
18.5 hours 
39 
1111 
1097 
- 
1126 
19 hours 
40 
1141 
1127 
- 
1156 
19.5 hours 
41 
1171 
1157 
- 
1186 
20 hours 
42 
1201 
1187 
- 
1216 
20.5 hours 
43 
1231 
1217 
- 
1246 
21 hours 
44 
1261 
1247 
- 
1276 
21.5 hours 
45 
1291 
1277 
- 
1306 
22 hours 
46 
1321 
1307 
- 
1336 
22.5 hours 
47 
1351 
1337 
- 
1366 
23 hours 
48 
1381 
1367 
- 
1396 
23.5 hours 
49 
1411 
1397 
- 
1426 
24 hours 
50 
1441 
1427 
- 
1501 
26 hours 
51 
1561 
1502 
- 
1621 
28 hours 
52 
1681 
1622 
- 
1741 
30 hours 
53 
1801 
1742 
- 
1861 


Protocol No. IAP312: FINAL REPORT 
Statistical Analysis Plan 
 
IAP312\STATDOC\PLAN\IAP312 Final SAP(061017) 
 
 15
32 hours 
54 
1921 
1862 
- 
1981 
34 hours 
55 
2041 
1982 
- 
2101 
36 hours 
56 
2161 
2102 
- 
2221 
38 hours 
57 
2281 
2222 
- 
2341 
40 hours 
58 
2401 
2342 
- 
2461 
42 hours 
59 
2521 
2462 
- 
2581 
44 hours 
60 
2641 
2582 
- 
2701 
46 hours 
61 
2761 
2702 
- 
2821 
48 hours 
62 
2881 
2822 
- 
2941 
50 hours 
63 
3001 
2942 
- 
3061 
52 hours 
64 
3121 
3062 
- 
3181 
54 hours 
65 
3241 
3182 
- 
3301 
56 hours 
66 
3361 
3302 
- 
3421 
58 hours 
67 
3481 
3422 
- 
3541 
60 hours 
68 
3601 
3542 
- 
3661 
62 hours 
69 
3721 
3662 
- 
3781 
64 hours 
70 
3841 
3782 
- 
3901 
66 hours 
71 
3961 
3902 
- 
4021 
68 hours 
72 
4081 
4022 
- 
4141 
70 hours 
73 
4201 
4142 
- 
4261 
72 hours 
74 
4321 
4262 
- 
4441 
76 hours 
75 
4561 
4442 
- 
4681 
Interim 
x.x 
 
 
--- 
 
Note:  Unscheduled evaluation time points and time points for premature 
termination are considered as regularly scheduled time points.  The time 
point closest to the target time will be used to determine the evaluation 
time-specific measurement.  If there are two measures that obtained at the 
same time distance away from the target time for the same evaluation time 
point number, the one prior to the target time will be used in the summary.  
Measures that do not fall within the evaluation windows will be considered 
as interim data and assigned a decimal evaluation time point number 
between two evaluation time point numbers in integers (e.g., 2.1 or 3.9).