Conditions: Pain Management
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 251
Healthy volunteers: yes

Brief summary:
The study evaluates the safety of IV tramadol managing post-operative pain following surgery.

Detailed description:
(Non-clinical summary) Tramadol is a centrally-acting synthetic analgesic of the aminocyclohexanol group with opioidlike effects. Tramadol is extensively metabolized following administration, which results in a number of enantiomeric metabolites that display different opioid-receptor binding properties, and monoaminergic reuptake inhibition.

Arms:
arm 1: IV Tramadol

Interventions: intervention 1: Tramadol
Intervention descriptions: intervention 1: IV; 50 mg given at Hours 0, 2, 4, 8 and every 4 hours thereafter, for a total of up to 43 doses

Protocol document:
Prot_000.pdf: 
Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
1 
 
 
 
 
 
 
IV TRAMADOL 
 
PROTOCOL AVE-901-104 
 
Tramadol Infusion - Postoperative Pain Safety Study 
 
A PHASE 3, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE SAFETY OF 
TRAMADOL INFUSION (AVE-901) IN THE 
MANAGEMENT OF POSTOPERATIVE PAIN 
FOLLOWING SURGERY 
 
Sponsor: 
 
Avenue Therapeutics, Inc. 
New York, NY 10014 
 
 
 
 
IND #: 108124 
DATE OF ISSUE: December 11, 2017 
Amendment 1: August 29, 2018 
 
 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
2 
 
 
 
 
APPROVAL SIGNATURES 
 
Protocol Number:  
 
 
AVE-901-104 
 
Protocol Title:  
A PHASE 3, MULTICENTER, SINGLE-ARM, OPEN-LABEL 
STUDY TO EVALUATE THE SAFETY OF TRAMADOL 
INFUSION (AVE-901) IN THE MANAGEMENT OF 
POSTOPERATIVE PAIN FOLLOWING SURGERY 
 
 
 
_______________________________________ 
 
 
 
 
_______________________ 
Lucy Lu, MD 
 
 
 
 
 
 
 
 
 
 
Date 
CEO, Avenue Therapeutics 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46



Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
3 
 
 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for Tramadol Infusion.  I confirm that I 
have read this protocol.  I understand it, and I will work according to the protocol and moral, 
ethical, and scientific principles governing clinical research as set out in the Declaration of 
Helsinki and the principles of ICH guidelines for GCP and according to applicable local 
regulatory requirements.  I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
4 
 
 
 
 
PROCEDURES IN CASE OF EMERGENCY 
Table 1. 
Emergency Contact Information (Study AVE-901-104) 
Role in Study 
Name 
Contact Information 
Clinical Study Contact 
Michael Ryan 
 
Avenue Therapeutics, Inc. 
95 Sawyer Road, Ste 110 
Waltham, MA 02453 
Office: (781) 652 – 4514 
Mobile: (617) 538 – 8949 
Avenue CEO 
Lucy Lu, MD 
Avenue Therapeutics, Inc. 
2 Gansevoort Place, 9th Floor 
New York, NY 10014 
Office: (781) 652 - 4511  
Mobile: (917) 847-6241 
CRO Responsible Physician 
Jon Ruckle, MD 
Principal, Pacific Pharma Group, LLC 
1402 S. Brookside Terrace 
Tacoma, WA  98465-1210 
Office: 253-448-8690 
Mobile: 808-349-9812 
Secondary: 1-877-508-8727 
24-Hour Emergency Contact 
Jon Ruckle, MD 
1-877-508-8727 (reference: SAE during 
the contact) 
 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
5 
 
 
 
 
1. 
SYNOPSIS 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
Title of Study: A Phase 3, Multi center, Single-Arm, Open-Label Study to Evaluate the Safety of 
Tramadol Infusion (AVE-901) in the Management of Postoperative Pain Following Surgery 
Study center:  Up to approximately 10 centers in the United States 
Studied period:  
Estimated date first patient enrolls: Q4 2017 
Estimated date last patient enrolls: Q2 2019 
Estimated date primary analysis: Q2 2019 
Phase of development: 3 
 
Objectives:  
The primary objective of this study is to evaluate the safety of intravenous (IV) tramadol (AVE-901) 
50 mg for the management of postoperative pain.  Safety endpoints will include: 
x 
Adverse events (classified by the MedDRA System Organ Class (SOC) and preferred 
term).   
x 
Clinical laboratory, vital sign, and ECG changes 
x 
Local tolerability of the infusion site via pain, swelling, tenderness, and erythema.   
Throughout the protocol, AVE-901 will be used to indicate the treatment. 
Study Design:  
This study is a Phase 3, multicenter, single-arm, open-label, repeat-dose trial to assess the safety of 
AVE-901 in the management of postoperative pain. Eligible patients will be patients that are 
undergoing elective surgery and are willing to be confined in a healthcare facility and receive AVE-
901 for the treatment of post-surgical pain for at least 24 hours.  Approximately 250 patients will be 
enrolled into the study. Each patient will undergo the Screening Visit (Day -28 to Day -1), the Pre-
operative assessment (within 24 hours prior to surgery), the Surgery (Day 0), the Primary treatment 
period (hour 0 through hour 168), End of Treatment visit, and the Follow-up Visit (Day 14).  
Screening will occur up to 28 days prior to surgery.  Following the pre-operative assessments, after 
the patient has met eligibility criteria, patients will be enrolled into the study. 
Surgery will occur on Day 0.  There are no restrictions on the agents to be used for induction, 
neuromuscular blockade, maintenance of anesthesia, or on hypnotics, sedatives, analgesics (including 
narcotics) or anxiolytics. 
Following surgery, each patient will receive their study medication infusion at T0, T2, T4, and then 
every 4 hours for up to 168 hours after the first study drug administration (a total of up to 43 doses 
per patient).  The dosing time should always tie back to T0 for all doses.  The latest (last) dose that is 
allowed is at Hour 164.  Patients will be confined at an appropriate healthcare or research facility for 
as long as they are still using AVE-901. Following the first dose of study drug, the patients will be 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
6 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
allowed to use non-opioid-based analgesics per treating physician’s discretion, if additional pain relief 
is required.  
Study Periods and Methodology 
There are 5 periods in this study:   
x 
Screening 
x 
Preoperative 
x 
Surgery 
x 
Treatment Period/Post Surgery 
x 
Follow-up.  
Procedures for each study period are described below. 
Screening: 
Screening will occur from Day -28 through Day -1 and will be conducted as a clinic visit. Patients 
will have the purpose and procedures of the study explained to them and, those who elect to 
participate in the study, will provide written informed consent and be screened for participation 
according to the eligibility criteria. Screening will include eligibility assessment, medical history, 
physical examination, demographics, height and weight, BMI, vital signs (heart rate, systolic blood 
pressure, and diastolic blood pressure, respiratory rate, temperature, pulse oximetry), ASA Physical 
Status, 12-lead electrocardiogram (ECG), hematology panel, chemistry panel, urinalysis, serum 
pregnancy test (in females of childbearing potential), and prior/current treatments.  All screening 
laboratory evaluations must be within acceptable limits as determined by the investigator prior to 
enrollment.  For patients that screen within 5 days of surgery, central laboratory values may not be 
available to assess eligibility.  For these patients it is acceptable for sites to draw local labs to assess 
eligibility in addition to the central lab which will still be used as the baseline in the study.  The local 
laboratory listed on the FDA 1572 Form must be used for all local blood draws. At a minimum the 
following analytes must be reviewed from the local laboratory prior to dosing; magnesium, calcium, 
potassium, sodium, serum creatinine, ALT, AST and hemoglobin.  
Preoperative: 
Preoperative assessments to confirm the patient’s eligibility will be performed within 24 hours of 
scheduled surgery start time.  This visit will include reassessment of eligibility criteria, interim 
medical history, vital signs, physical exam, ASA Physical Status, urine pregnancy test (in females of 
childbearing potential), and concomitant treatments.     
Note: If the patient’s scheduled surgery has time considerations, patients may have Screening and 
Preoperative Visits combined into one visit if required (at the time of pre-op).  The procedures 
associated with the Screening Visit will be acceptable for both visits. Both central and local labs 
should be drawn for eligibility.  
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
7 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
Surgery:  
Surgery will occur on Day 0.  Sites will follow their standard operating procedures. 
Treatment Period/Post Surgery: 
Patients will receive their first dose of study medication (T0) within 8 hours of meeting the 
postsurgical eligibility criteria. Patients will be dosed at Hour T0, T2, T4, and then every 4 hours 
thereafter, for a total of up to 43 doses administered over the 168-hour treatment period (with the last 
possible dose at Hour 164).  Treatment is anticipated to occur from Hours 0 to 48, and may extend 
through to Hour 168.  .  
Safety will be assessed by recording vital signs including: ECG’s, respiratory rate, heart rate, pulse 
oximetry (SpO2), temperature, and blood pressure as per the schedule of events. 
A Patient Global Assessment (PGA – Appendix 1) of efficacy will be obtained at Hour 24 and End of 
Treatment. If the patient continues treatment beyond Hour 24, PGA will be conducted at Hour 24 and 
End of Treatment (total of 2 PGAs). If the patient ends treatment prior to Hour 24, PGA will be 
conducted as part of the End of Treatment visit (total of 1 PGA).  
At the End of Treatment assessment, patients will undergo a brief physical examination, vital signs 
measurements, ECG, PGA and clinical laboratory evaluations for safety. AEs and concomitant 
medication use will be recorded.  
Follow up: 
A final safety assessment will be conducted on Day 14 (± 2 days) from the first dose via a telephone 
call to check on general well-being, including spontaneous reports of adverse events and concomitant 
medications. 
Concomitant Medication: 
Medications deemed necessary for the patient’s welfare are permitted.  The following drugs are 
EXCLUDED from use: 
x 
Moderate or strong inhibitors of CYP3A4 or CYP2D, inducers of CYP3A4, drugs which 
may increase serotonergic tone including SSRIs, SNRIs, tricyclic antidepressants, 
trazodone, cyclobenzaprine triptans, 5-HT3 antagonists including ondansetron, and 
amphetamines; and drugs which may lower seizure threshold. 
x 
Any opioid based analgesic (post dosing).   
Postoperative adverse events (AEs) such as nausea, vomiting and pruritus should be managed using 
standard of care, excluding medications specifically noted in the study protocol. 
Number of patients (planned):  
A total of approximately 250 patients in United States (US) who meet all of the inclusion and none of 
the exclusion criteria are planned to be enrolled.  Every patient treated will receive AVE-901. 
 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
8 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
Diagnosis and main criteria for Eligibility 
This study intends to enroll patients undergoing elective surgery who are willing to be confined in a 
healthcare facility and receive AVE-901 for at least 24 hours as their primary treatment for post-
surgical pain. 
Inclusion Criteria:  
1. The patient is male or female 18-75 years of age 
2. The patient or legal representative has voluntarily signed and dated an Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent. 
3. Female patients must be of non-childbearing potential (surgically sterile or post-menopausal 
for at least 1 year) or be practicing a highly effective contraception method from consent to at 
least 7 days after the last dose of study medication. Surgically sterile is defined as status post 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation. Highly effective 
contraception methods include:  abstinence, vasectomized partner (at least 6 months prior to 
dosing); double barrier (diaphragm with spermicide; condoms with spermicide); intrauterine 
device; implanted or intrauterine hormonal contraceptives in use for at least 6 consecutive 
months prior to study dosing and throughout the study duration; oral, patch, or injected 
contraceptives in use for at least 3 consecutive months prior to study dosing. 
4. Female patients of childbearing potential have a negative pregnancy test (serum human 
chorionic gonadotropin [HCG]) during screening and a negative pregnancy test (urine) ≤ 24 
hours prior to surgery, and are not lactating. 
5. Patient is undergoing elective surgery and, in the opinion of the investigator, is an appropriate 
candidate for IV Tramadol for pain management post-operatively. 
6.  The study patient is willing to be housed in a healthcare facility capable of administering 
parenteral analgesia for at least 24 hours after surgery.  Treatment may extend through Hour 
168 if deemed appropriate. 
7. The patient meets definition of American Society of Anesthesiologists (ASA) Physical Class 
1 or 2.  
8. The patient is willing and able to understand the study procedures to communicate 
meaningfully with the study personnel, and to comply with the study protocol. 
Exclusion Criteria: 
1. The patient has current or historical evidence of any clinically significant disease or 
condition that might place the patient at unacceptable risk due to receiving the study 
medication, in the opinion of the investigator. 
2. The patient has allergy or hypersensitivity (or is intolerant) to opioids or tramadol. 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
9 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
3. The patient has used chronic opioid therapy, defined as >= 20 MEQs of morphine per day 
>=3 days out of 7 days over the past 4 weeks.   
4. The patient has a recent (within 2 years) and/or current history of alcohol, opiate or 
tranquilizer abuse or dependence. 
5. The patient is taking herbal or dietary supplements or medications that are moderate or 
strong inhibitors of CYP2D6 or CYP3A4 (e.g., fluoxetine, paroxetine, amitriptyline, 
quinidine, ketoconazole, erythromycin, grapefruit juice) or inducers of CYP3A4 (e.g., 
carbamazepine, rifampin, St. John's Wort) and cannot go through a minimum washout 
period of 7 days prior to surgery. 
6. The patient has a history of epilepsy, is susceptible to seizures.  
7. The patient cannot be withdrawn from medications (at least 7 days prior to surgery) that 
may lower the seizure threshold (e.g. anti-psychotic agents, MAOI inhibitors) or which 
increase serotonergic tone (e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin 
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, triptans, 
amphetamines). 
8. The patient has had a recent (within 6 months) cardiovascular event or clinically 
significant abnormal ECG finding at screening. 
9. The patient has a history of Long QT Syndrome or a relative with this condition. 
10. The patient has expressed suicidal ideation within the past 3 months or is considered to be 
at risk of suicide. 
11. The patient is morbidly obese (body mass index [BMI] ≥ 40 kg/m2) or has documented 
sleep apnea requiring CPAP or other treatment. 
12. Female patient is pregnant and/or undergoing a pregnancy-related surgery, or 
breastfeeding. 
13. The patient has a history of cardiopulmonary, neurological or psychiatric condition that 
may confound the assessments of efficacy or safety. 
14. The patient has cirrhosis, moderate or severe hepatic impairment or an alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) value > 3X upper limit of 
normal (ULN) at Screening. 
15. The patient has severe renal impairment or a serum creatinine value of > 2x upper limit of 
normal (ULN) at Screening. 
16. The patient has potassium, sodium, calcium or magnesium levels outside of the normal 
range at Screening. 
17. The patient has a hemoglobin level at screening which, in the judgment of the 
Investigator, is not suitable for participation in this study. 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
10 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
18. The patient was administered an investigational drug product within 30 days prior to 
Screening. 
19. The patient has previously participated in a clinical study with AVE-901. 
POST SURGICAL EXCLUSION CRITERIA 
The patient is to be evaluated post-operatively prior to the initial treatment with the study drug and 
will be withdrawn prior to treatment with the study drug if any of the following exclusion criteria are 
met: 
1. Patients who, in the opinion of the investigator, are not likely to tolerate the protocol’s 
allowed analgesic regimen (tramadol plus non-opioid adjuvants).  
2. Patients who have been admitted to the ICU post-surgery or have experienced complications 
during the surgical procedure that would put them at increased risk from receipt of the 
investigational product in the opinion of the investigator.  
3. The patient is not clinically stable and not able to answer questions and follow commands. 
4. The patient has evidence of respiratory insufficiency, such as a respiratory rate that is less 
than 8 breaths per minute or arterial oxygen saturation by pulse oximetry of less than 90% 
with supplemental oxygen. 
5. Use of 5-HT3 antagonists (e.g. ondansetron, granisetron, palonosetron) preoperatively, 
intraoperatively, or postoperatively 
Investigational product, dosage and mode of administration:  
AVE-901, 50 mg. Assigned study treatment (51 mL) doses will be administered IV over 15 minutes 
(+/- 4 minutes) via infusion pump.  A trained health care professional will flush the line with normal 
saline at the end of each infusion.  
Duration of treatment:  
Study drug will be administered for up to 7 days following initiation of the first dose.  
Total patient participation in this study, from initial screening through the final assessment, is 
expected to be between 1 and 7 weeks. 
Reference therapy, dosage and mode of administration:  
None. 
Criteria for evaluation: 
This study is designed to assess the safety profile of IV Tramadol post-surgery for patients having 
elective surgery.  Therefore, the primary evaluations will be based on safety outcomes.  Efficacy is 
considered a secondary outcome. 
 
 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
11 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
Safety:  
x 
Treatment-Emergent AEs, including assessment of infusion site local reactions (skin and 
vein) 
x 
Clinical laboratory tests (hematology panel, chemistry panel and urinalysis) pre-treatment 
and discharge 
x 
Vital signs including: respiratory rate, heart rate, pulse oximetry and blood pressure,   
x 
Physical examination pre-treatment and discharge 
x 
12-lead ECG at protocol specified time points 
x 
Concomitant treatments 
Efficacy: 
x 
Patient Global Assessment at 24 hours and/or end of treatment  
Statistical methods: 
Sample Size 
A sample size of approximately 250 patients will be enrolled.  This sample size of 250 patients will 
provide approximately 90% power to detect at least one incidence of uncommon adverse events 
(those events with a true underlying incidence of 1%). 
General Statistical Methods 
This is an open-label study in which the objective is to assess the safety of Tramadol for post-surgical 
pain in patients having elective surgery.  The statistical methods utilized will be consistent with this 
objective.   
Outcomes will be tabulated utilizing descriptive methods only (e.g., mean, standard deviation, 
median, min, max for continuous variables, and number and percent for categorical variables). 
The baseline for all variables will be the last measurement obtained prior to the patient receiving the 
first dose of study drug.  
Patient disposition (including the number and percent of patients who are enrolled, who receive 
treatment, who prematurely discontinue and reasons for discontinuation, and who complete the study) 
will be tabulated.  The number (%) of patients by exposure (number of doses given, total dose given, 
time from first dose to last dose) will be tabulated.   
Study Populations 
The Safety Population is defined as all patients who receive at least one dose of study medication.  
This will be the primary population for which conclusions will be drawn. 
Alpha Levels 
No inferential testing is planned for this safety-based study.  If inferential statistics are used, they will 
only be applied to allow for better understanding of any treatment effects, but will not be used for 
hypothesis testing. 
 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
12 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 (Tramadol) 
Name of Active Ingredient: Tramadol for intravenous infusion 
Subgroups 
Incidences of treatment-emergent AEs, serious AEs, and discontinuations for AEs, will be provided 
by the following subgroups: 
x 
Surgery type 
x 
Gender 
x 
Race 
x 
Age (using the median age of the treated population) 
Safety 
All AEs will be classified with respect to the MedDRA System Organ Class (SOC) and preferred 
term.  The number and percent of patients who report treatment-emergent adverse events (TEAEs) 
will be summarized. Additional summaries by severity, relationship, and subgroup will be presented.  
Serious AEs (SAEs) will be summarized similarly.   
For purposes of analysis, TEAEs will be defined as any AE with a start time ‘on or after the start of 
the first IV infusion’.  Thus, the start day AND start time of AEs will be collected.  Adverse events 
occurring prior to the start of the first treatment infusion will be classified as Medical History for the 
purposes of the analysis.  Events occurring > 168 hours (7 days) after the END of the last infusion 
will be classified as Post-Treatment AEs. 
As the infusions are given intermittently according to the dosing instructions, an assessment of onset 
of TEAEs within 1 hour after the start of any infusion will be tabulated separately.  The incidence of 
TEAEs will also be tabulated by infusion number (e.g., Infusion 1, Infusion 2, etc.) to explore the 
safety profile over multiple doses.  Summaries of the time to onset of TEAEs will also be included. 
Exploratory analyses of use of anti-emetics may be performed.   
Clinical laboratory, and vital sign data will be summarized descriptively by time point.  Local 
tolerability of the infusion site will be assessed via AE’s. 
Other safety data presentations will be descriptive in nature, with no formal inferential testing 
planned. 
Efficacy 
Patient Global Assessment at 24 hours, and/or end of treatment 
 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
13 
 
 
 
 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
4. 
INTRODUCTION ......................................................................................................20 
4.1. 
Tramadol Infusion ......................................................................................................20 
4.2. 
Nonclinical Summary .................................................................................................21 
4.3. 
Pharmacokinetic Profile ..............................................................................................21 
4.4. 
Rationale for this Study ..............................................................................................25 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................26 
6. 
INVESTIGATIONAL PLAN .....................................................................................27 
6.1. 
Overall Study Design ..................................................................................................27 
6.2. 
Number of Patients .....................................................................................................27 
6.3. 
Treatment Assignment and Randomization ................................................................27 
6.4. 
Criteria for Study Termination ...................................................................................27 
6.4.1. 
Individual Patient Stopping Rules ..............................................................................28 
6.5. 
Schedule of Events .....................................................................................................28 
6.6. 
Description of Visits ...................................................................................................30 
6.6.1. 
Screening ....................................................................................................................30 
6.6.2. 
Preoperative ................................................................................................................31 
6.6.3. 
Surgery ........................................................................................................................31 
6.6.4. 
Treatment Period/Post Surgery ...................................................................................31 
6.6.5. 
End of Treatment ........................................................................................................32 
6.6.6. 
Follow up ....................................................................................................................32 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................33 
7.1. 
Patient Inclusion Criteria ............................................................................................33 
7.2. 
Patient Exclusion Criteria ...........................................................................................33 
7.2.1. 
Post-Surgical Additional Exclusion Criteria ..............................................................35 
7.3. 
Patient Withdrawal Criteria ........................................................................................35 
8. 
TREATMENT OF PATIENTS ..................................................................................36 
DocuSign Envelope ID: 8E82A4FD-9172-43C8-A2C7-6BB840869E46


Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
CONFIDENTIAL  
14 
 
 
 
 
8.1. 
Description of Study Drug ..........................................................................................36 
8.2. 
Concomitant Medications ...........................................................................................36 
8.3. 
Treatment Compliance ................................................................................................37 
8.4. 
Overdose .....................................................................................................................37 
8.5. 
Randomization, Blinding and Unblinding ..................................................................37 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
9.1. 
Study Drug Packaging and Labeling ..........................................................................38 
9.2. 
Packaging, Labeling, and Storage of Clinical Supplies ..............................................38 
9.3. 
Study Drug Preparation and Administration ..............................................................39 
9.4. 
Study Drug Accountability .........................................................................................39 
9.5. 
Study Drug Handling and Disposal ............................................................................39 
10. 
PHARMACOKINETIC ASSESSMENTS .................................................................40 
11. 
ASSESSMENT OF SAFETY .....................................................................................41 
11.1. 
Safety Parameters .......................................................................................................41 
11.1.1. 
Demographic/Medical History ...................................................................................41 
11.1.2. 
Vital Signs ..................................................................................................................41 
11.1.3. 
Weight and Height ......................................................................................................41 
11.1.4. 
Electrocardiogram (ECG) ...........................................................................................41 
11.1.5. 
Physical Examination .................................................................................................41 
11.1.6. 
Laboratory Assessments .............................................................................................41 
11.1.6.1. 
Hematology and Blood Chemistry .............................................................................41 
11.1.6.2. 
Urinalysis ....................................................................................................................41 
11.1.6.3. 
Pregnancy Screen ........................................................................................................42 
11.2. 
Adverse and Serious Adverse Events .........................................................................42 
11.2.1. 
Definition of Adverse Events .....................................................................................42 
11.2.1.1. 
Adverse Event (AE) ....................................................................................................42 
11.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................43 
11.3. 
Relationship to Study Drug ........................................................................................44 
11.4. 
Recording Adverse Events .........................................................................................45 
11.5. 
Reporting Adverse Events ..........................................................................................45 
12. 
STATISTICS ..............................................................................................................46 
12.1. 
Sample Size Considerations .......................................................................................46 
12.2. 
General Statistical Methods ........................................................................................46 
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12.3. 
Analysis Populations ..................................................................................................46 
12.4. 
Handling of Missing Data ...........................................................................................46 
12.5. 
Baseline Characteristics ..............................................................................................46 
12.6. 
Patient Disposition ......................................................................................................46 
12.7. 
Exposure .....................................................................................................................46 
12.8. 
Alpha Levels ...............................................................................................................46 
12.9. 
Subgroups ...................................................................................................................47 
12.10. 
Safety ..........................................................................................................................47 
12.10.1. 
Adverse Events ...........................................................................................................47 
12.10.2. 
Prior and Concomitant Medications ...........................................................................47 
12.10.3. 
Clinical Laboratories ..................................................................................................48 
12.10.4. 
Vital Signs ..................................................................................................................48 
12.10.5. 
Physical Examination .................................................................................................48 
12.11. 
Efficacy Analyses .......................................................................................................48 
13. 
STUDY MONITORING, AUDITS, IRB, AND QUALITY .....................................49 
13.1. 
Study Monitoring ........................................................................................................49 
13.2. 
Audits and Inspections ................................................................................................49 
13.3. 
Institutional Review Board/ Independent Ethics Committee .....................................50 
13.4. 
Quality Control and Quality Assurance ......................................................................50 
14. 
ETHICS ......................................................................................................................51 
14.1. 
Ethics Review .............................................................................................................51 
14.2. 
Ethical Conduct of the Study ......................................................................................51 
14.3. 
Written Informed Consent ..........................................................................................51 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................52 
15.1. 
Inspection of Records .................................................................................................52 
15.2. 
Retention of Records ..................................................................................................52 
15.3. 
Data Capture and Processing ......................................................................................52 
16. 
PUBLICATION POLICY ..........................................................................................53 
17. 
LIST OF REFERENCES ............................................................................................54 
18. 
APPENDIX.................................................................................................................55 
 
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LIST OF TABLES 
Table 1. 
Emergency Contact Information (Study AVE-901-104) ..............................................4 
Table 2 
Abbreviations and Specialist Terms (Study AVE 901-104) .......................................17 
Table 3: 
Additional Plasma Pharmacokinetic Parameters of Tramadol (Study AVE-
901-101) ......................................................................................................................24 
Table 4. 
Schedule of Assessments for each Study Period (Study AVE 901-104) ....................29 
Table 5: 
Investigational Product (Study AVE-901-104) ..........................................................36 
Table 6: 
CTCAE Grade (Study AVE 901-104) ........................................................................43 
 
LIST OF FIGURES 
Figure 1: 
Mean Plasma Tramadol Time-Concentration Profiles for 100 mg oral, 50 mg 
IV, and 75 mg IV Regimens (Study AVE-901-101) ..................................................23 
Figure 2: 
Mean Plasma O-desmethyltramadol Time-Concentration Profiles for 100 mg 
oral, 50 mg IV, and 75 mg IV Regimens (Study AVE-901-101) ...............................24 
 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2 
Abbreviations and Specialist Terms (Study AVE 901-104) 
Abbreviation or 
special term 
Explanation 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
μM 
Micromolar 
AE  
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC  
Area under the concentration-time curve 
AUC0-tlast 
Area under the concentration-time curve from time 0 to the last 
measurable concentration; calculated using linear trapezoid rule 
AUC0-inf 
Area under the concentration-time curve from time 0 to infinity 
AUC0-24 
Area under the plasma concentration vs. time curve from time 0 to 24 
hours 
BLQ 
Below the Lower Limit of Quantitation 
BMI 
Body Mass Index 
BP  
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C12 
Plasma concentration at 12 hours after oral drug administration 
C24 
Plasma concentration at 24 hours after oral drug administration 
Cmax 
Maximum plasma concentration  
Cmin 
Minimum plasma concentration 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CL/F 
Oral clearance 
CNS 
Central nervous system 
Conmed 
Concomitant Medication 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization  
CRU 
Clinical Research Unit 
CV 
Coefficient of variance 
dL 
Deciliter(s) 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
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Abbreviation or 
special term 
Explanation 
EDTA 
Ethylenediaminetetraacetic Acid 
FOB 
Functional Observational Battery 
FU 
Follow-up 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl-transferase 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HPBL 
Human Peripheral Blood Lymphocytes 
hr(s) 
Hour(s) 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
kg 
Kilogram 
L 
Liter 
LDL 
Low Density Lipoprotein 
mL 
Milliliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
min(s) 
Minute(s) 
mg 
Milligram 
mL 
Milliter 
mm 
Millimeter 
msec 
Millisecond 
N/A 
Not Applicable 
ng 
Nanogram 
NOAEL 
No Observed Adverse Effect Level 
pH 
Hydrogen Ion Concentration 
PHI 
Personal Health Information 
PI 
Protease inhibitor 
PIS 
Patient Information Sheet(s) 
PK 
Pharmacokinetic 
PR 
Pulse Rate 
QTc 
The QTc interval is the corrected QT interval, adjusted for heart rate 
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Abbreviation or 
special term 
Explanation 
RBC 
Red Blood Cell 
rpm 
Revolutions Per Minute 
RR 
Respiratory Rate 
RTV 
Ritonavir 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Document Verification 
t1/2  
Plasma elimination half-life 
tlag 
Time to the first measurable plasma concentration 
tmax  
Time to reach peak plasma concentration 
ULN 
Upper limit of normal 
Vss 
Apparent Volume of Distribution 
WBC  
White Blood Cell 
WHO 
World Health Organization 
 
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4. 
INTRODUCTION 
Effective postoperative pain control is a critical need as most patients undergoing surgical 
procedures experience pain immediately following the procedure, and require treatment for 
several days.  For instance, patients undergoing total knee arthroplasty (TKA) or bunionectomy 
typically demonstrate a need for short-term analgesia, which is critical for earlier mobilization 
and rehabilitation. In this setting, reducing pain intensity without providing extensive medical 
oversight required for some methods of treatment (such as neuraxial anesthesia) and prevention 
of effects such as opiate-induced respiratory depression and dependency would be highly 
beneficial (Sinatra 2002). 
Several options are available for postoperative pain management (Singelyn 1998; Sinatra 2002). 
Options include intermittent “on-demand” analgesia, including oral and via patient controlled 
analgesia (PCA) or by nurse-administered bolus injections of systemic opioids such as morphine. 
Second, continuous epidural analgesia with opioids and/or local anesthetics is effective, although 
this requires continued presence of the epidural catheter and oversight by an anesthesiologist. A 
third alternative is to provide a combination of nerve blocks with long-acting local anesthetics 
and/or opioids initiated intra-operatively and continued into the immediate postoperative period. 
4.1. 
Tramadol Infusion 
Tramadol is a centrally acting synthetic analgesic with a dual mechanism of action, comprised of 
μ-opioid activity and monoamine (serotonin and noradrenalin) reuptake inhibition. Tramadol is 
an analog of the phenanthrene group of opium alkaloids, which includes morphine and codeine, 
and is structurally related to these opioids (Grond 2004). Like codeine, there is a substitution of 
the methyl group on the phenol ring that imparts a relatively weak affinity for opioid receptors. 
Tramadol was originally developed by the German pharmaceutical company Grünenthal GmbH 
in the late 1970s and is marketed globally under the trade names TRAMAL® and others outside 
of the United States (US). The approved doses of tramadol are 50 mg or 100 mg administered as 
a slow injection every 4-6 hours (Tramadol Core Product Label, 2008). 
In the US, tramadol is approved by the Food and Drug Administration (FDA) and marketed as an 
oral tablet (the only available formulation) for moderate to moderately severe pain in adults. 
Tramadol was first approved in the US in April 1995 under the trade name ULTRAM® (Ortho-
McNeil-Janssen Pharmaceuticals, Inc). Tramadol is also an active agent in an extended release 
(ER) product, Ultram® ER, and as a combination product with acetaminophen, ULTRACET®. 
In the US, tramadol is only available as immediate release tablets or extended release tablets. 
Tramadol injection (IV/IM/SC) is approved and used for the management of moderate to severe 
acute postoperative pain in several regions, including Europe, India and Australia/New Zealand; 
however, this dosage form is not available in the US. Tramadol ampoules or vials for parenteral 
(intravenous [IV], intramuscular [IM] and subcutaneous [SC]) administration and preservative-
free solutions for injection by the various spinal routes (epidural, intrathecal, caudal, etc.) are 
available forms in these regions. Other tramadol formulations approved in several countries 
include tablets, capsules, effervescent powders, and suppositories (Grond 2004; Rosenberg 
2009).  
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There is extensive data demonstrating that tramadol use is not associated with the classic-opioid 
side effects seen with more potent opioids. There are numerous reports of the safety and efficacy 
of tramadol in this setting (Scott 2000; Grond 2004). 
4.2. 
Nonclinical Summary 
Tramadol is a centrally-acting synthetic analgesic of the aminocyclohexanol group with opioid-
like effects. Tramadol is extensively metabolized following administration, which results in a 
number of enantiomeric metabolites that display different opioid-receptor binding properties, and 
monoaminergic reuptake inhibition (Grond 2004).  
Both enantiomers of tramadol and (+)-M1 are responsible for the analgesic effect. The primary 
metabolite [(+)-M1 or (+)-O-desmethyltramadol] of tramadol confers significant μ-opioid 
activity; (+)-tramadol confers weak μ-opioid activity and significant serotonin reuptake 
inhibition; and (−)-tramadol is responsible for the inhibition of noradrenaline re-uptake (Gillen 
2000; Raffa 2008). Nonclinical studies have shown that antinociception induced by tramadol is 
only partially antagonized by the opiate antagonist, naloxone, indicating that non-opioid 
mechanisms are also involved in its pharmacodynamic action (Collart 1992). 
Consistent with the known clinical effects of opioids, non-clinical safety pharmacology studies 
have shown that tramadol at high doses affects the central nervous system (CNS), producing 
sedation, impaired mobility, vomiting (dogs), decreased activity, and convulsions (Matthiesen et 
al., 1998). Also consistent with clinical effects, changes in blood pressure have been observed in 
cardiovascular studies in rats at high doses (Raimundo 2006). 
The toxicity of tramadol has been summarized by Matthiesen (Matthiesen 1998). The single dose 
toxicity of tramadol was similar in all species tested, independent of the route of administration. 
Notable acute findings included restlessness, unsteady gait, reduced spontaneous activity, 
exophthalmus, mydriasis, salivation, vomiting (dog), tremor, convulsions, slight cyanosis and 
dyspnea. The principle findings in repeat-dose toxicity studies in rats and dogs were 
behavioral/clinical signs and convulsions at doses of ≥25 mg/kg/day. The kidney and liver were 
identified as potential target organs in rats, with mild effects (minimal tubular vacuolization and 
perivenular hydropic degeneration, respectively) following repeat intraperitoneal dosing at high 
doses of tramadol. 
There was no evidence of genotoxic potential for tramadol in standard in vitro and in vivo 
studies (Matthiesen 1998). Carcinogenicity bioassays in mice and rats showed no evidence of 
carcinogenic potential. An extensive reproductive and teratology program revealed no safety 
concerns with respect to fertility or teratogenic effects after oral administration (Matthiesen; 
Yamamoto 1972). Toxicity to offspring only occurred at doses associated with maternal toxicity. 
In conclusion, none of the results in non-clinical toxicity studies indicated a safety concern 
regarding administration of AVE-901 at the intended clinical dose. 
4.3. 
Pharmacokinetic Profile 
Following oral administration, tramadol is rapidly and almost completely absorbed. The 
pharmacokinetics (PK) of tramadol were evaluated in healthy male volunteers (n=10) in a 
crossover design using 100 mg (PO) or IV doses (Lintz 1986). Peak serum concentrations 
(Tmax) were reached approximately 2 hours after oral dosing and the peak serum concentration 
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(Cmax) for PO tramadol was 280±49 ng/mL. The terminal half-life was 5.1 hours for PO and 5.2 
hours for IV administration. The area under the serum tramadol concentration-time curve (AUC) 
was 2488±774 ng·h/mL for PO and 3709±977 ng·h/mL for IV administration. Total clearance 
was 467±124 mL/min for PO and 710±174 mL/min for IV administration. The absolute 
bioavailability of the oral dose was 68±13%, based on comparison of the AUC values, while the 
estimated absorption of the oral dose was 86-88%. The difference between absorption and 
bioavailability was attributed to first pass metabolism, which was estimated to be ~20%. 
However, the absolute bioavailability approaches 90-100% with continuous dosing, probably due 
to saturation of first pass metabolism (Liao et al., 1992). Other studies have corroborated these 
findings (Grond 2004). 
Tramadol undergoes hepatic metabolism and both the parent drug and the active metabolite are 
excreted by the kidneys. The only known active metabolite, M1 (O desmethyltramadol), is 
produced by the action of cytochrome P450 CYP2D6 isozyme of the cytochrome P450 enzyme 
system. It has a half-life of approximately 6.7 hours after oral administration (single dose of 100 
mg), compared to a half-life of 5.6 hours for tramadol. Hepatic impairment results in decreased 
metabolism of both the parent compound and the active metabolite. Elimination half-life 
increases approximately 2-fold in patients with renal or hepatic impairment. Patients who 
metabolize drugs poorly via CYP2D6 (Caucasian population prevalence ~ 8%) may obtain 
reduced benefit from tramadol due to reduced formation of M1 (Ultram® Prescribing 
Information, Ortho McNeil-Janssen, 2009). 
A Phase 1 study was performed to determine a treatment regimen of IV tramadol that would be 
comparable to the approved 100 mg dose of oral tramadol at steady state [Study title: “A Phase 
1, Open-Label, Single Center, Three-Period, Multi-dose Crossover Study to Evaluate the 
Pharmacokinetics of Two Different AVE-901 (Tramadol Infusion) Regimens versus Oral 
Tramadol Tablets” (Study AVE-901-101)]. 
The two different IV regimens were evaluated and compared to the oral regimen. A total of 18 
patients, ages 24 to 55 years (inclusive) were enrolled (3 patients to each of the 6 sequences). 
The study included 11 males and 7 females. 17 patients completed all 3 treatment sequences. 
The treatment regimens evaluated were: 
1. 75 mg IV REGIMEN: IV tramadol 75 mg administered at Hour 0, followed by 75 mg at 
Hour 3 and Hour 6, and 75 mg every 6 hours thereafter through Hour 42 
2. 50 mg IV REGIMEN: IV tramadol 50 mg administered at Hour 0, followed by 50 mg at 
Hour 2, 50 mg at Hour 4, and 50 mg every 4 hours thereafter through Hour 44 
3. ORAL REGIMEN: Oral tramadol 100 mg (50 mg tablets x 2) at Hour 0, 6, and every 6 
hours thereafter through Hour 42 
Examination of the parent (tramadol) as well as the primary metabolite, M1 (O-
desmethyltramadol), was performed over the 48-hour treatment period.  A focus of the analysis 
was on assessment of Cmax values (to ensure the Cmax for the IV formulation was similar to that 
of the oral formulation) as well as on early concentrations during the first doses (to ensure 
adequate medication would be provided during the initial 6 to 12 hours of treatment as the drugs 
reached steady-state concentrations). Overall exposure to tramadol was estimated primarily from 
average trough plasma concentrations.   
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Figure 1 provides the mean plasma tramadol time-concentration profiles for the 100 mg oral, 50 
mg IV, and 75 mg IV regimens from Study AVE 901-101. Mean plasma tramadol concentrations 
were higher after the 75 mg IV regimen compared to the 50 mg IV regimen and 100 mg PO q6h.  
As evidenced from the trough/pre-dose samples between 24 and 42 h, the mean tramadol trough 
concentrations were very similar for the 50 mg IV regimen and 100 mg PO q6h but somewhat 
lower for the 75 mg IV regimen.   
Tramadol peak and trough concentrations for the 50 mg IV and the 100 mg PO q6h regimens 
were very similar at the end of the pharmacokinetic sampling period, between approximately 44 
and 48 h.  
Figure 1: 
Mean Plasma Tramadol Time-Concentration Profiles for 100 mg oral, 50 mg 
IV, and 75 mg IV Regimens (Study AVE-901-101) 
 
Figure 2 provides the mean plasma O-desmethyltramadol time-concentration profiles for the 100 
mg oral, 50 mg IV, and 75 mg IV regimens from Study AVE 901-101. The mean plasma O-
desmethyltramadol concentrations were higher for the 75 mg IV regimen following the 3rd dose 
at 6 h, but there was appreciable overlap of the trough concentrations for the 75 mg IV and 50 
mg IV regimens between 24 and 42 h. The pre-dose concentrations as well as the concentrations 
after the last dose at 42 h were higher for 100 mg PO q6h compared to both IV arms, presumably 
due to first pass metabolism which results in a higher fraction of the active metabolite in 
systemic circulation after oral administration.   
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Avenue Therapeutics, Inc. 
 
August 29, 2018 
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Figure 2: 
Mean Plasma O-desmethyltramadol Time-Concentration Profiles for 100 mg 
oral, 50 mg IV, and 75 mg IV Regimens (Study AVE-901-101) 
 
Select pharmacokinetic parameters (overall Cmax, Cmax at steady state, trough at steady state, 
AUC over the last dosing interval for each regimen, i.e., AUCtau n) for tramadol are summarized 
in Table 3.  
Table 3: 
Additional Plasma Pharmacokinetic Parameters of Tramadol (Study AVE-
901-101) 
Parameter 
75 mg IV 
50 mg IV 
100 mg Oral 
 
n 
Mean 
SD 
CV% 
n 
Mean 
SD 
CV% 
n 
Mean 
SD 
CV% 
Cmax (ng/mL) 
14 
932 
199 
21.30 
14 
736 
152 
20.60 
17 
701 
178 
25.44 
Cmax(42-48) (ng/mL) 
14 
827 
234 
28.24 
- 
- 
- 
- 
17 
701 
178 
25.44 
Cmax(44-48) (ng/mL) 
- 
- 
- 
- 
14 
711 
152 
21.40 
- 
- 
- 
- 
T48 (ng/mL) 
14 
354 
85.9 
24.31 
14 
448 
131 
29.36 
17 
497 
144 
29.09 
Css (ng/mL) 
14 
506 
101 
20.03 
14 
557 
131 
23.60 
17 
579 
150 
25.96 
The 50 mg IV regimen provided favorable Cmax and AUC values over the full 48 hour treatment 
period. Specifically:   
x Overall Cmax was comparable between the 50 mg IV and 100 mg PO regimens 
x Exposure to tramadol at steady state (or near steady state, in the case of the oral 
regimen), based on Cmax and AUC, was also comparable between the 50 mg IV 
regimen and 100 mg PO q6h.   
x The 50 mg IV regimen, as compared to the 75 mg IV regimen, resulted in less peak to 
trough fluctuation with lower Cmax. This regimen also provided a pharmacokinetic 
profile very similar to the 100 mg oral dose regimen 
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x Exposure to O-desmethyltramadol was higher after 100 mg PO q6h compared to 
either IV treatment, 50 mg IV or 75 mg IV regimens, based on AUC and Cmax values 
Based on these findings, the 50 mg IV regimen will be studied in this current protocol. 
4.4. 
Rationale for this Study 
This open-label safety study will be conducted in parallel with two efficacy Phase 3 studies, one 
in an orthopedic model (AVE-901-102) and the other in a soft tissue model (AVE-901-103). 
Data from this current study will be combined with data from those two efficacy studies into an 
overall safety database for tramadol infusion. 
A brief summary of the two double-blind studies follows. 
x Protocol AVE-901-102:  Orthopedic surgery study in a Phase 3, multicenter, double-
blind, randomized, placebo-controlled, multiple-dose, parallel-group trial to evaluate 
the safety, tolerability and efficacy of 2 doses (50 mg and 25 mg) of IV Tramadol 
hydrochloride injection (AVE-901) versus placebo in the management of 
postoperative pain in consenting patients undergoing an orthopedic surgery 
(bunionectomy). The primary objective of this study is to evaluate the analgesic 
efficacy of intravenous (IV) Tramadol (AVE-901) in the management of 
postoperative pain following orthopedic surgery. The Sum of Pain Intensity 
Differences (SPID) through 48 hours post first dose (SPID48) at rest will be used as 
the primary measure of efficacy.  Up to approximately 405 patients will be 
randomized.  This study has commenced and expected to be completed second 
quarter 2018 
x Protocol AVE-901-103:  Soft tissue surgery study is a Phase 3, multicenter, double-
blind, randomized, placebo-controlled, multiple-dose, parallel-group trial to evaluate 
the safety, tolerability and efficacy of IV Tramadol (AVE-901) versus placebo in the 
management of postoperative pain in consenting patients undergoing elective 
abdominoplasty. The primary objective of this study is to evaluate the analgesic 
efficacy of intravenous (IV) Tramadol (AVE-901) in the management of 
postoperative pain following soft tissue surgery. The Sum of Pain Intensity 
Differences (SPID) through 24 hours post first dose (SPID24) at rest will be used as 
the primary measure of efficacy.  Up to approximately 360 patients will be 
randomized.  A smaller morphine comparator arm will be included in the study. 
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5. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to evaluate the safety of intravenous (IV) tramadol (AVE-
901) 50 mg for the management of postoperative pain.  Safety endpoints will include: 
x Adverse events (classified by the MedDRA System Organ Class (SOC) and preferred 
term).   
x Clinical laboratory, vital sign, and ECG changes 
x Local tolerability of the infusion site via pain, swelling, tenderness, and erythema.   
Throughout the protocol, AVE-901 will be used to indicate the treatment. 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This study is a Phase 3, multicenter, single-arm, open-label, uncontrolled, repeat-dose trial to 
assess the safety of AVE-901 in the management of postoperative pain. Eligible patients will be 
patients that are undergoing elective surgery and are deemed appropriate to receive IV AVE-901 
for the treatment of post-surgical pain.  Approximately 250 patients will be enrolled into the 
study. Each patient will undergo the Screening Visit (Day -28 to Day -1), the Pre-operative 
assessment (within 24 hours prior to surgery), the Surgery (Day 0), the Primary treatment period 
(hour 0 through hour 168), End of Treatment visit, and the Follow-up Visit (Day 14).   
Note: Patients may have Screening and Preoperative visits combined into one visit if required to 
accommodate timelines for scheduled surgeries. The procedures associated with the Screening 
Visit should be completed.  
Screening will occur up to 28 days prior to surgery.  Eligible patients will be made aware of the 
use of additional pain medication, and of the various post-treatment safety measures.  These 
patient training procedures may be conducted on different days as appropriate during Screening. 
Surgery will occur on Day 0.  There are no restrictions on the agents to be used for induction, 
neuromuscular blockade, maintenance of anesthesia, or on hypnotics, sedatives, or anxiolytics. 
Following surgery, each patient will receive their study medication infusion at T0, T2, T4, and 
then every 4 hours for up to 168 hours after the first study drug administration (a total of up to 43 
doses per patient).  The latest (last) dose that is allowed is at Hour 164.  Patients will be confined 
at the healthcare facility for as long as they are still using AVE-901. Following the first dose of 
study drug, the patients will be allowed to use non-opioid pain medication per the treating 
physician’s discretion, if additional pain relief is required. 
6.2. 
Number of Patients 
A total of approximately 250 patients in United States (US) at approximately 8-10 study sites 
who meet all inclusion and none of the exclusion criteria are planned to be enrolled.  Every 
patient treated will receive AVE-901.  Patients who withdraw from the trial are not planned to be 
replaced. 
6.3. 
Treatment Assignment and Randomization 
No randomization will be utilized in this study; all patients will receive tramadol infusion per the 
treatment dosing regimen. 
6.4. 
Criteria for Study Termination 
If the Investigator, Study Medical Monitor, or Avenue Therapeutics discovers conditions arising 
during the study, which indicate that the clinical investigation should be halted, the study must 
be terminated after appropriate consultation between Avenue Therapeutics, Study Medical 
Monitor, and the Investigators.  Conditions that may warrant termination include, but are not 
limited to: 
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x The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study, 
x Failure of the Investigator to enter patients at an acceptable rate, 
x Insufficient adherence to protocol requirements and good clinical practices, or; 
x A decision on the part of the Avenue Therapeutics to suspend or discontinue 
development of the drug. 
6.4.1. 
Individual Patient Stopping Rules 
If a patient experiences a serious or severe adverse event assessed as possibly, probably or 
definitely related to study drug, the Investigator will review the patient’s medical record, consult 
with the Medical Monitor if necessary and determine whether the patient should have study 
treatment either temporarily interrupted or permanently discontinued. 
6.5. 
Schedule of Events 
Table 4 provides the schedule of events.  Note that patients who discontinue treatment at any time 
after receiving their first dose of study drug (T0) will have all End of Treatment assessments 
performed.  
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Table 4. 
Schedule of Assessments for each Study Period (Study AVE 901-104) 
Assessments 
Screening 
Day -28 to  
Day -14 
Pre-op 
Day -1/04 
Surgery 
Day 0 
Treatment Hours Post Start of First Infusion  
Hour 0 to Hour 164 (assessments + 10 minute window) 
End of Treatment 
(completed prior to discharge) 
Phone Call Day 14±2 
 
 
 
0 
0.5 
1 
2 
3 
4 
Every 4 hours 
EoT 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
Height and Weight (BMI) 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
X 
 
ASA Physical Status 
X 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs (and SpO2)1 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Hem/Chem/Urinalysis3 
X 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
X 
 
X5 
X 
(Done 20 to 30 minutes after start of each dose for first 24 hours) 
X 
 
Eligibility Criteria 
X 
X 
 
X4 
 
 
 
 
 
 
 
 
Surgery 
 
 
X  
 
 
 
 
 
 
 
 
 
Study Drug Admin 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
PGA 
 
 
 
 
 
 
 
 
 
X (24 hours only) 
X  
 
Adverse Events 
 
                                                                                                          X (ongoing) 
Prior/Conmeds 
 
     X (ongoing) 
 
                                                 
 
1 Post 48 hour treatment, vitals drawn only every 8 hours 
2 Screening and End of Treatment Pregnancy test (serum) by central laboratory, Pre-op pregnancy test (urine) conducted locally for female patients of childbearing potential.   
3 Hematology, Chemistry, Urinalysis sent to central laboratory for analysis.  Patients screened and not receiving results from central labs prior to surgery may have local lab done to assess eligibility. 
4 If necessary, Screening and Pre-Op procedures may be combined into one visit assessment for time considerations associated with scheduled surgeries. Screening Visit procedures should take 
precedent.   
5ECG should be taken post-surgery, prior to dosing at T0 
 
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6.6. 
Description of Visits 
There are 5 distinct periods in this study: 
x Screening (Days -28 to -1) 
x Pre-operative (within 24 hours of scheduled surgery) 
x Surgery (Day 0) 
x Treatment Period/Post Surgery (Hours 0 up to Hour 168) 
x Follow–up (approximately Day 14) 
Procedures for each study period are described below. 
6.6.1. 
Screening 
Screening will occur from Day -28 through Day -1 and will be conducted as a clinic visit. 
Patients will have the purpose and procedures of the study explained to them and, those who 
elect to participate in the study, will provide written informed consent and be screened for 
participation according to the eligibility criteria. Patients will undergo protocol specific 
education including but not limited to the various post-treatment efficacy and safety measures.  
The following information and procedures will be performed and documented as part of the 
screening assessment: 
x Demographics, including gender, race and ethnic origin, date of birth, height, weight 
and calculated BMI. 
(https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm) 
x Inclusion/exclusion eligibility criteria 
x Physical examination 
x ASA Physical Status 
x Medical history 
x Prior and ongoing medications (taken in previous 30 days) 
x Vital signs: blood pressure, heart rate, respiratory rate, and oral temperature (after 
seated or supine for 5 minutes) and SpO2 
x 12-lead ECG (after supine for 5 minutes) 
x Blood samples for hematology and clinical chemistry 
x Pregnancy test (serum) for women of child-bearing potential 
x Urine samples for urinalysis 
Compliance with inclusion criteria and exclusion criteria will be verified against information 
collected and documented in the source documents and the eCRF. 
 
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For patients that screen within 5 days of surgery, central laboratory values may not be available 
to assess eligibility.  For these patients it is acceptable for sites to draw local lab to assess 
eligibility, in addition to the central lab, which will still be used as the baseline in the study.  If 
local labs are used to access eligibility at screening, at a minimum the following analytes must be 
reviewed from the local laboratory prior to dosing; magnesium, calcium, potassium, sodium, 
serum creatinine, ALT, AST, hemoglobin. The local laboratory listed on the FDA 1572 Form 
must be used for all local blood draws.  
 
Central labs supersede local labs for eligibility. If during the screening process the central labs 
are received prior to the subject being dosed/treated, even though local labs were drawn, the 
central lab values will be used to indicate eligibility. If central labs show exclusionary lab values 
discrepant from the local labs and the subject has not yet been treated, subject will be deemed a 
screen failure and will not be treated. If the subject is treated based on local lab values and the 
central lab values show exclusionary labs after subject is dosed, the PI will inform the Medical 
Monitor and discuss patient safety and suitability to continue treatment.  
 
6.6.2. 
Preoperative 
Preoperative assessments to confirm the patient’s eligibility will be performed within 24 hours of 
scheduled surgery start time.  This visit will include reassessment of: 
x Inclusion/exclusion eligibility criteria 
x Physical examination  
x ASA Physical Status 
x Medical history within 2 years 
x Prior and ongoing medications (taken in previous 30 days) 
x Vital signs: blood pressure, heart rate, respiratory rate, and oral temperature (after 
seated or supine for 5 minutes) and SpO2 
x Urine pregnancy test for women of child-bearing potential 
6.6.3. 
Surgery 
Surgery will occur on Day 0.  Standard of care procedures should be followed. 
6.6.4. 
Treatment Period/Post Surgery 
Patients will receive their first dose of study medication (T0) within 8 hours of meeting the 
postsurgical eligibility. Treatment is anticipated to occur from Hours 0 up to Hour 168.  The 
latest (last dose) that is allowed is at Hour 164. Patients will be dosed at Hour T0, T2, T4, and 
then every 4 hours thereafter, for a total of up to 43 doses administered over the 168-hour 
treatment period. Assessments will have a + 10 minute window. 
Antiemetic treatments (with the exception of Zofran or other 5-HT3 antagonists) are allowed.  
 
 
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Treatment period assessments include: 
x Recording vital signs including: respiratory rate, heart rate, pulse oximetry (SpO2), 
temperature, and blood pressure at 0, 0.5, 1, 2, 3, 4, and then every 4 hours thereafter 
during the first 48 hours.  After 48 hours patients continuing treatment should have 
vitals taken every 8 hours. 
x ECGs will be assessed at screening, post-surgery prior to dosing (T0), and at 20 to 30 
minutes after the start of each infusion for the first 24 hours.  With the 10-minute 
window allowed per assessments, the on-treatment ECGs need to be done between 10 
to 40 minutes after the start of each dosing infusion. 
x Patient Global Assessment at 24 hours   
x Adverse events and concomitant medications will be collected as appropriate.   
x Following the first dose of study drug, the patient will be allowed to use non-opioid 
analgesics if additional pain relief is required.  These medications will be captured on 
the concomitant medications page 
x Concomitant medication use 
6.6.5. 
End of Treatment 
 
At the End of Treatment patients will undergo: 
x A brief symptom driven physical examination  
x Vital signs: blood pressure, heart rate, respiratory rate, and oral temperature (after 
seated or supine for 5 minutes) and SpO2 
x 12-lead ECG (after supine for 5 minutes) 
x Blood samples for hematology, clinical chemistry, urinalysis, and pregnancy test 
x Patient Global Assessment  
x AEs 
x Concomitant medication use 
End of Treatment assessments do not follow a +/- 10 minute window, but just need to be 
completed prior to discharge 
6.6.6. 
Follow up 
A final safety assessment will be conducted on Day 14 (± 2 days) from the first dose via a 
telephone call to check on general well-being, including spontaneous reports of adverse events 
and concomitant medications. 
 
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7. 
SELECTION AND WITHDRAWAL OF PATIENTS 
7.1. 
Patient Inclusion Criteria 
The following are patient inclusion criteria for this study; each patient must meet all inclusion 
criteria in order to be enrolled into this study. 
1. The patient is male or female 18-75 years of age 
2. The patient or legal representative has voluntarily signed and dated an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed 
consent. 
3. Female patients must be of non-childbearing potential (surgically sterile or post-
menopausal for at least 1 year) or be practicing a highly effective contraception method 
from consent to at least 7 days after the last dose of study medication. Surgically sterile is 
defined as status post hysterectomy, bilateral oophorectomy or bilateral tubal ligation. 
Highly effective contraception methods include:  abstinence, vasectomized partner (at 
least 6 months prior to dosing); double barrier (diaphragm with spermicide; condoms 
with spermicide); intrauterine device; implanted or intrauterine hormonal contraceptives 
in use for at least 6 consecutive months prior to study dosing and throughout the study 
duration; oral, patch, or injected contraceptives in use for at least 3 consecutive months 
prior to study dosing. 
4. Female patients of childbearing potential have a negative pregnancy test (serum human 
chorionic gonadotropin [HCG]) during screening and a negative pregnancy test (urine) ≤ 
24 hours prior to surgery, and are not lactating. 
5. Patient is undergoing elective surgery and, in the opinion of the investigator, is an 
appropriate candidate for IV Tramadol for pain management post-operatively. 
6. The study patient is willing to be housed in a healthcare facility capable of administering 
parenteral analgesia for at least 24 after surgery.  Treatment may extend through Hour 
168 if deemed appropriate. 
7. The patient meets definition of American Society of Anesthesiologists (ASA) Physical 
Class 1 or 2.  
8. The patient is willing and able to understand the study procedures to communicate 
meaningfully with the study personnel, and to comply with the study protocol. 
7.2. 
Patient Exclusion Criteria 
The following are patient exclusion criteria for this study; each patient must not meet any of 
these exclusion criteria in order to be enrolled into this study. 
1. The patient has current or historical evidence of any clinically significant disease or 
condition that might place the patient at unacceptable risk due to receiving the study 
medication, in the opinion of the investigator. 
2. The patient has allergy or hypersensitivity (or is intolerant) to opioids or tramadol. 
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3. The patient has used chronic opioid therapy, defined as >= 20 MEQs of morphine per day 
>=3 days out of 7 days over the past 4 weeks.   
4. The patient has a recent (within 2 years) and/or current history of alcohol, opiate or 
tranquilizer abuse or dependence. 
5. The patient is taking herbal or dietary supplements or medications that are moderate or 
strong inhibitors of CYP2D6 or CYP3A4 (e.g., fluoxetine, paroxetine, amitriptyline, 
quinidine, ketoconazole, erythromycin, grapefruit juice) or inducers of CYP3A4 (e.g., 
carbamazepine, rifampin, St. John's Wort) and cannot go through a minimum washout 
period of 7 days prior to surgery. 
6. The patient has a history of epilepsy, is susceptible to seizures.  
7. The patient cannot be withdrawn from medications (at least 7 days prior to surgery) that 
may lower the seizure threshold (e.g. anti-psychotic agents, MAOI inhibitors) or which 
increase serotonergic tone (e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin 
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, triptans, 
amphetamines). 
8. The patient has had a recent (within 6 months) cardiovascular event or clinically 
significant abnormal ECG finding at screening. 
9. The patient has a history of Long QT Syndrome or a relative with this condition 
10. The patient has expressed suicidal ideation within the past 3 months or is considered to 
be at risk of suicide. 
11. The patient is morbidly obese (body mass index [BMI] ≥ 40 kg/m2) or has documented 
sleep apnea requiring CPAP or other treatment. 
12. Female patient is pregnant and/or undergoing a pregnancy-related surgery, or 
breastfeeding. 
13. The patient has a history of cardiopulmonary, neurological or psychiatric condition that 
may confound the assessments of efficacy or safety. 
14. The patient has cirrhosis, moderate or severe hepatic impairment or an alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) value > 3X upper limit of 
normal (ULN) at Screening. 
15. The patient has severe renal impairment or a serum creatinine value of > 2x upper limit of 
normal (ULN) at Screening. 
16. The patient has potassium, sodium, calcium or magnesium levels outside of the normal 
range at Screening 
17. The patient has a hemoglobin level at screening which, in the judgment of the 
Investigator, is not suitable for participation in this study. 
18. The patient was administered an investigational drug product within 30 days prior to 
Screening. 
19. The patient has previously participated in a clinical study with AVE-901. 
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7.2.1. 
Post-Surgical Additional Exclusion Criteria 
The patient is to be evaluated post-operatively prior to the initial treatment with the study drug and will 
be withdrawn prior to treatment with the study drug if any of the following exclusion criteria are met: 
1. Patients who, in the opinion of the investigator, are not likely to tolerate the protocol’s 
allowed analgesic regimen (tramadol plus non-opioid adjuvants).  
2. Patients who have been admitted to the ICU post-surgery or have experienced 
complications during the surgical procedure that would put them at increased risk from 
receipt of the investigational product in the opinion of the investigator.  
3. The patient is not clinically stable and not able to answer questions and follow 
commands. 
4. The patient has evidence of respiratory insufficiency, such as a respiratory rate that is less 
than 8 breaths per minute or arterial oxygen saturation by pulse oximetry of less than 
90% with supplemental oxygen. 
5. Use of 5-HT3 antagonists (e.g. ondansetron, granisetron, palonosetron) preoperatively, 
intraoperatively, or postoperatively   
7.3. 
Patient Withdrawal Criteria 
If a patient is discontinued from the study prematurely, the Investigator must select the primary 
reason for discontinuation on the End of Study eCRF.  In addition, every effort should be made 
to complete the assessments listed under the End of Treatment/Discharge from Clinic column on 
the Schedule of Assessments.  
Patients withdrawn from the study will be considered evaluable for statistical assessment. 
A patient may be removed from the study for the following medical or administrative reasons: 
x Adverse Event: If a patient experiences an adverse event that the patient finds 
unacceptable or that, in the judgment of the Investigator or the Medical Monitor 
presents an unacceptable consequence or risk to the patient, the patient may be 
discontinued from further participation in the study. If doses are missed due to an 
Adverse Event and the event resolves, the patient can resume their scheduled 
treatment at the discretion of the Investigator. Missed doses should be recorded in the 
eCRF.  
x Administrative Discontinuation:  After consultation with the Investigator or Medical 
Monitor, a patient may be discontinued from the study for failure to comply with 
protocol requirements.  All instances of noncompliance must be documented in the 
eCRF. 
x Refusal of Assessments:  If for any reason, following dosing, the patient refuses 
further assessment during the study, the patient shall be discontinued from the study 
and the reasons for refusal documented.  Reasonable efforts shall be made to monitor 
the patient for adverse events following such discontinuation.  Such efforts shall be 
documented. 
 
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8. 
TREATMENT OF PATIENTS 
8.1. 
Description of Study Drug 
Investigational product will be packaged in identical ampoules containing 1ml of AVE-901.  
Each ampoule of AVE-901 contains 50 mg of tramadol hydrochloride and sodium acetate 
trihydrate as buffering agent diluted in water. Ampoules will be packaged in bulk cartons. 
Study drugs will be distributed to the clinic using a designated distribution center.  The Sponsor 
will provide the investigator with adequate quantities of investigational product and supplies to 
conduct the study. Specific details regarding investigational product supplies, dose preparation, 
and accountability will be described in a pharmacy manual at the clinic. 
Table 5 provides a summary description of the drug products, including the dosage form, the unit 
dose, and a physical description of the product.   
Table 5: 
Investigational Product (Study AVE-901-104) 
 
Investigational Product 
Product Name: 
Tramadol for infusion 50 mg 
Dosage Form: 
Liquid 
Unit Dose: 
50 mg/1mL ampoule 
Route of Administration: Intravenous infusion 
Physical Description: 
Clear solution 
Manufacturer: 
Siegfried Hameln 
8.2. 
Concomitant Medications 
Medications deemed necessary for the patient’s welfare are permitted.  The following drugs are 
EXCLUDED from use: 
x Moderate or strong inhibitors of CYP3A4 or CYP2D, inducers of CYP3A4, drugs 
which may increase serotonergic tone including SSRIs, SNRIs, tricyclic 
antidepressants, trazodone, cyclobenzaprine triptans, 5-HT3 antagonists including 
ondansetron, and amphetamines; and drugs which may lower seizure threshold. 
x Any opioid based analgesic (post dosing)   
Adverse events (AEs) such as nausea, vomiting and pruritus should be managed using standard 
of care, excluding medications specifically noted in the study protocol. 
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8.3. 
Treatment Compliance 
Treatment compliance with study medication during the treatment periods is expected to be high, 
as patients will be dosed directly in the clinic under well-controlled conditions.  The date and 
time of study drug administration will be recorded on the eCRF.   
8.4. 
Overdose 
Tramadol products in excessive doses, either alone or in combination with other CNS 
depressants, including alcohol, are a cause of drug-related deaths. Acute over dosage with 
tramadol can be manifested by respiratory depression, somnolence progressing to stupor or 
coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, 
hypotension, cardiac arrest, and death. Serious potential consequences of over dosage with 
tramadol are CNS depression, respiratory depression and death. Some deaths have occurred as a 
consequence of the accidental ingestion of excessive quantities of tramadol alone or in 
combination with other drugs, while others were associated with abuse of tramadol.  Review of 
case reports has indicated that the risk of fatal overdose is further increased when tramadol is 
abused concurrently with alcohol or other CNS depressants, including other opioids (Ultram® 
Prescribing Information, 2009). 
Of note, while naloxone will reverse some, but not all, symptoms caused by over dosage with 
tramadol, the risk of seizures is also increased with naloxone administration. In animals 
convulsions following the administration of toxic doses of tramadol could be suppressed with 
barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did 
not change the lethality of an overdose in mice.  Hemodialysis is not expected to be helpful in an 
overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period 
(Ultram® Prescribing Information, 2009). 
Additional details may be found in the Investigator’s Brochure. 
8.5. 
Randomization, Blinding and Unblinding 
This is an open-label study in which all patients will receive the same treatment.  Thus, there is 
no randomization or blinding applied in this study. 
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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
Study drug will be provided to the investigational centers. 
9.1. 
Study Drug Packaging and Labeling 
Single-use, glass ampoules with labels and an outer fiberboard carton with a single panel label 
will have the following information: 
1. Protocol #: AVE-901-104 
2. Each 1ml ampoule contains 50mg of IV Tramadol (C-IV) 
3. Intravenous injection administration only. Use as directed per protocol. 
4. Store at 20°C to 25°C (68°F to 77°F). Store away from heat sources and direct sunlight. 
5. Caution: New Drug – Limited by Federal (United States) Law to Investigational Use. 
6. Sponsor: Avenue Therapeutics, New York, NY 10019 
7. Manufactured by: Siegfried Hameln 
8. Lot number: __________________  
The clinical trial supply label will be in accordance with ICH GCP and local requirements for 
investigational product labelling. 
9.2. 
Packaging, Labeling, and Storage of Clinical Supplies 
Investigational products are for investigational use only and the study drug supplied for this 
study is intended for use only within the context of this study. The study drug supplied for this 
study should be stored in a secure place and maintained under adequate security until dispensed 
for patient use or returned to the Sponsor.  Tramadol is classified as a Schedule IV controlled 
drug and security requirements as per 21CFR 1301.71-77 are to be followed at the clinic. 
Investigational products should be stored at room temperature (20-25°C or 68-77°F). 
Investigational products should be stored away from heat sources and direct sunlight. 
The Investigator, pharmacist, or their designee, will verify that study drug supplies are received 
intact and in the correct amounts by signing and dating the investigational product receipt log. 
The person receiving the supplies must verify that the shipment contains all the items noted in 
the shipment inventory. Any damaged or unusable drug in a given shipment will be documented 
in the study files. The Investigator must notify the Sponsor or designee of any damaged or 
unusable investigational product supplied to the Investigator’s site. 
The site will maintain a Drug Inventory Log (includes, but not limited to, the following: lot 
number, number of units received and number of ampoules dispensed).  The site will also 
maintain patient-specific drug dispensing logs. 
An overall accountability of investigational product will be performed and verified throughout 
the study and at the site closeout visit. Upon completion of the study, copies of the 
investigational product accountability records will be returned to the Sponsor. All used and 
unused study drug supplies will be inventoried, accounted, and returned to the Sponsor at the end 
of the study. By signing the Investigator Agreement page of this protocol, the investigator or 
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named sub-investigator agrees not to supply study drug to any person(s) not enrolled in the 
study.  
9.3. 
Study Drug Preparation and Administration 
Study drug will be dispensed by the qualified, licensed study personnel and administered to the 
patient by a licensed designated staff member.  The designated personnel will prepare the 
treatments for administration and maintain accountability records.   
AVE-901 will be provided in ampoules containing 1 mL of IV Tramadol.  Directions for 
preparation of study medication will be recorded in the pharmacy manual prior to initiation of 
the study.  The pharmacy manual will provide procedures for preparation (and destruction) that 
correspond to the dose of study medication used in this study. 
9.4. 
Study Drug Accountability 
Patients will be treated at the investigational center and therefore the Pharmacist or other 
investigational staff via documentation of receipt of the study drug and dosing/treatment given 
will perform drug accountability.   
9.5. 
Study Drug Handling and Disposal 
Records of receipt, dispensing records and inventory forms, as applicable, will be examined and 
reconciled during and at the end of the study.  Both the investigational drug that is used during 
the course of the study, as well as any remaining unused investigational drug, must be accounted 
for on a drug accountability record provided to the PI by the Sponsor or its designee.  Drug 
destruction will be completed following the clinical sites SOP on destruction and a destruction 
certificate will be maintained at the clinic.  
If directed and if drug is not destroyed on site, at the end of the study, all unused investigational 
drug, accompanied by a packing slip will be shipped to designee provided by the sponsor. 
In addition, a copy of all completed drug accountability records must be retained in the 
Investigators’ Study Files, with a copy sent to the Sponsor or its designee. 
The products are to be stored in a safe place (locked facility) at the appropriate temperature and 
without exposure to freezing. 
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10. 
PHARMACOKINETIC ASSESSMENTS 
There are no pharmacokinetic assessments being performed in this study. 
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11. 
ASSESSMENT OF SAFETY 
11.1. 
Safety Parameters 
Safety assessments will include collection of adverse events. In addition, safety assessments 
include clinical laboratory tests, vital signs, physical examination, concomitant medications, and 
12-lead ECGs.   
11.1.1. 
Demographic/Medical History 
Demographic information and medical history will be collected at Screening for determination of 
eligibility. Demographic information will include the following: age, gender, race and ethnic 
origin. Significant medical history within the past two years should be recorded on the eCRF.  
11.1.2. 
Vital Signs 
Vital sign assessments include blood pressure, pulse, temperature, respiratory rate, and SpO2, 
and are collected at varied times as per the Schedule of Events.  Vital signs will be performed 
after the patient has rested sitting or supine for 5 minutes.  
11.1.3. 
Weight and Height 
Height and weight will be captured as per the Schedule of Events.  BMI will be calculated using 
the NIH website BMI calculator. 
https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm 
11.1.4. 
Electrocardiogram (ECG) 
All scheduled ECGs will be performed after the patient has rested supine for approximately 5 
minutes as per the schedule of events. 
11.1.5. 
Physical Examination 
A physical examination will be conducted and abnormalities will be described.  After the initial 
full physical exam only symptom-driven examinations will be performed. 
11.1.6. 
Laboratory Assessments 
All laboratory assessments will be collected as per the schedule of events and as described in the 
study laboratory manual. 
11.1.6.1. Hematology and Blood Chemistry 
Clinical Laboratories (Hematology and Serum Chemistry) will be performed as per the schedule 
of events and will be described in the study laboratory manual. 
11.1.6.2. Urinalysis 
Urinalysis will be performed as per the schedule of events and will be described in the study 
laboratory manual.   
Instruct patient to obtain a "clean-catch" urine sample, collected in midstream.  
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11.1.6.3. Pregnancy Screen 
Pregnancy screening will be performed for all females of childbearing potential in accordance 
with the schedule of events. 
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Event (AE) 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Adverse events may include safety findings 
considered to be clinically significant by the Investigator.  An adverse drug event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not it is related to 
the medicinal product.  Reporting an adverse event does not necessarily reflect a conclusion by 
the Investigator that the event is causally related to the drug. 
All adverse events should be captured and documented along with any supporting 
documentation.  Adverse events should be spontaneously reported or elicited by non-suggestive 
probing.  Signs or symptoms associated with a worsening in either severity or frequency as 
compared to a baseline condition should be evaluated by the Investigator for clinical significance 
and adverse event reporting.  
Each adverse event in this study will be assessed for Grade, where Grade of an AE refers to the 
severity of the AE.  Grade will be assessed according to CTCAE Version 4.03 or higher.  The 
CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE 
that are based on this general guideline.  Table 6  provides the CTCAE grades and grade 
descriptions to be used in this study. 
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Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
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Table 6: 
CTCAE Grade (Study AVE 901-104) 
CTCAE Grade  
CTCAE Grade Description 
Grade 1: Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: 
Moderate 
Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL1. 
Grade 3: Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL2. 
Grade 4: Life-
threatening 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death 
Death related to the AE. 
Activities of Daily Living (ADL) 
1 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
2 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03 will be used for AE 
grading.  A complete CTCAE list can be downloaded at http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
11.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during the study that fulfills one or more of the 
following: 
x Results in death 
x It is immediately life-threatening 
x It requires in-patient hospitalization or prolongation of existing hospitalization 
x It results in persistent or significant disability or incapacity 
x Results in a congenital abnormality or birth defect 
x It is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
Reporting serious adverse events requires additional detailed reports and follow-up, depending 
upon the Investigator's estimate of a causal relationship between the test agent and the adverse 
event(s), and whether the adverse event(s) is identified in nature, severity, and frequency in the 
Investigator's Brochure or other risk information supplied to the Investigator. 
All serious adverse events (SAEs) should be submitted promptly to the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC).  The investigator must make an effort to obtain 
all hospital medical records including discharge summary confirming final diagnosis.  The death 
of a patient must be immediately (within 24 hours) reported to the IRB.  All serious and non-
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August 29, 2018 
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serious adverse events should be thoroughly documented and followed out by the Investigator 
until the event resolves or until the termination visit.  The event may be followed longer, if 
deemed necessary.  For any death occurring during the trial, the medical condition that led to the 
death should also be noted.  The “outcome” status should be noted as “death” in these cases of 
SAEs that resulted in death.  In addition, all SAEs that occur from treatment through the follow-
up phone call should be recorded and reported as noted previously. 
11.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE.  The Investigator should decide whether, in his or her 
medical judgment, there is a reasonable possibility that the event may have been caused by the 
investigational product.  For purposes of the definitions below, “temporal sequence” is defined 
as an association between administration of a drug and the observed reaction or event such that 
the drug was present prior to the reaction or event. 
DEFINITE - The adverse event: 
x follows a reasonable temporal sequence from drug administration, 
x abates upon discontinuation of the drug (dechallenge), AND 
x is confirmed by reappearance of the reaction on repeat exposure (rechallenge). 
PROBABLE - The adverse event: 
x follows a reasonable temporal sequence from drug administration, 
x abates upon discontinuation of the drug (dechallenge), and 
x cannot be reasonably explained by the known characteristics of the patient’s clinical 
state. 
POSSIBLE - The adverse event: 
x follows a reasonable temporal sequence from drug administration, and; 
x could have been produced by the patient's clinical state or by other modes of therapy 
administered to the patient. 
REMOTE  
x There is another more likely explanation for the adverse event, such as a concomitant 
therapy or procedure.  The known pharmacology of the drug is not consistent with the 
event and the temporal relationship to study drug is unknown or may be consistent 
with the drug being present at the time of event. 
DEFINITELY NOT – The adverse event: 
x is definitely produced by the patient's clinical state or by other modes of therapy 
administered to the patient. The temporal relationship indicates that the drug was not 
present at the time of the event. 
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11.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient/caregiver and/or in response to an open 
question from the study personnel or revealed by observation will be recorded during the study at 
the investigational site.  The AE term should be reported in standard medical terminology when 
possible.  For each AE, the Investigator will evaluate and report the onset (date and time), 
resolution (date and time), severity, causality, action taken, serious, outcome (if applicable), and 
whether or not it caused the patient to discontinue the study. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 11.2.1.2.  An AE of severe intensity 
may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on a pregnancy reporting form.  
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 
handled as AEs. 
11.5. 
Reporting Adverse Events 
Information about AEs and SAEs will be collected from treatment (i.e. from time of first dose) 
through the follow-up phone call.  AEs or SAEs occurring prior to first dose of study treatment 
will be considered Medical History.  AEs or SAEs occurring during or after the first dose of 
study treatment will be treatment-emergent (S)AE.  Any SAEs considered at least possibly 
related to the investigational product and discovered by the Investigator at any time after the 
study should be reported.  The Investigator must complete, sign and date the SAE pages, verify 
the accuracy of the information recorded on the SAE pages with the corresponding source 
documents.  
Additional follow-up information, if required or available, should all be communicated within 
one business day of receipt and this should be completed on a follow-up SAE form and placed 
with the original SAE information and kept with the appropriate section of the eCRF and/or 
study file. 
The Sponsor is responsible for notifying the relevant regulatory authorities of certain events.  It 
is the Investigator’s responsibility to notify the IRB of all SAEs that occur at his or her site.  
Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day 
Safety Reports) that occur during the clinical trial.  Each site is responsible for notifying its IRB 
or IEC of these additional SAEs. 
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Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
August 29, 2018 
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12. 
STATISTICS 
This is an open-label treatment study in which all patients will be treated with the study 
medication.  The primary objective of this study is to assess safety.  The statistical methods to be 
used in the analysis are consistent with both the study design and the study objectives.  
12.1. 
Sample Size Considerations 
A sample size of approximately 250 patients will be enrolled.  This sample size of 250 patients 
will provide approximately 90% power to detect at least one incidence of uncommon adverse 
events (those events with a true underlying incidence of 1%). 
12.2. 
General Statistical Methods 
Data will be tabulated using descriptive statistics where specified.  A comprehensive statistical 
analysis plan (SAP) will be written and approved prior to completion of the final analysis. This 
SAP will detail how missing values, windows for study visits, and other analysis considerations 
will be addressed. 
12.3. 
Analysis Populations 
There is one populations identified for purposes of the statistical analysis. 
x Safety Population:  All patients treated with the study treatment will be included in 
the Safety Population.   
12.4. 
Handling of Missing Data 
Missing data will not be replaced.   
12.5. 
Baseline Characteristics 
Baseline characteristics will be tabulated descriptively (eg, number and percent of patients for 
each category for categorical parameters, and the number, mean, standard deviation, and range 
for continuous parameters).  
12.6. 
Patient Disposition 
Patient completion status and reasons for end of treatment will be tabulated descriptively.   
12.7. 
Exposure 
Exposure to AVE-901 will be tabulated via the number of infusions given, the total amount of 
drug given over the course of treatment, and the duration of treatment. 
12.8. 
Alpha Levels 
This is a safety study with only one treatment arm and therefore inferential testing will not be 
performed. 
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12.9. 
Subgroups 
Analysis of the primary and key secondary endpoints, as well as treatment-emergent AE and 
serious AE incidence, will be provided by the following subgroups: 
x Surgery type 
x Gender 
x Race 
x Age (using the study median age) 
12.10. 
Safety 
The safety analysis will be descriptive in nature.  All safety data will be listed, and data will be 
tabulated where the data warrant.  An assessment of the association between AE incidence and 
exposure will be explored. 
Safety data include: 
x AEs, including assessment of infusion site local reactions (skin and vein) 
x Clinical laboratory tests pre-treatment and discharge 
x Vital signs including: respiratory rate, heart rate, pulse oximetry temperature and 
blood pressure.   
x Physical examination pre-treatment and discharge 
x 12-lead ECG at protocol specified time points 
x Concomitant treatments 
Exploratory analyses of use of anti-emetics may be performed.  Other safety data presentations 
will be descriptive in nature and no formal statistical tests will be performed. 
12.10.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding dictionary; patient incidence of each 
system organ class and unique term will be tabulated.  AE incidence will also be tabulated 
according to relationship to study medication and severity.  Serious AEs and AEs resulting in 
premature discontinuation will be tabulated.   
Adverse events starting before the first dose of treatment will be recorded as Medical History.  
Adverse events starting after the first dose of treatment will be considered treatment-emergent 
adverse events.  
Local tolerability of the infusion site will be assessed for pain, swelling, tenderness, and 
erythema via AE’s. 
12.10.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be reviewed and coded using the WHO Drug Dictionary, 
and tabulated by treatment.  Concomitant medications will be reported in a fashion similar to that 
of AEs. 
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Avenue Therapeutics, Inc. 
 
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12.10.3. 
Clinical Laboratories 
Clinical laboratory observed values and changes from pre-treatment to on-treatment time points 
may be tabulated for continuous parameters, as warranted.   
12.10.4. 
Vital Signs 
Vital sign parameter outcomes (including SpO2) will be assessed for clinical significance; 
observed values and changes from pre-treatment to on-treatment time points may be tabulated 
for continuous parameters, as warranted.   
12.10.5. 
Physical Examination 
Physical examination outcomes will be listed in data listings.   
12.11. 
Efficacy Analyses 
PGA (Appendix 1) will be measured at Hour 24 and at the End of Treatment and summarized 
descriptively. If the patient continues treatment beyond Hour 24, PGA will be conducted at Hour 
24 and End of Treatment (total of 2 PGAs). If the patient ends treatment prior to Hour 24, PGA 
will be conducted as part of the End of Treatment visit (total of 1 PGA). 
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Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
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13. 
STUDY MONITORING, AUDITS, IRB, AND QUALITY 
13.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a Sponsor representative will 
visit the investigational study site to: 
x Determine the adequacy of the facilities 
x Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the Sponsor or its representatives.  This 
will be documented in a Clinical Study Agreement between the Sponsor (or its delegate) 
and the investigator. 
During the study, a monitor or Sponsor representative will have regular contacts with the 
investigational site, for the following: 
x Provide information and support to the investigator(s) 
x Confirm that facilities remain acceptable 
x Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRF, and that investigational product accountability checks 
are being performed 
x Perform source data verification.  This includes a comparison of the data in the eCRF 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the study.  This will require direct access to all original (or faxed/copied, if requested) 
records for each patient (e.g. clinic charts) which may include access to medical records 
for purposes of remote (i.e. not on-site at the Investigator’s clinic) source data 
verification 
x Record and report any protocol deviations not previously sent to the Sponsor (or its 
delegate) 
x Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sponsor (or its delegate) and those SAEs that met criteria 
for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
13.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, its delegate, a regulatory authority, an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements.  The 
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investigator should contact the Sponsor or its delegate immediately if contacted by a regulatory 
agency about an inspection.   
13.3. 
Institutional Review Board/ Independent Ethics Committee 
The Investigator must obtain appropriate IRB approval prior to study initiation.  A copy of the 
written approval from the IRB and a copy of the approved ICF should be sent to the Sponsor or 
its delegate.  It is also necessary to submit a list of the IRB members (including their Institution 
affiliations, gender makeup, and occupations) or supply a statement from the IRB specifying that 
the membership comply with applicable regulations. 
The study protocol, patient information and consent form, the Investigator Brochure, available 
safety information, patient recruitment procedures (e.g., advertisements), information about 
payments and compensation available to the patients and documentation evidencing the 
Investigator’s qualifications should be submitted to the IRB/Ethics Committee for ethical review 
and approval according to local regulations, prior to the study start.  The written approval should 
identify all documents reviewed by name and version. 
13.4. 
Quality Control and Quality Assurance 
The investigator is responsible for all quality control and quality assurance for the performance 
of the study. 
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14. 
ETHICS 
14.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate.  The 
investigator must submit written approval to the Sponsor or its delegate before he or she can 
enroll any patient into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The Sponsor or its delegate will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
14.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the Sponsor or its delegate’s policy on Bioethics. 
14.3. 
Written Informed Consent 
The Investigator(s) will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The patient’s signed and dated ICF and assent if applicable must be obtained before conducting 
any study procedures. 
The Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient. 
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Protocol AVE-901-104 Phase 3 Open-Label Safety Study                                Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Inspection of Records 
The Sponsor or its delegate will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, patient charts and 
study source documents, and other records relative to study conduct. 
15.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for the Sponsor, its 
delegate, or the Regulatory Authority to review any documentation relating to the study, the 
Investigator must permit access to such records. 
15.3. 
Data Capture and Processing 
Data will be captured on source documents and will be entered into an electronic data capture 
system via electronic case report forms (eCRFs) and will be processed according to a data 
management plan.  The database will be cleaned and ‘locked’ according to that data management 
plan prior to the final statistical analysis being performed. 
eCRFs will be completed for each study patient.  It is the investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data entered in each patient’s eCRF.  Source 
documentation supporting the eCRF data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, adverse events, and patient 
status.   
The investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected.  Any outstanding entries must be entered immediately after the 
final examination.  An explanation should be given for all missing data.  
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16. 
PUBLICATION POLICY 
All information concerning the product, as well as any matter concerning the operation of the 
Sponsor or its delegate, such as clinical indications for the drug, its formula, methods of 
manufacture, and other scientific data relating to it, that have been provided by the Sponsor or its 
delegate and are unpublished, are confidential and must remain the sole property of the Sponsor 
or its delegate.  The Investigator will agree to use the information only for the purposes of 
carrying out this study and for no other purpose unless prior written permission from the Sponsor 
or its delegate is obtained.  The Sponsor has full ownership of the eCRFs completed as part of 
the study. 
All publications and presentations of the results of the Study are governed by the applicable 
provisions of the Clinical Trial Agreement between the Sponsor (or its delegate) and the 
institution.  By signing the study protocol, the investigator agrees that the results of the study 
may be used for the purposes of national and international registration, publication, and 
information for medical and pharmaceutical professionals by the Sponsor or its delegate.  If 
necessary, the authorities will be notified of the Investigator’s name, address, qualifications, and 
extent of involvement.  The Investigator may not publish or present any information on this 
study without the express written approval of the Sponsor or its delegate.  Additionally, the 
Sponsor or its delegate may, for any reason, withhold approval for publication or presentation.  
Such manuscript or materials should be provided for Sponsor/delegate review only after the final 
database, which has been approved by Quality Assurance, is available. 
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17. 
LIST OF REFERENCES 
Collart L, Luthy C, Dayer P. Partial inhibition of tramadol antinociceptive effect by naloxone in 
man [Abstract]. Proc Br Pharmacol Soc. 1992 Sep 9-11, Queen Mary and Westfield College, 
Univ of London, p73P. 
Gillen C, Haurand M, Kobelt DJ, Wendt S. Affinity, potency and efficacy of tramadol and its 
metabolites at the cloned human μ-opioid receptor. Naunyn-Schmiedeberg's Arch Pharmacol. 
2000;362:116–121. 
Grond S and Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43:879-
923. 
Liao S, Hill JF, Nayak RK. Pharmacokinetics of tramadol following single and multiple oral 
doses in man [Abstract Number PPDM 8206]. Pharm Res. 1992;9 Suppl Oct:S308. 
Lintz W, Barth H, Osterloh G, Schmidt-Böthelt E. Bioavailability of enteral tramadol 
formulations. 1st communication: capsules. Arzneim.-Forsch/Drug Res. 1986;36:1278 1283. 
Matthiesen T et al. The experimental toxicology of tramadol: an overview. Toxicol Lett. 
1998;95:64-71. 
Raffa RB. Basic pharmacology relevant to drug abuse assessment: tramadol as example. J Clin 
Pharm Ther. 2008;33:101–108. 
Raimundo JM et al. In vitro and in vivo vasodilator activity of racemic tramadol and its 
enantiomers in Wistar rats. Eur J Pharmaco.l 2006;530:117-123. 
Rosenberg MT. The role of tramadol ER in the treatment of chronic pain. Int J Clin Pract. 
2009;63(10):1531-1543. 
Rubin DB.  Inference and Missing Data.  Biometrika 63 (3): 581-592.  1976.  
Schafer J., Imputation of missing covariates under a multivariate linear mixed model. Technical 
report 1997: 1-21 (http://sites.stat.psu.edu/reports/1997/tr9704.pdf1997) 
Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs. 2000 
Jul;60(1):139-76. 
Sinatra RS, Torres J, Bustos AM. Pain management after major orthopedic surgery: Current 
strategies and new concepts. J Am Acad Orthop Surg. 2002;10:117-129. 
Ultram® Full Prescribing Information, Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, 
NJ. Approved by FDA September 9, 2009. 
Yamamoto H et al. A study of teratogenicity of both CG-315 and morphine in mice and rats. 
Pharmacometrics. 1972;6:1055-1069. 
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18. 
APPENDIX 
Patient Global Assessment (PGA) 
Instructions to Study Subject: Please respond to the question below.  When completed, please 
initial at the bottom of the assessment. 
 
How would you rate the study medication in terms of its effectiveness in controlling your 
pain? 
(Please mark an ‘X’ in one box) 
 
  Poor (0) 
 
  Fair (1) 
 
  Good (2) 
 
  Very Good (3) 
 
  Excellent (4) 
 
 
Subject Initials: __________ 
 
 
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SAP_001.pdf: 
Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 1 of 43 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A PHASE 3, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE SAFETY OF 
TRAMADOL INFUSION (AVE-901) IN THE 
MANAGEMENT OF POSTOPERATIVE PAIN 
FOLLOWING SURGERY 
PROTOCOL AVE-901-104 
Protocol Version 1.0 (11DEC2017) 
 
SPONSORED BY 
Avenue Therapeutics, Inc. 
New York, NY 10014 
PREPARED BY 
Lotus Clinical Research®, LLC 
100 W California Blvd, Unit 25 
Pasadena, CA 91105 
626-397-2390 office 
info@LotusCR.com 
www.LotusCR.com 
 
This document is confidential and proprietary to Avenue Therapeutics, Inc.  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein 
will be reproduced, published, or otherwise disclosed without the prior written approval of Avenue 
Therapeutics, Inc., except that this document may be disclosed to appropriate Institutional Review 
Boards under the condition that they keep the information confidential. 
 
 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 2 of 43 
 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
v0.1 
07SEP2018 
For Statistical Review 
v0.2 
12OCT2018 
Update per sponsor feedback 
v0.3 
12DEC2018 
Update per sponsor feedback 
v1.0 
07FEB2019 
Update per sponsor feedback 
 
 
 
 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
Tramadol Infusion
Avenue Therapeutics, Inc. 
  07FEB2019
CONFIDENTIAL 
Page 3 of 43
APPROVALS 
Author: 
 
 
 
 
 
 
 
 
 
Song Liou 
Biostatistician 
Lotus Clinical Research®, LLC 
 
Date 
 
 
 
 
Reviewed: 
 
 
 
 
 
 
 
 
 
Jennifer Nezzer 
Director, Biometrics 
Lotus Clinical Research®, LLC 
 
Date 
 
 
 
 
Approved: 
 
 
 
 
 
 
 
 
 
Michael Ryan 
Vice President 
Avenue Therapeutics, Inc. 
 
Date 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C
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Protocol AVE-901-104 Phase 3 Open-Label 
Tramadol Infusion
Avenue Therapeutics, Inc. 
  07FEB2019
CONFIDENTIAL 
Page 4 of 43
APPROVALS 
Approved: 
(cont.) 
 
 
 
 
 
 
 
 
 
Scott Reines  
Chief Medical Officer 
Avenue Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
Lucy Lu 
Chief Executive Officer 
Avenue Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
Mark Harnett 
Tramadol Program Biostatistician 
Avenue Therapeutics, Inc. 
 
Date 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C
	
	
	


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 5 of 43 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PURPOSE OF THE ANALYSES ................................................................................9 
2. 
PROTOCOL SUMMARY ..........................................................................................10 
2.1. 
Study Objectives .........................................................................................................10 
2.1.1. 
Primary Objective .......................................................................................................10 
2.2. 
Overall Study Design and Plan ...................................................................................10 
2.3. 
Description of Study Periods ......................................................................................10 
2.3.1. 
Screening ....................................................................................................................11 
2.3.2. 
Preoperative ................................................................................................................11 
2.3.3. 
Surgery ........................................................................................................................11 
2.3.4. 
Treatment Period/ Post Surgery ..................................................................................11 
2.3.5. 
Follow up: ...................................................................................................................12 
2.4. 
Study Population .........................................................................................................12 
2.5. 
Treatment Regimens ...................................................................................................12 
2.5.1. 
Study Material ............................................................................................................12 
2.5.2. 
Comparator Group ......................................................................................................12 
2.6. 
Treatment Assignment and Randomization ................................................................13 
2.7. 
Sample Size Determination ........................................................................................13 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................14 
4. 
PATIENT SUMMARIES ...........................................................................................16 
4.1. 
Analysis Populations ..................................................................................................16 
4.2. 
Disposition of Patients ................................................................................................16 
4.3. 
Protocol Deviations ....................................................................................................16 
5. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................18 
5.1. 
Demographics and Baseline Characteristics ...............................................................18 
5.2. 
Medical History ..........................................................................................................18 
5.3. 
Prior and Concomitant Medications ...........................................................................18 
6. 
MEASUREMENTS OF TREATMENT EXPOSURE ...............................................20 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 6 of 43 
 
7. 
OVERVIEW OF ANALYSIS ISSUES ......................................................................21 
7.1. 
Handling of Dropouts or Missing Data ......................................................................21 
7.2. 
Assessment Time Windows ........................................................................................21 
8. 
EFFICACY EVALUATION ......................................................................................22 
8.1. 
Efficacy Outcome .......................................................................................................22 
9. 
SAFETY EVALUATION ..........................................................................................23 
9.1. 
Overview of Safety Analysis Methods .......................................................................23 
9.2. 
Adverse Events ...........................................................................................................23 
9.2.1. 
Subgroups ...................................................................................................................27 
9.3. 
Deaths and Serious Adverse Events ...........................................................................27 
9.4. 
Clinical Laboratory Evaluation ...................................................................................27 
9.5. 
Vital Signs ..................................................................................................................29 
9.6. 
Physical Examination .................................................................................................30 
9.7. 
ECG Examinations .....................................................................................................30 
10. 
PHARMACOKINETIC EVALUATION ...................................................................32 
11. 
INTERIM ANALYSES AND DATA MONITORING .............................................33 
12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................34 
13. 
REFERENCES ...........................................................................................................35 
14. 
APPENDICES ............................................................................................................36 
14.1. 
Tables, Figures and Listings for Final Study Report ..................................................36 
14.1.1. 
Tables ..........................................................................................................................37 
14.1.2. 
Figures ........................................................................................................................41 
14.1.3. 
Listings .......................................................................................................................42 
15. 
DOCUMENT HISTORY ...........................................................................................43 
 
 
 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 7 of 43 
 
 
 
LIST OF TABLES 
Table 1: 
Protocol-Specified Visits and Visit Windows (Study AVE-901-104) .......................12 
Table 2: 
Table of Imputation Rules for Missing AE Start Date Times (Study AVE-
901-104) ......................................................................................................................26 
Table 3: 
List of Potentially Clinically Significant Ranges for Clinical Laboratory 
Parameters (Study AVE-901-104) ..............................................................................28 
Table 4: 
List of Potentially Clinically Significant Ranges for Vital Sign Parameters 
(Study AVE-901-104) ................................................................................................29 
Table 5: 
List of Potentially Clinically Significant Ranges for ECG Parameters (Study 
AVE-901-104) ............................................................................................................30 
 
 
 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 8 of 43 
 
 
LIST OF ABBREVIATIONS 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ASA 
American Society of Anesthesiologists 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CDER 
Center for Drug Evaluation and Research 
eCRF 
Electronic Case Report Form 
CSR 
Clinical Study Report  
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonization  
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
Potential Clinically Significant 
PE 
Physical Exam 
PGA 
Patient Global Assessment 
PT 
Preferred Term 
SAE 
Serious Adverse Event/Experience 
SAP 
Statistical Analysis Plan 
SDTM  
Standard Data Table Model 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 9 of 43 
 
1. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number AVE-901-104 Amendment 1.0 
(29AUG2018) from Avenue Therapeutics, Inc.  The SAP will be signed off before the final 
database lock.  The SAP contains detailed information to aid in the performance of the statistical 
analysis and reporting of the study data for use in the final clinical study report (CSR).  This SAP 
is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical Principles for Clinical Trials, the most recent ICH E3 Guideline and the Guidance for 
Industry: Structure and Content of Clinical Study and the most recent FDA draft Guidance for 
Industry - Analgesic Indications: Developing Drug and Biological Products, dated February 
2014. 
This SAP describes the data sets that will be analyzed and the patient characteristics, safety, and 
efficacy assessments that will be evaluated.  This SAP provides details of the specific statistical 
methods that will be used.  If additional analyses are performed after database lock to 
supplement the planned analyses described in this SAP, they will be completed and will be 
clearly identified as post-hoc in the CSR. 
 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 10 of 43 
 
2. 
PROTOCOL SUMMARY 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety of intravenous (IV) tramadol (AVE-
901) 50 mg for the management of postoperative pain.  
Safety endpoints will include 
x Adverse event (classified by the Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class (SOC) and preferred term (PT)). 
x Clinical laboratory, vital sign, and electrocardiogram (ECG) changes.  
x Local tolerability of the infusion site via pain, swelling, tenderness, and erythema.  
2.2. 
Overall Study Design and Plan 
This study is a Phase 3, multicenter, single-arm, open-label, repeat-dose trial to assess the safety 
of AVE-901 in the management of postoperative pain. Eligible patients will be patients that are 
undergoing elective surgery and are willing to be confined in a healthcare facility and receive 
AVE-901 for the treatment of post-surgical pain for at least 24 hours.  Approximately 250 
patients will be enrolled into the study. Each patient will undergo the Screening Visit (Day -28 to 
Day -1), the Pre-operative assessment (within 24 hours prior to surgery), the Surgery (Day 0), the 
Primary treatment period (hour 0 through hour 168), end of treatment (EOT) visit, and the 
Follow-up Visit (Day 14).  
Screening will occur up to 28 days prior to surgery.  Following the pre-operative assessments, 
after the patient has met eligibility criteria, patients will be enrolled into the study. 
Surgery will occur on Day 0.  There are no restrictions on the agents to be used for induction, 
neuromuscular blockade, maintenance of anesthesia, or on hypnotics, sedatives, analgesics 
(including narcotics) or anxiolytics. 
Following surgery, each patient will receive their study medication infusion at T0, T2, T4, and 
then every 4 hours for up to 168 hours after the first study drug administration (a total of up to 43 
doses per patient).  The dosing time point will always be defined relative to T0 for all doses.  The 
latest (last) dose that is allowed is at Hour 164.  Patients will be confined at an appropriate 
healthcare or research facility for as long as they are still using AVE-901. Following the first 
dose of study drug, the patients will be allowed to use non-opioid-based analgesics per treating 
physician’s discretion, if additional pain relief is required. 
2.3. 
Description of Study Periods  
There are 5 periods in this study:  Screening, Preoperative, Surgery, Treatment Period/Post 
Surgery, and Follow-up.  Procedures for each study period are described below. 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 11 of 43 
 
2.3.1. 
Screening 
Screening will occur from Day -28 through Day -1 and will be conducted as a clinic visit. 
Patients will have the purpose and procedures of the study explained to them and, those who 
elect to participate in the study, will provide written informed consent and be screened for 
participation according to the eligibility criteria. Screening will include eligibility assessment, 
medical history, physical examination (PE), demographics, height and weight, body mass index 
(BMI), vital signs (heart rate, systolic blood pressure (BP), and diastolic BP, respiratory rate, 
temperature, pulse oximetry), American Society of Anesthesiologists (ASA) Physical Status, 12-
lead ECG, hematology panel, chemistry panel, urinalysis, serum pregnancy test (in females of 
childbearing potential), and prior/current treatments.  All screening laboratory evaluations must 
be within acceptable limits as determined by the investigator prior to enrollment.  For patients 
that screen within 5 days of surgery, central laboratory values may not be available to assess 
eligibility.  For these patients it is acceptable for sites to draw local labs to assess eligibility in 
addition to the central lab which will still be used as the baseline in the study.  The local 
laboratory listed on the FDA 1572 Form must be used for all local blood draws. At a minimum 
the following analytes must be reviewed from the local laboratory prior to dosing; magnesium, 
calcium, potassium, sodium, serum creatinine, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) and hemoglobin. 
2.3.2. 
Preoperative 
Preoperative assessments to confirm the patient’s eligibility will be performed within 24 hours of 
scheduled surgery start time.  This visit will include reassessment of eligibility criteria, interim 
medical history, vital signs, PE, ASA Physical Status, urine pregnancy test (in females of 
childbearing potential), and concomitant treatments.     
Note: If the patient’s scheduled surgery has time considerations, patients may have Screening 
and Preoperative Visits combined into one visit if required (at the time of pre-op).  The 
procedures associated with the Screening Visit will be acceptable for both visits. Both central 
and local labs should be drawn for eligibility 
2.3.3. 
Surgery  
Surgery will occur on Day 0.  Sites will follow their standard operating procedures. 
2.3.4. 
Treatment Period/ Post Surgery 
Patients will receive their first dose of study medication (T0) within 8 hours of meeting the 
postsurgical eligibility criteria. Patients will be dosed at Hour T0, T2, T4, and then every 4 hours 
thereafter, for a total of up to 43 doses administered over the 168-hour treatment period (with the 
last possible dose at Hour 164).  Treatment is anticipated to occur from Hours 0 to 48 and may 
extend through to Hour 168.  
Safety will be assessed by recording vital signs including: ECG’s, respiratory rate, heart rate, 
pulse oximetry (SpO2), temperature, and BP as per the schedule of events. 
A PGA will be obtained at Hour 24 and EOT. If the patient continues treatment beyond Hour 24, 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 12 of 43 
 
PGA will be conducted at Hour 24 and EOT (total of 2 PGAs). If the patient ends treatment prior 
to Hour 24, PGA will be conducted as part of the EOT visit (total of 1 PGA).  
At the EOT assessment, patients will undergo a brief PE, vital signs measurements, ECG, PGA 
and clinical laboratory evaluations for safety. AEs and concomitant medication use will be 
recorded. 
2.3.5. 
Follow up: 
A final safety assessment will be conducted on Day 14 (± 2 days) from the first dose via a 
telephone call to check on general well-being, including spontaneous reports of adverse events 
and concomitant medications. 
The protocol-defined visits are presented in Table 1. 
Table 1: 
Protocol-Specified Visits and Visit Windows (Study AVE-901-104) 
Study Phase 
Visit Time 
Screening 
From days -28 to -1 
Pre-Operative 
0 - 24 Hours prior to surgery 
Surgery 
Day 0 
Treatment Period /Post Surgery  
Hours 0 up to Hour 168 after infusion of first study drug 
administration 
Follow-up 
Day 14 (approximately Day 14±2 days) 
2.4. 
Study Population 
Approximately 250 patients in United States (US) who meet all the inclusion and none of the 
exclusion criteria (Described in Sections 7.1, 7.2 and 7.2.1 of Protocol) are planned to be 
enrolled.  Every patient treated will receive AVE-901.  
2.5. 
Treatment Regimens 
2.5.1. 
Study Material 
AVE-901, 50 mg. Assigned study treatment (51 mL) doses will be administered IV over 15 
minutes (+/- 4 minutes) via infusion pump.  
All patients will receive tramadol infusion per the treatment dosing regimen. A trained health 
care professional will flush the line with normal saline at the end of each infusion. Throughout 
the SAP, AVE-901 will be used to indicate the study treatment. 
2.5.2. 
Comparator Group 
NA as this is a single arm study. 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 13 of 43 
 
2.6. 
Treatment Assignment and Randomization 
No randomization will be utilized in this study. 
2.7. 
Sample Size Determination 
A sample size of approximately 250 patients will be enrolled.  This sample size of 250 patients 
will provide approximately 90% power to detect at least one incidence of uncommon adverse 
events (those events with a true underlying incidence of 1%).   
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 14 of 43 
 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study.  Departures from these general policies are provided in the specific detailed 
sections of this SAP.  When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
All continuous study assessments will be summarized by time point (as applicable) using the 
descriptive statistics n, mean, SD, median, and range (minimum, and maximum).  All of the 
categorical study assessments will be summarized by time point (as applicable) using frequency 
counts and rates of occurrence (%).   
The treatment group will be labeled as ‘Tramadol 50 mg’ for all outputs. All study data will be 
listed by study center, patient, and time point (as applicable).   
No preliminary rounding will be performed; rounding will only occur after the analysis.  To 
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then round up.  Means and medians will be presented with one more decimal place than the 
precision of the raw data.  Standard deviations will be presented with two more decimal places 
than the precision of the raw data.  Percentages will be presented with one decimal place.  
Minimums and maximums will be presented with the same precision as the original data. 
All analyses will be performed using the SAS System® version 9.3 or higher.  The domain 
(Study data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets 
will be taken as input to the SAS programs that generate the report-ready tables, figures and 
listings.  The submission ready SDTM and ADaM data sets will be provided to the sponsor along 
with display deliveries.   
The following conventions will be used throughout the study analysis: 
x Time T0 is the time of start of the first study drug administration.  
x Study Day is defined as (Date of Assessment minus Date of First Dose of Study 
Medication).  The first day of dosing is Study Day 0.  The day immediately prior to 
first dose is Study Day -1.  Study Day will be calculated for every record in the 
database and presented alongside the date fields in the data listings, where applicable.  
For instance, the start date of each TEAE will also have the Start Day presented in the 
listings. 
x Assessment and visit times are defined relative to time T0.  
x Baseline value is defined as the last valid measurement prior to the first treatment 
administration. 
x Change from baseline is defined as post-baseline value minus baseline value. 
x Unscheduled visits and measurements will be included in subject listings but will not 
be used in analyses. 
DocuSign Envelope ID: 0709CFD0-5808-479E-B07C-DD202170566C


Protocol AVE-901-104 Phase 3 Open-Label 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
  07FEB2019 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
Page 15 of 43 
 
x If duplicate values are obtained at a given visit (e.g., lab assay is repeated on a sample 
resulting in two results, or vital sign repeated during a visit), the last reported value 
will be used unless it is noted that the measurement was in error for that value. 
x Values that compromise interpretation will not be used in summaries (e.g., values that 
were obtained post-dose will not be summarized as pre-dose values). 
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4. 
PATIENT SUMMARIES 
4.1. 
Analysis Populations 
Three population are identified for purposes of the statistical analysis:  
x Screened Population, defined as all screened patients. 
x Screened Not Treated, defined as the subset of patients who are screened but not 
treated due to not moving forward to surgery or not meeting post-surgical dosing 
criteria.   
x The Safety Population is defined as all patients who receive study medication.  
Patients will be analyzed according to the actual treatment they receive.  
In general, data listings will include only subjects who receive study treatment (Safety 
population).  
4.2. 
Disposition of Patients 
Disposition of all patients screened will be tabulated.  The Inclusion/Exclusion criteria failed for 
screen failures will be presented.  The denominator will be based on all screened patients. 
Patient completion status (completer, screen failure, or post-op failure) and reasons for study 
completion will be tabulated descriptively in a patient disposition summary table. Reasons for 
study completion include: 
x Dosing Completed (patient discharged and did not stop dosing for the other items listed 
below) 
x Adverse Event 
x Lost to Follow-Up 
x Death 
x Protocol Violation 
x Subject Non-compliance or uncooperativeness 
x Withdrawal of Consent 
x Other 
The number of days in the study will also be summarized. The number of days is computed as: 
[Date of study completion (i.e., date of discharge) or withdrawal minus the date of first treatment 
administration (Day 1)] + 1.    
All patient disposition data will be presented in listings.   
4.3. 
Protocol Deviations 
Protocol deviations will be documented in the electronic case report from (eCRF), categorized 
according to type of deviation (e.g., out of window, etc.) and classified as major or minor by the 
Sponsor’s medical monitor.  Protocol deviations, both minor and major, will be presented in a 
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data listing and major violations will be summarized by category of deviation and classification.  
A listing describing patients excluded from the Per Protocol Population will be provided. 
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5. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Demographic variables include age, sex, race, and ethnicity.  Baseline characteristics include 
American Society of Anesthesiologists (ASA) physical status, previous opioid history (Y/N), 
height, weight (kg) and BMI (kg/m2).  Demographics and baseline characteristics will be 
presented in by-patient listings and summarized. 
5.2. 
Medical History 
Medical history, as collected at screening and prior to surgery, will be presented in a by-patient 
listing and summarized by body system.  
5.3. 
Prior and Concomitant Medications 
Prior and concomitant medications are collected at screening and updated throughout the study 
as needed.  Prior and concomitant medications will be coded using WHODDE (C Format) 
version 01SEP2017.  The number and percentage of patients who take concomitant medications 
will be summarized by drug class (Anatomical Therapeutic Chemical (ATC) Level 3) and PT for 
the safety population and presented in a by-patient listing. 
Prior medications, including medications given during surgery, and non-medical therapies will 
appear in a data listing but will not be summarized.  
Medications will be classified as follows: 
x Prior medications.  Prior medications/therapies are those that have a start date/time 
and end date/time prior to the start of the first treatment administration. Prior 
medications will not be tabulated but will be included in the data listings. 
x Concomitant medications.  Medications will be considered as concomitant if the 
medication is taken on or after the date/time of first intake of treatment product and 
has a start date/time that is no later than 1 day (24 hours) after the start of the last 
administration of study medication.   
x New-onset concomitant medications are defined as those medications starting 
between the start of the first dose of study medication and 1 day (24 hours) after the 
start of the last dose of study medication.  Medications with no start time but starting 
on the day of study medication will be assumed to be new-onset. 
x Post-treatment medications.  Post-treatment medications are defined as a medication 
with a start date/time at least 24 hours (1 day) after the start of the last dose of study 
medication. 
If a missing medication start date cannot be definitively determined as having started after first 
dose, the medication will be considered as started prior to first dose; similarly, if a missing 
medication stop date/time cannot be determined as having stopped prior to first dose, the 
medication will be considered concomitant (taken after first dose).  Imputation of missing start 
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and stop date/times will be performed in the same manner as described for AEs in Table 2. 
Medications with entirely missing start and stop dates will be listed but not included in the 
tabulations. 
 
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6. 
MEASUREMENTS OF TREATMENT EXPOSURE 
Patient dosing data will be listed and the number of doses per subject and total exposure (mg) per 
subject will be tabulated.  If less than the complete volume of study medication is infused, total 
exposure will be calculated as the intended dosage (50mg) times the proportion of total saline 
volume infused (xx mL / 50 mL). 
x The duration of exposure will be defined in hours, in which the time from the start of 
the first dose to start of the last dose, plus 4 hours (i.e., exposure is assumed to be 4 
hours for each dose), will be tabulated. 
x The number (%) of patients by number of doses received will be presented.  The 
maximum total number of doses is 43. 
x The total exposure (mg) will be summarized through 24, 48, 72, 96, 120, 144 and 164 
hours, respectively.  Maximum exposure is 2150 mg (given at Hours 0, 2, 4, and then 
4 hours up to 164). 
x If infusion end time is not available, the end time will be imputed as 15 minutes after 
the infusion start time for use in calculations dependent upon the end time.  
In addition, cumulative percent of subjects (%) versus total study drug exposure will be provided 
graphically. 
 
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7. 
OVERVIEW OF ANALYSIS ISSUES 
No inferential testing is planned for this safety-based single arm study. 
7.1. 
Handling of Dropouts or Missing Data  
No study outcomes will be imputed. 
7.2. 
Assessment Time Windows 
Summaries will be based on the nominal protocol-specified visits as appropriate. 
 
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8. 
EFFICACY EVALUATION 
The primary objective of this study is to evaluate the safety of AVE-901. Efficacy is considered 
a secondary, exploratory, given that this is an uncontrolled study in patients with various surgery 
types. Efficacy will be assessed by patient global assessments (PGAs) using a 5-point scale. 
8.1. 
Efficacy Outcome 
Patient Global Assessment of efficacy will be collected at 24 hours post first dose and EOT.  The 
question to be posed is “How would you rate the study medication in terms of its effectiveness in 
controlling your pain?” (0=poor; 1=fair; 2=good; 3=very good; 4=excellent). If the patient 
continues treatment beyond Hour 24, PGA will be conducted at Hour 24 and EOT (total of 2 
PGAs). If the patient ends treatment prior to Hour 24, PGA will be conducted as part of the EOT 
visit (total of 1 PGA). 
The PGA results will be presented in a summary table by time point.  The number (%) of 
subjects answering in each category will also be presented by time point.  
Individual PGA scores will be listed 
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9. 
SAFETY EVALUATION 
9.1. 
Overview of Safety Analysis Methods 
The safety analysis will be descriptive in nature.  All safety data will be listed, and data will be 
tabulated where the data warrant.  Safety data include: 
x AEs, including assessment of infusion site local reactions (skin and vein) 
x Clinical laboratory tests (hematology panel, chemistry panel and urinalysis) pre-
treatment and discharge 
x Vital signs including: respiratory rate, heart rate, oral temperature, pulse oximetry 
(SpO2) and BP, as per the schedule of events  
x PE at pre-treatment and discharge 
x 12-lead ECG at protocol specified time points 
x Concomitant treatments 
Anti-emetic usage data will be included with the concomitant treatments.  Exploratory analyses 
of use of anti-emetics may be performed if warranted.  Other safety data presentations will be 
descriptive in nature and no formal statistical tests will be performed.  
ECG results will be analyzed on an ongoing basis by a central ECG reader on an individual 
patient level. 
9.2. 
Adverse Events 
Any events starting before the first dose of treatment will be reported as Medical History.  
Verbatim terms used by investigators to identify AEs in the CRFs will be mapped to the 
appropriate PT and SOC using a standardized coding dictionary (MedDRA Version 20.1).  All 
coding will be reviewed prior to database lock.  All recorded AEs will be listed; adverse events 
starting on or after the first dose of treatment are considered treatment-emergent adverse events 
as per the protocol, but the definition of treatment emergent will be further categorized for 
summaries as follows: 
x Adverse events occurring on or after the first dose of study medication, and within 1 
day (up to 24 hours) after the start of the last dose of study medication. For simplicity, 
these will be referred to as Treatment Emergent AEs (TEAEs) in the summaries. 
x Events occurring after that will be presented as Post-Treatment AEs. 
Separate tabulations will be presented for TEAEs and for Post-Treatment AEs. 
For evaluation of causal relatedness to treatment, the categories are definite, probable, possible, 
remote or definitely not.  For categorization in the summary tables, AEs designated as definite, 
probable, or possible will be considered to be related. 
For the evaluation of event severity, the criteria are based on National Cancer Institute Common 
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Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03:   
 
CTC Grade 
CTCAE Grade Description 
Grade 1: Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
Grade 2: Moderate 
Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL1. 
Grade 3: Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL2. 
Grade 4: Life-threatening Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death 
Death related to the AE. 
1 ADL = Activities of Daily Living. Instrumental ADL refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
2 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Local tolerability at the infusion site will be assessed for pain, swelling, tenderness, and 
erythema.  Any such AEs related to tolerability at the infusion site will be identified by the 
sponsor and medical monitor for listing and possible summarization.  
In addition to a listing of all TEAEs, treatment related TEAEs, serious TEAEs, TEAEs leading to 
premature discontinuation from the study, and TEAEs related to local tolerability at the infusion 
site will be provided. 
An overall summary will be prepared including both the number of TEAEs, and the number of 
patients with TEAEs, as well as SAEs, treatment related TEAEs, TEAEs by severity and TEAEs 
leading to premature discontinuation from study.  
Incidence of TEAEs will be summarized by SOC and PT sorted in descending frequency by 
SOC, and then by PT within SOC.  These summaries will be given in separate tables for each of 
the following TEAE event sets: 
x All events (Post-Treatment AEs will be tabulated separately) 
x Treatment related events (defined by a relationship to study drug of possible, 
probable, or definite). (Post-Treatment AEs will be tabulated separately) 
x Events leading to premature discontinuation from study 
x Events related to local tolerability at the infusion site 
x Events by maximum severity 
If a given patient experiences a TEAE that maps to the same PT more than once, the patient will 
be counted once for the PT at its greatest severity (i.e., mild, moderate, or severe) and causality 
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(i.e., attribution to study material).   
TEAEs occurring within 1 hour of any infusion will be summarized. 
The number/ percentages of subjects with any TEAE will also be presented by Infusion #.   Each 
AE will be matched to an Infusion # by the start date/time of the AE (after all imputation for 
missing dates).  E.g., An AE with start date/time on or after the start date/time of Infusion #3 and 
prior to start date/time of Infusion #4, will be counted under Infusion #3.  Percentages will be 
calculated from the number of subjects receiving the referenced injection (i.e., Subjects receiving 
4 injections will be counted in the denominator for Infusion #1, #2, #3 and #4, and will not be 
included in the denominator for other Infusions).  
Duration of a TEAE will be computed in days as the stop date of the event minus the start date 
plus 1. If reported as ongoing at the time of database lock, the duration of the AE will be 
calculated using the date/time of the last visit or the last date of any adverse event for the patient 
in the database, whichever is later.  If a TEAE is considered resolved, but the stop date is 
missing, the last day of the month will be imputed if the month and year are available. If only the 
year is available, and the year is the same as the year of the last visit, the stop date will be 
imputed as the latest of the last visit date or latest event for the patient in the database.  If the 
year of the event is prior to the year of the last treatment, the end day and month will be imputed 
as 31 December. 
For missing or partial start dates, they will be imputed as temporally related to the first dose of 
study medication. Table 2 demonstrates the rules to be used to impute any missing AE start 
dates. 
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Table 2: 
Table of Imputation Rules for Missing AE Start Date Times (Study AVE-
901-104) 
Missing Start Date 
Portion 
Prior to 
Treatment 
Same as 
Treatment Start 
Date 
After Treatment Start 
Date 
Day 
Month and Year < 
Month and Year of first 
treatment: 
 
Start Day = 1 
Stop Day = last day of 
the month 
Month and Year = 
Month and Year of 
first treatment: 
 
Start Day = Day of 
first treatment 
Stop Day= last 
day of the month 
Month and Year > 
Month and Year of 
First Treatment: 
 
Start Day = 1  
Stop Day= last day of 
the month 
Day and Month 
Define Day as 
above, then: 
Year < Year of first 
treatment: 
 
Start Month = July 
Stop Month = Dec 
Year = Year of 
first treatment: 
 
Start Month = 
Month of first 
treatment 
Stop Month = Dec 
Year > Year of first 
treatment: 
 
Month = January 
Stop Month = Dec 
Day, Month, and 
Year 
 
To be conservative, completely missing start dates will be set to the date 
of first treatment, completely missing end dates will be set to the date of 
last contact. 
Time 
Missing start times will be imputed as 00:01 (or the start time of the first 
dose administration if AE occurred on the date of first dose 
administration) 
Missing stop times will be imputed as 23:59  
 
 
After following these imputation rules, if the start date/time is imputed as a date after the end 
date/time, the start date/time will be set to the end date/time to provide a positive duration for the 
event incidence.   
Missing assessments for AE study medication relationship or severity will be analyzed as related 
or severe respectively.  No other imputation is planned for safety data. 
 
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9.2.1. 
Subgroups 
Descriptive analysis of treatment-emergent AEs (TEAEs), serious adverse events (SAEs), and 
discontinuations due to AEs, will be provided by the following subgroups: 
x Gender (male versus female) 
x Race (White versus non-White) 
x $JHXVLQJWKHVWXG\PHGLDQDJHOHVVRUHTXDOWRPHGLDQDJHJURXSYHUVXV
greater than (>) median age group) 
x Age (<65 vs >=65 years) 
x BMI (> versus <= median value) 
x Surgery Type (Orthopedic versus soft tissue) 
9.3. 
Deaths and Serious Adverse Events  
A serious adverse event is an AE occurring during the study that fulfills one or more of the 
following: 
x Results in death 
x It is immediately life-threatening 
x It requires in-patient hospitalization or prolongation of existing hospitalization 
x It results in persistent or significant disability or incapacity 
x Results in a congenital abnormality or birth defect 
x It is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
Serious adverse events and deaths will be listed and summarized separately for the safety 
population. 
9.4. 
Clinical Laboratory Evaluation 
 
Clinical laboratory test results (blood chemistry, hematology and urinalysis) will be listed for 
individual patients.  Baseline for clinical laboratory parameters will be defined as the last 
evaluation before dosing with study treatment. For each individual lab test value, results and 
change from baseline will be summarized by time point (baseline and at discharge).   
The number and percent of patients with potentially clinically significant (PCS) values will be 
summarized.  Only new-onset PCS values, i.e., patients with pre-existing PCS values at pre-
treatment will not be considered to have new-onset values on-treatment.  The criteria used to 
identify potentially clinically significant laboratory values are listed in Table 3. 
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Table 3: 
List of Potentially Clinically Significant Ranges for Clinical Laboratory 
Parameters (Study AVE-901-104) 
Variable Name (Normal Range) 
Low  
High 
Hematology 
 
 
White Blood Cells  (NR: 3.7 - 11.0x K/cu /mm) 
d2.8 x 103 /mm3 
t16 x 103 /mm3 
Neutrophils  (NR: 46 - 72%) 
d 15% 
NA 
Lymphocytes  (NR: 14 - 46%) 
NA 
t75% 
Monocytes  (NR: 0 - 11%) 
NA 
t15% 
Eosinophils  (NR: 0 - 7%) 
NA 
t10% 
Basophils  (NR: 0 - 3%) 
NA 
t10% 
Red Blood Cells 
 Female:  (NR: 3.8 - 5.1 x 106 /mm3) 
 Male:  (NR: 4.1 - 5.6 x 106 /mm3) 
 
d3 x 106 /mm3 
d3.5 x 106 /mm3 
 
t6 x 106 /mm3 
t6.5 x 106 /mm3 
Hematocrit 
 Female:  (NR: 36.4 – 48.9%)  
 Male:  (NR: 41.6 – 54.1%) 
 
d32% 
d37% 
 
NA 
NA 
Hemoglobin 
 Female:  (NR: 11.5 – 16.0 g/dL) 
 Male:  (NR: 13.0 – 17.5 g/dL) 
 
d9.5 g/dL 
d11.5 g/dL 
 
NA 
NA 
Platelets  (NR: 125 - 375 K/cu /mm) 
d75 x 103 /mm3 
t700 x 103 /mm3 
Serum Chemistry 
 
 
Total protein  (NR: 6.0 - 8.0 g/dL) 
d4.0 g/dL 
t10 g/dL 
Albumin  (NR: 3.5 - 5.5 g/dL) 
d2.0 g/dL  
NA 
Creatinine    (NR: 0.7 - 1.4 mg/dL) 
NA 
t2 mg/dL 
    BUN  (NR: 5 - 20 mg/dL) 
NA 
t30 mg/dL 
    Uric Acid: (NR: 2.0 - 6.0 mg/dL 
NA 
t9.0 mg/dL 
Bilirubin total (NR: 0.1 – 1.1 mg/dL)   
NA 
t2.5 mg/dL 
Bilirubin direct  (NR: 0 - 0.4 mg/dL) 
NA 
t0.6 mg/dL 
Alkaline phosphatase  (NR: 30 - 115 U/L) 
NA 
t390 IU/L 
AST/SGOT 
NA 
150 U/L 
ALT/SGPT  
NA 
165 U/L 
CPK   (NR: 24 - 169 U/L)  
NA 
t702 IU/L 
Glucose random  (NR: 60 - 115 mg/dL) 
d40 mg/dL 
t250 mg/dL 
Calcium  (NR: 8.5 - 10.5 mg/dL) 
d8.0 mg/dL 
t12 mg/dL 
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Variable Name (Normal Range) 
Low  
High 
Phosphorous   (NR: 2.5 - 4.5 mg/dL) 
d1.7 mg/dL 
NA 
Sodium  (NR: 133 - 145 mEq/L) 
d126 mEq/L 
t156 mEq/L 
Potassium  (NR: 3.5 - 5.0 mEq/L) 
d3 mEq/ 
t6 mEq/L 
Chloride  (NR: 95 - 110 mEq/L) 
d90 mEq/L 
t118 mEq/L 
Bicarbonate  (CO2) (NR: 21 - 33 mEq/L) 
d19 mEq/L 
t35 mEq/L 
Urinalysis 
 
 
Specific gravity  (NR: 1.002 - 1.035) 
d1.001 
NA 
pH  (NR: 5.0 – 8.0) 
d4 
t9 
UA Ketones  (Normal = negative) mg/dL 
NA 
t2+ 
UA Protein  (Normal = negative) mg/dL 
NA 
t2+ 
UA Blood  (Normal = negative) 
NA 
t3+ 
    UA Leukocyte Esterase   
NA 
t3+ 
Nitrates  
NA 
t2   
 
Each clinical laboratory test will be defined to be “Low”, “Normal”, or “High”, according to the 
normal reference range from the clinical laboratory.  The number and percentage of patients who 
have a shift from within to outside the normal reference range from baseline (and vice versa) to 
each follow-up visit will be summarized by time point.  
9.5. 
Vital Signs 
Vital signs results including BP (systolic and diastolic), heart rate, respiration rate, pulse 
oximetry, and temperature will be listed for individual patients.  Baseline for vital signs 
measurements will be defined as the last evaluation before dosing with study medication. Vital 
signs and changes from baseline will be summarized by time point.   
Vital sign parameter outcomes will be assessed for potential clinical significance; observed 
values and changes from pre-treatment to on-treatment time points will be tabulated for 
continuous parameters, as warranted.   
The number and percent of patients with potentially clinically significant (PCS) values during 
the treatment phase will be summarized.  A focus will be on new-onset PCS values, i.e., patients 
with pre-existing PCS values at pre-treatment will not be considered to have new-onset values 
on-treatment.  The criteria for identifying potentially clinically significant vital signs values are 
provided in Table 4. 
Table 4: 
List of Potentially Clinically Significant Ranges for Vital Sign Parameters 
(Study AVE-901-104)  
Variable Name 
LOW 
HIGH 
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Systolic BP  
<86 mm Hg OR a decrease of  
PP+J from baseline 
>200 mm Hg OR an increase 
RIPP+J from baseline 
Diastolic BP 
<48 mm Hg OR a decrease of  
PP+J from baseline 
>110 mm Hg OR an increase 
RIPP+J from baseline 
Heart rate 1 
1) <45 bpm OR a decrease of 
5 bpm from baseline  
 
!ESPDQGLQFUHDVH5 
bpm from baseline OR  >125 
bpm  
1 bpm: beats per minute 
 
9.6. 
Physical Examination 
Physical examination results will be listed for individual patients. 
9.7. 
ECG Examinations 
ECG examination interpretation results and heart rate and interval duration results will be listed 
for individual patients.  Baseline for ECG continuous measurements will be defined as the last 
evaluation before dosing with study medication. Continuous ECG values and changes from 
baseline will be summarized by time point.   The proportion of subjects with Normal, Abnormal: 
Not Clinically Significant, and Abnormal: Clinically Significant will be summarized by time 
point. 
The ECG analysis will include a careful review of QTcF values.  As part of this review, a 
summary of the number (percent) of patients with QTcF values in the following ranges will be 
SURYLGHGPVHF!WRPVHF!WRPVHFDQG!PVHF7KLVZLOOEH
performed by visit as well as at ANY time during the treatment period (where the highest QTcF 
value will be used for that assessment). 
The incidence of PCS values will be presented, with a focus on new-onset PCS values.  The 
criteria for identifying potentially clinically significant ECG values are provided in Table 5. 
Table 5: 
List of Potentially Clinically Significant Ranges for ECG Parameters (Study 
AVE-901-104) 
PR Interval 
High: >200 msec OR Increase t20 msec from baseline 
QRS Interval 
High: >100 msec OR Increase t10 msec from baseline  
QT Interval 
High: >500 msec OR Increase t60 msec from baseline 
QTcF Interval 
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High: > 450 msec (Males); >470 msec (Females) OR Increase t50 msec from baseline 
Heart Rate  
Low: ESP25DGHFUHDVHRIESP from baseline  
+LJK!ESPDQGLQFUHDVHESP from baseline OR >125 bpm 
 
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10. 
PHARMACOKINETIC EVALUATION 
There are no pharmacokinetic assessments being performed in this study. 
 
 
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11. 
INTERIM ANALYSES AND DATA MONITORING 
There are no planned interim analyses for this study. 
 
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12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
This SAP analysis is consistent with that described in the study protocol, with clarifications and 
minor modifications to ensure a robust and scientifically valid analysis.   
 
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13. 
REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry: 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration.  Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry: 
Structure and Content of Clinical Study Reports. Department of Health and Human Services: 
Food and Drug Administration.  Federal Register Vol. 61, July 17, 1996, page 37320.  
Guidance for Industry (2014) Analgesic Indications: Developing Drug and Biological Products -  
Draft Guidance.  Department of Health and Human Services: Food and Drug Administration.  
Center for Drug Evaluation and Research (CDER) February 2014 Clinical/Medical. 
 
 
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14. 
APPENDICES 
 
14.1. 
Tables, Figures and Listings for Final Study Report 
 
 
 
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14.1.1. 
Tables 
 
Table Number  
Table Title 
Analysis Populations 
Subgroups 
Topline 
Unique or 
Repeat 
Table 14.1.1 
Summary of Subject Disposition 
All Screened Subjects 
 
 
Unique 
Table 14.1.2 
Summary of Subjects by Study Center 
Safety Population 
 
 
Unique 
Table 14.1.3 
Summary of Major Protocol Deviations   
FAS Population 
 
 
Repeat  
Table 14.1.4 
Summary of Demographic and Baseline 
Characteristics  
FAS Population 
 
Yes 
Unique  
Table 14.1.5 
Summary of Medical/ Surgical History by Body 
System 
Safety Population 
 
 
Unique  
Table 14.1.6.1 
Summary of Concomitant Medications by ATC 
Class and Preferred Term  
Safety Population 
 
 
Unique 
Table 14.1.6.2 
Summary of New-Onset Concomitant 
Medications by ATC Class and Preferred Term  
Safety Population 
 
 
Repeat 
Table 14.1.7 
Summary of Study Medication Exposure   
Safety Population 
 
Yes 
Unique  
Table 14.2 
Summary of Patient Global Assessment (PGA)  
Safety Population 
 
 
Unique 
Table 14.3.1 
Overall Incidence of Treatment-Emergent 
Adverse Events 
Safety Population 
 
Yes 
Unique  
Table 14.3.1.1 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Treatment-Emergent 
Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
 
Yes 
Unique  
Table 14.3.1.1.1 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Treatment-Emergent 
Adverse Events by System Organ Class, Preferred 
Term and Surgery Type  
Safety Population  
Surgery Type 
 
Unique 
Table 14.3.1.1.2 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Treatment-Emergent 
Adverse Events by System Organ Class, Preferred 
Term and Gender  
Safety Population  
Gender 
 
Repeat 
Table 14.3.1.1.3 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Treatment-Emergent 
Adverse Events by System Organ Class, Preferred 
Term and Race  
Safety Population  
Race 
 
Repeat 
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Table 14.3.1.1.4.1 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Treatment-Emergent 
Adverse Events by System Organ Class, Preferred 
Term and Age Group (Median) 
Safety Population  
Age (<=, > 
Median) 
 
Repeat  
Table 14.3.1.1.4.2 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Treatment-Emergent 
Adverse Events by System Organ Class, Preferred 
Term and Age Group (65 Years Old) 
Safety Population  
Age (<65, >= 
65 years old) 
 
Repeat  
Table 14.3.1.1.5 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Treatment-Emergent 
Adverse Events by System Organ Class, Preferred 
Term and BMI  
Safety Population  
BMI 
 
Repeat  
Table 14.3.1.2 
Incidence of Post-Treatment Adverse Events and 
Treatment Related Post-Treatment Adverse 
Events by System Organ Class and Preferred 
Term 
Safety Population 
 
 
Repeat 
Table 14.3.1.3 
Incidence of Treatment-Emergent Adverse Events 
Leading to Discontinuation from Study by System 
Organ Class and Preferred Term 
Safety Population 
 
 
Repeat 
Table 14.3.1.3.1 
Incidence of Treatment-Emergent Adverse Events 
Leading to Completion from Study by System 
Organ Class, Preferred Term and Surgery Type 
Safety Population 
Surgery Type 
 
Repeat 
Table 14.3.1.3.2 
Incidence of Treatment-Emergent Adverse Events 
Leading to Discontinuation from Study by System 
Organ Class, Preferred Term and Race 
Safety Population 
Gender 
 
Repeat 
Table 14.3.1.3.3 
Incidence of Treatment-Emergent Adverse Events 
Leading to Discontinuation from Study by System 
Organ Class, Preferred Term and Race 
Safety Population 
Race 
 
Repeat 
Table 14.3.1.3.4.1 
Incidence of Treatment-Emergent Adverse Events 
Leading to Discontinuation from Study by System 
Organ Class, Preferred Term and Age Group 
(Median) 
Safety Population 
Age (<=, > 
Median) 
 
Repeat 
Table 14.3.1.3.4.2 
Incidence of Treatment-Emergent Adverse Events 
Leading to Discontinuation from Study by System 
Organ Class, Preferred Term and Age Group (65 
Years Old) 
Safety Population 
Age (<65, >= 
65 years old) 
 
Repeat 
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Table 14.3.1.3.5 
Incidence of Treatment-Emergent Adverse Events 
Leading to Discontinuation from Study by System 
Organ Class, Preferred Term and BMI 
Safety Population 
BMI 
 
Repeat 
Table 14.3.1.4 
Incidence of Treatment-Emergent Adverse Events 
Leading to Death by System Organ Class and 
Preferred Term 
Safety Population 
 
 
Repeat 
Table 14.3.1.5 
Incidence of Treatment-Emergent Adverse Events 
Related to Local Tolerability at the Infusion Site 
by Preferred Term 
Safety Population 
 
 
Repeat 
Table 14.3.1.6 
Incidence of Treatment Adverse Events by 
System Organ Class, Preferred Term and 
Maximum Severity 
Safety Population 
 
 
Unique  
Table 14.3.1.7.1 
Incidence of Treatment-Emergent Adverse Events 
and Treatment Related Adverse Events by 
Infusion Number 
Safety Population 
 
 
Unique 
Table 14.3.1.7.2 
Incidence of Treatment Adverse Events and 
Treatment Related Adverse Events within One 
Hour of Any Infusion by System Organ Class and 
Preferred Term 
Safety Population 
 
 
Repeat 
Table 14.3.1.8 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term  
Safety Population 
 
Yes 
Repeat 
Table 14.3.1.8.1 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term and Surgery Type  
Safety Population 
Surgery Type 
 
Repeat 
Table 14.3.1.8.2 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term and Gender  
Safety Population 
Gender 
 
Repeat 
Table 14.3.1.8.3 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term and Race  
Safety Population 
Race 
 
Repeat 
Table 14.3.1.8.4.1 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term and Age Group 
(Median) 
Safety Population 
Age (<=, > 
Median) 
 
Repeat 
Table 14.3.1.8.4.2 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term and Age Group (65 
Years Old) 
Safety Population 
Age (<65, >= 
65 years old) 
 
Repeat 
Table 14.3.1.8.5 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term and BMI  
Safety Population 
BMI 
 
Repeat 
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Table 14.3.2.1.1 
Chemistry Laboratory Parameters: Results and 
Change from Baseline to End of Treatment 
Safety Population 
 
 
Unique  
Table 14.3.2.1.2 
Shift from Baseline to End of Treatment in Serum 
Chemistry Parameters  
Safety Population 
 
 
Repeat 
Table 14.3.2.1.3 
Potentially Clinically Significant Results in 
Chemistry values 
Safety Population 
 
 
Unique 
Table 14.3.2.2.1 
Hematology Laboratory Parameters: Results and 
Change from Baseline to End of Treatment 
Safety Population 
 
 
Repeat 
Table 14.3.2.2.2 
Shift from Baseline to End of Treatment in 
Hematology Parameters  
Safety Population 
 
 
Repeat 
Table 14.3.2.2.3 
Potentially Clinically Significant Results in 
Hematology values 
Safety Population 
 
 
Unique 
Table 14.3.2.3.1 
Urinalysis Parameters: Continuous Results and 
Change from Baseline to End of Treatment 
Safety Population 
 
 
Repeat 
Table 14.3.2.3.2 
Urinalysis Parameters: Categorical Results  
Safety Population 
 
 
Repeat 
Table 14.3.2.3.3 
Shift from Baseline to End of Treatment in 
Urinalysis Parameters  
Safety Population 
 
 
Repeat 
Table 14.3.2.3.4 
Potentially Clinically Significant Results in 
Urinalysis values 
Safety Population 
 
 
Unique 
Table 14.3.3.1 
Vital Signs: Results and Change from Baseline  
Safety Population 
 
 
Repeat 
Table 14.3.3.2 
Potentially Clinically Significant Results in Vital 
Signs 
Safety Population 
 
 
Unique 
Table 14.3.4.1 
12-Lead ECG Exam: Results and Change from 
Baseline 
Safety Population 
 
 
Repeat 
Table 14.3.4.2 
ECG Interpretation in 12-Lead ECG Exam 
Safety Population  
 
 
Repeat 
Table 14.3.4.3 
Potentially Clinically Significant Results in 12-
Lead ECG Exam 
Safety Population 
 
 
Repeat 
 
 
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14.1.2. 
Figures 
 
Figure Number 
Figure Title 
Study Population 
Figure 14.2.1 
Cumulative Proportion of Subjects (%) Versus Total Exposure (mg)  
Safety Population  
 
 
 
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14.1.3. 
Listings 
Listing Number 
Listing Title 
Study Population 
Listing 16.2.1 
Screening, Informed Consent and Study Population  
All Screened Subjects  
Listing 16.2.2.1 
List of Inclusion/Exclusion Eligibility Criteria 
 
Listing 16.2.2.2 
Subjects not Meeting I/E or Pre-Operative Criteria  
Safety Population 
Listing 16.2.3 
Local Laboratory Tests for Eligibility checking 
Safety Population 
Listing 16.2.4 
Protocol Deviations 
Safety Population 
Listing 16.2.5 
Subject Completion/Early Termination  
Safety Population 
Listing 16.2.6 
Demographics and Baseline Characteristics 
Safety Population 
Listing 16.2.7 
Medical/Surgical History 
Safety Population 
Listing 16.2.8 
Opioid History 
Safety Population 
Listing 16.2.9 
Pregnancy Test 
Safety Population 
Listing 16.2.10  
ASA Physical Status  
Safety Population 
Listing 16.2.11 
Surgery Information 
Safety Population 
Listing 16.2.12 
Prior and Concomitant Medications 
Safety Population 
Listing 16.2.13 
Non-Medication Therapy 
Safety Population 
Listing 16.2.14 
Study Drug Administration 
Safety Population 
Listing 16.2.15 
Summary of Study Drug Exposure  
Safety Population 
Listing 16.2.16 
Patient Global Assessment (PGA)  
Safety Population 
Listing 16.2.17 
Adverse Events  
Safety Population 
Listing 16.2.18 
Serious Adverse Events  
Safety Population 
Listing 16.2.19 
At Least Possibly Related Treatment Emergent Adverse Events 
Safety Population 
Listing 16.2.20 
Adverse Events Leading to Study Discontinuation 
Safety Population 
Listing 16.2.21 
Adverse Events Leading to Death  
Safety Population 
Listing 16.2.22 
Adverse Events Related to Local Tolerability at The Infusion Site 
Safety Population 
Listing 16.2.23.1 
Chemistry Laboratory Results 
Safety Population 
Listing 16.2.23.2 
Hematology Laboratory Results 
Safety Population 
Listing 16.2.23.3 
Urinalysis Laboratory Results 
Safety Population 
Listing 16.2.24 
Vital Signs 
Safety Population 
Listing 16.2.25 
Physical Examination 
Safety Population 
Listing 16.2.26 
12-Lead ECG Exam Assessments 
Safety Population 
 
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15. 
DOCUMENT HISTORY 
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# 
Summary of Changes 
Section Changed 
Date 
1.0 
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NA 
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