Clinical trial NCT03290378
Conditions: Pain Management
Sponsor: Avenue Therapeutics, Inc.
Start date: 2017-09-19; Completion date: 2018-04-23
Enrollment: 409 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study evaluates the effectiveness and safety of IV tramadol compared to placebo managing postoperative pain following a bunionectomy

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: None arm 2: None arm 3: None
Interventions: intervention 1: Tramadol intervention 2: Placebo
Intervention descriptions: intervention 1: IV; 25 mg or 50 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 intervention 2: IV; Placebo, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44

Protocol documents:
Prot_SAP_000.pdf: 
Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
1 
 
 
 
 
 
 
IV TRAMADOL 
 
PROTOCOL AVE-901-102 
 
Tramadol Infusion - Postoperative Pain in Orthopedic Surgery 
 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE 
BLIND, THREE-ARM STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF TRAMADOL INFUSION 
(AVE-901) VERSUS PLACEBO IN THE MANAGEMENT 
OF POSTOPERATIVE PAIN FOLLOWING 
BUNIONECTOMY 
 
Sponsor: 
Avenue Therapeutics, Inc. 
New York, NY 10019 
 
 
 
 
IND #: 108124 
DATE OF ISSUE: October 24, 2017 
VERSION: 3.0  
 
 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
2 
 
 
 
 
APPROVAL SIGNATURES 
 
Protocol Number: 
AVE-901-102 
 
Protocol Title:  
A Phase 3, Multicenter, Randomized, Double Blind, Three-Arm 
Study to Evaluate the Efficacy and Safety of Tramadol Infusion 
(AVE-901) versus Placebo in the Management of Postoperative 
Pain Following Bunionectomy 
 
 
 
 
 
 
 
Lucy Lu, MD 
CEO, Avenue Therapeutics  
 
Date 
 
 
 
 
 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
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 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
4 
 
 
 
 
EMERGENCY CONTACTS 
Table 1. 
Emergency Contact Information (Study AVE-901-102) 
Role in Study 
Name 
Contact Information 
Executive Director of 
Clinical Research and 
Operations 
Michael Ryan 
 
Avenue Therapeutics, Inc. 
95 Sawyer Road, Suite 110 
Waltham, MA 02453 
Office: (781) 652 – 4514  
Mobile: (617) 538-8949 
CEO 
Lucy Lu, MD 
Avenue Therapeutics, Inc. 
2 Gansevoort Place, 9th Floor 
New York, NY 10019 
Office: (781) 652 - 4511  
Mobile: (917) 847 - 6241 
Medical Monitor 
Royce Morrison, MD 
1603 Boyer Avenue East 
Seattle, WA 
98112-3019 
Mobile: 206-799-7386 
24-Hour Emergency Contact 
Royce Morrison, MD  
206-799-7386 
 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
5 
 
 
 
 
1. 
SYNOPSIS 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
Title of Study: A Phase 3, Multicenter, Randomized, Double Blind, Three-Arm Study to Evaluate 
the Efficacy and Safety of Tramadol Infusion (AVE-901) versus Placebo in the Management of 
Postoperative Pain Following Bunionectomy 
Study center:  Approximately 6 centers in the United States 
Studied period:  
Estimated date first patient enrolls: Q3 2017 
Estimated date last patient enrolls: Q2 2018 
Estimated date primary analysis: Q2 2018 
Phase of development: 3 
 
Objectives:  
The primary objective of this study is to evaluate the analgesic efficacy of intravenous (IV) tramadol 
(AVE-901) compared to placebo in the management of postoperative pain following orthopedic 
(bunionectomy) surgery.  The Sum of Pain Intensity Differences (SPID) through 48 hours post first 
dose (SPID48) measured at rest will be used as the primary measure of efficacy. 
The secondary efficacy endpoints are: 
• 
SPID through 24 hours post first dose (SPID24) measured at rest  
• 
Total consumption of rescue (supplemental) analgesia. This is the total amount of rescue 
analgesia given to the patient after first dose of study medication through 48 hours post-
first dose. 
• 
Patient Global Assessment of efficacy at 24 and 48 hours post first dose using a 5-point 
scale.  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). 
Additional analgesia endpoints are: 
• 
Time-specific pain intensity profile over time 
• 
Time (in minutes) to first rescue analgesia from the time of first dose of study 
medication. 
• 
Number (percent) of patients who require no rescue analgesia from T0-T48. 
• 
Rate of consumption of rescue analgesia.  The total amount of rescue analgesia 
will be expressed as a function of duration of treatment  
• 
Time (in minutes) to meaningful pain relief after first dose.  
• 
Time (in minutes) to perceptible pain relief after first dose.  


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
6 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
Safety endpoints will include: 
• 
Adverse events (classified by the MedDRA System Organ Class (SOC) and preferred 
term), including assessment of AE’s related to substance abuse.   
• 
Clinical laboratory, vital sign, PE, and ECG changes 
• 
Use of anti-emetics and other concomitant medications 
• 
Local tolerability at the infusion site via pain, swelling, tenderness, and erythema.   
Population pharmacokinetic outcomes will be assessed through collection of plasma samples for a 
subset of the randomized patients.  Exposure-response relationships will be assessed for safety 
outcomes. 
Study Design:  
This study is a Phase 3, multicenter, double-blind, three-arm, randomized, placebo-controlled, 
multiple-dose, parallel-group trial to evaluate the safety, tolerability and the efficacy of IV Tramadol 
(AVE-901) versus placebo in the management of postoperative pain in consenting patients 
undergoing a unilateral primary first metatarsal bunionectomy surgery.  The treatment groups will be: 
• 
AVE-901 50 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
• 
AVE-901 25 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
• 
Placebo, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
Approximately 405 patients will be randomized (135 per treatment group).  
Each patient will undergo the Screening Visit (Day -28 to Day -1), the pre-operative assessment 
(within 24 hours prior to surgery start time), the Surgical/Treatment Visit, the first day of which is 
when the bunionectomy will be performed (Day 0), the primary treatment period through Hour 48 
(the last on treatment assessment, and the time of End of Treatment visit assessments), and the 
Follow-up Visit (Day 14).  Confinement is anticipated to be a 4-day 3 night stay from Day -1 to hour 
48. 
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 randomized in a double-blinded fashion, 
stratified by study center, in a 1:1:1 ratio to the treatment groups.   
Following surgery, patients that have met post-surgical dosing criteria will receive his or her assigned 
study medication infusion regimen over a period of 48 hours. Patients will be confined at the 
healthcare facility during study drug administration, and will be discharged only if clinically stable.   
Efficacy will be assessed by patient reports of pain intensity (PI) performed at rest immediately prior 
to T0 (the first administration of study drug) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 
24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, and 48 hours after first treatment (ie, post T0). PI is 
reported by the patient on a numeric rating scale for pain (NPRS Pain, See Appendix 1) anchored at 0 
for no pain and 10 for the worst pain imaginable.  In addition, efficacy and safety will be measured by 
other parameters.   
Rescue medication (Ibuprofen 400 mg Q4 PRN) will be available any time after the initial dose of 
study medication to keep the patient comfortable. However, patients will be encouraged to wait at 
least 60 minutes after the initial dose of study medication before they receive rescue therapy.  A pain 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
7 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
intensity measure will be obtained immediately prior to each administration of rescue medication.  
Patient controlled analgesia (PCA) will not be allowed in this study. 
Study Periods and Methodology 
There are 5 periods in this study:  Screening, Preoperative, Operative, Post-operative/Treatment 
Period, and 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 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 measures.  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, coagulation 
tests, infectious disease testing, urinalysis, urine drug screen, Alcohol breath test, 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 randomization. 
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, brief physical exam, ASA Physical Status, chemistry panel, hematology 
panel, coagulation tests, urinalysis, urine drug screen, Alcohol breath test, urine pregnancy test (in 
females of childbearing potential), and concomitant treatments.  These safety laboratory tests will not 
be used for determining eligibility. Patients with Baseline laboratory values that are subsequently 
found to meet any exclusion criteria may be discontinued from the trial at the discretion of the 
investigator, medical monitor and sponsor. A blood sample will be obtained during the preoperative 
period and stored for possible analysis of CYP2D6 metabolizer status, in case such information is 
deemed to be of interest during the analysis. If all preoperative assessments meet eligibility (with the 
exception of the laboratory values noted) the subject will be randomized prior to surgery. 
 
Operative:  
Operative procedures are described in the Surgical and Anesthetic Regimen. 
Post-operative/Treatment Period: 
In addition to meeting all eligibility criteria prior to surgery, patients must ALSO meet all 
postsurgical dosing criteria. Treatment will occur from Hour 0 through Hour 44 (T0-T44).   
• 
Following surgery, patients will have their popliteal block withdrawn approximately between 4 
and 5 AM. Post removal of the popliteal block, patients must be assessed for the dosing eligibility 
criteria prior to dosing. Patients must be awake and alert, and must have a pain intensity of 5 or 
greater on the NPRS and report a score of moderate or severe on a 4-point categorical rating scale 
(with categories of none, mild, moderate, or severe) just before the first dose of the study drug.  
Patients who do not report pain at this level within 8 hours of the removal of the block will be 
discontinued from the study. 
• 
Antiemetic treatment with Reglan or Emend (not Zofran or other 5HT3 antagonists) is allowed. 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
8 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
T0 will be time of start of infusion of first study drug administration.  Pain intensity will be recorded 
using a NPRS from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable (See Appendix 1).  
Pain intensity assessments will be recorded immediately prior to first dose (baseline) and at the times 
indicated in the Schedule of Assessments.  The patient must rest for 15 minutes (+/- 5 minutes) prior 
to NPRS assessments. The Patient Global Assessment (PGA) of efficacy will be completed by the 
patient at 24 hours and 48 hours post T0.  Ratings will be assessed as: 0=poor; 1=fair, 2=good, 
3=very good or 4=excellent.  
Two stopwatches will be started at the start of infusion of first study drug dose.  Patients will be 
instructed to stop the first stopwatch when pain relief is first perceptible and the second when pain 
relief is considered meaningful.  Safety will be assessed by recording vital signs including: respiratory 
rate, pulse oximetry reading, temperature, heart rate and blood pressure throughout the study period.   
At the end of treatment (post T48), patients will undergo End of Treatment assessments, including a 
brief physical examination, vital signs measurements, electrocardiogram (ECG) NPRS, PGA, and 
clinical laboratory evaluations for safety. AEs and concomitant medication use will be recorded. If 
feasible, any patient who prematurely discontinues study medication or the study prior to the T48 will 
undergo the procedures required at the end of treatment.   Post T48, pain management will be per 
investigator standard of care preference. 
Follow up: 
A final safety assessment via telephone call will be conducted on Day 14 (± 2 days); this will be a 
telephone contact. 
Rescue medication: 
Inadequate analgesia may be treated with 400 mg Q4 of ibuprofen PRN administered by a trained 
nurse or study clinician to the patients who request rescue medication any time after administration of 
the initial dose of study medication.  However, patients will be encouraged to avoid rescue 
medications for at least 60 minutes after their first dose of study drug.  A NPRS will be obtained 
immediately (approximately 5 minutes) prior to administering any rescue medication.  Patients will 
continue to take study medication for the remainder of the 48-hour period even if they take rescue 
medication. Ibuprofen dosing is allowed: 400 mg PRN every 4 hours up to 2400 mg per day. The 
time of rescue medication must be recorded in the case report form.  Investigator study team 
personnel will monitor the patient carefully for 48 hours following the surgery to assess the patient's 
condition and provide rescue medication whenever requested, within the above limits.  This will 
minimize the patient's inconvenience caused due to pain.   
Pharmacokinetics: 
Approximately 33% of the total number of patients will be enrolled in the pharmacokinetic (PK) 
portion of this study at select sites.  Blood will be collected for analysis of tramadol and O-
desmethyltramadol (active metabolite) at Hour 0, Hour 0.25, Hour 0.5, Hour 2.25, Hour 2.5, Hour 4, 
Hour 4.25, Hour 4.5, Hour 8, Hour 8.25, Hour 24.5, Hour 44, Hour 44.25, Hour 44.5, and Hour 48. 
Number of patients (planned):  
A total of approximately 405 patients in United States (US) undergoing bunionectomy who meet all 
of the inclusion and none of the exclusion criteria, randomized, have at least one pain intensity 
measurement and receive at least a partial dose of study drug will be included in the study population. 
Patients will be randomized to one of three treatment arms (AVE-901 50 mg, AVE-901 25 mg, or 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
9 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
placebo) in a 1:1:1 ratio (approximately 135 patients per treatment group).  Randomization will be 
stratified by study center.  
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1. The patient is male or female 18-75 years of age undergoing unilateral first metatarsal 
bunionectomy surgery 
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.  Highly effective contraception methods 
include:  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 must not be lactating. 
5. The patient must be willing to be housed in a healthcare facility and able to receive parenteral 
analgesia for at least 72 hours after surgery. 
6. The patient meets definition of American Society of Anesthesiologists (ASA) Physical Class 
1, or 2. 
7. The patient is willing and able to understand the study procedures and the use of pain scales, 
to communicate meaningfully with the study personnel, and to comply with the study 
protocol. 
Exclusion Criteria: 
1. Patient is not expected to receive a continuous infusion nerve block as described in the Post-
Op anesthetic procedures protocol. 
2. Patient is currently using, or is expected to receive gabapentin, pregabalin, ketamine or other 
peri- or postoperative analgesic adjuncts or any analgesics not allowed in the Surgical and 
Anesthesia protocol. 
3. Patient is undergoing bilateral or revision bunionectomy surgery.  
4. Patient has a history of primary or metastatic bone cancer or Paget’s disease. 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
10 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
5. The patient has current or historical evidence of any clinically significant disease or condition 
that might increase the risk of surgery or complicate the patient’s postoperative course. 
6. The patient has allergy or hypersensitivity (or is intolerant) to opioids or tramadol. 
7. The patient has known physical dependence on opioids. 
8. Patients who have taken any opioids, including tramadol for a total of 3 days, within 30 days 
prior to surgery. 
9. The patient has a recent (within 5 years) and/or current history of chronic analgesic, opiate or 
tranquilizer abuse or dependence or is a user of illicit drugs, or has had a recent history 
(within 2 years) of drug or alcohol abuse. 
10. The patient has another painful physical condition that, in the opinion of the investigator, may 
confound the assessments of postoperative pain.  
11. The patient has taken other prior/concurrent chronic medications that have not been at a 
stable dose for at least 2 weeks prior to screening. 
12. 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.  
13. The patient has taken monoamine oxidase (MAO) inhibitors, trazodone, or cyclobenzaprine 
within 14 days prior to surgery. 
14. The patient has a history of epilepsy, or is known to be susceptible to seizures.  
15. 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). 
16. The patient has a history of Long QT Syndrome or a relative with this condition. 
17. The patient has had a recent cardiovascular event or a clinically significant abnormal ECG at 
screening.  
18. The patient has used (within 30 days of surgery), is currently using or is anticipated to use 
chronic corticosteroids. 
19. The patient has expressed suicidal ideation or is considered to be at risk of suicide. 
20. The patient is morbidly obese (body mass index [BMI] ≥ 40 kg/m2) or has documented sleep 
apnea requiring pharmacological or device intervention. 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
11 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
21. The patient has a history of cardiopulmonary, neurological or psychiatric condition that may 
confound the assessments of efficacy or safety. 
22. 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.    
23. The patient has severe renal impairment or a serum creatinine value of > 2.0 mg/dL at 
Screening. 
24. The patient has potassium, sodium, calcium or magnesium levels outside of the normal range, 
or any other clinically significant abnormalities in blood chemistry at Screening. 
25. The patient has a hemoglobin level at screening which, in the judgment of the Investigator, is 
not suitable for participation in this study. 
26. The patient used narcotics or alcohol within 24 hours prior to surgery. 
27. The patient was administered an investigational product within 30 days prior to Screening. 
28. The patient has previously participated in a clinical study with AVE-901.  
POST SURGICAL DOSING CRITERIA 
The patient is to be evaluated post-operatively prior to the initial treatment with the study drug and 
will be given the study drug only if all of the following criteria are met: 
1. The patient reports a score of moderate or severe on a 4-point categorical rating scale (with 
categories of none, mild, moderate, or severe) and has a NPRS pain score of ≥5 (on a scale 
from 0 to 10) within 8 hours after removal of popliteal block.   
2. The patient is alert and oriented. She/he is able to answer questions and follow commands 
and has appropriate cognitive function to properly interpret and answer protocol mandated 
assessments. 
3. The patient has no 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. 
4. The surgical procedure from incision to closure was not longer than 180 min. 
5. There have been no significant deviations from the surgical or anesthetic protocol that would, 
in the opinion of the investigator, put the patient at risk of participation in the trial, confound 
the analgesic endpoints of the trial or cause concern regarding the patient’s ability to 
participate in the trial.   
6. There have been no use of gabapentanoids, or 5-HT3 antagonists (e.g. ondansetron, 
granisetron, palonosetron) preoperatively, intraoperatively, or postoperatively. 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
12 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
7. Subject has not experienced complications during the surgical procedure and in the opinion of 
the investigator is a candidate to continue in the study. 
Investigational product, dosage and mode of administration:  
AVE-901 50 mg, or 25 mg will be added to a 50 ml saline bag and administered intravenously 
approximately over 15 minutes +/- 2 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 as 13 infusions, given at T0, T2, T4 and one infusion every 4 hours 
thereafter. T0 is defined as the start of the infusion of the first dose.  The last dose will be 
administered at 44 hours following initiation of the first dose.  
Total patient participation in this study, from initial screening through the Day 14 final assessment, is 
expected to be between 3 and 6 weeks. 
Reference therapy, dosage and mode of administration:  
Placebo (saline) (51 mL) will be administered in the same manner as the investigational product. 
Criteria for evaluation: 
Efficacy: 
Primary Endpoint 
• 
SPID48 for pain at rest 
Key Secondary Endpoints 
• 
SPID through 24 hours post first dose (SPID24) at rest 
• 
Total consumption of rescue (supplemental) analgesia. This is the total amount of rescue 
analgesia given to the patient after first dose of study medication through 48 hours post-
first dose. 
• 
Patient Global Assessment of efficacy at 24 and 48 hours  
Tertiary Endpoints 
Additional analgesia endpoints are: 
• 
Time-specific pain intensity profile over time 
• 
Clock time (in minutes) to first use of rescue medication from the time of first dose of 
study medication. 
• 
Number (percent) of patients who require no rescue analgesia from T0-T48 
• 
The rate of consumption of rescue analgesia 
• 
Time (in minutes) to meaningful pain relief after first dose 
• 
Time (in minutes) to perceptible pain relief after first dose 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
13 
 
 
 
 
Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
Safety:  
• 
AEs, including assessment of infusion site local reactions (skin and vein)  
• 
AEs related to substance abuse 
• 
Clinical laboratory tests (hematology panel, chemistry panel, coagulation and urinalysis) 
• 
Vital signs  
• 
Physical examination 
• 
12-lead ECG.  Of special note, an ECG will be performed between 20 and 30 minutes 
following the start of EACH dose during the first 24 hours of treatment. 
• 
Use of anti-emetics and other concomitant medications 
PK: 
• 
Plasma sampling in a subset (approximately 33%) of the population is planned at 
designated time points.  Exposure-safety relationships will be assessed (including but not 
necessary limited to ECG, adverse event, and concomitant therapy/drug-drug interaction 
outcomes). 


Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
October 24, 2017 
CONFIDENTIAL  
14 
 
 
 
 
Statistical methods: 
Sample Size Considerations: 
A sample size of 135 patients per arm (405 patients in total) provides over 90% power to detect a 
SPID48 difference of 250 between treatment with placebo and treatment with AVE-901, assuming a 
common SPID48 standard deviation of 600 (and thus an approximate 40% effect size), an alpha of 
0.05 using a two-sided test of mean differences.   
General Statistical Methods 
The baseline for all variables will be the last measurement obtained prior to the patient receiving the 
first dose of randomized study drug.  
Patient disposition (including the number and percent of patients who are randomized, who receive 
randomized treatment, who prematurely discontinue and reasons for discontinuation, and who 
complete the study) will be tabulated by treatment group.  The number (%) of patients by exposure 
will be tabulated. 
Baseline comparability among the two treatment groups with respect to demographic and other 
baseline characteristics will be assessed for quantitative variables with a two-way analysis of variance 
(ANOVA) with treatment group and study center as main effects. For categorical variables, the 
Cochran-Mantel-Haenszel test will be used, stratified by center. 
Study Populations 
• 
The Full Analysis Set (FAS) population is defined as all randomized patients who 
receive study medication.  Patients will be analyzed according to the treatment group 
they were randomized to.   
• 
The Safety Population is defined as all patients who receive study medication.  
Patients will be analyzed according to the actual treatment they receive. 
Alpha Levels 
There are 2 pairwise comparisons of interest: 
• 
High-dose tramadol (50 mg) vs placebo 
• 
Low-dose tramadol (25 mg) vs placebo 
All inferential assessments will be 2-sided tests performed at the 0.05 alpha level.  A hierarchical 
alpha testing strategy will be utilized to control for the overall experiment-wise alpha.  As there are 
multiple tests being performed (the single primary efficacy variable pairwise test and the 3 key 
secondary efficacy tests), the following strategy will be applied:   
The high-dose tramadol arm vs placebo comparison will be assessed for the primary endpoint at the 
0.05 alpha level.  If and only if the p-value is ≤ 0.05 for this pairwise comparison will the lower dose 
tramadol arm vs placebo comparison be assessed.  If the p-value for the high-dose arm is NOT 
significant, all testing will cease and it will be concluded that neither tramadol treatment arm provides 
better pain relief than placebo. 
If the primary endpoint is significant for the AVE-901 vs. placebo comparison (in favor of the 
tramadol arm) for one or both pair-wise tests, then statistical testing will proceed to the secondary 
endpoints within each pair-wise grouping, to be tested in the following order: 
• 
SPID24 
• 
Total consumption of rescue analgesia 


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• 
Patient Global Assessment of efficacy at 24 and 48 hours (the two time points will be 
tested simultaneously) 
If a statistical test within each pairwise comparison is significant at the nominal 0.05 level, two-sided 
(in favor of the tramadol arm), then testing will proceed to the next endpoint in the list.  Once a non-
significant test occurs, endpoints lower in the list are considered not statistically significant. 
Note that while inferential comparison of the high dose to the low dose is not a key aspect of the 
statistical analysis, assessment of the dose-response will be performed across the 3 doses in order to 
allow visual comparison of the outcomes for the primary and key secondary endpoints.  
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: 
• 
Gender 
• 
Race 
• 
Age (using the study median age) 
• 
Investigational center 
Efficacy 
Primary Endpoint 
SPID48 (the sum of the time-weighted pain intensity differences for the time period 0-48 hours) is the 
primary efficacy endpoint.   
Handling of Missing Data 
For the primary causal estimate in this study (to reflect the true treatment effects of tramadol 
compared to placebo), missing values within a patient during the 48-hour treatment period will be 
handled in the following manner: 
• 
When rescue medication is used, the last pain intensity measure prior to the use of 
rescue medication will be used (imputed) for the subsequent protocol-specified time 
points for measurement of pain intensity through 4-hours after the time of the rescue 
medication. 
All other missing data will be imputed utilizing multiple imputation methods.  Multiple imputation 
provides a useful strategy for analyzing data sets with missing values. Instead of filling in a single 
value for each missing value, Rubin’s (1976) multiple imputation strategy replaces each missing value 
with a set of plausible values that represent the uncertainty about the correct value to impute. 
For patients with arbitrary missing data patterns (missing at random, MAR), a pattern-mixture 
approach will be taken to the imputation.  The first step will be to apply a Markov Chain Monte Carlo 
(MCMC) method (Schafer 1997) that assumes multivariate normality will be used to impute all 
missing values to make the imputed (resulting) data sets have strictly monotone missing patterns.  The 
resulting monotone missing pattern will then, in a second imputation step, be used to impute the 
remaining missing values; specifically, a regression-based method for continuous variables will be 
applied. 
For patients with missing data as a result of discontinuation due to adverse event (missing not at 
random, MNAR), the pattern-mixture approach will also be taken to the imputation (as for the 


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monotone MAR data), with the difference that while a similar regression-based method for 
continuous variables will be applied, a scaled (constant) adjustment to the imputed values will be 
made such that the outcomes that are imputed are distributionally ‘worse’ than those imputed for the 
monotone MAR data.  This scaled adjustment will increase each imputed value (from the regression) 
for these MNAR data by a constant of ‘1’, eg, if the regression provides an imputed value of 4.6 for a 
given missing value for a patient at a given timepoint, the MNAR imputed value will be set to 4.6 + 1 
= 5.6 for that patient at that time point.  This will, in effect, guarantee that the overall distribution of 
missing values for discontinuations due to adverse event is WORSE than that for other reasons. 
The SAS software system will be used to perform this imputation.  Because the imputation of missing 
data is a key aspect to the analysis of pain data, explicit details regarding this imputation are provided 
via sample SAS code that is intended to demonstrate the application of these strategies.  Variable 
definitions are: 
• 
TRT=treatment group (1 or 0) 
• 
Pain_1 is the first time point for the pain score 
• 
Pain_2 is the second time point for the pain score 
• 
Pain_last is the last time point for the pain score. Additional pain scores (between 
Pain_1 and Pain_last) would be included in this model according to the time points 
for collection. 
The first step will be to impute partially in order to obtain a monotone missing data pattern. 
proc mi data=DATAIN out=DATAIN_MONO nimpute=100 seed=123;  
var TRT Pain_1 Pain_2 …. Pain_last; 
mcmc chain=multiple impute=monotone;  
run; 
The second step will be to impute the remaining (monotone) missing data that is MAR for each of the 
100 imputed datasets from the first step. 
proc mi data=DATAIN_MONO out=DATAIN_REG seed=465 nimpute=1;  
by _Imputation_;  
var TRT Pain_1 Pain_2 …. Pain_last;  
class TRT;  
monotone regression;  
run; 
In the case of missing data due to an adverse event, the following step will be used: 
proc mi data=DATAIN_MONO out=DATAIN_REG seed=465 nimpute=1;  
by _Imputation_;  
var TRT Pain_1 Pain_2 …. Pain_last;  
class TRT;  
monotone regression (pain1 pain2 … Pain_last);  
mnar adjust (pain1 pain2 … Pain_last / shift=1);  
run; 
Note that the regressions do not include the treatment variable, and thus the imputed data at each time 
point will be based on the distribution of all data rather than treatment-group specific distributions.  A 
total of 100 imputed datasets will be created using these imputed data and analyzed according to the 
primary method of statistical analysis. 
Primary Method of Statistical Analysis 
Each of the 100 imputed datasets will be analyzed as follows:   


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Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
• 
An analysis of covariance (ANCOVA) model will be used to test the primary efficacy 
endpoint.  The model will use treatment and study center as main effects, and baseline 
pain intensity (NPRS scale 0 to 10) as the covariate (See Appendix 1).  Data from all 
three treatment groups will be included in the same ANCOVA model for purposes of the 
testing procedures. 
The 100 resulting treatment effect parameters and standard errors from these ANCOVA will be 
combined to provide a distribution of parameters (and standard errors) upon which the primary 
hypothesis of treatment effect will be determined. 
Key Secondary Endpoints 
The key secondary endpoints will be assessed as follows: 
• 
24-hour pain intensity (SPID24) will be assessed in a similar manner as the primary 
endpoint.  
• 
Total consumption of rescue analgesia will be analyzed nonparametrically using the 
Wilcoxon rank sum test.   
• 
Patient Global Assessment at scheduled evaluations will be assessed for treatment 
group differences using an ANCOVA comparison with center and the baseline pain 
score as the stratification factor. 
Tertiary endpoints 
• 
Time-specific pain intensity profile over time will be assessed using a mixed models 
repeated measures (MMRM), with fixed effects for treatment, time, the treatment by 
time interaction, and random patient effect.  Pairwise comparisons at each time point 
will be determined from the MMRM, and model-based means (LSMeans) and 
standard errors will be plotted for visual comparison of the treatment group 
outcomes. 
• 
The time to pain relief (meaningful and perceptible), as well as time to first rescue 
medication, will be assessed using a log-rank statistic, stratified by center.  A Kaplan-
Meier plot will be provided for each of these outcomes.  The time to event analyses 
will include the times to events of death or withdrawal from study as endpoints.  


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Name of Sponsor/Company: Avenue Therapeutics, Inc. 
Name of Investigational Product: AVE-901 
Name of Active Ingredient: Tramadol for intravenous infusion 
Patients will be censored at 4 hours for time to pain relief, while time to first rescue 
medication will be censored at 48 hours.   
• 
The number (%) of patients who require no rescue analgesia during the 48-hour 
period following T0 will be assessed using a CMH test stratified by center. 
• 
The rate of consumption of rescue analgesia will be analyzed nonparametrically 
using the Wilcoxon rank sum test.   
Pharmacokinetics 
For the subset of patients undergoing PK blood sampling, descriptive statistics will be calculated for 
the plasma concentrations of tramadol and O-desmethyltramadol collected at the designated sample 
collection times.  An assessment of the exposure-response profile for key safety outcomes (ECG 
changes, select adverse events, drug-drug interactions) will be performed for both parent and 
metabolite.  Population pharmacokinetic methods (via exploration of potential intrinsic and extrinsic 
factors) may be applied if numerical assessments demonstrate potential associations between 
exposure and response. 
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 for each treatment group. Additional summaries by severity, relationship, and 
subgroup will be presented.  Serious AEs (SAEs) will be summarized similarly.  
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.  
ECG results will be analyzed on an ongoing basis by a central ECG reader on an individual patient 
level and as well as by group analysis 
Clinical laboratory and vital signs will be summarized descriptively by time point.  Local tolerability 
at the infusion site will be assessed for pain, swelling, tenderness, and erythema.  Adverse events 
suggestive of abuse liability will be summarized separately.  These abuse-related AEs include 
euphoria-type adverse events, hallucinations and inappropriate affect, and withdrawal events after 
abrupt discontinuation of treatment. 
 


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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 ...................................................... 19 
3. 
List of Abbreviations and Definitions of Terms .............................................................. 23 
4. 
Introduction .................................................................................................................. 26 
4.1. 
Tramadol Infusion ............................................................................................................ 26 
4.2. 
Nonclinical Summary ....................................................................................................... 27 
4.3. 
Pharmacokinetic Profile ................................................................................................... 27 
4.4. 
Rationale for this Study .................................................................................................... 31 
5. 
Trial Objectives and purpose ......................................................................................... 32 
6. 
Investigational plan ....................................................................................................... 33 
6.1. 
Overall Study Design ........................................................................................................ 33 
6.2. 
Number of Patients .......................................................................................................... 34 
6.3. 
Treatment Assignment and Randomization ...................................................................... 34 
6.4. 
Criteria for Study Termination .......................................................................................... 34 
6.4.1. 
Individual Patient Stopping Rules .................................................................................... 34 
6.5. 
Schedule of Events ........................................................................................................... 34 
6.6. 
Description of Visits ......................................................................................................... 37 
6.6.1. 
Screening ........................................................................................................................ 37 
6.6.2. 
Preoperative ................................................................................................................... 38 
6.6.3. 
Operative ........................................................................................................................ 38 
6.6.4. 
Post operative/Treatment Period ................................................................................... 39 
6.6.4.1. 
Rescue medication during the Treatment Period ................................................................... 40 
6.6.5. 
Follow up......................................................................................................................... 40 
7. 
Selection and Withdrawal of patients ............................................................................ 41 
7.1. 
Patient Inclusion Criteria .................................................................................................. 41 
7.2. 
Patient Exclusion Criteria ................................................................................................. 41 
7.2.1. 
Post-Surgical Dosing Criteria ........................................................................................... 43 
7.3. 
Patient Withdrawal Criteria .............................................................................................. 44 
8. 
Treatment of Patients ................................................................................................... 45 
8.1. 
Description of Study Drug ................................................................................................ 45 
8.2. 
Concomitant Medications ................................................................................................ 45 
8.3. 
Treatment Compliance ..................................................................................................... 46 
8.4. 
Overdose ......................................................................................................................... 46 
8.5. 
Randomization, Blinding and Unblinding .......................................................................... 46 
9. 
Study Drug Materials and Management ........................................................................ 48 
9.1. 
Study Drug Packaging and Labeling ................................................................................... 48 
9.2. 
Packaging, Labeling, and Storage of Clinical Supplies ......................................................... 48 
9.3. 
Study Drug Preparation and Administration ..................................................................... 49 
9.4. 
Study Drug Accountability ................................................................................................ 49 


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9.5. 
Study Drug Handling and Disposal .................................................................................... 49 
10. 
Pharmacokinetic Assessments ................................................................................... 50 
11. 
Assessment of Efficacy ............................................................................................... 51 
12. 
Assessment of Safety ................................................................................................. 52 
12.1. 
Safety Parameters............................................................................................................ 52 
12.1.1. 
Demographic/Medical History ........................................................................................ 52 
12.1.2. 
Vital Signs ........................................................................................................................ 52 
12.1.3. 
Weight and Height .......................................................................................................... 52 
12.1.4. 
Electrocardiogram (ECG) ................................................................................................. 52 
12.1.5. 
Physical Examination ....................................................................................................... 52 
12.1.6. 
Laboratory Assessments ................................................................................................. 52 
12.1.6.1. 
Hematology and Blood Chemistry .......................................................................................... 52 
12.1.6.2. 
Urinalysis ............................................................................................................................... 53 
12.1.6.3. 
Infectious Disease Testing ...................................................................................................... 53 
12.1.6.4. 
Coagulation Factor Testing ..................................................................................................... 53 
12.1.6.5. 
Pregnancy Screen ................................................................................................................... 53 
12.1.6.6. 
Urine Drug Screen .................................................................................................................. 53 
12.1.6.7. 
Alcohol Breath Test ................................................................................................................ 53 
12.2. 
Adverse and Serious Adverse Events ................................................................................ 53 
12.2.1. 
Definition of Adverse Events ........................................................................................... 53 
12.2.1.1. 
Adverse Event (AE) ................................................................................................................. 53 
12.2.1.2. 
Serious Adverse Event (SAE) ................................................................................................... 54 
12.3. 
Relationship to Study Drug ............................................................................................... 55 
12.4. 
Recording Adverse Events ................................................................................................ 56 
12.5. 
Reporting Adverse Events ................................................................................................ 56 
13. 
Statistics .................................................................................................................... 58 
13.1. 
Sample Size Considerations .............................................................................................. 58 
13.2. 
General Statistical Methods ............................................................................................. 58 
13.3. 
Analysis Populations ........................................................................................................ 58 
13.4. 
Baseline Characteristics .................................................................................................... 58 
13.5. 
Patient Disposition ........................................................................................................... 58 
13.6. 
Efficacy Analyses .............................................................................................................. 59 
13.6.1. 
Primary Endpoint ............................................................................................................ 59 
13.6.2. 
Handling of Missing Efficacy Data ................................................................................... 59 
13.6.3. 
Primary Method of Statistical Analysis ............................................................................ 60 
13.6.4. 
Key Secondary Endpoints ................................................................................................ 60 
13.6.5. 
Tertiary endpoints ........................................................................................................... 61 
13.7. 
Alpha Levels .................................................................................................................... 61 
13.8. 
Subgroups ....................................................................................................................... 62 
13.9. 
Safety .............................................................................................................................. 62 
13.9.1. 
Adverse Events ................................................................................................................ 63 
13.9.2. 
Prior and Concomitant Medications ............................................................................... 63 
13.9.3. 
Clinical Laboratories ........................................................................................................ 63 
13.9.4. 
Vital Signs ........................................................................................................................ 63 
13.9.5. 
Physical Examination ....................................................................................................... 63 
14. 
Study Monitoring, Audits, IRB, and Quality ................................................................ 64 


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14.1. 
Study Monitoring ............................................................................................................. 64 
14.2. 
Audits and Inspections ..................................................................................................... 64 
14.3. 
Institutional Review Board/ Independent Ethics Committee ............................................. 65 
14.4. 
Quality Control and Quality Assurance ............................................................................. 65 
15. 
ETHICS ....................................................................................................................... 66 
15.1. 
Ethics Review ................................................................................................................... 66 
15.2. 
Ethical Conduct of the Study............................................................................................. 66 
15.3. 
Written Informed Consent ............................................................................................... 66 
16. 
Data handling and recordkeeping .............................................................................. 67 
16.1. 
Inspection of Records ....................................................................................................... 67 
16.2. 
Retention of Records ....................................................................................................... 67 
16.3. 
Data Capture and Processing ............................................................................................ 67 
17. 
Publication Policy ...................................................................................................... 68 
18. 
List of References ...................................................................................................... 69 
Appendix 1 ........................................................................................................................... 70 
 


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LIST OF TABLES 
Table 1. 
Emergency Contact Information (Study AVE-901-102) ..............................................4 
Table 2 
Abbreviations and Specialist Terms (Study AVE 901-102) .......................................23 
Table 3: 
Additional Plasma Pharmacokinetic Parameters of Tramadol (Study AVE-
901-101) ......................................................................................................................30 
Table 4. 
Schedule of Assessments for each Study Period (Study AVE 901-102)....................35 
Table 5: 
Investigational Product (Study AVE-901-102) ..........................................................45 
Table 6: 
CTCAE Grade (Study AVE 901-102) ........................................................................54 
 
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) ..................................................29 
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) ...............................30 
 


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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 901-102) 
Abbreviation or 
special term 
Explanation 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
μM 
Micromolar 
5-HT3 
5-Hydroxytryptamine 
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 


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Abbreviation or 
special term 
Explanation 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 
FOB 
Functional Observational Battery 
FU 
Follow-up 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl-transferase 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HCV  
Hepatitis C virus  
HIV, HIV-1 
Human Immunodeficiency Virus 
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 
MAOI 
Monoamine Oxidase Inhibitors 
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 


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Abbreviation or 
special term 
Explanation 
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 
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 
SSRI 
Selective serotonin reuptake inhibitor 
t1/2  
Plasma elimination half-life 
tlag 
Time to the first measurable plasma concentration 
tmax  
Time to reach peak plasma concentration 
UDS 
Urine Drug Screen 
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 et al., 2002). 
Several options are available for postoperative pain management (Singelyn et al., 1998; Sinatra 
et al., 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 and Sablotzki, 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 and Sablotzki, 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 and Perry, 2000; Grond and Sablotzki, 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 and Sablotzki, 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 et 
al., 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 et al., 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 et al., 2006). 
The toxicity of tramadol has been summarized by Matthiesen et al. (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 et al., 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 et 
al., 1998; Yamamoto et al., 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 et al., 1986). Peak serum concentrations 


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(Tmax) were reached approximately 2 hours after oral dosing and the peak serum concentration 
(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 and Sablotzki, 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 Difference 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 


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reached steady-state concentrations). Overall exposure to tramadol was estimated primarily from 
average trough plasma concentrations.   
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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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:   
• Overall Cmax was comparable between the 50 mg IV and 100 mg PO regimens but 
was achieved earlier with the IV regimen 
• 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   
• The 50 mg IV regimen, as compared to the 75 mg IV regimen, resulted in less peak to 
trough fluctuation with lower Cmax  


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• 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 double-blind efficacy and safety study will be conducted in addition to one other efficacy 
Phase 3 study and one open-label safety study.  This efficacy study is being performed in an 
orthopedic model (AVE-901-102), while the other Phase 3 efficacy study is being performed in a 
soft tissue model (AVE-901-103).  The safety study (AVE-901-104) will be performed in a 
range of surgical types.   
Data from this current study will be combined with data from the other studies into an overall 
safety and efficacy database for tramadol infusion. 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to evaluate the analgesic efficacy of intravenous (IV) 
tramadol (AVE-901) compared to placebo in the management of postoperative pain following 
orthopedic (bunionectomy) surgery.   
The Sum of Pain Intensity Differences (SPID) through 48 hours post first dose (SPID48) 
measured at rest will be used as the primary measure of efficacy.   
Secondary efficacy endpoints are: 
• SPID through 24 hours post first dose (SPID24) measured at rest  
• Total consumption of rescue (supplemental) analgesia. This is the total amount of 
rescue analgesia given to the patient after first dose of study medication through 48 
hours post-first dose. 
• Patient Global Assessment of efficacy at 24 and 48 hours post first dose using a 5-
point scale.  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). 
Additional analgesia endpoints are: 
• Time-specific pain intensity profile over time 
• Time (in minutes) to first rescue analgesia from the time of first dose of study 
medication. 
• Number (percent) of patients who require no rescue analgesia from T0-T48. 
• Rate of consumption of rescue analgesia.  The total amount of rescue analgesia will 
be expressed as a function of duration of treatment  
• Time (in minutes) to meaningful pain relief after first dose.  
• Time (in minutes) to perceptible pain relief after first dose.  
Safety endpoints will include: 
• Adverse events (classified by the MedDRA System Organ Class (SOC) and preferred 
term), including assessment of AE’s related to substance abuse.   
• Clinical laboratory, vital sign, PE and ECG changes 
• Use of anti-emetics and other concomitant medicine 
• Local tolerability at the infusion site via pain, swelling, tenderness, and erythema.   
Population pharmacokinetic outcomes will be assessed through collection of plasma samples for 
a subset of the randomized patients.  Exposure-response relationships will be assessed for safety 
outcomes. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This study is a Phase 3, multicenter, double-blind, three-arm, randomized, placebo-controlled, 
multiple-dose, parallel-group trial to evaluate the safety, tolerability and the efficacy of IV 
Tramadol (AVE-901) versus placebo in the management of postoperative pain in consenting 
patients undergoing a unilateral primary first metatarsal bunionectomy surgery.  The treatment 
groups will be: 
• AVE-901 50 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
• AVE-901 25 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
• Placebo, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
Approximately 405 patients will be randomized (135 per treatment group).  
Each patient will undergo the Screening Visit (Day -28 to Day -1), the pre-operative assessment 
(within 24 hours prior to surgery start time), the Surgical/Treatment Visit, the first day of which 
is when the bunionectomy will be performed (Day 0), the primary treatment period through Hour 
48 (the last on treatment assessment, and the 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, 
and after the patient has met eligibility criteria, patients will be randomized in a double-blinded 
fashion, stratified by study center, in a 1:1:1 ratio to the treatment groups.   
Following surgery, patients that have met the post-surgical dosing criteria will receive his or her 
assigned study medication infusion regimen over a period of 48 hours. Patients will be confined 
at the healthcare facility during study drug administration, and will be discharged only if 
clinically stable.   
Efficacy will be assessed by patient reports of pain intensity (PI) performed immediately prior to 
T0 (the first administration of study drug) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 
24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, and 48 hours after first treatment (ie, post T0). PI is 
reported by the patient on a numeric rating scale for pain (NPRS Pain) anchored at 0 for no pain 
and 10 for the worst pain imaginable (See Appendix 1).  In addition, efficacy and safety will be 
measured by other parameters.   
Rescue medication (Ibuprofen 400 mg Q4 PRN) will be available any time after the initial dose 
of study medication to keep the patient comfortable. However, patients will be encouraged to 
wait at least 60 minutes after the initial dose of study medication before they receive rescue 
therapy.  An NPRS measure will be obtained immediately (approximately 5 minutes) prior to 
each administration of rescue medication.  Patient controlled analgesia (PCA) will not be 
allowed in this study. 
Approximately 33% of the total number of patients will be enrolled in the pharmacokinetic (PK) 
portion of this study at select sites.  Blood will be collected for analysis of tramadol and O-
desmethyltramadol (active metabolite) at Hour 0, Hour 0.25, Hour 0.5, Hour 2.25, Hour 2.5, 
Hour 4, Hour 4.25, Hour 4.5, Hour 8, Hour 8.25,  Hour 24.5, Hour 44, Hour 44.25, Hour 44.5, 
and Hour 48. 


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6.2. 
Number of Patients 
A total of approximately 405 patients in United States (US) undergoing elective orthopedic 
surgery who meet all of the inclusion and none of the exclusion criteria, randomized, have at 
least one pain intensity measurement and receive at least a partial dose of study drug will be 
included in the study population. 
6.3. 
Treatment Assignment and Randomization 
Patients will be randomized to one of three treatment arms (AVE-901 50 mg AVE-901 25 mg, or 
placebo) in a 1:1:1 ratio (approximately 135 patients per treatment group).  Randomization will 
be stratified by study center. 
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: 
• The finding of an unacceptable risk to the patients enrolled in the study, 
• Failure to enroll patients at an acceptable rate, 
• Insufficient adherence to protocol requirements and good clinical practices, or; 
• 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 Medical Monitor and Investigator will review the patient’s 
medical record 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 discontinuing prematurely from the 
study will have all End of Treatment assessments performed.  


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Table 4. 
Schedule of Assessments for each Study Period (Study AVE 901-102) 
Assessments 
Screen 
Day -28 
to -1 
Pre-op 
Day  
-1/ 0 
Surgery 
Day 01 
Treatment Hours Post Start of First Infusion  
Hour 0 to Hour 48 : Assessments must be done after 15 minutes of rest. The assessments must be performed +/- 10 minutes from the targeted time point.  
Phone 
Call 
Day 14 
+ 2 
 
 
 
0 
0.5 
1 
2 
3 
4 
 
5 
6 
8 
10 
12 
14 
 
16 
18 
20 
22 
24 
 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48/ 
EOT 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X8 
 
ASA Physical Status 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Lab blood draw 3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CYP2D6 blood sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
X (Collect ECG 20 to 30 minutes after the start of each dose for the first 24 hours) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Inclusion/Exclusion 
Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Education 
Video 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Pain 
Assessment Training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Op Dosing 
criteria assessment  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4-Point Pain Scale 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Admin 
 
 
 
X6 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Pain Intensity NPRS7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Initiate 2 stopwatches  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Global Assess 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PopPK Sampling 
 
 
 
Blood will be collected Hour 0, Hour 0.25, Hour 0.5, Hour 2.25, Hour 2.5, Hour 4, Hour 4.25, Hour 4.5, Hour 8, Hour 8.25, Hour 24.5 Hour 44, Hour 44.25, Hour 44.5, and Hour 48. 
 
Record rescue med 
 
 
 
                                                                                                                                                                           Ongoing 
Adverse Events 
 
 
Ongoing 
                                                 
 
1 Preoperative assessments to confirm the patient’s eligibility will be performed within 24 hours of scheduled surgery start time. 
2 Pre-Op Pregnancy test (urine) performed on-site for female patients of childbearing potential. Serum pregnancy test is performed at Screening and End of Treatment 
3 Hem, Chem, Coag, Urinalysis Pre-op labs only needed for patients whose screening laboratory tests were performed >7 days prior to randomization 
4 Urine drug screen should be performed at screening  and Day 0 (on-site)  
5 Randomization is to occur pre surgery after all eligibility criteria are met 
6 First dose of study drug at first report of moderate or severe pain from a 4 point scale and a score of ≥5 on NPRS pain intensity, See Appendix 1 
7 In addition Pain Intensity Assessment must be completed prior to each rescue medication use or dosing. Note there is no rest period required for NPRS prior to rescue drug administration 
8 Hour 48 PE can be done at any time prior to discharge (+ 10 minute window not applicable) 


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Prior/Conmeds 
X 
X 
Ongoing 


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6.6. 
Description of Visits 
There are 5 distinct periods in this study: 
• Screening (Days -28 to -1) 
• Pre-operative (within 24 hours of scheduled surgery) 
• Operative (Day 0) 
• Post-operative/Treatment Period 48 hours 
• 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: 
• Demographics, including gender, race and ethnic origin, date of birth, height, weight 
and calculated BMI.   
− BMI Calculation: Sites should use the NIH website BMI calculator: 
https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm 
• Inclusion/exclusion eligibility criteria 
• Physical examination 
• ASA Physical Status 
• Medical history 
• Prior and ongoing medications (taken in previous 30 days) 
• Vital signs: blood pressure, heart rate, respiratory rate, and oral temperature (after 
seated or supine for 5 minutes) and SpO2 
• 12-lead ECG (after supine for 5 minutes) 
• Blood samples for hematology, clinical chemistry, coagulation, HIV-1/HIV-2 
antibody, hepatitis B surface antigen, hepatitis C antibody, Pregnancy test for women 
of child-bearing potential (serum) 
• Urine sample for urinalysis  
• Urine drug screen for drugs of abuse (onsite) 
• Alcohol breath Test  


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• Patient Education Video and Patient Pain Assessment Training 
Compliance with inclusion criteria and exclusion criteria will be verified against information 
collected and documented in the source documents and the eCRF.   
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: 
• Inclusion/exclusion eligibility criteria 
• Brief Physical examination (symptom driven) 
• ASA Physical Status 
• Medical history 
• Prior and ongoing medications (taken in previous 30 days) 
• Vital signs: blood pressure, heart rate, respiratory rate, and oral temperature (after 
seated or supine for 5 minutes) and SpO2 
• Blood samples for hematology, clinical chemistry, coagulation (not required if pre-op 
visit is within 7 days of screening) 
• A blood sample will be obtained and stored for possible analysis of CYP2D6 
metabolizer status, in case such information is deemed to be of interest during the 
analysis.  Collection and processing of these samples will be addressed in a lab 
manual.  
• Urine Sample for urinalysis  
• Urine Pregnancy test for women of child-bearing potential (onsite) 
• Urine drug screen for drugs of abuse (onsite) 
• Alcohol breath Test (onsite) 
• Patient Education Video Training 
The safety laboratory tests done centrally will not be used for determining eligibility; however, 
they may be used to exclude a patient from receiving further study medication at the discretion of 
the investigator, medical monitor and sponsor.   
 Randomization may occur at any time after confirmation that all inclusion and exclusion criteria 
have been met and before surgery. Dosing will occur once the subject has met all post-operative 
dosing criteria 
6.6.3. 
Operative 
Surgery will occur on Day 0. Operative procedures are described in the Surgical and Anesthetic 
Regimen.   


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6.6.4. 
Post-operative/Treatment Period 
In addition to meeting all eligibility criteria prior to surgery, patients must ALSO meet all 
postsurgical dosing criteria. Treatment will occur from Hour 0 through Hour 44 (T0-T44).   
• Following surgery, patients will have their popliteal block withdrawn at 
approximately between 4 AM and 5 AM. Post removal of the popliteal block, Patients 
must be assessed for the dosing eligibility criteria prior to dosing. Patients must be 
awake and alert, and must have a pain intensity of 5 or greater and report a score of 
moderate or severe on a 4-point categorical rating scale (with categories of none, 
mild, moderate, or severe) just before the first dose of the study drug.  Patients who 
do not report pain at this level within 8 hours of the removal of the block will be 
discontinued (ie, not treated). 
• Antiemetic treatment with Reglan or Emend (not Zofran or other 5HT3 antagonists) 
is allowed. 
During the Treatment phase, patients will undergo: 
• NPRS -  T0 will be time of start of infusion of first study drug administration.  Pain 
intensity will be recorded using a NPRS from 0 to 10, where 0 is no pain and 10 is the 
worst pain imaginable.  Pain intensity assessments will be recorded immediately prior to 
first dose (baseline) and at the times indicated in the Schedule of Assessments.  The 
patient must rest for 15 minutes (+/- 5 minutes) prior to assessments.  
• The Patient Global Assessment (PGA) of efficacy will be completed by the patient at 24 
hours and 48 hours post T0.  Ratings will be assessed as: 0=poor; 1=fair, 2=good, 3=very 
good or 4=excellent.  
• Two stopwatches will be started at the start of infusion of first study drug dose.  Patients 
will be instructed to stop the first stopwatch when pain relief is first perceptible and the 
second when pain relief is considered meaningful. 
• Vital signs: blood pressure, heart rate, respiratory rate, and oral temperature (after seated 
or supine for 5 minutes) and SpO2 as per the schedule of events 
• Study Drug dosing at 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 hours 
• 12 lead ECG (after supine for 5 minutes) at 20 to 30 minutes after the start  of each dose 
for the first 24 hours 
• AEs 
• Concomitant medication use 
• Rescue medication use 
• For those patients enrolled in the PK portion of this study (at select sites), blood will be 
collected for analysis of tramadol and O-desmethyltramadol (active metabolite) at: 
Hour 0, Hour 0.25, Hour 0.5, Hour 2.25, Hour 2.5, Hour 4, Hour 4.25, Hour 4.5, 
Hour 8, Hour 8.25, Hour 24.5, Hour 44, Hour 44.25, Hour 44.5, and Hour 48. 
 


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At the End of Treatment or Early Termination, patients will undergo: 
• A brief (symptom driven) physical examination (may be completed any time prior to 
discharge)  
• Vital signs: blood pressure, heart rate, respiratory rate, and oral temperature (after 
seated or supine for 5 minutes) and SpO2 
• 12-lead ECG (after supine for 5 minutes) 
• Blood samples for hematology, clinical chemistry, urinalysis, and pregnancy test 
(serum) 
• Pain Intensity NPRS and Patient Global Assessment 
• AEs 
• Concomitant medication use 
• For those patients enrolled in the PK portion of this study (at select sites), blood will 
be collected for analysis of tramadol and O-desmethyltramadol (active metabolite) 
At time points when multiple assessments are required, the order of assessments will be: Pain 
assessment, vital signs, blood draw, and then study drug administration 
If feasible, any patient who prematurely discontinues study medication or the study prior to the 
T48 will undergo the procedures required at the end of treatment.   Post T48, pain management 
will be per investigator standard of care preference. 
6.6.4.1. 
Rescue medication during the Treatment Period 
Inadequate analgesia may be treated with 400 mg of ibuprofen q 4 hours PRN administered by a 
trained nurse or study clinician to the patients who request rescue medication after administration 
of the initial dose of study medication.  However, patients will be encouraged to avoid rescue 
medications for at least 60 minutes after their first dose of study drug.  A NPRS measure will be 
obtained immediately (approximately 5 minutes) prior to administering any rescue medication.  
Patients will continue to take study medication for the remainder of the 48-hour period even if 
they take rescue medication.  Ibuprofen dosing is allowed: 400 mg PRN every 4 hours up to 
2400 mg per day. The time of rescue medication must be recorded in the case report form.  
Investigator study team personnel will monitor the patient carefully for 48 hours following the 
surgery to assess the patient's condition and provide rescue medication whenever requested, 
within the above limits.  This will minimize the patient's inconvenience due to pain.   
6.6.5. 
Follow up 
A final safety assessment will be conducted on Day 14 (± 2 days) via a telephone call. 


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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 undergoing unilateral first metatarsal 
bunionectomy surgery 
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.  Highly effective 
contraception methods include:  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 negative pregnancy test (urine) 
within 24 hours prior to surgery, and must not be lactating. 
5. The patient must be willing to be housed in a healthcare facility and able to receive 
parenteral analgesia for at least 72 hours after surgery. 
6. The patient meets definition of American Society of Anesthesiologists (ASA) Physical 
Class 1 or 2. 
7. The patient is willing and able to understand the study procedures and the use of pain 
scales, 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. Patient is not expected to receive a continuous infusion nerve block as described in the 
Post-Op anesthetic procedure protocol. 
2. Patient is currently using, or is expected to receive gabapentin, pregabalin, ketamine or 
other peri- or postoperative analgesic adjuncts or any analgesics not allowed in the 
Surgical and Anesthesia protocol. 
3. Patient is undergoing bilateral or revision bunionectomy surgery.  
4. Patient has a history of primary or metastatic bone cancer or Paget's disease. 


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5. The patient has current or historical evidence of any clinically significant disease or 
condition that might increase the risk of surgery or complicate the patient's postoperative 
course. 
6. The patient has allergy or hypersensitivity (or is intolerant) to opioids or tramadol. 
7. The patient has known physical dependence on opioids. 
8. Patients who have taken any opioids, including tramadol for a total of 3 days, within 30 
days prior to surgery. 
9. The patient has a recent (within 5 years) and/or current history of chronic analgesic, 
opiate or tranquilizer abuse or dependence or is a user of illicit drugs, or has had a recent 
history (within 2 years) of drug or alcohol abuse. 
10. The patient has a painful physical condition that, in the opinion of the investigator, may 
confound the assessments of postoperative pain.  
11. The patient has taken other prior/concurrent chronic medications that have not been at a 
stable dose for at least 2 weeks prior to screening. 
12. 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 (eg, 
carbamazepine, rifampin, St. John's Wort) and cannot go through a minimum washout 
period of 7 days prior to surgery. 
13. The patient has taken monoamine oxidase (MAO) inhibitors, trazodone or 
cyclobenzaprine within 14 days prior to surgery. 
14. The patient has a history of epilepsy, or is known to be susceptible to seizures.  
15. 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). 
16. The patient has a history of Long QT Syndrome or a relative with this condition. 
17. The patient has had a recent cardiovascular event or a clinically significant abnormal 
ECG at screening.  
18. The patient has used (within 30 days of surgery), is currently using or is anticipated to 
use chronic corticosteroids . 
19. The patient has expressed suicidal ideation or is considered to be at risk of suicide. 
20. The patient is morbidly obese (body mass index [BMI] > 40 kg/m2) or has documented 
sleep apnea requiring pharmacological or device intervention. 
21. The patient has a history of cardiopulmonary, neurological or psychiatric condition that 
may confound the assessments of efficacy or safety. 


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22. 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.    
23. The patient has severe renal impairment or a serum creatinine value of > 2.0 mg/dL at 
Screening. 
24. The patient has potassium, sodium, calcium or magnesium levels outside of the normal 
range, or any other clinically significant abnormalities in blood chemistry at Screening. 
25. The patient has a hemoglobin level at screening which, in the judgment of the 
Investigator, is not suitable for participation in this study. 
26. The patient used narcotics or alcohol within 24 hours prior to surgery. 
27. The patient was administered an investigational product within 30 days prior to 
Screening. 
28. The patient has previously participated in a clinical study with AVE-901.  
7.2.1. 
Post-Surgical Dosing Criteria 
The patient is to be evaluated post-operatively prior to the initial treatment with the study drug 
and will be given the study drug only if all of the following criteria are met: 
1. The patient reports a score of moderate or severe on a 4-point categorical rating scale 
(with categories of none, mild, moderate, or severe) and has a NPRS pain score of ≥5 (on 
a scale from 0 to 10) within 8 hours after removal of popliteal block.   
2. The patient is alert and oriented. She/he is able to answer questions and follow 
commands and has appropriate cognitive function to properly interpret and answer 
protocol mandated assessments. 
3. The patient has no 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. 
4. The surgical procedure from incision to closure was not longer than 180 min. 
5. There have been no significant deviations from the surgical or anesthetic protocol that 
would, in the opinion of the investigator, put the patient at risk of participation in the 
trial, confound the analgesic endpoints of the trial or cause concern regarding the 
patient’s ability to participate in the trial.   
6. There have been no use of gabapentanoids, or 5-HT3 antagonists (e.g. ondansetron, 
granisetron, palonosetron) preoperatively, intraoperatively, or postoperatively. 
7. Subject has not experienced complications during the surgical procedure and in the 
opinion of the investigator is a candidate to continue in the study.   
 


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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 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: 
• 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. 
• 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. 
• 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. Placebo ampules contain only the liquid vehicle. 
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 products.  
Table 5: 
Investigational Product (Study AVE-901-102) 
 
Investigational Product 
Product Name: 
Tramadol for infusion 
50 mg 
Tramadol for infusion 
25 mg 
Placebo 
Dosage Form: 
Liquid 
Liquid 
Liquid 
Unit Dose: 
50 mg/1mL ampoule  
50 mg/1mL ampoule 
1mL ampoule 
Route of 
Administration: 
Intravenous infusion 
Intravenous infusion 
Intravenous infusion 
Physical 
Description: 
Clear solution 
Clear solution 
Clear solution 
Manufacturer: 
Pharmaceutical Works 
PolPharma S. A. 
Pharmaceutical Works 
PolPharma S. A. 
Pharmaceutical 
Works PolPharma 
S.A. 
8.2. 
Concomitant Medications 
All concomitant medications, whether prescription, over-the-counter, herbal treatments or other 
therapy, taken or used by the patient within 30 days of screening through end of study 
assessments (f/u phone call Day 14) will be recorded in the patient’s medical record and in the 
Concomitant Medications eCRF.  Concomitant medications will be coded using the WHO Drug 
Dictionary. 
Rescue medication (Ibuprofen 400 mg Q4 PRN) will be available q 4 hours after the initial dose 
of study medication to keep the patient comfortable. However, patients will be encouraged to 
wait at least 60 minutes after the initial dose of study medication before they receive rescue 
therapy. The rescue medication is the only analgesic allowed within the study.  Other non-pain 


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relieving medications deemed necessary for the patient’s welfare are permitted, other than 
medications specified in the inclusion/exclusion criteria. 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. 
If medication is needed to treat any adverse events during the study, patient study continuation 
will be evaluated. 
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 
start/stop 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 
Patients will be randomized to one of 3 treatment groups, as follows: 
• AVE-901 50 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
• AVE-901 25 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
• Placebo, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
Patients will be randomized to one of the three treatment arms (AVE-901 50 mg, AVE-901 25 
mg, or placebo) in a 1:1:1 ratio (approximately 135 patients per treatment group).  
Randomization will be stratified by study center.  The study will remain blinded until all patients 
have completed their treatment period and completed all study procedures and the clinical 


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database has been locked.  Procedures for emergency unblinding will be described in the Study 
Blinding Plan. 


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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-901-102 
2. Each 1ml ampoule contains 50 mg of IV Tramadol (C-IV) or placebo 
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: Pharmaceutical Works PolPharma S. A. 
8. Lot number: __________________  
9. Kit number:___________________ 
The clinical trial supply labels 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/tablets 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 (according to the randomization allocation) and maintain 
accountability records.  Study treatment for each period will be prepared according to the 
treatment sequence assignments.   
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 that correspond to the 
doses of study medication used in this study. 
Unblinded personnel will be designated to prepare the treatment according to the randomization 
allocation.  Study blinding and unblinding will be described in the Study Blinding Plan. 
9.4. 
Study Drug Accountability 
Patients will be treated at the investigational center and therefore the unblinded Pharmacist or 
other unblinded 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, at the end of the study, all unused investigational drug, accompanied by a packing 
slip will be shipped to a 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 
Approximately 33% of the total number of patients will be enrolled in the pharmacokinetic (PK) 
portion of this study at select sites.  Blood will be collected for analysis of tramadol and O-
desmethyltramadol (active metabolite) at Hour 0, Hour 0.25, Hour 0.5, Hour 2.25, Hour 2.5, 
Hour 4, Hour 4.25, Hour 4.5, Hour 8, Hour 8.25, Hour 24.5 Hour 44, Hour 44.25, Hour 44.5, and 
Hour 48.  A separate population PK analysis plan will be written to describe the assessment of 
the PK data.  PK sample processing will be addressed in the lab manual. 


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11. 
ASSESSMENT OF EFFICACY 
The primary endpoint in this study is SPID48 for pain at rest.  Pain intensity will be recorded 
using a NPRS from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable (See 
Appendix 1).   
Key secondary endpoints are: 
• SPID through 24 hours post first dose (SPID24) at rest 
• Total consumption of rescue (supplemental) analgesia. This is the total amount of 
rescue analgesia given to the patient after first dose of study medication through 48 
hours post-first dose. 
• Patient Global Assessment of efficacy at 24 and 48 hours.  The Patient Global 
Assessment (PGA) of efficacy will be completed by the patient at 24 hours and 48 
hours post T0.  Ratings will be assessed as: 0=poor; 1=fair, 2=good, 3=very good or 
4=excellent. 
Tertiary endpoints (additional analgesia endpoints) are: 
• Time-specific pain intensity profile over time 
• Clock time (in minutes) to first use of rescue medication from the time of first dose of 
study medication. 
• Number of patients who require no rescue analgesia from T0-T48 
• The rate of consumption of rescue analgesia 
• Time (in minutes) to meaningful pain relief after first dose.  Two stopwatches will be 
started at the start of infusion of first study drug dose.  Patients will be instructed to 
stop the first stopwatch when pain relief is first perceptible and the second when pain 
relief is considered meaningful. 
• Time (in minutes) to perceptible pain relief after first dose 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
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.   
12.1.1. 
Demographic/Medical History 
Demographic information and medical history will be collected at Screening and pre-operatively 
for determination of eligibility.  
12.1.2. 
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.  Vitals will be performed after 
the patient has rested sitting or supine for approximately 5 minutes. 
12.1.3. 
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 http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-
m.htm. 
12.1.4. 
Electrocardiogram (ECG) 
All scheduled ECGs will be performed after the patient has rested supine for approximately 5 
minutes. 
12.1.5. 
Physical Examination 
A physical examination will be conducted and abnormalities will be described.  After the initial 
physical exam, only symptom-driven examinations will be performed according to the treating 
physician. 
12.1.6. 
Laboratory Assessments 
All laboratory assessments will be collected as per the schedule of events. 
12.1.6.1. Hematology and Blood Chemistry 
Clinical Laboratories (Hematology and Serum Chemistry) will be performed as described below 
and as indicated in the schedule of events. 
• CLINICAL CHEMISTRY  - Total protein, albumin, serum creatinine, blood urea 
nitrogen (BUN), uric acid, bilirubin (total & direct), alkaline phosphatase, alanine 
aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT), creatine 
phosphokinase (CPK), glucose, calcium, magnesium, phosphorus, sodium, potassium, 
chloride, bicarbonate 


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• HEMATOLOGY - White blood cell (WBC) count, differential white cell count 
(lymphocytes, monocytes, basophils, eosinophils, neutrophils), red blood cell (RBC) 
count, hematocrit, hemoglobin and platelet count. 
12.1.6.2. Urinalysis 
Urinalysis will be performed.   
• URINALYSIS - Color, specific gravity, pH, glucose, ketones, blood, protein, nitrates, 
leukocyte esterase, appearance. 
Instruct patient to obtain a "clean-catch" urine sample, collected in midstream.  
12.1.6.3. Infectious Disease Testing 
Infectious disease testing at screening will include:  HIV-1/HIV-2 antibody, hepatitis B surface 
antigen, hepatitis C antibody. 
12.1.6.4. Coagulation Factor Testing 
Coagulation Factor Testing will be performed at screening and pre-op in accordance with the 
schedule of events. 
12.1.6.5. Pregnancy Screen 
Pregnancy screening will be performed for all females of childbearing potential in accordance 
with the schedule of events via central lab blood test at screening and EOT and via urine test 
onsite at pre-op.  
12.1.6.6. Urine Drug Screen 
Drug screening will minimally include:  THC, Opiates, Amphetamines, Cocaine, Barbiturates 
and Benzodiazepines and will be performed onsite in accordance with the schedule of events.  
12.1.6.7. Alcohol Breath Test 
Alcohol Breath Test will be performed onsite in accordance with the schedule of events.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. 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. 


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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. 
Table 6: 
CTCAE Grade (Study AVE 901-102) 
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. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during the study that fulfills one or more of the 
following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 


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• 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-
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 within 1 week following early 
termination visit should be recorded and reported as noted previously. 
12.3. 
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: 
• follows a reasonable temporal sequence from drug administration, 
• abates upon discontinuation of the drug (dechallenge), AND 
• is confirmed by reappearance of the reaction on repeat exposure (rechallenge). 
PROBABLE - The adverse event: 
• follows a reasonable temporal sequence from drug administration, 
• abates upon discontinuation of the drug (dechallenge), and 
• cannot be reasonably explained by the known characteristics of the patient’s clinical 
state. 
POSSIBLE - The adverse event: 
• follows a reasonable temporal sequence from drug administration, and; 
• could have been produced by the patient's clinical state or by other modes of therapy 
administered to the patient. 
REMOTE  


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• The temporal sequence between the adverse event and the drug administration is such 
that the drug is not likely to have had any reasonable association with the observed 
event. 
DEFINITELY NOT – The adverse event: 
• is definitely produced by the patient's clinical state or by other modes of therapy 
administered to the patient. 
12.4. 
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 12.2.1.2.  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. 
12.5. 
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.  Events occurring prior to first dose of study treatment will be 
recorded as medical history.  AEs or SAEs occurring after the first dose of study treatment will 
be treatment-emergent (S)AEs.  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.  


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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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13. 
STATISTICS 
This is a double-blind, 3-arm, placebo-controlled treatment study to determine the efficacy and 
safety of tramadol infusion in patients undergoing bunionectomy.  The statistical methods to be 
used in the analysis are consistent with both the study design and the study objectives.  
13.1. 
Sample Size Considerations 
A sample size of 135 patients per arm (405 patients in total) provides over 90% power to detect a 
SPID48 difference of 250 between treatment with placebo and treatment with AVE-901, 
assuming a common SPID48 standard deviation of 600 (and thus an approximate 40% effect 
size), an alpha of 0.05 using a two-sided test of mean differences.   
13.2. 
General Statistical Methods 
Data will be tabulated (by treatment group) using descriptive and inferential statistics, where 
specified.  A comprehensive statistical analysis plan (SAP) will be written and approved prior to 
unblinding.  This SAP will detail how missing values, windows for study visits, and other 
analysis considerations will be addressed. 
13.3. 
Analysis Populations 
Populations identified for purposes of the statistical analysis are listed below. 
• The Full Analysis Set (FAS) population is defined as all randomized patients who 
receive study medication.  Patients will be analyzed according to the treatment group 
they were randomized to.   
• The Safety Population is defined as all patients who receive study medication.  
Patients will be analyzed according to the actual treatment they receive. 
• The All Enrolled Population will include the FAS and subset of patients who are 
randomized but not treated due not meeting post-surgical dosing criteria.  The 
handling of these patients will be described in the Statistical Analysis Plan. 
13.4. 
Baseline Characteristics 
Baseline characteristics will be tabulated descriptively (e.g., number and percent of patients for 
each category for categorical parameters, and the number, mean, standard deviation, and range 
for continuous parameters).  Baseline comparability among the treatment groups with respect to 
demographic and other baseline characteristics will be assessed for quantitative variables with a 
two-way analysis of variance (ANOVA) with treatment group and study center as main effects. 
For categorical variables, the Cochran-Mantel-Haenszel test will be used, stratified by center. 
13.5. 
Patient Disposition 
Patient disposition (including the number and percent of patients who are randomized, who 
receive randomized treatment, who prematurely discontinue and reasons for discontinuation, and 
who complete the study) will be tabulated by treatment group.  The number (%) of patients by 
exposure will be tabulated. 


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13.6. 
Efficacy Analyses 
13.6.1. 
Primary Endpoint 
SPID48 (the sum of the time-weighted pain intensity differences for the time period 0-48 hours) 
is the primary efficacy endpoint.   
13.6.2. 
Handling of Missing Efficacy Data 
For the primary causal estimate in this study (to reflect the true treatment effects of tramadol 
compared to placebo), missing values within a patient during the 48-hour treatment period will 
be handled in the following manner: 
• When rescue medication is used, the last pain intensity measure prior to the use of 
rescue medication will be used (imputed) for the subsequent protocol-specified time 
points for measurement of pain intensity through 4-hours after the time of the rescue 
medication. 
All other missing data will be imputed utilizing multiple imputation methods.  Multiple 
imputation provides a useful strategy for analyzing data sets with missing values. Instead of 
filling in a single value for each missing value, Rubin’s (1976,) multiple imputation strategy 
replaces each missing value with a set of plausible values that represent the uncertainty about the 
correct value to impute. 
For patients with arbitrary missing data patterns (missing at random, MAR), a pattern-mixture 
approach will be taken to the imputation.  The first step will be to apply a Markov chain Monte 
Carlo (MCMC) method (Schafer 1997) that assumes multivariate normality will be used to 
impute all missing values to make the imputed (resulting) data sets have strictly monotone 
missing patterns.  The resulting monotone missing pattern will then, in a second imputation step, 
be used to impute the remaining missing values; specifically, a regression-based method for 
continuous variables will be applied. 
For patients with missing data as a result of discontinuation due to adverse (missing not at 
random, MNAR), the pattern-mixture approach will also be taken to the imputation (as for the 
monotone MAR data),with the difference that while a similar regression-based method for 
continuous variables will be applied, a scaled (constant) adjustment to the imputed values will be 
made such that the outcomes that are imputed are distributionally ‘worse’ than those imputed for 
the monotone MAR data.  This scaled adjustment will increase each imputed value (from the 
regression) for these MNAR data by a constant of ‘1’, e.g., if the regression provides an imputed 
value of 4.6 for a given missing value for a patient at a given timepoint, the MNAR imputed 
value will be set to 4.6 + 1 = 5.6 for that patient at that time point.  This will, in effect, guarantee 
that the overall distribution of missing values for discontinuations due to adverse event is 
WORSE than that for other reasons. 
The SAS software system will be used to perform this imputation.  Because the imputation of 
missing data is a key aspect to the analysis of pain data, explicit details regarding this imputation 
are provided via sample SAS code that is intended to demonstrate the application of these 
strategies.  Variable definitions are: 
• TRT=treatment group (1 or 0) 


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• Pain_1 is the first time point for the pain score 
• Pain_2 is the second time point for the pain score 
• Pain_last is the last time point for the pain score. Additional pain scores (between 
Pain_1 and Pain_last) would be included in this model according to the time points 
for collection. 
The first step will be to impute partially in order to obtain a monotone missing data pattern. 
proc mi data=DATAIN out=DATAIN_MONO nimpute=100 seed=123;  
var TRT Pain_1 Pain_2 …. Pain_last; 
mcmc chain=multiple impute=monotone;  
run; 
The second step will be to impute the remaining (monotone) missing data that is MAR for each 
of the 100 imputed datasets from the first step. 
proc mi data=DATAIN_MONO out=DATAIN_REG seed=465 nimpute=1;  
by _Imputation_;  
var TRT Pain_1 Pain_2 …. Pain_last;  
class TRT;  
monotone regression;  
run; 
In the case of missing data due to an adverse event, the following step will be used: 
proc mi data=DATAIN_MONO out=DATAIN_REG seed=465 nimpute=1;  
by _Imputation_;  
var TRT Pain_1 Pain_2 …. Pain_last;  
class TRT;  
monotone regression (pain1 pain2 … Pain_last);  
mnar adjust (pain1 pain2 … Pain_last / shift=1);  
run; 
Note that the regressions do not include the treatment variable, and thus the imputed data at each 
time point will be based on the distribution of all data rather than treatment-group specific 
distributions.  A total of 100 imputed datasets will be created using these imputed data and 
analyzed according to the primary method of statistical analysis. 
13.6.3. 
Primary Method of Statistical Analysis 
Each of the 100 imputed datasets will be analyzed as follows:   
• An analysis of covariance (ANCOVA) model will be used to test the primary efficacy 
endpoint.  The model will use treatment and study center as main effects, and baseline 
pain intensity (NPRS scale 0 to 10) as the covariate.  Data from all three treatment 
groups will be included in the same ANCOVA model for purposes of the testing 
procedures. 
The 100 resulting treatment effect parameters and standard errors from these ANCOVA will be 
combined to provide a distribution of parameters (and standard errors) upon which the primary 
hypothesis of treatment effect will be determined. 
13.6.4. 
Key Secondary Endpoints 
The key secondary endpoints will be assessed as follows: 


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• 24-hour pain intensity (SPID24) will be assessed in a similar manner as the primary 
endpoint.  
• Total consumption of rescue analgesia will be analyzed nonparametrically using the 
Wilcoxon rank sum test.   
• Patient Global Assessment at scheduled evaluations will be assessed for treatment 
group differences using an ANCOVA comparison with center and the baseline pain 
score as the stratification factor. 
13.6.5. 
Tertiary endpoints 
Tertiary endpoints will be assessed as follows: 
• Time-specific pain intensity profile over time will be assessed using a mixed models 
repeated measures (MMRM), with fixed effects for treatment, time, the treatment by 
time interaction, and random patient effect.  Pairwise comparisons at each time point 
will be determined from the MMRM, and model-based means (LSMeans) and 
standard errors will be plotted for visual comparison of the treatment group outcomes. 
• The time to pain relief (meaningful and perceptible), as well as time to first rescue 
medication, will be assessed using a log-rank statistic, stratified by center.  A Kaplan-
Meier plot will be provided for each of these outcomes.  The time to event analyses 
will include the times to events of death or withdrawal from study as endpoints.  
Patients will be censored at 4 hours for time to pain relief, while time to first rescue 
medication will be censored at 48 hours.   
• The number (%) of patients who require no rescue analgesia during the 48-hour 
period following T0 will be assessed using a CMH test stratified by center. 
• The rate of consumption of rescue analgesia will be analyzed nonparametrically using 
the Wilcoxon rank sum test.   
13.7. 
Alpha Levels 
There are 2 pairwise comparisons of interest: 
• High-dose tramadol (50 mg) vs placebo 
• Low-dose tramadol (25 mg) vs placebo 
All inferential assessments will be 2-sided tests performed at the 0.05 alpha level.  A hierarchical 
alpha testing strategy will be utilized to control for the overall experiment-wise alpha.  As there 
are multiple tests being performed (the single primary efficacy variable pairwise test and the 2 
key secondary efficacy tests), the following strategy will be applied:   
The high-dose tramadol arm vs placebo comparison will be assessed for the primary endpoint at 
the 0.05 alpha level.  If and only if the p-value is ≤ 0.05 for this pairwise comparison will the 
lower dose tramadol arm vs placebo comparison be assessed.  If the p-value for the high-dose 
arm is NOT significant, all testing will cease and it will be concluded that neither tramadol 
treatment arm provides better pain relief than placebo. 


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If the primary endpoint is significant for the AVE-901 vs. placebo comparison (in favor of the 
tramadol arm) for one or both pair-wise tests, then statistical testing will proceed to the 
secondary endpoints within each pair-wise grouping, to be tested in the following order: 
• SPID24 
• Total consumption of rescue analgesia 
• Patient Global Assessment of efficacy at 24 and 48 hours (the two time points will be 
tested simultaneously) 
If a statistical test within each pairwise comparison is significant at the nominal 0.05 level, two-
sided (in favor of the tramadol arm), then testing will proceed to the next endpoint in the list.  
Once a non-significant test occurs, endpoints lower in the list are considered not statistically 
significant. 
Note that while inferential comparison of the high dose to the low dose is not a key aspect of the 
statistical analysis, assessment of the dose-response will be performed across the 3 doses in order 
to allow visual comparison of the outcomes for the primary and key secondary endpoints. 
13.8. 
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: 
• Gender 
• Race 
• Age (using the study median age) 
• Investigational center 
13.9. 
Safety 
The safety analysis will be descriptive in nature.  All safety data will be listed, and data will be 
tabulated by treatment group where the data warrant.  Safety data include: 
• AEs, including assessment of infusion site local reactions (skin and vein) 
• Clinical laboratory tests (hematology panel, chemistry panel and urinalysis) pre-
treatment and discharge 
• Vital signs including: respiratory rate, heart rate, and blood pressure, as per the 
schedule of events  
• Physical examination pre-treatment and discharge 
• 12-lead ECG at protocol specified timepoints 
• Concomitant treatments 
Exploratory analyses of use of anti-emetics may be performed.  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.  


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ECG results will be analyzed on an ongoing basis by a central ECG reader on an individual 
patient level and as well as by group analysis. 
13.9.1. 
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 reported as Medical History  
Adverse events starting after the first dose of treatment will be considered treatment-emergent 
adverse events.  
Local tolerability at the infusion site will be assessed for pain, swelling, tenderness, and 
erythema. 
13.9.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be reviewed and coded using the WHO Drug Dictionary, 
and tabulated by treatment.  
13.9.3. 
Clinical Laboratories 
Clinical laboratory observed values and changes from pre-treatment to on-treatment time points 
may be tabulated for continuous parameters, as warranted.   
13.9.4. 
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.   
13.9.5. 
Physical Examination 
Physical examination outcomes will be listed in data listings.   


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14. 
STUDY MONITORING, AUDITS, IRB, AND QUALITY 
14.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a Sponsor representative will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• 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: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• 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 
• 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 
• Record and report any protocol deviations not previously sent to the Sponsor (or its 
delegate) 
• 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. 
14.2. 
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.   
14.3. 
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. 
14.4. 
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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15. 
ETHICS 
15.1. 
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. 
15.2. 
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. 
15.3. 
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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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
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. 
16.2. 
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. 
16.3. 
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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17. 
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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18. 
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. 
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Protocol AVE-901-102 Phase 3 Orthopedic 
 
Tramadol Infusion 
Avenue Therapeutics, Inc. 
 
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APPENDIX 1 
Numerical Pain Rating Scale (NPRS)