Clinical trial NCT02922582
Conditions: Total Knee Arthroplasty
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2016-10-28; Completion date: 2017-11-27
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, single-blind, active-controlled dose-ranging study in subjects scheduled to undergo total knee arthroplasty (TKA).

Detailed description:
Approximately 60 subjects (15 per arm) are planned for enrollment. Subjects will be randomized in a 1:1:1:1 ratio to receive either DepoTXA 400 mg, DepoTXA 800 mg, DepoTXA 1200 mg, or IV TXA (Cyklokapron® 1 gram).

Arms: arm 1: 400mg Intracapsular at the end of surgery one time arm 2: 800mg Intracapsular at the end of surgery one time arm 3: 1200mg Intracapsular at the end of surgery one time arm 4: 1 g of IV TXA at the end of surgery
Interventions: intervention 1: DepoTXA intervention 2: Tranexamic Acid
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Clinical Study Protocol 
A Randomized, Single-Blind, Active-Controlled, Dose-Ranging Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of Local Administration of DepoTXA 
for Reduced Postsurgical Bleeding in Subjects Undergoing Total Knee Arthroplasty 
Amendment 2 
 
 
Protocol No.: 404-C-201 
EudraCT No.: Not applicable 
IND No.: 128950 
Study Phase: 2 
Study Drug: DepoTXA 
Date: 27-Sep-2017 
Investigator(s) or Study Site(s): Multicenter study in the US 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Telephone: (973) 254-3560 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira Pharmaceuticals, Inc. 
It should not be reproduced, revealed, or sent to third parties other than Institutional Review Boards/Independent 
Ethics Committees and the Investigator’s research support staff participating in the conduct of the study without 
the prior written authorization of Pacira Pharmaceuticals, Inc. 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
2 of 56 
27-Sep-2017 
 
 
 
1. 
SIGNATURE PAGE 
 
 
 
 
James Brian Jones, 
MD, PharmD 
 
 
Digitally signed by James Brian Jones, MD, PharmD 
DN: cn=James Brian Jones, MD, PharmD, o=Pacira, 
ou=Chief Medical Officer, 
email=jim.jones@pacira.com, c=US 
Date: 2017.09.27 09:00:16 -04'00' 
 
James B Jones, MD, PharmD, FACEP 
Sr Vice President and Chief Medical Officer 
Michael 
Digitally signed by Michael Rozycki 
DN: cn=Michael Rozycki, o=Regulatory 
Affairs, ou=Clinical Regulatory, 
Rozycki 
email=michael.rozycki@pacira.com,  c=US 
Date: 2017.09.27 11:23:39 -04'00' 
Date 
Michael Rozycki, PhD 
Vice President, Regulatory Affairs 
Digitally signed by Vincent Yu 
Vincent Yu 
DN: cn=Vincent Yu, o=Pacira, 
ou=Biometrics, 
email=vincent.yu@pacira.com, c=U 
Date: 2017.09.27 11:25:39 -04'00' 
S 
Date 
Vincent Yu, PhD 
Sr Director, Biometrics 
Date 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
3 of 56 
27-Sep-2017 
 
 
 
2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority Use 
Only) 
Name of Finished Product: 
DepoTXA 
Name of Active Ingredient: 
Tranexamic acid 
Title of Study: A Randomized, Single-Blind, Active-Controlled, Dose-Ranging Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of Local Administration of DepoTXA for Reduced Postsurgical Bleeding 
in Subjects Undergoing Total Knee Arthroplasty 
Principal Investigator(s): To be determined 
Study Center(s): Multicenter study in the United States 
Publications (Reference): None 
Objectives: 
Primary objective: The primary objective of this study is to evaluate the pharmacokinetics of DepoTXA 
compared to intravenous (IV) tranexamic acid (TXA). 
Secondary objectives: The secondary objectives of this study are (1) to evaluate the safety of DepoTXA, (2) to 
evaluate the efficacy of DepoTXA (over 5 days) compared to IV TXA, and (3) to evaluate DepoTXA for a 
dose-related response at 800 and 1200 mg (33 mg/mL or 37 mg/mL, whichever formulation is available at the 
time of the study). 
Methodology: 
This is a Phase 2, randomized, single-blind, active-controlled dose-ranging study in patients scheduled to undergo 
total knee arthroplasty (TKA). Approximately 45 patients (15 per treatment group) are planned for enrollment. 
Patients will be randomized in a 1:1:1 ratio to receive either DepoTXA 800 mg, DepoTXA 1200 mg, or IV TXA 
(CYKLOKAPRON® 1 gram). 
Screening 
Patients will be screened within 30 days prior to surgery. During the screening visit, which must take place at 
least 1 day prior to surgery, patients will be assessed for any past or present medical conditions that, in the 
opinion of the Investigator, would preclude them from study participation. After the informed consent form 
(ICF) is signed, patient demographics and baseline characteristics will be recorded, and a medical/surgical 
history, concomitant medications, physical examination, knee flexion up to 90 degrees, timed-up-and-go (TUG) 
test, vital sign measurements, clinical laboratory tests (hematology [including hemoglobin and hematocrit], 
chemistry, and coagulation), neurological assessment, and urine pregnancy test for women of childbearing 
potential will be conducted.. 
Day 1 (Day of Surgery) 
On Day 1 prior to surgery, the patient’s eligibility for participation in the study will be confirmed, any adverse 
events (AEs) or changes to concomitant medications or medical/surgical history since screening will be recorded, 
vital signs will be measured, knee and thigh measurements (both legs) will be collected, and clinical laboratory 
tests (hematology [including hemoglobin and hematocrit], chemistry [with creatinine clearance calculation], and 
coagulation), a neurological assessment, a 12-lead ECG, numerical rating scale at rest (NRS-R; 0 [no pain] to 10 
[worst possible pain]) pain score, and a urine pregnancy test for women of childbearing potential will be 
conducted. A pre-dose pharmacokinetics (PK) sample will be collected from all patients eligible for 
randomization. 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
4 of 56 
27-Sep-2017 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority Use 
Only) 
Name of Finished Product: 
DepoTXA 
Name of Active Ingredient: 
Tranexamic acid 
Qualified Investigators will use their standard technique (open) to perform the TKA. Drains are not permitted. 
Patients randomized to DepoTXA will receive a single dose of 800 or 1200 mg (33 mg/mL or 37 mg/mL, 
whichever formulation is available at the time of the study). DepoTXA will be administered by instillation into  
the joint space by injection through the capsular repair suture line via a catheter just prior to complete watertight 
capsular closure. Patients randomized to IV TXA will receive 1 gram of IV TXA at the end of surgery prior to 
tourniquet release or at the end of the surgery if a tourniquet is not used. The tourniquet pressure, if used, should 
be at least 20 mm Hg above systolic blood pressure. Blood transfusion will be indicated based on each individual 
institution’s protocol. Each institution may follow its own routine venous thromboembolism (VTE) prophylaxis 
regimen. Additionally, each institution may follow its standard protocol for the control of postsurgical pain; 
however, patient-controlled analgesia is not permitted. Adverse events will be recorded from the time the ICF is 
signed through Day 60 (±3 days). 
Patients will be required to remain in the research facility for at least 48 hours after study drug administration in 
order to undergo postsurgical assessments. After discharge, a nurse will visit the patients to conduct the 
postsurgical assessments through 120 hours. All patients will return for a follow-up visit on Day 7. A telephone 
call will be made to each patient on Day 14 (±1 day), Day 30 (±3 days) and Day 60 (±3 days) for AE assessments 
and to record whether the patient has achieved independent ambulation. 
Postsurgical Efficacy Assessments 
Postsurgical efficacy assessments will include measurement of blood loss (as assessed by hemoglobin [Hb] and 
hematocrit [Hct] levels), transfusion requirement, knee flexion to 90 degrees, timed up-and-go (TUG) test, 
numerical rating scale at rest (NRS-R; 0 [no pain]-10 [worst possible pain]) pain score, knee and thigh 
measurements, days to independent ambulation, and the surgical wound aspect score (SWAS; See Appendix 4). 
Postsurgical Safety Assessments 
Postsurgical safety assessments will include physical examination, vital signs, neurological assessment, clinical 
laboratory testing (hematology, chemistry, and coagulation), 12-lead ECGs, and AE monitoring. Patient 
monitoring will include, but not be limited to, changes in vision, neurologic function, or renal function; and 
occurrence of hematoma, wound dehiscence/disruption, surgical site infection (per Centers for Disease Control 
and Prevention definition), nausea, vomiting, and diarrhea. 
Adverse events of special interest will include VTE or pulmonary embolism (PE), and oliguria. If an AE of 
special interest or serious AE (SAE) occurs during the study, an unscheduled PK blood sample must be collected. 
In addition, vital signs, the neurological assessment, and clinical laboratory tests must be conducted, as 
appropriate. 
Pharmacokinetic Assessment 
Blood samples (drawn into pediatric tubes to minimize blood loss) for PK analysis will be obtained at baseline 
(Day 1 pre-op, prior to study drug administration); at 5, 15, and 30 minutes; and at 1, 2, 4, 6, 8, 12, 16, and 24 
hours after the end of study drug administration for all treatment groups. Additional blood samples will be 
collected at 36, 48, 60, 72, and 96 hours after the end of study drug administration for DepoTXA-treated patients. 
It is important that blood draws for PK assessment be timed from the END of infusion of DepoTXA. 
Number of Subjects (Planned): Approximately 45 subjects (15 per treatment group) are planned for enrollment. 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
5 of 56 
27-Sep-2017 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority Use 
Only) 
Name of Finished Product: 
DepoTXA 
Name of Active Ingredient: 
Tranexamic acid 
Eligibility Criteria: 
Inclusion Criteria: 
1. Male or female, ≥18 years of age at screening. 
2. Scheduled to undergo elective unilateral open TKA under general, spinal, or regional anesthesia. 
3. Currently receiving anticoagulation or antiplatlet therapy for cardiovascular disease or thromboembolic risk. 
4. American Society of Anesthesiology (ASA) physical status 1, 2, or 3. 
5. Female patient must be surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner 
who is surgically sterile; or practicing double-barrier contraception; or practicing abstinence (must agree to 
use double-barrier contraception in the event of sexual activity); or using an insertable, injectable, or 
transdermal, contraceptive approved by the FDA for greater than 2 months prior to screening. All women of 
childbearing potential (ie, premenopausal without permanent sterilization) must commit to the use of an 
acceptable form of birth control for the duration of the study and for 30 days after completion of the study. 
6. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments. 
Exclusion Criteria: 
1. Currently pregnant, nursing, or planning to become pregnant during the study or within 30 days after study 
drug administration. 
2. Planned concurrent surgical procedure (eg, bilateral TKA). 
3. Prior open knee surgery on ipsilateral knee. Prior arthroscopy is permitted. 
4. Patients taking a medication with a known procoagulant effect (eg, combination hormonal contraceptives, 
Factor IX complex concentrates or anti-inhibitor coagulant concentrates, or all-trans retinoic acid). 
5. Contraindication or hypersensitivity to TXA. 
6. Known active intravascular clotting. 
7. Prior subarachnoid hemorrhage. 
8. History of epilepsy. 
9. History of impaired kidney function, chronic respiratory disease, rheumatoid arthritis, congenital 
coagulopathy, or loss of sensation in extremities. 
10. Renal insufficiency as indicated by serum creatinine >upper limit of normal (by central laboratory 
assessment). 
11. Anemia (Hb level <10 g/dL). 
12. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments. 
13. Acquired defective color vision. 
14. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of 
the skin or localized carcinoma in situ of the cervix. 
15. Suspected or known history of drug or alcohol abuse within the previous year. 
16. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2. 
17. Administration of an investigational drug within 30 days or 5 elimination half-lives of such investigational 
drug, whichever is longer, prior to study drug administration, or planned administration of another 
investigational product or procedure during the patient's participation in this study. 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
6 of 56 
27-Sep-2017 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority Use 
Only) 
Name of Finished Product: 
DepoTXA 
Name of Active Ingredient: 
Tranexamic acid 
Test Product, Dose, Mode of Administration, and Lot Number: 
Name: DepoTXA 
Active Ingredient: TXA 
Dosage: Single dose of 800 mg or 1200 mg (33 mg/mL or 37 mg/mL, whichever formulation is available at the 
time of the study) according to the randomization schedule. 
Lot Number: To be determined. 
Mode of Administration: Instillation 
Meal Relationship: None 
Reference Product, Dose, Mode of Administration, and Lot Number: 
Name: CYKLOKAPRON (tranexamic acid injection solution) 
Active Ingredient: TXA 
Dosage: 1 gram. 
Lot Number: To be determined. 
Mode of Administration: IV. The IV dose (1 gram) is to be administered at 50 mg/min (ie, over 20 minutes). 
Meal Relationship: None 
Duration of Patient Participation in Study: 
Participation will begin upon signing of the ICF. No more than 30 days should pass between signing the ICF and 
surgery. A follow-up telephone call will occur on Day 14 (±1 day) Day 30 (±3 days) and Day 60 (±3 days). 
Therefore, each patient may participate in the study for a maximum of 93 days. 
Efficacy Assessments: 
The following efficacy measurements will be conducted at the times specified after the beginning of study drug 
administration: 
• 
Total blood loss as measured by Hb and Hct levels upon arrival at the post-anesthesia care unit (PACU) 
and at 6, 12, 24, 48, 72, and 120 hours, and Day 7. 
• 
Transfusion requirements consistent with each institution’s transfusion policy. 
• 
Physical therapy assessment (TUG test) will be conducted once postsurgically on Day 1; at approximately 
8:00 am and 8:00 pm (±2 hours) on Day 2 (ie, the day after surgery); at hospital discharge; and on Day 7 
(see Appendix 1). 
• 
Maximum passive and active knee flexion to 90 degrees twice daily at the time of the physical therapy 
assessment (ie, approximately 8:00 am and 8:00 pm [±2 hours] daily) until hospital discharge. 
• 
Knee and thigh measurements on the morning of Day 2 (ie, the day after surgery), Day 3, and the Day-7 
follow-up visit. 
• 
NRS-R pain score (see Appendix 3; 0 [no pain] to 10 [worst possible pain]) upon arrival at the PACU; at 
each in-hospital vital sign assessment beginning with the 2-hour assessment and ending with the 72-hour 
assessment; on Day 3; and the Day-7 follow-up visit. 
• 
Days to independent ambulation 
• 
SWAS on the morning of Day 2 (ie, the day after surgery), Day 3, and on Day 7 (at the time of knee 
measurement; See Appendix 4) 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
7 of 56 
27-Sep-2017 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority Use 
Only) 
Name of Finished Product: 
DepoTXA 
Name of Active Ingredient: 
Tranexamic acid 
Efficacy Endpoints: 
• 
Hb and Hct levels at baseline; upon arrival at the PACU; and at 6, 12, 24, 48, 72, and 120 hours. 
• 
Incidence of transfusion (number of units, number of units/patient, number of patients transfused). 
• 
Time to 90 degrees passive and active knee flexion. 
• 
Time to complete TUG test. 
• 
Change in knee and thigh measurements. 
• 
Pain scores. 
Pharmacokinetic Assessment: 
Pharmacokinetic parameters will be estimated from plasma TXA measurements using non-compartmental 
analysis based on the sampling schedule of baseline (Day 1 pre-op, prior to study drug administration); at 5, 15, 
and 30 minutes; and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all treatment groups. 
Additional blood samples will be collected at 36, 48, 60, 72, and 96 hours after study drug administration for 
DepoTXA-treated patients. 
Pharmacokinetic Endpoints: 
The following PK parameters will be determined: 
• 
Area under the plasma concentration-versus-time curve (AUC) from time 0 to the last collection time after 
drug administration (AUC0-tlast). 
• 
Area under the plasma concentration-versus-time curve from time 0 extrapolated to infinity after drug 
administration (AUC0-∞). 
• 
Maximum plasma concentration (Cmax). 
• 
Time to maximum plasma concentration (Tmax). 
• 
The apparent terminal elimination rate constant (λz). 
• 
The apparent terminal elimination half-life (t1/2el). 
Safety Assessments: 
The following safety assessments will be conducted after the beginning of study drug administration: 
• 
Presurgical 12-lead ECG and 12-lead ECGs at 1 hour (±15 minutes) and 12 (±2) hours after study drug 
administration. 
• 
Physical examination at 48 hours. 
• 
Vital signs (resting heart rate and blood pressure) at 5, 15, and 30 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 
36, 48, 60, 72, and 96 hours after study drug administration. 
• 
Neurological assessment at 12, 24, 36, 48, 60, 72, and 96 hours after study drug administration 
(see Appendix 2). 
• 
Clinical laboratory testing (chemistry [including lipid profile], hematology, and coagulation [fibrinogen 
and fibrin split products]) at 48 hours and on Day 7 (see Appendix 5). 
• 
Creatinine clearance calculation at 48 hours and Day 7. 
• 
Reoperation due to hematoma or wound dehiscence. 
• 
Adverse events through Day 60 (±3 days). 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
8 of 56 
27-Sep-2017 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority Use 
Only) 
Name of Finished Product: 
DepoTXA 
Name of Active Ingredient: 
Tranexamic acid 
Safety Endpoints: 
• 
Change from baseline in vital signs at each assessed timepoint. 
• 
Summary of neurological assessments (proportion of patients who are oriented, and proportion of patients 
who have any of the neurologic events) at each assessed timepoint. 
• 
Change from baseline in clinical laboratory data at each assessed timepoint. 
• 
Incidence of reoperation due to hematoma or wound dehiscence. 
• 
Incidence of treatment-emergent AEs (TEAEs) and SAEs through Day 60 (±3 days). 
Statistical Methods: 
A comprehensive statistical analysis plan will be developed for this study. Demographic and baseline 
characteristics will be summarized descriptively by treatment group. Blood loss will be estimated using two 
methods. Efficacy of DepoTXA will be evaluated by each method. Dose response will be evaluated for both 
efficacy and PK. Safety endpoints will be summarized descriptively by treatment group. 
Sample Size 
Sample size was not based on statistical considerations. 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
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27-Sep-2017 
 
 
 
 
Table 1. 
Time and Events Schedule of Study Procedures 
Screen 
D1 
PACU 
5 
15 
30 
D14 D30 D60 
Visit1 
Preop   OR 
Arrival min min  min  1h    2h    4h    6h    8h   12h  16h  24h  36h  48h  60h  72h  96h  120h Day 7 
Call Call Call 
Time 
Within 
±2    ±3 
±5   ±10  ±15  ±15  ±15  ±30  ±30 
Window 
30 days 
min min min min min min min min min ±1h  ±1h  ±2h  ±2h  ±2h  ±4h  ±6h   ±6h 
±1d 
±1d    ±3d    ±3d 
Obtain signed ICF 
X 
Assess/confirm eligibility 
X 
X 
Record medical and surgical history 
X 
X 
Record demographics and baseline characteristics 
X 
Conduct pregnancy test for WOCBP 
X 
X 
Perform physical examination14 
X 
X 
Clinical labs (hematology, chemistry)2 
X 
X 
X 
X 
Coagulation (fibrinogen and fibrin split products) 
X 
X 
X 
X 
Creatinine clearance calculation2 
 
X 
 
 
 
 
X 
 
 
X 
Hemoglobin and hematocrit2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perform neurological assessment3 
X 
X 
 
 
X 
X     X     X     X     X     X 
Perform 12-lead ECG recordings4 
X 
X4 
X4 
Measure vital signs5 
X 
X 
X     X     X     X     X     X     X     X     X     X     X     X     X     X     X     X 
Collect NRS-R pain score 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect knee and thigh measurements6 
X6 
 
 
 
 
 
 
 
 
 
X6 
X6 
X6 
Assess surgical wound for SWAS parameters7 
X 
X 
X 
Collect PK blood sample from all treatment groups; 
record date and time8,15 
X 
X     X     X     X     X     X     X     X     X     X     X 
Collect additional PK blood samples for DepoTXA 
treatment groups; record date and time15 
X     X     X     X     X 
Randomize patient, prepare study drug 
X 
Administer study drug 
 
X 
Record start and end time of tourniquet use and max 
pressure (mm Hg) used 
X 
Record surgery start and stop times 
X 
Perform knee flexion assessment13 
X 
Perform TUG test; record date and time11 
X 
11             X 
Record date and time of discharge 
Record any blood transfusion data (eg, start and stop 
times, units) 
Record any reoperations due to hematoma or wound 
dehiscence 
Record prior and concomitant medications12 
Record whether patient has achieved independent 
ambulation 
Record AEs beginning at time ICF is signed2,3,5,8,10 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
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Abbreviations: AE = adverse event; d = day; D = day; ECG = electrocardiogram; h = hours; ICF = informed consent form; max = maximum; min = minutes; 
OR = operating room; PACU = post-anesthesia care unit; PK = pharmacokinetic; Preop = preoperative; TUG = timed up-and-go; WOCBP = women of childbearing 
potential. 
* 
Postsurgical assessments will be conducted at the timepoints specified after the beginning of study drug administration. 
1 
The screening visit must take place at least 1 day prior to surgery. 
2 
Also conduct clinical laboratory tests if a patient experiences an AE of special interest or a serious AE (SAE), if appropriate; see footnote 10. 
3 
Also conduct a neurological assessment if a patient experiences an AE of special interest or an SAE, if appropriate; see footnote 10. 
4 
Postsurgical 12-lead ECGs will be performed at 1 hour (±15 minutes) and 12 (±2) hours after study drug administration 
5 
Vital signs will be measured after the patient has rested in a supine position for at least 5 minutes. Also measure vital signs if a patient experiences an AE of special 
interest or an SAE, if appropriate; see footnote 10. 
6 
Collect knee and thigh measurements of both legs on Day 1 pre-op and of the surgical leg only on the morning of Day 2 (ie, the day after surgery), Day 3, and Day 7. 
7 
The surgical wound will be assessed for the SWAS parameters (wound oozing, erythema, ecchymosis, and blisters) at the time of knee measurements on the morning 
of Day 2 (ie, the day after surgery), Day 3, and on Day 7. 
8 
Also collect a PK sample if a patient experiences an AE of special interest or an SAE; see footnote 10. 
9 
Record date and time of all medications starting at least 30 days prior to study drug administration through 120 hours after study drug administration. Record 
medications administered for treatment of an AE through Day 60 (±3 days). 
10 
Adverse events of special interest include VTE or PE, and oliguria. If an AE of special interest or serious AE (SAE) occurs during the study, an unscheduled PK 
blood sample must be collected. In addition, vital signs, the neurological assessment, and clinical laboratory tests should be conducted, as appropriate. 
11 
Postsurgical “Timed Up-and-Go” will be assessed once on the day of the surgery following surgery; at approximately 8:00 am and 8:00 pm (±2 hours) on Day 2 (ie, 
the day after surgery); at hospital discharge; and on Day 7. 
12 
Each institution may follow its standard protocol for the control of postsurgical pain; however, patient-controlled analgesia is not permitted. 
13 
Maximum passive and active knee flexion to 90 degrees will be assessed twice daily at the time of the physical therapy assessment (ie, approximately 8:00 am and 
8:00 pm [±2 hours] daily) until hospital discharge. 
14 
Collect weight during the physical examination at screening 
15 
It is important that blood draws for PK assessment be timed from the END of infusion of DepoTXA. 


Pacira Pharmaceuticals, Inc. 
DepoTXA 
404-C-201 (TKA) 
Clinical Study Protocol Amendment 2 
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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ...................................................................................................... 2 
2. 
SYNOPSIS ..................................................................................................................... 3 
3. 
TABLE OF CONTENTS ............................................................................................. 11 
4. 
LIST OF ACRONYMS/ABBREVIATIONS AND DEFINITIONS OF 
TERMS ......................................................................................................................... 14 
4.1. 
List of Acronyms/Abbreviations .................................................................................. 14 
4.2. 
Definition of Terms ...................................................................................................... 15 
5. 
ETHICS ........................................................................................................................... 16 
5.1. 
Institutional Review Board/Independent Ethics Committee ....................................... 16 
5.2. 
Ethical Conduct of the Study ..................................................................................... 16 
5.3. 
Patient Information and Consent .................................................................................. 16 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE ................. 16 
7. 
INTRODUCTION ........................................................................................................ 16 
7.1. 
Summary of Nonclinical Studies of DepoTXA ........................................................... 18 
7.2. 
Relevant Clinical Studies of TXA in Humans ............................................................. 19 
8. 
OBJECTIVES ............................................................................................................... 19 
8.1. 
Primary Objectives ....................................................................................................... 19 
8.2. 
Secondary Objectives ................................................................................................... 19 
9. 
STUDY DESIGN AND PLAN .................................................................................... 19 
9.1. 
Study Design................................................................................................................. 19 
9.2. 
Discussion of Study Design ......................................................................................... 22 
10. 
STUDY POPULATION .............................................................................................. 22 
10.1. 
Inclusion Criteria .......................................................................................................... 22 
10.2. 
Exclusion Criteria ......................................................................................................... 23 
10.3. 
Removal of Patients From Therapy or Assessment ..................................................... 24 
11. 
TREATMENTS ............................................................................................................ 24 
11.1. 
Treatment to be Administered ...................................................................................... 24 
11.2. 
Identity of Investigational Product(s) ........................................................................... 25 
11.3. 
Method of Assigning Patients to Treatment ................................................................ 26 
11.4. 
Selection of Doses in the Study ................................................................................. 26 
11.5. 
Blinding ........................................................................................................................ 28 


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Clinical Study Protocol Amendment 2 
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11.6. 
Prior and Concomitant Therapy and Medications ....................................................... 29 
11.7. 
Treatment Compliance ................................................................................................. 29 
11.8. 
Accountability of Study Drug .................................................................................... 29 
12. 
STUDY ENDPOINTS AND MEASUREMENTS ..................................................... 30 
12.1. 
Efficacy Assessments ................................................................................................... 30 
12.2. 
Efficacy Endpoints ....................................................................................................... 30 
12.3. 
Pharmacokinetic Analysis ............................................................................................ 30 
12.4. 
Pharmacokinetic Endpoints ....................................................................................... 31 
12.5. 
Safety Assessments ...................................................................................................... 31 
12.6. 
Safety Endpoints ........................................................................................................... 32 
12.7. 
Appropriateness of Measures ....................................................................................... 32 
13. 
STUDY PROCEDURES .............................................................................................. 33 
13.1. 
Instructions for Conducting Procedures and Measures ............................................... 33 
13.2. 
Screening Procedures ................................................................................................... 35 
13.3. 
Baseline Procedures (Day 1 Pre-op - Prior to Study Drug Administration) ............... 35 
13.4. 
Intraoperative Procedures ............................................................................................. 36 
13.5. 
Upon Arrival at the Post-Anesthesia Care Unit ........................................................... 36 
13.6. 
Postsurgical Assessments Through Hour 120 ............................................................ 36 
13.7. 
Day 7 Visit .................................................................................................................... 37 
13.8. 
Day 14 (±1 day) Telephone Call .................................................................................. 38 
13.9. 
Day 30 (±3 days) Telephone Call ................................................................................ 38 
13.10. 
Day 60 (±3 days) Telephone Call ................................................................................ 38 
14. 
ADVERSE EVENT REPORTING .............................................................................. 38 
14.1. 
Adverse Events .......................................................................................................... 38 
14.2. 
Serious Adverse Events ............................................................................................. 41 
15. 
STATISTICAL METHODS ........................................................................................ 43 
15.1. 
Study Hypothesis .......................................................................................................... 43 
15.2. 
Study Endpoints ............................................................................................................ 43 
15.3. 
Determination of Sample Size ................................................................................... 43 
15.4. 
Analysis Populations .................................................................................................... 43 
15.5. 
Handling Patient Dropouts and Discontinuations ........................................................ 43 
15.6. 
Statistical Analyses ....................................................................................................... 43 


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15.7. 
Significance Testing ................................................................................................... 46 
16. 
REFERENCES ............................................................................................................. 47 
17. 
INVESTIGATOR AGREEMENT ............................................................................... 50 
18. 
APPENDICES .............................................................................................................. 51 
Appendix 1: Timed Up-and-Go Test ............................................................................................ 51 
Appendix 2: Neurological Assessment ......................................................................................... 53 
Appendix 3: Numerical Rating Scale at Rest Pain Scores ........................................................... 54 
Appendix 4: Surgical Wound Aspect Score ................................................................................. 55 
Appendix 5: Clinical Laboratory Tests ......................................................................................... 56 
LIST OF TABLES 
1.   Table 1. ........................................................... Time and Events Schedule of Study Procedures 
9 


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4. 
LIST OF ACRONYMS/ABBREVIATIONS AND DEFINITIONS 
OF TERMS 
 
4.1. 
List of Acronyms/Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ASA 
American Society of Anesthesiologists 
AUC0-tlast 
Area under the plasma concentration-versus-time curve from the time of 
administration to the time of the last quantifiable concentration 
AUC0-∞ 
Area under the plasma concentration-versus-time curve from the time of 
administration extrapolated to infinity 
BV 
Blood volume 
CFR 
Code of Federal Regulations 
cm 
Centimeter 
Cmax 
The maximum observed plasma concentration obtained directly from the 
experimental data without interpolation 
CRF 
Case report form 
Ctlast 
Time of the last quantifiable concentration 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
NRS-R 
Numerical rating scale at rest 
PCA 
Patient-controlled analgesia 
PACU 
Post-anesthesia care unit 
PE 
Pulmonary embolism 


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4.1. 
List of Acronyms/Abbreviations 
PI 
Package insert 
PK 
Pharmacokinetic 
PT 
Preferred term 
PTAE 
Pretreatment adverse event 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SWAS 
Surgical wound aspect score 
TUG 
Timed up-and-go 
t1/2el 
The apparent terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
TKA 
Total knee arthroplasty 
Tmax 
The time to maximum plasma concentration 
TXA 
Tranexamic acid 
ULN 
Upper limit of normal 
US 
United States of America 
VTE 
Venous thromboembolism 
WHO 
World Health Organization 
λz 
The apparent terminal elimination rate constant 
 
4.2. 
Definition of Terms 
Pharmacokinetic (PK) terms are defined in Section 12.4. 


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5. 
ETHICS 
5.1. 
Institutional Review Board/Independent Ethics Committee 
Prior to screening patients into this study, each study site will obtain the approval of an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that complies with the 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and/or the 
United States (US) Food and Drug Administration (FDA) Title 21 Code of Federal Regulations 
(CFR) Part 56.  Attention is directed to the basic elements that are required to be incorporated 
into the informed consent form (ICF) under 21 CFR Part 50.25 and ICH GCP. 
5.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the clinical research guidelines established by 
the FDA Title 21 CFR, Parts 50, 54, 56, and 312, and the ICH GCP. Study documents will be 
maintained in accordance with applicable regulations. 
5.3. 
Patient Information and Consent 
Before a patient undergoes any study-specific screening procedures, the Investigator or designee 
will thoroughly explain to the patient the purpose of the study, the associated procedures, and 
any expected effects and potential adverse reactions.  A copy of the IRB- or IEC-approved ICF 
will be provided to the patient, who will be given sufficient time and opportunity to inquire about 
the details of the study and decide whether or not to participate. The patient, and the study staff 
with whom he or she discusses the ICF, will sign and date the ICF.  A photocopy of the signed 
ICF will be given to the patient. 
The Investigator will explain to the patient that he or she is completely free to decline entry into 
the study and may withdraw from the study at any time, for any reason, without risking his or her 
medical care.  Similarly, the Investigator and/or Pacira Pharmaceuticals, Inc. (Pacira) is free to 
withdraw the patient at any time for safety or administrative reasons. Any other requirements 
necessary for the protection of the human rights of the patient will also be explained, according 
to the current ICH GCP (E6) and the Declaration of Helsinki (1964, and as amended through 
2013). 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION 
STRUCTURE 
Information regarding the Investigators, sites, laboratories, and other service providers is 
available upon request to the IRB/IECs and regulatory agencies. 
7. 
INTRODUCTION 
Tranexamic acid (TXA) is a well-recognized antifibrinolytic that is marketed world-wide and 
used for a variety of clinical conditions where hemorrhage or significant blood loss and 
associated complications are a concern.  In the US, LYSTEDA® (tranexamic acid) tablets are 
approved for the treatment of cyclic heavy menstrual bleeding, and CYKLOKAPRON® 
(tranexamic acid injection) is approved for short-term use in patients with hemophilia to reduce 


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or prevent hemorrhage and to reduce the need for replacement therapy during and following 
tooth extraction (LYSTEDA package insert [PI]; CYKLOKAPRON PI). 
During the 18th Expert Committee on the Selection and Use of Essential Medicines by the 
World Health Organization (WHO), the Committee agreed in March 2011 to the addition of 
TXA injection to the Model List of Essential Medicines for the treatment of adult patients with 
trauma and significant risk of ongoing hemorrhage. The Committee concluded that there is 
sufficient evidence to support the proposal that listing TXA may contribute to a reduction in 
trauma-related deaths. 
Based upon the WHO recommendation and published literature, off-label use of TXA to reduce 
blood loss in a variety of postsurgical settings is widespread.  This trend has been seen in the US 
as evidenced by the clinical practice guidelines finalized in December 2015 for the American 
Academy of Orthopedic Surgeons, which concluded that there is strong evidence to support that, 
in patients with no known contraindications, treatment with TXA decreases postsurgical blood 
loss and reduces the necessity of postsurgical transfusions following total knee arthroplasty 
(TKA). 
Patients undergoing TKA are at an increased risk of postsurgical bleeding.  In a survey from 
Maniar (2012), estimated blood losses reported for TKA ranged from 800 to 1800 mL. Such 
blood loss may have a negative impact on patient recovery.  In regard to the need for transfusion, 
Seo (2013) reported that 10 to 38% of patients undergoing TKA or hip replacement surgery 
required 1 to 2 units of blood.  However, a study of patients undergoing TKA and receiving TXA 
or placebo with a well-established blood conservation program, showed that relatively few 
patients require allogeneic transfusion (approximately 2.2% of TXA-treated patients and 12% of 
placebo-treated patients; Álvarez, 2008) when such a program is incorporated (note that in this 
study the percentage of patients in each treatment group receiving reinfusion of blood recovered 
from drains was 4% and 73%, respectively). Allogeneic transfusion carries risks of 
immunological reaction and the transmission of disease and, thus, is avoided when possible. The 
application of a pneumatic tourniquet during surgery may also decrease intra-operative blood 
loss, but trauma induces fibrinolysis, and release of the tourniquet may contribute to postsurgical 
bleeding (Fahmy, 1981; Burkart, 1994). 
The DepoFoam® drug delivery system is a proprietary, injectable technology that provides a 
sustained release of therapeutic compounds.  The DepoFoam system consists of microscopic, 
spherical, lipid-based particles composed of numerous non-concentric, aqueous chambers 
containing the drug in solution. Each chamber in this multivesicular liposome is separated from 
adjacent chambers by lipid membranes. The DepoFoam particle components are naturally 
occurring or synthetic analogues of common lipids. 
DepoTXA is a DepoFoam-based product containing encapsulated TXA, and is intended to 
prolong the delivery of TXA locally (at the surgical site), thereby enhancing its efficacy in the 
reduction of postoperative hemorrhage. 


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7.1. 
Summary of Nonclinical Studies of DepoTXA 
7.1.1. 
Summary of Nonclinical DepoTXA Studies 
The toxicology studies completed to support the local and systemic safety of the DepoTXA 
product include the following: 
1. A subcutaneous single-dose local tolerability study in rats 
2. A surgical wound instillation single-dose local tolerance study in dogs 
3. A subcutaneous 14-day (4-dose) study evaluating both local and systemic safety in dogs. 
In all toxicology studies, TXA was present in the DepoTXA formulation at a concentration of 
approximately 40 mg/mL, with an equal amount of TXA on the inside and outside of the 
DepoTXA particles. The concentration of TXA in the DepoTXA formulation evaluated is 
similar to the initial clinical formulation (33 mg/mL, with an approximately equal amount of 
TXA on the inside and outside of the particles [encapsulated in DepoFoam and unencapsulated, 
respectively]).  The dog was selected as the most appropriate nonclinical species for the bridging 
toxicity studies because of dose volume limitations in the rat. Toxicokinetics were studied in the 
surgical single-dose and subcutaneous multiple-dose dog studies to compare systemic exposure 
following the administration of TXA alone vs. DepoTXA. 
In the dog studies, both reference TXA and DepoTXA were well tolerated both locally and 
systemically at doses up to 120 mg/kg.  The only compound-related findings were local 
inflammation associated with TXA and granulomatous infiltration at the administration site 
observed with DepoTXA.  Both of the observed local inflammatory findings were minimal to 
moderate in severity, displayed reversibility, and were not considered adverse.  The 
granulomatous infiltration is thought to be associated with the clearance of excess lipid and has 
been commonly observed in toxicology studies with the other approved products utilizing the 
DepoFoam formulation.  The high dose of 120 mg/kg TXA evaluated in the dog represented the 
maximum feasible dose based on the formulation and dose volume.  In both dog studies, the 
mean values for terminal elimination half-life (t1/2) were roughly equivalent for DepoTXA vs. 
the reference TXA, but there was a notable difference with respect to mean residence time 
(MRT; defined as the average time drug resides in a compartment before being eliminated). The 
average MRT for the DepoTXA groups at 120 mg/kg was approximately 2 to 2.6-fold greater 
than the average MRT for the reference TXA group. As MRT describes the average amount of 
time that a molecule of drug is in the systemic circulation and takes into account the totality of 
the plasma concentration vs. time data, this increase in MRT indicates that the DepoTXA 
formulation functions as it was designed. 
In conjunction with (a) historical nonclinical studies demonstrating no biologically significant 
microscopic changes considered to be related to DepoFoam (alone) in the joint area of rabbits or 
dogs, and (b) clinical studies demonstrating that instillation of TXA in solution into the joint 
space of humans undergoing TKA is safe and effective (Shemshaki 2015, Wang 2015b, Yue 
2015, Zhang 2014), the results of the nonclinical studies summarized here are sufficient 


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justification for testing of DepoTXA via instillation into the joint space in humans undergoing 
TKA. 
7.1.2. 
Safety Margins 
The recommended dose regimen for LYSTEDA is 1.3 grams orally, 3 times per day for up to 5 
days per month (which represents a total daily dose of 3.9 grams/day). The recommended dose 
regimen for CYKLOKAPRON is 10 mg/kg (700 mg for a 70 kg person), IV, up to 4 times per 
day (the total recommended daily dose is 2.8 grams/day) for 2 to 8 days. 
Refer to Section 11.4.1 for the rationale behind the IV dose of 1 gram selected for the 
comparator treatment group in this study. 
The TXA 120 mg/kg high dose evaluated in the dog is 6-fold higher than the maximum TXA 
dose of 1200 mg in this first-time-in human DepoTXA Phase 2 study.  In addition, the 
120 mg/kg high dose evaluated in the dog studies is 12-fold higher than the approved 10 mg/kg 
IV dose of CYKLOKAPRON and 6-fold higher than the approved 20 mg/kg oral dose of 
LYSTEDA. 
7.2. 
Relevant Clinical Studies of TXA in Humans 
Relevant published clinical studies of TXA in humans are discussed in Section 11.4. 
8. 
OBJECTIVES 
8.1. 
Primary Objectives 
The primary objective of this study is to evaluate the pharmacokinetics of DepoTXA compared 
to intravenous (IV) TXA. 
8.2. 
Secondary Objectives 
The secondary objectives of this study are (1) to evaluate the safety of DepoTXA, (2) to evaluate 
the efficacy of DepoTXA (over 5 days) compared to IV TXA, and (3) to evaluate DepoTXA for 
a dose-related response at 800 and 1200 mg (33 mg/mL or 37 mg/mL, whichever formulation is 
available at the time of the study). 
9. 
STUDY DESIGN AND PLAN 
9.1. 
Study Design 
This is a Phase 2, randomized, single-blind, active-controlled dose-ranging study in patients 
scheduled to undergo TKA.  Approximately 45 patients (15 per treatment group) are planned for 
enrollment. Patients will be randomized in a 1:1:1 ratio to receive either DepoTXA 800 mg, 
DepoTXA 1200 mg, or IV TXA (CYKLOKAPRON 1 gram). 
9.1.1. 
Screening 
Patients will be screened within 30 days prior to surgery. During the screening visit, which must 
take place at least 1 day prior to surgery, patients will be assessed for any past or present medical 
conditions that, in the opinion of the Investigator, would preclude them from study participation. 


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After the ICF is signed, patient demographics and baseline characteristics will be recorded, and a 
medical/surgical history, physical examination, vital sign measurements, clinical laboratory tests 
(hematology, chemistry, and coagulation), neurological assessment, and urine pregnancy test for 
women of childbearing potential will be conducted. 
9.1.2. 
Day 1 (Day of Surgery) 
Prior to surgery on Day 1, the patient’s eligibility for participation in the study will be confirmed, 
any adverse events (AEs) or changes to concomitant medications or medical/surgical history 
since screening will be recorded, vital signs will be measured, knee and thigh measurements 
(both legs) will be collected using the measuring tape provided, and clinical laboratory tests 
(hematology, chemistry [with creatinine clearance calculation], and coagulation), a neurological 
assessment, a urine pregnancy test for women of childbearing potential, and a12-lead 
electrocardiogram (ECG) will be conducted. A pre-dose PK sample will be collected from all 
patients eligible for randomization. 
Qualified Investigators will use their standard technique (open) to perform the TKA. Drains are 
not permitted. 
Patients randomized to DepoTXA will receive a single dose of 800 or 1200 mg (33 mg/mL or 
37 mg/mL, whichever formulation is available at the time of the study). DepoTXA will be 
administered by instillation into the joint space by injection through the capsular repair suture 
line via a catheter just prior to complete watertight capsular closure. Patients randomized to IV 
TXA will receive 1 gram of IV TXA at the end of surgery prior to tourniquet release or at the 
end of the surgery if a tourniquet is not used.  The tourniquet pressure, if used, should be at least 
20 mm Hg above systolic blood pressure. 
Blood transfusion will be indicated based on each individual institution’s protocol.  Each 
institution may follow its own routine venous thromboembolism (VTE) prophylaxis regimen. 
Additionally, each institution may follow its standard protocol for the control of postsurgical 
pain; however, patient-controlled analgesia is not permitted. Adverse events will be recorded 
from the time the ICF is signed through Day 60 (±3 days). 
Patients will be required to remain in the research facility for at least 48 hours after study drug 
administration in order to undergo postsurgical assessments. After discharge, a nurse will visit 
the patients to conduct the postsurgical assessments through 120 hours. All patients will return 
for a follow-up visit on Day 7.  A telephone call will be made to each patient on 
Day 14 (±1 day), Day 30 (±3 days) and Day 60 (±3 days) for an AE assessment and to record 
whether the patient has achieved independent ambulation. 
9.1.3. 
Postsurgical Efficacy Assessments 
Postsurgical efficacy assessments will include measurement of blood loss (as assessed by 
hemoglobin [Hb] and hematocrit [Hct] levels), transfusion requirement, knee flexion to 90 
degrees, timed up-and-go (TUG) test, knee and thigh measurements (surgical leg only), pain 
scores and days to independent ambulation.  In addition, a modification of the surgical wound 
aspect score (SWAS) developed by Torres-Claramunt, et al (Torres-Claramunt, 2015) will be 


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calculated from the knee measurements collected on the morning of Day 2 (ie, the day after 
surgery) and on Day 7 and an assessment of the surgical wound at these times for signs of 
oozing, erythema, ecchymosis, and blisters (see Appendix 4). 
9.1.4. 
Postsurgical Safety Assessments 
Postsurgical safety assessments will include physical examination, vital signs, neurological 
assessment, clinical laboratory testing (hematology, chemistry, and coagulation), 12-lead ECG, 
and AE monitoring.  Patient monitoring will include, but not be limited to, changes in vision, 
neurologic function, or renal function; and occurrence of hematoma, wound 
dehiscence/disruption, surgical site infection (per Centers for Disease Control and Prevention 
definition), nausea, vomiting, and diarrhea. 
Adverse events of special interest (AESI) include VTE or pulmonary embolism (PE), and 
oliguria.  If an AESI or serious AE (SAE) occurs during the study, an unscheduled PK blood 
sample must be collected.  In addition, vital signs, the neurological assessment, and clinical 
laboratory tests must be conducted, as appropriate. 
Pharmacokinetic Assessment 
Blood samples (drawn into pediatric tubes to minimize blood loss) for PK analysis will be 
obtained at baseline (Day 1 pre-op, prior to study drug administration); at 5, 15, and 30 minutes; 
and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after the end of study drug administration for all 
treatment groups.  Additional blood samples will be collected at 36, 48, 60, 72, and 96 hours 
after the end of study drug administration for DepoTXA-treated patients. It is important that 
blood draws for PK assessment be timed from the END of infusion of DepoTXA. 
9.1.5. 
Duration of the Study and Patient Participation 
Participation will begin at the signing of the ICF.  No more than 30 days should pass between 
signing of the ICF and the administration of study drug. The time from study drug 
administration through the end of participation is 60 ± 3 days.  Therefore, patients may 
participate in the study for up to 93 days. 
9.1.6. 
Study Stopping Rules 
Patient data will be reviewed by the Pacira Medical Monitoring Team on a continuous basis. If 4 
or more patients experience serious AESIs prior to or when the first 12 patients have been dosed, 
a review process will be triggered for prompting the Safety Stopping Rules. Subject dosing 
and/or study enrollment will be halted until the toxicity data can be further reviewed. After this 
review is completed the study may be amended or terminated. 
If after the first 12 patients have been treated and the Safety Stopping Rules have not been 
triggered, the Pacira Medical Monitoring Team will continue to evaluate subject data on an 
ongoing basis which also includes documented periodic reviews of patient safety data, the 
frequency of which will be determined by the pace of enrollment into the trial. 
Any unexplained death will be thoroughly reviewed and appropriate action taken. 


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9.2. 
Discussion of Study Design 
This Phase 2, multicenter, randomized, single-blind, active-controlled, dose-ranging study is 
designed to evaluate the pharmacokinetics, safety, and efficacy of local administration of 
DepoTXA for reduced postsurgical bleeding in patients undergoing TKA.  The single-blind 
study design is intended to eliminate bias resulting from the patient’s knowledge of the assigned 
treatment. 
Patients will receive a single dose of either DepoTXA (800 mg or 1200 mg) or IV TXA 1 gram. 
The DepoTXA dosage will be selected from this first-in-human study for further evaluation 
based on the PK, safety, and efficacy data for DepoTXA compared to standard of care IV TXA. 
TXA is used in TKA in many countries globally but no specific recommendations are provided 
in the US PI. Therefore, Pacira is utilizing an administration technique from the Australian 
PI that supports a recommended rate of infusion for a bolus or loading dose of 50 mg/min. 
To administer 50 mg/min to the patient, the solution is diluted to 1% TXA with normal saline 
for injection (ie, 1 g in 100 mL or 10 mg/mL). TXA may be administered at 5 mL/min 
(20 minutes). 
The AEs of special interest (VTE or PE, and oliguria) were selected based on the known adverse 
effects of TXA.  If an AE of special interest or SAE occurs during the study, an unscheduled PK 
blood sample must be collected.  In addition, vital signs, the neurological assessment, and 
clinical laboratory tests must be conducted, as appropriate. 
Refer to Section 12.7 for the rationale behind the selection of key efficacy endpoints and the use 
of Hb as a surrogate marker for blood loss. 
10. 
STUDY POPULATION 
10.1. 
Inclusion Criteria 
Patients eligible for study entry must meet all of the following criteria: 
1. 
Male or female, ≥18 years of age at screening. 
2. 
Scheduled to undergo elective unilateral open TKA under general, spinal, or regional 
anesthesia. 
3. 
Currently receiving anticoagulation or antiplatlet therapy for cardiovascular disease or 
thromboembolic risk. 
4. 
American Society of Anesthesiology (ASA) physical status 1, 2, or 3. 
5. 
Female patient must be surgically sterile; or at least 2 years postmenopausal; or have a 
monogamous partner who is surgically sterile; or practicing double-barrier contraception; 
or practicing abstinence (must agree to use double-barrier contraception in the event of 
sexual activity); or using an insertable, injectable, or transdermal, contraceptive approved 
by the FDA for greater than 2 months prior to screening. All women of childbearing 
potential (ie, premenopausal without permanent sterilization) must commit to the use of 


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an acceptable form of birth control for the duration of the study and for 30 days after 
completion of the study. 
6. 
Able to provide informed consent, adhere to the study visit schedule, and complete all 
study assessments. 
10.2. 
Exclusion Criteria 
A patient will not be eligible for the study if he or she meets any of the following criteria: 
1. 
Currently pregnant, nursing, or planning to become pregnant during the study or within 
30 days after study drug administration. 
2. 
Planned concurrent surgical procedure (eg, bilateral TKA). 
3. 
Prior open knee surgery on ipsilateral knee.  Prior arthroscopy is permitted. 
4. 
Patients taking a medication with a known procoagulant effect (eg, combination 
hormonal contraceptives, Factor IX complex concentrates or anti-inhibitor coagulant 
concentrates, or all-trans retinoic acid). 
5. 
Contraindication or hypersensitivity to TXA. 
6. 
Known active intravascular clotting. 
7. 
Prior subarachnoid hemorrhage. 
8. 
History of epilepsy. 
9. 
History of impaired kidney function, chronic respiratory disease, rheumatoid arthritis, 
congenital coagulopathy, or loss of sensation in extremities. 
10. 
Renal insufficiency as indicated by serum creatinine >upper limit of normal (by central 
laboratory assessment). 
11. 
Anemia (Hb level <10 g/dL). 
12. 
Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study 
assessments. 
13. 
Acquired defective color vision. 
14. 
Malignancy in the last 2 years, with the exception of non-metastatic basal cell or 
squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. 
15. 
Suspected or known history of drug or alcohol abuse within the previous year. 
16. 
Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2. 
17. 
Administration of an investigational drug within 30 days or 5 elimination half-lives of 
such investigational drug, whichever is longer, prior to study drug administration, or 
planned administration of another investigational product or procedure during the 
patient's participation in this study 


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10.3. 
Removal of Patients From Therapy or Assessment 
Every reasonable effort should be made to maintain patient compliance and participation in the 
study.  Reasons for discontinuation of any patient from the study will be recorded. 
If a patient who withdraws from the study has an ongoing AE, every effort must be made to 
follow such events until satisfactory resolution is obtained, or further follow-up is otherwise no 
longer warranted. 
10.3.1. 
Withdrawal Secondary to Adverse Events 
If a patient experiences an AE that renders him or her incapable of continuing with the remaining 
study assessments, then he or she will be discontinued from further participation in the study. A 
final evaluation should be performed so that the patient’s study participation can be terminated in 
a safe and orderly manner. 
10.3.2. 
Voluntary or Study Investigator Withdrawal 
Patients are free to discontinue from the study at any time, without prejudice to future treatment. 
Nevertheless, patients will be encouraged to complete at least the study safety assessments.  In 
addition, a patient may be discontinued from the study if he or she refuses to comply with study 
procedures.  Reasons for discontinuation from the study will be recorded. 
If a patient is discontinued by the Investigator or voluntarily withdraws from the study after 
receiving study drug, the patient will be asked to complete a final evaluation so that he or she can 
be withdrawn in a safe and orderly manner.  In the final evaluation, vital signs (heart rate and 
blood pressure), the neurological assessment, and clinical laboratory tests will be conducted, and 
any changes in the patient's health status will be recorded. 
After termination from the study, the patient may be followed for safety including monitoring of 
AEs through Day 60 (±3 days). 
11. 
TREATMENTS 
11.1. 
Treatment to be Administered 
Patients will receive a single dose of either DepoTXA DepoTXA 800 mg, DepoTXA 1200 mg, 
or IV TXA (CYLOKAPRON 1 gram) according to the randomization schedule. 
11.1.1. 
Administration Technique 
Patients randomized to DepoTXA will receive a single dose, which will be administered by 
instillation into the joint space at the time of watertight closure of the capsule by injection 
through the capsular repair suture line. DepoTXA will be applied to the joint space via a catheter 
beneath the closed capsule using a steady pressure and rate. 
Patients randomized to IV TXA will receive a single IV dose at the end of surgery after closure 
of the capsule.  This will occur at a parallel timepoint to when DepoTXA patients receive their 
instillation into the joint space.  The IV dose (1 gram) is to be administered at 50 mg/min (ie, 
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11.1.2. 
Study Drug Administration Considerations 
The potential risks of TXA are well characterized (CYKLOKAPRON PI, LYSTEDA PI, 
DepoTXA Investigator’s Brochure) and include dizziness, hypotension, visual or ocular adverse 
effects, allergic reaction (rash), nausea, and thromboembolism (particularly in persons with a 
history of intravascular clotting or persons taking other medications with a procoagulant effect). 
The CYKLOKAPRON PI cautions that because TXA is eliminated unchanged in urine, plasma 
levels increase with decreasing renal function, and a reduction in dosage is recommended in 
patients with renal impairment.  These risks are widely believed to be outweighed by the 
potential benefits of reduced postsurgical bleeding (eg, reduced blood loss, reduced red blood 
cell [RBC] transfusion requirement, and reduced Hb decrease) (Yue 2015). 
Because DepoTXA has not yet been studied in humans, its non-TXA-related potential risks are 
surmised from nonclinical studies of DepoFoam (approved) and of DepoTXA. The known 
safety of the DepoFoam component of already approved products using the DepoFoam delivery 
technology (EXPAREL®, DepoDur®, and DepoCyt®) in humans also contributes to the safety 
profile of DepoFoam.  No clinical or nonclinical findings have been considered to be adverse (ie, 
there have been no identified risks) for DepoFoam. The DepoFoam membrane constituents (ie, 
triglycerides, phospholipids, cholesterol) are believed to be cleared through the lymphatics and 
metabolized as nutrients.  Refer to the Investigator's Brochure for additional details. 
11.2. 
Identity of Investigational Product(s) 
11.2.1. 
Description of DepoTXA 
DepoTXA is a sterile, non-pyrogenic, white to off-white, preservative-free, aqueous suspension 
of multivesicular lipid-based particles (DepoFoam drug delivery system) containing TXA, 
intended for local prolonged release following administration for the reduction of postsurgical 
bleeding.  Tranexamic acid, the drug substance, is present in DepoTXA at a concentration of 
approximately 33 mg/mL or 37 mg/mL, whichever formulation is available at the time of the 
study. The free drug is thought to provide an immediate effect for initial clot stabilization 
followed by the slow release of additional TXA to further aid in clot stabilization and 
minimization of blood loss. 
The DepoFoam technology developed by Pacira provides a platform by which drugs are 
encapsulated within aqueous chambers of the multivesicular liposomal particles. After 
administration of the drug product, drug is slowly released from the particles providing high 
local concentration of the drug at the site of administration. The release profile and duration of 
drug release are largely dependent on the lipid composition of the particles but other factors such 
as physicochemical properties of the drug and the presence of other excipients that may interact 
or retain the drug within the particles may also have an impact. 
11.2.2. 
Description of Reference Product 
CYKLOKAPRON (TXA) is a white crystalline powder. The aqueous solution for injection has 
a pH of 6.5 to 8.0.  Each mL of the sterile solution for IV injection contains 100 mg TXA and 
Water for Injection to 1 mL. 


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11.2.3. 
Description of Diluents 
Not applicable. 
11.3. 
Method of Assigning Patients to Treatment 
11.3.1. 
Randomization Scheme 
Approximately 45 patients (15 per treatment group) are planned for enrollment. Patients will be 
randomized in a 1:1:1 ratio to receive a single dose of DepoTXA 800 mg, DepoTXA 1200 mg, 
or IV TXA (CYKLOKAPRON 1 gram). 
The randomization code will be generated by a centralized randomization system, which will 
also be used to communicate patient randomizations to study sites.  All randomized patients will 
have both a unique patient identifier and a unique random code identifier.  No patient or random 
code identifiers are to be reused once assigned. 
11.3.2. 
Randomization Procedures 
Once a patient is identified as being qualified for the study per the eligibility criteria (see 
Section 10.1 and Section 10.2), and is at the study site for surgery, the research pharmacist or 
designee will obtain a randomization assignment.  The patient will be considered randomized 
into the study once the study treatment assignment is received. 
11.3.3. 
Replacement of Patients 
Patients who are randomized but are withdrawn from the study before receiving study drug or do 
not undergo the surgical procedure may be replaced. Once assigned, patient numbers will not be 
reused; patients enrolled to replace those who withdraw will be assigned a unique patient number 
and randomized to treatment according to the procedures outlined above. 
11.4. 
Selection of Doses in the Study 
11.4.1. 
Justification of the Dose, Route, and Timing of Administration of the 
Comparator 
Precedent includes five published randomized, placebo-controlled studies of TXA in TKA, each 
of which included one group of patients that received a single IV dose of TXA at the end of 
surgery (Maniar 2012; Drosos 2016; Hiippala 1995; Orpen 2006; and Tanaka 2001).  Doses 
ranged from less than 1000 mg to an estimated approximately 1200 mg, a similar IV dosing 
regimen to that of the comparator group in the current study (IV TXA 1 gram at the end of 
surgery). 
• 
In a prospective, randomized, partially blinded (patients, floor nurses, and laboratory 
technicians), controlled trial, Maniar (2012) gave patients IV TXA 10 mg/kg 15 minutes 
before deflation of the tourniquet (weight was not reported, but mean body mass index in the 
group was 29.4; for a 65-kg patient, this would represent a dose of 650 mg).  Drain loss, 
blood loss on postsurgical Days 1 and 2, total blood loss, and number of patients indicated 
for transfusion, respectively, were lower in the TXA group (n=40) by 12.8%, 26.8%, 24.9%, 
and 20% than in the control group (n=40; not significant).  Two TXA-treated patients had 


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clinical suspicion of deep vein thrombosis (DVT); however, neither was confirmed by duplex 
Doppler. 
• 
In a prospective, randomized, controlled trial, Drosos (2016) gave patients IV TXA (1 g) at 
the start of wound suturing. The treated group showed significantly lower blood loss 
(16.3%) and a significantly lower likelihood of transfusion (90%) than the saline control 
group. There were no thromboembolic complications in either group. 
• 
In a prospective, randomized, controlled trial, Hiippala (1995) gave patients IV TXA 
15 mg/kg 2 to 5 minutes before deflating the tourniquet (mean weight of patients in the 
group was 72 kg, so the average dose was 1080 mg). Total blood loss among TXA-treated 
patients (n=15) was 45.3% lower than that reported for the placebo-treated patients (n=13; 
p<0.001). Units of blood transfused per patient were 54.5% lower in the TXA group than in 
the placebo group (p<0.005).  Two placebo-treated patients experienced confirmed DVT vs. 
none in the TXA-treated group. 
• 
In a prospective, randomized, double-blind, controlled trial, Orpen (2006) gave patients 
15 mg/kg at the time of cementing of the prosthesis, before deflation of the tourniquet (mean 
weight of patients in the group was 83 kg, so the average dose was 1245 mg). Compared to 
saline controls (n=14), a statistically significant (p=0.006) decrease in blood loss in the early 
postoperative period was noted in the group receiving TXA (n=15).  Total blood loss and Hb 
drop were also lower in the TXA-treated patients than in controls (not significant). There 
was no evidence of DVT in either group on duplex ultrasound screening of the lower limbs. 
• 
In a prospective, randomized, double-blind (patients and surgeons), controlled trial Tanaka 
(2001) gave patients IV TXA 20 mg/kg 10 minutes before deflation of the tourniquet (mean 
weight of patients in the group was 60 kg, so the average dose was 1200 mg). Total blood 
loss in the TXA-treated patients (n=22) was 39.1% lower than that in placebo-treated patients 
(n=26), and the number of patients transfused was 23% lower. (Statistics were reported for 
this TXA dosing regimen combined with two others, ie, pooled TXA groups, and were 
significant in favor of TXA over placebo.)  One TXA-treated patient had mild nausea, and no 
patients had clinical signs of DVT or pulmonary embolism. 
The dose and timing of IV TXA for the comparator group in this study were also selected based 
on their suitability for later side-by-side comparison of PK parameters of a single dose given at 
the end of surgery for both IV TXA- and DepoTXA-treated patients. 
11.4.2. 
Justification of the Route and Timing of Administration of DepoTXA 
Note that the justification for the dose of (and the safety margins for) DepoTXA are included in 
the discussion of nonclinical studies in Section 7.1. 
A review of six high-level-of-evidence meta-analyses published between 2013 and 2015 
comparing TXA routes of administration revealed the following safety and efficacy findings 
relevant to “topical” administration of TXA, so named to include various methods gleaned from 
the literature of surgical instillation into the joint space (Panteli 2013, Zhang 2014, Wang 2015b, 


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and Yue 2015 [topical TXA and placebo control]; Shemshaki 2015 and Wu 2015 [topical TXA, 
systemic TXA, and placebo control]): 
• 
There was no significant difference in the incidence of DVT reported between TXA and 
control.  Shemshaki (2015) reported the risk ratio for “thromboembolic events” as 0.68 
(not significant). Panteli (2015) did not report on DVT or PE.  In the 4 meta-analyses that 
reported DVT, the risk ratio ranged from 0.78 to 1.02.  A risk ratio <1.0 indicates a reduction 
in risk.  In the 3 meta-analyses that reported PE, risk ratio ranged from 0.49 to 0.66. Wu 
(2015) reported PE in 2/705 TXA patients (all TXA, meaning IV + topical) and 7/706 
controls. 
• 
Mean total blood loss was significantly lower with topical TXA than without it.  In the 5 
meta-analyses reporting mean difference between control and topical TXA (ie, control minus 
TXA), the mean differences ranged from 220 mL to 396 mL. Wu reported standard mean 
difference as significant (significance in the same direction).The Hb drop reduction between 
topical TXA and control was significant in the 5 meta-analyses that reported it, and ranged 
from 0.65 g/dL to 0.94 g/dL. Shemshaki did not report Hb drop. 
• 
The transfusion requirement risk ratio was significantly reduced with topical TXA compared 
to control in 5/6 meta-analyses and ranged from 0.22 to 0.47. Wang (2015b) reported the 
risk ratio as 0.33 and p-value as 0.14. 
Much clinical evidence supports that topical administration of TXA in solution is both safe and 
effective at reducing blood loss, but no consensus has been reached in the published literature on 
the most effective dose, regimen, or technique of application. Successful reduction of blood loss 
has been demonstrated using intra-articular TXA application after closure (Craik 2014; 
Yang 2015; Wang 2015a) and in the absence of a drain (Craik 2014; Yang 2015; Wang 2015a; 
Wong 2010). 
The nonclinical studies of DepoTXA indicate that TXA stays at a surgical wound site in dogs 
and is released from DepoTXA over a period of up to 72 hours. The first 6 hours of plasma 
TXA was due primarily to the free TXA in the DepoTXA formulation used in the toxicology 
studies. 
Given the short half-life of approximately 2 hours following IV administration of TXA and the 
extended period of fibrinolysis associated with surgery (approximately 2 to 3 days), a 
combination DepoFoam and TXA product (DepoTXA) may provide an opportunity to 
significantly improve the PK profile of a vital medication by creating a long-acting product to 
reduce ongoing bleeding over an extended duration. 
11.5. 
Blinding 
11.5.1. 
Blinding Procedures 
This is a single-blind study (ie, the study staff, but not the patients, know which patients are 
receiving which treatment). 


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11.5.2. 
Unblinding Procedures 
Not applicable. 
11.6. 
Prior and Concomitant Therapy and Medications 
Medications with a known procoagulant effect (eg, combination hormonal contraceptives, Factor 
IX complex concentrates or anti-inhibitor coagulant concentrates, or all-trans retinoic acid) are 
not permitted. 
At all times during the study, administration of TXA by any mode is prohibited except for the 
single dose of study treatment to which the patient is randomized. 
The physicochemical incompatibilities of DepoTXA with other drugs/compounds has not been 
assessed.  Direct contact of DepoTXA with certain drugs/compounds may alter the intended 
release profile of TXA from the particles. Therefore, do not admix DepoTXA with other 
drugs/compounds (including antiseptics [eg, povidone iodine [Betadine®]) prior to 
administration. 
All medications taken within 30 days prior to study drug administration through 120 hours after 
study drug administration or until the patient is withdrawn from the study, whichever is sooner, 
will be recorded on the case report form (CRF). 
Each institution may follow its standard protocol for the control of postsurgical pain; however, 
patient-controlled analgesia is not permitted. 
Additionally, any medications administered in association with an AE will be recorded through 
Day 60 (±3 days). 
11.7. 
Treatment Compliance 
Not applicable, since study drug will be administered by the study staff during surgery. 
11.8. 
Accountability of Study Drug 
Any shipment of study drug will contain an investigational drug transmittal and receipt form to 
assist the Investigator or designee (eg, pharmacist) in maintaining current and accurate inventory 
records.  At a minimum, the pharmacist or designee will maintain accurate records 
demonstrating dates and units of drug received, lot numbers, patients to whom drug was 
administered, and accounts of any drug destroyed accidentally or deliberately. The Investigator 
must retain vials containing used, unused, or expired study drug for return or destruction, as 
instructed by Pacira, following confirmation of drug accountability data by a study monitor. 
A record of drug return or destruction will be maintained and provided to Pacira.  Inventory 
records must be readily available for inspection by the study monitor and appropriate regulatory 
authorities at any time. A copy of the inventory records, drug accountability information, and 
notice of return or destruction will be returned to Pacira at the end of the study. Only authorized 
personnel identified by the Investigator will have the ability to access and administer the drug. 


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12. 
STUDY ENDPOINTS AND MEASUREMENTS 
12.1. 
Efficacy Assessments 
The following efficacy measurements will be conducted at the times specified after the 
beginning of study drug administration: 
• 
Total blood loss as measured by Hb and Hct levels upon arrival at the post-anesthesia 
care unit (PACU) and at 6, 12, 24, 48, 72, and 120 hours, and Day 7. 
• 
Transfusion requirement. 
• 
Postsurgical “Timed Up-and-Go” will be assessed once on the day of the surgery 
following surgery; at approximately 8:00 am and 8:00 pm (±2 hours) on Day 2 (ie, the 
day after surgery); at hospital discharge; and on Day 7 (see Appendix 1). 
Maximum passive and active knee flexion twice daily at the time of the physical therapy 
assessment (ie, approximately 8:00 am and 8:00 pm [±2 hours] daily) until hospital 
discharge. 
• 
Knee and thigh measurements (surgical leg only) on the morning of Day 2 (ie, the day 
after surgery), Day 3, and at the Day-7 follow-up visit. 
• 
Numerical rating scale at rest (NRS-R) pain score (see Appendix 3; 0 [no pain] to 10 
[worst possible pain]) upon arrival at the PACU; at each in-hospital vital sign assessment 
beginning with the 2-hour assessment and ending with the 72-hour assessment; on Day 3; 
and at the Day-7 follow-up visit. 
• 
Days to independent ambulation, assessed beginning at the Day-7 follow-up visit 
• 
SWAS on the morning of Day 2 (ie, the day after surgery), and on Day 7 
12.2. 
Efficacy Endpoints 
The efficacy endpoints listed below will be assessed based on the efficacy measurements 
conducted at the times specified after the beginning of study drug administration: 
• 
Total blood loss as measured by Hb and Hct levels upon arrival at the PACU and at 6, 12, 
24, 48, 72, and 120 hours, and Day 7. 
• 
Incidence of transfusion (number of units, number of units/patient, number of patients 
transfused). 
• 
Time to 90 degrees passive and active knee flexion. 
• 
Time to complete TUG test. 
• 
Change in knee and thigh measurements. 
• 
Pain scores. 
12.3. 
Pharmacokinetic Analysis 
Blood samples (drawn into pediatric tubes to minimize blood loss) for PK analysis will be 
obtained at baseline (Day 1 pre-op, prior to study drug administration); at 5, 15, and 30 minutes; 


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and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after the end of study drug administration for all 
treatment groups.  Additional blood samples will be collected at 36, 48, 60, 72, and 96 hours 
after the end of study drug administration for DepoTXA-treated patients.  It is important that 
blood draws for PK assessment be timed from the END of infusion of DepoTXA. 
Blood samples for PK analysis may be drawn using a properly maintained indwelling cannula 
(PICC line) at the discretion of the Investigator. 
12.4. 
Pharmacokinetic Endpoints 
Pharmacokinetic parameters will be estimated from the plasma TXA measurements using non- 
compartmental analysis.  The following parameters will be determined: 
AUC0-tlast 
The area under the plasma concentration-versus-time curve from the time of 
administration to the time of the last quantifiable concentration calculated using 
the log-linear trapezoidal rule. 
AUC0-∞ 
The area under the plasma concentration-versus-time curve from the time of 
administration extrapolated to infinity.  The residual area from the time of the last 
quantifiable concentration (Ctlast) to infinity is to be calculated using the 
approximation: AUCt-∞ = Ctlast/λz. 
Cmax 
The maximum observed plasma concentration obtained directly from the 
experimental data without interpolation. 
Tmax 
The time to maximum plasma concentration (Cmax). 
λz 
The apparent terminal elimination rate constant determined by log-linear 
regression of the terminal log-linear segment of the plasma concentration-versus- 
time curve. 
t1/2el 
The apparent terminal elimination half-life calculated as 0.693/λz. 
12.5. 
Safety Assessments 
The following safety assessments will be conducted after the beginning of study drug 
administration: 
• 
Physical examination at 48 hours. 
• 
Vital signs, (resting heart rate and blood pressure) at 5, 15, and 30 minutes, and at 1, 2, 4, 
6, 8, 12, 16, 24, 36, 48, 60, 72, and 96 hours after study drug administration. 
• 
Neurological assessment at 12, 24, 36, 48, 60, 72, and 96 hours after study drug 
administration (see Appendix 2). 
• 
12-lead ECG at 1 hour (±15 minutes) and 12 (±2) hours. 
• 
Clinical laboratory testing (chemistry [including lipid profile], hematology, and 
coagulation [fibrinogen and fibrin split products]) at 48 hours and on Day 7. 
• 
Creatinine clearance calculations at 48 hours and on Day 7. 
• 
Reoperation due to hematoma or wound dehiscence. 
• 
Adverse events through Day 60 (±3 days). 


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12.6. 
Safety Endpoints 
The following safety endpoints will be assessed based on the safety measurements conducted at 
the specified timepoints: 
• 
Change from baseline in vital signs at each assessed timepoint. 
• 
Summary of neurological assessments (proportion of patients who are oriented, and 
proportion of patients who have any of the neurologic events) at each assessed timepoint. 
• 
Change from baseline in clinical laboratory data at each assessed timepoint. 
• 
Change from baseline in ECG data at each assessed timepoint. 
• 
Incidence of reoperation due to hematoma or wound dehiscence. 
• 
Incidence of treatment-emergent AEs (TEAEs) and SAEs through Day 60 (±3 days). 
12.7. 
Appropriateness of Measures 
Endpoints selected for this study were based on validated methodologies and other well 
established clinical measurements used in peer-reviewed studies in both the peer reviewed 
literature and at regulatory authorities. 
12.7.1. 
Rationale for Key Efficacy Endpoints 
Pacira recently (March 2016) performed a systematic literature review of 12 large (≥50 patients), 
randomized, placebo-controlled trials published in the past 10 years that used TXA (IV and/or 
topical) in TKA (Alshryda 2013; Wong 2010; Yang 2015; Maniar 2012; Carvalho 2015; Roy 
2012; Georgiadis 2013; Wang 2015a; Wang 2015c; Aguilera 2015; Seo 2013; Craik, 2014). 
12.7.2. 
Hb and Hct as Surrogate Markers for Total Blood Loss 
Statistical significance was achieved in favor of a better Hb outcome (for patients) with TXA 
than with placebo control for all the studies that reported Hb values (n=11 studies; Maniar did 
not report Hb). The Hb findings (all findings significant) were consistent with the blood loss 
results (better outcome [for patients] with TXA than with placebo control, all findings 
significant).  Thus, and logically, decrease in Hb is an excellent surrogate marker for blood loss. 
By extension, analogous reasoning can be applied to Hct. 
 
12.7.2.1. Calculated Total Blood Loss 
As a widely accepted reporting convention, in all 12 studies, blood volume (BV) was estimated 
(calculated) adjusted for the weight, height, and sex of the patient. Blood loss was estimated 
(calculated) by one of several published methods, which were based on the maximum 
postsurgical decrease in Hb level. Some formulae also took transfusion volumes into account. 
Calculated blood loss should theoretically give a better estimation of the combined external loss 
(ie, intraoperative loss plus drain loss) and the internal (hidden) blood loss.  In some studies, 
intraoperative blood loss was not included in the total blood loss figures; however, it will be 
included in the calculated blood loss metric for this study. 


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13. 
STUDY PROCEDURES 
A time and events schedule for all study procedures is provided in Table 1. 
13.1. 
Instructions for Conducting Procedures and Measures 
All assessments conducted after baseline will be timed from the beginning of study drug 
administration. 
At timepoints when multiple assessments coincide, the vital signs will be conducted first, the 
blood draw for PK analysis will be collected second, and the physical therapy assessment will be 
conducted last, as applicable. 
Day 1 is defined as the day on which study drug is administered. The beginning of surgery is 
defined as the time of the first incision.  The end of surgery is defined as the time of the last 
suture.  Postsurgical is defined as after the end of surgery. 
13.1.1. 
Knee Flexion Assessment 
The knee flexion to 90 degrees assessment will be conducted during the screening visit and twice 
daily at the time of the physical therapy assessments (ie, approximately 8:00 am and 8:00 pm [±2 
hours] daily) until hospital discharge). 
Knee flexion (passive and active) will be measured by a standard physical 
medicine/rehabilitation technique with the patient stable in either a sitting or supine position 
using a goniometer, aligning the fulcrum of the goniometer with the fulcrum of the joint. 
13.1.2. 
Timed Up-and-Go Test 
The TUG test will be conducted during the screening visit.  Postsurgical TUG will be assessed 
once on the day of the surgery following surgery; at approximately 8:00 am and 8:00 pm (±2 
hours) on Day 2 (ie, the day after surgery); at hospital discharge; and on Day 7.  Details are 
provided in Appendix 1. 
13.1.3. 
Neurological Assessment 
A neurological assessment will be conducted at screening; baseline (Day 1 pre-op, prior to 
surgery); and at 12, 24, 36, 48, 60, 72, and 96 hours.  The examination will include the patient's 
orientation.  Additionally, the patient will be asked whether he or she is experiencing any 
numbness of the lips, the tongue, or around the mouth; a metallic taste in the mouth; vision 
problems; hearing problems; or muscle twitching (see Appendix 2). 
If the patient answers “yes” to any of these questions, the event must be recorded as an AE. 
13.1.4. 
Clinical Laboratory Tests 
Hemoglobin and hematocrit will be measured at screening; baseline (Day 1 pre-op, prior to 
surgery); upon arrival at the PACU; and at 6, 12, 24, 48, 72, and 120 hours, and Day 7.  Clinical 
laboratory tests (chemistry [including lipid profile], hematology, and coagulation [fibrinogen and 
fibrin split products]) will be conducted at screening; baseline (Day 1 pre-op, prior to surgery); at 


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48 hours; and on Day 7 (see Appendix 5). Creatinine clearance will be calculated for Day 1 prior 
to surgery, for 48 hours, and for Day 7. 
Clinical laboratory tests, as appropriate, must also be conducted if a patient experiences an AE of 
special interest or an SAE (see Section 13.1.10). 
13.1.5. 
Vital Signs 
The scheduled vital signs (heart rate and blood pressure) will be measured after the patient has 
rested in a supine position for at least 5 minutes at screening; baseline (Day 1 pre-op, prior to 
surgery); at 5, 15, and 30 minutes; and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, and 96 hours 
after study drug administration. Vital signs must also be measured if a patient experiences an 
AE of special interest or an SAE (see Section 13.1.10). The patient will remain in a supine 
position during the assessment. 
13.1.6. 
Physical Examination 
A physical examination will be conducted at screening and at 48 hours. 
13.1.7. 
Knee and Thigh Measurements 
Knee and thigh measurements of both legs will be collected on the day of surgery prior to 
surgery.  Knee and thigh measurements of the surgical leg only will be collected on the morning 
of Day 2 (ie, the day after surgery), on Day 3, and at the Day-7 follow-up visit. 
With the patient in the supine position and using the measuring tape provided, measure the 
circumference of the knee at 1 centimeter (cm) proximal to the base of the patella and the thigh 
at 10 cm above the border. Measurements are to be recorded to the nearest tenth of a cm. 
The provided tape measure should be used for all patients. Additionally, to reduce inter-rater 
variability in the placement of the measuring tape, the first examiner (prior to surgery) should 
make multiple marks (no fewer than four marks per measurement) on the patient’s surgical leg 
along the top of the measuring tape for each of the four measurements. These marks will be used 
to position the tape measure for subsequent measurements. 
13.1.8. 
Electrocardiogram 
The scheduled 12-lead ECGs will be conducted after the patient has rested in a supine position 
for at least 5 minutes at baseline (Day 1 pre-op, prior to surgery) and at 1 hour (±15 minutes) and 
12 (±2) hours after study drug administration. 
13.1.9. 
Numerical Rating Scale at Rest Pain Score 
The NRS-R (0 [no pain]-10 [worst possible pain]) provided in Appendix 3 will be used to record 
pain scores on the day of surgery prior to surgery; upon arrival at the PACU; at each in-hospital 
vital sign assessment beginning with the 2-hour assessment and ending with the 72-hour 
assessment; and at the Day-7 follow-up visit. 
13.1.10. 
Adverse Events of Special Interest 
Adverse events of special interest include VTE or PE, and oliguria.  If an AE of special interest 
or SAE occurs during the study, an unscheduled PK blood sample must be collected.  In 


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addition, vital signs, the neurological assessment, and clinical laboratory tests must be 
conducted, as appropriate. 
13.1.11. 
Surgical Wound Aspect Score 
A modification of the surgical wound aspect score developed by Torres-Claramunt, et al (Torres- 
Claramunt, 2015) will be calculated from the knee measurements collected on the morning of 
Day 2 (ie, the day after surgery) and on Day 7 and an assessment of the surgical wound at these 
times for signs of oozing, erythema, ecchymosis, and blisters (see Appendix 4). 
13.2. 
Screening Procedures 
• 
Explain study purpose and procedures. 
• 
Obtain signed ICF. 
• 
Assess eligibility. 
• 
Record relevant medical/surgical history, demographics, and baseline characteristics. 
• 
Conduct urine pregnancy test for women of childbearing potential. 
• 
Perform physical examination (including height and weight). 
• 
Conduct TUG test (see Appendix 1). 
• 
Perform passive and active knee flexion assessment. 
• 
Perform neurological assessment (see Appendix 2). 
• 
Conduct clinical laboratory tests (hematology [including Hb and Hct], chemistry, and 
coagulation; see Appendix 5). 
• 
Measure vital signs (heart rate and blood pressure) after patient has rested in a supine 
position. 
• 
Record prior and concomitant medications. 
• 
Record AEs starting at signing of the ICF. 
13.3. 
Baseline Procedures (Day 1 Pre-op - Prior to Study Drug 
Administration) 
• 
Confirm eligibility. 
• 
Update relevant medical and surgical history. 
• 
Conduct urine pregnancy test for women of childbearing potential. 
• 
Perform neurological assessment (see Appendix 2). 
• 
Measure vital signs (heart rate and blood pressure) after patient has rested in a supine 
position. 
• 
Record NRS-R pain score (see Appendix 3; 0 [no pain] to 10 [worst possible pain]) 
• 
Collect knee and thigh measurements of both legs (mark position of tape measure on the 
subject’s surgical leg to aid in collection of future measurements). 


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• 
Collect blood samples for clinical laboratory testing (hematology [including Hb and Hct], 
chemistry [including calculation of creatinine clearance] and coagulation; 
see Appendix 5). 
• 
Collect baseline blood sample for PK analysis. 
• 
Perform presurgical 12-lead ECG after patient has rested a supine position 
• 
Randomize patient and prepare study drug. 
• 
Record changes to concomitant medications since screening. 
• 
Record AEs and any treatment(s) for the events. 
13.4. 
Intraoperative Procedures 
• 
Administer study drug per Section 11.1.1; record start and stop times. 
• 
Record start and stop times of tourniquet use and the maximum pressure (mmHg) used. 
• 
Record start and stop times of surgery. 
• 
Record concomitant medications. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.10 for additional procedures in the event an AESI or SAE occurs. 
13.5. 
Upon Arrival at the Post-Anesthesia Care Unit 
• 
Collect blood sample for hemoglobin and hematocrit. 
• 
Record any blood transfusion data (eg, start and stop times, number of units). 
• 
Record concomitant medications. 
• 
Record AEs and any treatment(s) for the events. 
• 
Record NRS-R pain score (see Appendix 3; 0 [no pain] to 10 [worst possible pain]) 
• 
Refer to Section 13.1.10 for additional procedures in the event an AESI or SAE occurs. 
13.6. 
Postsurgical Assessments Through Hour 120 
• 
Measure vital signs (heart rate and blood pressure) after patient has rested in a supine 
position at 5, 15, and 30 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, and 
96 hours. 
• 
Record NRS-R pain score (see Appendix 3; 0 [no pain] to 10 [worst possible pain]) at 
each in-hospital vital sign assessment beginning with the 2-hour assessment and ending 
with the 72-hour assessment. 
• 
For all patients: Collect scheduled blood samples for PK analysis at 5, 15, and 
30 minutes; and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after the end of study drug 
administration for all treatment groups.  Record the date and time each sample is 
collected. It is important that blood draws for PK assessment be timed from the 
END of infusion of DepoTXA. 
• 
For DepoTXA-treated patients only: Additional blood samples will be collected at 36, 48, 
60, 72, and 96 hours after the end of study drug administration. Record the date and time 


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each sample is collected.  It is important that blood draws for PK assessment be 
timed from the END of infusion of DepoTXA. 
• 
Collect blood sample for hemoglobin and hematocrit at 6, 12, 24, 48, 72, and 120 hours. 
• 
Collect blood samples for clinical laboratory testing (hematology [includes hemoglobin 
and hematocrit], chemistry [including calculation of creatinine clearance], and 
coagulation) at 48 hours. 
• 
Perform 12-lead ECG at 1 hour (±15 minutes) and 12 (±2) hours after study drug 
administration 
• 
Perform physical examination at 48 hours. 
• 
Collect knee and thigh measurements of the surgical leg on the morning of Day 2 (ie, the 
day after surgery) and Day 3. 
• 
Assess the surgical wound for the SWAS parameters (see Appendix 4) when collecting 
the knee measurement on the morning of Day 2 (ie, the day after surgery). 
• 
Conduct the TUG test once on the day of the surgery following surgery; at approximately 
8:00 am and 8:00 pm (±2 hours) on Day 2 (ie, the day after surgery); at hospital 
discharge; and on Day 7 (see Appendix 1). 
• 
Perform passive and active knee flexion assessment twice daily at the time of the physical 
therapy assessments (ie, approximately 8:00 am and 8:00 pm [±2 hours] daily) until 
hospital discharge. 
• 
Perform neurological assessment at 12, 24, 36, 48, 60, 72, and 96 hours (see Appendix 2). 
• 
Record any blood transfusion data (eg, start and stop times, number of units). 
• 
Record any reoperations due to hematoma or wound dehiscence. 
• 
Record concomitant medications (patient-controlled analgesia for control of postsurgical 
pain is not permitted) 
• 
Record date and time of discharge from hospital. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.10 for additional procedures in the event an AESI or SAE occurs. 
13.7. 
Day 7 Visit 
• 
Record NRS-R pain score (see Appendix 3; 0 [no pain] to 10 [worst possible pain]) 
• 
Collect blood sample for hemoglobin and hematocrit 
• 
Collect blood samples for clinical laboratory testing (hematology [including Hb and 
hematocrit], chemistry [with creatinine clearance calculation], and coagulation). 
• 
Collect knee and thigh measurements of the surgical leg. 
• 
Assess the surgical wound for the SWAS parameters (see Appendix 4) when collecting 
the knee measurement. 
• 
Conduct TUG test (see Appendix 1). 


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• 
Record date and time of discharge, if applicable. 
• 
Record any blood transfusion data (eg, start and stop times, number of units). 
• 
Record any reoperations due to hematoma or wound dehiscence. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.10 for additional procedures in the event an AESI or SAE occurs. 
• 
Record whether patient has achieved independent ambulation 
13.8. 
Day 14 (±1 day) Telephone Call 
• 
Record any blood transfusion data (eg, start and stop times, number of units). 
• 
Record any reoperations due to hematoma or wound dehiscence. 
• 
Record AEs and any treatment(s) for the events. 
• 
Record whether patient has achieved independent ambulation 
13.9. 
Day 30 (±3 days) Telephone Call 
• 
Record any blood transfusion data (eg, start and stop times, number of units). 
• 
Record any reoperations due to hematoma or wound dehiscence. 
• 
Record AEs and any treatment(s) for the events. 
• 
Record whether patient has achieved independent ambulation 
13.10. 
Day 60 (±3 days) Telephone Call 
• 
Record SAEs, AESI, other AEs, and any treatment(s) for the events. 
• 
Record whether patient has achieved independent ambulation 
14. 
ADVERSE EVENT REPORTING 
Consistent with the current regulatory guidance provided by the US FDA CFR Part 312 and the 
ICH GCP, AEs and SAEs are defined in Section 14.1.1 and Section 14.2.1, respectively. 
The concepts of AEs and SAEs represent regulatory instruments used to evaluate and monitor 
the safety of clinical study patients.  Therefore, these terms only apply in light of their regulatory 
definition.  The term serious, in a regulatory sense, does not necessarily mean severe. The SAE 
concept is used primarily to identify, during the conduct of the study, those SAEs that may 
require expedited reporting to regulatory authorities. 
14.1. 
Adverse Events 
14.1.1. 
Definitions 
Definition of Adverse Event (AE): Any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (eg, abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment about 


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causality.  An AE can arise from any use of the drug (eg, off-label use in combination with 
another drug) and from any route of administration, formulation, or dose, including an overdose. 
An AE can be any unfavorable and unintended change in a body structure or body function. 
Adverse events include any clinically significant deterioration of a patient’s medical status. 
The AE may involve any organ or system and can be represented by the new onset or 
deterioration of a disease, a syndrome, a symptom, a physical sign, as well as by findings and 
results of instrumental examinations and laboratory tests.  Any medically relevant and untoward 
change after the patient signs the ICF, including frequency or pattern changes for a fluctuating 
condition (eg, migraine) is considered an AE. 
An AE that occurs after the ICF is signed and before the start of the study drug administration is 
identified as a pretreatment AE (PTAE). A TEAE will be any adverse event or pre-existing 
medical condition that worsens in intensity after the start of study drug and within 30 days of the 
last dose. 
Definition of Adverse Reaction: Any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Definition of Suspected Adverse Reaction: Any AE for which there is a reasonable possibility 
that the drug caused the AE.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug. Suspected adverse 
reactions are a subset of all AEs for which there is a reasonable possibility that the drug caused 
the event. 
14.1.2. 
Recording Adverse Events 
It is the responsibility of the Investigator to document all AEs (ie, PTAEs and TEAEs) with an 
onset after the patient signs the ICF.  For the purpose of this study, all AEs that occur through 
Day 60 (±3 days) must be recorded regardless of whether or not they are considered related to 
study drug.  Whenever feasible, AE terms should be documented as medical diagnoses (highest 
possible level of integration); otherwise, the AEs should be reported separately as individual 
signs or symptoms.  Only one AE per line should be recorded in the AE CRF; for example, an 
AE of nausea and vomiting should be listed as two separate events: the event of nausea and the 
event of vomiting.  If a diagnosis is established after symptoms are recorded on the AE CRF, 
the diagnosis should be recorded and the symptoms collapsed (removed; ie, lined through and 
initialed).  Whenever possible, abnormal laboratory results should be reported as their clinical 
corollary (eg, low potassium should be recorded as hypokalemia). 
A continuous AE with varying grades of severity should be recorded as one AE. The highest 
grade of severity experienced by that patient during the course of the continuous AE should be 
recorded. 
Any condition noted before the patient signs the ICF will be listed as medical history and is 
considered a pre-existing condition.  If a pre-existing condition changes (ie, becomes more 
severe or more frequent) at any time after the ICF is signed, or after study drug administration, 


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it is considered an AE.  Note: A change in treatment for a pre-existing condition (eg, new high 
blood pressure medication), does not necessarily indicate an AE. 
Information recorded on the AE CRF will include the AE term, the date and time of onset, 
severity, seriousness, relationship to study drug, action taken with patient because of an AE, and 
the outcome of the AE, including the date and time of resolution, if applicable. 
14.1.3. 
Severity of Adverse Events 
In general, the severity of an AE should be categorized using the following guidelines: 
Mild: 
An AE that is easily tolerated by the patient, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate: 
An AE that is discomforting and interferes with normal everyday 
activities. 
Severe: 
An AE that prevents normal everyday activities. 
The term severe is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as serious, which is based 
on patient/event outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
14.1.4. 
Relationship of Adverse Events to Study Drug 
The Investigator will assess the relationship of the AE to study drug after careful medical 
consideration on a case-by-case basis. General guidelines for determining the AE’s causality to 
the study drug are provided below. 
Unrelated: 
A causal relationship between the study drug and the AE can be 
easily ruled out (eg, based on the temporal sequence, absence of a 
reasonable pathophysiological mechanism, or direct evidence of 
actual cause). 
Unlikely: 
A clinical event with a temporal relationship to study drug 
administration which makes a causal relationship improbable and in 
which other drugs, chemicals, or underlying disease provide a 
plausible explanation; 
Possible: 
A clinical event with a reasonable time sequence to administration 
of the study drug but which could also be explained by a concurrent 
disease or other drugs or chemicals; 
Probable: 
A clinical event with a reasonable time sequence to administration 
of the study drug unlikely to be attributed to a concurrent disease or 
other drugs or chemicals and which follows a clinically reasonable 
response on withdrawal (dechallenge); or 


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Definite: 
The pharmacological properties of the study drug(s) or of the 
substance class, and the course of the AE after dechallenge and, if 
applicable, after rechallenge, and/or specific test indicate 
involvement of the study drug(s) in the occurrence/worsening of the 
AE, and no indication of other causes exists. 
14.1.5. 
Outcome of Adverse Events 
The Investigator will assess the outcome of the AE after careful medical consideration, on a 
case-by-case basis.  General guidelines are provided below: 
 
Recovered/Resolved: 
The event resolved and the patient recovered from the AE. 
Recovered/Resolved 
with Sequelae: 
The initial event resolved, but has a continuing abnormal condition 
as a result of the AE. 
Not Recovered/ 
Not Resolved: 
At the time of last assessment, the event was ongoing, with an 
undetermined outcome.  Note: ongoing AEs are not to be considered 
resolved as a result of death. 
Recovering/Resolving: 
At the time of last assessment, the event was decreasing in 
frequency, severity, etc., and a resolution was expected. 
Fatal: 
The AE directly caused death. 
Unknown: 
There was an inability to access the patient or the patient’s records 
to determine the outcome (eg, patient withdrew consent or was 
lost to follow-up). 
14.1.6. 
Action Taken with Patient Because of an Adverse Event 
The Investigator will provide any actions taken regarding the patient (eg, treatment, diagnostic 
tests, laboratory tests, or therapy) for each reported AE. 
• 
None. 
• 
Medication. 
• 
Non-pharmaceutical therapy.  (The specific therapy used must be recorded in the 
CRF.) 
• 
Discontinued from study. 
• 
Other.  (The specific action taken must be recorded.) 
14.2. 
Serious Adverse Events 
14.2.1. 
Definition of a Serious Adverse Event 
Definition of a Serious Adverse Event (SAE): An AE or suspected adverse reaction is considered 
“serious” if, in the view of either the Investigator or Sponsor, it results in any of the following 
outcomes: 
• 
Death1 


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• 
A life-threatening adverse event2 
• 
Inpatient hospitalization or prolongation of existing hospitalization3 
• 
A persistent or significant incapacity4 
• 
Congenital anomaly/birth defect 
• 
Medically significant5 
1Death: Any event resulting in a patient’s death must be reported as an SAE. However, death, in 
and of itself, is not an AE; it is an outcome.  The cause of death is the AE.  Therefore, the 
Investigator should make every effort to obtain and document the cause of death for all patients 
who die during the study.  If, despite all efforts, the cause of death remains unknown, the AE 
should be documented as an “unspecified fatal event.” 
2Life-threatening: An AE is considered life-threatening if, in the view of either the Investigator 
or Sponsor, its occurrence places the patient at immediate risk of death.  It does not include an 
AE that had it occurred in a more severe form might have caused death. 
3Hospitalization: It should be noted that hospitalization, in and of itself, does not represent an 
SAE.  It is the AE leading to the patient’s hospitalization that becomes “serious” when it requires 
inpatient care.  Consequently, an SAE should not be reported in case of preplanned 
hospitalizations for a pre-existing condition that did not worsen during the study.  However, any 
medical condition that delays a patient’s discharge from the hospital (ie, prolonged 
hospitalization) or requires the patient to be readmitted should be reported as an SAE. 
4Persistent or significant incapacity: A substantial disruption of a person’s ability to conduct 
normal life functions. 
5Medically Significant: Important medical events that may not result in death, be life- 
threatening, or require hospitalization, may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medically 
significant events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
14.2.2. 
Reporting Serious Adverse Events 
Any SAE or death that occurs at any time after the patient signs the ICF through Day 60 
(±3 days), whether or not related to study drug, must be reported by the Investigator or designee 
to Pacira Drug Safety within 24 hours of discovery by either email (drugsafety@pacira.com) or 
fax (973-201-0649).  In addition, the Investigator or designee is encouraged to contact the 
Medical Monitor to discuss the case, as needed. 
Investigators should not wait to receive additional information to fully document the event 
before notifying Pacira Drug Safety or designee of the SAE. The fax or email report should be 
followed by a full written summary using the SAE Form detailing relevant aspects of the SAE in 
question.  Where applicable, information from relevant hospital records and autopsy reports 


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should be obtained and all patient-identifying information redacted prior to forwarding to Pacira. 
In the event of a fatal or life-threatening SAE, any required follow-up must be provided to Pacira 
Drug Safety or designee immediately. The Investigator will follow all SAEs until resolved or the 
condition stabilizes and further follow-up is not warranted. 
If the Investigator is made aware of any SAEs after Day 60 (±3 days), these should also be 
reported to Pacira Drug Safety or designee provided the SAE is considered related to study drug. 
The site would then provide a completed SAE form within 1 business day and the event would 
be followed until resolution, or until adequate stabilization is met. 
15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be developed for this study. 
15.1. 
Study Hypothesis 
No formal hypothesis testing will be conducted in this study. 
15.2. 
Study Endpoints 
The endpoints to be assessed in this study are listed in Section 12.2 (Efficacy Endpoints), 
Section 12.4 (PK Endpoints), and Section 12.6 (Safety Endpoints). 
15.3. 
Determination of Sample Size 
Sample size was not based on statistical considerations. 
15.4. 
Analysis Populations 
The following analysis sets are planned: 
Safety: The safety analysis set will include all patients who receive study drug and will be based 
on actual treatment received. 
Efficacy: The efficacy analysis set will include all patients in the safety analysis set who undergo 
the planned surgery and will be based on randomized treatment, regardless of actual treatment 
received. 
Pharmacokinetic: The PK analysis set will include all patients in the safety analysis set who 
receive study drug, provide sufficient samples to allow for calculation of PK parameters required 
for analysis, and do not have significant protocol deviations that may invalidate or bias the 
results. 
15.5. 
Handling Patient Dropouts and Discontinuations 
Data imputation rules will be described in the SAP. 
15.6. 
Statistical Analyses 
15.6.1. 
Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group. 


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15.6.2. 
Study Compliance 
The percentage of patients in each analysis set and the percentage who fail to complete the study 
(as well as the reasons for discontinuation) will be displayed by treatment group. 
15.6.3. 
Efficacy Analyses 
All efficacy analyses will be based on randomized treatment, regardless of actual treatment 
received. 
15.6.3.1. Total Blood Loss 
Total loss will be calculated separately using two separate methods. The first method is based on 
Hct and the second method is based upon Hb for 6, 12, 24, 48, 72, and 120 hours postsurgically 
and Day 7 for each patient.  Descriptive statistics summarizing the total blood loss will be 
summarized by postsurgical timepoint and treatment group for the efficacy analysis population 
for each method.  Baseline is considered the last value measured before the surgery. 
Total BV in mL will be calculated using the Nadler formula (Nadler 1962) at baseline by 
𝐵𝐵𝑉𝑉𝑏𝑏𝑎𝑎𝑎𝑎𝑒𝑒𝑙𝑙𝑖𝑖𝑛𝑛𝑒𝑒  =  (𝑎𝑎 ∗ ℎ3 + 𝑏𝑏 ∗ 𝑤𝑤 + 𝑐𝑐) 
where  h = height (m), w = baseline weight (kg), {a=0.3669, b=0.03219, c=0.6041} for males 
and {a=0.3561, b=0.03308, c=0.1833} for females.  The BV at baseline is used in methods 1 and 
2 to determine blood loss. 
Method 1 (Gibon 2013): 
Total blood loss is in mL calculated by the following formula: 
=     𝐵𝐵𝑉𝑉𝑏𝑏𝑎𝑎𝑎𝑎𝑒𝑒𝑙𝑙𝑖𝑖𝑛𝑛𝑒𝑒    ∗  ೦𝐻𝐻𝐻𝐻𝑡𝑡𝑏𝑏𝑎𝑎𝑎𝑎𝑒𝑒𝑙𝑙𝑖𝑖𝑛𝑛𝑒𝑒    − 𝐻𝐻𝐻𝐻𝑡𝑡𝑝𝑝𝑝𝑝𝑠𝑠𝑡𝑡−𝑜𝑜𝑜𝑜    ℎ𝑜𝑜𝑢𝑢𝑟𝑟 ೦     +    BV𝑡𝑡𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑓𝑓𝑢𝑢𝑢𝑢𝑒𝑒𝑒𝑒 
where 𝐻𝐻𝐻𝐻𝐻𝐻𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 is measured as a proportion, 𝐻𝐻𝐻𝐻𝐻𝐻𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑜𝑜𝑜𝑜 ℎ𝑜𝑜𝑜𝑜𝑜𝑜 is measured as a proportion 
at the specified postsurgical timepoint in hours, total BV is measured in mL, and BV𝑡𝑡𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑓𝑓𝑢𝑢𝑢𝑢𝑒𝑒𝑒𝑒     
is 
the mL volume of blood transfused to the patient. 
Method 2 (Goa 2015): 
Total blood loss in mL is calculated by the following formula: 
1000 ∗ ೦𝐵𝐵𝑉𝑉𝑏𝑏𝑎𝑎𝑎𝑎𝑒𝑒𝑙𝑙𝑖𝑖𝑛𝑛𝑒𝑒 ∗ ೦𝐻𝐻𝑏𝑏𝑏𝑏𝑎𝑎𝑎𝑎𝑒𝑒𝑙𝑙𝑖𝑖𝑛𝑛𝑒𝑒  − 𝐻𝐻𝐻𝐻𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑜𝑜𝑜𝑜 ℎ𝑜𝑜𝑜𝑜𝑜𝑜೦ ∗ 0.001 + BV𝑡𝑡𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑓𝑓𝑢𝑢𝑢𝑢𝑒𝑒𝑑𝑑೦ 
= 
𝐻𝐻𝐻𝐻𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 
where   𝐻𝐻𝐻𝐻𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏   is measured in g/L, 𝐻𝐻𝐻𝐻𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑜𝑜𝑜𝑜 ℎ𝑜𝑜𝑜𝑜𝑜𝑜   is measured in g/L at the 
specified postsurgical timepoint in hours, BV𝑡𝑡𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑓𝑓𝑢𝑢𝑢𝑢𝑒𝑒𝑒𝑒   is the mL volume of blood 
transfused to the 
patient, and total BV is measured in mL. 
15.6.3.2. Other Efficacy Analyses 
Descriptive statistics will be provided for the incidence of transfusion, the time to 90 degrees 
passive and active knee flexion, results of the TUG test, knee and thigh measurements, pain 
scores, days to independent ambulation, and SWAS by postsurgical timepoint and treatment 
group for the efficacy analysis population.  Further details will be described in the SAP. 


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15.6.4. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters will be estimated from the PK analysis set, using plasma drug 
concentration-time profiles, where appropriate, by non-compartmental analysis. 
Actual sampling time will be used for all calculations of the PK parameters.  If there is any doubt 
in the actual time a sample was taken, then the scheduled time will be used. 
Descriptive statistics will be used to summarize the PK parameters. 
Dose Modeling based on Pharmacokinetic Parameters 
Dose models will be estimated from the PK analysis set, using pharmacokinetic parameters, to 
aid in the dose selection (DepoTXA 800 mg, DepoTXA 1200 mg) for future studies. 
15.6.5. 
Safety Analyses 
All safety analyses will be based on actual treatment received. 
15.6.5.1. Adverse Events 
Adverse event verbatim terms will be mapped to preferred terms and related system organ class 
using the Medical Dictionary for Regulatory Activities (MedDRA). Events that start prior to the 
start of study drug administration will be identified in listings only.  Incidence rates of TEAEs 
and the proportion of patient prematurely withdrawn from the study because of a TEAE will be 
shown for each treatment group.  Incidence rates will also be displayed for each treatment group 
for study drug-related TEAEs and by severity.  Incidence rates of SAEs will also be shown for 
each treatment group. All incidence rates will be categorized and displayed by system organ 
class and preferred term. 
15.6.5.2. Vital Signs 
Descriptive statistics for each vital sign for baseline, each timepoint, and change from baseline at 
each timepoint will be summarized for each treatment group. 
15.6.5.3. Clinical Laboratory Data 
Descriptive statistics for each laboratory test for baseline, each timepoint, and change from 
baseline at each timepoint will be summarized for each treatment group. 
15.6.5.4. Electrocardiograms 
Descriptive statistics for each ECG parameter for baseline, each timepoint, and change from 
baseline at each timepoint will be summarized for each treatment group. 
15.6.5.5. Neurological Assessment 
The proportion of patients who are oriented at each timepoint will be summarized for each 
treatment group.  The proportion of patients who have at least one of the neurological events will 
be summarized for each treatment group. 


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15.7. 
Significance Testing 
No formal significance testing will be conducted in this study. 


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16. 
REFERENCES 
Aguilera X, Martinez-Zapata MJ, Hinarejos P, et al. Topical and intravenous tranexamic acid 
reduce blood loss compared to routine hemostasis in total knee arthroplasty: a multicenter, 
randomized, controlled trial. Arch Orthop Trauma Surg. 2015;Jul;135(7):1017-25. 
Alshryda S, Mason J, Vaghela M, et al. Topical (intra-articular) tranexamic acid reduces blood 
loss and transfusion rates following total knee replacement. J Bone Joint Surg Am. 2013;Nov 
6;95(21):1961-8. 
Álvarez JC, Santiveri FX, Ramos I, et al. Tranexamic acid reduces blood transfusion in total 
knee arthroplasty even when blood loss conservation program is applied. Transfusion. 2008; 48: 
519-525. 
Burkart BC, Bourne RB, Rorabeck CH, et al. The efficacy of tourniquet release in blood 
conservation after total knee arthroplasty. Clin Orthop Relat Res. 1994;299:147-52. 
Carvalho LH Jr, Frois Temponi E, Machado Soares LF, et al. Bleeding reduction after topical 
application of tranexamic acid together with Betadine solution in total knee arthroplasty. 
A randomised controlled study. Orthop Traumatol Surg Res. 2015;101(1):83-7. 
Craik JD, Ei Shafie SA, Kidd AG, Twyman RS.  Can local administration of tranexamic acid 
during total knee arthroplasty reduce blood loss and transfusion requirements in the absence of 
surgical drains? Eur J Orthop Surg Traumatol. 2014;24(3):379-84. 
CYKLOKAPRON [package insert]. New York, NY: Pfizer; 2014. 
CYKLOKAPRON [package insert]. Australia: Pfizer; 08 October 2010. 
DepoTXA Investigator's Brochure; 2016. 
Drosos GI, Ververidis A, Valkanis C, et al. A randomized comparative study of topical versus 
intravenous tranexamic acid administration in enhanced recovery after surgery (ERAS) total 
knee replacement. J Orthop. 2016;13(3):127-31. 
Fahmy NR, Patel DG. Hemostatic changes and postoperative deep-vein thrombosis associated 
with use of a pneumatic tourniquet. J Bone Joint Surg Am. 1981;63(3):461-5. 
Georgiadis AG, Muh SJ, Silverton CD, et al. A prospective double-blind placebo controlled trial 
of topical tranexamic acid in total knee arthroplasty. J Arthroplasty. 2013;Sep;28(8Suppl):78-82. 
Gibon E, Courpied JP, Hamadouche M. Total joint replacement and blood loss: what is the best 
equation? Int Orthop. 2013;37(4):735-739. 
Goa F, Li Z, Zhang K, et al. Four methods for calculating blood-loss after total knee arthroplasty. 
Chin Med J. 2015;128(21):2856-2860. 
Hiippala S, Strid L, Wennerstrand M, et al. Tranexamic acid (Cyklokapron) reduces 
perioperative blood loss associated with total knee arthroplasty. Br J Anaesth. 
1995 May;74(5):534-7. 
LYSTEDA [package insert]. Parsippany, NJ: Ferring Pharmaceuticals; 2013. 


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Maniar RN, Kumar G, Singhi T, et al. Most effective regimen of tranexamic acid in knee 
arthroplasty: a prospective randomized controlled study in 240 patients. Clin Orthop Relat Res. 
2012;Sep;470(9):2605-12. 
Nadler SB, Hidalgo JU, Bloch T. Prediction of blood volume in normal human adults. Surgery. 
1962 Feb;51(2):224-32. 
Orpen NM, Little C, Walker G, Crawfurd EJ. Tranexamic acid reduces early post-operative 
blood loss after total knee arthroplasty: a prospective randomised controlled trial of 29 patients. 
Knee. 2006 Mar;13(2):106-10. 
Panteli M, Papakostidis C, Dahabreh Z, Giannoudis PV. Topical tranexamic acid in total knee 
replacement: a systematic review and meta-analysis. Knee. 2013;Oct;20(5):300-9. 
Roy SP, Tanki UF, Dutta A, et al. Efficacy of intra-articular tranexamic acid in blood loss 
reduction following primary unilateral total knee arthroplasty. Knee Surg Sports Traumatol 
Arthrosc. 2012;20(12):2494-501. 
Seo JG, Moon YW, Park SH, et al. The comparative efficacies of intra-articular and IV 
tranexamic acid for reducing blood loss during total knee arthroplasty. Knee Surg Sports 
Traumatol Arthrosc. 2013;21(8):1869-74. 
Shemshaki H, Nourian SM, Nourian N, et al. One step closer to sparing total blood loss and 
transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic 
acid administration. Arch Orthop Trauma Surg. 2015;135(4):573-88. 
Tanaka N, Sakahashi H, Sato E, Hirose K, Ishima T, Ishii S. Timing of the administration of 
tranexamic acid for maximum reduction in blood loss in arthroplasty of the knee. J Bone Joint 
Surg Br. 2001 Jul;83(5):702-5. 
Torres-Claramunt R, Gil-González S, Leal J, et al. A new score assessing the surgical wound of 
a TKA and its relation with pain, infection and functional outcome. Acta Orthop. Belg., 2015, 81, 
713-719. 
Wang CG, Sun ZH, Liu J, et al. Safety and efficacy of intra-articular tranexamic acid injection 
without drainage on blood loss in total knee arthroplasty: A randomized clinical trial. Int J Surg. 
2015a Aug;20:1-7. 
Wang H, Shen B, Zeng Y. Blood loss and transfusion after topical tranexamic acid 
administration in primary total knee arthroplasty. Orthopedics. 2015b. Nov;38(11): e1007-16. 
Wong J, Abrishami A, El Beheiry H, et al. Topical application of tranexamic acid reduces 
postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint 
Surg Am. 2010;Nov 3;92(15):2503-13. 
Wu Q, Zhang HA, Liu SL, et al. Is tranexamic acid clinically effective and safe to prevent blood 
loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. Eur J Orthop 
Surg Traumatol. 2015 Apr;25(3):525-41. 
Yang Y, Lv YM, Ding PJ, et al. The reduction in blood loss with intra-articular injection of 
tranexamic acid in unilateral total knee arthroplasty without operative drains: a randomized 
controlled trial. Eur J Orthop Surg Traumatol. 2015;Jan;25(1):135-9. 


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Yue C, Pei F, Yang P, et al. Effect of topical tranexamic acid in reducing bleeding and 
transfusions in TKA. Orthopedics. 2015;May;38(5):315-24. 
Zhang Y, Fu X, Liu WX, et al. Safety and efficacy of intra-articular injection of tranexamic acid 
in total knee arthroplasty. Orthopedics. 2014;Sep;37(9):e775-82. 


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17. 
INVESTIGATOR AGREEMENT 
Printed Name of Investigator: 
Printed Title/Position: 
Printed Institution Address: 
  
 
 
 
 
 
 
 
 
 
 
 
 
I have reviewed this protocol (including Appendices) and agree: 
• 
To assume responsibility for the proper conduct of the study at this site; 
• 
To conduct the study in compliance with this protocol, with any future amendments, 
and with any other study conduct procedures provided by Pacira Pharmaceuticals, 
Inc. (Pacira) or designee.  I also agree to comply with Good Clinical Practice and all 
regulatory requirements; 
• 
Not to implement any changes to the protocol without agreement from Pacira or 
designee and prior review and written approval from the Independent Ethics 
Committee, except where it is necessary to eliminate an immediate hazard to the 
patients or for administrative aspects of the study (where permitted by applicable 
regulatory requirements); 
• 
That I am thoroughly familiar with the appropriate use of the investigational 
product(s), as described in this protocol, and with other relevant information 
(eg, the Investigator’s Brochure); 
• 
To ensure that all persons assisting me with the conduct of this study are adequately 
informed about the investigational product(s) and about their study-related duties and 
functions as described in this protocol; 
• 
That I am aware that regulatory authorities may require Investigators to disclose all 
information about significant ownership interests and/or financial ties related to the 
Sponsor and/or the investigational product(s).  Consequently, I agree to disclose all 
such significant financial information to Pacira and to update this information 
promptly if any relevant changes occur during the course of the study through 1 year 
following completion of the study.  I also agree that any information regarding my 
significant financial interest related to Pacira and/or the investigational product(s) 
will be disclosed to the regulatory authorities by Pacira. 
 
 
Signature of Investigator 
Date 


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18. 
APPENDICES 
Appendix 1:  Timed Up-and-Go Test 
The TUG test will be conducted during the screening visit.  Postsurgically, conduct the TUG test 
once on the day of the surgery following surgery; at approximately 8:00 am and 8:00 pm (±2 
hours) on Day 2 (ie, the day after surgery); at hospital discharge; and on Day 7. 
 
EQUIPMENT REQUIRED 
• 
Timer/stop watch 
• 
Standard chair (seat height: approximately 17 inches) with two arm rests (arm rest height: 
approximately 26 inches) 
• 
Ruler to measure seat height and arm rest height 
• 
Measuring tape to measure 3 meters away from the chair (approximately 9 feet 10 inches) 
• 
Tape or other marker to mark the distance so that it is easily seen by the patient 
 
Therapist Instructions 
 
1. Patient begins seated on a standard chair with arm rests. Ensure the chair cannot slide 
backwards by placing it against a wall or otherwise bracing it (eg, physical therapist braces 
with foot). 
2. Patient is instructed to sit facing forward, with both feet on the floor, and their buttocks 
touching the back of the seat 
3. A line is placed on the floor 3 meters in front of the chair. Use a measuring tape to measure 
this distance.  Alternatively, place the chair 3 meters away from an existing marker (eg, floor 
tile). 
4. Patient is instructed that “On the word GO you will stand up, walk to the line on the floor, 
turn around, and walk back to the chair and sit down.  Walk at your regular pace.” 
5. The physical therapist then says “GO” and starts the stopwatch and records the time of 
assessment. 
6. The physical therapist walks alongside the patient, for safety purposes, and notes the amount 
of physical assistance required. 
a. Total assistance (patient contributes <25% of the effort or is unable to do the task) 
b. Maximal assistance (patient provides less than half of the effort (25–49%)) 
c. Moderate assistance (patient still performs 50–75% of the task) 
d. Minimal assistance (requiring incidental hands-on help only (patient performs >75% 
of the task) 
e. Supervision (requiring only standby assistance or verbal prompting or help with 
set-up) 
f. Modified independence (requiring the use of a device but no physical help) 
g. Complete independence (fully independent) 


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7. The goal of the test is to measure the patient’s ability to complete the activity without 
assistance.  The therapist should endeavor to not provide assistance unless required for safety 
reasons. 
8. After the patient has completed the activity, the physical therapist stops the stopwatch and 
records the time lapsed in seconds 
a. If the test is not performed, the physical therapist will record the specific reason. 
b. Patient should be encouraged to complete the test.  Time will continue to run until 
therapist determines it cannot be completed and the test is stopped. 
9. The same chair should be used for all assessments, while on study. 
Patient Instructions 
 
1. Start by sitting in the chair with your back resting on the backrest and your hands on the 
armrest. 
2. On “GO,” stand up, walk to the mark, turn around, return, and sit back into the chair with 
your back resting on the back of the chair. 
3. Walk at your normal pace as safely as you can. 
4. Get ready and GO. 
 
Scoring 
 
1. The test starts on the signal to start (“GO”) and terminates once the participant sits back 
down fully with their back resting on the back of the chair. 
2. The duration of the test is recorded to nearest 10th of a second. 
3. A walking aid is allowed and should be recorded, if used. 
4. Record the physical assistance required. 


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Appendix 2: 
Neurological Assessment 
The neurological assessment will be conducted at screening, baseline (Day 1 pre-op, prior to 
surgery); and at 12, 24, 36, 48, 60, 72, and 96 hours. 
 
 
The examination will include the patient's orientation. 
• Is the patient oriented? 
  Yes 
∆ No 
∆ Not Assessable 
 
If the patient is not oriented, the event must be recorded as an AE. 
 
 
Additionally, the patient will be asked the following questions: 
 
• Do you have numbness of the lips, the tongue, or around the mouth? 
  Yes 
∆ No 
 
• Do you have a metallic taste in your mouth? 
  Yes 
∆ No 
 
• Are you having problems with your hearing not related to the use of a hearing aid? 
  Yes 
∆ No 
 
• Are you having problems with your vision not related to the use of eye glasses? 
  Yes 
∆ No 
 
• Are your muscles twitching? 
  Yes 
∆ No 
 
If the patient answers “yes” to any of these questions, the event must be recorded as an AE 
(see Section 13.1.10). 


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Appendix 3: 
Numerical Rating Scale at Rest Pain Scores 
Patients will be evaluated for pain using the numerical rating scale at rest (NRS-R) on the day of 
surgery prior to surgery, upon arrival at the PACU, at each in-hospital vital sign assessment 
beginning with the 2-hour assessment and ending with the 72-hour assessment, and at the Day-7 
follow-up visit. 
 
 
Pain Intensity Scale 
On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, circle the number that best 
describes how much pain you are having right now. (Circle only one number.) 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain 
Worst 
possible 
pain 


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Appendix 4: 
Surgical Wound Aspect Score 
The surgical wound aspect score, adapted from Torres-Claramunt, et al (Torres-Claramunt, 
2015), will be calculated based on the knee measurements collected on the morning of Day 2 
(ie, the day after surgery) and on Day 7 and the following wound parameters scored at the time 
of the knee measurements on the morning of Day 2 (ie, the day after surgery), and on Day 7. 
 
 
WOUND OOZING 
Upon removal of the dressing, assess the surgical wound for oozing and score oozing as: 
 
No signs of blood on the gauze 
0 
1-2 spots of blood on the gauze 
1 
>2 spots of blood on the gauze 
2 
 
 
ERYTHEMA 
Assess the surgical wound for the presence/extent of erythema and score the presence/extent of 
erythema as: 
 
Erythema absent 
0 
Erythema at wound edges 
1 
Erythema beyond wound edges 
2 
 
 
ECCHYMOSIS 
Assess the surgical wound for the presence/extent of ecchymosis and score the presence/extent 
of ecchymosis as: 
 
Ecchymosis absent 
0 
Ecchymosis at wound edges 
1 
Ecchymosis beyond wound edges 
2 
 
 
BLISTERS 
Assess the surgical wound for the presence/size of blisters and score the presence/size of blisters 
as: 
 
Blisters absent 
0 
1-2 blisters of < 2 cm each 
1 
>2 blisters of any size or ≥1 blister >2 cm 
2 


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Appendix 5: 
Clinical Laboratory Tests 
The scheduled clinical laboratory tests (hematology, coagulation, and chemistry) will be 
conducted at screening; baseline (Day 1 pre-op, prior to surgery); 48 hours; and Day 7.  Clinical 
laboratory tests, as appropriate, must also be conducted if a patient experiences an AE of special 
interest or an SAE (see Section 13.1.10). 
 
Basic Metabolic Profile 
Hematology 
Glucose 
White blood cells 
Calcium 
Red blood cells 
Sodium 
Hemoglobin 
Potassium 
Hematocrit 
Carbon dioxide (bicarbonate) 
Mean corpuscular volume 
Chloride 
Mean corpuscular hemoglobin 
Blood urea nitrogen 
Mean corpuscular hemoglobin concentration 
Creatinine 
Red cell distribution width 
Total cholesterol 
Platelets 
High-density lipoprotein (HDL) cholesterol 
Mean platelet volume 
Low-density lipoprotein (LDL) cholesterol 
Absolute/percent neutrophil count 
Triglycerides 
Absolute/percent lymphocyte count 
Absolute/percent monocyte count 
Coagulation 
Absolute/percent eosinophil count 
Fibrinogen 
Absolute/percent basophil count 
Fibrin split products 
 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
 29JAN2018 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A Randomized, Single-Blind, Active-Controlled, Dose-Ranging Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of Local Administration of DepoTXA 
for Reduced Postsurgical Bleeding in Subjects Undergoing Total Knee Arthroplasty 
 
 
 
 
Protocol No.: 404-C-201 
IND No.: 128,950  
Study Phase: 2 
Study Drug: DepoTXA 
Date/Version: January 29, 2018 / Final  
Prepared by: Vincent Yu, PhD 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 973-254-3560 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira 
Pharmaceuticals, Inc.  It should not be reproduced, revealed, or sent to third parties other than 
Institutional Review Boards/Independent Ethics Committees and the Investigator’s research 
support staff participating in the conduct of the study without the prior written authorization of 
Pacira Pharmaceuticals, Inc. 


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Statistical Analysis Plan 
 
CONFIDENTIAL 
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1. 
SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hassan Danesi, MD  
Senior Medical Director, Clinical Research 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Rich Scranton, MD, MPH 
Chief Scientific Officer 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Michael Rozycki, PhD 
Vice President, Regulatory Affairs and Pharmacovigilance  
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Vincent Yu, PhD 
Senior Director, Biometrics 
Date 
 
 




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Statistical Analysis Plan 
 
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2. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE 
2 
2. 
TABLE OF CONTENTS 
3 
3. 
LIST OF ACRONYMS/ABBREVIATIONS 
5 
4. 
INTRODUCTION 
6 
5. 
STUDY OBJECTIVES 
7 
5.1. 
Primary Objective 
7 
5.2. 
Secondary Objectives 
7 
6. 
STUDY OVERVIEW 
8 
7. 
DEFINITIONS 
9 
8. 
ANALYSIS SETS 
11 
9. 
STATISTICAL METHODS OF ANALYSIS 
12 
9.1. 
General Principles 
12 
9.1.1. 
Handling Missing Values 
12 
9.1.1.1. 
Post-baseline Cummulative Blood Loss 
12 
9.1.1.2. 
Adverse Event Date or Time 
13 
9.1.1.3. 
Concomitant Medications Date or Time 
13 
9.1.1.4. 
Adverse Event Severity or Relationship to Study Drug 
13 
9.1.2. 
Multiplicity Adjustments 
13 
9.2. 
Subject Disposition 
13 
9.3. 
Description of Demographics and Baseline Characteristics 
14 
9.3.1. 
Demographics 
14 
9.3.2. 
Baseline Characteristics 
14 
9.4. 
Surgery Characteristics 
15 
9.5. 
Medical and Surgical History 
15 
9.6. 
Prior and Concomitant Medications 
15 
9.7. 
Measurements of Treatment Compliance 
15 
9.8. 
Efficacy Analysis 
15 
9.8.1. 
Total Blood Loss 
16 
9.8.2. 
Incidence of transfusion 
17 
9.8.3. 
Time to 90o Passive and Active Knee Flexion 
17 
9.8.4. 
Time to Complete TUG Test 
17 
9.8.5. 
NRS Pain Scores 
17 
9.8.6. 
Change in Knee and Thigh Circumferences 
18 
9.8.7. 
Days to First Independent Ambulation 
18 


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9.8.8. 
Surgical Wound Aspect Score (SWAS) 
18 
9.9. 
Safety Analyses 
18 
9.9.1. 
Electrocardiograms 
18 
9.9.2. 
Vital Signs 
19 
9.9.3. 
Neurological Assessments 
19 
9.9.4. 
Clinical Laboratory Assessments 
19 
9.9.5. 
Reoperation Due to Hematoma or Wound Dehiscence 
19 
9.9.6. 
Adverse Events 
19 
9.10. 
Pharmacokinetic Analysis 
21 
9.10.1. 
Sample Collections for Pharmacokinetic Analysis 
21 
9.10.2. 
Pharmacokinetic Parameter Calculation Methods 
21 
9.10.3. 
Pharmacokinetic Concentrations and Variables 
22 
9.11. 
Interim Analysis 
23 
10. 
SAMPLE SIZE CALCULATION 
24 
11. 
REFERENCES 
25 
12. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
26 
13. 
TABLE OF CONTENTS FOR TABLES 
28 
14. 
TABLE OF CONTENTS FOR LISTINGS 
72 
15. 
TABLE OF CONTENTS FOR FIGURES 
104 


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Statistical Analysis Plan 
 
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Page 5 of 113 
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3. 
LIST OF ACRONYMS/ABBREVIATIONS 
Acronym/Abbreviation Description 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ATC 
Anatomical therapeutic class 
AUC 
Area under the curve 
BLOQ 
Below the limit of quantification 
BMI 
Body mass index 
BV 
Blood volume 
CRF 
Case report form 
CSR 
Clinical study report 
CV 
Coefficient of variation 
D1 Preop 
Day 1 pre-operation 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GMR 
Geometric Mean Ratio 
Hct 
hematocrit 
Hb 
hemoglobin 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IV 
Intravenous 
MedDRA 
Medical dictionary for regulatory affairs 
n 
Number of subjects 
NRS 
Numeric Rating Scale 
PACU 
Post-anesthesia care unit 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System Organ Class 
SWAS 
Surgical Wound Aspect Score 
TEAE 
Treatment-emergent adverse event 
TKA 
Total knee arthroplasty 
TLF 
Tables, listings and figures 
TUG 
Timed Up-and-Go 
TXA 
Tranexamic Acid 
WHO-DD 
World Health Organization - Drug Dictionary Enhanced 
 


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Statistical Analysis Plan 
 
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4. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting of 
the clinical study 404-C-201 titled “A Randomized, Single-Blind, Active-Controlled, Dose-
Ranging Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Local Administration 
of DepoTXA for Reduced Postsurgical Bleeding in Subjects Undergoing Total Knee 
Arthroplasty”. The primary objective of this study is to evaluate pharmacokinetics of DepoTXA 
compared to intravenous (IV) tranexamic acid (TXA).   
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the US Food and Drug Administration (FDA), European Medicines Agency 
(EMA), and International Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (US Federal Register, 1998).  All work planned and reported for this SAP will follow 
internationally accepted guidelines, published by the American Statistical Association (American 
Statistical Association, 1999) and the Royal Statistical Society (Royal Statistical Society, 1993), 
for statistical practice.   
The purposes of this SAP are to: 
 
Outline the types of analyses and presentations of data that will form the basis for 
drawing conclusions regarding the study objectives and hypotheses outlined in the 
protocol. 
 
Explain in detail how the data will be handled and analyzed, adhering to commonly 
accepted standards and practices for Good Statistical Practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or manuscripts.  Post-hoc exploratory analyses not necessarily identified 
in this SAP may be performed to further examine study data.  Any post-hoc, unplanned, or 
exploratory analyses performed will be clearly identified as such in the final CSR. 
The following documents were reviewed in preparation of this SAP: 
 
Amendment 2 of Protocol 404-C-201 issued on 27SEP2017. 
 
CRF issued on 01MAR2017.  
 
ICH Guidance on Statistical Principles for Clinical Trials (E9). 
The reader of this SAP is encouraged to also read the clinical protocol and other identified 
documents for details on the planned conduct of this study.  Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analyses. 
 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective  
The primary objective of this study is to evaluate the pharmacokinetics of DepoTXA compared 
to IV TXA. 
 
5.2. 
Secondary Objectives 
The secondary objectives of this study are to evaluate (1) the safety of DepoTXA, (2) the 
efficacy of DepoTXA (over 5 days) compared to IV TXA, and (3) a potential dose-related 
response to DepoTXA at 400, 800, and 1200 mg (33 mg/mL). 
 


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Statistical Analysis Plan 
 
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6. 
STUDY OVERVIEW 
This is a Phase 2, randomized, single-blind, active-controlled dose-ranging study in patients 
scheduled to undergo total knee arthroplasty (TKA).  Approximately 60 subjects (15 per 
treatment group) are planned for enrollment.  Subjects will be randomized in a 1:1:1:1 ratio to 
receive DepoTXA 400 mg, DepoTXA 800 mg, DepoTXA 1200 mg, or IV TXA (Cyklokapron® 
1 gram).   
Blood samples for PK analysis will be obtained at baseline (prior to study drug administration); 
at 5, 15, and 30 minutes; and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration 
for all treatment groups.  Additional blood samples will be collected at 36, 48, 60, 72, and 
96 hours after study drug administration for DepoTXA-treated subjects. 
Postsurgical efficacy assessments will include measurement of blood loss (as assessed by 
hemoglobin [Hb] and hematocrit [Hct] levels), transfusion requirement, knee flexion, timed up-
and-go (TUG) test, knee and thigh measurements, numeric rating scale (NRS_ pain scores), days 
to independent ambulation, and the surgical wound aspect score (SWAS). 
Postsurgical safety assessments will include vital signs, neurological assessment, clinical 
laboratory testing (hematology, chemistry, and coagulation), 12-lead electrocardiogram (ECG), 
and adverse event (AE) monitoring.  Subject monitoring will include, but not be limited to, 
changes in vision, neurologic function, or renal function; and occurrence of hematoma, wound 
dehiscence/disruption, surgical site infection (per Centers for Disease Control and Prevention 
definition), nausea, vomiting, and diarrhea.     
Adverse events of special interest (AESI) include changes in color vision, venous 
thromboembolism or pulmonary embolism, and oliguria.  If an AESI or serious AE (SAE) occurs 
during the study, an unscheduled PK blood sample must be collected.  In addition, vital signs, the 
neurological assessment, and clinical laboratory tests must be conducted, as appropriate.  If a 
subject experiences changes in color vision, an ophthalmological consultation must be ordered.   
 


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7. 
DEFINITIONS 
Study Day 
Study Day 1 is defined as the day of surgery.  Study day is calculated as the date of event minus 
the date of surgery plus one (1), if the date of event is on or after the date of surgery.  Study day 
is based on the calendar dates, thus days before the date of study drug administration have 
negative values while those on or after the date of surgery have positive values.   
Treatment-emergent Adverse Events 
A TEAE will be any adverse event or pre-existing medical condition that worsens in intensity 
after the start of study drug and within 30 days of the last dose. 
Time 0 (zero) 
Time 0 is defined as the date and time of the start of study drug administration. 
Time Periods 
All schedule times have a window associated with them (see Time and Events Schedule in the 
Protocol for individual timepoint windows).  Various time frames that are dependent on these 
windows are used in the data analyses.  Table 1 defines the actual elapsed times with allowance 
for the windows that can be included in the window.  
Table 1: Time Periods 
Defined time frame  Acceptable elapsed times 
5 min 
3-7 min 
15 min 
12-18 min 
30 min 
25-35 min 
1h 
50-70 min 
2h  
105-135 min 
4h 
225-255 min 
6h 
345-375 min 
8h 
450-510 min 
12h 
690-750 min 
16h 
15-17h 
24h 
23-25h 
36h 
34-38h 
48h 
46-50h 
60h 
57-63h 
72h 
68-76h 
96h 
90-102h 
120h 
114-126h 
Study Day 7 
Study Day 6-8 
Study Day 14 
Study Day 13-15 
Study Day 30 Call 
Study Day 27-33 
Study Day 60 Call 
Study Day 57-63 


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If there are two or more data points that fit the time window the data point that occurs the closest, 
in absolute value, to the scheduled observation will be used.   
Baseline 
Baseline is defined as the last available measurement or assessment prior to the start of study 
drug administration. 


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8. 
ANALYSIS SETS 
The safety analysis set will include all subjects who received study drug.  Subjects in the safety 
analysis set will be assessed according to the actual treatment they received. 
The efficacy analysis set will include all subjects who received study drug and underwent the 
planned surgery.  Subjects in the efficacy analysis set will be assessed according to their 
randomized treatment, regardless of the actual treatment they received. 
The PK analysis set will include all subjects who received study drug, provided sufficient 
samples to allow for calculation of PK parameters (AUC[0-tlast] and global, Cmax and Tmax) 
required for analysis, and who do not have significant protocol deviations that may invalidate or 
bias the results.  Subjects in the PK analysis set will be assessed according to the actual treatment 
they received. 
 
 


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9. 
STATISTICAL METHODS OF ANALYSIS 
9.1. 
General Principles 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs).  All 
analyses and tabulations will be performed using SAS Version 9.1 or later.  Continuous 
variables will be summarized using descriptive statistics and categorical variables will be 
tabulated with the number and percentage of subjects.  Unless otherwise noted, percentages will 
be based on the number of subjects in the treatment group within the population. 
Individual subject data will be provided in listings.  All listings will be sorted by treatment, site, 
subject, and, if applicable, collection date and time. 
Unless otherwise stated summaries will present data across all sites (overall). 
Unless otherwise noted, tabulations of categorical data will present only those categories 
appearing in the data. 
On all figures presenting multiple treatments,  
 
IV TXA will be represented in black with solid lines and dots;  
SAS Code: symbol interpol=spline width=1 value=dot line=1 c=black;  
 
DepoTXA 400 will be represented in red with solid lines and hollow triangles;  
SAS Code: symbol interpol=spline width=1 value=triangle line=1 c=red; 
 
DepoTXA 800 will be represented in green with solid lines and hollow circles;  
SAS Code: symbol interpol=spline width=1 value=circle line=1 c=green; 
 
DepoTXA 1200 will be represented in purple with solid lines and hollow squares;   
SAS Code: symbol interpol=spline width=1 value=square line=1 c=purple. 
Figures presenting a single subject will be represented in black with solid lines and dots.    
All tables will present DepoTXA 400 mg, DepoTXA 800 mg, DepoTXA 1200 mg, and IV TXA 
as separate columns, in this order.      
9.1.1. Handling Missing Values 
9.1.1.1. 
Post-baseline Cummulative Blood Loss 
It is expected that all necessary information to calculate post-baseline cumulative blood loss will 
be complete.  Any such information that is missing and cannot be obtained through query 
resolution may be imputed, on a case-by-case basis.  There will be no hypothesis testing and it is  
assumed that missing data on cumulative blood loss will be rare or non-existent, thus a single 
imputation method is expected to provide useful enough information to plan for the next phase of 
DepoTXA development.  The following single imputation procedures will be used: 
a) A simple linear imputation will be used for a missing value from the closest observed 
values prior and post for non-monotone missing data. 
b) If the missing data are monotone, then last observed carried forward will be used.     


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It is currently assumed that approximately 84% of the total cumulative blood loss will occur 
within 12 hours post-surgery and approximately 94% of the total cumulative blood loss will 
occur within 24 hours post-surgery (Kumar, 2005).  
9.1.1.2. 
Adverse Event Date or Time 
It is expected that all necessary information on adverse events and the surgeries (start and stop 
date and time) will be complete.  Unless an adverse event can be excluded as a treatment 
emergent by the known start and stop date/time, the adverse event should be considered 
treatment emergent.     
9.1.1.3. 
Concomitant Medications Date or Time 
It is expected that all necessary information on medications and surgeries (start and stop date and 
time) will be complete.  Unless a medication can be excluded as a concomitant by the known 
start and stop date/time, the medication should be considered concomitant. 
9.1.1.4. 
Adverse Event Severity or Relationship to Study Drug 
If severity of an AE is not reported, then for tables of AEs by severity, the missing severity will 
not be imputed, but will be described in the footnote for the table.  If relationship to study drug is 
not reported for an AE, then for tables of study-drug related AEs, the event will be assigned the 
relationship of ‘definite’.  Tables presenting related AEs will include all AEs with relationships 
of ‘possible’, ‘probable’ or ‘definite’ as assessed by the investigator or defined as ‘definite’ when 
no investigtor assessment is made. 
9.1.2. Multiplicity Adjustments 
Not applicable. 
9.2. 
Subject Disposition 
Subject disposition summaries will include the number of subjects that were: 
 Screened, 
o Screen failure 
o Reasons for screen failure (Did not meet Inclusion #1, ect.) 
 Randomized  
o Randomized not treated  
o Randomized treated  
o Randomized did not undergo surgery  
o Randomized underwent surgery 
 In the safety analysis set 
 In the efficacy analysis set  
 In the PK analysis set 
 Completed the study as planned 
 Discontinued from the study 
 By reason for discontinuation from the study. 
Percentages will be reported for the screen failures and enrolled subjects using the number of 
subjects screened as the denominator and for the safety, efficacy and PK analysis sets, completed 
study, discontinued from study, and reasons for discontinuation with the number of subjects 


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randomized as denominator.  The percentages for the safety analysis set will use the number of 
subjects randomized and treated as the denominator.   
Safety and PK analysis sets data will be presented as treated.  All other data will be presented as 
randomized.  
The disposition summary will present the data for each treatment group and across treatment 
groups (Total).  This summary table will present overall sites and for each site separately. 
9.3. 
Description of Demographics and Baseline Characteristics  
9.3.1. Demographics  
The summary of demographic data will present: 
 Age (years) – descriptive statistics 
 Sex – n (%) 
 Ethnicity – n (%) 
 Race – n (%) 
 ASA classification – n (%) 
 Country – n (%) 
Age is calculated from the date the subject signed the informed consent form (ICF) and birth 
date.  It is presented as the number of years between, rounding down to the nearest integer year.  
The following macro will be used to derive age:   
%macro age_integer (dob=,eventdate=); 
floor((intck('month',&dob.,&eventdate.) - (day(&eventdate.)<day(&dob.)))/12); 
%mend age_integer; 
For partial birthdates, impute the first of the month for missing day and January for missing 
month to calculate age.  It is presumed that birth year is known. 
The demographic summary will present the data for each treatment group.  Summaries will be 
provided for all (safety, efficacy, and PK) analysis sets.  This summary will present overall sites 
and for each site separately. 
9.3.2. Baseline Characteristics 
The summary of baseline characteristic data will present: 
 Total Blood Volume (BV; in mL) 
 Height (cm) 
 Weight (kg) 
 Body Mass Index (BMI) (kg/m2) 
The formula for BMI is       , where w is weight in kilograms and h is height in meters.  
Weight in pounds will be converted to kilograms using the conversion factor of 2.2046 pounds to 
1 kilogram.  Height in inches will be converted to centimeters using the conversion factor of 2.54 
centimeters to 1 inch.  Height in centimeters will be converted to meters using the conversion 
factor of 100 centimeters to 1 meter. 


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Baseline characteristics summaries will present the data for each treatment group and across 
treatment groups (Total).  Summaries will be provided for all (safety, efficacy and PK) analysis 
sets.  This summary table will show summaries across all sites and for each site separately.  
Descriptive statistics (n, mean, standard deviation [SD], median, minimum and maximum) will 
be provided for total blood volume, height, weight, and BMI. 
9.4. 
Surgery Characteristics 
The following surgery characteristics will be summarized: duration of surgery, length of incision, 
trouniquet use, duration of tourniquet use, maximum pressure of tourniquet, and type of 
anesthesia.   
9.5. 
Medical and Surgical History 
Medical and surgical history recorded at the screening visit will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.1 or higher. Medical and surgical 
history will be listed by treatment and subject as well as summarized by system organ class 
(SOC) and preferred term (PT). 
9.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary Enhanced (WHO-DD) September 2016 and will be classified according to the default 
anatomical therapeutic chemical (ATC) classification system term and PT. 
Prior medications are defined as medications with a stop date and time prior to the start of study 
drug administration.   
Concomitant medications are defined as medications taken after the start of study drug 
administration (i.e., started prior to the start of study drug administration and continued after or 
started within 30 days after the start of study drug administration). 
Prior and concomitant medications will be summarized separately using n (%) of subjects for 
each treatment group and across treatment groups by ATC class term and PT for the safety 
analysis set.  Subjects may have more than one medication per ATC category and PT.  At each 
level of subject summarization, a subject will be counted once if one or more medications are 
reported by the subject at that level.  
A listing mapping the ATC term and PT to verbatim term will be presented. 
9.7. 
Measurements of Treatment Compliance 
Study treatment is administered by a party other than the subject, therefore compliance is 
ensured.   
9.8. 
Efficacy Analysis 
No formal statistical hypothesis testing will be performed.  The following endpoints will be 
summarized using descriptive statistics: 
 Total blood loss as measured by Hb and Hct levels upon arrival at the post-anesthesia 
care unit (PACU) and at 6, 12, 24, 48, 72, 120 hours, and Day 7   
 Incidence of transfusion (number of units/subject, number of subjects transfused)   


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 Time to 90˚ passive and active knee flexion at 24, 48, and 72 hours for patients enrolled 
prior to Amendment 2 and by AM/PM at 24, 48, and 72 hours for patients enrolled on 
Amendment 2    
 Time to complete TUG test once on study day 1 (postsurgical day 0), twice a day on 
study day 2 (6:00 - 10:00 and 18:00 - 22:00), at hospital discharge, and on study day 7 
 Change in knee and thigh measurements on the morning of postsurgical day 2 and at the 
day 7 follow-up visit  
 NRS Pain Scores upon arrival at the PACU, at each in-hospital vital sign assessment 
beginning with the 48-hour assessment, and at the Day 7 follow-up visit 
 Days to Independent Ambulation assessed beginning at Day 7 follow-up visit 
 Surgical Wound Aspect Score (SWAS) on the morning of postsurgical day 2 and on 
day 7 
9.8.1. Total Blood Loss 
Total loss will be calculated separately using two separate methods.  The first method is based on 
Hct and the second method is based upon Hb.  Total blood loss will be calculated at 6, 12, 24, 
48, 72, 120 hours, and Day 7 postsurgery for each subject.  Descriptive statistics summarizing 
the total blood loss will be summarized by postsurgical timepoint and treatment group for the 
efficacy analysis population for each method.  Baseline is considered the last value measured 
before the surgery.   
Total BV in mL will be calculated using the Nadler formula (Nadler 1962) at baseline by 
                         
where  h = height (m), w = baseline weight (kg), {a=0.3669, b=0.03219, c=0.6041} for males 
and {a=0.3561, b=0.03308, c=0.1833} for females.  The BVbaseline is used in methods 1 and 2 to 
determine blood loss.  
Method 1 (Gibon 2013): 
Total RBC loss is in mL calculated by the following formula: 
                    (                          )               
where             is measured as the volume percentage of red blood cells in the blood at 
baseline,                 is measured as the volume percentage of red blood cells in the blood at 
the specified postsurgical timepoint in hours, total BVbaseline is measured in mL, and              
is the mL volume of blood transfused to the subject.  
Method 2 (Gao et al, 2015): 
Another method of calculating blood loss is presented by Gao as follows: 
Hbloss [g] = BVbaseline [mL] · (Hbbaseline [g/L] – Hbpostop [g/L]) · 0.001 [L/mL] + Hbt [g],  
Hbt = BVtransfused [Unit] · 52 [g/Unit], and 
RBClost [mL] = 1000 x Hbloss [g] / Hbbaseline [g/L],  


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where Hbloss is the total loss of hemoglobin in gram, BVbaseline is the presurgery blood volume in 
mL, Hbbaseline and Hbpostop are the presurgery and post surgery hemoglobin concentration in g/L, 
Hbt is the amount of hemoglobin transfused in gram, BVtransfused is the banked blood transfused in 
Unit, and RBClost is the total volume of RBC lost.  The above formulae can be simplified as 
        
           (                   )                   
          
. 
 
Total blood loss upon arrival at the PACU and at 6, 12, 24, 48, 72, 120 hours, and Day 7 will be 
summarized using descriptive statistics [n, mean, SD, minimum, median, and maximum] for 
method 1 and method 2 serperately.  When both methods are presented together on the same 
graph, method 1 will be represented using a solid line (line=1) and method 2 will be represented 
using a dashed line (line 2). 
9.8.2. Incidence of transfusion 
The incidence of transfusion (number of units/subject and number of subjects transfused) will be 
tabulated by postsurgical timepoint and treatment group for the efficacy analysis population with 
number and percentage of subjects.  Percentages will be based on the number of subjects in the 
treatment group within the efficacy population.  
9.8.3. Time to 90o Passive and Active Knee Flexion 
The proportion of subjects capable of 90˚ passive and active knee flexion, separately, at 24, 48, 
and 72 hours will be tabulated with the number and percentage of subjects by postsurgical 
timepoint and treatment group for the efficacy analysis population.  For patients enrolled after 
on/after Protocol Amendment 2, the summary table will be broken down by time of the day (AM 
or PM) of the assessment.  The time to 90˚ knee flexion, for both passive and active separately, 
will be summarized using Kaplan-Meier estimates (n, 25th percentile, median, and 75th 
percentile). The actual time of assessment will be used for this calculation.       
9.8.4. Time to Complete TUG Test 
The time (seconds) to complete TUG test on study day 1 (postsurgical day 0), twice a day on 
study day 2 (6:00am - 10:00 am and 6:00pm - 10:00pm), at hospital discharge, and on study day 
7 will be summarized by postsurgical timepoint and treatment group for the efficacy analysis 
population using descriptive statistics (n, mean, SD, minimum, median, and maximum).  In 
addition, the amount of physical assistance required to complete the TUG test at each time point 
will be tabulated with the number and percentage of subjects in each category.        
9.8.5. NRS Pain Scores 
The NRS pain scores will be summarized using descriptive statistics (n, mean, SD, minimum, 
median, and maximum) at each scheduled timepoint.  In addition, the AUC from the time a 
subject is admitted to the PACU through 72 hours will be calculated and summarized by 
treatment group for the efficacy analysis population using descriptive statistics (n, mean, SD, 
minimum, median, and maximum).           
 
 


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9.8.6. Change in Knee and Thigh Circumferences 
Prior to Protocol Amendment 2, knee and thigh circumferences were collected for both surgical 
and non-surgical legs.  Protocol Amendment 2 requires the collection only for the surgical leg.  
As such, for subjects enrolled prior to Amendment 2, the circumferences for the surgical and non 
surgical legs, the differences between the two, and their changes from baseline within subject 
will be summarized separately for the knee and thigh by treatment group for the efficacy analysis 
population using descriptive statistics (n, mean, SD, minimum, median, and maximum) for 
postsurgical day 2 (study day 3) and study day 7.  For subjects enrolled after Amendment 2, only 
the circumferences of the surgical legs and their changes from baseline will be summarized.     
9.8.7. Days to First Independent Ambulation 
The number of days until the first independent ambulation will be summarized using Kaplan-
Meier estimates (n, 25th percentile, median, and 75th percentile).     
9.8.8. Surgical Wound Aspect Score (SWAS) 
The SWAS will be tabulated by treatment group for the efficacy analysis population with 
number and percentage of subjects for the score of wound oozing, erythema, ecchymosis, and 
blisters for postsurgical day 2 (study day 3) and study day 7.  In addition, the sum of the wound 
oozing, erythema, ecchymosis, and blister scores will also be tabulated by treatment group for 
the efficacy analysis population for postsurgical day 2 (study day 3) and study day 7.  
Percentages will be based on the number of subjects in the treatment group within the efficacy 
population.  
9.9. 
Safety Analyses 
The following safety assessments will be summarized:  
 
12-lead ECGs at day 1 Preop (D1 Preop), and 1 hour and 12 hours after study drug 
administration. 
 
Vital signs (resting heart rate and blood pressure) at Baseline, and 5min, 15min, 30min, 
1hr, 2hr, 4hr, 6hr, 8hr, 12hr, 16hr, 24hr, 36hr, 48hr, 60hr, 72hr, and 96hr after study drug 
administration.    
 
Neurological assessment at D1 Preop and at 12, 24, 36, 48, 60, 72, and 96 hours after study 
drug administration. 
 
Clinical laboratory testing (hematology [including fibrinogen and fibrin split products, lipid 
profile] and chemistry) at D1 Preop, at 48 hours, and at day 7. 
 
Creatinine clearance measurement at 48 hours  and at day 7. 
 
Reoperations due to hematoma or wound dehiscence. 
 
Adverse events through study day 60. 
No inferential statistics are planned for any of the safety assessments. 
9.9.1. Electrocardiograms 
Investigators will classify ECG tracings as ‘normal, ‘abnormal not clinically significant’ or 
‘abnormal clinically significant’.  The investigator classifications will be tabulated by treatment 
and overall treatments at any time during the study and each assessment timepoint.  A shift table 
comparing the investigator classification of the ECG results at baseline to each scheduled 
timepoint will also be provided. 


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9.9.2. Vital Signs 
Vitals signs are resting heart rate (bpm), systolic blood pressure (mmHg), and diastolic blood 
pressure (mmHg).  Vital signs will be summarized by treatment group at each assessment 
timepoint.  Summaries will present both actual and change-from-baseline results.  Baseline 
statistics will be presented at each assessment timepoint for those subjects reporting data at that 
timepoint. 
9.9.3. Neurological Assessments 
The neurological assessments summary will include the proportion of subjects who are oriented, 
and proportion of subjects who have any of the neurologic events (answered “Yes” to any of the 
additional questions regarding numbness, taste, hearing, vision, or twitching).  Percentages will 
be based on the number of subjects in the treatment group. The number and percentage of 
subjects will be tabulated by treatment group at each assessment timepoint.   
9.9.4. Clinical Laboratory Assessments 
Clinical laboratory assessments are collected at D1 Preop and at 48 hours after study drug 
administration. Laboratory results will be summarized by treatment group at each assessment 
timepoint.  Summaries will present both actual results and change from baseline results for each 
clinical laboratory parameter.  Baseline statistics will also be presented for each clinical 
laboratory parameter. 
Tabulations of the number and percentage of subjects with values outside the normal range will 
be provided by treatment group at baseline 48 hours, and day 7 for each parameter. 
Shifts in laboratory results categorized as low (below the lower limit of the normal range), 
normal (within the normal range, limits inclusive) and above (above the upper limit of the 
normal range) will be presented in shift tables with baseline categories across the columns and 
48 hour categories for the rows.  Each treatment group separately and all DepoTXA subjects, in 
the safety analysis set, will be presented.  Each cell will present the number and percentage of 
subjects in that cell.  Due to the width of these tables, only one treatment will be presented per 
page.   
Creatine clearance will be summarized for study day 7 in a similar manner as the other 
laboratory parameters at 48 hours. 
9.9.5. Reoperation Due to Hematoma or Wound Dehiscence 
The number and percentage of subjects with reoperations due to hematoma or wound dehiscence 
will be tabulated by treatment group and for All DepoTXA. 
9.9.6. Adverse Events 
Adverse events will be coded using MedDRA version 19.1 or higher.   
A TEAE will be any adverse event with the onset date and time on or after the start date and time 
of study drug administration and within 30 days of the dose, or a pre-existing medical condition 
that worsens in intensity after the start of study drug (date and time) and within 30 days of the 
dose.   
If an AE has a partial onset date and time the imputed start and stop dates and times will be used 
to determine treatment-emergence (e.g., stop date and time is before start date and time of study 


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treatment). All AE summaries will present TEAEs only; AEs that are not treatment-emergent 
will be included in listings but not summarized. 
The incidence of subjects reporting TEAEs will be tabulated by the number and percentage of 
subjects reporting the TEAE.  Incidence is defined as a subject reporting at least one TEAE 
within the summary level.  Summary levels are ‘at least one TEAE’, system organ class and 
preferred term.  Subjects will be counted only once within each reporting level on the table.  For 
example if a subject reports a TEAE of headache on two separate occasions, the subject will be 
counted only once in the headache row of the table.  Similarly if a subject reports two separate 
TEAEs within the same system organ class the subject will only be counted once in the summary 
row for that system organ class.  A summary of subjects reporting at least one TEAE during the 
study will also be presented. 
The first row on every TEAE table will be the number and percentage of subjects reporting at 
least one TEAE.  Subsequent rows will be presented in descending order of subject counts for 
the overall treatment group with the most common system organ class first, followed within each 
system organ class by the preferred terms in descending subject count order.  For tables 
presenting the severity or relation to study treatment of TEAE, the sort order will be determined 
by the number and percentage of subjects reporting the preferred term, thus the sort order of 
rows will remain the same for the relation or severity tables as the tables by preferred term.  
The following summaries will be presented for the TEAEs reported by the subjects: 
An overview of all TEAEs, serious TEAEs and TEAEs of Special Interest will present the 
number and percentage of subjects in the following categories: 
 Any TEAE 
o Maximum severity: Mild 
o Maximum severity: Moderate 
o Maximum severity: Severe 
 At least one related TEAE 
 At least one serious TEAE  
 At least one related serious TEAE 
 Subjects discontinued because of a TEAE 
 Died during the study 
Subjects will be counted once in each of the above categories except for maximum severity.  
Subjects will be counted only once at the highest severity reported.  For example, if a subject has 
a mild and severe headache and a moderate rash, the subject will be counted under maximum 
severity of severe only. 
Adverse event tables will present the data by treatment group and across all treatment groups.  
Incidence tables will be created for the following groups of TEAEs: 
 All TEAEs 
 Study treatment-related TEAEs 
 TEAEs leading to study withdrawal 
 Study treatment-related TEAEs leading to study withdrawal 
 All TEAEs by severity  
 All TEAEs by relationship to study treatment 


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 All Serious TEAEs  
 All Nonserious TEAEs (CT.gov only) 
 Study treatment-related serious TEAEs 
 Serious TEAEs leading to study withdrawal 
 Study treatment-related serious TEAEs leading to study withdrawal 
 Serious TEAEs resulting in death 
 Study treatment-related serious TEAEs resulting in death 
 All TEAEs of special interest 
 Study treatment-related TEAEs of special interest 
 TEAEs of special interest leading to study withdrawal 
 Study treatment-related TEAEs of special interest leading to study withdrawal 
 TEAEs of special interest resulting in death 
 Study treatment-related TEAEs of special interest resulting in death 
If there are no AEs to report on any of the above tables, the table should be created with the line 
‘no adverse events were reported’ in the body of the table. 
Adverse events will be considered related if the investigator assessment of relationship to study 
treatment is either ‘possible’, ‘probable’ or ‘definite’ or if no investigator assessment is provided.    
Treatment emergent AESIs include changes in color vision, venous thromboembolism or 
pulmonary embolism, and oliguria.   
A listing of the mapping of the SOC and PTs to verbatim terms will be presented.  
9.10. Pharmacokinetic Analysis 
9.10.1. Sample Collections for Pharmacokinetic Analysis 
Blood samples for the PK analysis will be obtained at baseline (prior to study drug 
administration); at 5, 15, and 30 minutes; and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study 
drug administration for all treatment groups.  Additional blood samples will be collected at 36, 
48, 60, 72, and 96 hours after study drug administration for DepoTXA-treated subjects. 
9.10.2. Pharmacokinetic Parameter Calculation Methods 
Pharmacokinetic parameters will be calculated by a noncompartmental analysis method from 
concentration-time data using WinNonlin Professional (Version 5.2 or later) or SAS following 
these guidelines: 
 Actual sampling times relative to study drug administration will be used for all 
calculations of the PK parameters.  If there is any doubt as to the actual time a sample 
was taken, then the scheduled time will be used.  Descriptive statistics will be used to 
summarize the PK parameters.  
 Concentrations from unscheduled PK blood samples will be used in the analysis of the 
parameters. 
 There will be no imputation of missing data. 
For the calculation of AUC from PK concentrations, concentration below the limit of 
quantification (BLOQ) will be handled as follows: 


Pacira Pharmaceuticals, Inc. 
404-C-201 (TKA) 
DepoTXA 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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 Pre-dose values will be set to zero. 
 All remaining BLOQ values will be set to missing. 
Pharmacokinetic parameters will be estimated according to the following guidelines: 
 
The maximum observed plasma concentration (Cmax) will be obtained directly from 
the concentration-time data. 
 
Time to maximum concentration (Tmax) is the time at which Cmax is observed. 
 
The apparent terminal elimination rate constant (λZ) will be estimated at terminal 
phase by linear regression after log-transformation of the concentrations: 
o Only those data points that are judged to describe the terminal log-linear 
decline will be used in the regression.  
o A minimum number of three data points in the terminal phase will be used in 
calculating λz with the line of regression starting at post-Cmax data point (Cmax 
should not be part of the regression slope) and including Clast and tlast. 
o The adjusted correlation coefficient (R2 adjusted) in general should be greater 
than 0.90.  Any value less than 0.90 may be used according to the 
pharmacokineticist's best knowledge and judgment. 
o An appropriate number of decimal places should be used for λz for an precise 
calculation of the of half-life (t½). 
 
Half-life (t1/2) will be calculated as ln(2)/λZ. 
 
AUC will be calculated as follows:  
o The linear trapezoidal method will be employed for all incremental trapezoids 
arising from increasing concentrations and the logarithmic trapezoidal method 
will be used for those arising from decreasing concentrations. 
o 



 t
0
)
0
(
)
( dt
t
C
AUC
t
 
o 
z
t
t
t
O
C
AUC
dt
t
C
dt
t
C
AUC

/
)
(
)
(
)
0
(
 t
0
)
(










 
 
Ct is last observed quantifiable concentration. 
9.10.3. Pharmacokinetic Concentrations and Variables 
The analysis of the PK data will be based on the PK analysis set. 
TXA plasma concentrations will be listed by treatment group, subject, nominal time, and actual 
time.  Concentrations that are BLOQ will be indicated by BLOQ in this listing.  
Plasma concentrations will be summarized by treatment at each time point.  The following 
descriptive statistics will be presented for plasma concentrations obtained at each nominal time 
point: n, arithmetic mean, SD, coefficient of variation (%CV), geometric mean, median, 
minimum and maximum. 
Pharmacokinetic parameters will be summarized for each treatment group.  Descriptive statistics 
for calculated PK parameters will include: n, arithmetic mean, SD, %CV, geometric mean, 


Pacira Pharmaceuticals, Inc. 
404-C-201 (TKA) 
DepoTXA 
Statistical Analysis Plan 
 
CONFIDENTIAL 
Page 23 of 113 
 29JAN2018 
median, minimum and maximum values.  Geometric mean will not be presented for Tmax. Values 
of %AUC extrapolated > 20% will be flagged in the listings. 
Individual plasma concentration versus actual times will be plotted by treatment in linear and 
semi-logarithmic scale. 
The geometric mean ratios (GMRs) for DepoTXA 400 mg, DepoTXA 800 mg, and DepoTXA 
1200 mg to IV TXA will be presented separately along with their corresponding 95% confidence 
intervals for AUC0-t and Cmax. 
9.11. Interim Analysis 
No Interim analyses are planned. 


Pacira Pharmaceuticals, Inc. 
404-C-201 (TKA) 
DepoTXA 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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 29JAN2018 
10. 
SAMPLE SIZE CALCULATION 
The sample size was not based on statistical considerations. 


Pacira Pharmaceuticals, Inc. 
404-C-201 (TKA) 
DepoTXA 
Statistical Analysis Plan 
 
CONFIDENTIAL 
Page 25 of 113 
 29JAN2018 
11. 
REFERENCES 
 
American Statistical Association.  Ethical Guidelines for Statistical Practice.  Prepared by the 
Committee on Professional Ethics, 07 August 1999.  
http://www.amstat.org/profession/ethicalstatistics.html 
 
Gibon E, Courpied JP, Hamadouche M. Total joint replacement and blood loss: what is the best 
equation? Int Orthop. 2013;37(4):735-739. 
 
Gao F, Li Z, Zhang K, et al. Four methods for calculating blood-loss after total knee arthroplasty. 
Chin Med J. 2015;128(21):2856-2860. 
 
Senthil Kumar G, Von Arx OA, Pozo JL. Rate of blood loss over 48 hours following total knee 
replacement. Knee 2005;12:307-9. 
 
Nadler SB, Hidalgo JU, Bloch T. Prediction of blood volume in normal human adults. Surgery. 
1962 Feb;51(2):224-32. 
Royal Statistical Society.  The Royal Statistical Society: Code of Conduct, August 1993. 
http://www.rss.org.uk/about/conduct.html. 
 
US Federal Register.  International Conference on Harmonisation; Guidance on Statistical 
Principles for Clinical Trials.  Department of Health and Human Services: Food and Drug 
Administration [Docket No. 97D-0174].  Federal Register Volume 63, Number 179, pages 
49583-49598.  16 September 1998. 
 


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DepoTXA  
                                            Clinical Study Protocol Amendment 2  
 
 
 
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12. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
 
 
Screen 
Visit1 
D1 
Preop OR 
PACU 
Arrival 
5 
min 
 15 
min 
30 
min 1h 
2h 
4h 
6h 
8h 12h 16h 24h 36h 48h 60h 72h 96h 120h Day 7 D14 
Call 
D30 
Call 
D60 
Call 
Time 
Window 
Within 
30 days 
 
 
 
±2 
min 
±3 
min 
±5 
min 
±10 
min 
±15 
min 
±15 
min 
±15 
min 
±30 
min 
±30 
min ±1h ±1h ±2h ±2h ±2h ±4h ±6h ±6h 
±1d 
±1d ±3d ±3d 
Obtain signed ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record medical and surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record demographics and baseline characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct pregnancy test for WOCBP 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Clinical labs (hematology, chemistry)2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Coagulation (fibrinogen and fibrin split products) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Creatinine clearance calculation2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Hemoglobin and hematocrit2 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
Perform neurological assessment3 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Perform 12-lead ECG recordings4 
 
X 
 
 
 
 
 
X4 
 
 
 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
Measure vital signs5 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Collect NRS-R pain score 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
Collect knee and thigh measurements (both legs) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
X6 
 
 
X6 
 
 
 
Assess surgical wound for SWAS parameters7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
Collect PK blood sample from all treatment groups; 
record date and time8 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Collect additional PK blood samples for DepoTXA 
treatment groups; record date and time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Randomize patient, prepare study drug 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study drug  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record start and end time of tourniquet use and max 
pressure (mm Hg) used 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record surgery start and stop times 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform knee flexion assessment13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform TUG test; record date and time11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
X 
 
 
 
Record date and time of discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record any blood transfusion data (eg, start and stop 
times, units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record any reoperations due to hematoma or wound 
dehiscence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record prior and concomitant medications12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Record whether patient has achieved independent 
ambulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record AEs beginning at time ICF is signed2,3,5,8,10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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DepoTXA  
                                            Clinical Study Protocol Amendment 2  
 
 
 
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Abbreviations: AE = adverse event; d = day; D = day; ECG = electrocardiogram; h = hours; ICF = informed consent form; max = maximum; min = minutes; 
OR = operating room; PACU = post-anesthesia care unit; PK = pharmacokinetic; Preop = preoperative; TUG = timed up-and-go; WOCBP = women of childbearing 
potential. 
* 
Postsurgical assessments will be conducted at the timepoints specified after the beginning of study drug administration.   
1 
The screening visit must take place at least 1 day prior to surgery. 
 
2 
Also conduct clinical laboratory tests if a patient experiences an AE of special interest or a serious AE (SAE), if appropriate; see footnote 10. 
3 
Also conduct a neurological assessment if a patient experiences an AE of special interest or an SAE, if appropriate; see footnote 10. 
4 
Postsurgical 12-lead ECGs will be performed at 1 hour (±15 minutes) and 12 (±2) hours after study drug administration 
5 
Vital signs will be measured after the patient has rested in a supine position for at least 5 minutes.  Also measure vital signs if a patient experiences an AE of special 
interest or an SAE, if appropriate; see footnote 10. 
6 
Collect knee and thigh measurements (both legs) on the morning of postsurgical Day 2. 
7 
The surgical wound will be assessed for the SWAS parameters (wound oozing, erythema, ecchymosis, and blisters) at the time of knee measurements on the morning 
of postsurgical Day 2 and on Day 7. 
8 
Also collect a PK sample if a patient experiences an AE of special interest or an SAE; see footnote 10. 
9 
Record date and time of all medications starting at least 30 days prior to study drug administration through 120 hours after study drug administration.  Record 
medications administered for treatment of an AE through Day 60 (±3 days). 
10 
Adverse events of special interest include changes in color vision, VTE or PE, and oliguria.  If an AE of special interest or serious AE (SAE) occurs during the study, 
an unscheduled PK blood sample must be collected.  In addition, vital signs, the neurological assessment, and clinical laboratory tests should be conducted, as 
appropriate.  If a patient experiences changes in color vision, an ophthalmological consultation must be ordered. 
11 
Postsurgical “Timed Up-and-Go” will be assessed once on the day of the surgery; at approximately 8:00 am and 8:00 pm (±2 hours) daily from Day 2 through 
hospital discharge; and on Day 7. 
12 
Each institution may follow its standard protocol for the control of postsurgical pain; however, patient-controlled analgesia is not permitted.  
13 
Each institution may follow its standard protocol for the control of postsurgical pain; however, patient-controlled analgesia is not permitted.  
 


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13. 
TABLE OF CONTENTS FOR TABLES 
Table 14.1-1: Tabulation Of Subject Disposition – All Screened Subjects 
31 
Table 14.1-2.1: Tabulation Of Subject Demographics - Safety Analysis Set 
33 
Table 14.1-2.2: Tabulation Of Subject Demographics – Efficacy Analysis Set 
34 
Table 14.1-2.3: Tabulation Of Subject Demographics - Pk Analysis Set 
34 
Table 14.1-3.1: Summary Of Subject Baseline Characteristics - Safety Analysis Set 
35 
Table 14.1-3.2: Summary Of Subject Baseline Characteristics – Efficacy Analysis Set 
35 
Table 14.1-3.3: Summary Of Subject Baseline Characteristics - Pk Analysis Set 
35 
Table 14.1-4.1: Summary Of Surgery Characteristics - Safety Analysis Set 
36 
Table 14.1-4.2: Summary Of Surgery Characteristics – Efficacy Analysis Set 
37 
Table 14.1-4.3: Summary Of Surgery Characteristics– Pk Analysis Set 
37 
Table 14.1-5.1: Tabulation Of Medical History - Safety Analysis Set 
38 
Table 14.1-5.2: Tabulation Of Medical History - Efficacy Analysis Set 
38 
Table 14.1-5.3: Tabulation Of Medical History - Pk Analysis Set 
38 
Table 14.2-1.1: Summary Of Total Blood Volume (Ml) By Scheduled Timepoint (Method 1 Hct)–Efficacy Analysis 
Set 
39 
Table 14.2-1.2: Summary Of Total Blood Loss (Ml) By Scheduled Timepoint (Method 2 Hb)– Efficacy Analysis Set39 
Table 14.2-2: Summary Of Incidence Of Transfusion – Efficacy Analysis Set 
40 
Table 14.2-3.1a: Summary Of Time To 90o Active Knee Flexion (Pre-Amendment 2) – Efficacy Analysis Set 
41 
Table 14.2-3.2a: Summary Of Time To 90o Passive Knee Flexion – Efficacy Analysis Set 
41 
Table 14.2-3.1b: Summary Of Time To 90o Active Knee Flexion (Amendment 2 And After) – Efficacy Analysis Set42 
Table 14.2-3.2b: Summary Of Time To 90o Passive Knee Flexion – Efficacy Analysis Set 
42 
Table 14.2-3.1c: Kaplan-Meier Estimate Of Time To 90o Active Knee Flexion – Efficacy Analysis Set 
43 
Table 14.2-3.2c: Summary Of Time To 90o Passive Knee Flexion – Efficacy Analysis Set 
43 
Table 14.2-4.1: Summary Of Time To Complete Timed Up-And-Go (Tug) Test - Efficacy Analysis Set 
44 
Table 14.2-4.3: Tabulation Of Physical Assistance Required To Complete The Tug Test - Efficacy Analysis Set 
45 
Table 14.2-4.4: Shift Table Of Physical Assistance Required To Complete The Tug Test - Efficacy Analysis Set 46 
Table 14.2-5.1: Summary Of Nrs At Assessment Timepoints – Efficacy Analysis Set 
48 
Table 14.2-5.2: Summary Of Nrs Auc - Efficacy Analysis Set 
49 
Table 14.2-6.1.1: Knee Circumference At Assessment Timepoints – Efficacy Analysis Set 
50 
Table 14.2-6.1.2: Leg Difference In Knee Circumference (For Subjects Enrolled Prior To Protocol Amendment 2) – 
Efficacy Analysis Set 
51 
Table 14.2-6.1.3: Leg Difference In Change From Baseline In Knee Circumference (For Subjects Enrolled Prior To 
Protocol Amendment 2) – Efficacy Analysis Set 
52 
Table 14.2-6.1.4: Change From Baseline In Surgical Knee Circumference – Efficacy Analysis Set 
52 
Table 14.2-6.2.1: Thigh Circumference At Assessment Timepoints – Efficacy Analysis Set 
52 
Table 14.2-6.2.2: Leg Difference In Thigh Circumference (For Subjects Enrolled Prior To Protocol Amendment 2) – 
Efficacy Analysis Set 
52 


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Table 14.2-6.2.3: Leg Difference In Change From Baseline In Thigh Circumference (For Subjects Enrolled Prior To 
Protocol Amendment 2) – Efficacy Analysis Set 
52 
Table 14.2-6.2.4: Change From Baseline In Surgical Thigh Circumference – Efficacy Analysis Set 
52 
Table 14.2-7: Summary Of Days To First Independent Ambulation – Efficacy Analysis Set 
53 
Table 14.2-8: Tabulation Of Surgical Wound Aspect Score On Postsurgical Day – Efficacy Analysis Set 
54 
Table 14.3-1.1: Tabulation Of Electrocardiogram – Investigator Read - Safety Analysis Set 
56 
Table 14.3-1.2: Shift Table Of Electrocardiogram – Investigator Read - Safety Analysis Set 
57 
Table 14.3-2: Summary Of Vital Signs – Safety Analysis Set 
58 
Table 14.3-3: Tabulation Of Neurological Assessments By Timepoint- Safety Analysis Set 
59 
Table 14.3-4.1: Summary Of Clinical Laboratory Assessments - Safety Analysis Set 
60 
Table 14.3-4.2: Tabulation Of Incidence Of Abnormal Clinical Laboratory Assessments - Safety Analysis Set 
61 
Table 14.3-4.3: Shift Table Of Clinical Laboratory Assessments - Safety Analysis Set 
62 
Table 14.3-5.1.1: Overview Of Treatment-Emergent Adverse Events (Teaes) - Safety Analysis Set 
63 
Table 14.3-5.1.2: Tabulation Of Incidence Of Treatment-Emergent Adverse Events (Teaes) - Safety Analysis Set 64 
Table 14.3-5.1.3: Tabulation Of Incidence Of Study Drug-Related Treatment-Emergent Adverse Events (Teaes) - 
Safety Analysis Set 
64 
Table 14.3-5.1.4: Tabulation Of Incidence Of Treatment-Emergent Adverse Events (Teaes) Leading To Study 
Withdrawal - Safety Analysis Set 
64 
Table 14.3-5.1.5: Tabulation Of Incidence Of Study Drug-Related Treatment-Emergent Adverse Events (Teaes) 
Leading To Study Withdrawal - Safety Analysis Set 
64 
Table 14.3-5.1.6: Tabulation Of Incidence Of Treatment-Emergent Adverse Events (Teaes) By Severity - Safety 
Analysis Set 
65 
Table 14.3-5.1.7: Tabulation Of Incidence Of Treatment-Emergent Adverse Events (Teaes) By Relationship To 
Study Drug - Safety Analysis Set 
66 
Table 14.3-5.2.1: Tabulation Of Incidence Of Serious Treatment-Emergent Adverse Events (Teaes) - Safety 
Analysis Set 
67 
Table 14.3-5.2.1.Ct: Tabulation Of Incidence Of Non-Serious Treatment-Emergent Adverse Events (Teaes) - Safety 
Analysis Set 
67 
Table 14.3-5.2.2: Tabulation Of Incidence Of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(Teaes) - Safety Analysis Set 
67 
Table 14.3-5.2.3: Tabulation Of Incidence Of Serious Treatment-Emergent Adverse Events (Teaes) Leading To 
Study Withdrawal - Safety Analysis Set 
67 
Table 14.3-5.2.4: Tabulation Of Incidence Of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(Teaes) Leading To Study Withdrawal - Safety Analysis Set 
67 
Table 14.3-5.2.5: Tabulation Of Incidence Of Serious Treatment-Emergent Adverse Events (Teaes) Resulting In 
Death - Safety Analysis Set 
67 
Table 14.3-5.2.6: Tabulation Of Incidence Of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(Teaes) Resulting In Death - Safety Analysis Set 
67 
Table 14.3-5.3.1: Tabulation Of Incidence Of Treatment-Emergent Adverse Events (Teaes) Of Special Interest - 
Safety Analysis Set 
67 
Table 14.3-5.3.2: Tabulation Of Incidence Of Study Drug-Related Treatment-Emergent Adverse Events (Teaes) Of 
Special Interest - Safety Analysis Set 
67 


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Statistical Analysis Plan 
 
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Table 14.3-5.3.3: Tabulation Of Incidence Of Treatment-Emergent Adverse Events (Teaes) Of Special Interest 
Leading To Study Withdrawal - Safety Analysis Set 
67 
Table 14.3-5.3.4: Tabulation Of Incidence Of Study Drug-Related Treatment-Emergent Adverse Events (Teaes) Of 
Special Interest Leading To Study Withdrawal - Safety Analysis Set 
67 
Table 14.3-5.3.5: Tabulation Of Incidence Of Treatment-Emergent Adverse Events (Teaes) Of Special Interest 
Resulting In Death - Safety Analysis Set 
67 
Table 14.3-5.3.6: Tabulation Of Incidence Of Study Drug-Related Treatment-Emergent Adverse Events (Teaes) Of 
Special Interest Resulting In Death - Safety Analysis Set 
67 
Table 14.3-6.1: Tabulation Of Incidence Of Prior Medications - Safety Analysis Set 
68 
Table 14.3-6.2: Tabulation Of Incidence Of Concomitant Medications – Safety Analysis Set 
68 
Table 14.3-7: Tabulation Of Incidence Of Reoperations Due To Hematoma Or Wound Dehiscence – Safety 
Analysis Set 
69 
Table 14.4-1: Summary Of Pharmacokinetic Parameters - Pk Analysis Set 
70 
This Table Will Be Created Separately For Pre-Amendment And Post-Amendment Patients Because Of The 
Changes In Reference Time For Pk Sampling. 
ERROR! BOOKMARK NOT DEFINED. 
Table 14.4-2: Summary Of Depotxa (Ng/Ml) Over Time - Pk Analysis Set 
71 
This Table Will Be Created Separately For Pre-Amendment And Post-Amendment Patients Because Of The 
Changes In Reference Time For Pk Sampling. 
ERROR! BOOKMARK NOT DEFINED. 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
31 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.1-1: Tabulation of Subject Disposition – All Screened Subjects 
Site: Overall 
 
DepoTXA 400 
[N=XX] 
n (%) 
DepoTXA 800 
[N=XX] 
n (%) 
DepoTXA 1200 
[N=XX] 
n (%) 
IV TXA 
[N=XX] 
n (%) 
Total 
[N=XX] 
n (%) 
Screened 
 
 
 
 
xx 
Screen Failure 
 
 
 
 
xx (xx.x) 
  Did Not Meet Inclusion #1 
 
 
 
 
xx (xx.x) 
  Did Not Meet Inclusion #2 
 
 
 
 
xx (xx.x) 
  … 
 
 
 
 
xx (xx.x) 
 
 
 
 
 
 
Randomized [2] 
xx 
xx 
xx 
xx 
xx 
  Not Treated 
xx 
xx 
xx 
xx 
xx 
  Treated 
xx 
xx 
xx 
xx 
xx 
  Underwent Surgery 
xx 
xx 
xx 
xx 
xx 
  Did Not Undergo Surgery 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Safety Analysis Set [1] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Efficacy Analysis Set [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
PK Analysis Set [1] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
NA 
NA 
 
 
 
 
 
 
Completed Study [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Discontinued from Study [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 Reasons for Discontinuation 
 
 
 
 
 
    Death [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Adverse Event [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lack of Efficacy [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lost to Follow-up [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Withdrawal by Subject [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Other [2] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
[1] As treated 
[2] As randomized 
Number of subjects randomized is used as denominator for all percentages except screened.  Screen Failure 
and the associated reasons reported uses the number of subjects screened as the denominator. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 


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404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
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29JAN2018 
 
Note to programmer: First page will present overall sites; subsequent pages will present each site – one 
site per page. For individual sites the label should be the site number.  If no subjects were mistreated, 
then no footnote will be needed; otherwise list all subjects who were mistreated in this study by site and 
subject number in the footnotes of each applicable table.   
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
33 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.1-2.1: Tabulation of Subject Demographics - Safety Analysis Set 
Site: Overall 
 
 
 
Statistic 
DepoTXA 
400 
[N=XX] 
DepoTXA 
800 
[N=XX] 
DepoTXA 
1200 
[N=XX] 
IV TXA 
[N=XX] 
 
Total 
[N=XX] 
Age (yrs) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Sex 
 
 
 
 
 
 
  Female 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Male 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
  Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
  American Indian or Alaska Native 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Black or African American 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Hawaiian or Pacific 
Islander 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Other 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
ASA Classification 
 
 
 
 
 
 
   1 
n (%) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
xx (xx.x) xx (xx.x) 
   2 
n (%) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
xx (xx.x) xx (xx.x) 
   3 
n (%) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
Country 
 
 
 
 
 
 
   United States of America 
n (%) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
34 of 113 
 
 
 
29JAN2018 
 
 
Note to programmer: Use table 14.1-2.1 as a template for the following tables: 
Table 14.1-2.2: Tabulation of Subject Demographics – Efficacy Analysis Set  
Table 14.1-2.3: Tabulation of Subject Demographics - PK Analysis Set  


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
35 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.1-3.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
Site: Overall 
 
 
 
Statistic 
DepoTXA 
400 
[N=XX] 
DepoTXA 
800 
[N=XX] 
DepoTXA 
1200 
[N=XX] 
IV TXA 
[N=XX] 
 
Total 
[N=XX] 
Height (cm) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Weight (kg) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Body Mass Index (kg/m^2) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Total Blood Volume (mL) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Use table 14.1-3.1 as a template for the following tables: 
Table 14.1-3.2: Summary of Subject Baseline Characteristics – Efficacy Analysis Set  
Table 14.1-3.3: Summary of Subject Baseline Characteristics - PK Analysis Set  
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
36 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.1-4.1: Summary of Surgery Characteristics - Safety Analysis Set 
Site: Overall 
Characteristics 
Statistic 
DepoTXA 
400 
[N=XX] 
DepoTXA 
800 
[N=XX] 
DepoTXA 
1200 
[N=XX] 
IV TXA 
[N=XX] 
Total 
[N=XX] 
Duration of Surgery (hrs) 
N 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Incision Length (cm) 
N 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Tourniquet Used 
n(%) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
Tourniquet Duration (hrs) 
N 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Tourniquet Maximum Pressure (mmHg) N 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Type of Anesthesia 
 
 
 
 
 
 
   General 
n(%) 
xx (xx.x) xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Spinal 
n(%) 
xx (xx.x) xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Other  
n(%) 
xx (xx.x) xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
37 of 113 
 
 
 
29JAN2018 
 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template also for table: 
Table 14.1-4.2: Summary of Surgery Characteristics – Efficacy Analysis Set  
Table 14.1-4.3: Summary of Surgery Characteristics– PK Analysis Set 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
38 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.1-5.1: Tabulation of Medical History - Safety Analysis Set 
 
Site: Overall 
System Organ Class 
  Preferred Term 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
 
 
 
 
 
 
SOC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.2 
 
 
 
 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC2 
 
 
 
 
 
  PT2.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT2.2 
 
 
 
 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ETC. 
 
 
 
 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Medical History coded using the Medical Dictionary for Regulatory Activities (MedDRA version 19.1 or 
higher).  Sorted by descending total incidence by system organ class and preferred term within system organ 
class.  Subjects with the same Medical History reported more than once are counted only once at each 
summary level. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites for Medical History.  Use mock-up Table 14.1-5.1 for the 
following tables: 
Table 14.1-5.2: Tabulation of Medical History - Efficacy Analysis Set  
Table 14.1-5.3: Tabulation of Medical History - PK Analysis Set 
 
 
 
 
 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
39 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-1.1: Summary of Total Blood Volume (mL) by Scheduled Timepoint (Method 1 Hct)–Efficacy Analysis 
Set  
Site: Overall 
Timepoint 
Value 
Statistic 
DepoTXA 400  
[N=XX] 
DepoTXA 800  
[N=XX]  
DepoTXA 1200  
[N=XX]  
IV TXA  
[N=XX] 
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
5 min 
Actual 
n 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Blood Loss 
n 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: This table should include the PACU, 6, 12, 24, 48, 72, 120 hour, and Day 7 timepoints. 
Use this template for the following table: 
 
Table 14.2-1.2: Summary of Total Blood Loss (mL) by Scheduled Timepoint (Method 2 Hb)– Efficacy Analysis 
Set  
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
40 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-2: Summary of Incidence of Transfusion – Efficacy Analysis Set 
Site: Overall 
 
 
 
 
Statistic 
DepoTXA 400  
[N=XX] 
DepoTXA 800  
[N=XX] 
DepoTXA 1200  
[N=XX] 
IV TXA  
[N=XX] 
Number of Units/Subject n 
    xx 
    xx 
    xx 
    xx 
 
Mean 
     x.x 
     x.x 
     x.x 
     x.x 
 
SD 
     x.xx 
     x.xx 
     x.xx 
     x.xx 
 
Median 
     x.x 
     x.x 
     x.x 
     x.x 
 
Minimum 
     x.x 
     x.x 
     x.x 
     x.x 
 
Maximum 
     x.x 
     x.x 
     x.x 
     x.x 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects Transfused 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
41 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-3.1a: Summary of Time to 90o Active Knee Flexion (for Subjects Enrolled Prior to Protocol 
Amendment 2) – Efficacy Analysis Set  
Site: Overall 
 
 
 
Timepoint 90o Knee Flexion 
 
 
Statistic 
DepoTXA 
400  
[N=XX] 
DepoTXA 
800  
[N=XX] 
DepoTXA 
1200  
[N=XX] 
IV TXA 
[N=XX] 
 
 
 
 
 
 
 
Day 1 
Yes 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No  
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Censored 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Day 2 
Yes 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No  
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Censored 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Day 3 
Yes 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No  
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Censored 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KM Estimates of Time to 90o Knee Flexion 
 
 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
25th Percentile 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
75th Percentile 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer:  Use the mock-up from Table 14.2-3.1a for the following table: 
Table 14.2-3.2a: Summary of Time to 90o Passive Knee Flexion – Efficacy Analysis Set 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
42 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-3.1b: Summary of Time to 90o Active Knee Flexion (for Subjects Enrolled After Protocol Amendment 
2) – Efficacy Analysis Set  
Site: Overall 
 
 
 
Timepoint 90o Knee Flexion 
 
 
Statistic 
DepoTXA 
400  
[N=XX] 
DepoTXA 
800  
[N=XX] 
DepoTXA 
1200  
[N=XX] 
IV TXA 
[N=XX] 
 
 
 
 
 
 
 
Day 1 AM 
Yes 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No  
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Censored 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Day 1 PM 
Yes 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No  
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Censored 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 AM 
Yes 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No  
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Censored 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Day 2 PM 
Yes 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No  
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Censored 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue through Day 5 PM) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer:  Use the mock-up from Table 14.2-3.1b for the following table: 
Table 14.2-3.2b: Summary of Time to 90o Passive Knee Flexion – Efficacy Analysis Set 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
43 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-3.1c: Kaplan-Meier Estimate of Time to 90o Active Knee Flexion – Efficacy Analysis Set  
Site: Overall 
 
 
 
 
 
Statistic 
DepoTXA 400  
[N=XX] 
DepoTXA 800  
[N=XX] 
DepoTXA 1200  
[N=XX] 
IV TXA [N=XX] 
 
 
 
 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
25th Percentile 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
75th Percentile 
xx.x 
xx.x 
xx.x 
xx.x 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
Note: + indicates a censored value; KM = Kaplan-Meier 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer:  Use the mock-up from Table 14.2-3.1c for the following table: 
Table 14.2-3.2c: Summary of Time to 90o Passive Knee Flexion – Efficacy Analysis Set 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
44 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-4.1: Summary of Time to Complete Timed Up-and-Go (TUG) Test - Efficacy Analysis Set  
 
Site: Overall 
Timepoint[1] 
Value 
Statistic 
DepoTXA 400  
[N=XX] 
DepoTXA 800  
[N=XX]  
DepoTXA 1200  
[N=XX]  
IV TXA  
[N=XX] 
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Study Day 1 
Actual 
n 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Change from Baseline 
n 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Note: Only subjects who completed the TUG test at a timepoint are included in the summary at that 
timepoint.  All times are measured in seconds. 
[1] Hospital Discharge only applies to the subjects enrolled after Protocol Amendment 2.  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: This table should include the Study Day 1, Study Day 2 morning and evening timepoints, 
hospital discharge (post amendment) and on Study Day 7.  
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
45 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-4.2: Tabulation of Physical Assistance Required to Complete the TUG Test - Efficacy Analysis Set 
Site: Overall 
 
 
 
 
Timepoint[1] 
 
 
Category 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Baseline 
Did Not Complete TUG Test 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Completed TUG Test 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Total Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Maximal Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Moderate Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Minimal Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Supervision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Modified Independance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Complete Independence 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Was any Aid used for the test? 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  NA 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Unknown 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Study Day 1 
Did Not Complete TUG Test 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Completed TUG Test 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Total Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Maximal Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Moderate Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Minimal Assistance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Supervision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Modified Independance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  Complete Independence 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Was any Aid used for the test? 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  … 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
[1] Hospital Discharge only applies to the subjects enrolled after Protocol Amendment 2.  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Note to programmer: Do not split study day across pages. This table should include the Baseline, Study Day 
1, Study Day 2 morning and evening timepoints, and on Study Day 7.   
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
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29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-4.3: Shift Table of Physical Assistance Required to Complete the TUG Test - Efficacy Analysis 
Set 
Site: Overall 
 
 
Baseline 
Timepoint[1] 
Treatment 
 
1 
n(%) 
2 
n(%) 
3 
n(%) 
4 
n(%) 
5 
n(%) 
6 
n(%) 
7 
n(%) 
8 
n(%) 
Study Day 1 
DepoTXA 400 
1 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
2 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
3 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
4 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
5 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
6 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
7 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
8 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
Study Day 1 
DepoTXA 800 
1 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
2 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
3 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
4 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
5 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
6 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
7 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
8 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
Study Day 1 
DepoTXA 1200 
1 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
2 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
3 
xx (xx.x) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
… 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
Note: 1- Did Not Complete TUG Test, 2- Total Assistance, 3- Maximal Assistance, 4- Moderate Assistance,     
5- Minimal Assistance, 6- Supervision, 7- Modified Independence, and 8- Complete Independence. 
[1] Hospital Discharge only applies to the subjects enrolled after Protocol Amendment 2.  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
47 of 113 
 
 
 
29JAN2018 
 
Note to programmer: Do not split study day and treatment across pages. This table should include the 
Baseline, Study Day 1, Study Day 2 morning and evening timepoints, hospital discharge, and on Study Day 7. 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-5.1: Summary of NRS at Assessment Timepoints – Efficacy Analysis Set 
Site: Overall 
 
Timepoint 
Statistic 
DepoTXA 400 
[N=XX] 
DepoTXA 800 
[N=XX] 
DepoTXA 1200 
[N=XX] 
IV TXA 
[N=XX] 
 
 
 
 
 
 
D1 Preop 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
PACU 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Etc. 
n 
xx 
xx 
xx 
xx 
     
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
PACU is Postanesthesia Care Unit 
Number of subjects randomized is used as denominator for all percentages. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name  
 
Note to programmer: Timepoints to appear on this table are, in order, D1 Preop and PACU, 2, 4, 6, 8, 12, 
16, 24, 36, and 48 hours, 72 hours (Amendment 2) and Study Day 7.   
 
 
 


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DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
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Note to programmer: Use the indicated mock-up for the following tables: 
 
Use mock-up 14.2-5.1: 
 
Table 14.2-5.2: Summary of NRS AUC - Efficacy Analysis Set 
 
AUC parameters for Table 14.2-5.2 are: AUC(0-24), AUC(0-48), AUC(0-72), AUC(24-48), and AUC(48-72). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-6.1.1: Knee Circumference at Assessment Timepoints – Efficacy Analysis Set 
 
Site: Overall 
 
 
 
 
 
Timepoint 
Statistic 
DepoTXA 400 
[N=XX] 
DepoTXA 800 
[N=XX] 
DepoTXA 1200 
[N=XX] 
IV TXA 
[N=XX] 
 
 
Surgical 
Leg 
Non- 
Surgical 
Leg 
Surgical 
Leg 
Non- 
Surgical 
Leg 
Surgical 
Leg 
Non- 
Surgical 
Leg 
Surgical 
Leg 
Non- 
Surgical 
Leg 
D1Preop 
 
 
 
 
 
 
 
 
 
 
n 
xx
xx
xx 
xx 
xx 
xx
xx
xx
 
Mean 
xx.x
xx.x
xx.x 
xx.x 
xx.x 
xx.x
xx.x
xx.x
 
SD 
x.xx
x.xx
x.xx 
x.xx 
x.xx 
x.xx
x.xx
x.xx
 
Minimum 
xx
xx
xx 
xx 
xx 
xx
xx
xx
 
Median 
xx.x
xx.x
xx.x 
xx.x 
xx.x 
xx.x
xx.x
xx.x
 
Maximum 
xx
xx
xx 
xx 
xx 
xx
xx
xx
 
 
 
 
 
Postsurgical Day 2 
 
 
 
 
n 
xx
xx
xx 
xx 
xx 
xx
xx
xx
 
Mean 
xx.x
xx.x
xx.x 
xx.x 
xx.x 
xx.x
xx.x
xx.x
 
SD 
x.xx
x.xx
x.xx 
x.xx 
x.xx 
x.xx
x.xx
x.xx
 
Minimum 
xx
xx
xx 
xx 
xx 
xx
xx
xx
 
Median 
xx.x
xx.x
xx.x 
xx.x 
xx.x 
xx.x
xx.x
xx.x
 
Maximum 
xx
xx
xx 
xx 
xx 
xx
xx
xx
 
 
 
 
 
Postsurgical Day 2 Change from Baseline 
 
 
 
     
n 
xx
xx
xx 
xx 
xx 
xx
xx
xx
Mean 
xx.x
xx.x
xx.x 
xx.x 
xx.x 
xx.x
xx.x
xx.x
SD 
x.xx
x.xx
x.xx 
x.xx 
x.xx 
x.xx
x.xx
x.xx
Minimum 
xx
xx
xx 
xx 
xx 
xx
xx
xx
Median 
xx.x
xx.x
xx.x 
xx.x 
xx.x 
xx.x
xx.x
xx.x
Maximum 
xx
xx
xx 
xx 
xx 
xx
xx
xx
 
 
 
 
 
 
 
 
 
 
Note: Data for non-surgical legs were collected only from subjects enrolled prior to Protocol Amendment 2. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name  
Note to programmer: Timepoints to appear on this table are, in order, D1 Preop, Postsurgical Day 2, 
Postsurgical Day 2 from Baseline, Study Day 7, and Study Day 7 Change from Baseline.  
 


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404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
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Pacira Pharmaceuticals 
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Protocol: 404-C-201 
Table 14.2-6.1.2: Leg Difference in Knee Circumference (for Subjects Enrolled Prior to Protocol Amendment 
2) – Efficacy Analysis Set 
 
Site: Overall 
 
 
 
 
 
Timepoint 
Statistic 
DepoTXA 400 
[N=XX] 
DepoTXA 800 
[N=XX] 
DepoTXA 1200 
[N=XX] 
IV TXA 
[N=XX] 
 
 
 
 
 
 
Postsurgical Day 2 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Study Day 7 
n 
xx 
xx 
xx 
xx 
     
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Leg difference in change from baseline is calculated by = (Operated Leg) – (Non-Operated Leg) 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name  
 
 
Note to programmer: This table is only for pre-amendment.  
 
 
 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
52 of 113 
 
 
 
29JAN2018 
 
 
 
  
Note to programmer: Use the indicated mock-up for the following tables: 
 
Use mock-up 14.2-6.1.2: 
 
Table 14.2-6.1.3: Leg Difference in Change from Baseline in Knee Circumference (for Subjects Enrolled Prior 
to Protocol Amendment 2) – Efficacy Analysis Set 
Change the footnote to: Leg difference in change from baseline is calculated by  
= (Operated Leg Change from Baseline) – (Non-Operated Leg Change from Baseline) 
Note to programmer: this table is only for pre-amendment 
 
Table 14.2-6.1.4: Change from Baseline in Surgical Knee Circumference – Efficacy Analysis Set 
Remove the footnote 
Note to programmer: this table is only for pre-amendment 
 
 
 
Use mock-up 14.2-6.1.1: 
 
Table 14.2-6.2.1: Thigh Circumference at Assessment Timepoints – Efficacy Analysis Set 
Note to programmer: same comment as for knee 
 
Use mock-up 14.2-6.1.2: 
 
Table 14.2-6.2.2: Leg Difference in Thigh Circumference (for Subjects Enrolled Prior to Protocol Amendment 
2) – Efficacy Analysis Set  
 
Table 14.2-6.2.3: Leg Difference in Change from Baseline in Thigh Circumference (for Subjects Enrolled 
Prior to Protocol Amendment 2) – Efficacy Analysis Set 
Note to programmer: same comment as for knee 
 
 
Use mock-up 14.2-6.1.2: 
 
Table 14.2-6.2.4: Change from Baseline in Surgical Thigh Circumference – Efficacy Analysis Set  
Note to programmer: same comment as for knee 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
53 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-7: Summary of Days to First Independent Ambulation – Efficacy Analysis Set  
Site: Overall 
 
 
 
 
 
 
Statistic 
DepoTXA 
400 mg 
[N=XX] 
DepoTXA 
800 mg 
[N=XX] 
DepoTXA  
1200 mg 
[N=XX] 
IV TXA 
[N=XX] 
 
 
 
 
 
 
Number of subjects ambulating 
n (%) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
xx (xx.x) 
Number of subjects censored 
n (%) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
KM Estimates of Days to First Independent 
Amulation  
n 
xx 
xx 
xx 
xx 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
25th Percentile 
xx.x 
xx.x 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Note: + indicates a censored value; KM = Kaplan-Meier 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
54 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.2-8: Tabulation of Surgical Wound Aspect Score on Postsurgical Day – Efficacy Analysis Set 
Site: Overall 
Study 
Day 
 
DepoTXA 
400  
[N=XX] 
n (%) 
DepoTXA 800  
[N=XX] 
n (%) 
DepoTXA 
1200   
[N=XX] 
n (%) 
IV TXA  
[N=XX] 
n (%) 
2 
Wound Oozing 
 
 
 
 
 
  0: No signs of blood on the gauze 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  1: 1-2 spots of blood on the gauze 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  2: >2 spots of blood on the gauze 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Erythema 
 
 
 
 
 
  0: Erythema absent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  1: Erythema at wound edges 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  2: Erythema beyond wound edges 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Ecchymosis 
 
 
 
 
 
  0: Ecchymosis absent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  1: Ecchymosis at wound edges 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  2: Ecchymosis beyond wound edges 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Blisters 
 
 
 
 
 
  0: Blisters absent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  1: 1-2 blisters of <2 cm each 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  2: >2 blisters of any size or ≥1 blister >2 cm 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Sum of Categories 
 
 
 
 
 
  0 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  6 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  8 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 


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DepoTXA 
 
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Descriptive Statistics of the Sum of Categories 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
  Minimum 
xx 
xx 
xx 
xx 
 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
  Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Number of subjects randomized is used as denominator for all percentages. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name  
 
Note to programmer:  Put study day 7 on the next page 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
56 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-1.1: Tabulation of Electrocardiogram – Investigator Read - Safety Analysis Set 
Site: Overall 
 
 
Time Point 
Interpretation 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
D1 PreOp 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, N.C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Any Post-
Baseline 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, N.C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
1 hour 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, N.C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
12 hours 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, N.C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal, C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Note: C.S. is Clinically Significant and N.C.S is Not Clinically Significant. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Note to programmer: Only present overall sites.   
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
57 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-1.2: Shift Table of Electrocardiogram – Investigator Read - Safety Analysis Set 
Site: Overall 
 
 
 
D1PreOp 
Treatment 
Group 
 
Time Point 
Interpretation 
Normal 
n(%) 
Abnormal N.C.S  
n(%) 
Abnormal C.S.  
n(%) 
DepoTXA 400 
Any Post-Baseline 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal, N.C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal, C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
1 hour 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal, N.C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal, C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
12 hours 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal, N.C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal, C.S. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Note: C.S. is Clinically Significant and N.C.S is Not Clinically Significant. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Note to programmer: Present each treatment group and the Total on separate pages; DepoTXA 400, DepoTXA 800, 
DepoTXA 1200, IV TXA, and Total. 
 
 


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404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
58 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-2: Summary of Vital Signs – Safety Analysis Set 
Site: Overall 
Vital Sign: Resting Heart Rate (bpm) 
Timepoint 
Value 
Statistic 
DepoTXA 400  
[N=XX] 
DepoTXA 800  
[N=XX]  
DepoTXA 1200  
[N=XX]  
IV TXA  
[N=XX] 
Total 
[N=XXX]  
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
5 min 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Change from 
Baseline 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. Vital signs are ‘Resting Heart Rate (bpm)’, ‘Systolic Blood 
Pressure (mmHg)’ and ‘Diastolic Blood Pressure (mmHg)’. Timepoints to appear on this table are Baseline, 
5min, 15min, 30min, 1hr, 2hr, 4hr, 6hr, 8hr, 12hr, 16hr, 24hr, 36hr, 48hr, 60hr, 72hr, and 96hr.  Don’t 
split timepoints across pages.  See SAP section 9.9.2 for further details.  
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
59 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-3: Tabulation of Neurological Assessments by Timepoint- Safety Analysis Set  
Site: Overall 
Timepoint: Baseline 
Assessment 
Score 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
 
 
 
 
 
 
 
Subject Oriented 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Numbness  
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Metallic taste 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Hearing problems 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Vision problems 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Muscle twitching 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Note: Numbness referes to the numbness of the lips, tongue, and/or mouth. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  Timepoints to appear on this table are, in order of 
appearance, Baseline (prior to surgery), At anytime after baseline, 12, 24, 36, 48, 60, 72, 84 and 96 
hours.  Do not split a timepoint across pages.  For the timepoint ‘anytime after baseline’ if there is at 
least one ‘yes’ at any timepoint but baseline, the subject will be a ‘yes’.  
 
 
 
 
 
 


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404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
60 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-4.1: Summary of Clinical Laboratory Assessments - Safety Analysis Set 
Site: Overall 
Clinical Laboratory Parameter: Albumin (g/L) 
Timepoint 
Value 
Statistic 
DepoTXA 400  
[N=XX] 
DepoTXA 800  
[N=XX]  
DepoTXA 1200  
[N=XX]  
IV TXA  
[N=XX] 
Total 
[N=XXX]  
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
48 Hours 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Change from 
Baseline 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. Each clinical labortory parameter (w/ unit) should have a 
unique page. Clinical labortory parameters should be presented in alphabetical order.  Clinical Labs are 
collected at baseline, 48 hours, and day 7, with the exception of Creatine Clearance only at Baseline and 
Day 7.   
 
 
 
 
 


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404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
61 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-4.2: Tabulation of Incidence of Abnormal Clinical Laboratory Assessments - Safety Analysis Set  
Site: Overall 
Parameter 
Timepoint 
Range 
DepoTXA  
400  
[N=XX] 
n(%) 
DepoTXA  
800  
[N=XX]  
n(%) 
DepoTXA 
1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
 
 
 
 
 
 
 
 
Albumin (g/L) 
Baseline 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
 
 
48 hours 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
 
 
Day 7 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
 
Note: Low indicates the the parameter was below the lower limit of the normal range, Normal indicates the 
the parameter was within the normal range, limits inclusive, and above indicates the the parameter was 
above the upper limit of the normal range. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Note to programmer: Only present overall sites.  Timepoints to appear on this table are, in order of 
appearance, Baseline and 48 hours and Day 7.  Do not split a parameter across multiple pages.   
  
 
 
 
 
 
 
 
 
 
 


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404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
62 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-4.3: Shift Table of Clinical Laboratory Assessments - Safety Analysis Set 
Site: Overall 
Parameter: Albumin (g/L) 
 
Baseline 
Timepoint 
Treatment Group 
Range 
Low 
n(%) 
Normal 
n(%) 
Above 
n(%) 
48 hours 
DepoTXA 400 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
DepoTXA 800 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
DepoTXA 1200 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
IV TXA 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Total 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Above 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Note: Low indicates the the parameter was below the lower limit of the normal range, Normal indicates the 
the parameter was within the normal range, limits inclusive, and Above indicates the the parameter was 
above the upper limit of the normal range. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Present each Laboratory Parameter on a separate page, Day 7 parameters should occur 
after all parameters have been presented for 48 hours.  
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
63 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-5.1.1: Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
Site: Overall 
Number of 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
 
 
 
 
 
 
Subjects with Any TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
  At least one Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  At least one Serious 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  At least one Related Serious 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Subjects Discontinued due to TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Died on Study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Note to programmer: Only present overall sites.  
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
64 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-5.1.2: Tabulation of Incidence of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis 
Set 
 
Site: Overall 
System Organ Class 
  Preferred Term 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
 
 
 
 
 
 
Subjects with at least one TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
SOC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
SOC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT2.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT2.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
ETC. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  ETC. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  ETC. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA version 19.1 or 
higher).  Sorted by descending total incidence by system organ class and preferred term within system organ 
class.  Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  Use mock-up Table 14.3-2.1.2 for the following tables: 
 
Table 14.3-5.1.3: Tabulation of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) - 
Safety Analysis Set  
Table 14.3-5.1.4: Tabulation of Incidence of Treatment-Emergent Adverse Events (TEAEs) Leading to Study 
Withdrawal - Safety Analysis Set 
Table 14.3-5.1.5: Tabulation of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) 
Leading to Study Withdrawal - Safety Analysis Set 
 
For related tables add the following footnote to the table: 
Related TEAEs are those AEs indicated as ‘possible’, ‘probable’ or ‘definite’ related by the investigator 
on the AE CRF or if no investigator assessment is provided. 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
65 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-5.1.6: Tabulation of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Severity - Safety 
Analysis Set 
Site: Overall 
System Organ Class 
  Preferred Term 
Severity 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
Subjects with at least one 
TEAE 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
SOC1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
  PT1.1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
  PT1.2 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
SOC2 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
PT2.1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
ETC. 
 
 
 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA version 19.1 or 
higher).  Sorted by descending total incidence by system organ class and preferred term within system organ 
class.  Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DepoTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
66 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Table 14.3-5.1.7: Tabulation of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Relationship to 
Study Drug - Safety Analysis Set 
Site: Overall 
System Organ Class 
  Preferred Term 
Relation 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
Subjects with at least one 
TEAE 
Unrelated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Reported 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
SOC1 
Unrelated 
 
 
 
 
 
 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Reported 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
  PT1.1 
Unrelated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Reported 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
  PT1.2 
Unrelated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Reported 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ETC. 
 
 
 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA version 19.1 or 
higher).  Sorted by descending total incidence by system organ class and preferred term within system organ 
class.  Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 


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Note to programmer: Only present overall sites. Use template 14.3-5.1.2 for the following tables:  
Table 14.3-5.2.1: Tabulation of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) - Safety 
Analysis Set  
Table 14.3-5.2.1.CT: Tabulation of Incidence of Non-Serious Treatment-Emergent Adverse Events (TEAEs) - 
Safety Analysis Set 
Table 14.3-5.2.2: Tabulation of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) - Safety Analysis Set 
Table 14.3-5.2.3: Tabulation of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) Leading to 
Study Withdrawal - Safety Analysis Set 
Table 14.3-5.2.4: Tabulation of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) Leading to Study Withdrawal - Safety Analysis Set 
Table 14.3-5.2.5: Tabulation of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) Resulting in 
Death - Safety Analysis Set 
Table 14.3-5.2.6: Tabulation of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) Resulting in Death - Safety Analysis Set 
Table 14.3-5.3.1: Tabulation of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
- Safety Analysis Set 
Table 14.3-5.3.2: Tabulation of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) 
of Special Interest - Safety Analysis Set 
Table 14.3-5.3.3: Tabulation of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
Leading to Study Withdrawal - Safety Analysis Set 
Table 14.3-5.3.4: Tabulation of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) 
of Special Interest Leading to Study Withdrawal - Safety Analysis Set 
Table 14.3-5.3.5: Tabulation of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
Resulting in Death - Safety Analysis Set 
Table 14.3-5.3.6: Tabulation of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) 
of Special Interest Resulting in Death - Safety Analysis Set 
 
 
 


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DepoTXA 
 
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Table 14.3-6.1: Tabulation of Incidence of Prior Medications - Safety Analysis Set 
Site: Overall 
System Organ Class 
  Preferred Term 
DepoTXA 400  
[N=XX] 
n(%) 
DepoTXA 800  
[N=XX]  
n(%) 
DepoTXA 1200  
[N=XX]  
n(%) 
IV TXA  
[N=XX]  
n(%) 
Total 
[N=XXX]  
n(%) 
 
 
 
 
 
 
Subjects taking at least one 
medication 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
ATC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
ATC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN2.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN2.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
ETC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications are coded using World Health Organization Drug Dictionary Enhanced (WHO-DD) September 2016. 
Sorted by descending total incidence by ATC and preferred name within ATC. 
Prior medications are those stopped before end of surgery. 
Subjects using the same prior medication more than once are counted only once at each summary level. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  Use this template for the following tables: 
 
Table 14.3-6.2: Tabulation of Incidence of Concomitant Medications – Safety Analysis Set.  
 
On these tables change the footnote ‘Prior medications are those stopped before end of surgery’ to read 
‘Concomitant medications are those taken between the end of surgery and discharge from study’ on Table 
14.3-6.2.  
 
 
 
 
 


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DepoTXA 
 
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Table 14.3-7: Tabulation of Incidence of Reoperations Due to Hematoma or Wound Dehiscence – Safety Analysis 
Set 
Site: Overall 
 
 
DepoTXA 400  
[N=XX] 
n (%) 
DepoTXA 800  
[N=XX] 
n (%) 
DepoTXA 
1200   
[N=XX] 
n (%) 
IV TXA  
[N=XX] 
n (%) 
 
Total 
[N=XX] 
n (%) 
 
 
 
 
 
 
Did the Subject have a Reoperation due to 
a Hematoma or Wound Dehiscence? 
 
 
 
 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of subjects treated with the respective treatment is used as denominator for the respective 
percentages. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 


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404-C-201 (TKA) 
DepoTXA 
 
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Table 14.4-1a: Summary of Pharmacokinetic Parameters (for Subjects Enrolled Prior to Prorocol Amendment 2) 
- PK Analysis Set 
Site: Overall 
PK Parameter 
 
 
Statistic 
DepoTXA 400 
[N=XX] 
DepoTXA 800 
[N=XX] 
DepoTXA 1200 
[N=XX] 
 
 
IV TXA  
[N=XX] 
 
 
 
 
 
 
AUC(0-infinity) (hr*ng/mL) 
n 
      xx 
      xx 
      xx 
      xx 
 
Mean 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
SD 
       x.xx 
       x.xx 
       x.xx 
       x.xx 
 
Minimum 
      xx 
      xx 
      xx 
      xx 
 
Median 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
Maximum 
      xx 
      xx 
      xx 
      xx 
 
 
 
 
 
 
AUC(0-last) (hr*ng/mL) 
n 
      xx 
      xx 
      xx 
      xx 
 
Mean 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
SD 
       x.xx 
       x.xx 
       x.xx 
       x.xx 
 
Minimum 
      xx 
      xx 
      xx 
      xx 
 
Median 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
Maximum 
      xx 
      xx 
      xx 
      xx 
 
 
 
 
 
 
Etc. 
n 
      xx 
      xx 
      xx 
      xx 
 
Mean 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
SD 
       x.xx 
       x.xx 
       x.xx 
       x.xx 
 
Minimum 
      xx 
      xx 
      xx 
      xx 
 
Median 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
Maximum 
      xx 
      xx 
      xx 
      xx 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Pharmacokinetic parameters to appear on this table are, in order of appearance, AUC(0-
infinity) (hr*ng/mL), AUC(0-last) (hr*ng/mL), Global Cmax (ng/mL), Global Tmax (hr), Early Cmax (ng/mL), 
Early Tmax (hr), Late Cmax (ng/mL), Late Tmax (ng/mL), half-life (hr), Lambda_z (/hr).  
 
Table 14.4-1b: Summary of Pharmacokinetic Parameters (for Subjects Enrolled After Protocol Amendment 2) - 
PK Analysis Set 
 
 


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Table 14.4-2a: Summary of DepoTXA (ng/mL) Over Time (for Subjects Enrolled Prior to Protocol Amendment 2) - 
PK Analysis Set 
Site: Overall 
Time 
 
Statistic 
DepoTXA 400 
[N=XX] 
DepoTXA 800 
[N=XX] 
DepoTXA 1200 
[N=XX] 
   IV TXA  
[N=XX] 
 
 
 
 
 
 
5 min 
n 
      xx 
      xx 
      xx 
      xx 
 
Mean 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
SD 
       x.xx 
       x.xx 
       x.xx 
       x.xx 
 
Minimum 
      xx 
      xx 
      xx 
      xx 
 
Median 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
Maximum 
      xx 
      xx 
      xx 
      xx 
 
 
 
 
 
 
15 min 
n 
      xx 
      xx 
      xx 
      xx 
 
Mean 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
SD 
       x.xx 
       x.xx 
       x.xx 
       x.xx 
 
Minimum 
      xx 
      xx 
      xx 
      xx 
 
Median 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
Maximum 
      xx 
      xx 
      xx 
      xx 
 
 
 
 
 
 
Ect. 
n 
      xx 
      xx 
      xx 
      xx 
 
Mean 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
SD 
       x.xx 
       x.xx 
       x.xx 
       x.xx 
 
Minimum 
      xx 
      xx 
      xx 
      xx 
 
Median 
      xx.x 
      xx.x 
      xx.x 
      xx.x 
 
Maximum 
      xx 
      xx 
      xx 
      xx 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Timepoints to appear on this table are, in order of appearance, For all subjects: at 5, 
15, and 30 minutes; and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all 
treatment groups and for DepoTXA-treated subjects only: additional timepoints at 36, 48, 60, 72, and 
96 hours after study drug administration.   
 
Table 14.4-2a: Summary of DepoTXA (ng/mL) Over Time (for Subjects Enrolled After Protocol Amendment 2) - PK 
Analysis Set 
 
 
 


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Document No. <  > 
 
CONFIDENTIAL 
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05OCT2016 
 
14. 
TABLE OF CONTENTS FOR LISTINGS 
Listing 16.2-1: Subject Disposition – All Subjects 
73 
Listing 16.2-2: Randomization and Analysis Sets – Randomized Subjects 
74 
Listing 16.2-3: Demographics – All Subjects 
75 
Listing 16.2-4.1: Surgery Characteristics – Randomized Subjects 
76 
Listing 16.2-4.2: Tourniquet Characteristics – Randomized Subjects 
77 
Listing 16.2-5: Study Drug Administration – Randomized Subjects 
78 
Listing 16.2-6.1.1: Calculated Blood Loss - Method 1 – Randomized Subjects 79 
Listing 16.2-6.1.2: Calculated Blood Loss - Method 2 – Randomized Subjects 80 
Listing 16.2-6.2: Blood Transfusion - Randomized Subjects 
81 
Listing 16.2-6.3: Passive and Active Knee Flexion - Randomized Subjects 
82 
Listing 16.2-6.4: TUG Test - Randomized Subjects 
83 
Listing 16.2-6.5: Numeric Rating Scale (NRS) - Randomized Subjects 
84 
Listing 16.2-6.6: Knee and Thigh Circumfrence Measurements (cm) - Randomized 
Subjects 
85 
Listing 16.2-6.7: Surgical Wound Aspect Score (SWAS) - Randomized Subjects 86 
Listing 16.2-7: Phone Calls – Randomized Subjects 
87 
Listing 16.2-8: Neurological Assessment – Randomized Subjects 
88 
Listing 16.2-9: Electrocardiogram Findings – Investigator Assessment – All 
Subjects 
89 
Listing 16.2-10: Vital Signs – All Subjects 
90 
Listing 16.2-11.1: All Adverse Events – All Subjects 
91 
Listing 16.2-11.2.1: Treatment-Emergent Adverse Events – Randomized Subjects91 
Listing 16.2-11.2.2: Treatment-Emergent Study Drug Related Adverse Events – 
Randomized Subjects 
91 
Listing 16.2-11.3: All Serious Adverse Events – All Subjects 
91 
Listing 16.2-11.3.CT: All Non-Serious Adverse Events – All Subjects 
91 
Listing 16.2-11.4.1: Treatment-Emergent Serious Adverse Events – Randomized 
Subjects 
91 
Listing 16.2-11.4.1.CT: Treatment-Emergent Non-Serious Adverse Events – 
Randomized Subjects 
91 
Listing 16.2-11.4.2: Treatment-Emergent Study Drug Related Serious Adverse 
Events – Randomized Subjects 
91 
Listing 16.2-12.1: All Prior Medications – Randomized Subjects 
92 
Listing 16.2-12.2: Concomitant Medications – Randomized Subjects 
92 
Listing 16.2-13: Medical/Surgical History – Randomized Subjects 
93 
Listing 16.2-14: Informed Consent – All Subjects 
94 
Listing 16.2-15.1: Subject Eligibility – All Subjects 
95 
Listing 16.2-15.2: Subject Eligibility – Inclusion/Exclusion Criteria 
96 
Listing 16.2-16: Pregnancy Test – All Subjects 
98 
Listing 16.2-17: Protocol Deviations – All Subjects 
99 
Listing 16.2-18.1: Pharmacokinetic Concentrations – All Subjects 
100 
Listing 16.2-18.2: Pharmacokinetic Parameters – All Subjects 
101 
Listing 16.2-19: Unique Adverse Events Terms and Associated Coded Terms 
102 
Listing 16.2-20: Unique Medication Terms and Associated Coded Terms 
103 
 


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Listing 16.2-1: Subject Disposition – All Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Date of 
Last Visit 
End of Study Status 
Specify 
XXX 
XXX-YYYY 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: End of study status for subject who early terminated from the study is the primary 
reason for termination.  If subject discontinued due to an AE then the reason should read ‘ADVERSE EVENT, 
AE # X’. If subject discontinued due to death the reason should read ‘DEATH ON DDMONYYYY’.  For those 
reasons that also collected a specify text, that text belongs in the specify column.  Screen Failures 
should be indicated under treatment at the top of the table and the reason for screen failure should be 
provided. 
 
 


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Listing 16.2-2: Randomization and Analysis Sets – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
 
Analysis Sets 
 
 
Site 
Subject 
Date and Time 
Randomization 
Number 
Safety 
PK 
Efficacy  
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXXXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Listing 16.2-3: Demographics – All Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Birth 
Date 
Age 
(yrs) 
ASA 
Class 
Sex 
Race 
Ethnicity 
XXX 
XXX-YYYY DDMONYYYY 
XX 
 
XXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
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Listing 16.2-4.1: Surgery Characteristics – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
Surgery Time 
 
 
 
 
 
Site 
 
Subject 
Date 
Start 
Stop 
Duration 
(hr) 
Procedure 
Name 
Incision 
Length (cm) 
Anesthesia 
Type  
Primary 
Surgeon 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XX.X 
Right TKA 
xx.x 
xxxxxxx 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XX.X 
Left TKA 
xx.x 
xxxxxxx 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XX.X 
Right TKA 
xx.x 
xxxxxxx 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XX.X 
Left TKA 
xx.x 
xxxxxxx 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XX.X 
Right TKA 
xx.x 
xxxxxxx 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XX.X 
Right TKA 
xx.x 
xxxxxxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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404-C-201 (TKA) 
DEPOTXA 
 
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Listing 16.2-4.2: Tourniquet Characteristics – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
 
Tourniquet Time 
 
Site Subject 
Date 
Tourniquet Used? 
Start 
Stop 
Duration (hr) Maximum Pressure (mmHg) 
XXX 
XXX-YYYY 
DDMONYYYY 
xxx 
HH:MM 
HH:MM 
XX.X 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
xxx 
HH:MM 
HH:MM 
XX.X 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
xxx 
HH:MM 
HH:MM 
XX.X 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
xxx 
HH:MM 
HH:MM 
XX.X 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
xxx 
HH:MM 
HH:MM 
XX.X 
xxx 
XXX 
XXX-YYYY 
DDMONYYYY 
xxx 
HH:MM 
HH:MM 
XX.X 
xxx 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


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404-C-201 (TKA) 
DEPOTXA 
 
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Listing 16.2-5: Study Drug Administration – Randomized Subjects 
 
 
Study Treatment 
 
Start 
Time 
Stop 
Time 
Total Volume 
(mL) 
Site 
Subject 
Randomized 
Actual 
Date 
XXX 
XXX-YYYY 
XXXXXXXXXXXXXXX XXXXXXXXXXXXXXX DDMONYYYY 
HH:MM 
HH:MM 
X 
XXX 
XXX-YYYY 
XXXXXXXXXXXXXXX XXXXXXXXXXXXXXX DDMONYYYY 
HH:MM 
HH:MM 
X 
XXX 
XXX-YYYY 
XXXXXXXXXXXXXXX XXXXXXXXXXXXXXX DDMONYYYY 
HH:MM 
HH:MM 
X 
XXX 
XXX-YYYY 
XXXXXXXXXXXXXXX XXXXXXXXXXXXXXX DDMONYYYY 
HH:MM 
HH:MM 
X 
XXX 
XXX-YYYY 
XXXXXXXXXXXXXXX XXXXXXXXXXXXXXX DDMONYYYY 
HH:MM 
HH:MM 
X 
XXX 
XXX-YYYY 
XXXXXXXXXXXXXXX XXXXXXXXXXXXXXX DDMONYYYY 
HH:MM 
HH:MM 
X 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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404-C-201 (TKA) 
DEPOTXA 
 
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Listing 16.2-6.1.1: Calculated Blood Loss - Method 1 – Randomized Subjects 
Randomized Treatment: TTTTTTT 
Site Subject 
Date and Time 
Timepoint 
Blood Volume 
Transfused 
(mL) 
Hematocrit 
(%) 
Calculated 
Blood Volume 
(mL) 
Calculated 
Blood Loss 
(mL) 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Baseline 
xxx.x 
xxx.x 
xxxx.x 
N/A 
 
 
DDMONYYYYTHH:MM 
PACU 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
6 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
12 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
24 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
48 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
72 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
120 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
Day 7 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Baseline 
xxx.x 
xxx.x 
xxxx.x 
N/A 
 
 
DDMONYYYYTHH:MM 
PACU 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
6 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
12 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
24 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
48 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
72 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
120 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
Day 7 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
 
 
 
 
 
 
Note: Blood volume transfused is since the last Timepoint.  Blood Volume is calculated according to section 
9.8.1 of the Statistical Analysis Plan for study 404-C-201: For method 1, blood loss is in mL calculated 
by:                    (                           )               
  
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by collection date and time.  Timepoints outside of the schedule windows should be 
listed under “Scheduled Timepoint” as “Unscheduled”.  Do not split a subject’s data across pages.  
 
 


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Listing 16.2-6.1.2: Calculated Blood Loss - Method 2 – Randomized Subjects 
Randomized Treatment: TTTTTTT 
Site Subject 
Date and Time 
Timepoint 
Blood Volume 
Transfused 
(g) 
Hemaglobin 
(g/dL) 
Calculated 
Blood Volume 
(mL) 
Calculated 
Blood Loss 
(mL) 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Baseline 
xxx.x 
xxx.x 
xxxx.x 
N/A 
 
 
DDMONYYYYTHH:MM 
PACU 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
6 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
12 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
24 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
48 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
72 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
120 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
Day 7 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Baseline 
xxx.x 
xxx.x 
xxxx.x 
N/A 
 
 
DDMONYYYYTHH:MM 
PACU 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
6 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
12 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
24 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
48 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
72 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
120 hrs 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
DDMONYYYYTHH:MM 
Day 7 
xxx.x 
xxx.x 
xxxx.x 
xxx.x 
 
 
 
 
 
 
 
 
Blood volume transfused is since the last Timepoint.  Blood Volume is calculated according to section 9.8.1 
of the Statistical Analysis Plan for study 404-C-201: For method 2, blood loss is in mL calculated by: 
        
     (           (                         )                      )
          
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by collection date and time.  Timepoints outside of the schedule windows should be 
listed under “Scheduled Timepoint” as “Unscheduled”.  Do not split a subject’s data across pages. 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
81 of 113 
 
 
 
29JAN2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-6.2: Blood Transfusion - Randomized Subjects 
Treatment: TTTTTTT 
Site Subject 
Start Date and Time 
End Date and Time 
# of Units 
Associated Adverse Event 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
x 
Preferred Term 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
82 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-6.3: Passive and Active Knee Flexion - Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
 
Timepoint
[1] 
 
Time of 
Assesment[2] 
Date and Time 
Passive Knee Flexion 
(Degrees) 
Active Knee Flexion 
(Degrees) 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
Baseline 
N/A 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 1 
N/A 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 2 
N/A 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 3 
N/A 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
Baseline 
AM 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 1 
AM 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 1 
PM 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 2 
AM 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 2 
PM 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
Day 3 
AM 
DDMONYYYYTHH:MM 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
. . . 
 
 
 
 
 
 
 
 
 
 
 
[1] Timepoints are Day 1 through Day 3 prior to Protocol Amendment 2 and Day 1 through Day 5 after Protocol 
Amendment 2. 
[2] AM/PM is collected only after Amendment 2. 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
83 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-6.4: TUG Test - Randomized Subjects 
Treatment: TTTTTTT 
Site Subject 
 
Timepoint[1] Date and Time 
Done? Reason not done 
Duration 
of Test 
(seconds) 
Aid 
Used? 
Physical 
Assistance 
 
 
 
 
 
 
 
XXX 
XXX-
YYYY 
Baseline 
DDMONYYYYTHH:MM 
Y 
 
XXX 
XXX 
X 
 
 
Day 1 
DDMONYYYYTHH:MM 
N 
XXXXXXXXXXXXXXX 
 
 
 
 
 
Day 2-AM 
DDMONYYYYTHH:MM 
Y 
 
XXX 
XXX 
X 
 
 
Day 2-PM 
DDMONYYYYTHH:MM 
Y 
 
XXX 
XXX 
X 
 
 
Unscheduled 
DDMONYYYYTHH:MM 
Y 
 
XXX 
XXX 
X 
 
 
Unscheduled 
DDMONYYYYTHH:MM 
Y 
 
XXX 
XXX 
X 
 
 
Day 7 
DDMONYYYYTHH:MM 
Y 
 
XXX 
XXX 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Assistance: 
1=Total Assistance 
2=Maximal Assistance 
3=Moderate Assistance 
4=Minimal Assistance 
5=Supervision 
6=Modified Independence 
7=Complete Independence  
[1] Hospital Discharge only applies to the subjects enrolled after Protocol Amendment 2.  
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
84 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-6.5: Numeric Rating Scale (NRS) - Randomized Subjects 
TREATMENT: treatment-name 
 
 
 
 
Time From Dose 
NRS 
Score 
 
  
Site Subject 
Timepoint 
Date Time 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(hrs) 
NRS-R Performed? 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
D1 Preop 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
PACU 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
2h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
4h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
6h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
8h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
12h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
16h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
24h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
36h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
48h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
72h 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
Day 7 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
 
 
 
 
 
 
 
NRS: 0=No pain to 10=Worst Pain Imaginable 
 
ND=Not Done  NA=Not Applicable 
* = out of window 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
85 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-6.6: Knee and Thigh Circumfrence Measurements - Randomized Subjects 
TREATMENT: treatment-name 
 
 
 
 
Thigh  
(cm) 
 
Knee  
(cm) 
 
Site Subject 
Timepoint 
Date Time 
Right 
Left 
 
Right 
Left 
Procedure Name 
XXX 
XXX-YYYY 
D1 Preop 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Right TKA 
 
 
48h 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Right TKA 
 
 
Day7 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Right TKA 
 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
D1 Preop 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Left TKA 
 
 
48h 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Left TKA 
 
 
Day7 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Left TKA 
 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
D1 Preop 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Right TKA 
 
 
48h 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Right TKA 
 
 
Day7 
DDMONYYYYTHH:MM 
XX.X 
XX.X 
 
XX.X 
XX.X 
Right TKA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ND=Not Done, NA=Not Applicable 
 
 
* = out of window 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
86 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-6.7: Surgical Wound Aspect Score (SWAS) - Randomized Subjects 
TREATMENT: treatment-name 
 
 
 
 
Numerical Score 
Site Subject 
Timepoint Date Time 
Wound Oozing 
Erythema 
Ecchymosis 
Blisters 
XXX 
XXX-YYYY D1 Preop 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
48h 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
Day7 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY D1 Preop 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
48h 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
Day7 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY D1 Preop 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
48h 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
Day7 
DDMONYYYYTHH:MM 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ND=Not Done, NA=Not Applicable,  
* = out of window 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
87 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-7: Phone Calls – Randomized Subjects 
Treatment: TTTTTTT 
 
 
Site 
Subject 
Date of Phone 
Contact 
Scheduled 
Timepoint 
Was the 
Call Made? 
Was there a 
reoperation? 
Number of 
Reoperations 
Independent 
Ambulation? 
Date of 
Ind. Amb. 
XXX 
XXX-YYYY 
DDMONYYYY 
Day 14 
Y 
N 
NA 
N 
NA 
 
XXX-YYYY 
DDMONYYYY 
Day 30 
Y 
N 
NA 
Y 
DDMONYYYY 
 
XXX-YYYY 
DDMONYYYY 
Day 60 
Y 
N 
NA 
Y 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYY 
Day 14 
N 
ND 
NA 
ND 
NA 
 
XXX-YYYY 
DDMONYYYY 
Day 30 
Y 
N 
NA 
N 
NA 
 
XXX-YYYY 
DDMONYYYY 
Day 60 
Y 
N 
NA 
Y 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYY 
Day 14 
Y 
N 
NA 
N 
NA 
 
XXX-YYYY 
DDMONYYYY 
Day 30 
Y 
N 
NA 
N 
NA 
 
XXX-YYYY 
DDMONYYYY 
Day 60 
Y 
Y 
x 
N 
NA 
 
 
 
 
 
 
 
 
 
ND=Not Done, NA=Not Applicable 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
88 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-8: Neurological Assessment – Randomized Subjects 
Treatment: TTTTTTTT 
 
 
Date and Time 
Of 
Assessment 
Time From Dose 
Questions 
Site 
Subject 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
1 
2 
3 
4 
5 
6 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Screening 
NA 
 
NA 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
D1 PREOP 
NA 
 
NA 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
12 
0.XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
24 
X 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
36 
ND 
 
 
 
 
 
 
 
 
 
DDMONYYYYTHH:MM 
48 
X 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
60 
X 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
Screening 
NA 
 
NA 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
D1 PREOP 
NA 
 
NA 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
12 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
24 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
36 
XX 
 
-X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
48 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
60 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
1) Is subject oriented? 
 
 
2) Do you have numbness of the lips, the tongue or around the mouth? 
3) Do you have a metallic taste in your mouth? 
4) Are you having problems with your hearing not related to the use of a hearing aid? 
5) Are you having problems with your vision no related to the use of eye glasses? 
6) Are your muscles twitching? 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
89 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-9: Electrocardiogram Findings – Investigator Assessment – All Subjects 
Treatment: DepoTXA 400 
 
 
 
Time From Dose 
 
 
Site Subject 
Date and Time of 
Sample 
Scheduled 
Timepoint 
Actual 
(hr) 
Deviation 
(mins) 
Finding 
If “Abnormal”, specify 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
D1PreOp 
NA 
NA 
Normal 
 
 
 
DDMONYYYYTHH:MM 
1h 
XX.X 
X 
Normal 
 
 
 
DDMONYYYYTHH:MM 
12h 
XX.X 
X 
Normal 
 
 
 
 
 
 
 
 
 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
D1PreOp 
NA 
NA 
Normal 
 
 
 
DDMONYYYYTHH:MM 
1h 
XX.X 
X 
Normal 
 
 
 
DDMONYYYYTHH:MM 
12h 
XX.X 
X 
Normal 
 
 
 
 
 
 
 
 
 
 
XXX-YYYY 
DDMONYYYYTHH:MM 
D1PreOp 
NA 
NA 
Normal 
 
 
 
DDMONYYYYTHH:MM 
1h 
XX.X 
X 
Normal 
 
 
 
DDMONYYYYTHH:MM 
12h 
XX.X 
X 
Normal 
 
 
 
 
 
 
 
 
 
NA=Not applicable 
 
ND=Not done 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
90 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-10: Vital Signs – All Subjects 
Treatment: TTTTTTTT 
SITE: XXX 
 
Time from Dose 
 
Blood  
Pressure  
 
 
Body 
Mass 
Index 
(m/kg2) 
Subject 
Visit 
Date and Time 
Sched 
(hr) 
Actual 
(hr) 
Devi-
ation 
(mins) 
Heart 
Rate 
(bpm) 
Sys.  
(mmHg) 
Dia.  
(mmHg) 
Height 
(cm) 
Weight 
(kg) 
XXX-YYYY 
Screening DDMONYYYYTHH:MM 
NA 
NA 
NA 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
D1 Preop 
DDMONYYYYTHH:MM 
0 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
5 min 
DDMONYYYYTHH:MM 
0.08 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
15 min 
DDMONYYYYTHH:MM 
0.25 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
30 min 
DDMONYYYYTHH:MM 
0.50 
X 
-X 
XX 
XXX 
XXX 
 
 
 
 
1h 
DDMONYYYYTHH:MM 
1 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
2h 
DDMONYYYYTHH:MM 
2 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
4h 
DDMONYYYYTHH:MM 
4 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
6h 
DDMONYYYYTHH:MM 
6 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
8h 
DDMONYYYYTHH:MM 
8 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
12h 
DDMONYYYYTHH:MM 
12 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
16h 
DDMONYYYYTHH:MM 
16 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
24h 
DDMONYYYYTHH:MM 
24 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
36h 
DDMONYYYYTHH:MM 
36 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
48h 
DDMONYYYYTHH:MM 
48 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
60h 
DDMONYYYYTHH:MM 
60 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
72h 
DDMONYYYYTHH:MM 
72 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
96h 
DDMONYYYYTHH:MM 
96 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


Pacira Pharmaceuticals, Inc. 
 
404-C-201 (TKA) 
DEPOTXA 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
91 of 113 
 
 
 
29JAN2018 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Listing 16.2-11.1: All Adverse Events – All Subjects 
Treatment: TTTTTTT 
Site Subject 
TEAE Data Type 
Data 
XXX 
XXX-YYYY 
N 
Start 
DDMONYYYYTHH:MM 
 
 
 
Stop 
DDMONYYYYTHH:MM 
 
 
 
AE Number 
X 
 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
Severity 
XXXXXXXX 
 
 
 
Relationship to Study Drug XXXXXXXX 
 
 
 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
 
Serious 
XXX 
 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row.  Do not split an AE across pages.  Insert a 
page break between subjects.  This this template for the following listings: 
Listing 16.2-11.2.1: Treatment-Emergent Adverse Events – Randomized Subjects  
Listing 16.2-11.2.2: Treatment-Emergent Study Drug Related Adverse Events – Randomized Subjects  
Listing 16.2-11.3: All Serious Adverse Events – All Subjects  
Listing 16.2-11.3.CT: All Non-Serious Adverse Events – All Subjects  
Listing 16.2-11.4.1: Treatment-Emergent Serious Adverse Events – Randomized Subjects  
Listing 16.2-11.4.1.CT: Treatment-Emergent Non-Serious Adverse Events – Randomized Subjects  
Listing 16.2-11.4.2: Treatment-Emergent Study Drug Related Serious Adverse Events – Randomized Subjects 
 
 


Pacira Pharmaceuticals, Inc. 
 
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Listing 16.2-12.1: All Prior Medications – Randomized Subjects 
Treatment: TTTTTTT 
Site Subject 
Category 
Data Type 
Data 
XXX 
XXX-YYYY 
 
Start 
DDMONYYYYTHH:MM 
 
 
 
Stop 
DDMONYYYYTHH:MM 
 
 
 
Medication Number 
X 
 
 
 
ATC Level 1 
XXXXXXXXXXXXXXXXXX 
 
 
 
  ATC Level 2 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    ATC Level 3 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
      ATC Level 4 
      XXXXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred Name 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
Route 
XXXXXXXX 
 
 
 
Frequency 
XXXXXXXX 
 
 
 
Given for AE or MH? 
XXXXXXXXXXXXXXXXXXXXX AE # XX (or MH # XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC=Anatomical therapeutic class 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If medication is ongoing, put ONGOING in stop row.  Do not split an medication across 
pages.  Insert a page break between subjects.  Values for category column are: CONCOMITANT; 
SURGICAL/ANESTHESIA; NON-MEDICATION; PRIOR.  Use this template for the following listings: 
Listing 16.2-12.2: Concomitant Medications – Randomized Subjects  
 
 
 
 
 
 


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Listing 16.2-13: Medical/Surgical History – Randomized Subjects 
Treatment: TTTTTTT 
 
 
Date 
 
 
 
Site Subject 
Start  
Stop 
Number Classification 
Term 
XXX 
XXX-YYYY 
DDMONYYYY 
DDMONYYYY 
X 
System Organ Class: 
 
 
 
 
 
 
Preferred Term: 
 
 
 
 
 
 
Verbatim: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If ongoing put ONGOING in stop date column. 
 
 


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Listing 16.2-14: Informed Consent – All Subjects 
Treatment: TTTTTTT 
 
 
 
Date 
 
Met Criteria 
Site 
Subject 
Subject  
Initials 
Screening 
Visit 
Signed 
Consent 
Protocol 
Version 
Inclusion 
Exclusion 
XXX 
XXX-YYYY 
ABC 
DDMONYYYY 
DDMONYYYY 
AMENDMENT 2 
YES 
YES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Listing 16.2-15.1: Subject Eligibility – All Subjects  
Treatment: TTTTTTTTTTTTTT 
 
 
Date of 
 
Site 
Subject 
Informed 
Consent 
Eligibility 
Assessment 
Criteria Failed 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
Inclusion: 1, 4  
Exclusion: 8, 10, 12 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If subject was not randomized treatment should be ‘NOT RANDOMIZED’.  Criteria Failed 
may take any or all of the following values: Inclusion 1, 2, 3, 4 or 5 and Exclusion 1 through 12.  Insert 
a page break after each treatment group. 
 
 
 


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404-C-201 (TKA) 
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Listing 16.2-15.2: Subject Eligibility – Inclusion/Exclusion Criteria  
Inclusion/Exclusion Criteria 
Inclusion 1 
Male or female, ≥18 years of age at screening. 
Inclusion 2 
Scheduled to undergo elective unilateral open TKA under general, spinal, or regional 
anesthesia. 
Inclusion 3 
American Society of Anesthesiology (ASA) physical status 1, 2, or 3.  
Inclusion 4 
Female patient must be surgically sterile; or at least 2 years postmenopausal; or have a 
monogamous partner who is surgically sterile; or practicing double-barrier contraception; or 
practicing abstinence (must agree to use double-barrier contraception in the event of sexual 
activity); or using an insertable, injectable, or transdermal, contraceptive approved by the 
FDA for greater than 2 months prior to screening.  All women of childbearing potential (ie, 
premenopausal without permanent sterilization) must commit to the use of an acceptable form 
of birth control for the duration of the study and for 30 days after completion of the study.  
Inclusion 5 
Able to provide informed consent, adhere to the study visit schedule, and complete all study 
assessments.  
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name  
 
 


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Protocol: 404-C-201 
Listing 16.2-15.2: Subject Eligibility – Inclusion/Exclusion Criteria  
Inclusion/Exclusion Criteria 
Exclusion 1 
Currently pregnant, nursing, or planning to become pregnant during the study or within 30 
days after study drug administration.  
Exclusion 2 
Planned concurrent surgical procedure (eg, bilateral TKA).  
Exclusion 3 
Prior open knee surgery on ipsilateral knee.  Prior arthroscopy is permitted. 
Exclusion 4 
Patients taking a medication with a known procoagulant effect (eg, combination hormonal 
contraceptives, Factor IX complex concentrates or anti-inhibitor coagulant concentrates, or 
all-trans retinoic acid). 
Exclusion 5 
Contraindication or hypersensitivity to TXA. 
Exclusion 6 
History of thrombosis or prior VTE. 
Exclusion 7 
Known coagulopathy or active intravascular clotting. 
Exclusion 8 
Prior myocardial infarction. 
Exclusion 9 
Prior cardiovascular accident (stroke) or subarachnoid hemorrhage. 
Exclusion 10 
History of epilepsy. 
Exclusion 11 
Presence of an intravascular stent. 
Exclusion 12 
History of impaired kidney function, chronic respiratory disease, rheumatoid arthritis, 
coagulopathy, or loss of sensation in extremities. 
Exclusion 13 
Renal insufficiency as indicated by serum creatinine >upper limit of normal (by central 
laboratory assessment). 
Exclusion 14 
Anemia (Hb level <10 g/dL). 
Exclusion 15 
Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study 
assessments. 
Exclusion 16 
Acquired defective color vision. 
Exclusion 17 
Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous 
cell carcinoma of the skin or localized carcinoma in situ of the cervix. 
Exclusion 18 
Suspected or known history of drug or alcohol abuse within the previous year. 
Exclusion 19 
Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2. 
Exclusion 20 
Administration of an investigational drug within 30 days or 5 elimination half-lives of such 
investigational drug, whichever is longer, prior to study drug administration, or planned 
administration of another investigational product or procedure during the patient's 
participation in this study. 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 
 


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404-C-201 (TKA) 
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Listing 16.2-16: Pregnancy Test – All Subjects 
Treatment: TTTTTTTTTT 
 
 
Site 
Subject 
Visit 
Date 
Sex 
Childbearing Potential Pregnancy Test Result 
XXX 
XXX-YYYY 
Screening 
DDMONYYYY 
Female 
YES 
NEGATIVE 
 
 
D1 Preop 
DDMONYYYY 
 
 
NEGATIVE 
 
 
 
 
 
 
 
 
XXX-YYYY 
Screening 
DDMONYYYY 
Female 
NO 
NOT APPLICABLE 
 
 
D1 Preop 
DDMONYYYY 
 
 
NOT APPLICABLE 
 
 
 
 
 
 
 
 
XXX-YYYY 
Screening 
DDMONYYYY 
Male 
 
NOT APPLICABLE 
 
 
D1 Preop 
DDMONYYYY 
 
 
NOT APPLICABLE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer:  Possible results for screening tests are: POSITIVE, NEGATIVE, NOT DONE, or NOT 
APPLICABLE (if Childbearing Potential = ‘NO’ or Sex = ‘Male’). 
 
 


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Listing 16.2-17: Protocol Deviations – All Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Start Date and 
Time 
Protocol Deviation 
Coded Term 
Description 
Action Taken 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 


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Listing 16.2-18.1: Pharmacokinetic Concentrations – All Subjects 
Treatment: DepoTXA 400 (Enrolled After Protocol Amendment 2) 
 
 
Date and Time of 
Time From Dose 
 
Site Subject 
Dose 
Infusion 
Date 
Start 
Time 
End 
Time 
PK Sample 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
Concentration 
(ng/mL) 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
DDMONYYYYTHH:MM 
0 
XX 
 
X 
 
BLOQ 
 
 
 
 
 
DDMONYYYYTHH:MM 
0.08 
0.XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
0.25 
0.XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
0.50 
X 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
1 
ND 
 
 
 
 
 
 
 
 
DDMONYYYYTHH:MM 
2 
X 
 
-X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
6 
X 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
8 
XX 
 
-X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
12 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
16 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
24 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
36 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
48 
XX 
 
-X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
60 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
 
 
 
 
 
BLOQ=below limit of quantitation 
 
ND=Not Done 
Note: Actual time (hr) is calculated from Infusion End Time. 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: Insert a page break after each subject.  If a sample was not collected – put ND in 
actual column under time from dose.  Sort listing within subject by sample date and time. 
Sort by Treatment, Enrolled Prior to Protocol Amendment 2, then Enrolled After Protocol Amendment 2, 
Subject, PK date/time 


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Listing 16.2-18.2: Pharmacokinetic Parameters – All Subjects 
Treatment: DepoTXA 400 (Enrolled Prior to Protocol Amendment 2) 
 
 
 
 
Early 
 
Late 
 
 
Site Subject 
AUC(0-inf) 
(ng*hr/mL) 
AUC(0-last)  
(ng*hr/mL) 
Cmax 
ng/mL 
Tmax 
(hr) 
 
Cmax 
ng/mL 
Tmax 
(hr) 
Half-life 
(hr) 
Lamba_z 
(hr) 
XXX 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
XXX-YYYY  
NC 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
NC 
 
NC 
 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
 
 
 
 
 
 
 
 
 
 
YYY 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
XXX-YYYY  
XXXX.XX  
XXXX.XX 
 XXX.X 
 XX.X 
 
 XX.X 
 XX.X 
 
X.XXX  
X.XXX 
 
 
 
 
 
 
 
 
 
 
 
NC=Not Calculated 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: If a parameter was not calculated – put NC in column. 
Sort by Treatment, Enrolled Prior to Protocol Amendment 2, then Enrolled After Protocol Amendment 2, 
Subject 
 
 


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Listing 16.2-19: Unique Adverse Events Terms and Associated Coded Terms 
MedDRA Terms 
SOC 
  Preferred Term 
Verbatim(s) 
SOC1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
  PT1.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
  PT1.2 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
   
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
SOC2 
 
  PT2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
Coded using MedDRA version 19.1 or higher. 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by SOC and preferred term in alphabetical order 
 
 


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Listing 16.2-20: Unique Medication Terms and Associated Coded Terms 
Who Drug Dictionary Terms 
ACT1 
  ACT2 
    ACT3 
      ACT4 
        Preferred name 
Verbatim(s) 
ATC1 
 
  ATC1.2 
 
        PN1.2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
        PN1.2.2 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
ATC2 
 
  ATC2.2 
 
    ATC2.3 
 
      ATC2.4 
 
        PN2.2.3.4.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
Coded using World Health Organization Drug Dictionary Enhanced (WHO-DD) September 2016 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by ATC1, ATC2, ATC3, ATC4 and preferred name in alphabetical order  
 


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15. 
TABLE OF CONTENTS FOR FIGURES 
 
Figure 14.2-9.1: Plot of Total Blood Loss over Time by Treatment (Method 1 HcT) – Efficacy Analysis Set 105 
Figure 14.2-9.2: Plot of Total Blood Loss over Time by Treatment (Method 2 Hb) – Efficacy Analysis Set 
106 
Figure 14.2-9.3: Plot of Total Blood Loss over Time by Treatment (Both Methods) – Efficacy Analysis Set 107 
Figure 14.4-3.1: Plot of Mean (± SE) TXA Concentration (ng/mL) over Time by Treatment – PK Analysis Set 108 
Figure 14.4-3.2: Plot of ln Mean (± SE) TXA Concentration (ng/mL) over Time by Treatment – PK Analysis Set109 
Figure 14.4-3.3: Plot of Individual Subject TXA Concentrations (ng/mL) over Time – PK Analysis Set 
110 
Figure 14.4-3.4: Plot of Mean TXA 24h AUC vs 24h Blood Loss by Method – PK Analysis Set 
113 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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404-C-201 (TKA) 
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Protocol: 404-C-201 
Figure 14.2-9.1: Plot of Total Blood Loss over Time by Treatment (Method 1 Hct) – Efficacy Analysis Set 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
0
100
200
300
400
500
600
700
800
900
1000
0
24
48
72
96
120
Treatment Group
DepoTXA 400
DepoTXA 800
DepoTXA 1200
IV TXA


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Note to programmer: Margins on the y-axis should be adjusted, but consistent for figures 14.2-9.1, 14.2-
9.2, and 14.2-9.3.  Use template Figure 14.2-9.1 for the following Figure:  
 
Figure 14.2-9.2: Plot of Total Blood Loss over Time by Treatment (Method 2 Hb) – Efficacy Analysis Set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
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Figure 14.2-9.3: Plot of Total Blood Loss over Time by Treatment (Both Methods) – Efficacy Analysis Set 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
0
100
200
300
400
500
600
700
800
900
1000
0
24
48
72
96
120
Treatment Group
DepoTXA 400 (Method 1)
DepoTXA 800 (Method 1)
DepoTXA 1200 (Method 1)
IV TXA (Method 1)
DepoTXA 400 (Method 2)
DepoTXA 800 (Method 2)
DepoTXA 1200 (Method 2)
IV TXA (Method 2)


Pacira Pharmaceuticals, Inc. 
404-C-201 (TKA) 
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Protocol: 404-C-201 
Figure 14.4-3.1: Plot of Mean (± SE) TXA Concentration (ng/mL) over Time by Treatment – PK Analysis Set 
  
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 


Pacira Pharmaceuticals, Inc. 
404-C-201 (TKA) 
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Figure 14.4-3.2: Plot of ln Mean (± SE) TXA Concentration (ng/mL) over Time by Treatment (for Subjects 
Enrolled After Protocol Amendment 2) – PK Analysis Set 
  
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  


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SAS X.Y 
 
program_name 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 404-C-201 
Figure 14.4-3.3: Plot of Individual Subject TXA Concentrations (ng/mL) over Time – PK Analysis Set 


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Pacira Pharmaceuticals, Inc. 
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Note to programmer: Margins on the y-axis should be adjusted, but consistent for figures 14.4-3.1, 14.4-
3.2, and 14.4-3.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
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Protocol: 404-C-201 
Figure 14.4-3.4: Plot of Mean TXA 24h AUC vs 24h Blood Loss by Method – PK Analysis Set 
  
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
Note to programmer: Set margins on the x-axis and y-axis as appropriate. 
 
400
500
600
700
800
900
5000
10000
15000
20000
25000
30000
Blood Loss Calculation Method
1
2