Study of Local Administration of DepoTXA for Reduced Postsurgical Bleeding in Subjects Undergoing TKA

Phase 2

Terminated

• Conditions: Total Knee Arthroplasty
• Interventions: Drug: DepoTXA; Drug: Tranexamic Acid

• Registration Number: NCT02922582
• Lead Sponsor: Pacira Pharmaceuticals, Inc

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).

Study Timeline

• Study First Submitted: 2016-09-28
• Study First Submitted QC: 2016-10-03
• Study First Posted: 2016-10-04
• Study Start: 2016-10-28
• Primary Completion: 2017-11-27
• Study Completion: 2017-11-27
• Results First Submitted: 2020-09-18
• Status Verified: 2020-12
• Results First Submitted QC: 2020-12-10
• Last Update Submitted: 2020-12-10
• Results First Posted: 2020-12-11
• Last Update Posted: 2020-12-11

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 16

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. American Society of Anesthesiology (ASA) physical status 1, 2, or 3.
4. Female subject 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 and 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.
5. 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 1 month after study drug administration.
2. Planned concurrent surgical procedure (e.g., bilateral TKA).
3. Prior open knee surgery on ipsilateral knee. Prior arthroscopy is permitted.
4. Subjects taking a medication with a known procoagulant effect (e.g., combination hormonal contraceptives, Factor IX complex concentrates or anti-inhibitor coagulant concentrates, or all-trans retinoic acid).
5. Contraindication or hypersensitivity to TXA.
6. History of thrombosis or prior Venous thromboembolism (VTE).
7. Known coagulopathy or active intravascular clotting.
8. Prior myocardial infarction.
9. Prior cardiovascular accident (stroke) or subarachnoid hemorrhage.
10. History of epilepsy.
11. Presence of an intravascular stent.
12. History of impaired kidney function, chronic respiratory disease, rheumatoid arthritis, coagulopathy, or loss of sensation in extremities.
13. Renal insufficiency (serum creatinine level >2 mg/dL).
14. Anemia (Hb level <10 g/dL).
15. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments.
16. Acquired defective color vision.
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.
18. Suspected or known history of drug or alcohol abuse within the previous year.
19. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2.
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 subject's participation in this study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
DepoTXA 400mg	DepoTXA	400mg Intracapsular at the end of surgery one time
DepoTXA 800mg	DepoTXA	800mg Intracapsular at the end of surgery one time
DepoTXA 1200mg	DepoTXA	1200mg Intracapsular at the end of surgery one time
IV Tranexamic acid (TXA)	Tranexamic Acid	1 g of IV TXA at the end of surgery

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-versus-time Curve From Time 0 Extrapolated to Infinity After Drug Administration	Baseline; 5, 15, and 30 min; at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all treatment groups. Additional blood samples were collected at 36, 48, 60, 72, and 96 hours for DepoTXA-treated subjects.
Area Under the Plasma Concentration-versus-time Curve From Time 0 to the Last Collection Time After Drug Administration	Baseline; 5, 15, and 30 min; at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all treatment groups. Additional blood samples were collected at 36, 48, 60, 72, and 96 hours for DepoTXA-treated subjects.
The Apparent Terminal Elimination Rate Constant	Baseline; 5, 15, and 30 min; at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all treatment groups. Additional blood samples were collected at 36, 48, 60, 72, and 96 hours for DepoTXA-treated subjects.
Maximum Plasma Concentration (Cmax)	Baseline; 5, 15, and 30 min; at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all treatment groups. Additional blood samples were collected at 36, 48, 60, 72, and 96 hours for DepoTXA-treated subjects.
Time to Maximum Plasma Concentration (Tmax)	Baseline; 5, 15, and 30 min; at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all treatment groups. Additional blood samples were collected at 36, 48, 60, 72, and 96 hours for DepoTXA-treated subjects.
The Apparent Terminal Elimination Half-life	Baseline; 5, 15, and 30 min; at 1, 2, 4, 6, 8, 12, 16, and 24 hours after study drug administration for all treatment groups. Additional blood samples were collected at 36, 48, 60, 72, and 96 hours for DepoTXA-treated subjects.

Secondary Outcome Measures

Name	Time	Method
Incidence of Reoperation Due to Hematoma or Wound Dehiscence	Through day 60	Number of subjects who underwent reoperation due to hematoma or wound dehiscence
Summary of Neurological Assessments (Proportion of Subjects Who Were Oriented and Proportion of Subjects Who Had Any of the Neurologic Events) at Each Assessed Timepoint	12, 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
Incidence of Transfusion (Number of Units, Number of Units/Subject, Number of Subjects Transfused)	Day 60
Number of Participants With 90˚ Passive and Active Knee Flexion	24, 48, and 72 hours
Time to Complete Timed Up-and-Go (TUG) Test	Day 1; at approximately 8:00 am and 8:00 pm (±2 hours) daily from Day 2 through hospital discharge; and on Day 7	Physical therapy assessment (Timed Up-and-Go (TUG) test) was conducted once postsurgically on Day 1; at approximately 8:00 am and 8:00 pm (±2 hours) daily from Day 2 through hospital discharge; and on Day 7
Change in Knee and Thigh Measurements	48 hours and Day 7	Leg difference in change from baseline is calculated by = (Operated Leg Change from Baseline) - (Non-Operated Leg Change from Baseline)
Area Under the Curve (AUC) of NRS From 0-24 Hours, 0-48 Hours, and 24-48 Hours	Preoperative; arrival in Post-Anesthesia Care Unit (PACU); 2, 4, 6, 8, 12, 16, 24, 36, 48 hours, Day 7	Numerical rating scale (NRS) at rest pain score (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 48-hour assessment; and the Day-7 follow-up visit. Summary is provided as area under the curve (AUC) of NRS from timepoint 0 to 24 hours, 0 to 48 hours, and 24 to 48 hours.

Trial Locations

Locations (5)

Ortho Arizona; 🇺🇸 Gilbert, Arizona, United States

University of Miami Hospital; 🇺🇸 Miami, Florida, United States

Ohio State University/Wexner Medical Center; 🇺🇸 Columbus, Ohio, United States

Kendall Regional Medical Center; 🇺🇸 Miami, Florida, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States