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

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

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

Study Overview

• Status: Terminated
• Conditions: Total Knee Arthroplasty
• Intervention / Treatment: Drug: Tranexamic Acid; Drug: DepoTXA

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 Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85296
      • Ortho Arizona
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Hospital
    • Miami, Florida, United States, 33175
      • Kendall Regional Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University/Wexner Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DepoTXA 400mg; 400mg Intracapsular at the end of surgery one time	Drug: DepoTXA
Experimental: DepoTXA 800mg; 800mg Intracapsular at the end of surgery one time	Drug: DepoTXA
Experimental: DepoTXA 1200mg; 1200mg Intracapsular at the end of surgery one time	Drug: DepoTXA
Active Comparator: IV Tranexamic acid (TXA); 1 g of IV TXA at the end of surgery	Drug: Tranexamic Acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.
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 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.
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

Outcome Measure	Measure Description	Time Frame
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	Neurological assessment at 12, 24, 36, 48, 60, 72, and 96 hours after study drug administration	12, 24, 36, 48, 60, 72, and 96 hours after study drug administration
Incidence of Reoperation Due to Hematoma or Wound Dehiscence	Number of subjects who underwent reoperation due to hematoma or wound dehiscence	Through day 60
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	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	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	Leg difference in change from baseline is calculated by = (Operated Leg Change from Baseline) - (Non-Operated Leg Change from Baseline)	48 hours and Day 7
Area Under the Curve (AUC) of NRS From 0-24 Hours, 0-48 Hours, and 24-48 Hours	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.	Preoperative; arrival in Post-Anesthesia Care Unit (PACU); 2, 4, 6, 8, 12, 16, 24, 36, 48 hours, Day 7

Collaborators and Investigators

• Sponsor: Pacira Pharmaceuticals, Inc
• Investigators: Study Director: Hassan Danesi, MD, Pacira Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2016
• Primary Completion (Actual): November 27, 2017
• Study Completion (Actual): November 27, 2017

Study Registration Dates

• First Submitted: September 28, 2016
• First Submitted That Met QC Criteria: October 3, 2016
• First Posted (Estimate): October 4, 2016

Study Record Updates

• Last Update Posted (Actual): December 11, 2020
• Last Update Submitted That Met QC Criteria: December 10, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: 404-C-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided