Effect of Tergase Injection on Reducing Edema After Bilateral Total Knee Arthroplasty (ALT-TKA)

A Randomized, Split Body, Evaluator-blinded, Trial on the Effect of Tergase Injection (Berahyaluronidase Alfa) on Reducing Edema After Both Total Knee Arthroplasty

This clinical trial is conducted to compare and evaluate the efficacy and safety of Tergase injection (4,500 IU) in reducing postoperative edema between treated and untreated knees in patients undergoing bilateral total knee arthroplasty (TKA).

Prior to participation, all subjects receive a full explanation of the study and provide voluntary written informed consent. Only subjects who meet the inclusion and exclusion criteria through screening procedures are enrolled. Enrolled subjects are randomly assigned to the experimental and control groups in a 1:1 ratio per knee, utilizing a split-body clinical trial design that compares both knees of the same subject.

The analysis target is 60 knees obtained from a total of 30 subjects. According to the randomization results, the knee assigned to the experimental group receives a subcutaneous injection of 3 vials (4,500 IU) of Tergase, while the contralateral knee serves as the untreated control group.

By including both the experimental and control groups within the same subject, inter-individual variation is minimized. While the investigator performing the injection is aware of the assignment, the subject remains blinded.

To overcome the physical impossibility of blinding the injector due to the route of administration and drug characteristics, an 'Evaluator-Blinded' design is adopted to maintain objectivity equivalent to a double-blind study. To achieve this, the unblinded injector and the blinded evaluator who measures efficacy outcomes are strictly separated, and operational blinding is maintained by blocking information exchange between the two groups.

Subjects are evaluated for efficacy and safety during hospitalization or outpatient visits at Day 1, 2, 3, 5, Week 2, Week 6, and Month 3 after bilateral TKA. Participation ends upon completion of the planned visits.

Study Overview

• Status: Not yet recruiting
• Conditions: Osteoarthritis, Knee; Postoperative Edema; Bilateral Total Knee Arthroplasty
• Intervention / Treatment: Drug: Berahyaluronidase alfa

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult males and females aged 60 years or older and 85 years or younger.
2. Patients scheduled for bilateral total knee arthroplasty due to degenerative knee osteoarthritis with a Kellgren-Lawrence grade of III or IV confirmed by imaging within the last 4 weeks.
3. Patients experiencing knee joint pain of 5 or higher on a 10-point Visual Analogue Scale (VAS) during daily activities, such as walking on flat ground.
4. Patients with the willingness and ability to follow the physician's instructions, including joint exercises.
5. Patients classified as American Society of Anesthesiologists (ASA) Physical Status Class I or II.
6. Patients who have received a full explanation of the clinical trial and have voluntarily provided written informed consent to participate.

Exclusion Criteria:

1. Participants or their family members with ongoing or a history of autoimmune diseases.
2. Patients with secondary osteoarthritis of the knee.
3. Patients with inflammatory arthritis (such as rheumatoid arthritis, lupus arthropathy, psoriatic arthritis) or crystal-induced arthropathy.
4. Patients with a serum protein level of 5.5 g/dL or less.

5. Patients with clinical laboratory results that are contraindications for total knee arthroplasty:

   1. WBC <3,000/μL or >12,000/μL
   2. CRP >10 mg/L
   3. Hb <10 g/dL
   4. Platelet count <100,000/μL
   5. INR >1.5
   6. eGFR <30 mL/min/1.73 m²
   7. AST or ALT >3 times the upper limit of normal
   8. Fasting blood glucose >200 mg/dL
6. Patients with a history of drug abuse or dependence.
7. Presence of local infection or sepsis in the affected lower limb, or a history of neurological abnormalities within the past 6 months.
8. History of major joint surgery within 90 days.
9. Patients who received systemic steroid treatment within 3 months prior to surgery.
10. Patients who sustained a serious injury or received an injection in the target knee that may interfere with evaluation within 3 months prior to the screening visit.
11. Patients with infections requiring hospitalization and administration of antibiotics or antimicrobics.

12. Patients with any clinically significant medical condition that may interfere with study completion or outcome assessment, including but not limited to:

    1. Congenital heart disease, clinically significant cardiovascular disease, renal dysfunction, or uncontrolled diabetes.
    2. Neuromuscular disorders affecting the lower limbs.
    3. Severe bleeding or coagulation disorders.
    4. Severe knee instability that cannot be corrected with cruciate-retaining total knee arthroplasty.
    5. Severe knee deformity, defined as flexion contracture ≥30 degrees or varus/valgus deformity ≥30 degrees.
    6. Opioid dependence, defined as consumption of ≥100 mg morphine-equivalent opioids per week for more than 3 months before surgery.
    7. Inability to assess pain using the Visual Analogue Scale, including cognitive or language impairment.
    8. Venous congestion of the lower extremity.
    9. Morbid obesity, defined as body mass index >40 kg/m².
13. History of shock or hypersensitivity to Tergase inj. or its components.
14. Patients deemed unsuitable for this study by the investigator, such as those with psychiatric disorders.
15. Patients currently participating in another clinical trial.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tergase Injection Knee; One knee of the subject, randomly assigned to receive a subcutaneous injection of 4,500 IU (3 vials) of Tergase (Berahyaluronidase alfa) at 8 points immediately after total knee arthroplasty (TKA).	Drug: Berahyaluronidase alfa; A total dose of 4,500 IU (3.0 mL; 3 vials) of berahyaluronidase alfa is administered subcutaneously around the suture line of the randomly assigned knee immediately after total knee arthroplasty. The dose is divided into 8 injection points, approximately 0.375 mL per point.; Other Names: Recombinant human hyaluronidase; Tergase Inj.
No Intervention: Untreated Control Knee; The contralateral knee of the same subject which does not receive any injection, serving as a self-control for efficacy and safety comparisons.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Composite Edema Index Based on Leg Circumference Measurements	The Composite Edema Index is calculated as the arithmetic mean of the percent change from preoperative baseline in leg circumference measured at four prespecified anatomical locations: calf at the thickest part, suprapatellar area just above the patella, infrapatellar area just below the patella, and thigh 10 cm above the patella. A higher percentage indicates greater postoperative edema.	Baseline, Postoperative Day 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Mean Leg Circumference Swelling Rate	Mean leg circumference swelling rate is calculated as the arithmetic mean of the percent change from preoperative baseline in leg circumference measured at the same four prespecified anatomical locations. A higher percentage indicates greater postoperative swelling.	Baseline, Postoperative Day 1, Day 3, Day 5, Week 2, Week 6, and Month 3
Change From Baseline in Mean Pain Intensity Score on a 0-to-10 Visual Analog Scale	Pain intensity is assessed using a 0-to-10 visual analog scale, where 0 indicates no pain and 10 indicates the worst imaginable pain. The mean pain intensity score is calculated as the arithmetic mean of pain scores assessed at rest, during 60-degree knee flexion, and during walking. A higher score indicates greater pain intensity.	Baseline, Postoperative Day 1, Day 2, Day 3, Day 5, Week 2, Week 6, and Month 3
Change From Baseline in Active Knee Flexion Range of Motion Measured With a Goniometer	Active knee flexion range of motion is measured in degrees using a goniometer. A higher value indicates greater knee flexion range of motion.	Baseline, Postoperative Day 1, Day 2, Day 3, Day 5, Week 2, Week 6, and Month 3
Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index Total Score	The Western Ontario and McMaster Universities Osteoarthritis Index is a self-reported questionnaire consisting of 24 items across three domains: pain, stiffness, and physical function. The total score ranges from 0 to 96, with higher scores indicating greater pain, stiffness, and functional impairment.	Baseline, Week 6, and Month 3
CT-Measured Mean Lower Extremity Soft Tissue Thickness at Postoperative Day 2	Lower extremity CT scans are used to measure soft tissue thickness at prespecified anatomical locations corresponding to the circumference measurement sites. The value is reported in millimeters as the mean thickness across the prespecified locations. A higher value indicates greater soft tissue thickness.	Postoperative Day 2
Change From Baseline in Serum C-Reactive Protein Concentration	Serum C-reactive protein concentration is measured using fasting blood samples to evaluate the systemic inflammatory response after surgery. Values are reported in mg/L. A higher value indicates a greater inflammatory response.	Baseline, Postoperative Day 1, Week 2, and Month 3
Change From Baseline in Serum Amyloid A Concentration	Serum amyloid A concentration is measured using fasting blood samples to evaluate the systemic inflammatory response after surgery. Values are reported in mg/L. A higher value indicates a greater inflammatory response.	Baseline, Postoperative Day 1, Week 2, and Month 3
Number of Participants With at Least One Predefined Postoperative Complication	Predefined postoperative complications include nausea, vomiting, falls, subcutaneous hemorrhage, vascular injury, wound complications, and venous thromboembolism. Participants are counted once if they experience one or more predefined postoperative complications during the assessment period.	From immediately after surgery through postoperative Month 3
Number of Participants With at Least One Adverse Event	Adverse events and serious adverse events occurring after investigational product administration are collected during the study period. Participants are counted once if they experience one or more adverse events, excluding predefined postoperative complications captured separately.	From investigational product administration through postoperative Month 3
Number of Participants With Clinically Significant Abnormal Vital Sign Findings	Clinically significant abnormal vital sign findings are defined as any investigator-assessed clinically significant abnormality in blood pressure, pulse rate, or body temperature during the study period. Participants are counted once if they experience one or more clinically significant abnormal vital sign findings.	From Screening Visit through postoperative Month 3
Number of Participants With Clinically Significant Abnormal Physical Examination Findings	Clinically significant abnormal physical examination findings are defined as any new or worsened abnormal finding identified by the investigator during the study period. Participants are counted once if they experience one or more clinically significant abnormal physical examination findings.	From Screening Visit through postoperative Month 3
Number of Participants With Clinically Significant Abnormal Clinical Laboratory Test Results	Clinically significant abnormal clinical laboratory test results are defined as any investigator-assessed clinically significant abnormality in hematology, blood chemistry, coagulation, or urinalysis results during the study period. Participants are counted once if they experience one or more clinically significant abnormal clinical laboratory test results.	From Screening Visit through postoperative Month 3

Collaborators and Investigators

• Sponsor: Man Soo Kim

Publications and helpful links

General Publications

• Wang Q, Jin Q, Cai L, Zhao C, Feng P, Jia J, Xu W, Qian Q, Ding Z, Xu J, Gu C, Zhang S, Shi H, Ma H, Deng Y, Zhang T, Song Y, Wang Q, Zhang Y, Zhou X, Pei L, Yang Y, Liang J, Jiang T, Li H, Liu H, Wu L, Kang P. Efficacy of Diosmin in Reducing Lower-Extremity Swelling and Pain After Total Knee Arthroplasty: A Randomized, Controlled Multicenter Trial. J Bone Joint Surg Am. 2024 Mar 20;106(6):492-500. doi: 10.2106/JBJS.23.00854. Epub 2023 Dec 18.
• Kwon H, Park HS, Shim JY, Lee KW, Choi SJ, Choi GY. Randomized, Double-Blind, Placebo-Controlled Trial on the Efficacy of Hyaluronidase in Preventing Perineal Trauma in Nulliparous Women. Yonsei Med J. 2020 Jan;61(1):79-84. doi: 10.3349/ymj.2020.61.1.79.
• Alam M, Hughart R, Geisler A, Paghdal K, Maisel A, Weil A, West DP, Veledar E, Poon E. Effectiveness of Low Doses of Hyaluronidase to Remove Hyaluronic Acid Filler Nodules: A Randomized Clinical Trial. JAMA Dermatol. 2018 Jul 1;154(7):765-772. doi: 10.1001/jamadermatol.2018.0515.
• Kwoen MJ, Choi YH, Kim KS, Chang NH, Kim YK, Lee HJ. Efficacy of local hyaluronidase administration in guided bone regeneration surgery: a randomized controlled trial. J Korean Assoc Oral Maxillofac Surg. 2021 Apr 30;47(2):91-98. doi: 10.5125/jkaoms.2021.47.2.91.
• Koc O, Er N, Karaca C, Bilginaylar K. Comparison of the effects of submucosal hyaluronidase and dexamethasone on postoperative edema, pain, trismus, and infection following impacted third molar surgery. BMC Oral Health. 2024 Aug 30;24(1):1018. doi: 10.1186/s12903-024-04729-1.

Helpful Links

• Clinical Research Information Service (CRIS) registration record

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): March 31, 2028

Study Registration Dates

• First Submitted: May 14, 2026
• First Submitted That Met QC Criteria: July 12, 2026
• First Posted (Actual): July 15, 2026

Study Record Updates

• Last Update Posted (Actual): July 15, 2026
• Last Update Submitted That Met QC Criteria: July 12, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Total Knee Arthroplasty; Recombinant human hyaluronidase; Postoperative Edema; Tergase; Berahyaluronidase alfa; Split-body trial
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: XC26MIDI0010; KCT0011945 (Registry Identifier: Clinical Research Information Service (CRIS))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No