Clinical Trial Results:
Efficacy of topical tranexamic acid versus intravenous administration to reduce blood transfusion rate in total knee arthroplasty surgery: phase III, unicentric, controlled, double-blind, randomized non-inferiority clinical trial.
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Summary
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EudraCT number |
2011-003218-17 |
Trial protocol |
ES |
Global end of trial date |
28 Oct 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Jan 2022
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First version publication date |
11 Jan 2022
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Other versions |
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Summary report(s) |
JBJ article |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TRANEX1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01881568 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Hospital Universitario La Paz-Cantoblanco
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Sponsor organisation address |
Pso. de la Castellana 261, Madrid, Spain, 28046
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Public contact |
PharmD. MPH Norma G. Padilla Eguiluz, Universidad Autónoma de Madrid-Hospital Universitario La Paz-IdiPAZ, 34 654807102, norma.padilla@uam.es
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Scientific contact |
Prof. Enrique Gómez Barrena, Department of Orthopaedic Surgery and Traumatology,
Hospital Universitario La Paz, 34 917277085, egomezb@salud.madrid.org
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Oct 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Oct 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the efficacy and safety of topical intra-articular application of 3 g of TXA compared with IV administration of two 15-mg/kg doses during primary unilateral total knee replacement with cemented implants.
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Protection of trial subjects |
Patients with preoperative anaemia (haemoglobin, <13 g/dL) were not excluded; instead, they were offered the current standard preoperative protocol at our institution (IV administration of iron and/or subcutaneous administration of 40,000 IU of erythropoietin), and surgery was postponed until the haemoglobin level was ‡13 g/dL. All patients were instructed to discontinue aspirin, anti-platelet agents, and nonselective cyclooxygenase inhibitors at least seven days prior to surgery. T
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Background therapy |
- | ||
Evidence for comparator |
The use of tranexamic acid (TXA) in primary total knee replacement with cemented implants is supported by studies with a level of evidence of I that confirm its efficacy for decreasing blood loss(1-4), although safety concerns have not been confirmed in studies comparing TXA treatment against placebo, which showed equivalent safety(3,5-8). Although blood loss prevention protocols have been adopted at many institutions, there are concerns regarding intravenous (IV) administration of TXA in some settings, and topical administration may be considered an appealing alternative that is potentially less risky than systemic administration. 1. Tan J et al. A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. J Surg Res. 2013 Oct;184(2):880-7. 2. Kim TK et al. Practical issues for the use of tranexamic acid in total knee arthroplasty: a systematic review. Knee Surg Sports Traumatol Arthrosc. 2013 Mar 31. 3. Gandhi R et al. Tranexamic acid and the reduction of blood loss in total knee and hip arthroplasty: a meta-analysis. BMC Res Notes. 2013;6(1):184. 4. Yang ZG et al. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: a meta-analysis. J Bone Joint Surg Am. 2012 Jul 3;94(13):1153-9. 5. Alshryda S et al. Tranexamic acid in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br. 2011 Dec;93(12):1577-85. 6. Dunn CJ et al. Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999 Jun;57(6):1005-32. 7. Engel JM et al. Regional hemostatic status and blood requirements after total knee arthroplasty with and without tranexamic acid or aprotinin. Anesth Analg. 2001 Mar;92(3):775-80. 8. Gillette BP et al. Low risk of thromboembolic complications with tranexamic acid after primary total hip and knee arthroplasty. Clin Orthop Relat Res. 2013 Jan;471(1):150-4. | ||
Actual start date of recruitment |
08 Jan 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 78
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Worldwide total number of subjects |
78
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EEA total number of subjects |
78
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
19
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From 65 to 84 years |
58
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85 years and over |
1
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Recruitment
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Recruitment details |
All adult patients scheduled to undergo primary unilateral total knee replacement with cemented implants in Cantoblanco University Hospital of Madrid, Spain, from January to October 2013 were eligible for inclusion. | |||||||||
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Pre-assignment
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Screening details |
Of the 93 candidate patients screened, 15 were excluded, and 78 were randomized in the control (n=39) or experimental (n=39) arm. None lost during follow up were observed in any arm of treatment. | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator | |||||||||
Blinding implementation details |
Patient assignments were prepared by a research statistician and were placed into sequentially numbered opaque sealed envelopes, only opened before each surgery. Uninvolved anesthesiologists prepared study medication and placebo (both identical in appearance) under the supervision of a research pharmacist not involved in patient care. Patients, surgeons, and health care participating in treatment and evaluation were blinded to the group allocation.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Control | |||||||||
Arm description |
Patients in the control group received a slow IV infusion of 100 mL of physiological saline solution containing a 15 mg/kg dose of TXA fifteen to twenty minutes before tourniquet release and a second identical dose three hours after surgery, on the basis of previous efficacy studies. In addition, patients in this group received a topical intra-articular placebo (100 mL of physiological saline solution). | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Tranexamic Acid
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Investigational medicinal product code |
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Other name |
Amchafibrin
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
slow IV infusion of 100 mL of physiological saline solution containing a 15 mg/kg dose of TXA fifteen to twenty minutes before tourniquet release and a second identical dose three hours after surgery
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Arm title
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Experimental | |||||||||
Arm description |
The experimental group received a topical intra-articular dose of 3 g of TXA (Amchafibrin; Rottapharm) in 100 mL of physiological saline solution (0.9% sodium chloride solution; Grifols). Half of the volume was administered by irrigation to achieve tissue impregnation before joint closure, and the other half was administered intra-articularly after skin closure (through a 12-mm drain tube with the knee in a fully extended position after stapling and before tourniquet release). In addition, patients in this group received 100 mL of an IV placebo solution (physiological saline solution) fifteen to twenty minutes before tourniquet release and 100 mL three hours later. P | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Tranexamic Acid
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Investigational medicinal product code |
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Other name |
Amchafibrin
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intraarticular use, Topical
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Dosage and administration details |
3 g of TXA (Amchafibrin; Rottapharm) in 100 mL of physiological saline solution (0.9% sodium chloride solution; Grifols). Half of the volume was administered by irrigation to achieve tissue impregnation before joint closure, and the other half was administered intra-articularly after skin closure (through a 12-mm drain tube with the knee in a fully extended position after stapling and before tourniquet release)
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Baseline characteristics reporting groups
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Reporting group title |
Control
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Reporting group description |
Patients in the control group received a slow IV infusion of 100 mL of physiological saline solution containing a 15 mg/kg dose of TXA fifteen to twenty minutes before tourniquet release and a second identical dose three hours after surgery, on the basis of previous efficacy studies. In addition, patients in this group received a topical intra-articular placebo (100 mL of physiological saline solution). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Experimental
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Reporting group description |
The experimental group received a topical intra-articular dose of 3 g of TXA (Amchafibrin; Rottapharm) in 100 mL of physiological saline solution (0.9% sodium chloride solution; Grifols). Half of the volume was administered by irrigation to achieve tissue impregnation before joint closure, and the other half was administered intra-articularly after skin closure (through a 12-mm drain tube with the knee in a fully extended position after stapling and before tourniquet release). In addition, patients in this group received 100 mL of an IV placebo solution (physiological saline solution) fifteen to twenty minutes before tourniquet release and 100 mL three hours later. P | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Control
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Reporting group description |
Patients in the control group received a slow IV infusion of 100 mL of physiological saline solution containing a 15 mg/kg dose of TXA fifteen to twenty minutes before tourniquet release and a second identical dose three hours after surgery, on the basis of previous efficacy studies. In addition, patients in this group received a topical intra-articular placebo (100 mL of physiological saline solution). | ||
Reporting group title |
Experimental
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Reporting group description |
The experimental group received a topical intra-articular dose of 3 g of TXA (Amchafibrin; Rottapharm) in 100 mL of physiological saline solution (0.9% sodium chloride solution; Grifols). Half of the volume was administered by irrigation to achieve tissue impregnation before joint closure, and the other half was administered intra-articularly after skin closure (through a 12-mm drain tube with the knee in a fully extended position after stapling and before tourniquet release). In addition, patients in this group received 100 mL of an IV placebo solution (physiological saline solution) fifteen to twenty minutes before tourniquet release and 100 mL three hours later. P | ||
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End point title |
Transfusion rate | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
48h post surgery
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Statistical analysis title |
Non-inferiority | |||||||||
Comparison groups |
Control v Experimental
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
P-value |
> 0.05 [1] | |||||||||
Method |
Wilson | |||||||||
Parameter type |
proportion | |||||||||
Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.9 | |||||||||
upper limit |
0.9 | |||||||||
Variability estimate |
Standard deviation
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| Notes [1] - No transfusion was performed in either group, confirming noninferiority for the primary efficacy endpoint (transfusion rate) and suggesting equivalence (95% CI according to the Wilson test, 29% to 9%). |
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End point title |
Total blood loss | ||||||||||||
End point description |
The estimated total blood loss was calculated using the Nadler formula
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End point type |
Secondary
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End point timeframe |
48h post-operative
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Statistical analysis title |
Non-inferiority | ||||||||||||
Comparison groups |
Control v Experimental
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.205 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
During hospital stay and post-operative
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
0
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Reporting groups
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Reporting group title |
Experimental
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| As no transfusion was needed in either group, the analysis was likely underpowered for confirming the superiority of either treatment with respect to blood loss, and larger studies may be warranted. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25471907 |
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