Tranexamic Acid Use to Reduce Blood Transfusion in Pediatric Cancer Patients Undergoing Limb Salvage Procedure

Study Overview
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Brief Summary
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This is a randomized double-blind control trial evaluating the use Tranexamic acid (TXA) to decrease blood loss and transfusion requirements in pediatric and young adult cancer patients undergoing a limb salvage procedure that frequently requires perioperative or post-operative transfusions of blood products. Primary Objective To evaluate the difference in intra-or post-operatively transfused blood volume (mL/kg) for patients undergoing limb salvage procedures of the distal femur or proximal tibia who are randomized to receive perioperative tranexamic acid (TXA) versus placebo. Secondary Objectives To evaluate changes in platelets and in hemoglobin from pre-op to post-op level for patients randomized to receive perioperative TXA versus placebo. To evaluate differences in post-operative daily surgical drain output for patients randomized to receive perioperative TXA versus placebo. To evaluate changes in estimated blood loss (EBL) for patients randomized to receive perioperative TXA versus placebo. To evaluate the association between the intra-or post-operatively transfused blood volume and estimated blood loss (EBL) for patients randomized to receive perioperative TXA and placebo, respectively. Exploratory Objectives To evaluate differences in functional outcomes post-operatively for patients randomized to receive perioperative TXA versus placebo. To explore if significant correlations are observed between parameters reported with rotational thromboelastometry (ROTEM®) and EBL and transfusion requirements in pediatric and young adult patients undergoing limb salvage procedure who are randomized to perioperative TXA versus placebo. To evaluate differences in the prevalence and management of wound complications such as superficial or periprosthetic infections, wound dehiscence, contact dermatitis, post- operative hematomas, or any other clinically significant wound complication between patients randomized to receive perioperative TXA versus placebo.

Detailed Description
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Eligible participants undergoing limb salvage procedures will be randomized to receive either tranexamic acid (TXA) or placebo peri-operatively. The initial dose of tranexamic acid/placebo will be given at the initiation of surgical preparation. The second dose will be given 6 hours after the first dose (either intraoperatively or post-operatively). All doses will be given intravenously. Doses will be double blinded and randomized for each surgical procedure.

Official Title
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Tranexamic Acid (TXA) to Reduce Volume Of Blood Transfused In Pediatric And Young Adult Cancer Patients Undergoing Limb Salvage Procedure Of A Lower Extremity

Conditions
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Cancer of the Bone, Limb Salvage

Intervention / Treatment
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* Drug: Tranexamic Acid
* Other: 0.9% sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant undergoing limb salvage procedure of malignant bone tumor of the distal femur or proximal tibia, which typically requires blood transfusions. Patient under the age of 25 Adequate bone marrow function defined as: Upward trending peripheral absolute neutrophil count (ANC) Platelet count ≥ 100,000/mm^3 (transfusion independent defined as no platelets required for 4 days) Hemoglobin ≥ 8.0 g/dL No RBC transfusion within 24 hours Adequate renal function defined as: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73m^2 OR Maximum serum creatinine based on age/gender as follows: Age 1 day to < 1 years: maximum serum creatinine (mg/dL) 0.6 for males and 0.5 for females; Age 1 to < 2 years: maximum serum creatinine (mg/dL) 0.6 for males and 0.6 for females; Age 2 to < 6 years: maximum serum creatinine (mg/dL) 0.8 for males and 0.8 for females; Age 6 to < 10 years: maximum serum creatinine (mg/dL) 1.0 for males and 1.0 for females; Age 10 to < 13 years: maximum serum creatinine (mg/dL) 1.2 for males and 1.2 for females; Age 13 to < 16 years: maximum serum creatinine (mg/dL) 1.5 for males and 1.4 for females; Age ≥ 16 years: maximum serum creatinine (mg/dL) 1.7 for males and 1.4 for females Adequate liver function defined as: Total bilirubin ≤ 1.5x the institutional upper limit of normal (IULN) for age ALT (SGPT) and AST (SGOT) ≤ 2.5x IULN for age (or <5x IULN for patients with documented disease involving the liver or 10x IULN for patients receiving HDMTX) Serum albumin > 2 g/dL Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5 Female participants of child-bearing potential (>10 years old) must have a negative serum or urine pregnancy test within 72 hours of sedation Exclusion Criteria: Participants whose limb salvage procedure may require significant manipulation of major blood vessels. Participants with known bone marrow deficiency resulting in red blood cell deficiency (e.g. Diamond-Blackfan anemia) Participants receiving erythropoietin-stimulating agents (e.g. epoetin alfa) Participants with active hemorrhagic cystitis (e.g. alkylator-induced) with gross hematuria or >50 RBCs per high powered field on urinalysis Participants actively receiving all-trans retinoic acid (ATRA) or isotretinoin (Accutane) Participants with known allergies to antifibrinolytics Participants with known hypercoagulopathies Personal history of a thrombosis or active thrombus Participants currently on anticoagulation medications (e.g. warfarin, enoxaparin) Participants with a history of seizures. Patients with a history of febrile seizure are eligible. Persisting toxicity related to other systemic therapies (e.g. chemotherapy) which constitutes an unacceptable safety risk based on the judgment of the PI and/or the primary treating physician. Female participants who are currently pregnant or actively breastfeeding. Female participants who are currently receiving estrogen-based contraception therapy. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent. Participants enrolled in another clinical trial utilizing an IND/IDE experimental therapy. Participants with a history of CNS disease. Participants with known bleeding disorder. Participants with known platelet dysfunction.

Ages Eligible for Study
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Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tranexamic Acid<br>At initiation of surgical preparation, participants randomized to the active treatment arm will receive tranexamic acid 10 mg/kg (max 1 g), given via syringe pump programmed to infuse over 15 minutes. If no unacceptable toxicities occur, a second dose of tranexamic acid IV push over 5 to 15 minutes will be given 6 hours (with a window of +/- 30 minutes) after the first dose (either intra- or post-operatively). | Drug: Tranexamic Acid<br>* Given IV<br>* Other names: Cyklokapron®;|
| Placebo Comparator: Placebo<br>At initiation of surgical preparation, participants randomized to the placebo treatment arm will receive 0.9% sodium chloride (salt water). It will be matched in appearance, volume, and administration to the active treatment arm with tranexamic acid. If no unacceptable toxicities occur, a second dose of placebo IV push over 5 to 15 minutes will be given 6 hours (with a window of +/- 30 minutes) after the first dose (either intra- or post-operatively). | Other: 0.9% sodium chloride<br>* Given IV<br>* Other names: Salt water;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in intra-operatively transfused blood volume (mL/kg) | The intra-operative volumes of transfused blood for both the TXA treated group and placebo group will be estimated with a two-sided 95% confidence interval. The blood volumes transfused per kilogram of body weight of the two groups (TXA vs. Placebo) will be evaluated using a two-sided student's t-test after log(1+x) transformation. | During surgery | 
| Difference in post-operatively transfused blood volume (mL/kg) | The post-operative volumes of transfused blood for both the TXA treated group and placebo group will be estimated with a two-sided 95% confidence interval. The blood volumes transfused per kilogram of body weight of the two groups (TXA vs. Placebo) will be evaluated using a two-sided student's t-test after log(1+x) transformation. | After surgery; approximately 1-7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in platelet level | Summary statistics will be provided for the changes in platelet level from pre-op to post-op level, for both the TXA and placebo group. Two sample t-test or Wilcoxon rank sum test will be used to compare the differences between the two groups. Multiple comparison correction might be used for p-values to address the multiple testing issues due to measurements at multiple time points. | Pre-operatively (no more than 7 days prior to start of therapy), daily while inpatient and post operatively (approximately 1 week post-op) | 
| Changes in hemoglobin level (g/dL) | Summary statistics will be provided for the decline in hemoglobin from pre-op to post-op level, for both the TXA and placebo group. Two sample t-test or Wilcoxon rank sum test will be used to compare the differences between the two groups. Multiple comparison correction might be used for p-values to address the multiple testing issues due to measurements at multiple time points. | Pre-operatively (no more than 7 days prior to start of therapy), daily while inpatient and post operatively (approximately 1 week post-op) | 
| Post-operative daily surgical drain output | Summary statistics will be provided for postoperative daily surgical drain output (in milliliters per 24 hour period for the duration of the drain) for each group. The group difference will be compared using two-sample t-test or Wilcoxon rank sum test depending on the distribution of the observed data. Multiple comparison correction might be used for p-values to address the multiple testing issues due to measurements at multiple time points. | After surgery for the duration until the drain is pulled (approximately 1-7 days) | 
| Changes in estimated blood loss (EBL) | The EBL for pre-op to post-op level, for both the TXA treated group and placebo group will be estimated with a two-sided 95% confidence interval. The EBL of the two groups (TXA vs. Placebo) will be evaluated using a two-sample t-test or Wilcoxon rank sum test depending on the distribution of the observed data. | During surgery until the conclusion of surgery | 
| Intra-or post-operatively transfused blood volume | Regression model will be used to access the correlation between the log transformed intra-or post-operatively transfused blood volume and EBL. | During and after surgery (approximately 1-7 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood Transfusion, Cancer of the bone, Distal femur, Limb Salvage, Malignant Bone Tumor, Placebo, Proximal tibia, Randomized, Tranexamic acid, TXA