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

Phase 3

Terminated

Conditions: Cancer of the Bone
Limb Salvage

Interventions: Other: 0.9% sodium chloride
Drug: Tranexamic Acid

Registration Number: NCT04410042

Lead Sponsor: St. Jude Children's Research Hospital

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	0.9% sodium chloride	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).
Tranexamic Acid	Tranexamic Acid	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).

Primary Outcome Measures

Name	Time	Method
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.	intra- or post-operatively transfused blood volume (mL/kg), 6 months	The intra-or 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.

Secondary Outcome Measures

Name	Time	Method
To Evaluate Changes in Platelets From Pre-op to Post-op Level for Patients Randomized to Receive Perioperative TXA Versus Placebo.	changes in platelets from pre-op to post-op level, 6 months	Summary statistics will be provided for the changes in platelet 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.
To Evaluate Changes in Hemoglobin From Pre-op to Post-op Level for Patients Randomized to Receive Perioperative TXA Versus Placebo.	changes in hemoglobin from pre-op to post-op level, 6 months	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.
To Evaluate Differences in Post-operative Daily Surgical Drain Output for Patients Randomized to Receive Perioperative TXA Versus Placebo.	Conclusion of surgery to time of drain removal (prior to discharge from inpatient)	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.
To Evaluate Changes in Estimated Blood Loss (EBL) for Patients Randomized to Receive Perioperative TXA Versus Placebo.	At conclusion of surgery	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.
To Evaluate Log Transfused Blood Volume Between the intra-or Post-operatively for Patients Randomized to Receive Perioperative TXA and Placebo, Respectively.	At conclusion of surgery	Mean and Standard Deviation of log Transfused Blood Volume for both the TXA treated group and placebo group will be estimated.
To Evaluate Log Estimated Blood Loss (EBL) Between the intra-or Post-operatively for Patients Randomized to Receive Perioperative TXA and Placebo, Respectively.	At conclusion of surgery	Mean and Standard Deviation of log Estimated Blood Loss for both the TXA treated group and placebo group will be estimated.
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.	At conclusion of surgery	Regression model will be used to access the correlation between the log transformed intra-or post-operatively transfused blood volume and EBL.