Bleeding Reduction in Acute and Chronic Kidney Patients Having Surgery (BRACKETS) Pilot Trial

Phase 3

Not yet recruiting

• Conditions: Surgery; Chronic Kidney Diseases; Acute Kidney Injury; Bleeding
• Interventions: Drug: Desmopressin Injectable Solution; Drug: Tranexamic Acid Injectable Product; Other: Placebo

• Registration Number: NCT06337838
• Lead Sponsor: Hamilton Health Sciences Corporation

Brief Summary

The BRACKETS pilot study is a multicentre, prospective, randomized controlled trial of prophylactic preoperative tranexamic acid (TXA) versus placebo and, using a partial factorial design, of prophylactic preoperative desmopressin versus placebo.

Detailed Description

Perioperative administration of TXA reduces bleeding risk in surgical patients. However, large clinical trials have excluded patients with advanced kidney disease, so the benefits remain uncertain in this population, and there is potential for harm. The benefit of desmopressin, which is purported to more directly address the defect of primary hemostasis believed important in severe kidney disease more directly than TXA, has not been examined in adequate randomized control trials (RCTs). Both medications are generic and have been available for many years. To convincingly test these medications in patients with severe kidney disease, large, global trials are required. This pilot-phase trial will 1) inform the feasibility and design of a large international trial to evaluate the efficacy and safety of TXA and desmopressin in patients with advanced kidney disease undergoing noncardiac surgery, 2) provide preliminary data regarding the efficacy and safety of TXA and desmopressin in people with advanced kidney disease having noncardiac surgery, and 3) provide pharmacokinetic data to inform dose selection.

Study Timeline

• Study First Submitted: 2024-01-22
• Study First Submitted QC: 2024-03-22
• Study First Posted: 2024-03-29
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-16
• Last Update Posted: 2025-05-21
• Study Start: 2025-06
• Primary Completion: 2027-02
• Study Completion: 2027-06

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

1. One of either:

   1.1. eGFR <25 ml/min/1.73m2 estimated using the CKD-Epi 2009 or 2021creatinine-based equation from the most recent serum creatinine measurement done in the previous 6 months; or 1.2. Receipt of dialysis (including hemodialysis, peritoneal dialysis, hemofiltration, or hemodiafiltration) within the last 7 days;

2. Planned noncardiac surgery (elective, urgent, or emergency surgery);

3. Expected to require at least an overnight hospital admission after surgery;

4. Age ≥18 years; and

5. Informed consent is obtained to participate in the BRACKETS-Pilot Trial.

Exclusion Criteria

1. Undergoing cardiac surgery;
2. Undergoing intracranial neurosurgery;
3. Undergoing surgery for creation or revision of arteriovenous fistula or graft for dialysis access;
4. Planned use of prophylactic systemic TXA or ϵ-aminocaproic acid;
5. Hypersensitivity or known allergy to TXA;
6. History of seizure disorder;
7. Recent (within 90 days) stroke, myocardial infarction, acute arterial thrombosis, deep venous thrombosis, pulmonary embolism, or thrombosis of an arteriovenous fistula or graft;
8. History of thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome, or antiphospholipid antibody syndrome;
9. Women who are known to be pregnant, breastfeeding, or who meet both of the following criteria: i) are of childbearing potential and do not have a negative pregnancy test documented in the 7 days before surgery, AND ii) are not using effective contraception; or
10. Previously enrolled in the BRACKETS-Pilot Trial.

Eligibility criteria specific to the desmopressin factorial component of trial

Inclusion criteria:

1. Included in the TXA factorial.

Exclusion criteria:

1. The hospital does not have access to desmopressin;
2. Planned use of prophylactic desmopressin;
3. Most recent serum sodium concentration < 130 mEq/L;
4. Known or suspected von Willebrand disease (any kind), hemophilia, or platelet function disorder; or
5. Hypersensitivity or known allergy to desmopressin.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Prophylactic intravenous tranexamic acid and prophylactic intravenous desmopressin.	Tranexamic Acid Injectable Product	Within 20 minutes preceding anticipated skin incision, patients will receive preoperative prophylactic intravenous tranexamic acid at a dose of 1000 mg infused over 10 minutes for patients with estimated glomerular filtration rate (eGFR) \<25 ml/min/1.73m2 who do not receive dialysis before surgery and 500 mg infused over 10 minutes for patients who receive dialysis. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin intervention group will receive intravenous desmopressin at a dose of 20 mcg over 30 minutes.
Prophylactic intravenous tranexamic acid and placebo.	Tranexamic Acid Injectable Product	Within 20 minutes preceding anticipated skin incision, patients will receive preoperative prophylactic intravenous tranexamic acid at a dose of 1000 mg infused over 10 minutes for patients with eGFR \<25 ml/min/1.73m2 who do not receive dialysis before surgery and 500 mg infused over 10 minutes for patients who receive dialysis. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin control group will receive an intravenous infusion of 0.9% saline solution, administered over a duration of 30 minutes.
Prophylactic intravenous tranexamic acid and placebo.	Placebo	Within 20 minutes preceding anticipated skin incision, patients will receive preoperative prophylactic intravenous tranexamic acid at a dose of 1000 mg infused over 10 minutes for patients with eGFR \<25 ml/min/1.73m2 who do not receive dialysis before surgery and 500 mg infused over 10 minutes for patients who receive dialysis. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin control group will receive an intravenous infusion of 0.9% saline solution, administered over a duration of 30 minutes.
Prophylactic intravenous desmopressin and placebo.	Placebo	Within 20 minutes preceding anticipated skin incision, patients will receive intravenous desmopressin at a dose of 20 mcg over 30 minutes. Patients will not receive prophylactic tranexamic acid. Within 20 minutes preceding anticipated skin incision, patients allocated to the tranexamic acid control group will receive an intravenous infusion of 0.9% saline solution. This saline solution will be administered over a duration of 10 minutes in a volume equivalent to that received by patients in the tranexamic acid intervention group.
Placebo and placebo.	Placebo	Within 20 minutes preceding anticipated skin incision, patients allocated to the tranexamic acid control group will receive an intravenous infusion of 0.9% saline solution. This saline solution will be administered over a duration of 10 minutes in a volume equivalent to that received by patients in the tranexamic acid intervention group. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin control group will receive an intravenous infusion of 0.9% saline solution, administered over a duration of 30 minutes.
Prophylactic intravenous tranexamic acid and prophylactic intravenous desmopressin.	Desmopressin Injectable Solution	Within 20 minutes preceding anticipated skin incision, patients will receive preoperative prophylactic intravenous tranexamic acid at a dose of 1000 mg infused over 10 minutes for patients with estimated glomerular filtration rate (eGFR) \<25 ml/min/1.73m2 who do not receive dialysis before surgery and 500 mg infused over 10 minutes for patients who receive dialysis. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin intervention group will receive intravenous desmopressin at a dose of 20 mcg over 30 minutes.
Prophylactic intravenous desmopressin and placebo.	Desmopressin Injectable Solution	Within 20 minutes preceding anticipated skin incision, patients will receive intravenous desmopressin at a dose of 20 mcg over 30 minutes. Patients will not receive prophylactic tranexamic acid. Within 20 minutes preceding anticipated skin incision, patients allocated to the tranexamic acid control group will receive an intravenous infusion of 0.9% saline solution. This saline solution will be administered over a duration of 10 minutes in a volume equivalent to that received by patients in the tranexamic acid intervention group.

Primary Outcome Measures

Name	Time	Method
Receipt of the allocated study drug within 1 hour before start of surgery for the desmopressin factorial	Day of surgery	Account of whether the patient began to receive study drug for the desmopressin factorial within an hour before skin incision. Target ≥80% of participants
Completion of 30-day follow-up	30 days after randomization	Account of whether the patient or their next-of-kin could be contacted and completed the 30-day post-randomization assessment. Target ≥80% of participants
Rate of recruitment	Through study completion, an average of 1.5 years	A rate of 0.25 patients per study site per week
Receipt of the allocated study drug within 1 hour before start of surgery for the tranexamic acid factorial	Day of surgery	Account of whether the patient began to receive study drug for the TXA factorial within an hour before skin incision. Target ≥80% of participants

Secondary Outcome Measures

Name	Time	Method
Major arterial and venous thrombosis	30 days after randomization	(i.e., composite of myocardial injury after noncardiac surgery \[MINS\], stroke, peripheral arterial thrombosis, dialysis vascular access thrombosis requiring anticoagulation or intervention, and symptomatic venous thromboembolism)
Myocardial Injury after Noncardiac Surgery (MINS)	30 days after randomization	Number of patients who experience MINS
Myocardial Injury after Noncardiac Surgery (MINS) that meets criteria for myocardial infarction	30 days after randomization	Number of patients who experience MINS that meets criteria for myocardial infarction (based on the Fourth Universal Definition of myocardial infarction)
MINS that is an isolated ischemic troponin elevation	30 days after randomization	Number of patients who experience MINS that is an isolated ischemic troponin elevation
Stroke	30 days after randomization	Number of patients experiencing a stroke
Non-hemorrhagic stroke	30 days after randomization	Number of patients who experience a non-hemorrhagic stroke
Hemorrhagic stroke	30 days after randomization	Number of patients who experience a hemorrhagic stroke
Peripheral arterial thrombosis	30 days after randomization	Number of patients who experience a peripheral arterial thrombosis
Thrombosis of arteriovenous fistula or graft	30 days after randomization	Number of patients who have thrombosis of arteriovenous fistula or graft
Symptomatic proximal venous thromboembolism	30 days after randomization	Number of patients who experience symptomatic proximal venous thromboembolism
Symptomatic pulmonary embolism	30 days after randomization	Number of patients who experience a symptomatic pulmonary embolism
Symptomatic proximal leg or arm deep venous thrombosis (DVT)	30 days after randomization	Number of patients who experience a symptomatic proximal leg or arm DVT
Non-fatal cardiac arrest	30 days after randomization	Number of patients who experience non-fatal cardiac arrest
Coronary revascularization procedure	30 days after randomization	Number of patients who undergo coronary revascularization procedure
Clinically important atrial fibrillation or flutter	30 days after randomization	Number of patients who experience clinically important atrial fibrillation or flutter
Acute heart failure or clinically important volume overload	30 days after randomization	Number of patients who experience acute heart failure or clinically important volume overload.
Acute kidney injury (for patients not receiving dialysis before surgery)	30 days after randomization	Number of patients who experience an acute kidney injury
New start of dialysis	30 days after randomization	Number of patients who require new start of dialysis
Seizure	30 days after randomization	Number of patients who experience a seizure
Clinically significant intraoperative hypotension	30 days after randomization	Number of patients who experience clinically significant intraoperative hypotension
Clinically significant postoperative hypotension	Up to and including the end of postoperative day 1	Number of patients who experience clinically significant postoperative hypotension
Sepsis	30 days after randomization	Number of patients who experience sepsis
Duration of surgery	30 days after randomization	The time from skin incision to closure, in minutes.
Receipt of platelets	30 days after randomization	Any transfusion of this blood product
Receipt of fibrinogen	30 days after randomization	Any transfusion of this blood product
Receipt of fresh frozen plasma	30 days after randomization	Any transfusion of this blood product
Receipt of cryoprecipitate	30 days after randomization	Any transfusion of this blood product
Receipt of recombinant Factor VIIa	30 days after randomization	Number of patients receiving recombinant factor VIIa
Receipt of prothrombin complex concentrate	30 days after randomization	Number of patients who receive prothrombin complex concentrate
Prescribed erythropoiesis stimulating agent	30 days after randomization	Number of patients receiving a weekly dose of erythropoiesis stimulating agent on prescription active at 30 days
Severe hyponatremia	Up to and including the end of postoperative day 1	Measured serum sodium concentration \<125 meq/L
Duration of hospital stay after surgery	Day of surgery and ending the day of discharge	Cumulative number of nights spent in an acute care hospital
Duration of critical care stay after surgery	Day of surgery and ending the day of discharge	Cumulative number of nights spent in an intensive care unit
Delayed graft function after kidney transplantation	Within 7 days following kidney transplantation	Receipt of dialysis
Persistent dialysis dependence	30 days after randomization	Participant continues to receive dialysis after surgery.
Incisional site pain severity	30 days after randomization in the last 24 hours	Rating of pain using the 10-point ordinal scale where 0 corresponds to no pain and 10 corresponds to the worst pain imaginable.
Reoperation for reasons of bleeding	30 days after randomization	Number of patients who return to the operating room for surgical management of suspected documented bleeding
Blood (red blood cells or whole blood) transfused	Up to and including postoperative day 3 after surgery	Number of units of blood transfused.
Any blood transfusion (red blood cells or whole blood)	Up to and including postoperative day 3	Number of units of blood transfused.
Lowest measured hemoglobin concentration	30 days after randomization	The mean absolute difference for continuous outcomes using linear regression with treatment allocation
Most recent hemoglobin concentration	30 days after randomization	The mean absolute difference for continuous outcomes using linear regression with treatment allocation
Death	30 days after randomization	Number of patients who die of any cause
Bleeding Independently Associated with Mortality after noncardiac Surgery (BIMS)	30 days after randomization	Number of patients who experience BIMS
Bleeding Score	30 days after randomization	10-category ordinal score. Minimum scores mean a better outcome. 0 denotes no bleeding or bleeding in which the nadir hemoglobin is ≥70 g/L, no red blood transfusion was given, no reoperation for reasons of bleeding occurred, and there was no death imminently or directly caused by bleeding.; 1. denotes bleeding and post-operative hemoglobin \<70 g/L or 1 unit of blood (red blood cells or whole blood) transfused.; 2. denotes bleeding and 2 units transfused.; 3. denotes bleeding and 3 units transfused.; 4. denotes bleeding and 4 units transfused; 5. denotes bleeding and 5 units transfused.; 6. denotes bleeding and 6 units transfused.; 7. denotes bleeding and 7 units transfused.; 8. denotes bleeding and 8 or more units of blood transfused.; 9. denotes reoperation for reasons of bleeding.; 10. denotes death imminently or directly caused by bleeding.