MAGIC AKI: Magnesium for the Prevention of HIOC-Associated AKI

Study Overview
=================
Brief Summary
-----------------
In this research study, investigators will test whether prophylactic high-dose IV Mg administration attenuates the risk of AKI in patients with malignant mesothelioma receiving intraoperative chemotherapy (HIOC) with cisplatin compared to placebo .

Detailed Description
-----------------
In this phase 2, open-label randomized, placebo-controlled trial, investigators will test whether prophylactic high-dose IV Mg administration attenuates the risk of HIOC-associated AKI in patients with malignant mesothelioma undergoing surgery with HIOCC. Investigators will randomly assign 130 patients to receive IV Mg versus an equal volume of normal saline (0.9% NS) placebo, of whom it is anticipated 80 will complete the study. Investigators will also collect blood and urine pre- and postoperatively for exploration of secondary outcomes. Investigators will screen for eligibility at participant's preoperative visit with their thoracic surgeon. Intravenous magnesium will be administered as a continuous infusion, soon after induction and stabilization by anesthesia in the operating room. The magnesium drip will start at 1 g/hour and will be titrated to achieve target levels of 3-5 mg/dl. The total duration of the infusion will be 24 hours.

Official Title
-----------------
MAGIC-AKI: Magnesium for the Prevention of Hyperthermic Intraoperative Cisplatin-Associated AKI

Conditions
-----------------
Mesothelioma

Intervention / Treatment
-----------------
* Drug: Magnesium sulfate
* Drug: Normal Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. • Adult patients (≥18 years old) with malignant mesothelioma undergoing surgery with HIOC with Dr. Raphael Bueno or another BWH thoracic surgeon Exclusion Criteria: eGFR<45 ml/min/1.73m2 on either screening labs or preoperative labs, or end-stage kidney disease receiving renal replacement therapy. Screening labs refer to those obtained at the preoperative visit with the surgeon or within 90 days prior, whereas preoperative labs are obtained on the day of admission (typically one to three days priors to surgery). Serum Mg >3 mg/dl on either screening labs or preoperative labs Pregnant/breastfeeding Neuromuscular disease (e.g., myasthenia gravis, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, myositis) Coronary artery disease, defined as any of the following in the prior year: a positive stress test; coronary angiogram indicating 1 or more vessels with >70% stenosis; percutaneous coronary intervention with stents; or coronary artery bypass graft surgery Sinus bradycardia, defined as a heart rate (HR) <55 beats per minute (bpm) detected on any ECG in the preceding 6 months High grade AV block (2nd degree AV block type II or 3rd degree AV block) without a pacemaker Positive COVID test in the 10 days prior to surgery Prisoner Hypersensitivity to Mg sulfate Concurrent participation in a study with an alternative experimental therapy that may interact with IV Mg Any condition that, in the view of the PI, might place the patient at increased risk or compromise the integrity of the study Conflict with other study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Magnesium Sulfate<br>The IV Mg will start at 1 g/hour (25 ml/hour) within one hour following induction of anesthesia and stabilization of the patient. The infusion will continue for 24 hours and serum Mg levels will be monitored every 4 hours (+/-1 hour) for 28 hours following initiation of the Mg. Dose adjustments to the Mg infusion will be made as necessary to reach target serum Mg levels (3-5 mg/dl). | Drug: Magnesium sulfate<br>* Intravenous infusion of magnesium sulfate prior to intraoperative chemotherapy with cisplatin.<br>|
| Placebo Comparator: Normal Saline<br>Patients randomized to placebo will receive an equal volume of normal saline (0.9% NS) placebo which will be administered as a continuous infusion at 25 ml/hour. The infusion will continue for 24 hours. | Drug: Normal Saline<br>* Intravenous infusion of normal saline.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of SCr measured daily over 7 days in Mg- versus placebo-treated patients | The primary endpoint is the area under the curve (AUC) of SCr measured daily over 7 days in Mg- versus placebo-treated patients | 7 days | 
| Composite Global Rank | As a secondary endpoint, investigators will construct a composite global rank endpoint in which the highest rank is assigned to those who die within 7 days, the second highest rank is assigned to those who survive but require RRT within 7 days, and all others ranked according to their SCr AUC, since RRT and death are important competing risks. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incident AKI | Urine output <0.5 ml/kg/h x consecutive 6 hours in the first 48 hours following surgery with HIOC (this will only be assessed for the first 48 hours, as patients are transferred out of the ICU and/or their foley is removed, which prevents accurate hourly assessment of UOP); An absolute increase in SCr ≥0.3 mg/dl within 48 hours; C) A relative increase in SCr ≥50% compared to the baseline value in the first 7 days; D) Receipt of RRT in the first 7 days | 7 days | 
| Composite outcome of RRT/in-hospital death | Composite outcome | 7 days | 
| Maximum AKI stage | Based on KDIGO staging | 7 days | 
| Renal tubular injury | AUC of uNGAL, uKIM-1, and pKIM-1 at hours +4, +12, and +36 in relation to HIOC administration | 2 days | 
| AUC for platinum concentrations | Using blood and urine collected at various time points | 2 days | 
| Vasoactive-inotropic score (VIS) | Assessed every 4 hours for the first 24 hours, and then every 8 hours for the next 24 hours, in relation to the start of the Mg infusion. The VIS is a validated method for integrating all vasoactive medications (i.e., vasopressors and inotropes) and their doses on an hourly basis into a single measure, and has been used in multiple settings | 2 days | 
| Proportion of patients with serum Mg levels in the 3-5 mg/dl range in the treatment group | Between hours +8 and +24 in relation to the start of the Mg infusion | 1 day | 
| New onset of atrial fibrillation | Confirmed on an EKG | 7 days | 
| Myocardial injury | Defined as clinical evidence of myocardial injury and a troponin level above the 99th percentile | 7 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mesothelioma, Magnesium Sulfate, intraoperative cisplatin