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

• ClinicalTrials.gov Identifier: NCT05730816
• Recruitment Status: Recruiting
• First Posted: February 16, 2023
• Last Update Posted: April 5, 2023
• Sponsor: Brigham and Women's Hospital
• Collaborators: National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Shruti Gupta, Brigham and Women's Hospital

Study Description

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

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Condition or disease	Intervention/treatment	Phase
Mesothelioma	Drug: Magnesium sulfate; Drug: Normal Saline	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: MAGIC-AKI: Magnesium for the Prevention of Hyperthermic Intraoperative Cisplatin-Associated AKI
• Actual Study Start Date: April 4, 2023
• Estimated Primary Completion Date: April 3, 2027
• Estimated Study Completion Date: January 1, 2028

Arms and Interventions

Arm	Intervention/treatment
Experimental: Magnesium Sulfate; 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; Intravenous infusion of magnesium sulfate prior to intraoperative chemotherapy with cisplatin.
Placebo Comparator: Normal Saline; 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; Intravenous infusion of normal saline.

Outcome Measures

Primary Outcome Measures :

1. AUC of SCr measured daily over 7 days in Mg- versus placebo-treated patients [ Time Frame: 7 days ]
   The primary endpoint is the area under the curve (AUC) of SCr measured daily over 7 days in Mg- versus placebo-treated patients
2. Composite Global Rank [ Time Frame: 7 days ]
   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.

Secondary Outcome Measures :

1. Incident AKI [ Time Frame: 7 days ]
   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
2. Composite outcome of RRT/in-hospital death [ Time Frame: 7 days ]
   Composite outcome
3. Maximum AKI stage [ Time Frame: 7 days ]
   Based on KDIGO staging
4. Renal tubular injury [ Time Frame: 2 days ]
   AUC of uNGAL, uKIM-1, and pKIM-1 at hours +4, +12, and +36 in relation to HIOC administration
5. AUC for platinum concentrations [ Time Frame: 2 days ]
   Using blood and urine collected at various time points
6. Vasoactive-inotropic score (VIS) [ Time Frame: 2 days ]
   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
7. Proportion of patients with serum Mg levels in the 3-5 mg/dl range in the treatment group [ Time Frame: 1 day ]
   Between hours +8 and +24 in relation to the start of the Mg infusion
8. New onset of atrial fibrillation [ Time Frame: 7 days ]
   Confirmed on an EKG
9. Myocardial injury [ Time Frame: 7 days ]
   Defined as clinical evidence of myocardial injury and a troponin level above the 99th percentile

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

1. 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).
2. Serum Mg >3 mg/dl on either screening labs or preoperative labs
3. Pregnant/breastfeeding
4. Neuromuscular disease (e.g., myasthenia gravis, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, myositis)
5. 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
6. Sinus bradycardia, defined as a heart rate (HR) <55 beats per minute (bpm) detected on any ECG in the preceding 6 months
7. High grade AV block (2nd degree AV block type II or 3rd degree AV block) without a pacemaker
8. Positive COVID test in the 10 days prior to surgery
9. Prisoner
10. Hypersensitivity to Mg sulfate
11. Concurrent participation in a study with an alternative experimental therapy that may interact with IV Mg
12. Any condition that, in the view of the PI, might place the patient at increased risk or compromise the integrity of the study
13. Conflict with other study

Contacts and Locations

Contacts

Contact: Shruti Gupta, MD, MPH; 617-732-6383; Sgupta21@bwh.harvard.edu

Locations

United States, Massachusetts

Brigham and Women's Hospital; Recruiting

Boston, Massachusetts, United States, 02130

Contact: Shruti Gupta sgupta21@bwh.harvard.edu

Contact: David E. Leaf deleaf@bwh.harvard.edu

Sponsors and Collaborators

Brigham and Women's Hospital

National Institutes of Health (NIH)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Shruti Gupta, MD, MPH; Brigham and Women's Hospital
• Principal Investigator: David E. Leaf, MD, MMSc; Brigham and Women's Hospital

More Information

• Responsible Party: Shruti Gupta, Director of Onconephrology, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT05730816
• Other Study ID Numbers: 2023p000276; K23DK125672 ( U.S. NIH Grant/Contract )
• First Posted: February 16, 2023
• Last Update Posted: April 5, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Shruti Gupta, Brigham and Women's Hospital:

Mesothelioma; Magnesium Sulfate; intraoperative cisplatin

Additional relevant MeSH terms:

Mesothelioma; Mesothelioma, Malignant; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Magnesium Sulfate; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics; Central Nervous System Depressants; Anti-Arrhythmia Agents; Anticonvulsants; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Tocolytic Agents; Reproductive Control Agents