MAGNAM Trial, Magnesium Versus Amiodarone in Atrial Fibrillation in Critical Care (MAGNAM)

MAGNesium and Digoxin Versus AMiodarone for Fast Atrial Fibrillation in the ICU (MAGNAM Trial)

A multi-centre, non-blinded, comparative effectiveness, randomised controlled trial. Patients will be prospectively enrolled from Critical Care Units and will be assessed for study enrollment based on inclusion/exclusion criteria at the time of the onset of fast atrial fibrillation (AF)(irregular and often rapid heart rate). The authors hypothesize that high dose Magnesium Sulphate with the addition of Digoxin as a second line treatment will improve the success rate in returning the heart to normal rhythm as well as speed of resolution of critical illness in new onset rapid atrial fibrillation in the critically ill cared for in general ICUs.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation New Onset
• Intervention / Treatment: Drug: Amiodarone; Drug: Magnesium sulfate and then Digoxin

Detailed Description

This is a Multi-centre, randomised controlled, clinical trial that is comparing a Stepwise Strategy of Magnesium Followed by Digoxin, With an Amiodarone Backup vs a Strategy of First-line Amiodarone to See Which is More Effective in Returning the Heart to Normal Rhythm After Experiencing Rapid Atrial Fibrillation in General ICUs. It will take place in Critical Care Units in Toronto Health Sciences Centres over a course of 2 years. The sample size is 200 patients.

Investigational Product and Planned Use Magnesium sulphate

The trial intervention will be Magnesium sulphate followed by digoxin as second line therapy with Amiodarone as third line. The Standard of care intervention will be Amiodarone as first line treatment in the and then no more than 2g MgSO4 be delivered.

Data will be collected retrospectively at the outcome timepoints.

Statistical Analysis:

This analysis will be conducted using the intention to treat principle, therefore all randomised patients will be included in the main analysis. Crossovers and protocol violations will remain in their original study group.

Baseline data will be summarized per group for continuous variables using means and standard deviations or medians and interquartile ranges as indicated the distribution and for discrete variables using frequencies and percentages. For the rate / rhythm co-primary outcome the authors will use a sentinel time point analysis at the 6 and 24 hour time points assuming there no / very low competing risk for death using a multivariate regression model to test for differences between groups and adjusting for baseline variables such as age, hospital site, shock status (requirement for inotropes Y/N), mechanical ventilation (Y/N) and known chronic atrial fibrillation. For the ICU length of stay co-primary outcome the authors recognise the competing risk of death and for this outcome and the authors propose to use Fine and Gray models adjusting for the stratification variables (as above). Estimates will be presented as sub-distribution hazards and 95% confidence intervals. The authors will test for interaction between sub-group and treatment and present the estimates per sub-group.

All secondary outcomes are binary and differences between groups will be tested using Chi square test or Fisher exact test as appropriate. Missing data will be uncommon for our key outcome data considering the nature of this data. The authors do not propose to use imputation for missing data in these primary or secondary analyses.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Brian H Cuthbertson, MD; Phone Number: 2895 416 480 6100; Email: brian.cuthbertson@sunnybrook.ca
• Study Contact Backup: Name: Project Manager; Email: MAGNAM@sunnybrook.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
      • Recruiting
      • Mount Sinai Hospital
      • Contact: Jenna Spring, MD; Email: Jenna.Spring@sinaihealth.ca
      • Principal Investigator: Jenna Spring, MD
    • Toronto, Ontario, Canada, M4N3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Principal Investigator: Brian Cuthbertson, MD
      • Contact: Project Manager; Email: MAGNAM@sunnybrook.ca
    • Toronto, Ontario, Canada, M5B 1W8
      • Recruiting
      • St Michael's Hospital
      • Contact: Marlene Santos; Email: Marlene.Santos@unityhealth.to
      • Principal Investigator: Jan Friedrich, MD
    • Toronto, Ontario, Canada, M5G 2C4
      • Recruiting
      • University Health Network - Toronto General Hospital
      • Contact: David McAlpine, MD; Email: David.McAlpine@uhn.ca
      • Principal Investigator: Eddy Fan, MD
    • Toronto, Ontario, Canada, M5T 2S8
      • Recruiting
      • University Health Network - Toronto Western Hospital
      • Contact: Bourke Tillmann; Email: BourkeWilliam.Tillmann@uhn.ca
      • Principal Investigator: Bourke Tillmann, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria: Each participant must meet all of the following inclusion criteria to participate in this study:

1. Admitted to a participating hospital ICU
2. A newly documented episode of fast Atrial Fibrillation with heart rate >120/min confirmed by a 12-lead ECG assessment regardless of baseline rhythm (note- The AF can be acute or chronic diagnosis)
3. Undergoing, or able to commence continuous electrocardiographic monitoring ("telemetry") as part of their routine clinical care
4. Treating physician determines the patient has clinically significant AF that requires medical treatment

Exclusion Criteria:

1. Age <18 years
2. Palliative goals of care or expected to die in the next 12 hours
3. Fast Atrial Fibrillation (>120/min) present for > 48 hours
4. Treatment with digoxin or a class I or III anti-arrhythmic medication within the preceding 24 hours
5. MgSO4 dose of > 3g IV in the last 2 hours.
6. History of high grade Atrio-Ventricular conduction block or bradyarrhythmia without pacemaker
7. Non-cardiac indication or contraindication to one of the study treatments (hypertensive disorders of pregnancy, pre-term labour, neuromuscular junction disorders i.e. known Myasthenia gravis; documented prior history of amiodarone toxicity or relative contraindication such as thyroid disease, cirrhosis, pulmonary fibrosis, etc.)
8. Recent cardiac surgery during index hospital admission
9. Known pregnancy
10. Sustained (more than 10 continuous seconds documented on a rhythm strip) ventricular arrhythmia within the past 24 hours
11. Known or suspected pre-excitation syndrome
12. Persistent hyperkalemia > 6mmol/l despite treatment
13. Previously enrolled in the MAGNAM trial
14. Recent lung transplantation (during this admission)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care arm; Intravenous amiodarone as compactor group intervention	Drug: Amiodarone; We will test Amiodarone (150mg IV then 900mg IV over the next 24 hours ) as first line treatment in the standard of care group. No more than 2g MgSO4 be delivered over 2 hours maximum for this group in the first 24 hours after randomisation unless clinically indicated for measured hypomagnesaemia (a value below the index hospital laboratories lower limit of normal).
Experimental: Experimental arm; Intravenous magnesium sulphate as first line followed by digoxin IV loading as second line and then amiodarone IV as third line treatments for fast Atrial Fibrillation	Drug: Magnesium sulfate and then Digoxin; We will test MgSO4 and then digoxin IV (in 3 divided dose) as second line therapy with amiodarone IV as third line. Digoxin will be protocolised to commence between 30 minutes and 12 hours after MgSO4 if fast Atrial Fibrillation persists as initially designated (dose 1). Undiluted IV digoxin (12 mcg/kg) will be administered in 3 divided doses (6, 3 and 3 mcg/kg) separated by approximately 6 hrs (i.e. dose 1 at 30 mins - 12 hours after MgSO4, followed by dose 2 at -6 hrs and dose 3 at the approximately 12 hrs). Patients with renal dysfunction (creatinine clearance <60 ml/min measured by the Modification of diet in renal disease formula) will receive a reduced dose of 8 mcg/kg in 3 divided doses (4, 2, and 2 mcg/kg) separated by the same time intervals. In the trial intervention group, amiodarone will be given approximately 120 mins after digoxin if necessary whilst completing the digoxin dose. Amiodarone as a 150 mg infusion over 10 minutes followed by 900 mg over 24 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate control (<110 beats per minute) and/or restoration of normal sinus	heart rate control	6 hours
ICU free days	ICU free days	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital mortality	Hospital mortality	Up to 90 days
Heart rate	Maintenance rate control	24 hours
Continuation of trial intervention	Continuation of any of the drugs in the intervention (magnesium, digoxin or amiodarone) at the time of discharge from ICU	Up to 90 days
Presence of new rate and / or rhythm control medications at the time of first ICU discharge	Presence of new rate and / or rhythm control medications	Up to 90 days
Serious adverse events	Serious adverse events	Up to 90 days
Avoidance of amiodarone	Avoidance of amiodarone during the ICU admission	Up to 90 days

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Collaborators: Sunnybrook Research Institute
• Investigators: Principal Investigator: Brian H Cuthbertson, MD, Sunnybrook Health Sciences Centre

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2022
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: January 6, 2022
• First Submitted That Met QC Criteria: March 17, 2022
• First Posted (Actual): March 18, 2022

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Atrial fibrillation; critical illness
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics; Protective Agents; Cardiotonic Agents; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Anticonvulsants; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Calcium-Regulating Hormones and Agents; Reproductive Control Agents; Calcium Channel Blockers; Tocolytic Agents; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Digoxin; Magnesium Sulfate; Amiodarone
• Other Study ID Numbers: 3664

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Blinded data will be shared with other researchers after verification of their study plan and discussion about recognitions
• IPD Sharing Time Frame: 12 months after publication
• IPD Sharing Access Criteria: Contact PI
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No