A Pilot Randomized Controlled Trial of Intravenous N-acetyl Cysteine in STEMI (PANACEA)

A Pilot Randomized Controlled Trial of Intravenous N-acetyl Cysteine in Patients Undergoing Pharmaco-invasive Reperfusion Early After an ST-segment Elevation Myocardial Infarction

The PANACEA trial is an investigator-initiated prospective, single-center, two-arm, non-blinded pilot randomized controlled trial of high-dose IV N-Acetylcysteine therapy used as an adjunct to pharmaco-invasive reperfusion in patients presenting early after a large STEMI.

Study Overview

• Status: Completed
• Conditions: STEMI
• Intervention / Treatment: Drug: Intravenous N-Acetylcysteine

Detailed Description

Patients presenting with ST-segment elevation myocardial infarction within 3 hours of symptom onset and satisfying all of the inclusion criteria after informed consent would be randomly allocated to either intravenous N-Acetylcysteine or standard treatment using a 1:1 allocation ratio. Those randomized to IV N-Acetylcysteine would be administered a bolus of 1200 mg over 0.5 hours (in 5% Dextrose) followed by 600mg/hour for the remaining 47.5 hours (in 5% dextrose). A total N-acetylcysteine dose of 29.7 grams is administered over 48 hours. The infusion is continued during the primary percutaneous coronary intervention. Patients would be followed up for a minimum of 90 days. The primary clinical endpoint will be myocardial infarct size measured by late gadolinium enhancement CMR imaging at 3-5 days from first medical contact. Primary feasibility outcome will be the rate of recruitment, the number of patients undergoing cardiac MRI within the stipulated time frame, and completeness of the study data collection.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients presenting with STEMI within 3 hours of symptom onset and satisfying all of the following criteria:

1. Patient age ≥ 18 years
2. Have received thrombolysis, with intend to pursue a pharmaco-invasive reperfusion strategy. Onset of chest pain to reperfusion time of < 3hrs.
3. STEMI involving anterior and/or inferior wall
4. An absence of baseline Q-waves on the initial ECG: The presence of Q waves defined at baseline using the Selvester QRS screening criteria

5. Have a high-risk STEMI ECG defined as:

   • ≥2mm ST-segment elevation in 2 anterior or lateral leads; or
   • ≥2 mm ST-segment elevation in 2 inferior leads coupled with ST-segment depression in 2 contiguous anterior leads for a total ST-segment deviation of ≥4 mm

Exclusion Criteria:

1. Previous myocardial infarction
2. Known to have moderate to severe LV systolic dysfunction (LV EF< 45%)
3. Known allergy to thrombolytic therapy or NAC
4. Presence of left bundle branch block
5. Cardiogenic shock (defined as systolic blood pressure of < 90mm Hg, for at least 30 minutes, not responsive to fluid resuscitation)
6. Permanent pacemaker or cardioverter defibrillator implanted previously
7. Patients with contra-indications to thrombolytic therapy
8. Patients with loss of consciousness or confusion
9. Patients with known chronic kidney disease (GFR < 30ml/min/m2) or on dialysis
10. Current pregnancy
11. Planned therapy with primary PCI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intravenous N-Acetylcysteine arm; On arrival at the recruiting hospital, eligible and consenting STEMI patients randomly allocated to the experimental arm would be administered an intravenous N-Acetylcysteine bolus of 1200 mg over 0.5 hours (in 5% Dextrose) followed by 600mg/hour for the remaining 47.5 hours (in 5% dextrose). A total N-acetylcysteine dose of 29.7 grams is administered over 48 hours.	Drug: Intravenous N-Acetylcysteine; Intravenous N-acetyl cysteine bolus and infusion as described in the experimental arm.; Other Names: Generic
NO_INTERVENTION: Control arm; Patients randomized to this arm would receive no experimental therapies and would continue to receive all standard guideline recommended medical therapies and interventions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial infarct size	The primary clinical endpoint will be myocardial infarct size measured by late gadolinium enhancement CMR imaging at 3-5 days from first medical contact.	3-5 days after first medical contact
Feasibility outcomes	Primary feasibility outcomes would include the rate of recruitment, the number of patients undergoing cardiac MRI within the stipulated time frame, and completeness of the study data collection.	Assessed at the end of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial salvage	Myocardial salvage as measured by T2-weighted short tau inversion recovery on CMR assessed at 3-5 days after infarction	3-5 days after infarction
Left ventricular ejection fraction	Left ventricular ejection fraction on CMR at 3-5 days	3-5 days after infarction
ST-segment elevation resolution	ST-segment elevation resolution at 90 minutes after thrombolysis as assessed by the worst lead on electrocardiogram (ECG core lab).	90-minutes after thrombolysis
TIMI frame count in infarct related artery	TIMI frame count on baseline coronary angiogram in the infarct-related artery	During index coronary angiogram which will be performed within 24 hours of admission
Creatine kinase MB area under the curve	Creatine kinase MB area under the curve through 24 hours	24 hours after admission
Von Willebrand factor fragmentation	The proportion of Von Willebrand factor multimers in the low, intermediate and high molecular weight form at the time of angiography	At the time of angiography, assessed up to 7 days from admission
Bleeding	Bleeding research consortium type II, III and V bleeding; safety outcome	From time of randomization until the date of discharge or date of death from any cause, whichever came first, assessed up to 90 days
Allergic reactions	Allergic reactions including hypotension (SBP< 90 mm Hg or a fall in BP >30 mm Hg below baseline), urticaria, flushing, wheezing and/or angioedema	From time of randomization, upto 48 hours

Collaborators and Investigators

• Sponsor: University of Alberta
• Investigators: Study Chair: Michelle Graham, MD. FRCPC, University of Alberta

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 20, 2019
• Primary Completion (ACTUAL): November 15, 2020
• Study Completion (ACTUAL): January 1, 2022

Study Registration Dates

• First Submitted: July 9, 2019
• First Submitted That Met QC Criteria: July 16, 2019
• First Posted (ACTUAL): July 17, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 6, 2022
• Last Update Submitted That Met QC Criteria: October 3, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: STEMI
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: Pro00087545

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data regarding IPD will be made available on reasonable request
• IPD Sharing Time Frame: ON publication of trial the study protocol will be detailed. The ICF has been uploaded on this site.
• IPD Sharing Access Criteria: Study protocol will be published
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No