Efficacy and Safety Evaluation of PC-SOD for Injection in Reducing Myocardial Reperfusion Injury

Efficacy and Safety Evaluation of Phosphatidyl Choline Cu/Zn Superoxide Dismutase (PC-SOD) for Injection in Reducing Myocardial Reperfusion Injury: a Multicenter, Randomized, Single-blind, Placebo-controlled Dose-finding Study

The current study aims to evaluate different doses of PC-SOD injections for efficacy and safety in comparison to placebo, in order to provide a basis for future clinical trials in terms of experimental design and dose selection.

Study Overview

• Status: Unknown
• Conditions: Myocardial Reperfusion Injury
• Intervention / Treatment: Drug: PC-SOD; Drug: placebo

Detailed Description

The study is a randomized, single-blind, multi-center, placebo-controlled trial to preliminarily evaluate the efficacy and safety of PC-SOD, and to provide a basis for dose selection in the next stage of study.

For each participant, the trial will be divided into the screening/treatment (screening and treatment conducted during the first visit, 0 d) and safety follow-up (1 - 30 d) stages.

The study will screen 120 eligible subjects. After successful screening, the subjects will be randomly assigned into four groups of equal size, including the 40 mg PC-SOD, 80 mg PC-SOD, 160 mg PC-SOD and placebo control groups. Subjects in each group will be administered the corresponding intervention, followed by PCI treatment. During the safety follow-up stage, the subjects will receive basic treatment based on Guidelines for Management of Patients with ST-segment elevation myocardial infarction. Treatments will include dual anti-platelet therapy, beta-blockers, ACEI/ARB (angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker), statins, anticoagulants, and so on.

By comparing the efficacy and safety endpoints of patients in the experimental and placebo control groups, the study aims to preliminarily evaluate the efficacy and safety of different doses of PC-SOD in reducing myocardial reperfusion injury.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Not yet recruiting
      • Wuhan Asia Heart Hospital
      • Contact: Su Xi, MD
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Zhongshan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 - 75 years, male or female;
2. Meeting the diagnostic criteria of AMI (chest pain for over 10 - 20 min, which could not be relieved completely by oral nitroglycerin; ST elevation ≥ 2 mm in two or more adjacent leads in leads V1-V5 );
3. Killip classes I or II;
4. Coronary angiography possible within 6 hours of onset;
5. Emergent coronary angiography showing occlusion in left anterior descending artery (TIMI grade 0 - 1); patients with this symptom could also be included despite inconformity to criterion 2);
6. Willingness to participate in the trial with ethical approval and informed consent provision.

Exclusion Criteria:

General exclusion criteria

1. Previous history of myocardial infarction;
2. History of myocardial revascularization before screening;
3. Thrombolytic treatment after onset;
4. Cardiogenic shock;
5. Cardiopulmonary resuscitation between onset and screening;
6. Atrial fibrillation, atrioventricular block (degree I, II or III), and other severe arrhythmias that cannot be corrected and affect hemodynamics;
7. Suspected of aortic dissection;
8. Diabetes with long-term insulin use, or definite macrovascular or small vascular lesions (stroke, diabetic nephropathy, retinopathy, diabetic foot, and etc.);
9. History of major surgeries within 6 months;
10. History of stroke within 6 months;
11. History of immune disorders within 6 months (such as cancer, lymphoma, HIV or hepatitis), or use of immunosuppressive agents at doses that can cause immunosuppression within 10 days;
12. Clinically significant diseases of the respiratory, digestive, blood, immune, endocrine, nervous or urinary systems (renal insufficiency in particular), and diseases that might cause serious risk to patients based on the judgement of researchers;
13. Allergy to two or more drugs and/or foods, or known allergy to sucrose;
14. Any contraindications for cardiac MRI, such as implantation of metal objects (pacemakers and/or implantable defibrillators; insulin pumps, or any other electronic devices; cerebral clips, aneurysm clips, and etc.), and other contraindications (such as claustrophobia);
15. Pregnancy or lactation in women;
16. Participation in other clinical trials within 3 months;
17. Situations considered unsuitable for enrollment (such as disease condition or patient compliance).

Exclusion criteria for angiography

1. Occlusion of left main artery;
2. Apart from the left anterior descending branch, other blood vessels requiring revascularization in the same period or within a month.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 40 mg treatment group; PC-SOD 40 mg dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.	Drug: PC-SOD; PC-SOD will be dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.
Experimental: 80 mg treatment group; PC-SOD 80 mg dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.	Drug: PC-SOD; PC-SOD will be dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.
Experimental: 160 mg treatment group; PC-SOD 160 mg dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.	Drug: PC-SOD; PC-SOD will be dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.
Placebo Comparator: placebo control group; placebo dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.	Drug: placebo; Placebo will be dissolved in 10 mL of 5% glucose injection and intravenously administrated before recanalization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The myocardial salvage index at 7 d after PCI	The myocardial salvage index is defined as (area of myocardial edema - area of myocardial infarction)/area of myocardial edema.	7 days
The area of myocardial infarction at 7 d after PCI (detected by delayed-enhanced MRI [Magnetic Resonance Imaging] )	The area of myocardial infarction is defined as the percentage of left ventricular myocardium occupied by delayed enhancement.	7 days
Area of microvascular occlusion at 7 d after PCI	Microvascular occlusion is defined as the area with no enhancement in the infarcted regions where delayed enhancement can be observed on MRI scans.	7 days
The area of infarction determined by the AUC (area under curve) for CK-MB (creatine kinase-muscle/brain) at 72h after PCI.	The area of infarction at 72h after surgery will be roughly estimated by calculating the AUC for CK-MB (before operation, and at 6, 12, 24, 48 and 72h after operation, respectively).	72 hours
Cardiac function at 7 d after PCI	Cardiac function is assessed by assessing the left ventricular ejection fraction (percentage of stroke output to end-diastolic volume).	7 days
The TIMI (thrombolysis in myocardial infarction) grade of coronary blood flow after PCI.	Coronary artery reperfusion will be assessed by the TIMI grading system, whose grades include: Grade 0: no contrast filling at the occlusion site and distal end; Grade 1: the contrast passes some of the occluded sites, but cannot fill the distal vessels; Grade 2: the contrast can fill the distal end of coronary artery completely, but the filling and clearing of contrast is slower than that of normal coronary artery; Grade 3: the contrast can fill the distal end rapidly and completely, and can be removed quickly. The TIMI flow grades will be determined by two physicians separately. In case of disagreement, a lead physician will help make the final call.	within 24 hours
The corrected TIMI frame count (cTFC) after PCI.	The left anterior descending (LAD) artery will be analyzed in a 30º right anterior oblique view with 30º cranial angulation. The left circumflex (LCX) will be analyzed in a 30º right anterior oblique view with 30º caudal angulation. The right coronary artery (RCA) will be analyzed in a 45º left anterior oblique view.	within 24 hours
TIMI myocardial perfusion grade (TMPG) after PCI	Grade 0: no contrast entering the myocardium; Grade 1: the contrast enters myocardium slowly, with myocardial staining not disappearing or lasting for more than 30 s in the targeted vessels; Grade 2: delayed entering and disappearing of contrast in the myocardium, exceeding 3 cardiac cycles; Grade 3: normal entering and disappearing of contrast in the myocardium, occurring within 3 cardiac cycles.	within 24 hours
Percentage of ST-segment resolution on ECG (electrocardiogram) at 90 min after PCI	ST-resolution is defined as more than 50% of resolution.	90 minutes
Number of cardiovascular events within 30 d after PCI	Cardiovascular events included all-cause death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure.	30 days
SOD (Superoxide Dismutase) activity	Change from Baseline SOD activity at 6h, 12h, 24h, 48h, 72h and 7 d after surgery.	0 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours and 7 days after surgery
Occurence of adverse events	Occurence of adverse events	During patient hospitalization, up to 30 days
Cardiac function at 30 d after PCI	Cardiac function is assessed by assessing the left ventricular ejection fraction (percentage of stroke output to end-diastolic volume).	30 days

Collaborators and Investigators

• Sponsor: Beijing Tide Pharmaceutical Co., Ltd
• Collaborators: Peking University First Hospital

Publications and helpful links

General Publications

• Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007 Sep 13;357(11):1121-35. doi: 10.1056/NEJMra071667. No abstract available.
• Zweier JL. Measurement of superoxide-derived free radicals in the reperfused heart. Evidence for a free radical mechanism of reperfusion injury. J Biol Chem. 1988 Jan 25;263(3):1353-7.
• Werns SW, Lucchesi BR. Free radicals and ischemic tissue injury. Trends Pharmacol Sci. 1990 Apr;11(4):161-6. doi: 10.1016/0165-6147(90)90068-J.
• Kloner RA, Przyklenk K, Whittaker P. Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues. Circulation. 1989 Nov;80(5):1115-27. doi: 10.1161/01.cir.80.5.1115.
• Przyklenk K, Kloner RA. Superoxide dismutase plus catalase improve contractile function in the canine model of the "stunned myocardium". Circ Res. 1986 Jan;58(1):148-56. doi: 10.1161/01.res.58.1.148.
• Engler R, Gilpin E. Can superoxide dismutase alter myocardial infarct size? Circulation. 1989 May;79(5):1137-42. doi: 10.1161/01.cir.79.5.1137. No abstract available.
• Igarashi R, Hoshino J, Ochiai A, Morizawa Y, Mizushima Y. Lecithinized superoxide dismutase enhances its pharmacologic potency by increasing its cell membrane affinity. J Pharmacol Exp Ther. 1994 Dec;271(3):1672-7.
• Wu E, Ortiz JT, Tejedor P, Lee DC, Bucciarelli-Ducci C, Kansal P, Carr JC, Holly TA, Lloyd-Jones D, Klocke FJ, Bonow RO. Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of outcomes than left ventricular ejection fraction or end-systolic volume index: prospective cohort study. Heart. 2008 Jun;94(6):730-6. doi: 10.1136/hrt.2007.122622. Epub 2007 Dec 10.

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2019
• Primary Completion (Anticipated): October 31, 2020
• Study Completion (Anticipated): March 30, 2021

Study Registration Dates

• First Submitted: June 5, 2019
• First Submitted That Met QC Criteria: June 20, 2019
• First Posted (Actual): June 24, 2019

Study Record Updates

• Last Update Posted (Actual): September 26, 2019
• Last Update Submitted That Met QC Criteria: September 24, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Cardiomyopathies; Wounds and Injuries; Reperfusion Injury; Myocardial Reperfusion Injury
• Other Study ID Numbers: CY-RD101-2; GUSU18003 (Other Identifier: GUSU Group)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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