Mangafodipir as an Adjunct to Percutaneous Coronary Intervention

Myocardial Infarction Clinical Trial

— MANAMI  

Official title:

Mangafodipir as an Adjunct to Percutaneous Coronary Intervention in Acute Myocardial Infarction (MANAMI)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00966563
• Other study ID #: MANAMI PP01-09
• Status: Completed
• Phase: Phase 2
• First received: August 26, 2009
• Last updated: July 15, 2013
• Start date: December 2009
• Est. completion date: July 2013

Study information

• Verified date: July 2013
• Source: PledPharma AB
• Contact: n/a
• Is FDA regulated: No
• Health authority: Sweden: Medical Products Agency
• Study type: Interventional

Clinical Trial Summary

The present feasibility study is designed to find out whether pre-treatment with the compound mangafodipir (PP-099) provides an additional reduction in myocardial infarct size in patients treated with primary percutaneous coronary intervention (PCI) during acute myocardial infarction (AMI).

Description:

Mangafodipir, manganese (Mn) dipyridoxyl diphosphate (MnDPDP) and its lipophile metabolite Mn dipyridoxyl diethylene diamide (MnPLED), are catalytic antioxidants and iron chelators. In preclinical studies these agents reduce oxidative stress induced injuries related to chemotherapy of cancer and to reperfusion/reoxygenation of ischemic/hypoxic myocardium. Accordingly, in an in vivo pig model of AMI metabolite MnPLED applied at end of ischemia and during reperfusion reduced myocardial infarct size by 55 %. Mangafodipir most likely activates salvage pathways and prevents lethal reperfusion injuries.

Other advantages are that mangafodipir is already approved as a contrast agent for MRI of liver, and that the experience for more than a decade reveals a high safety with minor and tolerable side-effects.

The present study will include 20 patients treated for their first documented AMI. They will after admission to hospital undergo primary PCI. Reopening of an occluded coronary artery will be preceded by iv. infusion of mangafodipir or placebo in two groups , each consisting of 10 patients. The primary endpoint will be release to plasma of commonly accepted biomarkers of myocardial injury (Troponin T and CK-MB) measured at admission and 6 hours after PCI. The secondary endpoints include the accumulated release of plasma biomarkers over 48 hours and direct measurement of the final myocardial infarct size at 6-10 weeks after PCI.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: July 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Males 40-80 and females 50-80 years with first severe coronary attack

2. Chest pain up to 6 hours.

3. T segment elevation (= 0.2 mV in two neighbouring anterior and inferior wall leads.

4. Decided for treatment by primary PCI.

5. TIMI grade 0 flow in the occluded LAD or RCA artery

6. Written informed consent.

Exclusion Criteria:

1. Previous coronary artery bypass operation.

2. Previous AMI.

3. Chest pain more than 6 hours.

4. Angina within 48 hours before admission.

5. Cardiac arrest and cardiogenic shock.

6. Occlusion of the left main stem, circumflex and right coronary arteries at angiography.

7. Known hypersensitivity to mangafodipir (as contrast agent for MRI).

8. Received mangafodipir = 5 weeks before admission

9. History of prior serious allergic or pseudo-allergic reaction

10. Severely reduced liver or renal function

11. Any other serious illness or medical condition

12. Fertile females

13. Phaeochromocytoma

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction

Intervention

Drug:
• Mangafodipir
Administered dose: 2 µmol/kg b.w. Administration form: Ready-to-use formulation (solution). Mangafodipir or placebo (0.2 ml/kg b.w.) will be administered as an intravenous (iv.) infusion over 2-5 min prior to reopening of occluded coronary artery during PCI
• Placebo

Locations

Country	Name	City	State
Sweden	Department of Internal Medicine, County Hospital Ryhov	Jönköping

Sponsors (1)

Lead Sponsor	Collaborator
PledPharma AB

Country where clinical trial is conducted

Sweden, 

References & Publications (1)

1. Piot C, Croisille P, Staat P, Thibault H, Rioufol G et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. New Engl J Med 2008; 359: 473-481. 2. Yellon DM, Hausenloy DJ. Mechanisms of disease: Myocardial reperfusion injury. New Engl J Med 2007; 357: 1121-1135. 3. Karlsson JOG, Brurok H, Eriksen M, Towart R, Toft KG, Moen O, Engebretsen B, Jynge P and Refsum H. Cardioprotective effects of the MR contrast agent MnDPDP and its metabolite MnPLED upon reperfusion of the ischemic porcine myocardium. Acta Radiologica 2001;42:540-547. 4. Brurok H, Ardenkjær-Larsen JH, Hansson G, Skarra S, Berg K, Karlsson JOG, Jynge P. Manganese dipyridoxyl diphosphate: MRI contrast agent with antioxidative and cardioprotective properties. Biochem Biophys Res Commun 1999;254:768-772. 5. Karlsson JOG, Brurok H, Towart R, Jynge P. Letter to the Editor. The magnetic resonance imaging contrast agent mangafodipir exerts antitumor activity via a previously described superoxide mimetic activity. Cancer Res 2006;66:598. 6. MANFOL. Mangafodipir as an adjunct to FOLFOX6 chemotherapy in colon cancer stage Duke's C. Study NCT00671996. 2008. 7. Skjold A, Amundsen BH, Wiseth R, Støylen A, Haraldseth O, Larsson HB, Jynge P. Manganese dipyridoxyl-diphosphate (MnDPDP) as a viability marker in patients with myocardial infarction. J Magn Reson Imaging 2007; 26: 720-727. 8. Jynge P, Brurok H, Asplund A, Towart R, Refsum H, Karlsson JOG. Cardiovascular safety of MnDPDP and MnCl2. Acta Radiol 1997;38:740-749. 9. Karlsson JOG, Mortensen E, Pedersen HK, Sager G, Refsum H. Cardiovasular effects of MnDPDP and MnCl2 in dogs with acute ischemic heart failure. Acta Radiol 1997;38:750-758.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Reduction of myocardial infarct size assessed by biomarker release to plasma		Before and at 2 days after PCI	No
Secondary	Reduction of myocardial infarct size assessed by biomarker release to plasma and by magnetic resonance imaging (MRI) of the heart.		Accumulated biomarker release over 48 hours after PCI; MRI at 6-10 weeks after PCI.	No