Clinical trial NCT00966563: Mangafodipir as an Adjunct to Percutaneous Coronary Intervention
Official title: Mangafodipir as an Adjunct to Percutaneous Coronary Intervention in Acute Myocardial Infarction (MANAMI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myocardial Infarction
Keywords: Mangafodipir
Primary Percutaneous Coronary Intervention
Myocardial infarction
Troponin
CK-MB
Magnetic Resonance Imaging
Lead sponsor: Egetis Therapeutics
Sponsor class: INDUSTRY
First posted: 2009-08-27
Enrollment: 20
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Reduction of myocardial infarct size assessed by biomarker release to plasma
timeFrame: Before and at 2 days after PCI
Secondary outcomes:
measure: Reduction of myocardial infarct size assessed by biomarker release to plasma and by magnetic resonance imaging (MRI) of the heart.
timeFrame: Accumulated biomarker release over 48 hours after PCI; MRI at 6-10 weeks after PCI.
Other outcomes:
Locations:
city: Jönköping
country: Sweden
facility: Department of Internal Medicine, County Hospital Ryhov
Study officials:
affiliation: Department of Internal Medicine, County Hospital Ryhov, SE-551 85 Jönköping, Sweden
name: Jan-Erik Karlsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.