Sitagliptin Plus Granulocyte-colony Stimulating Factor in Acute Myocardial Infarction (SITAGRAMI)

• Segmental end-diastolic myocardial thickness, segmental systolic wall thickening, regional contractile reserve, end-diastolic and end-systolic volumes, stroke volume, and cardiac output in MRI [ Time Frame: 6 months of follow-up ] [ Designated as safety issue: No ]
• Extent of non-viable myocardium will be monitored from baseline up to 6 months measured by MRI delayed enhancement. [ Time Frame: 6 months follow up ] [ Designated as safety issue: No ]
• Change of myocardial perfusion at rest up to 6 months as measured by signal-time curve parameters using first-pass perfusion MRI [ Time Frame: 6 month follow up ] [ Designated as safety issue: No ]
• Occurrence of major adverse cardiac events (death, myocardial infarction, CABG, or re-intervention) up to 12 months. [ Time Frame: 12 months follow up ] [ Designated as safety issue: Yes ]
• Safety of a treatment of Sitagliptin in combination with G-CSF in CAD patients suffering from MI (spontaneously reported adverse events (AEs) up to 12 months). [ Time Frame: 12 months follow up ] [ Designated as safety issue: Yes ]
• Change of peripheral blood stem cell populations: CD34, CD34/KDR and CD34/CD26 positive cells prior to and 5 days after therapy initiation. [ Time Frame: 1 week follow up ] [ Designated as safety issue: No ]
• Change of plasma levels of NT-pro-BNP, glucose, complete blood count, CRP, platelets, CK, cTnI prior to and 5 and 28 days, and 6 months after therapy initiation [ Time Frame: 12 month follow up ] [ Designated as safety issue: No ]
• Assessment of in stent restenosis using angiography 6 months after facultative PCI [ Time Frame: 6 month follow up ] [ Designated as safety issue: Yes ]

• Segmental end-diastolic myocardial thickness, segmental systolic wall thickening, regional contractile reserve, end-diastolic and end-systolic volumes, stroke volume, and cardiac output in MRI [ Time Frame: 6 months of follow-up ] [ Designated as safety issue: No ]
• Extent of non-viable myocardium will be monitored from baseline up to 6 months measured by MRI delayed enhancement. [ Time Frame: 6 months follow up ] [ Designated as safety issue: No ]
• Change of myocardial perfusion at rest up to 6 months as measured by signal-time curve parameters using first-pass perfusion MRI [ Time Frame: 6 month follow up ] [ Designated as safety issue: No ]
• Occurrence of major adverse cardiac events (death, myocardial infarction, CABG, or re-intervention) up to 12 months. [ Time Frame: 12 months follow up ] [ Designated as safety issue: Yes ]
• Safety of a treatment of Sitagliptin in combination with G-CSF in CAD patients suffering from MI (spontaneously reported adverse events (AEs) up to 12 months). [ Time Frame: 12 months follow up ] [ Designated as safety issue: Yes ]
• Change of peripheral blood stem cell populations: CD34, CD34/KDR and CD34/CD26 positive cells prior to and 5 days after therapy initiation. [ Time Frame: 1 week follow up ] [ Designated as safety issue: No ]
• - Change of plasma levels of NT-pro-BNP, glucose, complete blood count, CRP, platelets, CK, cTnI prior to and 5 and 28 days, and 6 months after therapy initiation [ Time Frame: 12 month follow up ] [ Designated as safety issue: No ]
• Assessment of in stent restenosis using angiography 6 months after facultative PCI [ Time Frame: 6 month follow up ] [ Designated as safety issue: Yes ]

Trial design:

This Phase III, investigator-driven, randomised, placebo-controlled efficacy and safety study will compare the effects of Sitagliptin in combination with granulocyte-colony stimulating factor (Lenograstim, G-CSF) on the improvement of myocardial function in patients undergoing routine percutaneous coronary revascularisation for acute myocardial infarction (time from onset of infarction to intervention 2 to 24 hours). The primary objective of this study is to compare between a treatment of G-CSF plus Sitagliptin, (G-CSF/Sitagliptin treatment group, n=87) versus Placebo (control treatment group, n=87) in change of global myocardial function from baseline to 6 months of follow-up.

The trial will be conducted as a multi-centre trial. Secondary objectives of this study are to monitor changes of regional myocardial function, myocardial perfusion and extent of non-viable myocardium from baseline to 6 months after revascularisation between the treatment groups. Furthermore the following parameters over up to 12 months of follow-up are analysed: occurrence of major adverse cardiac events (death, myocardial infarction, coronary bypass grafting, or re-intervention), spontaneously reported adverse events. Analyses of cardiac function consists of evaluation of segmental systolic wall thickening, end-diastolic volume, end-systolic volume, stroke volume, ejection fraction and cardiac output by means of magnetic resonance imaging (MRI). The extent of non-viable myocardium and myocardial perfusion will be assessed using contrast enhanced MRI.

This study consists of a revascularisation period (angioplasty of the infarcted vessel), a treatment period (up to 28 days), and a follow-up period (up to 12 months). The Revascularisation Period starts with the treatment of the patient in the emergency room. As soon as possible the patient will be transferred to the catheterisation laboratory where acute percutaneous coronary intervention (PCI) of the infarct-related artery will be performed. The first phase of the Treatment Period consists of a screening period during which a patient's eligibility is preliminarily evaluated. The second phase of the Treatment Period is the randomisation for patients in the control or G-CSF/Sitagliptin treatment group. After baseline MRI, patients are randomised. Patients will be treated either with G-CSF (10µg/kg/d divided in two doses subcutaneously) over a period of 5 days and Sitagliptin 100 mg each day for 28 days or with placebo. Patients will be randomised in 1:1 ratio to the control and verum therapy treatment groups. Follow-up Period assessments will be performed in all patients at 6 months including clinical status, occurrence of adverse events, laboratory investigations, and MRI. To assess occurrence of in-stent restenosis, routine control angiography will be performed in all patients 6 months after initial PCI. Safety will be evaluated by monitoring treatment-emergent signs and symptoms, 12-lead ECGs, vital signs, physical examination, and clinical laboratory assessments after 1 month and 1 year.

• Drug: Lenograstim (GRANOCYTE)=GCSF
  10 µg/kg/d s.c. for 5 days divided in two dosages per day
• Drug: Sitagliptin (Januvia)
  100 mg p.o. per day for 28 days
• Drug: Sodium Chloride (NaCl) 0.9 %
  applied s.c. twice a day for 5 days
• Drug: Gelatin
  One capsule p.o. per day for 28 days

• Active Comparator: 1

  Application G-CSF (10µg/kg/d divided in two doses subcutaneously) over a period of 5 days and Sitagliptin 100 mg each day for 28 days.

  n=74

  Interventions:

  • Drug: Lenograstim (GRANOCYTE)=GCSF
  • Drug: Sitagliptin (Januvia)
• Placebo Comparator: 2

  NaCl 0.9% applied twice daily over a period of 5 days and oral Placebo given once a day for 28 days.

  n=74

  Interventions:

  • Drug: Sodium Chloride (NaCl) 0.9 %
  • Drug: Gelatin

Inclusion criteria

1. Be at least 18 years old, male or female
2. Have acute ST segment elevation myocardial infarction (typical chest pain of more than 30 minutes duration, presence of ST-segment elevation in at least two contiguous leads or left bundle-branch block) and/or occluded coronary artery
3. Intervention of infarct related artery by PCI/Stenting within 2-24 hours after onset of acute myocardial infarction.
4. have creatinin kinase elevation of more than three times of upper normal level (i.e. 540 U/l) accompanied by a significant elevation of CK-MB isoenzyme and/or Troponin I/T
5. Have regional wall motion abnormality (comprising hypo-, a- or dyskinesia) of at least one myocardial segment demonstrated with MRI.
6. Patients who are further suitable for coronary angiography and angioplasty with stenting of the infarct related artery.
7. Have the ability to understand the requirements of the study, and agree and be able to return for the required assessments.
8. Give a written informed consent.

Exclusion criteria

General:

1. Women of childbearing potential, pregnancy or being lactating.
2. Be unable to undergo percutaneous cardiac catheterisation
3. Have contraindications against magnetic resonance imaging (e.g. non-MR compatible implants or medical devices)
4. Have conditions that may severely degrade image quality (e.g. severe arrhythmia) or prevents from MR scanning (e.g. claustrophobia)
5. Previous enrolment in the present trial or administration of any study medication within the previous 30 days. Study drug is defined as any material (placebo or drug) dispensed under the provisions of a protocol.
6. Have other severe concurrent illness (e.g., active infection, malignancy).
7. Life expectancy of less than one year.
8. Have a history of alcohol or drug abuse within 3 months prior to admission or factors jeopardising follow-up.

Renal, hepatic, metabolic:

1. Moderate to severe renal impairment (Crea level >1.7 mg/dL or glomerular filtration rate <35 ml/min).
2. Diabetes type 1 patients.
3. Diabetic ketoacidosis.
4. Concomitant medications known to cause hypoglycemia, such as sulfonylureas.
5. Severe liver dysfunction.

Haematologic:

1. Malignant haematological diseases, i.e. chronic myeloic leukemia (CML) or myelodysplastic syndromes (MDS)
2. Severe congenital neutropenia with cytogenetic abnormalities
3. Known allergic reaction vs. Lenograstim

Cardiovascular:

1. Acute cardiogenic shock
2. Cardiomyopathy with an ejection fraction below 0.25 (i.e. ischemic or dilated cardiomyopathy resulting in congestive heart failure)
3. Infective endocarditis
4. Factors contraindicating cardiac catheterisation (e.g. severe allergy against iodine, severe thyroid disease)
5. Planned operative revascularisation
6. Left ventricular thrombus
7. Severe cardiac arrhythmias (i.e. malignant sustained or non-sustained ventricular tachycardia or ventricular fibrillation) within 24 hours after admission.

Pulmonary:

1. Acute massive pulmonary infiltrations
2. History of pneumonia in the last 4 weeks

Other:

1. Therapy with immunosuppressants, cytostatics, corticoids.