Study of Dutogliptin in Combination With Filgrastim in Post-Myocardial Infarction

Dutogliptin 60 mg administered by twice daily subcutaneous (SC) injection for 14 days in combination with a fixed standard dose of filgrastim (10 µg/kg) administered SC daily for 5 days. This study will be conducted in adults with ST-elevation myocardial infarction (STEMI) with successful revascularization following percutaneous coronary intervention (PCI) and stent implantation.

Primary Objective

• To evaluate the safety and tolerability of dutogliptin in combination with filgrastim in subjects with STEMI compared with placebo

Secondary Objectives

• To assess preliminary efficacy of dutogliptin in combination with filgrastim in subjects with STEMI compared with placebo as determined by cardiac magnetic resonance imaging (cMRI)
• To determine the pharmacokinetics (PK) of dutogliptin in a subset of the study population
• To establish the pharmacodynamics (PD) of dutogliptin (plasma DPP4 activity) in a subset of the study population

Exploratory Objectives

• To examine the effects of dutogliptin in combination with filgrastim on:
• Change from baseline in plasma stromal cell-derived factor (SDF)-1a levels
• Change from baseline in plasma biomarkers, including N-terminal pro-b-type natriuretic peptide (NT-proBNP) and high sensitivity troponin

Inclusion criteria

• 1. Male or female born between 1933 and 2000.
• Body weight <96 kg (212 lb).
• Able to provide written informed consent, including signing and dating the informed consent form (ICF).
• Diagnosis of STEMI (defined as new ST-segment elevation at the J point of at least 2 continuous leads of >2 mm [0.2 mV] in men or >1.5 mm [0.1 mV] in women in leads V2 and V3 OR >1 mm in any other contiguous precordial leads or the limb leads [for both men and women]) with PCI (bare metal or drug-eluting stent) and Thrombolysis in Myocardial Infarction flow grade 2 or 3 occurring >2 hours and <24 hours after symptom onset.
• LVEF ≤45% obtained by cECHO performed within 36 hours post-stent placement.
• Receiving standard medical therapy for post-MI treatment, according to local procedures and Principal Investigator discretion
• Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and an additional negative urine pregnancy test prior to the first dose of IMP unless regulated differently by national legislation.
• Sexually active female subjects of childbearing potential (i.e., women who are not postmenopausal or who have not had a bilateral oophorectomy, hysterectomy, or tubal ligation) and all male subjects (who have not been surgically sterilized by vasectomy) must agree to use effective contraception during the study.

Exclusion criteria

• Previous MI prior to Screening.
• Complex peri/post-MI clinical course, including arrhythmias, cardiogenic shock, pulmonary edema requiring mechanical ventilation, or requirement for vasopressor medications.
• Significant pre-existing cardiomyopathy with known LVEF ≤45% or moderate to severe mitral or aortic valvular disease.
• Amyloidosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis.
• Existing heart transplant.
• Ventricular tachycardia or fibrillation not associated with an acute ischemic episode.
• Uncontrolled hypertension (systolic >180 mmHg or diastolic >120 mmHg).
• Treatment with any DPP4 inhibitors (e.g., alogliptin, linagliptin, vildagliptin, saxagliptin, sitagliptin) or G-CSF medication (e.g., filgrastim, lenograstim, pegfilgrastim, lipegfilgrastim) within 4 months prior to Randomization.
• Contraindication to treatment with filgrastim, including known allergy to filgrastim or other G-CSF medication.
• Anemia defined as hemoglobin <9 g/dL prior to Randomization.
• Thrombocytosis (platelets >500 k/µL).
• Known positive serology for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
• Alanine aminotransferase (ALT) concentrations >3 times the upper limit of normal (ULN) or bilirubin >2 x ULN prior to Randomization, according to local laboratory assessments.
• History of cirrhosis and Child-Pugh score B or C.
• Current fever greater than 101.4 °F (38.6 °C) or recent systemic infection within 2 weeks prior to Randomization.
• Contraindication to cMRI procedure, including prior implantable cardioverter defibrillator placement, known reaction to gadolinium, claustrophobia, non-MRI-compatible, cochlear implant, morbid obesity, or presence of ferromagnetic material including shunts, shrapnel, penile prostheses, or blood vessel coil.
• Pregnant, planning to become pregnant, or nursing female subjects.
• Autoimmune disease requiring immunosuppressive therapy or chronic steroid treatment >5 mg/day prednisolone or equivalent.
• Significant renal impairment defined as estimated glomerular filtration rate <45 mL/min/1.73 m2, using the Chronic Kidney Disease Epidemiology Collaboration equation.
• Active neoplasm requiring surgery, chemotherapy, or radiation within the prior 12 months (subjects with a history of malignancy who have undergone curative resection or otherwise not requiring treatment for at least 12 months prior to Screening with no detectable recurrence are allowed).
• Malignant hematological disease, i.e., chronic myeloid leukemia or myelodysplastic syndrome.
• History of cerebrovascular accident or transient ischemic attack in the past 6 months.
• History of pneumonia in the last 4 weeks.
• History of any significant medical or psychiatric disorder that in the opinion of the investigator would make the subject unsuitable for participation in the study.
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) or treatment with an investigational biologic drug within 6 weeks prior to randomization.
• Participation in another concurrent clinical trial involving a therapeutic intervention (participation in observational studies and/or registry studies is permitted).
• Unable or unwilling to comply with the requirements of the study.
• Subject and/or an immediate family member is an employee of the investigational site directly affiliated with this study, the sponsor or the contract research organization.
• Considered by the investigator to be unsuitable to participate in the study for any other reason.
• Persons who are in an institution as a result of an administrative or judicial order, or soldiers.
• History of alcohol or drug abuse.