Studying Complement Inhibition in Complex Cardiac Surgery

Study Overview
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Brief Summary
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The trial enrolls patients undergoing a complex cardiac surgery. The primary goal of the trial is to evaluate the pharmacodynamic dose response relationship of the monoclonal antibody IFX-1 in these patients. In addition, this trial further aims to characterize the safety and the pharmacokinetics of IFX-1 as well as to collect first data on its efficacy on clinical surrogate endpoints.

Official Title
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A Phase II Randomized, Placebo-controlled, Double-blind, Dose-escalation Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamic Dose Response Relationship of IFX-1 in Patients Undergoing Complex Cardiac Surgery

Conditions
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Systemic Inflammatory Response Syndrome, C.Surgical Procedure; Cardiac

Intervention / Treatment
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* Biological: IFX-1
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥ 18 years old Written informed consent One of the following cardiac surgical procedures is planned with Cardiopulmonary bypass (CPB): Single valve surgery in combination with at least two coronary artery bypass grafts (CABGs) Multiple valve surgery with or without CABG Single or multiple valve surgery in combination with ascending aorta procedure with or without additional CABG Re-surgery of aortic valve, mitral valve, aortic arch or ascending aorta with or without CABG Cardiac surgery is performed electively Exclusion Criteria: Weight > 130 kg The following cardiac surgical procedures: Cardiac surgical procedure is planned as minimally invasive procedure (e.g., without thoracotomy or with lateral incision, minimal thoracotomy) Cardiac surgery with an expected CPB time less than 100 minutes Other cardiac and vascular diseases and/or procedures: Prior cardiac surgery within the past 6 months History of heart transplantation or planned heart transplantation Requiring inotropic, vasopressor or mechanical circulatory support Requiring ventilatory support Other disease or condition that is likely to interfere with the evaluation of the study drug: Active infective endocarditis Stroke or transient ischemic attack (TIA) within the last 6 months Concomitant disease with a life expectancy of less than 6 months Cardiopulmonary resuscitation within the last 4 weeks Patients requiring renal replacement therapy Cerebrovascular disease requiring concomitant carotid endarterectomy Active infection with or without a temperature greater than 38°C Presence of systemic inflammatory response syndrome defined as occurrence of at least 2 out of the following 4 criteria: Fever > 38.0°C or hypothermia < 36.0°C Tachycardia > 90 beats/minute Tachypnea > 20 breaths/minute Leucocytosis > 12 x 109/l or leucopenia < 4 x 109/l or > 10% immature neutrophils (bands) Positive test for human immunodeficiency virus (HIV), hepatitis B or C One of the following abnormal laboratory results: Hemoglobin < 5 mmol/l (< 8.06 g/dl) Total bilirubin ≥ 2 x upper normal limit (UNL) CRP > 3 x UNL ALAT > 3 x UNL ASAT > 3 x UNL White blood cell count < 2,500/mm³ White blood cell count > 12,000/mm³ Prohibited concomitant medications: Immunomodulatory drugs within past 30 days (e.g., TNF-inhibitors) Immunosuppressive drugs within past 30 days (e.g., cyclosporine, tacrolimus) High dose corticosteroids (e.g., > 50 mg prednisone/day or equivalent) within past 14 days Any systemic anticancer treatment within the past 3 months Planned corticosteroid pulse therapy to prevent SIRS Patients with known hypersensitivity to any constituent of the investigational medicinal product (IMP) General exclusion criteria: Pregnant (in women of childbearing potential an urine pregnancy test has to be performed) or breast-feeding women Women with childbearing potential (defined as within two years of their last menstruation) not willing to practice appropriate contraceptive measures (e.g., implanon, injections, oral contraceptives, intrauterine devices, partner with vasectomy, abstinence) while participating in the trial Participation in any interventional clinical trial within the last three months Prior randomization in this clinical trial (screen failures can be re-screened, if appropriate) Alcohol, drug, or medication abuse Employee at the study site, spouse/partner or relative of any study staff (e.g., investigator, sub-investigators, or study nurse) or relationship to the sponsor No commitment to full aggressive life support (e.g., DNR order)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IFX-1<br>dose escalating single i.v. administration of IFX-1 (verum) | Biological: IFX-1<br> <br> |
| Placebo Comparator: Placebo<br>dose escalating mimicing single i.v. administration of placebo | Biological: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak level of IL-6 |  | From prior study drug administration until 24h after start of cardiopulmonary bypass (CPB) (CPB) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of IFX-1 at each timepoint measured |  | Data will be collected at the following approximate time points: prior study drug administration; 30 min after start of infusion; up to 10 min after cessation of CPB; 3h, 12h, 24h, 48h, 96h, and 168h after start of CPB; Day 15 | 
| Maximum observed concentration (Cmax) of IFX-1 |  | Data will be collected at the following approximate time points: prior study drug administration; 30 min after start of infusion; up to 10 min after cessation of CPB; 3h, 12h, 24h, 48h, 96h, and 168h after start of CPB; Day 15 | 
| Area under the curve (AUC) of plasma concentration of IFX-1 |  | Data will be collected at the following approximate time points: prior study drug administration; 30 min after start of infusion; up to 10 min after cessation of CPB; 3h, 12h, 24h, 48h, 96h, and 168h after start of CPB; Day 15 | 
| Plasma concentration of free, detectable C5a at each timepoint measured |  | Data will be collected at the following approximate time points: prior study drug administration, prior start of CPB, up to 10 min after cessation of CPB; 3h, 6h, 12h, 24h, 48h, 96h, and 168h after start of CPB; Day 15 | 
| Serum levels of CH50 at each timepoint measured |  | Data will be collected at the following approximate time points: prior study drug administration, prior start of CPB, up to 10 min after cessation of CPB; 3h, 6h, 12h, 24h, 48h, 96h, and 168h after start of CPB; Day 15 | 
| Serum levels of IL-6 compared to baseline |  | Data will be collected at the following approximate time points: prior study drug administration, up to 10 min after cessation of CPB; 3h, 6h, 12h, 24h, 48h, and 96h after start of CPB; Day 15 | 
| Serum levels of IL-8 compared to baseline |  | Data will be collected at the following approximate time points: prior study drug administration, up to 10 min after cessation of CPB; 3h, 6h, 12h, 24h, 48h, and 96h after start of CPB; Day 15 | 
| Incidence of patients with Adverse Events (AEs) and Serious Adverse Events (SAEs) until Day 29 |  | From screening visit until Day 29 | 
| Number of patients with detection of anti-drug-antibodies |  | Up to Day 15 | 
| Number of patients that are successfully extubated 24h after end of surgery |  | 24h after end of surgery | 
| Number of patients with consecutive invasive ventilation for more than 48h after end of surgery |  | 48h after end of surgery | 
| Number of patients that are weaned of any vasopressor use 24h after end of surgery |  | 24h after end of surgery | 
| Number of patients with SIRS 24h, 48h and 96h after start of CPB |  | 24h, 48h and 96h after start of CPB | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammation, Systemic Inflammatory Response Syndrome, Pathologic Processes, Organ Dysfunction