Clinical trial NCT02866825: Studying Complement Inhibition in Complex Cardiac Surgery
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Systemic Inflammatory Response Syndrome
C.Surgical Procedure; Cardiac
Keywords: Inflammation
Systemic Inflammatory Response Syndrome
Pathologic Processes
Organ Dysfunction
Lead sponsor: InflaRx GmbH
Sponsor class: INDUSTRY
First posted: 2016-08-15
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Male or female patients ≥ 18 years old
2. Written informed consent
3. 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
4. Cardiac surgery is performed electively

Exclusion Criteria:

1. Weight \> 130 kg
2. 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
3. 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
4. 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
5. Cerebrovascular disease requiring concomitant carotid endarterectomy
6. Active infection with or without a temperature greater than 38°C
7. 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)
8. Positive test for human immunodeficiency virus (HIV), hepatitis B or C
9. 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
10. 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
11. Planned corticosteroid pulse therapy to prevent SIRS
12. Patients with known hypersensitivity to any constituent of the investigational medicinal product (IMP)
13. 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)

Primary outcomes:
measure: Peak level of IL-6
timeFrame: From prior study drug administration until 24h after start of cardiopulmonary bypass (CPB) (CPB)
Secondary outcomes:
measure: Plasma concentration of IFX-1 at each timepoint measured
timeFrame: 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
measure: Maximum observed concentration (Cmax) of IFX-1
timeFrame: 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
measure: Area under the curve (AUC) of plasma concentration of IFX-1
timeFrame: 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
measure: Plasma concentration of free, detectable C5a at each timepoint measured
timeFrame: 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
measure: Serum levels of CH50 at each timepoint measured
timeFrame: 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
measure: Serum levels of IL-6 compared to baseline
timeFrame: 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
measure: Serum levels of IL-8 compared to baseline
timeFrame: 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
measure: Incidence of patients with Adverse Events (AEs) and Serious Adverse Events (SAEs) until Day 29
timeFrame: From screening visit until Day 29
measure: Number of patients with detection of anti-drug-antibodies
timeFrame: Up to Day 15
measure: Number of patients that are successfully extubated 24h after end of surgery
timeFrame: 24h after end of surgery
measure: Number of patients with consecutive invasive ventilation for more than 48h after end of surgery
timeFrame: 48h after end of surgery
measure: Number of patients that are weaned of any vasopressor use 24h after end of surgery
timeFrame: 24h after end of surgery
measure: Number of patients with SIRS 24h, 48h and 96h after start of CPB
timeFrame: 24h, 48h and 96h after start of CPB
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Study Site
city: Dortmund
country: Germany
facility: Study Site
city: Dresden
country: Germany
facility: Study Site
city: Freiburg
country: Germany
facility: Study Site
city: Heidelberg
country: Germany
facility: Study Site
city: Jena
country: Germany
facility: Study Site
city: Kiel
country: Germany
facility: Study Site
city: Leipzig
country: Germany
facility: Study Site
city: Trier
country: Germany
facility: Study Site
city: Tuebingen
country: Germany
facility: Study Site
Study officials:
affiliation: University Hospital Jena
name: Torsten Doenst, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: