| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of organ dysfunction induced by inflammatory response after complex cardiac surgery |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063101 |
| E.1.2 | Term | Post procedural inflammation |
| E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062357 |
| E.1.2 | Term | SIRS |
| E.1.2 | System Organ Class | 100000004867 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of four different doses of IFX-1 on IL-6 peak levels in patients undergoing complex cardiac surgery compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the pharmacokinetics and pharmacodynamics of IFX-1 and to characterize the safety and tolerability at different doses.
To evaluate a potential efficacy of IFX-1 on clinical surrogate endpoints (e.g., duration of mechanical ventilation, use of vasopressor, number of patients with Systemic inflammatory response syndrome (SIRS), Sequential organ failure assessment (SOFA) Score, length of intensive care unit (ICU) stay).
|
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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):
a.Single valve surgery in combination with at least two coronary artery bypass grafts (CABGs)
b.Multiple valve surgery with or without CABG
c.Single or multiple valve surgery in combination with ascending aorta procedure with or without additional CABG
d.Re-surgery of aortic valve, mitral valve, aortic arch or ascending aorta with or without CABG
4.Cardiac surgery is performed electively |
|
| E.4 | Principal exclusion criteria |
1.Weight > 130 kg
2.The following cardiac surgical procedures:
a.Cardiac surgical procedure is planned as minimally invasive procedure (e.g., without thoracotomy or with lateral incision, minimal thoracotomy)
b.Cardiac surgery with an expected CPB time less than 100 minutes
3.Other cardiac and vascular diseases and/or procedures:
a.Prior cardiac surgery within the past 6 months
b.History of heart transplantation or planned heart transplantation
c.Requiring inotropic, vasopressor or mechanical circulatory support
d.Requiring ventilatory support
4.Other disease or condition that is likely to interfere with the evaluation of the study drug:
a.Active infective endocarditis
b.Stroke or transient ischemic attack (TIA) within the last 6 months
c.Concomitant disease with a life expectancy of less than 6 months
d.Cardiopulmonary resuscitation within the last 4 weeks
e.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:
a.Fever > 38.0°C or hypothermia < 36.0°C
b.Tachycardia > 90 beats/minute
c.Tachypnea > 20 breaths/minute
d.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:
a.Hemoglobin < 5 mmol/l (< 8.06 g/dl)
b.Total bilirubin ≥ 2 x upper normal limit (UNL)
c.CRP > 3 x UNL
d.ALAT > 3 x UNL
e.ASAT > 3 x UNL
f.White blood cell count < 2,500/mm³
g.White blood cell count > 12,000/mm³
10.Prohibited concomitant medications:
a.Immunomodulatory drugs within past 30 days (e.g., TNF-inhibitors)
b.Immunosuppressive drugs within past 30 days (e.g., cyclosporine, tacrolimus)
c.High dose corticosteroids (e.g., > 50 mg prednisone/day or equivalent) within past 14 days
d.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:
a.Pregnant (in women of childbearing potential an urine pregnancy test has to be performed) or breast-feeding women
b.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
c.Participation in any interventional clinical trial within the last three months
d.Prior randomization in this clinical trial (screen failures can be re-screened, if appropriate)
e.Alcohol, drug, or medication abuse
f.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
g.No commitment to full aggressive life support (e.g., DNR order) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The peak level of IL-6 in patients undergoing a complex cardiac surgery from prior to study drug administration until 24 hours after start of CPB. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From prior to study drug administration until 24 hours after start of CPB |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics (PK)
Measured by plasma concentration of IFX-1 which is determined several times after administration of IFX-1. Analysis of plasma concentration of IFX-1 will comprise the following measures:
•Plasma concentration at each timepoint,
•Maximum observed concentration (Cmax),
•Area under the curve (AUC) of plasma concentration,
•Terminal phase half-life.
Pharmacodynamics (PD)
PD is primarily measured by peak levels of IL-6 which are determined prior to study drug administration (i.e., baseline) until 24 hours after start of CPB.
Secondly, pharmacodynamics are investigated at each timepoint measured and compared to baseline (i.e., prior to study drug administration) and in between groups for the following parameters:
•Plasma concentration of free, detectable C5a,
•Bioactivity of IFX-1 at timepoints where the plasma concentration of IFX-1 is above 7.3 µg/ml,
•Complement activation:
oPlasma levels of C3a,
oSerum level of CH50,
•Cytokines: serum levels of IL-6, IL-8, IL-10, IFN-γ, TNF-α,
•Serum concentration of CRP,
•Serum concentration of Procalcitonin,
•Serum concentration of Troponin I,
•Serum concentration of CK-MB,
•Plasma concentration of Neutrophil Elastase,
•Arterial blood concentration of Lactate.
Safety and tolerability
•Number and percentage of patients with adverse events until Day 29,
•Number and percentage of patients with AEs grouped (i) by severity, and (ii) by causal relationship to study medication,
•Number and percentage of patients with Serious Adverse Events (SAEs) (i) in total and (ii) grouped by causal relationship to study medication,
•Changes in routine laboratory parameters (red blood cells, hemoglobin, platelets, white blood cells, total bilirubin, serum creatinine, urea, ALAT, ASAT, LDH, AP, GLDH, PPT, INR) as compared to baseline assessments (i.e., prior to study drug administration),
•Change in vital signs as compared to baseline assessment (during screening visit),
•Change in ECG as compared to baseline during screening visit,
•Number of patients with detection of anti-drug antibody (pre-/post-dosing).
Efficacy
•Invasive ventilation
•Vasopressor use
•SIRS (Systemic inflammatory response syndrome)
•SOFA (Sequential organ failure assessment_
•RRT (Renal replacement therapy ) and acute kidney injury
•Fluid balance
Other efficacy endpoints are described by:
•Invasive ventilation
•Vasopressor use
•SIRS
•SOFA
•RRT
•Fluid balance
•Body weight change at 24 hours, 48 hours, 96 hours and 168 hours after start of CPB as well as on Day 15 or day of hospital discharge compared to screening visit
•All-cause Mortality
•Number of patients with diagnosed VAP until Day 15 after end of surgery
•Number of patients with diagnosed HAP until Day 15 after end of surgery
•Metabolic Organ Dysfunction Score
•Length of stay on ICU/IMC
•Length of hospital stay
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK - various timepoints
PD - primarily, prior to baseline until 24 hours after start of cardiac pulmonary bypass
Safety and Tolerability - from baseline until follow up
Efficacy - various timepoints from baseline to follow up |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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