E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients undergoing invasive cardiac surgery with prolonged perfusion time. This often is associated with potentially life-threatening inflammatory complications due to ischemic periods during surgery both local (Damaged tissue release of nucleotide) and at sites distant from there (e.g. ischemia of the intestinal tract). Alkaline phosphatase detoxifies nucleotides and bacterial toxins and consequently reduces the overall inflammatory insult as demonstrated in the preceding APPIRED I study. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057944 |
E.1.2 | Term | Combined valvular disease |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of this study is to determine the efficacy of bIAP as a prophylactic agent against inflammation-mediated complications from more invasive cardiac surgery, valvular surgery and CABG with cardiopulmonary-bypass time of longer than 1 hour.
Primary study endpoint is the postulated reduction of the number of post-surgical SIRS cases in the bIAP-treated patient group as compared to the placebo-treated group. SIRS, in the sense of this study, is indicated by an increased TNF-α level of at least 10 pg/ml above the pre-surgical level, which is normally followed by an increase of IL-6 and IL-8. |
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E.2.2 | Secondary objectives of the trial |
The incidence of new organ dysfunction within 14 days of surgery will be assessed, next to the duration of organ dysfunction, lengths of organ dysfunction-associated intensive care unit (ICU) and hospital stays, ventilation-assistance and renal failure-dialysis days, volume of blood and blood products infused within 24 hours of surgery, incidence of hospital readmission and 30-day all-cause mortality. Safety will be assessed by incidence and severity of adverse events, changes in physical examination, vital signs and changes in clinical laboratory measurements. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or non-pregnant, non-lactating female patients of any race in the ages of >18 years. 2. Patients scheduled for combined aortic valve replacement and CABG surgery 3. Patients who have given written informed consent prior to participation in the trial and who undertake to comply with the protocol. |
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E.4 | Principal exclusion criteria |
1. Patients who are unwilling or unable to be fully evaluated for follow-up. 2. Patients who have base AP levels at > 125 IU/L, or levels < 30 IU/L (ammediol, DEA (diethanolamine) units) 3. Patients who show pre-operative infections or who are suspected of endocarditis or systemic infection. 4. Patients who refuse to accept medically-indicated blood products. 5. Patients who have evidence of significant hepatic disease, including history of clinical signs or laboratory values of total bilirubin > 34.2 µmol/L (> 2.0 mg/dL), ALT (>120) or AST (>135) corresponding to > 3X upper limit of normal. 6. Patients who received investigational drugs in the 30 days prior to study drug administration, or are currently participating in a study during which the administration of investigational drugs within one month is anticipated. 7. Patients who require pre-operative ventilatory support. 8. Patients who have renal insufficiency (history of creatinine >177µmol/L or >2.0 mg/dL) or chronic renal failure requiring dialysis. 9. Patients who are planned to receive leukocyte-depletion filtration as part of the bypass circuitry. 10. Patients with severe neurological deficits. 11. Patients who have a recent history of drug or alcohol abuse. 12. Patients with a diagnosis of idiopathic thrombocytopenia. 13. Patients with a history of cancer who have received chemotherapy or radiation therapy within the past 3 months. Patients receiving only adjuvant hormonal therapy are not excluded. 14. Patients who are scheduled to receive "stress doses" of glucocorticoids (i.e., doses >2 mg/kg/day of methylprednisolone or equivalent) prior to, during or following surgery. 15. Patients who are vegetarians or veganists or those patients that may be expected not to be tolerant for bovine proteins. 16. Patients who are, in the opinion of the investigator, unsuitable for the study. A well-documented screening log should be present in the clinic. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Main study primary endpoint is the reduction of post-surgical SIRS in bIAP–treated patients as compared to placebo–treated patients,that is the reduction of incidences of fulminate SIRS responses, indicated by pro-Inflammatory cytokines. The pro-inflammatory cytokine (TNF-α, IL-6 and IL-8) levels will be measured |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | Information not present in EudraCT |
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
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The expected mortality will be calculated within this study based on the individual EuroSCORE of the patients included. If at any time the 30-day mortality in the verum group exceeds the confidence interval, this will be reason to terminate the study.
If any new safety risk regarding the study drugs came aware to the sponsor or the investigator this will be reason to assess the ongoing study.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 2 |