E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
systemic inflammation as side-effect of heart-lung machine during cardiac surgery |
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E.1.1.1 | Medical condition in easily understood language |
side-effects of heart-lung machine during cardiac surgery |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
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 | 10017501 |
E.1.2 | Term | Functional disturbances following cardiac surgery |
E.1.2 | System Organ Class | 100000004863 |
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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 |
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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 |
Demonstrate that alkaline phosphatase reduces the incidence and extent of acute kidney injury after cardiopulmonary bypass as defined by the AKIN criteria. • Rise in serum creatinine of by 0.3 mg/dl or 26 µmol/L in 48 hours/ a percentage increase in the serum creatinine concentration of ≥50 percent 10 or • A drop in urine output to 0.5 ml/kg/hour for 6 hours Demonstrate that alkaline phosphatase reduces overall morbidity and mortality - time to extubation [ defined as removal of endotracheal tube] - reduce GI Complications : defined as demonstrable nasogastric bleeding > 12 hours , malena or positive faecal occult blood - reduce Neuro Complications : defined as focal neurological deficit of central origin lasting more than 72 hours demonstrable on a CT scan. |
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E.2.2 | Secondary objectives of the trial |
1. Measure cost-related outcomes associated to CPB and AP intervention including a) the incidence of renal replacement therapy, b) duration of renal replacement therapy, c) days spent in the ICU and hospital, and d) the incidence of arrhythmias in the two groups 2. Compare plasma levels of a set of inflammatory markers (IL-6, IL-8, IL-10, TNF-alpha) and increase endogenous alkaline phosphatase levels and kidney function markers (IL18, NGAL, TIMP-2, GFR) in the control and AP treated groups.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A potential subject must meet all of the following criteria to participate in the study: 1. > 21 years of age (legal adult in Singapore) 2. Undergoing cardiac surgery with planned cardiopulmonary bypass 3. EuroSCORE II >= 3 4. Ability to provide informed consent (not incapacitated) |
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E.4 | Principal exclusion criteria |
Any subjects meeting the following criteria at baseline will be excluded: 1. Already on renal replacement therapy 2. Patients with chronic kidney disease defined as estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m2. [ CKD stage > 3] 3. Patients who are pregnant 4. Concurrent enrolment in another clinical trial 5. Known allergic reaction to bovine alkaline phosphatase or patient is vegetarian, vegan, or does not consume any bovine meat products (beef) that is, the patient may not be tolerant for bovine proteins 6. Patients with ongoing infections or current use of steroids. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy We will have two efficacy endpoints that will be independently monitored by the data-safety monitoring board:
• Stop administering placebo but continue with experimental drug if AKI (defined by AKIN) is significantly lower in the experimental group • Stop administering placebo but continue with experimental drug if mortality is significantly lower in the experimental group.
Given the results of previous studies in sepsis patients, we anticipate that the greatest benefits will be seen in the prevention of AKI in the experimental group. If these benefits reach a level of statistical significance and are considered clinically relevant at any of the yearly reviews, the DSMB will recommend that the placebo arm be stopped and all patients receive the experimental drug.
Safety We will have two safety endpoints that will be independently monitored by the data-safety monitoring board.
• Stop if all cause mortality, cardiac mortality, acute kidney injury, or the primary compound outcome is significantly higher in the experimental group • Stop if more than 5% of patients have a serious adverse/allergic reaction to the administration of the drug.
The safety committee will review the safety endpoints once at the 30-day mark to ensure there are no immediate safety concerns with the trial and then proceed with a yearly review of the outcomes
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
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 | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Malaysia |
Russian Federation |
Singapore |
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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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• Stop after 2 years after enrollment of the first patient if the current enrollment rate will not allow the study to be finished in ultimately 5 years and likely less than 4 years. • Stop after 2 years if the event rate is significantly lower than anticipated and will not allow the study to be adequately powered with the estimated sample size |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |