E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cardioprotection for coronary artery bypass graft surgery |
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E.1.1.1 | Medical condition in easily understood language |
Protection of the heart and vital organs from oxygen deprivation during cardiac surgery |
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E.1.1.2 | Therapeutic area | Body processes [G] - Cell Physiological Phenomena [G04] |
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 | HLT |
E.1.2 | Classification code | 10007602 |
E.1.2 | Term | Cardiac and vascular procedural complications |
E.1.2 | System Organ Class | 100000004863 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066123 |
E.1.2 | Term | Cardiopulmonary bypass |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051624 |
E.1.2 | Term | Myocardial reperfusion injury |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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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 | 10018910 |
E.1.2 | Term | Haemolysis |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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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 |
To determine the optimum dose of 5-ALA to safely activate the cytoprotective molecule haem oxygenase-1 (HO-1) administered pre-operatively to patients undergoing CABG surgery.
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E.2.2 | Secondary objectives of the trial |
To evaluate how well-tolerated different doses of 5-ALA with sodium ferrous citrate (SFC) are in patients undergoing CABG surgery and identify the optimal dose based on how well it activates its target protective enzyme, HO-1.
Other questions this research study is designed to address include seeing whether 5-ALA can reduce the harmful effects of breakdown of red blood cells (haemolysis) that occurs during cardiac surgery. The study will also measure the inflammatory response to cardiac surgery and see whether 5-ALA can reduce this. The study will also examine whether normal genetic variation in HO-1 affects the response to 5-ALA (such as making it more or less effective). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age > 18 years • Scheduled for primary, isolated elective (non-emergent) CABG under cardiopulmonary bypass • Signed informed consent • Able and willing to comply with all study requirements
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E.4 | Principal exclusion criteria |
• Female participants who are pregnant, or breast feeding, or either unable or unwilling to use highly effective contraception if of child-bearing potential (under 55 years) • Acute or chronic types of porphyria • Known genetic haemochromatosis or clinically significant iron overload • History of clinically significant photosensitization • Current long-term (> 3 months) use of amiodarone • Concomitant use of hypericin extract (including St John’s Wort) or concomitant therapeutic dose oral iron replacement • History of allergic or adverse reaction to 5-ALA and/or SFC • Use of other investigational medical product(s) < 28 days prior to study • Intention to perform concomitant valve surgery (replacement and/or repair), emergency surgery (for catastrophic events) or redo surgery • Low cardiac output requiring catecholamine infusion and/or mechanical circulatory support prior to induction of anaesthesia for CABG • Recent acute myocardial infarction (within 3 weeks of surgery) – defined as elevated cardiac troponin > ULN together with symptoms of myocardial ischaemia and/or new ischaemic ECG changes within 2 weeks of surgery • Coronary surgery without cardiopulmonary bypass (i.e. off pump/OP-CABG) or induced fibrillating heart surgery • Inadequate renal or liver function defined as any of: o estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 o ALT and/or AST > 2.5 x ULN o total bilirubin > 2 x ULN (unless documented Gilbert’s syndrome) o known cirrhosis o known active hepatitis infection • Any other condition which, in the opinion of the investigator, which makes the patient unsuitable for or may compromise their participation in the study, e.g. due to safety concerns or compliance with clinical study procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HMOX1 mRNA expression (i.e. the target of 5-ALA which encodes the cytoprotective HO-1 protein) measured from peripheral blood mononuclear cells (PBMCs). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline –(i.e.after randomisation but before taking 5-ALA with SFC or placebo) and at the end of the oral dosing period prior to CABG surgery. |
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E.5.2 | Secondary end point(s) |
To (a) characterise the safety and tolerability profile of 5- ALA with sodium ferrous citrate and (b) to determine the pharmacodynamic response (change in HO-1 protein expression in PBMCs). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
A. From before the administration of the first IMP / placebo dose until 72 hours post-operatively B. At baseline – (i.e.after randomisation but before taking 5-ALA with SFC or placebo) and at the end of the oral dosing period prior to CABG surgery.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | Yes |
E.6.8 | Bioequivalence | Yes |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | No |
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 end of trial will be the date on which the last patient recruited completes the final follow-up visit as required by the protocol. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |