Aortic Valve Disease, Cardiac Surgical Procedures, Coronary Artery Bypass, Mitral Valve Disease
Conditions
Keywords
heme oxygenase, cardiopulmonary bypass, HO-1, aortic valve replacement, mitral valve surgery, 5-aminolevulinic acid, delta aminolevulinic acid, sodium ferrous citrate
Brief summary
TALEN is a prospective randomised double-blind placebo-controlled phase 2 study of 5-Aminolevulinic Acid with Sodium Ferrous Citrate (5-ALA-SFC) in adult patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). TALEN aims to identify the optimal biological dose (OBD) of 5-ALA-SFC.
Detailed description
TALEN is a prospective, randomised, double blind, placebo-controlled phase 2 study of 5-ALA-SFC administration in adults undergoing non-emergent cardiac surgery on CPB examining the potential of 5-ALA-SFC to induce haem oxygenase-1 (HO-1) as a novel cardio- and cyto-protective strategy for clinical benefit. 5-ALA is an amino acid found in several foods and a natural endogenous precursor in the synthesis of haem. Oral administration of 5-ALA-SFC has been shown to be safe and to induce a pharmacodynamic effect on the key effector, HO-1. TALEN is designed as a dose-finding trial with sequential dose cohorts, evaluating the safety, tolerability and PD response to 5-ALA-SFC to determine the optimum biological dose for further evaluation.
Interventions
DRUG5-Aminolevulinic Acid hydrochloride (5-ALA)
5-ALA: supplied for oral administration as a dark green, opaque, size 0, hypromellose (HPMC) capsule containing drug alone at a dosage strength of 75mg (58.7mg as 5-ALA). There are no excipients.
OTHERPlacebo
Supplied for oral administration as a dark green, opaque, size 0, HPMC capsule containing 125mg lactose. The capsule shells are of non-animal origin, and are comprised of HPMC, titanium dioxide, and a copper complex of chlorophyllins.
DRUGSodium ferrous citrate (SFC)
SFC: supplied for oral administration as a dark green, opaque, size 0, HPMC capsule containing drug alone at a dosage strength 118mg (12.5mg as Fe). There are no excipients.
Sponsors
SBI Pharmaceuticals Co, Ltd.
Emerald Clinical Inc.
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomisation will follow a sequential randomisation list prepared by the blinded trial statistician. As participants are randomised, they will be manually allocated the next available treatment kit (active or placebo) number from this list which will correspond to the randomisation number.
Intervention model description
Sequential dose escalation cohorts of 10 evaluable patients each (8 on active:2 on placebo) dosed twice daily (bd) with 5-ALA-SFC or placebo for three pre-operative days and once on the day of cardiac surgery. Up to 4 discrete dose levels are anticipated.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Scheduled for non-emergent cardiac surgery under CPB (including coronary artery bypass grafting, valve replacement, valve repair or a combination thereof) * Signed informed consent * Age ≥18 years * Able and willing to comply with all study requirements
Exclusion criteria
* Female participants who are of childbearing potential who are either unable or unwilling to use highly effective contraception, or who are pregnant or breast feeding * History of hypersensitivity to 5-ALA, SFC and/or porphyrins * 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 * Use of other investigational medical product(s) \< 28 days prior to study or 5 half-lives, whichever is longer * Cardiogenic shock/Low cardiac output syndrome requiring catecholamine infusion and/or mechanical circulatory support prior to induction of anaesthesia for cardiac surgery * Recent acute myocardial infarction * Cardiac surgery without cardiopulmonary bypass or induced fibrillating heart surgery * Inadequate renal or liver function * Any other condition which, in the opinion of the Investigator, makes the patient unsuitable for or may compromise their participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline HO-1 expression to time of cardiac surgery | Baseline at screening compared to post dose (measured within 12 hours of final dose, before cardiac surgery) | Normalised HO-1 expression in peripheral blood •Safety: Occurrence of adverse events / laboratory safety events defined as dose-limiting toxicity (DLTs) |
| Number of Participants With Dose Limiting Toxicity | Up to 72 hours post-surgery | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment related emergent AEs [safety and tolerability] | From time of administration of placebo or investigational medicinal product (IMP) (i.e. treatment-emergent AEs, TEAEs) to 72 hours post-operatively | Treatment-related AEs assessed using CTCAE v5.0 |
| Change from baseline HO activity to time of cardiac surgery | Baseline at screening compared to post dose (measured within 12 hours of final dose, before cardiac surgery) | HO enzyme activity |
| Preliminary evaluation of the kinetics of peri-operative myocardial injury | Serial measurements until 72 hours after release of aortic cross clamping | Cardiac troponin area under the curve for 72 hours |
Countries
United Kingdom
Outcome results
None listed