A randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN)
<p>Haem oxygenase-1 (HO-1) is an evolutionarily highly conserved, ubiquitously expressed protein with critical antioxidant and pro-survival effects, primarily responsible for catalysing haem breakdown into equimolar quantities of carbon monoxide, biliverdin, and ferrous iron – each bioactive s...
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| Formáid: | Tráchtas |
| Teanga: | English |
| Foilsithe / Cruthaithe: |
2024
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| Ábhair: |
| _version_ | 1826314449980489728 |
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| author | Kingwill, AC |
| author2 | Ashrafian, H |
| author_facet | Ashrafian, H Kingwill, AC |
| author_sort | Kingwill, AC |
| collection | OXFORD |
| description | <p>Haem oxygenase-1 (HO-1) is an evolutionarily highly conserved, ubiquitously expressed protein with critical antioxidant and pro-survival effects, primarily responsible for catalysing haem breakdown into equimolar quantities of carbon monoxide, biliverdin, and ferrous iron – each bioactive signalling molecules. Through its enzymatic role to catabolise haem, as well as through multiple non-enzymatic functions including favourable effects on immune cell regulation, immunometabolism and iron homeostasis, HO-1 represents an attractive therapeutic target for improving outcomes after cardiac surgery on cardiopulmonary bypass (CPB) which is associated with cardiac ischaemia-reperfusion injury, haem toxicity, sterile systemic inflammation with risk of organ injury. A prior Mendelian randomisation study in 2377 adult patients undergoing cardiac surgery on CPB linked genetically driven increased HO-1 function with lower acute kidney injury (AKI). Treatment with 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA-SFC) represents a pharmacological strategy to enhance HO-1 activity, mitigate haem-driven toxicity and reduce inflammation to potentially improve patient outcomes following cardiac surgery.</p>
<p>The TALEN trial was a phase II, single centre, randomised, double-blind, dose-finding adaptive translational trial evaluating the safety, tolerability and pharmacodynamic effects of oral 5-ALA-SFC administered pre-operatively for 3 days in 4 sequential dosing cohorts of patients (8 active:2 placebo) through evaluation of HO activity, immunophenotyping and biomarkers of organ injury to determine an optimal biological dose for future evaluation.</p>
<p>All dose level cohorts were successfully enrolled. A total of 48 patients were randomised with the resulting study population predominantly male with a median age of 69 years undergoing a mix of surgery (isolated coronary artery bypass grafting, aortic and mitral valve repair/replacement) on CPB. 5-ALA-SFC was well tolerated, with no adverse safety signals including no treatment-related serious adverse events or dose limiting toxicity. Drug compliance was excellent. A novel LC-MS/MS based HO activity assay developed for the trial in combination with monocyte immunoprofiling identified the highest dose of 5-ALA-SFC evaluated (300 mg/472 mg) as most robustly activating HO-1. Compared with placebo, treatment with 5-ALA-SFC was also associated with significantly reduced post-operative inflammation measured by CRP and IL-6. 5-ALA-SFC showed a significant renoprotective effect across all doses. No significant difference in peri-operative myocardial injury was identified using troponin I measurements although 5-ALA-SFC groups had numerically lower arrhythmia and inotrope requirements compared to placebo. Immunophenotyping by multiparameter flow cytometry revealed a 5-ALA-SFC treatment-associated monocyte phenotypic commitment to favour erythrophagocytosis and a ferrostatic, iron regulatory role.</p>
<p>The findings highlight the ability of pre-operative dosing with 5-ALA-SFC to induce HO-1, exert immunomodulatory effects including altered monocyte immunophenotype and induce renoprotection. These support the further evaluation of the potential of 5-ALA-SFC to improve clinical outcomes in patients undergoing cardiac surgery on CPB, particularly reducing risk of acute kidney injury, in appropriately powered larger trials.</p> |
| first_indexed | 2024-09-25T04:34:12Z |
| format | Thesis |
| id | oxford-uuid:e26bc0bf-0868-4c3a-a452-c7e78a154006 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:34:12Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:e26bc0bf-0868-4c3a-a452-c7e78a1540062024-09-05T07:56:37ZA randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN)Thesishttp://purl.org/coar/resource_type/c_db06uuid:e26bc0bf-0868-4c3a-a452-c7e78a154006Clinical trialsMedicineEnglishHyrax Deposit2024Kingwill, ACAshrafian, HRowland, MSayeed, RYavari, A<p>Haem oxygenase-1 (HO-1) is an evolutionarily highly conserved, ubiquitously expressed protein with critical antioxidant and pro-survival effects, primarily responsible for catalysing haem breakdown into equimolar quantities of carbon monoxide, biliverdin, and ferrous iron – each bioactive signalling molecules. Through its enzymatic role to catabolise haem, as well as through multiple non-enzymatic functions including favourable effects on immune cell regulation, immunometabolism and iron homeostasis, HO-1 represents an attractive therapeutic target for improving outcomes after cardiac surgery on cardiopulmonary bypass (CPB) which is associated with cardiac ischaemia-reperfusion injury, haem toxicity, sterile systemic inflammation with risk of organ injury. A prior Mendelian randomisation study in 2377 adult patients undergoing cardiac surgery on CPB linked genetically driven increased HO-1 function with lower acute kidney injury (AKI). Treatment with 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA-SFC) represents a pharmacological strategy to enhance HO-1 activity, mitigate haem-driven toxicity and reduce inflammation to potentially improve patient outcomes following cardiac surgery.</p> <p>The TALEN trial was a phase II, single centre, randomised, double-blind, dose-finding adaptive translational trial evaluating the safety, tolerability and pharmacodynamic effects of oral 5-ALA-SFC administered pre-operatively for 3 days in 4 sequential dosing cohorts of patients (8 active:2 placebo) through evaluation of HO activity, immunophenotyping and biomarkers of organ injury to determine an optimal biological dose for future evaluation.</p> <p>All dose level cohorts were successfully enrolled. A total of 48 patients were randomised with the resulting study population predominantly male with a median age of 69 years undergoing a mix of surgery (isolated coronary artery bypass grafting, aortic and mitral valve repair/replacement) on CPB. 5-ALA-SFC was well tolerated, with no adverse safety signals including no treatment-related serious adverse events or dose limiting toxicity. Drug compliance was excellent. A novel LC-MS/MS based HO activity assay developed for the trial in combination with monocyte immunoprofiling identified the highest dose of 5-ALA-SFC evaluated (300 mg/472 mg) as most robustly activating HO-1. Compared with placebo, treatment with 5-ALA-SFC was also associated with significantly reduced post-operative inflammation measured by CRP and IL-6. 5-ALA-SFC showed a significant renoprotective effect across all doses. No significant difference in peri-operative myocardial injury was identified using troponin I measurements although 5-ALA-SFC groups had numerically lower arrhythmia and inotrope requirements compared to placebo. Immunophenotyping by multiparameter flow cytometry revealed a 5-ALA-SFC treatment-associated monocyte phenotypic commitment to favour erythrophagocytosis and a ferrostatic, iron regulatory role.</p> <p>The findings highlight the ability of pre-operative dosing with 5-ALA-SFC to induce HO-1, exert immunomodulatory effects including altered monocyte immunophenotype and induce renoprotection. These support the further evaluation of the potential of 5-ALA-SFC to improve clinical outcomes in patients undergoing cardiac surgery on CPB, particularly reducing risk of acute kidney injury, in appropriately powered larger trials.</p> |
| spellingShingle | Clinical trials Medicine Kingwill, AC A randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN) |
| title | A randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN) |
| title_full | A randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN) |
| title_fullStr | A randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN) |
| title_full_unstemmed | A randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN) |
| title_short | A randomised control trial of 5-aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery (TALEN) |
| title_sort | randomised control trial of 5 aminolevulinic acid in combination with sodium ferrous citrate to enhance cardioprotection in adults undergoing cardiac surgery talen |
| topic | Clinical trials Medicine |
| work_keys_str_mv | AT kingwillac arandomisedcontroltrialof5aminolevulinicacidincombinationwithsodiumferrouscitratetoenhancecardioprotectioninadultsundergoingcardiacsurgerytalen AT kingwillac randomisedcontroltrialof5aminolevulinicacidincombinationwithsodiumferrouscitratetoenhancecardioprotectioninadultsundergoingcardiacsurgerytalen |