Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12 h regimen of N-acetylcysteine for paracetamol overdose (POP trial)
Emma E Morrison, Katherine Oatey, Bernadette Gallagher, Julia Grahamslaw, Rachel O'Brien, Polly Black, Wilna Oosthuyzen, Robert J Lee, Christopher J Weir, Dennis Henriksen, James W Dear, POP Trial Investigators, Emma E Morrison, Katherine Oatey, Bernadette Gallagher, Julia Grahamslaw, Rachel O'Brien, Polly Black, Wilna Oosthuyzen, Robert J Lee, Christopher J Weir, Dennis Henriksen, James W Dear, POP Trial Investigators
Abstract
Background: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose.
Methods: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 μmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395).
Findings: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 μmol/kg), 4/6; NAC + calmangafodipir (5 μmol/kg), 2/6; NAC + calmangafodipir (10 μmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 μmol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected.
Interpretation: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.
Conflict of interest statement
Dr. Dennis Henriksen and Ms. Marie Bengtson are employed by PledPharma AB. Dr. Dear is a member of the expert advisory group for the EU IMI funded TransBioLine Consortium.
Copyright © 2019. Published by Elsevier B.V.
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Source: PubMed