PMID- 31311721
OWN - NLM
STAT- MEDLINE
DCOM- 20200115
LR  - 20220317
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 46
DP  - 2019 Aug
TI  - 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).
PG  - 423-430
LID - S2352-3964(19)30448-7 [pii]
LID - 10.1016/j.ebiom.2019.07.013 [doi]
AB  - 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 mumol/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 mumol/kg), 4/6; NAC + calmangafodipir (5 
      mumol/kg), 2/6; NAC + calmangafodipir (10 mumol/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 mumol/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.
CI  - Copyright (c) 2019. Published by Elsevier B.V.
FAU - Morrison, Emma E
AU  - Morrison EE
AD  - Pharmacology, Therapeutics and Toxicology Unit, Centre for Cardiovascular 
      Science, University of Edinburgh, UK.
FAU - Oatey, Katherine
AU  - Oatey K
AD  - Edinburgh Clinical Trials Unit, UK.
FAU - Gallagher, Bernadette
AU  - Gallagher B
AD  - Emergency Medicine Research Group, Royal Infirmary of Edinburgh, UK.
FAU - Grahamslaw, Julia
AU  - Grahamslaw J
AD  - Emergency Medicine Research Group, Royal Infirmary of Edinburgh, UK.
FAU - O'Brien, Rachel
AU  - O'Brien R
AD  - Emergency Medicine Research Group, Royal Infirmary of Edinburgh, UK.
FAU - Black, Polly
AU  - Black P
AD  - Emergency Medicine Research Group, Royal Infirmary of Edinburgh, UK.
FAU - Oosthuyzen, Wilna
AU  - Oosthuyzen W
AD  - Pharmacology, Therapeutics and Toxicology Unit, Centre for Cardiovascular 
      Science, University of Edinburgh, UK.
FAU - Lee, Robert J
AU  - Lee RJ
AD  - Edinburgh Clinical Trials Unit, UK.
FAU - Weir, Christopher J
AU  - Weir CJ
AD  - Edinburgh Clinical Trials Unit, UK.
FAU - Henriksen, Dennis
AU  - Henriksen D
AD  - PledPharma AB, Stockholm, Sweden.
FAU - Dear, James W
AU  - Dear JW
AD  - Pharmacology, Therapeutics and Toxicology Unit, Centre for Cardiovascular 
      Science, University of Edinburgh, UK. Electronic address: james.dear@ed.ac.uk.
CN  - POP Trial Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT03177395
GR  - MC_PC_12014/MRC_/Medical Research Council/United Kingdom
GR  - RE/08/001/BHF_/British Heart Foundation/United Kingdom
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20190713
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Biomarkers)
RN  - 0 (Protective Agents)
RN  - 362O9ITL9D (Acetaminophen)
RN  - 5V5IOJ8338 (Pyridoxal Phosphate)
RN  - 9G34HU7RV0 (Edetic Acid)
RN  - P28BIW0UTB (N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
CIN - EBioMedicine. 2019 Sep;47:27. PMID: 31466917
MH  - Acetaminophen/*administration & dosage/*adverse effects
MH  - Acetylcysteine/*therapeutic use
MH  - Adult
MH  - Biomarkers
MH  - Chemical and Drug Induced Liver Injury/*drug therapy/*etiology/metabolism
MH  - Drug Interactions
MH  - Drug Overdose
MH  - Edetic Acid/*analogs & derivatives/therapeutic use
MH  - Female
MH  - Humans
MH  - Male
MH  - Protective Agents/*therapeutic use
MH  - Pyridoxal Phosphate/*analogs & derivatives/therapeutic use
MH  - Time Factors
MH  - Young Adult
PMC - PMC6710902
COIS- 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.
EDAT- 2019/07/18 06:00
MHDA- 2020/01/16 06:00
PMCR- 2019/07/13
CRDT- 2019/07/18 06:00
PHST- 2019/06/07 00:00 [received]
PHST- 2019/07/03 00:00 [accepted]
PHST- 2019/07/18 06:00 [pubmed]
PHST- 2020/01/16 06:00 [medline]
PHST- 2019/07/18 06:00 [entrez]
PHST- 2019/07/13 00:00 [pmc-release]
AID - S2352-3964(19)30448-7 [pii]
AID - 10.1016/j.ebiom.2019.07.013 [doi]
PST - ppublish
SO  - EBioMedicine. 2019 Aug;46:423-430. doi: 10.1016/j.ebiom.2019.07.013. Epub 2019 
      Jul 13.