PP100-01 (Calmangafodipir) for Overdose of Paracetamol (POP)

A Randomised Open Label Exploratory, Safety and Tolerability Study With PP100-01 in Patients Treated With the 12-hour Regimen of N-Acetylcysteine for Paracetamol/Acetaminophen Overdose (The POP Trial)

Investigate the safety and tolerability of PP100-01 add-on treatment to the 12hr NAC treatment regime in patients treated for paracetamol/acetaminophen overdose (POD) when NAC treatment is initiated before 24hours post POD.

Study Overview

• Status: Completed
• Conditions: Paracetamol Overdose
• Intervention / Treatment: Drug: PP100-01 (calmangafodipir); Drug: Acetylcysteine

Detailed Description

The study will be an open label, randomised, exploratory, rising dose design, NAC controlled, phase 1 safety and tolerability study in patients treated with NAC for paracetamol/acetaminophen overdose.

Entry into the study will depend on the patient's blood results confirming the need for NAC. A total of 24 patients will be assigned into one of 3 dosing cohorts of 8 patients (N=6 for PP100-01 and NAC; N=2 for NAC alone).

The study will primarily evaluate safety and tolerability for treatment with PP100-01 in combination with NAC as compared to NAC alone.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • City Of Edinburgh
    • Edinburgh, City Of Edinburgh, United Kingdom, EH16 4SA
      • Royal Infirmary of Edinburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Any patient with capacity admitted to hospital within 24 hrs either a single acute POD or more than one dose of paracetamol (staggered) and deemed to require treatment with NAC.
2. Provision of written informed consent
3. Males and females of at least 16 years of age

Exclusion Criteria:

1. Patients that do not have the capacity to consent to participate in the study
2. Patients detained under the Mental Health Act or deemed unfit by the Investigator to participate due to mental health.
3. Patients with known permanent cognitive impairment
4. Patients who are pregnant or nursing
5. Patients who have previously participated in the study
6. Unreliable history of POD
7. Patients presenting after 24hrs of POD
8. Patients who take anticoagulants (e.g. warfarin) therapeutically or have taken an overdose of anticoagulants
9. Patients who, in the opinion of the responsible clinician/nurse, are unlikely to complete the full course of NAC e.g. expressing wish to self-discharge
10. Prisoners
11. Non-English speaking patients. (Study information material will only be produced in English in view of the known and stable demographic of the Edinburgh self-harm population).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: Acetylcysteine (N-acetylcysteine; NAC); NAC infusion 100mg/kg in 200ml 'loading dose' at timepoint '0'. 12 hour NAC regime will be continued with the second dose: 200mg/kg NAC in 1000ml i.v. over 10hr as per standard care protocol in NHS Lothian.
EXPERIMENTAL: PP100-01 (Calmangafodipir)+ NAC; In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: Group A: PP100-01 (2 umol/kg calmangafodipir) after the "loading" dose of NAC; Group B: PP100-01 (5 umol/kg calmangafodipir) after the "loading" dose of NAC; Group C: PP100-01 (10 umol/kg calmangafodipir) after the "loading" dose of NAC PP100-01 treatment is administered intravenously over 5 minutes.	Drug: PP100-01 (calmangafodipir); PP100-01; Other Names: PP100-01; Drug: Acetylcysteine; NAC; Other Names: N-acetylcysteine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Events	Adverse Events and Serious Adverse Events	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ALT(U/L)	The alanine aminotransferase (ALT) test is a blood test that checks for liver damage.	Baseline
ALT(U/L)	The alanine aminotransferase (ALT) test is a blood test that checks for liver damage.	10 hours
ALT(U/L)	The alanine aminotransferase (ALT) test is a blood test that checks for liver damage.	20 hours
INR	international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)	Baseline
INR	international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)	10 hours
INR	international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)	20 hours
INR	international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)	value at 20 hours divided by baseline value for each patient
Additional NAC Infusion	participants required additional NAC infusions after the 12-hour NAC regimen	Additional NAC at 12 hour
K18 (U/L)	In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.	Baseline (2 hours)
K18(U/L)	In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.	10 hours
K18 (U/L)	In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.	20 hours
K18 (U/L)	In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.	Ratio - value at 20 hours divided by baseline value for each patient
ccK18 (U/L)	The shorter, Caspase cleaved form of K-18 is released following hepatocyte apoptosis (programmed cell death).	Baseline (2 hours)
ccK18 (U/L)	The shorter, Caspase cleaved form of K-18 is released following hepatocyte apoptosis (programmed cell death).	10 hours
ccK18 (U/L)	The shorter, Caspase cleaved form of K-18 is released following hepatocyte apoptosis (programmed cell death).	20 hours
ccK18 (U/L)	Caspace-cleaved Keratin-18	Ratio - value at 20 hours divided by baseline value for each patient
miR-122 (Delta Count)	MiR-122 is a biomarker specific for liver injury and fully conserved (translational) across in vitro models, in vivo models and humans. MiR-122 is an early marker for acute liver injury which predicts a rise in ALT activity following paracetamol overdose	Baseline (2 hours)
miR-122 (Delta Count)	MiR-122 is a biomarker specific for liver injury and fully conserved (translational) across in vitro models, in vivo models and humans. MiR-122 is an early marker for acute liver injury which predicts a rise in ALT activity following paracetamol overdose	10 hours
miR-122 (Delta Count)	MiR-122 is a biomarker specific for liver injury and fully conserved (translational) across in vitro models, in vivo models and humans. MiR-122 is an early marker for acute liver injury which predicts a rise in ALT activity following paracetamol overdose	20 hours
miR-122 (Copies/mcL)	MiR-122 is a biomarker specific for liver injury and fully conserved (translational) across in vitro models, in vivo models and humans. MiR-122 is an early marker for acute liver injury which predicts a rise in ALT activity following paracetamol overdose	Baseline (2 h)
miR-122(Copies/mcL)	MiR-122 is a biomarker specific for liver injury and fully conserved (translational) across in vitro models, in vivo models and humans. MiR-122 is an early marker for acute liver injury which predicts a rise in ALT activity following paracetamol overdose	10 hours
miR-122 (Copies/mcL)	MiR-122 is a biomarker specific for liver injury and fully conserved (translational) across in vitro models, in vivo models and humans. MiR-122 is an early marker for acute liver injury which predicts a rise in ALT activity following paracetamol overdose	20 hours
miR-122 (Copies/mcL)	MiR-122 is a biomarker specific for liver injury and fully conserved (translational) across in vitro models, in vivo models and humans. MiR-122 is an early marker for acute liver injury which predicts a rise in ALT activity following paracetamol overdose	Ratio - value at 20 hours divided by baseline value for each patient

Collaborators and Investigators

• Sponsor: Egetis Therapeutics
• Collaborators: University of Edinburgh; NHS Lothian

Publications and helpful links

General Publications

• Morrison EE, Oatey K, Gallagher B, Grahamslaw J, O'Brien R, Black P, Oosthuyzen W, Lee RJ, Weir CJ, Henriksen D, Dear JW; POP Trial Investigators. 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). EBioMedicine. 2019 Aug;46:423-430. doi: 10.1016/j.ebiom.2019.07.013. Epub 2019 Jul 13.
• POP Trial Investigators; Dear J. Randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with the 12-h regimen of N-acetylcysteine for paracetamol overdose-the PP100-01 for Overdose of Paracetamol (POP) trial: study protocol for a randomised controlled trial. Trials. 2019 Jan 8;20(1):27. doi: 10.1186/s13063-018-3134-1.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 8, 2017
• Primary Completion (ACTUAL): August 8, 2018
• Study Completion (ACTUAL): November 8, 2018

Study Registration Dates

• First Submitted: May 23, 2017
• First Submitted That Met QC Criteria: June 2, 2017
• First Posted (ACTUAL): June 6, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 3, 2019
• Last Update Submitted That Met QC Criteria: September 10, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Substance-Related Disorders; Drug Overdose; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: PP100-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No