PP100-01 (Calmangafodipir) for Overdose of Paracetamol

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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)

Conditions
-----------------
Paracetamol Overdose

Intervention / Treatment
-----------------
* Drug: PP100-01 (calmangafodipir)
* Drug: Acetylcysteine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. Provision of written informed consent Males and females of at least 16 years of age Exclusion Criteria: Patients that do not have the capacity to consent to participate in the study Patients detained under the Mental Health Act or deemed unfit by the Investigator to participate due to mental health. Patients with known permanent cognitive impairment Patients who are pregnant or nursing Patients who have previously participated in the study Unreliable history of POD Patients presenting after 24hrs of POD Patients who take anticoagulants (e.g. warfarin) therapeutically or have taken an overdose of anticoagulants 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 Prisoners 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).

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Acetylcysteine (N-acetylcysteine; NAC)<br>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<br>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)<br>* PP100-01<br>* Other names: PP100-01;Drug: Acetylcysteine<br>* NAC<br>* 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 |