PP100-01 (Calmangafodipir) for Overdose of Paracetamol

Phase 1

Completed

• Conditions: Paracetamol Overdose
• Interventions: Drug: PP100-01 (calmangafodipir); Drug: Acetylcysteine

• Registration Number: NCT03177395
• Lead Sponsor: Egetis Therapeutics

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.

Study Timeline

• Study First Submitted: 2017-05-23
• Study First Submitted QC: 2017-06-02
• Study First Posted: 2017-06-06
• Study Start: 2017-06-08
• Primary Completion: 2018-08-08
• Study Completion: 2018-11-08
• Results First Submitted: 2019-07-30
• Status Verified: 2019-09
• Results First Submitted QC: 2019-09-10
• Last Update Submitted: 2019-09-10
• Results First Posted: 2019-10-03
• Last Update Posted: 2019-10-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PP100-01 (Calmangafodipir)+ NAC	PP100-01 (calmangafodipir)	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.
PP100-01 (Calmangafodipir)+ NAC	Acetylcysteine	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.

Primary Outcome Measures

Name	Time	Method
Safety Events	90 days	Adverse Events and Serious Adverse Events

Secondary Outcome Measures

Name	Time	Method
ALT(U/L)	20 hours	The alanine aminotransferase (ALT) test is a blood test that checks for liver damage.
INR	value at 20 hours divided by baseline value for each patient	international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)
Additional NAC Infusion	Additional NAC at 12 hour	participants required additional NAC infusions after the 12-hour NAC regimen
K18 (U/L)	Ratio - value at 20 hours divided by baseline value for each patient	In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.
K18(U/L)	10 hours	In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.
ccK18 (U/L)	Ratio - value at 20 hours divided by baseline value for each patient	Caspace-cleaved Keratin-18
miR-122 (Delta Count)	20 hours	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
miR-122 (Copies/mcL)	Ratio - value at 20 hours divided by baseline value for each patient	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
miR-122(Copies/mcL)	10 hours	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

Trial Locations

Locations (1)

Royal Infirmary of Edinburgh; 🇬🇧 Edinburgh, City Of Edinburgh, United Kingdom