E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The objective of this study is to develop a therapeutic regimen for paracetamol/acetaminophen overdose (POD) where a novel NAC 12hr regime is combined with a superoxide dismutase (SOD) mimetic, PP100-01 in order to evaluate if reduction of the oxidative stress on the liver will be safe and well tolerated. |
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E.1.1.1 | Medical condition in easily understood language |
Paracetamol/acetaminophen (APAP) is the most common agent taken in overdose by patients in the United Kingdom and hospitalisation due to overdose accounted for approximately 80,000 bed days in the UK. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Injuries, poisonings, and occupational diseases [C21] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033295 |
E.1.2 | Term | Overdose |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Paracetamol can be harmful to the liver when an excessive dose has been taken. To help prevent liver damage, an antidote known as acetylcysteine is given. However a few patients can develop liver damage even if they get acetylcysteine. This study will give a new drug (calmangafodipir - PP100-01) in combination with a new 12-hour regimen for giving acetylcysteine. The principal research question is does the combination of calmangafodipir and acetylcysteine produce any unexpected side-effects? |
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E.2.2 | Secondary objectives of the trial |
To see if there is any evidence that PP100-01 can prevent liver damage caused by paracetamol overdose by testing blood samples to look for specific substances called biomarkers which would help to show this.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Collaborative research investigating markers of toxicity in samples from a clinical study (PP100-01)
This will be performed within the Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh. Dr James Dear is the Principal Investigator and the study is co-sponsored by the University and Pledpharma.
Serum and plasma will be collected from each patient in the main study.
The time points for sample collection are: immediately prior to PP100-01 administration (2h after starting NAC), 10h after starting NAC and 20h after starting NAC. The serum and plasma will be immediately separated from whole blood frozen at -80 C. There will be at least 3 aliquots of serum and plasma.
Therefore, each patient will have serum and plasma from 3 timepoints.
To complement standard clinical chemistry measurements the following biomarkers will be measured: miR-122, HMGB1, keratin-18, GLDH and mitochondrial DNA.
The key analysis will be to determine the effect of P100-01 on biomarker concentrations, both in terms of the absolute concentration and the change from baseline. This will be performed at each individual dose of P100-01 compared with NAC alone.
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E.3 | Principal inclusion criteria |
1. Any patient with capacity admitted to hospital within 24 hrs of either a single acute POD or more than one dose of paracetamol (staggered overdose) and deemed to require treatment with NAC. 2. Provision of written informed consent 3. Males and females of at least 16 years of age
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E.4 | Principal 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 paracetamol overdose 7. Patients presenting after 24hrs of overdose 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).
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E.5 End points |
E.5.1 | Primary end point(s) |
Adverse events and serious adverse events |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After each group there will be a review of the data by the DMC to approve commencement of the next group.
• Group A: PP100-01 (2 µmol/kg calmangafodipir) after the “loading” dose of NAC (N=6) (N=2 NAC alone) • Group B: PP100-01 (5 µmol/kg calmangafodipir) after the “loading” dose of NAC (N=6) (N=2 NAC alone) • Group C: PP100-01 (10 µmol/kg calmangafodipir) after the “loading” dose of NAC (N=6) (N=2 NAC alone)
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E.5.2 | Secondary end point(s) |
Determine if there is evidence of PP100-01 having efficacy with regard to treatment of paracetamol-induced liver injury by measurement of conventional clinical biomarkers and novel experimental biomarkers. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After each group there will be a review of the data by the DMC to approve commencement of the next group.
• Group A: PP100-01 (2 µmol/kg calmangafodipir) after the “loading” dose of NAC (N=6) (N=2 NAC alone) • Group B: PP100-01 (5 µmol/kg calmangafodipir) after the “loading” dose of NAC (N=6) (N=2 NAC alone) • Group C: PP100-01 (10 µmol/kg calmangafodipir) after the “loading” dose of NAC (N=6) (N=2 NAC alone)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description |
There are two IMPs in this study.1. Calmangadipofir - this has been safely administered to human |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is defined as when the last participant’s 90-day follow up is completed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |