Paracetamol Overdose
Conditions
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.
Interventions
DRUGPP100-01 (calmangafodipir)
PP100-01
DRUGAcetylcysteine
NAC
Sponsors
University of Edinburgh
NHS Lothian
Egetis Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Events | 90 days | Adverse Events and Serious Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| INR | Baseline | 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) | Baseline (2 hours) | 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. |
| ALT(U/L) | Baseline | The alanine aminotransferase (ALT) test is a blood test that checks for liver damage. |
| miR-122 (Delta Count) | Baseline (2 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) | Baseline (2 h) | 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 |
| ccK18 (U/L) | Baseline (2 hours) | The shorter, Caspase cleaved form of K-18 is released following hepatocyte apoptosis (programmed cell death). |
Countries
United Kingdom
Participant flow
Recruitment details
Studied period: 05 June 2017 to 08 August 2018 Study centres: Edinburgh Clinical Trials Unit (ECTU) The Emergency Medicine Research Group Edinburgh (EMERGE)
Pre-assignment details
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/dose) or NAC alone (n=2). Calmangafodipir doses were 2, 5, or 10 μmol/kg. Participants, study and clinical teams not blinded
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive:
PP100-01 (2 umol/kg calmangafodipir) after the loading dose of NAC
PP100-01 treatment is administered intravenously over 5 minutes.
PP100-01 (calmangafodipir): PP100-01 | 6 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive:
PP100-01 (5 umol/kg calmangafodipir) after the loading dose of NAC
PP100-01 treatment is administered intravenously over 5 minutes.
PP100-01 (calmangafodipir): PP100-01 | 6 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive:
• Group B: PP100-01 (5 umol/kg calmangafodipir) after the loading dose of NAC
PP100-01 (10 umol/kg calmangafodipir) after the loading dose of NAC
PP100-01 treatment is administered intravenously over 5 minutes.
PP100-01 (calmangafodipir): PP100-01 | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | Total | Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Acetylcysteine (N-acetylcysteine; NAC) |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants |
| Age, Continuous | 35.0 years STANDARD_DEVIATION 13.4 | 22.7 years STANDARD_DEVIATION 3.3 | 42.7 years STANDARD_DEVIATION 12.7 | 42.5 years STANDARD_DEVIATION 13.1 | 32.2 years STANDARD_DEVIATION 12.5 |
| Any other drug ingested No | 5 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants |
| Any other drug ingested Yes | 19 Participants | 5 Participants | 5 Participants | 4 Participants | 5 Participants |
| Presentation paracetamol concentration | 101 mg/L STANDARD_DEVIATION 66 | 127 mg/L STANDARD_DEVIATION 47 | 74 mg/L STANDARD_DEVIATION 44 | 127 mg/L STANDARD_DEVIATION 90 | 76 mg/L STANDARD_DEVIATION 81 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants |
| Region of Enrollment United Kingdom | 24 participants | 6 participants | 6 participants | 6 participants | 6 participants |
| Serum creatinine | 69.8 μmol/L STANDARD_DEVIATION 13.6 | 69.5 μmol/L STANDARD_DEVIATION 13.1 | 67.3 μmol/L STANDARD_DEVIATION 17.2 | 67.5 μmol/L STANDARD_DEVIATION 13.3 | 74.7 μmol/L STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 13 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 11 Participants | 3 Participants | 2 Participants | 2 Participants | 4 Participants |
| Time from ingestion of paracetamol to hospital presentation | 6.4 hours STANDARD_DEVIATION 6.2 | 4.9 hours STANDARD_DEVIATION 5.2 | 5.8 hours STANDARD_DEVIATION 7.2 | 6.0 hours STANDARD_DEVIATION 6.2 | 8.8 hours STANDARD_DEVIATION 6.2 |
| Time from ingestion of paracetamol to start of calmangafodipir | 11.7 hours STANDARD_DEVIATION 5.4 | 11.8 hours STANDARD_DEVIATION 5.4 | 10.8 hours STANDARD_DEVIATION 4.1 | 12.6 hours STANDARD_DEVIATION 6.8 | NA hours |
| Time from ingestion of paracetamol to start of NAC treatment | 10.2 hours STANDARD_DEVIATION 5.7 | 8.6 hours STANDARD_DEVIATION 4.1 | 10.2 hours STANDARD_DEVIATION 6.9 | 9.8 hours STANDARD_DEVIATION 6.5 | 12.1 hours STANDARD_DEVIATION 5.2 |
| Total paracetamol ingested | 262 mg/kg STANDARD_DEVIATION 195 | 397 mg/kg STANDARD_DEVIATION 476 | 229 mg/kg STANDARD_DEVIATION 72 | 235 mg/kg STANDARD_DEVIATION 77 | 185 mg/kg STANDARD_DEVIATION 156 |
| Type of overdose Acute, ≤8 h to NAC | 14 Participants | 4 Participants | 4 Participants | 4 Participants | 2 Participants |
| Type of overdose Acute, >8 h to NAC | 8 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants |
| Type of overdose Staggered intentional | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Type of overdose Supra-therapeutic | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 1 / 6 | 0 / 6 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 | 4 / 6 | 2 / 6 | 3 / 6 |
Outcome results
Primary
Safety Events
Adverse Events and Serious Adverse Events
Time frame: 90 days
Population: In addition to paracetamol overdose, 19 out of the 24 randomised participants reported taking overdoses of other medicines in addition to the paracetamol. All treatment groups included participants with paracetamol only overdoses and mixed overdoses
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Any serious adverse event | 2 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Serious AE after commencement of NAC treatment | 1 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event probably related to PP100-01 | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event unrelated to NAC | 3 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | SUSAR to NAC | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event where outcome was death | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event definitely related to PP100-01 | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Any Adverse event | 6 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event possibly related to NAC | 2 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | SUSAR to NAC and PP100-01 | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | SUSAR to PP100-01 | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event after commencement of NAC treatment | 6 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event probably related to NAC | 3 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event possibly related to PP100-01 | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event unrelated to PP100-01 | 6 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Any suspected unexpected serious adverse reaction | 0 participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Safety Events | Adverse event definitely related to NAC | 2 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | SUSAR to NAC | 0 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | SUSAR to PP100-01 | 0 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event definitely related to PP100-01 | 0 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event unrelated to PP100-01 | 6 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event possibly related to PP100-01 | 4 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event probably related to PP100-01 | 0 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Any serious adverse event | 4 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event after commencement of NAC treatment | 5 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event unrelated to NAC | 5 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event definitely related to NAC | 3 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Serious AE after commencement of NAC treatment | 1 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event where outcome was death | 0 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event possibly related to NAC | 2 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Any Adverse event | 6 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Any suspected unexpected serious adverse reaction | 0 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | Adverse event probably related to NAC | 2 participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Safety Events | SUSAR to NAC and PP100-01 | 0 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event after commencement of NAC treatment | 6 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event unrelated to NAC | 3 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event possibly related to PP100-01 | 2 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Any Adverse event | 6 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Any serious adverse event | 2 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Serious AE after commencement of NAC treatment | 1 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event where outcome was death | 1 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event possibly related to NAC | 2 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event probably related to NAC | 3 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event definitely related to NAC | 1 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event unrelated to PP100-01 | 5 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event probably related to PP100-01 | 0 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Adverse event definitely related to PP100-01 | 0 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | Any suspected unexpected serious adverse reaction | 0 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | SUSAR to NAC | 0 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | SUSAR to PP100-01 | 0 participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Safety Events | SUSAR to NAC and PP100-01 | 0 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event definitely related to PP100-01 | 0 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event probably related to NAC | 2 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event possibly related to NAC | 2 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event where outcome was death | 0 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Any suspected unexpected serious adverse reaction | 1 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Serious AE after commencement of NAC treatment | 2 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event after commencement of NAC treatment | 6 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event unrelated to NAC | 5 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | SUSAR to NAC | 0 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Any serious adverse event | 3 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Any Adverse event | 6 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event possibly related to PP100-01 | 2 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | SUSAR to NAC and PP100-01 | 0 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event probably related to PP100-01 | 0 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event unrelated to PP100-01 | 6 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | Adverse event definitely related to NAC | 1 participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Safety Events | SUSAR to PP100-01 | 1 participants |
Secondary
Additional NAC Infusion
participants required additional NAC infusions after the 12-hour NAC regimen
Time frame: Additional NAC at 12 hour
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | Additional NAC Infusion | None | 3 Participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Additional NAC Infusion | Two | 2 Participants |
| Acetylcysteine (N-acetylcysteine; NAC) | Additional NAC Infusion | One | 1 Participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Additional NAC Infusion | None | 5 Participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Additional NAC Infusion | Two | 0 Participants |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | Additional NAC Infusion | One | 1 Participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Additional NAC Infusion | One | 0 Participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Additional NAC Infusion | None | 6 Participants |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | Additional NAC Infusion | Two | 0 Participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Additional NAC Infusion | None | 6 Participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Additional NAC Infusion | Two | 0 Participants |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | Additional NAC Infusion | One | 0 Participants |
Secondary
ALT(U/L)
The alanine aminotransferase (ALT) test is a blood test that checks for liver damage.
Time frame: 10 hours
Population: All 24 participants received the full dose of PP100-01 according to the allocated dosing cohort, all participants received as a minimum 12 hours of NAC treatment (loading dose, plus further 10 hours). For both PP100-01 and NAC total dose was adjusted according to participant weight
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | ALT(U/L) | 41.4 U/L | Standard Deviation 3.3 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | ALT(U/L) | 22.9 U/L | Standard Deviation 1.8 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | ALT(U/L) | 25.3 U/L | Standard Deviation 2.1 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | ALT(U/L) | 15.0 U/L | Standard Deviation 1.3 |
Secondary
ALT(U/L)
The alanine aminotransferase (ALT) test is a blood test that checks for liver damage.
Time frame: 20 hours
Population: All 24 participants received the full dose of PP100-01 according to the allocated dosing cohort, all participants received as a minimum 12 hours of NAC treatment (loading dose, plus further 10 hours). For both PP100-01 and NAC total dose was adjusted according to participant weight
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | ALT(U/L) | 43.3 U/L | Standard Deviation 3.8 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | ALT(U/L) | 20.4 U/L | Standard Deviation 1.9 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | ALT(U/L) | 25.4 U/L | Standard Deviation 1.8 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | ALT(U/L) | 16.4 U/L | Standard Deviation 1.5 |
Secondary
ALT(U/L)
The alanine aminotransferase (ALT) test is a blood test that checks for liver damage.
Time frame: Baseline
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | ALT(U/L) | 42.5 U/L | Standard Deviation 3.6 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | ALT(U/L) | 24.6 U/L | Standard Deviation 2.1 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | ALT(U/L) | 29.4 U/L | Standard Deviation 2.3 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | ALT(U/L) | 17.7 U/L | Standard Deviation 1.5 |
Secondary
ccK18 (U/L)
The shorter, Caspase cleaved form of K-18 is released following hepatocyte apoptosis (programmed cell death).
Time frame: 10 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | ccK18 (U/L) | 72 U/L | Standard Deviation 2.24 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | ccK18 (U/L) | 53 U/L | Standard Deviation 1.25 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | ccK18 (U/L) | 56 U/L | Standard Deviation 1.57 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | ccK18 (U/L) | 78 U/L | Standard Deviation 2.12 |
Secondary
ccK18 (U/L)
The shorter, Caspase cleaved form of K-18 is released following hepatocyte apoptosis (programmed cell death).
Time frame: 20 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | ccK18 (U/L) | 149 U/L | Standard Deviation 3.34 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | ccK18 (U/L) | 66 U/L | Standard Deviation 1.34 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | ccK18 (U/L) | 85 U/L | Standard Deviation 1.62 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | ccK18 (U/L) | 111 U/L | Standard Deviation 2.56 |
Secondary
ccK18 (U/L)
Caspace-cleaved Keratin-18
Time frame: Ratio - value at 20 hours divided by baseline value for each patient
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | ccK18 (U/L) | 2.22 U/L | Standard Deviation 1.77 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | ccK18 (U/L) | 1.49 U/L | Standard Deviation 1.55 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | ccK18 (U/L) | 1.02 U/L | Standard Deviation 1.79 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | ccK18 (U/L) | 1.08 U/L | Standard Deviation 2.44 |
Secondary
ccK18 (U/L)
The shorter, Caspase cleaved form of K-18 is released following hepatocyte apoptosis (programmed cell death).
Time frame: Baseline (2 hours)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | ccK18 (U/L) | 67 U/L | Standard Deviation 1.99 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | ccK18 (U/L) | 45 U/L | Standard Deviation 1.33 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | ccK18 (U/L) | 84 U/L | Standard Deviation 1.8 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | ccK18 (U/L) | 104 U/L | Standard Deviation 2.44 |
Secondary
INR
international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)
Time frame: 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | INR | 1.18 ratio | Standard Deviation 0.21 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | INR | 1.07 ratio | Standard Deviation 0.19 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | INR | 1.08 ratio | Standard Deviation 0.04 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | INR | 1.22 ratio | Standard Deviation 1.17 |
Secondary
INR
international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)
Time frame: value at 20 hours divided by baseline value for each patient
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | INR | 1.15 ratio | Standard Deviation 1.17 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | INR | 1.07 ratio | Standard Deviation 1.12 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | INR | 1.10 ratio | Standard Deviation 1.07 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | INR | 1.10 ratio | Standard Deviation 1.1 |
Secondary
INR
international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)
Time frame: Baseline
Population: All 24 participants received the full dose of PP100-01 according to the allocated dosing cohort, all participants received as a minimum 12 hours of NAC treatment (loading dose, plus further 10 hours). For both PP100-01 and NAC total dose was adjusted according to participant weight
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | INR | 1.02 ratio | Standard Deviation 0.04 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | INR | 1.00 ratio | Standard Deviation 0.12 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | INR | 0.98 ratio | Standard Deviation 0.04 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | INR | 1.05 ratio | Standard Deviation 0.14 |
Secondary
INR
international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF)
Time frame: 10 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | INR | 1.30 ratio | Standard Deviation 0.18 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | INR | 1.17 ratio | Standard Deviation 0.2 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | INR | 1.20 ratio | Standard Deviation 0 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | INR | 1.22 ratio | Standard Deviation 0.25 |
Secondary
K18 (U/L)
In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.
Time frame: 20 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | K18 (U/L) | 347 U/L | Standard Deviation 3.18 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | K18 (U/L) | 229 U/L | Standard Deviation 1.94 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | K18 (U/L) | 172 U/L | Standard Deviation 1.45 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | K18 (U/L) | 181 U/L | Standard Deviation 1.73 |
Secondary
K18 (U/L)
In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.
Time frame: Ratio - value at 20 hours divided by baseline value for each patient
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | K18 (U/L) | 1.85 U/L | Standard Deviation 1.47 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | K18 (U/L) | 1.29 U/L | Standard Deviation 1.89 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | K18 (U/L) | 0.89 U/L | Standard Deviation 1.57 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | K18 (U/L) | 1.41 U/L | Standard Deviation 1.83 |
Secondary
K18 (U/L)
In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.
Time frame: Baseline (2 hours)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | K18 (U/L) | 187 U/L | Standard Deviation 2.2 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | K18 (U/L) | 177 U/L | Standard Deviation 1.82 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | K18 (U/L) | 193 U/L | Standard Deviation 1.56 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | K18 (U/L) | 128 U/L | Standard Deviation 1.25 |
Secondary
K18(U/L)
In paracetamol overdose, the full-length variant of Keratin-18 (K-18) is released by necrotic hepatocyte death.
Time frame: 10 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | K18(U/L) | 182 U/L | Standard Deviation 1.95 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | K18(U/L) | 152 U/L | Standard Deviation 1.56 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | K18(U/L) | 170 U/L | Standard Deviation 1.42 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | K18(U/L) | 111 U/L | Standard Deviation 1.18 |
Secondary
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
Time frame: Baseline (2 h)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | miR-122 (Copies/mcL) | 146,363 copies/mcL | Standard Deviation 11.7 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 116,749 copies/mcL | Standard Deviation 2.4 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 194,075 copies/mcL | Standard Deviation 13.5 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 36,051 copies/mcL | Standard Deviation 3.9 |
Secondary
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
Time frame: 20 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | miR-122 (Copies/mcL) | 216,256 copies/mcL | Standard Deviation 10.8 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 57,664 copies/mcL | Standard Deviation 3.8 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 202,271 copies/mcL | Standard Deviation 7.7 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 40,745 copies/mcL | Standard Deviation 3.2 |
Secondary
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
Time frame: Ratio - value at 20 hours divided by baseline value for each patient
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | miR-122 (Copies/mcL) | 1.48 copies/mcL | Standard Deviation 5.71 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 0.49 copies/mcL | Standard Deviation 1.98 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 1.04 copies/mcL | Standard Deviation 8.28 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | miR-122 (Copies/mcL) | 1.13 copies/mcL | Standard Deviation 2.96 |
Secondary
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
Time frame: 10 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | miR-122(Copies/mcL) | 206,205 copies/mcL | Standard Deviation 13 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | miR-122(Copies/mcL) | 109,882 copies/mcL | Standard Deviation 3.3 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | miR-122(Copies/mcL) | 196,732 copies/mcL | Standard Deviation 9.4 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | miR-122(Copies/mcL) | 37,066 copies/mcL | Standard Deviation 2.2 |
Secondary
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
Time frame: Baseline (2 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | miR-122 (Delta Count) | 5.58 DCt | Standard Deviation 3.36 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | miR-122 (Delta Count) | 5.85 DCt | Standard Deviation 1.5 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | miR-122 (Delta Count) | 4.43 DCt | Standard Deviation 3.92 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | miR-122 (Delta Count) | 8.73 DCt | Standard Deviation 2.36 |
Secondary
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
Time frame: 10 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | miR-122 (Delta Count) | 5.41 DCt | Standard Deviation 3.86 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | miR-122 (Delta Count) | 6.14 DCt | Standard Deviation 1.99 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | miR-122 (Delta Count) | 5.01 DCt | Standard Deviation 3.36 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | miR-122 (Delta Count) | 9.00 DCt | Standard Deviation 1.45 |
Secondary
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
Time frame: 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetylcysteine (N-acetylcysteine; NAC) | miR-122 (Delta Count) | 4.85 DCt | Standard Deviation 3.97 |
| Group A: PP100-01 (Calmangafodipir 2 Umol/kg)+ NAC | miR-122 (Delta Count) | 7.12 DCt | Standard Deviation 2.26 |
| Group B: PP100-01 (Calmangafodipir 5 Umol/kg)+ NAC | miR-122 (Delta Count) | 4.49 DCt | Standard Deviation 2.93 |
| Group C: PP100-01 (Calmangafodipir 10 Umol/kg)+ NAC | miR-122 (Delta Count) | 8.44 DCt | Standard Deviation 1.5 |