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Trial registered on ANZCTR


Registration number
ACTRN12623000647639
Ethics application status
Approved
Date submitted
26/05/2023
Date registered
15/06/2023
Date last updated
15/06/2023
Date data sharing statement initially provided
15/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of Fomepizole on the Metabolism of Paracetamol:
A Randomised Human Volunteer Crossover Trial
Scientific title
The effect of Fomepizole on Oxidative Metabolism of Paracetamol: A Randomised Human Volunteer Crossover Trial
Secondary ID [1] 309038 0
None
Universal Trial Number (UTN)
Trial acronym

Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paracetamol Poisoning 329089 0
Condition category
Condition code
Emergency medicine 326066 326066 0 0
Other emergency care
Injuries and Accidents 327111 327111 0 0
Poisoning

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive a single dose of oral paracetamol tablets 80 mg/kg, and intravenous fomepizole (15mg/kg) administered 2 hours post paracetamol ingestion.

Both immediate-release and modified-release paracetamol will be tested. Participants may participate in both or just one preparation. If they cross-over there will be at least a 2 week wash-out. There is also a 2 week washout between treatment arm and control.

The investigator will supervise and observe the participant swallow the paracetamol.
Intervention code [1] 326201 0
Treatment: Drugs
Comparator / control treatment
Participants will be randomised to immediate-release or modified release paracetamol .
Then participants will receive a single oral dose of tablets of paracetamol 80 mg/kg, without intravenous fomepizole (15mg/kg).

After completing one arm with either immediate-release or modified release paracetamol the participant may crossover to receive the other paracetamol prepartion.
Control group
Active

Outcomes
Primary outcome [1] 334900 0
Fraction of total oxidative APAP metabolites (APAP-CYS + APAP-Mer) / (total metabolites + unchanged paracetamol) in a 24-hour urine collection after paracetamol dosing. This will reflect the fraction of ingested paracetamol metabolised by CYP2E1.
Timepoint [1] 334900 0
24 hour of urine collection - from time 0 h paracetamol ingestion to 24 h post-ingestion.
Secondary outcome [1] 422371 0
Serum samples to measure the fraction of paracetamol metabolites: oxidative metabolites (APAP-CYS + APAP-Mer) and non-toxic metabolites
Timepoint [1] 422371 0
At baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [2] 422372 0
Serum samples to measure the peak serum paracetamol and metabolite concentrations (C max)
Timepoint [2] 422372 0
Cmax determined from samples taken at baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [3] 422373 0
Serum samples to measure fomepizole concentrations
Timepoint [3] 422373 0
Fomepizole levels taken at baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [4] 422618 0
Serum samples to measure area under the paracetamol and metabolite curve from paracetamol and metabolite concentrations.
Timepoint [4] 422618 0
Calculated by levels taken at baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [5] 422619 0
Serum samples to measure paracetamol and metabolite concentrations to assess time to peak paracetamol and metabolite concentrations (Tmax)
Timepoint [5] 422619 0
Tmax determined from samples taken at baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [6] 422620 0
Serum samples to measure paracetamol-protein adduct concentration C max
Timepoint [6] 422620 0
Cmax determined from samples taken at baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [7] 422621 0
Serum samples to measure paracetamol-protein adduct concentration Tmax
Timepoint [7] 422621 0
Tmax determined from samples taken at baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [8] 422622 0
Serum samples to measure paracetamol-protein adduct concentration AUC
Timepoint [8] 422622 0
Calculated by levels taken at baseline (pre-intervention), 30, 60, 90 min and 2, 3, 4, 6, 8, 10, 12 h, 16 and 24 h.
Secondary outcome [9] 422623 0
Side effects from fomepizole administration recorded by researcher.
Timepoint [9] 422623 0
Record any side effects that occur after fomepizole administration such as nausea, vomiting, allergic reaction, headache, flushing, pain in injection site, syncope, lightheadness. Within the up to 24 hours post injection.
Secondary outcome [10] 422624 0
Side effects from paracetamol administration recorded by researcher.
Timepoint [10] 422624 0
Record any side effects that occur after paracetamol administration such as nausea, vomiting, allergic reaction, headache, flushing, syncope, lightheadness. Within 24 hours post ingestion.

Eligibility
Key inclusion criteria
- Adults at least 18 years of age
- No underlying liver disease (baseline liver function tests to be performed after recruitment)
- No regular medications except for vitamins or oral contraceptive pill
- No history of chronic alcohol, tobacco (smoker), or illicit drug use.
- Weigh less than 100 kg and BMI < 29 kg/m2
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Pregnancy or lactation,
- Allergy to the medications administered in the study (paracetamol and fomepizole)
- Weight > 100kg or body mass index (BMI) > 29 kg/ m2 as obesity appears to increase activity of CYP2E1 and there are concerns of increased toxicity of paracetamol in the setting of non-alcoholic fatty liver disease.
- Pregnancy (females of child-bearing age to have urine BHCG).
- Pre-existing liver disease,
- Chronic alcohol consumption greater than 20 g per day,
- Any chronic illness,
- On regular medications (except for vitamins or the oral contraceptive pill)
- Before participation in the study, if on screening tests any abnormality in liver function tests performed 1 week before the study and 3 days after the first arm of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be by sequentially numbered opaque sealed envelopes (SNOSE)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be by sequentially numbered, opaque, sealed envelope (SNOSE) technique to start with one of two formulations (IR or MR) or one of two treatments (A or B). Followed by crossover to the other treatment (after at least 2 weeks) but remain in the same paracetamol formulation group. Envelopes will be in blocks of 2 or 4 or 6 (IR or MR) and blocks of 2 or 4 or 6 (group A or B).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Sample size calculation is based on a previous health human volunteer study that found the percentage excretion of toxic (CYP) urine metabolites following an ingestion of 80 mg/kg in healthy human volunteers of 4.48% (SD: 1.1%) (Kang AM, et al. The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers. J Med Toxicol. 2020;16(2):169-76). A significant effect of fomepizole will be a 50% reduction in oxidative metabolites in the urine. With an alpha = 0.05, beta =0.2 and power = 0.9, five volunteers are required in each intervention group.
Although the sample size in this study is too small to validly test for normality, it has been argued that a paired t test is appropriate even when sample sizes are small, as long as the effect size is large. Kang et al found a large effect size when fomepizole was administered at the time of paracetamol ingestion of 4.48% to 0.51% (95% CI = 2.31–5.63%, p = 0.003) percentage of oxidative metabolites. Based on this rationale, study treatments were compared using a paired t test to take advantage of the crossover design and projected large effect size.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2023
Actual
Date of last participant enrolment
Anticipated
31/05/2024
Actual
Date of last data collection
Anticipated
14/06/2024
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 24809 0
Prince of Wales Private Hospital - Randwick
Recruitment postcode(s) [1] 40455 0
2031 - Randwick
Recruitment postcode(s) [2] 40456 0
2032 - Kingsford

Funding & Sponsors
Funding source category [1] 313242 0
Hospital
Name [1] 313242 0
Prince of Wales Hospital
Country [1] 313242 0
Australia
Funding source category [2] 313945 0
Government body
Name [2] 313945 0
NHMRC
Country [2] 313945 0
Australia
Funding source category [3] 313946 0
Commercial sector/Industry
Name [3] 313946 0
Phebra Pty Ltd.
Country [3] 313946 0
Australia
Primary sponsor type
Hospital
Name
Prince of Wales Hospital
Address
Baker Street Randwick NSW 2031
Country
Australia
Secondary sponsor category [1] 315898 0
None
Name [1] 315898 0
Address [1] 315898 0
Country [1] 315898 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312474 0
South Eastern Sydney Local Health District HREC
Ethics committee address [1] 312474 0
Room G7, Level 2, Clinical Science Building
Prince of Wales Hospital, Randwick, NSW 2031
Ethics committee country [1] 312474 0
Australia
Date submitted for ethics approval [1] 312474 0
Approval date [1] 312474 0
08/05/2023
Ethics approval number [1] 312474 0
2023/ETH00352

Summary
Brief summary
Paracetamol poisoning can cause liver injury; the mainstay of treatment is administration of the antidote acetylcysteine. There is a subgroup of paracetamol poisoned patients who develop liver injury despite standard treatment. Fomepizole has been proposed as an antidote due to its ability to inhibit production of paracetamol’s toxic metabolite. However, the clinical evidence for its use is limited. Hence in this study we will utilise a healthy human volunteer simulated overdose crossover model. Each volunteer will serve as their own control. We will examine both immediate and modified release paracetamol formulations at a dose of 80mg/kg. We will investigate the efficacy of fomepizole at 2 hours post ingestion. If there is a significant effect we will then examine fomepizole at 4h. This study aims to provide valuable information on the potential use of fomepizole as an antidote for paracetamol poisoning.
Trial website
Trial related presentations / publications
Public notes
A/Prof Angela Chiew is funded by an NHMRC Investigator Grant (2022/GNT2016380) this grant will fund the metabolite assay and gift cards for participants

Contacts
Principal investigator
Name 124790 0
A/Prof Angela Chiew
Address 124790 0
Department of Clinical Toxicology / Emergency Department
Prince of Wales Hospital
Barker Street
Randwick, NSW , 2031
Country 124790 0
Australia
Phone 124790 0
+61 2 9382 4155
Fax 124790 0
Email 124790 0
angela.chiew@health.nsw.gov.au
Contact person for public queries
Name 124791 0
A/Prof Angela Chiew
Address 124791 0
Department of Clinical Toxicology / Emergency Department
Prince of Wales Hospital
Barker Street
Randwick, NSW , 2031
Country 124791 0
Australia
Phone 124791 0
+61 2 9382 4155
Fax 124791 0
Email 124791 0
angela.chiew@health.nsw.gov.au
Contact person for scientific queries
Name 124792 0
A/Prof Angela Chiew
Address 124792 0
Department of Clinical Toxicology / Emergency Department
Prince of Wales Hospital
Barker Street
Randwick, NSW , 2031
Country 124792 0
Australia
Phone 124792 0
+61 2 9382 4155
Fax 124792 0
Email 124792 0
angela.chiew@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Pharmacokinetic data may be stored non-identifiable in a data repository as required by some peer- reviewed journals
When will data be available (start and end dates)?
After publication of the data with no end date anticipated
Available to whom?
On request to the authors
Available for what types of analyses?
Pharmacokinetic analysis
How or where can data be obtained?
From the primary investigator by email or in a data repository if requested by the journal
Contact the principal investigator:
A/Prof Angela L Chiew
angela.chiew@health.nsw.gov.au


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.