Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001617459
Ethics application status
Approved
Date submitted
18/11/2016
Date registered
23/11/2016
Date last updated
2/11/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A comparison of two different durations of the antidote acetylcysteine for paracetamol overdose.
Scientific title
A non-inferiority randomised controlled trial of a Shorter Acetylcysteine Regimen for Paracetamol Overdose – the SARPO trial.
Secondary ID [1] 290568 0
Nil known
Universal Trial Number (UTN)
Trial acronym
SARPO trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paracetamol toxicity 301020 0
Condition category
Condition code
Oral and Gastrointestinal 300814 300814 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Mental Health 300842 300842 0 0
Suicide

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants in the study will be commenced on the standard acetylcysteine regimen. That is 200mg/kg acetylcysteine in 500mls 5% glucose over 4 hours followed by 100mg/kg acetylcysteine in 1000mls 5% glucose over 16 hours.

Participants randomised to the intervention arm will receive 12 hours of acetylcysteine only. To achieve this, they will have their 16 hour infusion of acetylcysteine ceased at eight hours (250mg/kg acetylcysteine) and then be commenced on the equivalent fluid and volume but not acetylcysteine for the remaining eight hours i.e. 500mL of 5% glucose over 8 hours.

This is administered in an emergency department short stay/observation ward with 24/7 nursing care to monitor adherence to above intervention.
Intervention code [1] 296436 0
Treatment: Drugs
Comparator / control treatment
200mg/kg acetylcysteine in 500mls 5% glucose over 4 hours followed by 100mg/kg acetylcysteine in 1000mls 5% glucose over 16 hours. This is administered in an emergency department short stay/observation ward with 24/7 nursing care to monitor adherence to above intervention.
Control group
Dose comparison

Outcomes
Primary outcome [1] 300238 0
The primary outcome will be a comparison between the standard and the experimental arm of the absolute difference between the alanine aminotransferase (ALT) on admission and 24 hours post ingestion. The ALT is measured by serum assay.
Timepoint [1] 300238 0
On admission to hospital and at 24 hours post ingestion of paracetamol.
Secondary outcome [1] 329456 0
Proportion of patients with a 50% increase in ALT over the admission ALT at 24 hours post ingestion. The ALT is measured by serum assay.
Timepoint [1] 329456 0
On admission to hospital and at 24 hours post ingestion of paracetamol.
Secondary outcome [2] 329457 0
Proportion of patients with an ALT >150IU/L and double the admission value (acute liver injury) at 24 hours post ingestion. The ALT is measured by serum assay.
Timepoint [2] 329457 0
On admission to hospital and at 24 hours post ingestion of paracetamol.
Secondary outcome [3] 329458 0
Proportion of patients with an ALT >1000IU/L (hepatotoxicity) at any time post ingestion assuming it did not rise to >1000 if no change after 24 hours. The ALT is measured by serum assay.
Timepoint [3] 329458 0
The ALT is measured at the following time points
1. On admission to hospital and between 4-8 hours post ingestion of paracetamol depending on arrival time at hospital post paracetamol ingestion..
2. At 12 hours post commencement of acetylcysteine.
3. At 24 post ingestion of paracetamol.
4. Twice daily there after until the ALT level is decreasing and the INR is improving and less than 2.
Secondary outcome [4] 329459 0
Differences in other biomarkers apart from ALT.

serum assay of miRNA-122
Timepoint [4] 329459 0
24 hours post ingestion
Secondary outcome [5] 329460 0
Proportion of patients with systemic hypersensitivity reactions in the first 12 hours of treatment with acetylcysteine. This is recorded on a pre formatted data sheet prospectively by nursing staff at set time intervals post commencement of acetylcysteine.
Timepoint [5] 329460 0
At 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours and 12 hours post commencement of acetylcysteine.
Secondary outcome [6] 329461 0
Proportion of patients with gastrointestinal adverse effects i.e. nausea and vomiting in the first 12 hours of treatment with acetylcysteine. This is recorded on a pre formatted data sheet prospectively by nursing staff at set time intervals post commencement of acetylcysteine.
Timepoint [6] 329461 0
At 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours and 12 hours post commencement of acetylcysteine.
Secondary outcome [7] 329536 0
Differences in other biomarkers apart from ALT.

Serum assay of INR
Timepoint [7] 329536 0
24 hours post ingestion

Eligibility
Key inclusion criteria
1.Single immediate release paracetamol overdoses of 30g or less with an initial paracetamol concentration above but less than twice the nomogram line (paracetamol ratio <2)
2.Acetylcysteine can be safely commenced within 8 hours of ingestion.
3.Informed consent can be obtained.

The paracetamol ratio is the first paracetamol concentration taken between four and 16 hours post ingestion divided by the paracetamol concentration on the 150mg/L at four-hour standard nomogram line at the same time point.
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Staggered or repeated immediate release paracetamol overdoses.
2. Single, staggered or repeated overdoses of sustained release paracetamol.
3. Repeated supratherapeutic ingestion of paracetamol.
4. Late presentation i.e. >8 hours since ingestion timea.
5. >30g paracetamolb or paracetamol ratio >2.

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)
Central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
A statistical approach will be used to set the equivalence boundary or minimally significant effect size for this non inferiority study. A statistical equivalence boundary is based on previous data of the existing treatment effect that the new alternative treatment is to be compared. The non-inferiority margin should be no more than half of the lower limit of the 95% confidence interval of the standard treatment (20 hours acetylcysteine) effect.

ALT data from 121 paracetamol overdoses (single ingestion, 30g or less and treated with a 20 hour acetylcysteine regimen within 8 hours of ingestion) from the three participating hospitals has been collected. The mean difference between admission and 24 hour ALT is 0.2IU/L with a standard deviation of 10.9 and 95% confidence interval of -21.2 to 21.6 IU/L. Half the lower limit of the 95% confidence interval is 10.7 hence 10 or less should be chosen as the non inferiority margin. A margin of 5 has been chosen which is also satisfactory for a clinical significance boundary. Therefore a mean difference in ALT (between baseline and 24 hours post ingestion) of -4.8 to 5.2 (0.2 +/- 5) in the new treatment arm (12 hour acetylcysteine regimen) would be considered as a non-inferior treatment of paracetamol toxicity.

A non-inferiority study aims to show that one treatment is not significantly worse than another treatment. Therefore this is a one sided test and the significance or alpha level is set at 0.025. With a power of 90% (higher power to minimize the risk of a non-inferior treatment being missed due to chance) and a standard deviation of 10.9 with a non-inferiority limit of 5, the total sample size required is 200 or 100 in each arm. Allowing for a 10% margin for failure to adhere to the study protocol, we aim to recruit 220 patients in total.

The continuous primary outcome of ALT difference between the two-acetylcysteine regimens will be analysed per protocol by student’s t-test or non-parametric equivalent depending on the distribution of the data. Secondary outcomes will be analysed using Chi-square or Fisher’s exact test, whichever is appropriate.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2017
Actual
10/07/2017
Date of last participant enrolment
Anticipated
30/06/2020
Actual
Date of last data collection
Anticipated
30/07/2020
Actual
Sample size
Target
220
Accrual to date
17
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 6950 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 6951 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [3] 6952 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 14640 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 14641 0
2298 - Waratah
Recruitment postcode(s) [3] 14642 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 295029 0
Hospital
Name [1] 295029 0
Princess Alexandra Hospital
Country [1] 295029 0
Australia
Funding source category [2] 295030 0
Hospital
Name [2] 295030 0
Calvary Mater Newcastle Hospital
Country [2] 295030 0
Australia
Funding source category [3] 295031 0
Hospital
Name [3] 295031 0
Prince of Wales Hospital
Country [3] 295031 0
Australia
Primary sponsor type
Individual
Name
Colin Page
Address
Department of Emergency Medicine
Princess Alexandra Hospital
Ipswich Road
Woolloongabba
Queensland 4102
Country
Australia
Secondary sponsor category [1] 293845 0
None
Name [1] 293845 0
Address [1] 293845 0
Country [1] 293845 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296358 0
Human Research Ethics Committee Metro South Health Service District.
Ethics committee address [1] 296358 0
PAH Centres for Health Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [1] 296358 0
Australia
Date submitted for ethics approval [1] 296358 0
17/11/2016
Approval date [1] 296358 0
17/01/2017
Ethics approval number [1] 296358 0
HREC/16/QPAH/801

Summary
Brief summary
Paracetamol is one of the commonest medications taken in overdose worldwide and is the leading cause of acute liver failure in the developed world. The antidote acetylcysteine which replenishes liver glutathione was developed in the 1970’s however the regimen (20 hours duration) was never subjected to either a randomised controlled trial or any dose ranging studies. The regimen gives a large loading dose and the remainder of the infusion (20 hours) is given to mirror the average time taken for paracetamol to be cleared by the liver. This time is only an average and depends on the degree of liver damage. We now know that this half-life is variable. For normal or undamaged livers it is much shorter (12 hours).

The aim of the study is to compare acetylcysteine given over 20 hours compared to 12 hours for patients presenting early with paracetamol overdose to see if it provides the same protection against liver damage.

The research design will be a multicentre non inferiority per protocol unblinded randomised controlled trial of a 20 hour versus a 12 hour regimen of acetylcysteine in paracetamol overdose. The study will be undertaken at the Princes Alexandra, Calvary Mater Newcastle and Prince of Wales hospitals. Eligible patients will be paracetamol overdoses less than 30g presenting within 8 hours of ingestion.

The primary outcome will be a comparison between the standard and the experimental arm of the absolute difference between the liver function test alanine aminotransferase (ALT) on admission and 24 hours post ingestion. This difference will be analysed per protocol by student’s t­test or non­parametric equivalent depending on the distribution of the data.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1239 1239 0 0
/AnzctrAttachments/371880-SARPO RCT_Version 2.pdf (Protocol)

Contacts
Principal investigator
Name 70578 0
Dr Colin Page
Address 70578 0
Department of Emergency Medicine Princess Alexandra Hospital Ipswich Road Woolloongabba Queensland 4102
Country 70578 0
Australia
Phone 70578 0
+610731762111
Fax 70578 0
Email 70578 0
[email protected]
Contact person for public queries
Name 70579 0
Colin Page
Address 70579 0
Department of Emergency Medicine Princess Alexandra Hospital Ipswich Road Woolloongabba Queensland 4102
Country 70579 0
Australia
Phone 70579 0
+610731762111
Fax 70579 0
Email 70579 0
[email protected]
Contact person for scientific queries
Name 70580 0
Colin Page
Address 70580 0
Department of Emergency Medicine Princess Alexandra Hospital Ipswich Road Woolloongabba Queensland 4102
Country 70580 0
Australia
Phone 70580 0
+610731762111
Fax 70580 0
Email 70580 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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