A trial of normal versus higher dose acetylcysteine in patients with paracetamol overdose
| ISRCTN | ISRCTN17516192 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17516192 |
| IRAS number | 1007520 |
| Secondary identifying numbers | AC23035, IRAS 1007520, CPMS 59286 |
- Submission date
- 12/05/2023
- Registration date
- 21/11/2023
- Last edited
- 24/03/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Injury, Occupational Diseases, Poisoning
Plain English summary of protocol
Background and study aims
Paracetamol overdose is very common. Someone presents to the hospital following an overdose every 5 minutes across the UK. This rate is the same as the rate for heart attacks. Despite having an effective antidote called acetylcysteine (NAC), 1 in 10 patients go on to develop liver damage. NAC causes side effects such as allergic reactions that are unpleasant for the patient and may result in this essential treatment being stopped. It is unknown whether increasing the dose of NAC is more effective at preventing liver damage partly because, until recently, dose increases have not been possible due to the side effects. To address this, we designed a new protocol for giving NAC (the SNAP regimen) that is now used across the UK and has dramatically reduced the risk of patients experiencing side effects. The improved safety of the SNAP regimen allows us to look at the potential benefits of treating patients with higher NAC doses. This trial will determine whether increasing the NAC dose results in an increase in the breakdown of paracetamol, without causing an unacceptable rate of side-effects.
Who can participate?
Patients who have had a paracetamol overdose from the Emergency Department at participating sites in Scotland.
What does the study involve?
The trial will compare the effects of NAC given for 12 hours at 1.5 times and double the standard dose with standard treatment (dose groups: standard = 300 mg/kg; 1.5 = 450 mg/kg and double=600 mg/kg). Paracetamol breakdown will be assessed by measurement of the breakdown products (metabolites) in the blood. Side effects will be assessed using a patient questionnaire. Participants will be followed up for 7 days using their medical notes to review their recovery. The results of this trial are essential information for the next step, a UK-wide trial to determine whether a higher dose of NAC improves the outcome for patients.
What are the possible benefits and risks of participating?
Patients treated with NAC may experience side effects such as nausea, vomiting, feeling flushed, feeling wheezy or skin rash. In rare cases, patients have more side effects such as lowering of their blood pressure or swelling of the tongue or lips. In most cases, the symptoms subside after stopping the medicine temporarily and the medical team will can give treatment to help with side effects. The SNAP protocol helps minimise the likelihood of these symptoms. The need for one additional blood sample may cause minor discomfort.
Where is the study run from?
University of Edinburgh (UK)
When is the study starting and how long is it expected to run for?
January 2023 to June 2026
Who is funding the study?
Chief Scientist Office, Scottish Government Health and Social Care Directorate (UK)
Who is the main contact?
HiSNAP Trial Management Team, Edinburgh Clinical Trial Unit, HiSNAP.Trial@ed.ac.uk (UK)
Contact information
Scientific
Usher Institute
NINE, Usher Building
5‒7 Little France Road
Edinburgh Bioquarter
Edinburgh
EH16 4UX
United Kingdom
| Phone | +44 (0)131 651 9913 |
|---|---|
| Hisnap.trial@ed.ac.uk |
Principal Investigator
Queen's Medical Research Institute
Room E3.20
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
| Phone | +44 (0)131 242 9214 |
|---|---|
| James.dear@ed.ac.uk |
Study information
| Study design | Multi-centre randomized open-label blinded-end-point safety efficacy study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomized open-label blinded-end-point |
| Study setting(s) | Hospital |
| Study type | Safety, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A multi-centre, randomised, open-label, blinded end-point, safety and efficacy trial of conventional (300 mg/kg) versus higher doses of acetylcysteine (450 mg/kg and 600 mg/kg) in patients with paracetamol overdose (HiSNAP) |
| Study acronym | HiSNAP |
| Study objectives | Testing whether increasing the dose of acetylcysteine (NAC) increases the breakdown of paracetamol in patients who have had paracetamol overdose. Safety - reviewing the side effects patient experience when taking the different doses, particularly those related to allergic reactions. Efficacy (how well NAC works) - see if there is evidence of reduced liver injury with higher NAC doses |
| Ethics approval(s) | Approved 26/09/2023, East Midlands - Derby Research Ethics Committee (2 Redman Place, London, EC20 1JQ, UK; Tel: Not Applicable; derby.rec@hra.nhs.uk), ref: 23/EM/0129 |
| Health condition(s) or problem(s) studied | Paracetamol overdose |
| Intervention | Participants will receive a 12-hour infusion of acetylcysteine (NAC) of either conventional (300 mg/kg), 1.5 times (450 mg/kg) or double (600 mg/kg) the conventional dose. Any preparation of acetylcysteine which has marketing authorisation in the UK to be used for this indication and is stocked by local hospital pharmacies at the participating sites may be prescribed in this study. Standard dosing (300 mg/kg) will be infused as per the SNAP regime: initial loading dose (100 mg/kg in 200 mL) given intravenously over 2h, followed by a second dose (200 mg/kg in 1000 mL) infused over 10h. OR HiSNAP group 1 (450 mg/kg): initial loading dose (150 mg/kg in 200 mL) given intravenously over 2h, followed by a second dose (300 mg/kg in 1000 mL) infused over 10h. OR HiSNAP group 2 (600 mg/kg): initial loading dose (200 mg/kg in 200 L) given intravenously over 2h, followed by a second dose (400 mg/kg in 1000 mL) infused over 10h. The dose of NAC assigned to each patient will be randomised using a centralised online randomisation system. Participants will be followed-up for 7 days following the infusion using their medical notes to review. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Dose response |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Acetylcysteine |
| Primary outcome measure | Glutathione (GSH) derived paracetamol metabolite concentration as a percentage of total metabolites (%GSH) in the circulation at the end of the infusion of the second NAC dose |
| Secondary outcome measures | Safety: Incidence of adverse events and serious adverse events occurring from the time of starting NAC until the end of follow-up. There are expected adverse reactions listed in the product summary of product characteristics (SPC). The protocol defines two adverse events of special interest (AESI). Symptoms of anaphylactoid reactions reported on Likert scale at baseline and 12h after starting NAC. Efficacy: Full paracetamol metabolite panel (APAP-Cys, APAP-Glu, APAP-Sul, APAP-GSH, APAPMer) in serum and urine. Measured at baseline (pre-NAC) for serum and urine. For serum, at 12h after NAC started. All urine is collected for the trial period. ALT (gold standard diagnostic liver injury marker), high sensitivity liver injury markers (keratin-18, microRNA-122, GLDH) and INR (a prognostic marker of liver synthetic function) measured at baseline and after 12 hrs NAC from blood. Length of hospital admission, repeat hospital admission within 7 days, acute liver failure, transfer to Scottish Liver Transplantation Unit, liver transplantation and death recorded from medical notes at 7 days follow-up. |
| Overall study start date | 01/01/2023 |
| Completion date | 30/06/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | At least 90 |
| Key inclusion criteria | Current participant inclusion criteria as of 25/10/2024: 1. Paracetamol overdose* presenting to hospital within 24 hours of taking their last dose of paracetamol. *All patterns of overdose (single, staggered overdoses and therapeutic excess); Accidental or deliberate; Paracetamol alone or mixtures of tablets are eligible. 2. Patient deemed to need NAC treatment by the clinical team 3. Blood paracetamol concentration and ALT results are available (clinical care bloods) 4. Provision of informed consent 5. Adult (16 years old or above) Previous participant inclusion criteria: 1. Single acute paracetamol overdose presenting to hospital within 24h of overdose. All tablets ingested over a period of 2 h or less. Accidental or deliberate overdoses are eligible. Overdose of paracetamol alone or mixtures of tablets are eligible. 2. Overdose at risk of toxicity: blood paracetamol concentration over ‘200 line’ on nomogram 3. Provision of informed consent 4. Adult (16 years old or above) |
| Key exclusion criteria | Current participant exclusion criteria as of 25/10/2024: 1. Patients that do not have the capacity to consent 2. Patients who are pregnant or breastfeeding 3. Patients who have previously participated in the study 4. 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 5. Patients detained under the Mental Health Act 6. Patients already started on NAC treatment 7. Patients with known viral hepatitis or HIV 8. Prisoners Previous participant exclusion criteria: 1. Patients that do not have the capacity to consent 2. Patients who are pregnant or breastfeeding 3. Patients who have previously participated in the study 4. 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 5. Patients detained under the Mental Health Act 6. Patients already started on NAC treatment 7. Known overdose of a modified/extended-release preparation of paracetamol 8. Patients with known viral hepatitis or HIV |
| Date of first enrolment | 19/02/2024 |
| Date of final enrolment | 31/01/2026 |
Locations
Countries of recruitment
- Scotland
- United Kingdom
Study participating centres
Old Dalkeith Road
Edinburgh
Lothian
EH16 4SA
United Kingdom
Howden, Livingston
Lothian
EH54 6PP
United Kingdom
Kirkcaldy
KY2 5AH
United Kingdom
Sponsor information
Hospital/treatment centre
Usher Building
5‒7 Little France Road
Edinburgh Bioquarter
Edinburgh
EH16 4UX
Scotland
United Kingdom
| Phone | +44 (0)131 242 6226 |
|---|---|
| resgov@accord.scot | |
| Website | http://accord.scot/ |
"ROR" |
https://ror.org/01x6s1m65 |
Funders
Funder type
Government
Government organisation / Local government
- Alternative name(s)
- Chief Scientist Office, Scottish Government Health Directorate CSO, Chief Scientist Office, Scottish Government Health Directorates, Chief Scientist Office of the Scottish Government Health Directorates, Scottish Government Health and Social Care Directorate of the Chief Scientist Office, Scottish Government Health Directorate Chief Scientist Office, The Chief Scientist Office, CSO
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on the website 5. Submission to regulatory authorities |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from ECTU Data Sharing Committee. Consent will be sought from participants to permit sharing of anonymised data with funders and collaborators or publishing on publicly available resources as appropriate. Following the publication of the primary HiSNAP Trial results, a de-identified individual participant data set will be prepared for sharing purposes. Access to de-identified data may be granted to other researchers upon reasonable request in line with ECTU policies at that time. Further information including contact information for the ECTU Data Sharing Committee can be accessed here: https://www.ed.ac.uk/usher/edinburgh-clinical-trials/publications/data-sharing. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 22/03/2025 | 24/03/2025 | Yes | No |
Editorial Notes
24/03/2025: Publication reference added.
25/10/2024: The following changes were made:
1. Contact and sponsor addresses were updated.
2. The scientific title and study design were updated from single-centre to multi-centre.
3. The participant inclusion and exclusion criteria were updated.
4. Victoria Hospital was added as a study participating centre
19/02/2024: The recruitment start date was changed from 31/01/2024 to 19/02/2024.
01/12/2023: Internal review.
27/09/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 27/09/2023.
12/05/2023: Trial's existence confirmed by Health Research Authority (HRA) (UK).
