Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning Study (SNAP)

This study has been completed.
Sponsor:
Collaborators:
NHS Lothian
Chief Scientist Office of the Scottish Government
Information provided by (Responsible Party):
University of Edinburgh
ClinicalTrials.gov Identifier:
NCT01050270
First received: January 14, 2010
Last updated: July 30, 2013
Last verified: July 2013
  Purpose

This study is designed to assess the impact of new approaches to therapy for paracetamol poisoning. Standard therapy is currently acetylcysteine by intravenous infusion over 20.25h. This regimen is given to those deemed "at risk" using standard criteria (British National Formulary 200920). It has 3 major problems, adverse events (nausea and vomiting and anaphylactoid reactions), therapy duration and complexity of administration.

This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy.

It will also provide sufficient experience and data from a modified shortened IV acetylcysteine regimen to adequately design and power a study of the modified regimen as a new treatment for this common poison. Such an approach has a major potential to reduce patient adverse events from acetylcysteine therapy and shorten duration of hospital stay.


Condition Intervention Phase
Overdose
Drug: Ondansetron
Drug: acetylcysteine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomised Trial to Assess the Effectiveness of Pre-treatment With Ondansetron at Reducing Nausea and Vomiting in Patients Treated With Either the Conventional Regimen or a Modified Regimen of Acetylcysteine for Paracetamol Poisoning

Resource links provided by NLM:


Further study details as provided by University of Edinburgh:

Primary Outcome Measures:
  • The primary endpoint is the proportion of patients who do not vomit or retch within 2 hours of initiation of acetylcysteine treatment and no use of rescue medication. Retching will be defined as a vomit not producing any liquid. [ Time Frame: 2 hours post start of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The secondary endpoint is nausea or vomiting within 12h of initiation of acetylcysteine treatment. [ Time Frame: 12 hours post start of treatment ] [ Designated as safety issue: No ]

Enrollment: 222
Study Start Date: September 2010
Study Completion Date: March 2013
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Ondansetron /acetylcysteine 20.25h
Ondansetron followed by conventional acetylcysteine regimen
Drug: Ondansetron
4mgs iv bolus
Other Name: CAS number: 99614-02-5
Drug: acetylcysteine
150 mg/kg over 15 mins 50 mg/kg over 4 hours 100 mg/kg over 16 hours
Other Name: CAS number: 616-91-1
Placebo/acetylcysteine 20.25h
placebo followed by conventional acetylcysteine regimen
Drug: acetylcysteine
150 mg/kg over 15 mins 50 mg/kg over 4 hours 100 mg/kg over 16 hours
Other Name: CAS number: 616-91-1
Ondansetron/acetylcysteine 12h
ondansetron followed by modified acetylcysteine regimen
Drug: Ondansetron
4mgs iv bolus
Other Name: CAS number: 99614-02-5
Drug: acetylcysteine
100 mg/kg over 2 hours then 200mg/kg over 10 hours, followed by glucose 5% for 8 hours
Other Name: cas number: 616-91-1
Placebo/acetylcysteine 12h
placebo followed by modified acetylcysteine regimen
Drug: acetylcysteine
100 mg/kg over 2 hours then 200mg/kg over 10 hours, followed by glucose 5% for 8 hours
Other Name: cas number: 616-91-1

Detailed Description:

Paracetamol is the commonest poison seen in the United Kingdom and is present in approximately 40% of patients admitted with self harm. Current treatment involves use of the antidote acetylcysteine in patients deemed at risk of potential liver damage. This is given by intravenous infusion over a period of 20.25 hours. This regimen was designed in the 1970s and is empirical, in that a large loading dose of the antidote is administered followed by 2 decreasing concentrations. It is cumbersome to calculate and dilute within the ward and therefore subject to error in preparation. The initial infusion is associated with a significant rate of adverse reactions, in particular nausea and vomiting and anaphylactoid reactions. The latter are particularly troublesome and occur in up to 15% of patients treated. Therapy is discontinued and there is often confusion as to whether it can be restarted in a timely manner.

Studying antidotes in the management of poisoning is challenging not least because of the patient population and of the limited time available to make decisions and gain consent. This will be the first major clinical trial of antidote therapy in this poisoning in the UK in 30 years.

The final objective of this work is to develop a therapeutic regimen of acetylcysteine that does not cause such a high rate of adverse reactions and is also easier for nurses to make up.

The present study focuses on the potential use of ondansetron, an anti-emetic, prior to the administration of acetylcysteine. It will also allow preliminary data to be collected on a new approach to giving acetylcysteine using a modified 12 h regimen, which includes a slower initial intravenous infusion.

The primary trial outcome will therefore inform on the efficacy of ondansetron pre-treatment as an anti-emetic in this situation. In addition valuable data on the incidence of adverse effects caused by the modified acetylcysteine regimen, and changes in liver function and the inflammatory response to paracetamol liver injury caused by paracetamol within this modified acetylcysteine treatment will be obtained.

In addition an opportunity will be taken in a convenience sample of 40 patients to study the pharmacokinetics of acetylcysteine in this group using the standard and modified regimens.

A factorial design is being used to answer the key clinical questions. In total a maximum of 250 patients will be recruited and it is anticipated the data from 200 will be available for final analysis.

The demographic of this patient group is essentially Caucasian English-speaking and at this stage we do not propose to recruit non-English-speaking subjects.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Any patient admitted to hospital within 36 hours of a single acute paracetamol overdose; AND
  • Requires treatment with acetylcysteine.

These patients will include:

  • Patients with no risk factors and timed paracetamol concentrations above the 200-line on the UK paracetamol overdose treatment nomogram.
  • Patients with at least 1 risk factor and timed paracetamol concentrations above the 100-line on the UK paracetamol overdose treatment nomogram
  • Patients presenting >8 hours, and at risk of liver damage based on history of dose ingested (BNF) that need immediate treatment

Risk factors are defined as follows:

  • Nutritional deficiency, malnourished and/or debilitating disease: acute or chronic starvation, eating disorders, cachexia, malabsorption syndromes, AIDS, cystic fibrosis, hepatitis C, chronic alcoholism.
  • Enzyme induction: use of drugs with this property (carbamazepine, rifampicin, barbiturates, phenytoin, rifabutin, efavirenz, nevirapine, St John's Wort; regular consumption of ethanol above advised amounts.

Exclusion Criteria:

Patients:

  • < 16 years old
  • Detained under the Mental Health Act
  • With known permanent cognitive impairment
  • With a life-threatening illness
  • Who are known to be pregnant
  • Who have previously participated in the study
  • Unreliable history of paracetamol overdose
  • Vomiting and requiring treatment antiemetic prior to randomisation
  • Presenting after 36 hours of a single acute paracetamol overdose
  • Presenting after taking a staggered paracetamol overdose (defined as when the overdose of paracetamol is taken over a period of more than 2 hours)
  • Who take anticoagulants (e.g. warfarin) therapeutically or have taken an overdose of anticoagulants
  • Who, in the opinion of the responsible clinician/nurse, are unlikely to complete the full course of acetylcysteine e.g. expressing wish to self-discharge
  • Who in the opinion of the responsible clinician/nurse are unable to complete the initial questionnaire either themselves or with nurse assistance.
  • Who have a history of hypersensitivity to 5HT3 antagonists
  • Non-English speaking patients. (Trial information material will only be produced in English in view of the known and stable demographic of the Edinburgh and Newcastle self harm population)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01050270

Locations
United Kingdom
Aberdeen Royal Infirmary
Aberdeen, United Kingdom, AB25 2ZN
Royal Infirmary of Edinburgh
Edinburgh, United Kingdom, EH16 4SA
Royal Victoria Infirmary
Newcastle upon Tyne, United Kingdom, NE1 4LP
Sponsors and Collaborators
University of Edinburgh
NHS Lothian
Chief Scientist Office of the Scottish Government
Investigators
Principal Investigator: Alasdair J Gray NHS Lothian
Principal Investigator: Harry K Thanacoody Newcastle Hospitals NHS Foundation Trust
Principal Investigator: Jamie G Cooper NHS Grampian
  More Information

No publications provided by University of Edinburgh

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Edinburgh
ClinicalTrials.gov Identifier: NCT01050270     History of Changes
Other Study ID Numbers: CZB/4/722, 2009-017800-10
Study First Received: January 14, 2010
Last Updated: July 30, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Drug Overdose
Poisoning
Substance-Related Disorders
Chemically-Induced Disorders
Acetaminophen
Ondansetron
Acetylcysteine
N-monoacetylcystine
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Antipyretics
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antidotes
Antiemetics
Autonomic Agents
Gastrointestinal Agents
Antipruritics

ClinicalTrials.gov processed this record on August 21, 2014