Contact information
Type
Scientific
Primary contact
Mr Michael Eddleston
ORCID ID
Contact details
Scottish Poisons Information Bureau
Royal Infirmary
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom
+44 (0)131 242 1383
eddlestonm@yahoo.com
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
GR063560
Study information
Scientific title
Acute organophosphate pesticide poisoning in Sri Lanka: management, complications and pharmacogenetics
Acronym
Study hypothesis
We propose to carry out a double-blind randomised controlled trial (RCT) of pralidoxime in adult patients presenting with a history and symptoms of organophosphate (OP) poisoning. Primary outcome will be in-hospital mortality; secondary outcomes will include the occurrence of serious complications (respiratory arrest, intermediate syndrome) and time requiring assisted ventilation. Analysis will be on an intention-to-treat basis; the effects of reported time to treatment after poisoning and status on admission will also be assessed.
This RCT will be nested into a study of activated charcoal in unselected cases of poisoning (ISRCTN02920054). All investigations and outcome assessments for ISRCTN02920054 will suffice for this RCT. Extra blood samples will not be taken from patients in this RCT.
The main hypothesis is that the pralidoxime will reduce the case fatality rate from 25% to 19%, hence the primary comparison will be pralidoxime versus placebo. The dimethyl versus diethyl state of the OPs is thought to be fundamental for the effectiveness of oximes in OP poisoning. Dimethylated acetylcholinesterase ages quickly such that oximes do not work in vitro more than 12 hours post-ingestion; in contrast, diethylated acetylcholinesterase age slower so that oximes in vitro work for three to four days post-ingestion. Therefore, once the dimethyl/diethyl status has been retrospectively determined, the analysis will be repeated separating the two groups of OP agents.
It is possible that the oxime, if effective in reducing case fatality rates, will be more effective the earlier it is started. Therefore we will assess the trends in clinical effectiveness according to time post-ingestion to start of therapy. This will be repeated once dimethyl compounds have been distinguished from diethyl compounds. We also want to determine whether treatment should be started irrespective of severity. We will therefore assess trends in case fatality rates across a gradient of severity.
We hypothesise that pralidoxime treatment will prevent the occurrence of the intermediate syndrome; this will therefore be an important secondary outcome. This analysis will be repeated once retrospective toxicological analysis has separated dimethyl compounds from diethyl compounds.
Subgroup analyses are planned to look at the consistency of treatment effect across different types of pesticide, i.e. dimethylated versus diethylated OP pesticides, and for locally common pesticides. A further subgroup analysis will be performed according to the presence of reactivatable acetylcholinesterase before treatment, following retrospective assays of ex-vivo reactivatability.
On 14/12/2007 the overall trial end date was changed from 31/05/2007 to 01/07/2007.
Ethics approval
Not provided at time of registration
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
Acute organophosphate self-poisoning
Intervention
Atropine and pralidoxime chloride (2 g stat followed by 500 mg/h for up to seven days) versus atropine and saline placebo.
Intervention type
Drug
Phase
Not Applicable
Drug names
Atropine, pralidoxime chloride
Primary outcome measure
All-cause mortality at hospital discharge
Secondary outcome measures
1. Percentage of patients requiring intubation
2. Time requiring ventilation
3. Percentage of patients developing the intermediate syndrome (cranial nerve palsies and/or proximal weakness, without distal weakness, after resolution of the cholinergic crisis)
Overall trial start date
01/05/2004
Overall trial end date
01/07/2007
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
All patients (aged 14 years of above, either sex) presenting with history and signs of acute organophosphate self-poisoning in selected Sri Lankan hospitals, requiring atropine.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
1500
Participant exclusion criteria
We hope to recruit all patients admitted to the medical wards with a history of acute poisoning and symptoms and signs of organophosphate poisoning, except for those:
1. Under the age of 14 years
2. Known to be pregnant
3. Have previously received Pralidoxime
4. Patients under the age of 16 or unconscious, who are present without relatives
Recruitment start date
01/05/2004
Recruitment end date
01/05/2007
Locations
Countries of recruitment
Sri Lanka
Trial participating centre
Scottish Poisons Information Bureau
Edinburgh
EH16 4SA
United Kingdom
Sponsor information
Organisation
University of Oxford (UK)
Sponsor details
University Offices
Wellington Square
Oxford
OX1 2JD
United Kingdom
+44 (0)1865 270000
Research.services@admin.ox.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Wellcome Trust
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19564902
Publication citations
-
Results
Eddleston M, Eyer P, Worek F, Juszczak E, Alder N, Mohamed F, Senarathna L, Hittarage A, Azher S, Jeganathan K, Jayamanne S, von Meyer L, Dawson AH, Sheriff MH, Buckley NA, Pralidoxime in acute organophosphorus insecticide poisoning--a randomised controlled trial., PLoS Med., 2009, 6, 6, e1000104, doi: 10.1371/journal.pmed.1000104.