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A randomized controlled trial of oral vs intravenous antidotes for acute paracetamol poisoning -

SLCTR Registration Number

SLCTR/2017/036


Date of Registration

09 Oct 2017

The date of last modification

Oct 09, 2017



Application Summary


Scientific Title of Trial

A randomized controlled trial of oral vs intravenous antidotes for acute paracetamol poisoning


Public Title of Trial

Paracetamol pilot study - Oral Vs Intravenous antidotes


Disease of Health Condition(s) Studied

Liver cell injury in paracetamol overdose


Scientific Acronym

None


Public Acronym

None


Brief title

Comparison of oral vs intravenous antidotes in acute paracetamol poisoning


Universal Trail Number

U1111-1199-2734


Any other number(s) assigned to the trial and issuing authority

2015/EC/67 (ERC: Peradeniya)


Trial Details


What is the research question being addressed?

Is oral N-acetylcysteine (NAC) or oral methionine better compared to intravenous NAC therapy in preventing liver cell injury (hepatotoxicity) following acute paracetamol overdose?


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Masking not used


Control

Active


Assignment

Parallel


Purpose

Treatment


Intervention(s) planned

Patients will be randomized 1:1:1 to the three treatments using the randomisation option in the REDCap software.

Randomisation will be done at the place where patient will be treated (in the emergency department or ward) by the research assistant in the presence of the treating doctor.

Arm 1: Intravenous acetylcysteine: 300 mg/kg given over a period of 21 hours. The above dose will be given at three different rates of infusion i.e. 150 mg/kg in 200 mL of normal saline over 60 min, followed by 50 mg/kg in 500 mL of normal saline over 4 hours and finally 100 mg/kg in 1000 mL of normal saline over 16 hours.
Arm 2: Oral acetylcysteine: 140 mg/kg loading dose and a dose of 70 mg/kg every 4 hours.
Arm 3: Oral Methionine: 2.5 g every 4 hours for 24 hours.
The intervention will be administered by the treating team and the outcomes will be assessed by study team who will be not blind to the interventional status.


Inclusion criteria

Patients >16 years of age with acute paracetamol poisoning. i.e who present within 10 hours of ingestion and whose plasma paracetamol levels falls above Prescott normogram line.


Exclusion criteria

  1. Patients presenting more than 10 hours after poisoning.
  2. Patients who have already received an antidote (possible in other hospitals prior to transfer).
  3. Patients who have received charcoal (which would interfere with oral antidotes).
  4. Patients under the age of 16.
  5. Patients who are unable to give the amount of paracetamol ingested and the time of ingestion
  6. Patients who are institutionalized for any mental health condition.
  7. Patients with known cognitive impairment (e.g. dementia).
  8. Patients with an unrelated life threatening illness (e.g. terminal cancer).
  9. Patients who are known to be pregnant or breast feeding. (This is simply a practical decision. There are no known risks these patients will be subjected to by being treated with these antidotes)
  10. Patients who have had a paracetamol overdose in the previous 4 weeks or have taken a significant dose of any other toxic substance in addition to paracetamol.
  11. Patients who are on warfarin.
  12. Patients who have taken a staggered dose of paracetamol (over more than a 2-hour period).


Primary outcome(s)

Rise of ALT to more than 50% of the baseline value within 24 hours.


Primary outcome(s) - Time of assessment(s)

On admission and at 8, 16, 24, and 36 hours post ingestion, and thereafter daily until discharge.


Secondary outcome

  1. ALT above 1000 IU/L at any time point
  2. INR > 2 at any time point
  3. miR122 levels.
  4. APAP-adduct concentrations: PPA – Paracetamol Protein Adduct Paracetamol cysteine (APAP – CYS)
  5. Length of hospital stay and number of days spent in the Intensive Care Unit.
  6. Adverse antidote effects including nausea, vomiting, rash, hypotension, bronchospasm.
  7. Proportion with full adherence to standard regimen in each arm for 24 hours
  8. Acute kidney injury: Serum creatinine (AKIN criteria)
  9. Severe acute liver injury: ALT level of above 150U/L or ALT level of above 50U/L when clinical symptoms and signs of hepatotoxicity are present. The clinical symptoms and signs of hepatotoxicity which would be used in this regard are:-
    (i) Liver tenderness
    (ii) Late onset (>24 hours) vomiting
    (iii) Signs of liver failure (Jaundice etc.)

  10. Death


Secondary outcome(s) - Time of assessment(s)

  1. ALT above 1000 IU/L at any time point
  2. INR > 2 at any time point
  3. miR122 levels.
  4. APAP-adduct concentrations: PPA – Paracetamol Protein Adduct Paracetamol cysteine (APAP – CYS)
  5. Length of hospital stay and number of days spent in the Intensive Care Unit.
  6. Adverse antidote effects including nausea, vomiting, rash, hypotension, bronchospasm.
  7. Proportion with full adherence to standard regimen in each arm for 24 hours
  8. Acute kidney injury: Serum creatinine (AKIN criteria)
  9. Severe acute liver injury: ALT level of above 150U/L or ALT level of above 50U/L when clinical symptoms and signs of hepatotoxicity are present. The clinical symptoms and signs of hepatotoxicity which would be used in this regard are:-
    (i) Liver tenderness
    (ii) Late onset (>24 hours) vomiting
    (iii) Signs of liver failure (Jaundice etc.)

  10. Death



Target number/sample size

300 (100 in each arm)


Countries of recruitment

Sri Lanka


Anticipated start date

2017-10-11


Anticipated end date

2020-10-11


Recruitment status

Pending


State of ethics review approval

• Approved by the Ethical Review Committee, Faculty of Medicine, University of Peradeniya on 13th October 2015 • Ref No. : 2015/EC/67; title “A randomized clinical trial of Oral vs. Intravenous antidotes for paracetamol poisoning “ • Amendment date:13/


Funding source

South Asian Clinical Toxicology Research Collaboration (SACTRC)



Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Prof.Indika Bandara Gawarammana
Professor in Medicine
Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
+94812384556
+94714225081
+94814479822
indikagaw@gmail.com

Contact Person for Public Queries

Seyed Shahmy
Manager Operations
SACTRC, Faculty of Medicine University of Peradeniya, Peradeniya, Sri Lanka
+94812387992
+94773938949
+94814479822
shahmy@sactrc.org


Primary study sponsor/organization

South Asian Clinical Toxicology Research Collaboration (SACTRC)

Faculty of Medicine University of Peradeniya Peradeniya
+94812384556 +94814479822
+94814479822
enquiry@sactrc.org
www.sactrc.org

Secondary study sponsor (If any)

None