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Original TRDS for trail "Paracetamol RCT - Oral Vs Intravenous antidotes" created on Jan 27, 2016


SLCTR Registration Number

SLCTR/2015/031

Date of Registration

31 Dec 2015

The date of last modification

Jan 27, 2016

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Application Summary

Scientific Title of Trial

A randomised clinical trial on the efficacy of intravenous N-acetylcysteine compared to oral N-acetylcysteine and oral methionine in reducing liver cell injury in paracetamol (acetaminophen) poisoning

Public Title of Trial

Paracetamol RCT - Oral Vs Intravenous antidotes

Disease or Health Condition(s) Studied

Liver cell injury in acetaminophen overdose.

Scientific Acronym

OvIVA (Oral Vs IV Antidotes in Paracetamol Poisoning)

Public Acronym

None

Brief title

None

Universal Trial Number

U1111-1177-8562

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

ERC Peradeniya Ref:2015/EC/67


Trial Details

What is the research question being addressed?

What is the efficacy of intravenous N-acetylcysteine (NAC) compared to oral NAC and oral methionine in the prevention of hepatotoxicity in patients with paracetamol (acetaminophen) overdose?

Type of study

Interventional

Study design

Allocation

Randomized controlled trial

Masking

Masking not used

Control

Active

Assignment

Parallel

Purpose

Treatment

Study Phase

Phase 3

Intervention(s) planned

A Phase III multi-centre prospective randomized clinical trial with three treatment arms.

The patients in each centre will also be stratified into 4 groups based on reported dose ingested (>10 g) and time to presentation (>10 hours) as these two factors are strong predictors of hepatotoxicity. Within these 4 strata patients will be randomized 1:1:1 to the three treatments with randomly selected blocks of 6 and 9 to maintain concealment of allocation prior to randomization.

Arm A Intravenous acetylcysteine 300 mg/kg given over a period of 21 hours. The standard regimen used in Sri Lanka is 150 mg/kg in 200mL over 60 min, then 50 mg/kg in 500 mL over 4 hours and 100 mg/kg in 1000mL of normal saline over 16 hours. NAC therapy will continue at the rate of the third bag if the patient has evidence of hepatotoxicity. [Modified regimens that still administer the same total dose over 20-21 hours may be used if this preferred by the physicians in particular hospitals]

Arm B Oral acetylcysteine (600mg tabs) therapy of 140mg/kg loading dose and a dose of 70mg/kg every 4 hours. This will be stopped after 24 hours if the patient does not show evidence of liver toxicity at 24 hours.

Arm C Oral Methionine, 2.5g every 4 hours for 24 hours

Management Plan for Treatment Arm B and C if there is evidence of hepatotoxicity at the end of 24 hours: The physician can decide to continue on the same treatment for up to 72 hours, or those receiving oral antidotes can change to IV NAC therapy at a rate of 150mg/kg/day by slow infusion

Inclusion criteria

  1. Age 16 years and above
  2. All patients who have taken a paracetamol overdose (>200mg/kg) where the physician determines an antidote is to be administered

Exclusion criteria

  1. Patients presenting 24 hours or more 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 institutionalized for any mental health condition.
  6. Patients with known cognitive impairment (e.g. dementia).
  7. Patients with unrelated life threatening illness (e.g. terminal cancer).
  8. Patients who are pregnant.
  9. 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.
  10. Patients who are on warfarin.

Primary outcome(s)

1.

Proportion of patients with miRNA (micro (Micro Ribonucleic acid) evidence of progressive hepatotoxicity following treatment for paracetamol overdose. This will be defined as a ten-fold or greater rise in miR122 over 24 hours from initial tests.

 [

miR122 (micro RNA miR122): On admission (t=0) otherwise t=-5(just before starting the treatment) if there is delay >2hrs to initiate the antidote, and at the 24 hours (end of the treatment).

]

Secondary outcome(s)

1.

  1. ALT > 50% elevated over pre-treatment value (ALT- alanine transaminase levels)

  2. ALT above 1000 IU/L at any time point

  3. INR > 2 at any time point (INR- international normalized ratio)

  4. APAP-adduct concentrations Length of hospital stay (APAP-acetyl-para-aminophenol)

  5. 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

  8. Log change in other miRNA (Micro Ribonucleic acid)

  9. Acute kidney injury

  10. Severe acute liver injury

  11. Death

 [

  1. ALT: on admission (t=0) and at t8, t16, t24, and t36 hours post ingestion, and thereafter daily (Dn) until discharge

  2. INR: t=0 and at 8, 16, 24, and 36 hours post ingestion, and thereafter daily until discharge.

  3. APAP adduct concentrations: t=0 otherwise t=-5 (just before starting the treatment if there is delay >2hrs to initiate the antidote) and at the 24 hours (end of the treatment).

  4. Length of Hospital Stay.

  5. Adverse antidote effects including nausea, vomiting,rash,hypotension,bronchospasm; t=0 and at 8, 16, 24 hrs

  6. Proportion with full adherence to standard regimen in each arm at 24 hours.

  7. Log change in other micro ribonucleic acids (miRNAs):On admission t=0 otherwise t=-5 (just before starting the antidote if there is delay >2hrs to initiate the antidote) and at the 24 hours (end of the treatment)

  8. Acute kidney injury: on admission and at 8, 16, 24, and 36 hours post ingestion, and thereafter daily until discharge.

  9. Severe acute liver injury: t=0 and at 8, 16, 24, and 36 hours post ingestion,

]

Target number/sample size

1530 (510 in each arm)

Countries of recruitment

Sri Lanka

Anticipated start date

2017-02-01

Anticipated end date

2020-06-01

Date of first enrollment

Date of study completion

Recruitment status

Pending

Funding source

South Asian Clinical Toxicology Research Collaboration (SACTRC)

Regulatory approvals


State of Ethics Review Approval

Status

Date of Approval

Approval number

Details of Ethics Review Committee

Name:
Institutional Address:
Telephone:
Email:

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
enquiry@sactrc.org
www.sactrc.org

Secondary study sponsor (If any)

None





Trial Completion details

Do the investigators plan to share identified individual clinical trial participant-level data (IPD)?

IPD sharing plan description

Study protocol available

Protocol version and date

Not Available

Protocol URL

Not Available

Results summary available

Date of posting results

Date of study completion

Final sample size

Date of first publication

Link to results

Brief summary of results