The Paracetamol AfteR Traumatic Brain InjurY Study (PARITY)

A Multi-centre Phase 2b Randomised Controlled Trial Investigating the Efficacy and Safety of Intravenous Paracetamol in Reducing Core Body Temperature After Traumatic Brain Injury

This primary aim is to investigate the effect of paracetamol in reducing body temperature in patients who have sustained traumatic brain injury. This study is also investigating the safety of paracetamol in this patient population.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Paracetamol; Drug: 0.9% Sodium Chloride Schedule:

Detailed Description

Traumatic head injury is a bruising of areas of the brain that occurs commonly as a result of a fall or a motor vehicle accident. Unfortunately, this is a common global occurrence and it occurs both in developing and developed countries. It causes death in nearly 1 in 3 of those who are most severely affected and a large proportion of those that survive have long-term physical or mental disability. Hence, traumatic head injury is a major global problem.

At present there are very few therapies that are known to be effective after a traumatic head injury. In particular the investigators are uncertain about whether modifying body temperature has any effect (good or bad) on the outcomes of patients. Although, this is practiced by some intensive care units around the world.

The investigators have searched extensively to look for any evidence that altering body temperature after traumatic head injury improves the outcome of patients (by reducing the amount of death or disability) and were unable to find any evidence at all. Some preliminary research in both animal experiments and clinical studies suggest that a raised temperature after forms of brain injury may in fact be harmful.

Therefore, at present the investigators believe that we do not really know what effect changing body temperature after head injury has on the outcome of patients.

The investigators are proposing to conduct a clinical study of patients who have had a severe head injury. The patients will be randomly allocated to 2 groups who will get either regular Paracetamol (dissolved in fluid) or a bottle of fluid without any Paracetamol. The 2 treatments will look identical and neither the patients nor the health care workers will know what treatment they are getting. Doing the study in this way will allow us to work out whether giving Paracetamol reduces the temperature of the body and whether there are any side effects that occur. If the study shows that Paracetamol can reduce body temperature safely in this setting then the investigators will work towards doing a larger study of treatments that reduce body temperature. The purpose of this larger study would be to see if the investigators can, not only reduce body temperature but also reduce amount of disability (physical and mental) as well as the death rate in traumatically brain injured patients.

In the proposed study the investigators will be using a higher dose of Paracetamol that is usually prescribed. Other research has shown that the dose that the investigators are proposing to use is safe and also that smaller doses in fact do not reduce body temperature.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia
      • St George Hospital
  • Queensland
    • Brisbane, Queensland, Australia
      • Royal Brisbane and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• Written informed consent has been obtained from the patient's next of kin
• Age > 18 and < 65
• Non penetrating head injury requiring mechanical ventilation, and, with an abnormal CT head (defined by the presence of haemorrhage, contusion, swelling, compression of basal cisterns or herniation)
• Within 72 hours of injury
• Presence (or imminent placement) of arterial cannula
• Alanine transferase level < 100

Exclusion Criteria:

• Suspected paracetamol overdose or allergy to paracetamol
• Confirmed or suspected pregnancy
• Use of pharmacological or physical intervention that reduces body temperature in the 6-hour period prior to randomisation.
• Clinician decision to institute any pharmacological or physical intervention that modifies body temperature
• Body temperature at time of recruitment less that 36°C or greater than 38.9°C
• History of chronic liver disease or chronic alcohol abuse
• Suspected malnutrition: BMI < 18 kg/m2 or weight < 60 kg
• BMI > 35 kg/m2
• Renal failure with serum creatinine > 200
• Haemodynamic instability defined as systolic blood pressure < 90 mmhg or requirement for noradrenaline or adrenaline exceeding 20mcg/minute
• Use of hepatic enzyme inducers, except for phenytoin
• Minor head injury: either normal CT head or not expected to be in intensive care for 72 hours
• GCS = 3 with fixed dilated pupils
• Moribund patient expected to die within 24 hours

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paracetamol; Paracetamol dissolved in 0.9% Sodium Chloride	Drug: Paracetamol; Intravenous paracetamol, 1 gram (100mls), administered over 30 minutes (every 4 hours for 3 days).; Other Names: Perfalgan
Placebo Comparator: 0.9% Sodium Chloride	Drug: 0.9% Sodium Chloride Schedule: Identical placebo: 100mls saline given intravenous over 30 minutes (every 4 hours for 3 days); Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Core body temperature: bladder temperature probe	30 minutes after final dose of study drug has been administered

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Pressure (systolic and mean arterial pressure) measured by intra-arterial pressure monitor		6 hourly during study treatment
Liver function test		daily from first dose of study treatment to the 7th day
serum Paracetamol levels (blood analysis) after a single dose of study drug and after final dose of study drug.		baseline, 30, 45, 90, 240 minutes after single dose. 240 minutes after final dose of study drug
Temperature (bladder and tympanic)	Time-weighted mean, area under the 3-day temperature curve, daily maximum and minimum temperature	Hourly from first study drug treatment until 4 hours after final study drug treatment
The use of physical cooling interventions		hourly during the period of study intervention
Intracranial pressure	Mean daily intracranial pressure for day 1, 2 and 3.	6 hourly during the period of study intervention
Incidence of cerebral hypoperfusion	Systolic blood pressure < 90 mmhg or Mean arterial pressure < 50 mmhg for > 15 minutes; Cerebral perfusion pressure < 50 mmhg for > 15 minutes	During study intervention period

Collaborators and Investigators

• Sponsor: Dr. M.K. Saxena
• Collaborators: The University of New South Wales; The George Institute; Royal Brisbane and Women's Hospital
• Investigators: Principal Investigator: Manoj Saxena, South East Sydney Illawarra Area Health Service

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: October 29, 2010
• First Submitted That Met QC Criteria: October 29, 2010
• First Posted (Estimate): November 1, 2010

Study Record Updates

• Last Update Posted (Estimate): October 28, 2014
• Last Update Submitted That Met QC Criteria: October 26, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: TBI; Temperature; Brain Injury; Paracetamol; Phase 2
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: PARITY

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No