Title: Aggression Following TBI: Effectiveness of Risperidone (AFTER)-a feasibility RCT.
Funder: Department of Health and Social Care

Abstract: Background: Traumatic Brain Injury (TBI) is a major public health concern and many people develop long lasting physical and neuropsychiatric consequences after TBI. Despite the emphasis on physical rehabilitation it is the emotional and behavioural consequences that have greater impact on people with TBI and their family carers. One such behavioural problem is aggression towards others, property and sometimes self. Aggression is reported to be common after TBI (37%-71%) and causes major stress for patients and their families. Both drug and non-drug interventions are used to manage this challenging behaviour. There are many different drugs used regularly off licence for this purpose but there is no good quality RCT based evidence available to either support or refute their use. This highlights the urgent need for properly designed RCTs in this field. However, as no large scale RCT has ever been carried out in this area it is important to conduct a feasibility trial before embarking on a full scale RCT. Most commonly used drug group for this purpose is antipsychotics, particularly the new generation drugs including risperdione. Although there is no RCT based evidence available involving people with TBI, currently there is strong RCT based evidence available to support use of risperidone for the management of aggressive and agitated behaviour among children and adults with intellectual disabilities (ID) and/ or autism spectrum disorder (ASD). This is the only drug for which strongest evidence exists for the management of aggression in any group. Although widely used, currently no good quality RCT without bias exists to support the use of mood stabilisers for this purpose. We have, therefore, decided to use risperidone to carry out a placebo-controlled feasibility RCT as this drug is also widely used in people with TBI. Aims: To conduct a multi-centre parallel design placebo controlled (1:1 ratio) double-blind feasibility RCT of risperidone for the management of aggression in adults with TBI in order to assess feasibility for a substantive full scale definitive RCT in future. Plan: To recruit 50 consecutive TBI patients from four centres in London and Kent over an 18 month period. Follow up participants for three months using a battery of assessment scales to measure changes in aggressive behaviour (MOAS, IRQ) as well as global functioning (GOS-E, CGI) and quality of life (EQ-5D, SF-12). We will also assess adverse effect profile with a standard scale (UKU) and carrying out appropriate blood tests (serum glucose/ HbA1c, lipid profile, prolactin), and checking body weight and blood pressure at baseline and at three months. Local clinicians will be allowed to use PRN medication if necessary. Benefit to patients: Aggressive behaviour causes immense distress among people with TBI and their families sometimes leading to family breakdown. This is a hidden disability within society as many of these patients suffer from lack of appropriate intervention and service provision. These patients believe that an effective intervention is urgently needed to help improve their quality of life. An appropriately designed RCT will provide much needed evidence to support a particular type of intervention such as drug therapy. Benefits to NHS: Each year 1.4 million people attend A & E departments in England and Wales with TBI and a high proportion of them develop long lasting consequences including irritable and aggressive behaviour. This is proving to be a major burden for the NHS. A clinically and cost effective intervention will reduce this burden on the NHS for which appropriately conducted RCTs are mandatory. This will also reduce pressure on resources in the mental health service, in-patients and emergency departments, where these patients are likely to present in the absence of an appropriate intervention.

Lay abstract: Each year 1.4 million people in the UK sustain a head injury/ traumatic brain injury (TBI) due to road traffic accidents, assaults, falls and other causes. Unfortunately a high proportion of them (37% - 71%) experience long lasting emotional problems such as irritability and anger which lead to aggressive behaviour. This behaviour can be extremely distressing for people with TBI and their family carers and extremely challenging to treat. Often aggression is caused by a complex interaction of underlying brain damage, physical health conditions and social consequences of the injury. Both drug and non-drug treatments are used to manage aggression in people with TBI. Although doctors use many drugs for this purpose including an antipsychotic called risperidone, these drugs are not licenced for use in treatment of aggression in TBI and no properly designed Randomised Controlled Trial (RCT) exists to support their use in TBI, although they are licenced for some psychiatric conditions and epilepsy. We propose a placebo controlled RCT of risperidone among people with TBI to see whether this drug is effective or not. We will do a feasibility RCT first involving 50 people with TBI from four different centres in London to see whether it is possible to do a full RCT in future. 25 of the 50 participants will be randomly chosen to receive risperidone and the rest will receive placebo (dummy pills). Standardised assessment scales and a carer wellbeing scale will be used at the beginning and end of 3 months of treatment to assess improvement in aggression and other aspects of quality of life among the participants. People with TBI helped to develop this proposal. They and their family carers will oversee the project and help to communicate the results of the study to other people who have been affected by this important problem.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS