The TREC-Rio study is a pragmatic study; it is randomised, controlled and open. The protocol is summarised in Figure and a Consort diagram is provided in Figure .
TREC-Rio is designed to fit into everyday practice
For the trialists to be able to detect important differences between the treatments, it will be necessary to treat hundreds of patients and this will only be possible if many professionals collaborate in each centre involved. The TREC-Rio trial is designed to not interfere with the routine care of people in participating centres. The process of randomisation is very similar to the normal procedure of beginning the treatment and the eligibility criteria are simple. Drugs will be provided in emergency sealed boxes. Data collection will be limited to the minimum necessary, and will involve little more than extraction of routine information by a person designated to spend time on the TREC-Rio trial. It is not envisaged that busy doctors and nurses will be spending time filling out complicated forms and all trial materials. The interventions will be supplied in a TREC-box that will be opened in the emergency situation.
A fundamental step in such a trial is the randomisation; the distribution of the treatments in a way that is not a function of a clinical decision, but of pure chance. Randomisation will be undertaken in the UK. Microsoft Excel 'RAND' function will be used to choose even numbered block sizes less than ten. Again using this function, the order of use of these block sizes will be randomised. Which drug regimen was represented by which number within the block was then selected, again at random. Finally a table of random numbers will be used to randomise within the blocks. Tables of TREC-box number by contents will be constructed and will be supplied to a Brazilian colleague. The tables will list the contents of the boxes in groups of ten, not disclosing the block sizes used. The Brazilian colleague, always working independently of the TREC-Rio team, will ensure that the correct drugs are in the TREC-box before it is sealed. Concealment of allocation will be ensured by not disclosing the randomly varied block sizes to the colleagues packing the boxes, the supply of tables to those colleagues that gives no suggestion that blocks are even being employed, the independence of those packing the boxes from the other researchers or the clinicians, and the identical nature of the packed boxes.
These easy-to-use boxes will be constructed of cardboard, identical and consecutively numbered. The final check to ensure that nothing has gone wrong with the randomisation will be by the principal investigator filling in a form for each block of ten opened boxes. She will record which intervention was in the box and these data will be returned to the UK so that any inconsistencies can quickly become known.
TREC-Rio is blinded for the initial ratings only
Because the TREC-Rio study evaluates care in the emergency situation, it is imperative that the doctors and nurses know which intervention is being given. The study is blind only up until the time that the TREC-Rio trial box is opened. Therefore, it is crucial that the evaluation of the severity of a person's disturbance and the first impression on the possible cause for the disturbed behavior are recorded before this box is opened. Once the box is opened, doctors and nurses will have knowledge of the drug to be used. It is perfectly feasible that the knowledge that one drug has been given will influence the care beyond the actual effects of the medication. Keeping the study open is not only practical in the emergency situation, but also desirable as the evaluation of care being undertaken is as near real-world circumstances as is possible.
Aggressive/violent patients who arrive at the emergency services of the public psychiatric hospitals of Rio de Janeiro-Brazil can be recruited for TREC-Rio.
Patients are eligible for trial entry if:
It is clear that they need acute intramuscular sedation because of agitation and disturbed and dangerous behaviour
The clinician is uncertain about the benefits and risks of the comparator medications.
For the purposes of this trial, people are considered to be agitated if uncontrollably and severely restless so as to cause concern for safety in carer, or aggressive if they present with threatening verbal behaviour, physical aggression against objects, self-aggression or physical aggression against other people.
People are not eligible for trial entry if:
The clinician believes that one treatment represents an additional risk for the patient.
Placebo controlled studies in this area are difficult to justify (see section on ethics). TREC-Rio will evaluate the existing care in the health services of Rio de Janeiro and this care involves the use of medication that is considered both safe and effective. Currently, this protocol includes a comparison of an intramuscular haloperidol-promethazine mix with an intramuscular rapid acting benzodiazepine, midazolam. In the future, other centers may wish to compare interventions such as a haloperidol-benzodiazepine mix with lorazepam or zuclopenthixol acetate.
The haloperideol-promethazine mix is an obvious choice as standard treatment for TREC-Rio. A pragmatic randomised trial should not substantially interfere with routine practice and, in Brazil, this combination was given to 61% of patients needing sedation in the public psychiatric rooms in Rio de Janeiro [13
]. It is perceived as effective, safe, and with adverse effects that are readily recognised by both medical and nursing staff. It is easy to administer by intra-muscular injection and has never been evaluated within a randomised control trial. Haloperidol and promethazine are both included in WHO's Model List of Essential Drugs [25
The comparison intervention in TREC-Rio is a rapidly acting intramuscular benzodiazepine. Only lorazepam and midazolam are indicated for IM use, as all other benzodiazepines are slowly and erratically absorbed by this method. Lorazepam is not available for IM use in Brazil, however, midazolam is widely used in Brazil as premedication prior to surgical procedures in general emergency rooms and its use for the management of acutely disturbed people is being reported. The use of midazolam for rapid tranquillisation in psychiatry has not been subject to rigorous evaluation within a large and well-designed randomised controlled trial.
All drugs, haloperidol, promethazine and midazolam are included in Rio de Janeiro's list of essential drugs.
Haloperidol – risks and benefits
Haloperidol is a highly potent, widely used, neuroleptic that is indicated to help promote adequate levels of tranquillisation when administered IM. Doses used are usually 5–10 mg and its onset of action is by 60–90 minutes. The half-life of haloperidol varies between 13 and 40 hours, although effects may occur even two days after administration. Adverse effects include akathisia (manifested as restlessness) in 20% and acute dystonic reactions (rigid muscles and involuntary movements) for about 2% of patients. Neuroleptic malignant syndrome (hypothermia, rigid muscles and alteration in the level of consciousness developing 24–72 hours after administration) is an idiosyncratic serious reaction occurring in 0.02–3.2% of people [23
]. Akathisia and acute dystonia are usually treated with the administration of antimuscarinic agents, although the optimal management of neuroleptic malignant syndrome is unclear. despite these adverse effects, which may happen even after a single injection, haloperidol is the elected treatment, widely available and used in the emergency situations.
Promethazine – risks and benefits
Promethazine is an antihistamine combined as an IM injection with haloperidol for the management of acutely disturbed people in both Brazil and India. The rational for this combination lies in the main sedative effects of promethazine and its antimuscarinic properties. Doses are usually between 25–50 mg but, as adjunctive sedative for emergency use, may reach 100 mg IM [23
]. The onset of action is about 1–2 hours after intramuscular administration and half-life is 5–14 hours. The main adverse reactions of promethazine are gastrointestinal disturbances, dry mouth and blurred vision. Paradoxical reactions such as CNS stimulation and extrapyramidal symptoms have also been reported. Overdose may lead to coma and convulsions, progressing to respiratory failure or possibly cardiovascular collapse.
Midazolam – risks and benefits
Doses of midazolam for IM sedation varies between 3–10 mg, depending on clinical condition of the patient and previous exposure to other drugs. The onset of action is rapid, and occurs in 15–30 minutes after IM administration. Midazolam's half-life is 2–3 hours, the duration of action being generally up to 120 minutes. Few adverse effects are associated with IM use of midazolam. Amnesia for the incident is likely to occur. Respiratory depression and paradoxical reactions are only rarely associated with IV use of the drug but with intramuscular administration important changes in respiratory function have not been observed. IM midazolam, however, can cause confusion in about 0.3% of people. Flumazenil, a benzodiazepine antagonist, can be used to reverse the sedation induced by midazolam [23
]. Flumazenil, a benzodiazepine antagonist, can be used to reverse the central effects induced by midazolam. The initial dose is 200 μ g given intravenously in 30 seconds, but additional doses may be needed, up to 3 mg. The onset of action occurs a few minutes after IV injection and can last up to 3 hours. The half-life is about 50 minutes. The adverse effects to flumazenil resemble those of withdrawal symptoms to benzodiazepines (nausea, headache, dizziness, blurred vision). Flumazenil should not be used in the presence of tryciclic intoxication or for patients who have used benzodiazepines for seizures for a long time.
All trial materials, and guidelines for their use, are provided in the TREC-Rio folder supplied by the co-ordinating centre. What follows here is a brief summary of all of trial procedures.
Whenever possible, carers accompanying the disturbed person should have an opportunity to see the information leaflet (Appendix 1, see Additional file 1
) before randomisation. Randomisation proceeds using a local pack system. Identical sealed treatment packs are provided.
As soon as the person enters the study, the clinician completes the trial entry form on the top of the next consecutive pack
(Appendix 2, see Additional file 1
). This must be completed before
the treatment pack is opened. It records brief baseline details about the person and the number of the treatment pack. The treatment packs must
be used in order in which they are removed, the lowest number first. Once the trial entry form has been completed the person is in the trial, even if the doctor changes his/her management and the treatment pack is not opened.
As soon as the person has been allocated a treatment pack, the pack is opened and the trial treatment inside given. Each pack contains:
1 × ampoule of midazolam 15 mg
1 × syringe
1 × needle
2 × swabs
2 × TREC-Rio stickers for the drug prescription form and medical notes
2 × ampoules of haloperidol 5 mg
1 × ampoule of promethazine 50 mg
1 × syringe
1 × needle
2 × swabs
2 × TREC-Rio stickers for the drug prescription form and medical notes
All doses used are at the discretion of the attending clinician. Ampoules will be clearly labelled and the clinician will be in no doubt as regards the treatment being given. If the contents of a trial pack are destroyed, or unfit for use, the person should not be randomised a second time and the equivalent material should be obtained from the usual hospital supplies.
In the event of continuing aggression despite the TREC-Rio medication, ongoing emergency management would be up to the discretion of the clinicians. Another pack is not opened and the doctor is free to use any standard interventions.
Toxicity and serious unexpected events
After trial entry, clinical events are recorded, as usual, in the patients' notes. Complications and adverse events should be managed as usual. A serious unexpected event form (Appendix 5, see Additional file 1
) is provided, and will be sent to the TREC-Rio Co-ordinator as soon it is completed.
Outcome and follow-up
It is crucial that follow-up is complete and accurate for everyone entered into the study. As a pragmatic study, causing minimal interference with routine care, TREC will not employ any rating scale outcomes. It is likely that completion of scales would be inaccurate, and incomplete, validity and reliability would be in question, and clinical utility problematic. The main outcome of TREC-Rio is tranquillisation by 20 minutes. This primary outcome was requested by the nursing and medical staff of the relevant hospitals. By asking the relevant clinical staff to select the primary outcome for TREC-Rio we hoped to ensure maximum compliance with the trial protocol. Therefore, upon injection of the patient, a timer is started, and this rings at 20 minutes and then again at 40, 60 and 120 minutes. At each period the attending nurse rates whether the person is tranquil, asleep, has shown adverse effects or needs additional treatment (see Appendix 2, see Additional file 1
). This attending nurse is not blinded. The person is considered tranquillised when they are felt to be calm and peaceful, but not asleep. They should not be agitated or restless, nor displaying threatening verbal behaviour, physical aggression against objects, self-aggression or physical aggression to other people. Blinding this rater for every participant would have added additional complexity to the study that would have made the trial much less acceptable to the emergency room staff. More importantly, it would have completely changed the emphasis of TREC-Rio. We are interested in evaluating the real-world practice of giving two different drug regimens in the psychiatric emergency setting. In the real world situation health care professionals know what treatment is being given. In addition, for 10% of participants an additional rater, blind to allocated treatment, will, unknown to the health professionals looking after the patient, time the period between injection and tranquillisation and / or sleep exactly. These data will be used to validate the rating of the follow up form (see Appendix 4, see Additional file 1
Additional data are then recorded at 24 hours and finally at two weeks (see Appendix 6, see Additional file 1
). All data is extracted from routine notes. If the person is transferred to another hospital, the co-ordinating centre will contact every hospital to find out further details on what happened after transfer.
Data collection, entry and analysis
All data for TREC-Rio will be collated from the TREC-box forms and routine notes of each emergency room or ward (see Appendix 6, see Additional file 1
). These data will be entered by the principal investigator into especially created forms in Epi-Info v 6.0 [5
Analysis will take place within this package and SPSS [21
]. Dummy tables for this analysis are prepared before recruitment of the first patient (see Appendix 7, see Additional file 1
). All analysis will be based on groups as randomly allocated; this will be an intention-to-treat analysis. For the principal comparisons statistical significance will be taken at a 5% level and for subsidiary comparisons at the 1% level, to minimise the impact of multiple comparisons. Relative risk, risk difference, number needed to treat and respective 95% confidence intervals will be estimated for tranquillisation by 20, 40 and 60 minutes.
For the continuous outcome mean difference will be assessed. As in most experiments, this study carried out a randomisation of a non random sample instead of a random sampling of a specific population. In order to be coherent with the adopted design, the statistical significance of the means difference will be evaluated by a randomisation model (not a population model), and a design-based permutation test will be used instead of an approximate test to preserve the type I error rate [3
]. Permutation test will be performed using StatXact 3.0 for Windows [8
]. For a subgroup of 10% of patients, quality of data on time to tranquillisation will be evaluated by two independent observers. The agreement of this measurement will be assessed using Kappa statistics.
The TREC-Rio Co-ordinating Group: The co-ordinating centre of the Rio de Janeiro arm is based at Fundação Osvaldo Cruz, Rio de Janeiro, Brazil. The Co-ordinating Group has overall responsibility for the design of the proposed trial and is responsible for all aspects of day to day trial administration. The Co-ordinating team is also responsible for preparing reports for the steering committee. Membership: Gisele Huf, Evandro SF Coutinho, Clive E Adams.
The TREC-Rio Steering Committee: The overall progress of the trial, adherence to protocol, patient safety and the consideration of new information will be monitored by a scientific and administrative steering committee. At the end of the proposed study period, the Steering Committee will consider the extension of the study, to allow the detection of other important effects. The membership of this committee is: Dr. Marco Antônio Brasil (chair), Dr. Gisele Huf, Dr. Evandro Coutinho, Prof. Clive Adams, Dr. Hugo Marques Fagundes Jr., Dr. José Ramón R. A. Lopez, Dr. Maurício Lima, Dr. Mário Barreira Campos, Dr. Suely Rozenfeld and Rosaura Maria Braz.
Should recruitment to TREC-Rio be slow (take more than one year) or very swift (more than 300 in the expected six month recruitment period), an independent data monitoring committee (DMC) will, in confidence, monitor results. Should recruitment to the TREC-Rio be slow or go beyond 300, interim results will be supplied, in strict confidence to the chair of DMC as frequently as requested. Meetings of the committee will be arranged periodically as considered appropriate by the chair of the committee. In the light of the interim data, and of any other evidence or advice they wish to seek, the data monitoring committee will inform the chair of the steering committee if, in their view: i. there is proof beyond reasonable doubt that for any particular group or subgroup treatment with one or other regiment is clearly indicated or contraindicated or: ii. it is evident that no clear outcome will be obtained. Proof beyond reasonable doubt may be taken as the difference of at least three standard deviations and at least one of the primary outcomes.
The data monitoring committee may communicate certain interim analysis to the steering committee or suggest certain protocol changes, but the steering committee will remain responsible for deciding which changes to adopt. The membership of this committee is: Claudio Jose Struchiner (chair), Luiz B. Camacho, Jair de Jesus Mari.
No participating centre will directly receive funds for involvement in TREC-Rio. By design, funding for the overall project is minimal. All funding is intramural and everyone involved is undertaking this project as part of their usual funded employment. This support s jointly funded by Fundação Osvaldo Cruz, Cochrane Schizophrenia Group, British Council and CAPES – Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Drugs to be used in the trial will be supplied by Secretaria Municipal de Saúde do Rio de Janeiro.
Proposed policy for publication and authorship
The success of the TREC-Rio trial depends on active collaboration of a large number of people in each of the participating hospitals. For this reason, authorship of any presentations or reports related to the trial will be in the name of the TREC-Rio Collaborative Group. Inevitably, for general publication it is not possible to name everybody that has contributed to a study such as this. Certificates of collaboration will be provided to those who have made a substantial contribution but whose name is not on the final report.
The results will be presented in confidence to the collaborators before publication. Once the final report has been published, collaborators will have access to the data in the hospital for additional descriptive analysis. Outcome by treatment group will not be presented for individual centres in the main reports of the TREC-Rio trial.