Early Human Development, 29 (1992) 305-308 Elsevier Scientific Publishers Ireland Ltd.

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EHD 01293

Rationale for and work of the Perinatal Trials Service

Adrian Grant

Perinatal Trials Service, Radcliffe Infirmary. Oxford OX2 6HE (UK)

The Perinatal Trials Service provides a service to busy clinicians who wish to mount large simple-in-design randomized trials. The trials aim to identify moderate, but clinically useful, effects of promising treatments for the most important prob- lems in perinatal care. A combination of a flexible five-person core resource and a cadre of staff employed to work on specific trials allows a programme of trials to be conducted successfully and efficiently. The Perinatal Trials Service has three main areas of work: prevention and treatment of immaturity and its consequent morbidi- ty; identification and management of the compromised fetus or baby; and prevention and treatment of maternal morbidity. Examples of projects from each area are described.

Key words: randomized controlled trials; perinatal; technology assessment; im- maturity; pre-eclampsia; eclampsia

Introduction

The purpose of the Perinatal Trials Service is to provide a service to busy clinicians who wish to mount large simple trials aimed at identifying moderate, but clinically useful, effects of promising treatments for the most important problems in perinatal care.

Rationale for the Perinatal Trials Service

The underlying philosophy is that reliable identification of such effects requires surprisingly large randomized controlled trials. In this context, reliable means that

Correspondence to: Adrian Grant, Perinatal Trials Service, National Perinatal Epidemiology Unit, Radcliffe Infirmary, Oxford OX2 6HE, UK.

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the results are sufficiently secure to be a basis for clinical practice. To ensure this, biases and random errors have to be kept sufficiently small so they do not obscure real treatment effects. We cannot expect the size of the effects of individual treat- ments to be large. A reduction of, perhaps, l&25% in a major endpoint would be worthwhile, but this is of moderate size compared with the size of effect which is often hypothesized in some randomized controlled trials.

Avoidance of bias and random error To minimize the chance of being misled by biased selection of the groups for com-

parison, the studies must use formal random allocation; that is, the decision to use one or other of the treatments being compared must be based on true random assign- ment and not left to the ‘clinical judgement’ of the care giver.

To avoid being misled by random errors, the sample sizes of randomized control- led trials have to be surprisingly large; very often thousands of pregnant women or newborn babies are required, not just tens or hundreds as are the usual sample sizes in current perinatal trials. The sample size of a trial primarily depends on securing an adequate number of ‘events’ of the primary endpoint and this determines the number of participants that is sufficient. Frequently, either because the outcome is statistically uncommon or because the condition to be studied is uncommon, multicentre collaboration is essential if these large sample sizes are to be obtained.

Skills required to conduct large, simple trials in perinatal medicine We now have over a decade’s experience of mounting large, simple-in-design,

multicentre trials in perinatal medicine and the formulation of the Perinatal Trials Service is based on that experience. In this context, it is convenient to consider the conduct of such trials in four phases: first, trial design and protocol development; second, organization and administration; third, data management and analysis; and fourth, interpretation and reporting of trial results. These phases require varying combinations of the following skills: clinical, epidemiological, statistical, computing, managerial, secretarial, data-management and clerical. Also, in addition to expert medical advice, input from social scientists, health economists and users of the health service may be needed. These various skills are required episodically over the time course of a study. For example, medical and statistical expertise are needed most in the first and last phases, whereas the middle phases depend predominantly on efficient clerical coordination, computer programming and data management.

The structure of the Perinatal Trials Service Not only is full-time funding impossible to justify for a team with all the skills

necessary for each trial project, but it is also common for the phase of trial design and protocol development to precede project funding and for extra analyses and the report writing to occur after the project grant has expired. For these reasons, the Perinatal Trials Service consists of two complementary components. The first com- ponent is staff employed to work on specific projects, their principal role being the day-to-day running of a trial while it is recruiting or while data are still being col- lected or processed. The other component consists of five ‘core’ staff whose role is to bring on new trials, to ‘complete’ trials whose recruitment and data collection

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have ended and to assist the project staff at special times, such as during col- laborators’ meetings or at the time of interim analyses. The live core staff are a medical trialist, a statistician, a computer programmer, a research administrator and a secretary/clerk. The make-up of this group reflects its role in the Perinatal Trials Service.

The work of tbe Perinatal Trials Service

The Perinatal Trial Service has three main areas of research: 1 Prevention and treatment of immaturity and its consequent morbidity 2 Identification and management of the compromised fetus or newborn baby 3 Prevention and treatment of maternal morbidity

Prevention and treatment of immaturity and its consequent morbidity An example of a trial aimed at reducing the morbidity due to immaturity is the

OSIRIS trial. The aim of this trial is to assess reliably (a) when exogenous surfactant should first be administered (early versus delayed selective and (b) how often exo- genous surfactant should be given, a fixed two-dose schedule of Exosurf administra- tion being compared with the option to give two additional doses if Respiratory Distress Syndrome persists or recurs. This trial involves over 200 clinical centres in 21 countries and 6780 babies have been recruited, making OSIRIS substantially the largest randomized trial in neonatology ever conducted. Recruitment will cease in all centres by the end of 1991 and the results will be presented at a final col- laborators’ meeting in September 1992. Most babies are recruited to OSIRIS by a telephone call to a central randomization service based in Oxford. At this call, basic identifying details and information about major prognostic variables is given over the telephone and then entered directly onto computer. The computer ensures even balance of these prognostic variables in generating a random allocation, which is then given to the referring clinician at the end of the telephone call. Data on clinical management and neonatal outcome are collected on a single, A3-sized, one-page form. The mortality rate in this group of babies is 20-25%, so this trial with 6000 entries will be able to identify any moderate, but clinically important, differential effects (if they exist) very reliably.

I4entification and management of the compromised fetus or newborn baby The Collaborative Low-dose Aspirin Study in Pregnancy (CLASP) is an example

of a trial in the second area of the Perinatal Trial Service’s programme of research. This is a randomized, placebo-controlled trial of daily low-dose aspirin (60 mg) for the prevention and treatment of pre-eclampsia and intrauterine growth retardation. The eligibility criteria have been kept simple. All women are eligible if: (a) between 12 and 32 weeks gestation; (b) at higher than average risk of developing severe pre- eclampsia or intrauterine growth retardation - either because of their previous obstetric or medical history or other risk factor (prophylactic entry), or because of possible early signs or symptoms in the current pregnancy (therapeutic entry); (c) the responsible clinician is substantially uncertain as to whether aspirin is clearly in- dicated or is clearly contra-indicated. Again, random allocation to packs of aspirin

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or placebo is organized through a telephone call to a central randomization service. This trial is being co-ordinated from Oxford jointly by the Clinical Trial Service Unit and the Perinatal Trials Service. So far, 8000 women have been recruited by 700 obstetricians in 200 centres in 17 countries. Recruitment will continue until the end of 1992. In addition to assessing maternal and neonatal outcome at the time of hospital discharge, a sample of children are being reviewed at one year and 18 months of age by questionnaires to their family doctors and parents.

Prevention and treatment of maternal morbidity An example of a project on prevention and treatment of maternal morbidity is the

trial of anticonvulsant management of eclampsia. Eclampsia remains a major cause of maternal mortality. In the short-term, improvement is most likely to come from a reduction in the case-fatality rate. Yet, the optimal management of eclampsia is not clear and practice varies widely. In this trial, first-line anticonvulsant manage- ment with diazepam is being compared with magnesium sulphate. This is being co- ordinated by my colleague, Dr Lelia Duley, in collaboration with the Centro Rosarino de Estudios Perinatales in Rosario, Argentina. So far, the trial involves 14 centres in Argentina, Colombia, Venezuela, Brazil and South Africa. One hundred women have been recruited in the first 10 months. It is hoped that centres in other parts of the world with be able to join the trial in 1992.

Future trials Looking to the future, there are two large multicentre trials co-ordinated by the

Perinatal Trials Service, that may start recruitment during 1992. The first of these will evaluate alternative methods of prenatal diagnosis, particularly early amniocen- tesis. The second will be a randomized trial of extra-corporeal membrane oxygena- tion (ECMO) for larger babies with ventilatory failure. Collaboration in these trials by anyone prepared to abide by the protocols would be welcome and potential par- ticipants are encouraged to contact the Perinatal Trials Service.

Conclusions

The Perinatal Trials Service is a new initiative for fostering evaluation of perinatal care. A combination of a flexible core resource and a cadre of staff employed to work on specific projects allows a programme of trials to be conducted successfully and efficiently. By helping busy clinicians to mount large simple randomized con- trolled trials, the aim is to identify moderate-sized, but clinically useful, effects of promising treatments for the most important problems in perinatal care.

Acknowledgements

The Perinatal Trials Service is supported by grants from the Department of Health and Birthright.