Sources or methods of recruitment

Illustrative example - WHO Pre-eclampsia trial

The women will be recruited at antenatal clinics.  It will be emphasised that enrolment in the study is voluntary, that she can withdraw at any time from all or part of the study, and that any decision she takes in this respect will have no bearing on the medical care she and her family receive.  The study will be explained verbally, according to the information sheet and consent will be recorded with a signature or thumbprint.

Enrolment will be at the discretion of the staff responsible for each mother.  No treatment of any kind will be withheld from a mother because of her participation in the study and mothers who develop hypertension or pre-eclampsia will be given appropriate therapy.

Informed consent for possible enrolment will be obtained antenatally following routine practices in the participating hospitals and a staff of the trial will inform women about consent for participation.  Depending on local requirements, verbal consent may be considered adequate to recruit women.  The consent form has been translated into local languages as necessary.  Participants will not be named in any reports arising from the trial.

Before recruitment
1. Previous RCTs conducted by some of the selected centres on this subject have assisted in optimising the procedures of the trial.
2. The survey among participating centres on baseline calcium intake of the served pregnant population will assist in determining the baseline calcium intake estimates of the study population.
3. All centres piloted the trial procedures, including the use of data collection forms.
4. Both the protocol and the trial report will include requirements laid out in the CONSORT statement.
5. Each centre has provided the Trial Coordination Unit in HRP/RHR/WHO, Geneva with their recruitment target based on their pre-trial obstetric statistics.

During recruitment
1. Completed data collection forms will be returned to WHO in Geneva monthly; data checking and entry will be continuous.  All data will be double entered, cleaned and queries checked immediately with the local investigators.  Prompt return of data collection forms and speedy clarification of queries will facilitate verification of data.
2. Double-blinding will reduce biases in the monitoring of women and assessment of outcomes.
3. Randomisation will take place when the woman's name and hospital number is written on the next treatment box and in the subject number list.  If a box is not used for whatever reason, it will be returned to WHO unopened with only the study number on it.  The used boxes and bottles will be kept in the centres until the WHO site visitor has checked them.
4. Good Clinical Practice (GCP) procedures will be followed.
5. A random sample of boxes will be sent for content testing to ascertain whether the content matches coding.  Similarly, a random sample of tablets will be analysed to check the calcium and placebo contents. This will be conducted by the manufacturer without the involvement of the trial unit in Geneva.
6. The storage conditions will be monitored by dataloggers, which record the temperature and humidity ensuring that the trial medications are kept under optimal conditions.
7. The following procedures will be adopted to standardize outcome assessment:
a) Training sessions will be conducted according to specific methods and audiovisual material developed by professional trainers in blood pressure measurements (Shared Care Inc., California) to ensure that blood pressure measurements will be standardized through all centres.  Before the initiation of the trial, specialized trainers from Shared Care will standardize and certify in blood pressure measurements all the principal investigators and the field coordinators from each centre during a training session to be held at the WHO headquarters in Geneva.
b) Intra- and inter-observer errors will be evaluated monthly during the trial using a double stethoscope according to a standard methodology developed by Shared Care Inc.
c) Staff will undergo regular retraining sessions for blood pressure measurement every three months using the audiovisual training material developed by Shared Care Inc.

(WHO Multicentre Randomized Trial of Calcium Supplementation for the Prevention of Pre-eclampsia - go to protocol)

Illustrative example - Perinatal care trial

CLAP coordination team will be responsible for the hospital selection.  The hospitals’ fulfillment of selection criteria will be obtained through a survey to the Heads of the Obstetrical Departments.

Besides the selection criteria, the coordination unit will invite the hospitals to participate according to:

• their participation in previous trials coordinated by CLAP;

• their participation in other trials or research activities; and

• their location.

Preselected hospitals will perform a baseline data collection.  According to the results of the analysis of the baseline data collection, hospitals will be excluded from the study if the episiotomy rate in primiparous women is below 70% or the rate of active management is higher than 15% (see section 3.2).  Those hospitals fulfilling the inclusion criteria will be randomized to either the intervention or the control group.

This study has a maximum of only 24 hospitals to allocate to the control or intervention group, and random allocation may not provide adequate balance in the groups (Treasure and MacRae, 1998).  In addition, stratified allocation may not be feasible due to there being too few numbers to stratify by all important variables (Treasure and MacRae, 1999). (CLAP Trial - go to protocol)

Illustrative example - INIS trial

Recruitment will depend on good teamwork, knowledge and confidence among all clinicians, particularly front line nursing and medical staff, so that parents receive appropriate information about the study before entry and throughout their baby’s stay.  The ORACLE study has recruited over 11,000 infants in 161 centres.  Experience from that trial suggests that it is helpful if nurses and doctors understand the study background, see clinical research as an integral part of neonatal care contributing to future quality of care, and if a named nurse is appointed and trained as a local trial co-ordinator.  If those caring for the baby are well informed about the study, they can discuss it without transmitting anxiety.  Indeed, parents are likely to feel less anxious if given the opportunity to discuss the options for their baby’s treatment in the context of the study with knowledgeable staff.

The named nursing and medical representative in each unit will therefore receive opportunities for training, regular information and support to enable them to orientate and update new and established nursing and medical staff.  The protocol, printed materials and relevant new research will be widely available and staff will be kept informed by newsletters, personal visits and the worldwide web (as in the UK Neonatal Staffing Study; www.child-health.dundee.ac.uk/research/ukneonatal-staffing/ ).

More than half of all babies receive antibiotics for sepsis during their stay in a neonatal unit.  Neonatal sepsis may present with subtle changes and clinicians normally have a low threshold for antibiotic treatment which should begin quickly, as infected infants can deteriorate rapidly.  The threshold for IVIG therapy in this study will be greater than for antibiotics, and infants must be considered at increased risk of mortality to be eligible for IVIG.  As there is evidence that nursing staff can estimate the risk of mortality as or more accurately than medical staff, it would be valuable to consult them.  Once an infant is considered sufficiently ill to be eligible, it is important that enrolment takes place as soon as practically possible.

All parents should routinely be given an information leaflet about INIS by the nursing staff when their baby is admitted to the neonatal unit.  This will include details of their local medical and nursing contact who they can discuss the study with.  If their baby becomes eligible they will be asked for consent to participate in the study and later follow up, by the most appropriate member of staff available, in person or by telephone.  If they consent in person a copy of the signed consent form will be given to the parent(s).  If telephone consent is considered necessary and appropriate by the recruiting clinician, a ‘Telephone consent’ form will be completed.  This form should then be read and signed by the parent(s) at their next visit to the hospital.  Once this has happened, a copy of the consent form will be given to the parent(s).

Treatment allocation

The practical arrangements for random allocation to trial groups will be as simple as possible, based on that used in the MRC ORACLE study.  Staff will open the next sequentially numbered study pack kept in the neonatal unit, which contains all the materials necessary to give a course of study drug.  (INIS Trial - go to protocol)