A total of 230 subjects were recruited into the “Infant Single Ventricle Trial”. Metrics and patterns of accrual varied across the three periods (; ). After the first 6 months, recruitment was only 28% of the target rate across the seven sites, which led to an intensive programme of calls to the sites. Key strategies for recruitment from those calls were incorporated into the Inventory of Best Recruitment Practices
() and focussed on three primary areas:
- maintaining equipoise in the trial and developing partnerships with providers of clinical care;
- fostering relationships with families while decreasing the burden of the study; and
- promoting an environment conducive to research.
Screening and randomisation by periods of time (seven original sites). ISV = infant single ventricle.
Trial recruitment during three periods of time (seven original sites).
Inventory of best recruitment practices collated from centre calls.
was distributed to all participating sites through multiple methods:
- electronic updates;
- conference calls held with the coordinators and the protocol committee; as well as
- calls held during meetings of the Pediatric Heart Network Steering Committee.
Over the remainder of the study, additional calls that focussed solely on recruitment were held with the Pediatric Heart Network Steering Committee and Study Coordinators.
From the Initial Period to the Intermediate Period, the rate of screening increased from 21 to 27 subjects per month (p = 0.007). Among those eligible for entry into the study, the rate of consent increased from 39% to 55% (p = 0.025), and the rate of randomisation increased from four to seven subjects per month (p = 0.010). Rates of eligibility did not change significantly over the course of the study despite an amendment to the protocol in the Intermediate Period to expand criteria of eligibility. The amendment at the beginning of the Intermediate Period consisted of the following:
- expand inclusionary criteria to permit infants at lower gestational ages and birth weights to be enrolled;
- simplify or eliminate some procedures during the study;
- allow some follow-up visits to be carried out at the office of the local physician of the patient; and
- add three new recruiting sites.
The protocol was also amended later to increase the sample size and extend the length of the accrual period of the trial because of the difficulties with recruitment and retention.
Once the “Single Ventricle Reconstruction Trial” started (Final Period), the mean number of patients randomised into the “Infant Single Ventricle Trial” per month decreased significantly compared with the Intermediate Period (6.5 versus 4.3, p = 0.012; ). Among the patients who were screened and eligible for both trials at the seven original sites, 49% of parents consented to both trials, whereas 43% consented to the “Single Ventricle Reconstruction Trial” but refused to participate in the “Infant Single Ventricle Trial”.
Three new sites began recruiting in the Intermediate Period; during the Final Period, they recruited an average of 0.3 subjects per month per site compared with the original seven sites, which recruited an average of 0.6 subjects per month per site during the same period (p = 0.165). The overall rate of patients who were lost to follow-up due to death, cardiac transplantation, or withdrawal from the study was higher than anticipated (20% versus 15%), necessitating an extension of the period of recruitment and an increase in sample size to maintain adequate unconditional power.
Results of the survey
All 10 participating sites completed and returned the survey (Appendix A
) at the end of the trial. The following characteristics of centres aided in recruitment ():
- a strong infrastructure for research;
- support from clinical staff; and
- a programme in foetal cardiology.
Post-trial survey responses: characteristics of centres and strategies of recruitment.
Strategies of recruitment described as beneficial closely mirrored the strategies in the Inventory of Best Recruitment Practices, falling primarily into three broad areas (). First, promoting partnerships with staff providing clinical care to infants in the study focussed on addressing lack of equipoise related to the drug being studied. Strategies included involving the primary cardiologist or surgeon in discussions about the study with parents and providing information about the study to providers of clinical care through standard educational activities such as Grand Rounds or “in-service training” sessions.
Second, fostering relationships with families included having a consistent Coordinator and an involved Principal Investigator to meet with families frequently to address issues of concern to families as well as to seek consent for participation in the study. The results of the survey identified an average of three visits with the family and 2 to 6 hours of time to describe the study, answer questions, and obtain consent. To reduce burden to families, the protocol was amended to permit more local visits for monitoring drug safety and effects, rather than requiring families to travel back to the centre where they were initially enrolled, which in some cases was a significant distance.
Third, the environment for research and clinical care was identified as an essential component for successful recruitment. The foetal cardiology visits provided opportunities to introduce families to the staff involved with the study, the concept of research, and, in some cases, information about the study, in a less stressful environment. Sites also reported that approaching both parents together and after the infant was more stable, to discuss the study and obtain consent, was beneficial. Most sites (90%) did not limit the number of studies in which children could participate, and 70% of sites reported that potential subjects were asked to participate in two or more studies in addition to the “Infant Single Ventricle Trial”.