End of the pilot phase
In these fascinating times of rapidly growing general inter-est in cryptogenic stroke, we are pleased to announce the first newsletter of the SECRETO study — an international consortium to search explanations for cryptogenic stroke in the young. Study procedures and online database have undergone rigorous testing and improvements since we started patient recruitment in November 2013, and we are now approaching the end of the pilot phase. We cordially thank all who have contributed to the study protocol and documents thus far.
Recruitment
The piloting has been ongoing in two study sites, Helsinki University Hospital and Kuopio University Hospital. Until March 20, 2015, a total of 50 patients and 9 stroke-free control subjects have been enrolled (in Helsinki: on average 2.7 patients/month, covering 33% of consecutively screened stroke patients and 80% of potentially eligible patients with eventual cryptogenic etiology). Two more Finnish study sites, Turku University Hospital and Tampere University Hospital, are now ready to begin enrollment — congratulations!
Cumulative recruitment until Mar 2015:
Overall, our patients have been highly motivated to participate in every component of the study, and adherent to follow-up. Moreover, no difficulties have emerged in the search of proper stroke-free control subjects since we started their recruitment in December 2014. Also among colleagues who treat these patients a tremendous interest has emerged towards the project. Rather than discharging a young patient with pointless information such as “I have no idea why you had your stroke and how to prevent you from having new strokes in the future”, there now is a project searching for the answers into which enroll these patients. There clearly has been a great demand for this type of study in the field!
Key numbers of progress
As a quality check we have picked up a few figures from the study online database.
Selected numbers of the first 50 pilot patients:
| Study procedures | |
| Per protocol TTE/TEE performed | 50 / 49 |
| TCD bubble screen performed | 40 |
| Blood samples taken at baseline | 50 |
| 3-month follow-up completed | 42 |
| Blood samples taken at 3-month visit | 42 |
| 12-month follow-up completed | 12 |
| Substudy participation | |
| Potentially eligible for Family Study | 18* |
| Extended Cardiovascular Study | 43† |
| Oral | 50‡ |
| Study population characteristics | |
| Mean age, years (±SD) | 38.4 (±7.7) |
| Female/male | 21 / 29 |
| NIH Stroke Scale score, median (range) | 2 (0-26) |
| DWI positive lesion(s) | 50 |
*18 probands fulfilling the Family Study inclusion criteria were selected among the consecutive patients screened for the main study since November 2013. The probands were entered into the Family Study database to pilot a semi-automated online grading system for family history informativeness. Consents or samples have not yet been obtained. †Substudy conducted in Helsinki = 100% participation. ‡Substudy conducted at all Finnish sites = 100% participation.
All the 9 control subjects enrolled to date have donated investigational blood samples and consented to undergo TTE/TEE and/or TCD bubble screen as well as participate in the Oral –substudy. All controls in Helsinki are also participating in the Extended Cardiovascular Study. The enthusiasm among the first volunteers is very encouraging!
With respect to the performance of the cardiac imaging protocol in control subjects, our minimum goal is that all controls enrolled in Finnish sites (estimated n=360) would undergo echocardiography per protocol and/or TCD bubble screen.
Protocol updates
A few changes will apply to the protocol since its last version 2.7, including:
- Incorporation of the Perceived Stress Scale as a self-completed quantitative measure of recent stress.
- Another idea that came as feedback from our patients, is to investigate the quality of sleep. Limited evidence is suggesting an association between poor sleep quality and stroke, and many patients have emphasized the fact that they have recently had trouble with sleeping. Among the affordable validated instruments to measure sleep quality would be the Pittsburgh Sleep Quality Index [open for discussion].
- Development of a semi-automated family history grading system to facilitate recruitment of informative families for the genetic family study (pilot ongoing).Inclusion of patients with PFO (or other source for right-to-left shunt) and concomitant venous thrombosis preceding or after the index event. This would ensure systematic enrollment of patients with presumed paradoxical embolism with or without documented venous thrombosis. Although one may say there is an evident cause if venous thrombosis preceded the stroke, the reason for the venous thrombosis per se remains open in most of such cases.
- Encourage to systematically screen of DVT in lower extremities with dupplex ultrasound in patients with PFO [open for discussion]. An eCRF has been created to capture the results of venous thrombosis screening studies.
Dr. Nicolas Martinez Majander, a neurology resident in Helsinki University Hospital, has been involved in patient recruitment since August 2014 and is responsible for running the vascular substudies: ”It has been absolutely fascinating to see so interesting and highly motivated patients. I have virtually done most of the study proce-dures in addition to my routine clinical duties, including the extras related to the substudy. I have a strong gut feeling that our patients get better diagnostic evaluation and care if enrolled in the study, which also keeps me motivated”, says Dr. Martinez Majander.
Translation of study documents
We have taken action to facilitate site activation by contracting a company to provide professional translations of the information and consent forms. We acknowledge that this is a lot of work (2 forms for patients, 2 for control subjects, and in the Family Study 2 for probands, 2 for family members). Therefore, the translations are best organized centrally. This also ensures high-quality translations since the process should involve both forward- and back-translation.
Furthermore, we have started to create different language versions of the questionnaire sets so that the translations will be provided for the forms that can be self-completed by the study subjects and those including a possibility for subjective interpretation. Availability of existing language versions of the forms will be plotted and the study secretariat may be in contact with you regarding the availability of local versions in case not found from other sources. In limited cases, we may have to ask the local investigator to provide short translations of a few items.
Questionnaire permissions
Use of the existing validated scales and questionnaires and their different language versions may necessitate appropriate permissions from the party holding copyrights for the particular item. All but 2 permissions are now granted. We expect to obtain the remaining permissions in a month.
Study implementation and opening new sites
Opening new sites is our next big challenge. We know that the economic situation and personnel capacity may make it hard to add anything extra to the current routines. However, the study procedures do actually not require too much of your time or resources, see below:
Examples of average time used to go through the minimum set of study procedures from baseline to follow-up (excluding substudies):
| Procedure (neurologist/study nurse): patient | Time spent |
| Screening of inpatients 2-3 times a week | 20 min |
| Consent and baseline questionnaires | 75-90 min |
| Clinical, laboratory, and imaging data registration | 30 min |
| BP and anthropometric measures (study nurse) | 5 min |
| Drawing/processing blood samples (study nurse) | 60 min |
| Online data entry (baseline) | 45 min |
| Processing images on DVD (study nurse) | 15 min |
| 3-m follow-up visit with online data entry | 45 min |
| Follow-up call (12-m –>) with online data entry | 30 min |
| Procedure (neurologist/study nurse): control subject | |
| Consent and questionnaires | 45-60 min |
| BP and anthropometric measures (study nurse) | 5 min |
| Drawing/processing blood samples (study nurse) | 60 min |
| Online data entry | 20 min |
| Procedure (cardiologist): patient (and control subject if done) | |
| Per protocol echocardiography | 30 min |
| Completion of echocardiography CRF | 5 min |
| Processing echocardiography on DVD (study nurse) | 15 min |
We are now putting all our efforts to facilitate opening new sites to eventually reach our goal of 2000 patients and control subjects (more precise sample size estimations for each target can be provided after 50-100 controls have been enrolled). Many similar academic projects have started from scratch and were first met with opposition and hesitation, but turned out to be success stories in the end. Currently, no direct compensation for patient recruitment can be provided to study sites, but we are constantly looking for further funding opportunities. We also hope that country coordinators take the responsibility of implementing the study in their countries.
All up-to-date documents needed for the ERB approval can be found at the study repository (email link sent to you). Please find a cardiologist collaborator at your site, obtain the ERB and institutional approvals, and begin this inspiring journey.