STUDY OVERVIEW
Prognostic Imaging Biomarkers for Diabetic Kidney Disease (iBEAt) is a prospective
observational multi-centre collaborative cohort study, conducted in 6 European countries. It
will have a first phase with a cross-sectional design (for an association study - primary
objective) and a second phase with a longitudinal design (for a prognostic objective -
secondary objective).
All 5 recruiting centres will follow the same recruitment criteria and take the same data
using a standardised methodology, including demographic, clinical and family history,
medication history, blood- and urine samples as well as MRI and US. Annual follow-up visits
will occur in years 2,3,4, where the same data will be collected except MRI and US (acquired
only at baseline). In addition, each of the centres will acquire additional centre-specific
data to address ancillary objectives.
All biofluids will be processed on site, stored temporarily and shipped in batches to a
central biobank for central analysis and long-term storage (University of Lund, Malmo,
Sweden). Hemoglobin, Hematocrit and HbA1c will be measured locally on fresh blood. A
proportion of the biofluids will be analysed centrally to address the objectives. The
remainder will be stored for future biomarker validation studies to be determined by the
study Steering Committee in line with objectives of the Biomarker Enterprise to Attack DKD
(BEAt-DKD).
All data generated by the study will be centralised in anonymised form in an archive hosted
by the Swiss Institute of Bioinformatics. Data access will be limited to licensed study
investigators and ancillary studies approved by the steering committee. MRI images will be
analysed centrally in the University of Leeds to extract the imaging biomarkers.
PRE-SCREENING
Study personnel will be trained to initiate screening at several points in the healthcare
system where the opportunity exists to identify potential study participants. Potential
participants will be identified by study team staff and/or investigators after reviewing the
medical records of patients being seen in clinic or in primary care for diagnosis of kidney
disease in the management of their diabetes. Some sites may be selecting participants from
pre-defined registries of potential patients. If necessary, a partial waiver of informed
consent will be sought from the local ethics board to pre-screen these potential participants
as possible, or pre-screening will be performed by the clinical care team in collaboration
with the study team staff.
Pre-screening includes but is not limited to review of medical records, appointment schedules
and laboratory databases with local primary care or specialty physicians as consistent with
local ethics review. Specifically, study team staff and/or investigators will be trained to
identify participants who satisfy the inclusion criteria. Study team staff and/or
investigators will also be trained to review the medical chart for exclusion criteria.
Once pre-screened and identified, potentially eligible patients will be approached by a
clinical caregiver to request permission for a study team member to initiate discussion of
the iBEAt study.
SCREENING/CONSENTING VISIT
As an introduction to the iBEAt study, a study team member will meet with a potential
participant, assess enthusiasm for the study, and complete an eligibility questionnaire with
the potential participant. Eligibility questionnaires will be inclusive of all inclusion and
exclusion data points with the exception of clinical laboratory values.
When appropriate, informed consent will be obtained. For this purpose the study team member
will review and explain necessary information with the potential participant in accordance
with the requirements of the respective ethics review and human subject research regulations.
The ethics-approved written comprehensive consent documents will be reviewed. Participants
will be asked to provide consent to access their local medical record for clinical data for
long-term follow-up (maximum 15 years after completion of the study), to store their
anonymised data for at least 50 years for future research, and to store their anonymised
samples indefinitely for future analyses.
If informed consent is obtained, a study identification number (Study ID) will be assigned
and limited demographic data should be collected, including information to contact the
participant if the need arises. A random urine sample will be taken at this point and
submitted for local Urine Albumin Creatinine Ratio (UACR) analysis. Baseline study visit 1
(V1) can be scheduled, which should occur within 90 days. The screening/consent visit will
last 30min - 2hrs depending on site.
The participant should be provided with urine collection materials for the V1 visit first
morning void and advised to arrive in a fasted state (fasting for 8 hours prior to
appointment), not to smoke for the 4 hours preceding the assessments, and to avoid strenuous,
out of the ordinary exercise in the 24hrs before the visit. Medications (hypoglycaemic) may
need to be withheld or altered for the study assessment visits to ensure participant
well-being (e.g. omitting morning insulin injection to maintain blood glucose levels) and
integrity of the study. If modifications are required, they will be discussed and agreed with
the participant during the screening visit (to be detailed in the manual of operations).
BASELINE VISIT (Year 1)
A checklist will be administered for key activities and adherence to instructions and
medication plan on the 24hrs before the visit. Blood glucose (fingertip) will be checked at
the start of the visit and study assessments will not be performed if blood glucose
<3.5mmol/l on arrival or if the participant reports a symptomatic hypoglycaemic event on the
morning of the visit prior to arrival.
Participants will be asked to provide a urine sample. Afterwards 69,5mL blood will be
collected using Standard Operating Procedures (SOPs) and collection materials provided by the
central lab in a kit labelled with the study ID.
The samples will be processed locally. UACR measurement and fresh blood analysis will be
performed in the local pathology lab. The rest of the samples will stored temporarily at the
lab before shipment to the central lab in Malmo, Sweden. If the analysis of the baseline UACR
shows a value that is inconsistent with the previous reading at screening, a 3d urine sample
will be obtained at a later stage in line with local practice.
After blood and urine collections patients will receive a standardised snack and drink.
A questionnaire will be administered including demographics and medical history, and local
lab values for common blood and urine biomarkers. The answers will be pre-populated before
the visit with information from medical records where possible, and checked/completed with
the participant. The questionnaire will be administered by an investigator and is not
patient-facing.
A brief clinical exam will be performed including height, weight, waist and hip
circumference, seated and standing blood pressure.
A routine MRI safety checklist will be completed with the participant, as required by local
MRI practice. An MRI scan will be performed, which will take about 1 hour and will involve a
contrast agent injection. The scan will be performed by a qualified research radiographer.
After MRI participants will undergo a standard renal ultrasound exam.
FOLLOW-UP VISITS (Year 2, 3, 4)
At the annual follow-up visits, all sites will perform a brief clinical exam and administer
study questionnaires, collect local lab values, blood, 1st and 2nd void urine. Patient
preparation, monitoring and management during the visit will be the same as for Visit 1 to
ensure comparable data as in other centres that acquire blood, urine and US at Visit 1.
Questionnaires will be inclusive for follow-up data points of those captured at baseline. The
study participant should be advised this visit will take 1.5 - 2 hours.
In order to retain patients that are unable to attend the follow-up visits, a system will be
set up to follow them up remotely (eg. by phone), and the study team will request access to
their clinical records to determine their progression rates.
LONG-TERM FOLLOW-UP (Years 5-19)
Long-term outcome data may continue to be collected on an annual basis from patient's medical
records, for a maximum of 15 years after the last study visit.
DATA HANDLING
The key file containing the link between identifiable patient ID and anonymous study ID will
be stored securely at the recruiting site. The file will be destroyed 15 years after the last
study visit. All other study documentation and data will be labelled by the study ID only.
All research data will initially be recorded on paper sheets that will be stored safely in
the anonymised participant file, which will be kept on record as per standard practice. The
data will then be entered manually into an electronic data capture system (RedCap) and
securely uploaded to a central server hosted by the Swiss Institute of Bio-informatics.
The recorded US and MRI images will be uploaded anonymously onto a central system hosted by
the Swiss Institute of Bioinformatics, and reviewed by a qualified radiologist to check for
incidental findings. If an incidental finding is recorded the radiologist will act according
the standard clinical practices and contact the referring physician, who can then set up a
management plan.
The MRI images will be processed by a trained member of the research team at Leeds University
to extract the relevant imaging biomarkers. For this purpose the anonymised images will be
stored temporarily on a local university PC for processing in dedicated software. All
extracted imaging biomarkers will be uploaded to the participant file in the electronic data
capture system RedCap hosted by the Swiss Institute of Bioinformatics. After that the local
copy of the images on the University PC will be deleted.
Investigators of the recruiting site will retain access to their centrally archived data.
Other selected investigators within the BEAt-DKD project, including industry collaborators,
can request and obtain access to the data in accordance with the standard grant agreement of
IMI projects. The data can also be made available to other researchers in the future, under
conditions laid out by the iBEAT steering committee based on a review of the scientific study
objectives.
HANDLING OF BLOOD- AND URINE SAMPLES
Urine and blood samples taken at baseline and follow-up visits will be sent to the local lab
for processing and temporary storage. A small sample of blood and urine will be forwarded to
the clinical lab for UACR reading and fresh-blood analysis, and those data will be recorded
in the participants medical records. Other samples will be stored locally at -80deg awaiting
regular shipments to the central biobank in Malmo.
The referring physician will review the locally analysed blood and urine readings for
incidental findings and take action according to standard clinical practice if abnormal
readings are found.
The central biochemical laboratory (Malmö, University of Lund) will prepare kits with sample
collection and processing materials for each patient labelled and bar-coded with the study
ID, and also arrange shipment from the recruiting site to Malmö. All samples will be stored
in Malmö under secure conditions and monitored with a dedicated electronic sample tracking
system. A small volume of blood and urine will be analysed in Malmö for known clinical
biomarkers according to standardised methods, and the remainder will be stored for future
analyses by BEAt-DKD investigators. The samples will also remain available for secondary
research provided approval is granted by the iBEAT steering committee.