CCM_Italia is an observational non interventional national multicentric registry.
Patients will be enrolled prospectively and followed for a 2 years period through annual
neurological evaluation, cerebrale MRI according to dedicated protocol (central reading)
and blood sample to assess circulating biomarkers.
The study has been funded by National Recovery and Resilience Plan.
In the contest of the present study, pediatric and adult patients affected by genetically
confirmed fCCM will be enrolled according to the inclusion and exclusion criteria which
have been developed to include a large number of fCCM patients, representative of the
heterogeneity of fCCM disease, spanning from the asymptomatic to the high-risk cases.
This registry is primarily designed to collect real-world data without influencing or
interfering with the standard clinical practice and external monitoring is not planned.
Since the data collection process is passive and observational by nature, the risk to
patient safety and data integrity is minimal compared to interventional studies. Internal
data quality controls and oversight mechanisms are planned. The use of standardized
protocols for data entry ensures consistency across all entries. This reduces variability
caused by different personnel and minimizes errors in recording patient information,
pathology findings, and other relevant data. We plan periodic audits of the registry data
helps identify discrepancies, incomplete records, or inconsistencies. Cross-checking data
entries against source documents or original reports will minimize data loss.
A comprehensive training for staff responsible for data entry ensures they understand the
data standards and procedures. Certifying personnel helps maintain high levels of
accuracy and consistency over time. Inter-observer reliability among neuroradiologist in
charge of imaging analysis ensures consistency in data collection. A constant feedback
from users and data contributors encourages reporting of issues or inconsistencies,
fostering ongoing improvements to data quality processes.
• Study procedures The quality assurance of the study is maintained through regular
training sessions and periodic online meetings. These initiatives ensure consistent
protocols are followed across all team members, promoting uniformity in patient
enrollment and data collection. Specifically, training sessions provide comprehensive
guidance on study procedures and data entry standards, while scheduled online meetings
allow for ongoing monitoring, clarification of any issues, and reinforcement of best
practices. This continuous educational approach helps to minimize variability, ensuring
that patient recruitment and data collection within the REDCap database are accurate,
reliable, and standardized throughout the study duration.
In accordance with clinical practice, annual cerebral MRI will be performed in the
Neuroradiology Unit of the referral hospital preferably on the same day as the clinical
assessment, otherwise planned within 1 month for inclusion visit/+/- 40 days for
follow-up visit (T0-T1-T2). The MRI protocol will include: sagittal 3D T1¬weighted turbo
field echo, sagittal 3D T2¬weighted turbo spin echo, sagittal 3D fluid¬ attenuated
inversion recovery, axial diffusion¬ weighted imaging, axial sus-ceptibility ¬weighted
imaging, and axial T2¬weighted gradient echo. The current protocol is in line with normal
clinical practice. The collected MRIs will be assessed centrally in the MRI core lab at
Fondazione Cà Granda by blinded personnel. The following variables will be collected:
different vascular lesion characteristics such as number, pattern and size of CCMs, signs
of bleeding (Za-bramski classification) and number of the novo lesions. Advanced MRI
techniques such as Quantitative Susceptibility Mapping, which is not routinely performed
in the follow-up of CCM patients, will be applied and performed centrally at Fondazione
Cà Granda in the MRI core lab to assess iron deposition and vessel permeability if
available in the centre.
The uniformity of the MRI protocol is ensured through dedicated training sessions and the
sharing of representative examinations. These measures serve to verify the correctness of
the settings and ensure the comparability of the scans across different centers.
Additionally, centralized image reading further strengthens the robustness of the project
by maintaining consistent interpretation standards and reducing inter-observer
variability. This comprehensive approach enhances the overall quality and reliability of
the imaging data.
Besides the "standard" annual clinical assessment as described above, adult patients will
annually be asked to complete specific questionnaires for Patient Reported Outcome
Measures (PROMs) and Patient Reported Experience Measures (PREMs). These include the
following standardized ques-tionnaires for depression: Beck Depression Inventory-II
(BDI-2); Anxiety: Stait-Trait Anxiety Inventory X1 & X2 (STAI X-1 & STAI X-2) and Quality
of Life: the Short Form 36 (SF-36), split into the physical and mental component scales
(PCS and MCS).
Moreover in addition to the "standard" annual clinical assessment, patients will undergo
blood sample collec-tion at the same moment as their annual clinical visit. Three vials,
a total of 15.5 ml of blood will be collected in the outpatient clinic of the referral
hospital.
All patients' clinical and radiological data as well as outcomes of questionnaires and
specific information on clinical events will be de-identified and recorded on electronic
case report files on the RedCap platform.
Blood samples (15,5 ml) will be collected during the clinical visits at baseline (T0) 12
months (T1) and 24 months (T2), according to specific standard operating procedures that
will be shared by the biobank with all clinical centers participating in the study. Blood
and plasma aliquots will be temporarily stored at -70°C at the local clinical centers
until shipment in dry ice to the SATURNE biobank at IRFMN in Milan. The samples will be
de-identified with a unique 6-digit code and centralized to the "Saturne" Biobank at
IRFMN (certified UN EN ISO 9001:2015) for long-term storage in -70°C freezer under
controlled condition for further analysis.A part of plasma samples will be used for
analysis of biomarkers related to inflammation, coagula-tion, angiogenesis (such as
C-reactive protein, PTX3, LBP, ROBO4, Tissue Factor, Endoglin, Thrombomodulin, CCL5,
CXCL-4) performed at Policlinico di Bari. These biomarkers will be measured by
enzyme-linked immunosorbent assay (ELISA) or using enzymatic-colorimetric and
immunoturbidimetric method (i.e. CRP). Remaining aliquots not used for the analyses
present in the protocol will be stored in the biobank and will be used for future studies
to identify new biomarkers of interest of CCM.
• Sample size and statistical analysis The primary objective is to evaluate the new
occurrence of CCM-related clinical events in patients with fCCM. CCM-related clinical
events, the primary endpoint, are defined as intra-cerebral hemor-rhage (ICH) and focal
neurological deficits (FND).
The primary endpoint, new occurrence of CCM-related clinical events, defined as
intra-cerebral hemorrhage (ICH) and focal neurological deficits (FND), excluding
seizures, are expected in about 5.6% of the population based on the Treat_CCM trial (1).
Assuming that 5,6% of the subjects in the population will develop an CCM-related clinical
event within the CCM_Italia cohort, we need to include at least 100 patients (including a
dropout of 8%) for estimating this expected proportion with 95% confidence and 4,7%
absolute precision.
Furthermore, it can be shown that including 100 patients with fCCM allows to obtain
sufficient power (equal to 80%) to evaluate the secondary endpoint. Once a patient cohort
has been created which includes a long-term standardized follow-up of patients, we can
leverage this cohort to assess potential biomarkers to monitor disease activity, aim 2.
Hypothetically, a cohort with at least 100 patients will allow us to have enough power to
detect a minimal hazard ratio of 2.15 for identifying patients with increased disease
activity (defined as CCM-related adverse events or the development of at least 5 new CCM
lesions during the two years of observation). The Treat_CCM study indicat-ed that 55% of
the fCCM patients will experience increased disease activity. Dividing the popula-tion by
the median level of a biomarker of interest (thus obtaining 2 groups of 50 persons) would
give us a statistically significant result if the HR of this biomarker is at least 2.15
(power 80% and alpha 0.05) (4,5). This was assessed by means of R, using function
ssizeEpi.default (Library Pow-erSurvEpi): power 80%, p=0.5 (population split 50/50 by
median biomarker level), psi=0.55 (55% experienced increased disease activity in
Treat_CCM), rho2= 0.025025 (based upon the correlation of CXCL4 with disease activity in
the Treat_CCM cohort), alpha 0.05, theta 2.15.Baseline characteristics will be presented
for the total population and by relevant characteristics (i.e. sex, age classes, number
of CCM lesions). Baseline subgroups will be compared by descriptive uni-variate
statistics.
1. Primary endpoint: Patient characteristics will be compared by means of descriptive
analyses to assess patients with clinical events.
2. Secondary Endpoints:
1. Clinical secondary endpoints: individual components of the primary endpoint,
ICH or FND, and other clinical secondary end-points such as seizures, headache
or hospitalization will be assessed by means of descriptive anal-yses. In
addition, Kaplan Meier curves will be constructed to illustrate the occurrence
of clinical events over time.
2. Biomarkers: in order to reach aim 2, assess biomarkers for the management of
fCCM, Cox proportional hazards regression analyses will be performed to assess
which circulating biomarkers are independently as-sociated with increased
disease activity (defined as CCM-related adverse events or the development of
at least 5 new CCM lesions during the two years of observation). All outcomes
will be reported including a 95% confidence interval.
3. Questionnaires: Global cognitive functioning, depression, anxiety and health
related quality of life will be assessed at multiple time points and any
changes over time will be described and assessed by repeated measures ANOVA.
4. Imaging: Different vascular lesion characteristics, measured by MR imaging will
be assessed for the total population and by relevant characteristics (i.e. sex,
age classes, number of CCM lesions, etc). The evolution of MRI markers such as
number of new lesions and size of lesions will be described and changes over
time will be assessed by repeated measures ANOVA. The assessment of changes
over time will be performed for all patients included in the cohort as change
from baseline to 2 year follow-up.
Implementation of Standard Operating Procedures (SOPs) for our registry is essential for
ensuring consistency, quality, and compliance in registry operations and analysis
activities. Firstly, SOPs for patient recruitment help standardize eligibility criteria,
recruitment strategies, and consent processes, thereby maximizing efficiency and ensuring
ethical standards are maintained. Clear shared guidelines on data collection and data
management are likely to ensure data accuracy, completeness, and confidentiality
throughout the registry lifecycle.
Using Standard Operating Procedures (SOPs) for imaging data collection ensures
consistency across different centers. SOPs provide detailed, standardized protocols that
all sites follow, minimizing variability in how images are acquired. This uniformity is
crucial for reliable comparison and analysis of imaging data, as it reduces discrepancies
caused by differences in equipment settings, patient positioning, or imaging techniques.
By adhering to SOPs, centers can maintain high-quality, reproducible data, which enhances
the validity of multi-center studies and facilitates accurate interpretation of results.
The impact of missing data will be minimized through data collection protocols to reduce
missingness, such as follow-up queries or alternative data sources.
