Page 43 - Haematologica March 2020

HISTORY, a plasminogen deficiency registry
European Network of Rare Bleeding Disorders
The Rare Bleeding Disorders Database (RBDD) project was established at UNIMI in 2004 to organize and ana- lyze clinical, genetic and treatment data on rare bleeding disorders, including deficiencies of fibrinogen and factors II, V, combined V and VIII, VII, X, XI and XIII. In 2007, this database was modified to include the use of a web- based application to create the retrospective European Network of Rare Bleeding Disorders (EN-RBD) project.42 Data on 592 patients from 11 European countries were included. These data led to the first authoritative under- standing of the relationship between coagulation factor activity level and clinical bleeding severity in ultra-rare bleeding disorders; in turn this resulted in the develop- ment of a new severity classification system for bleeding symptoms.43
Prospective Rare Bleeding Disorders Database
To overcome limitations of retrospective data collec- tion, EN-RBD was subsequently modified to incorporate prospective data on patients. This registry, the Prospective Rare Bleeding Disorders Database (PRO- RBDD), enrolled patients from 62 centers in Europe, Asia, the Middle East, the Americas, Africa, and Oceania.44 The greatly expanded international network of participating centers was considered essential for a registry focusing on diseases for which the prevalence may approach 1 per million population; this extended outreach may permit increased and more rapid enrollment, and greater pheno- typic and genetic diversity.
The aims of PRO-RBDD are a more accurate determi- nation of the prevalence of rare bleeding disorders, the incidence of bleeding episodes, the use of treatment prod- ucts, and the optimization of clinical management. Currently, subjects with deficiencies in fibrinogen and factors V, V/VIII, XI and XIII are being enrolled in PRO- RBDD with phenotype/genotype evaluation performed at a central laboratory to ensure consistency. Initial results have helped define minimal factor XIII plasma levels (15 IU/dL) necessary to prevent spontaneous major bleeding in people with factor XIII deficiency;45 this observation highlights the importance of registry data to clinical prac- tice.
The plasminogen deficiency registry (HISTORY project)
HISTORY is an extension of PRO-RBBD; it is an obser- vational cross-sectional study that will contain both retro- spective and prospective data from an international pop- ulation of people with PLGD and their immediate family members. PRO-RBDD was selected as the ideal infra- structure for HISTORY as previously gained experience, proven track-record and established collaborations should ensure timely and efficient achievement of study goals. Retrospective data will be collected for 1 year prior to study entry; prospective data will be collected for each subject for a 3-year on-study period.
The overarching goals driving data analysis are devel- opment of disease severity categories, disease course pre- dictors and need for specific surveillance in particular sub- populations, and treatment algorithms and recommenda- tions to guide clinical care and management. As such, the registry design will allow collection of general informa- tion about each subject’s health, with specific details regarding: original diagnosis (age, reason for screening); phenotype and genotype analysis; type, site and number
of clinical manifestations indicative of pseudomembrane formation; detailed information on type, intensity, and duration of any prophylactic treatment, frequency and dose; type, frequency and dose of therapy administered to treat acute or chronic pseudomembranes; laboratory parameters; use of concomitant therapy; detailed infor- mation of management of surgical procedures; obstetric data; and complications associated with treatment.
The coordinating centers for this study are the IHTC and IRCCS/UNIMI. The IHTC is enrolling subjects from North, South and Central America and IRCCS/UNIMI is enrolling subjects from the rest of the world. The data- base will be located at UNIMI and specimens will be stored at the IHTC and/or IRCCS/UNIMI biorepositories. Safeguards have been implemented to protect confiden- tial medical information to meet national regulations; all clinical information and biological samples will be stored in accordance with the Health Insurance Portability and Accountability Act of 1996 or General Data Protection Regulation in the USA and Europe, respectively.
Clinical study protocols and laboratory manuals have been developed and approved by local institutional review boards. HISTORY will be conducted in compli- ance with Good Clinical Practice as stated in the Declaration of Helsinki; it is registered at clinicaltrials.gov (NCT03797495).
Patient recruitment and study visits
There is currently no authoritative natural history study for PLGD; HISTORY is a 4-year study (Figure 1A) that will be the first international effort to define the natural history of this disorder by reviewing retrospective and prospective data from up to 100 probands and their first- degree family members (approximately 500 subjects in total). Asymptomatic family members will be recruited in addition to symptomatic individuals. Asymptomatic fam- ily members are not routinely tested for PLGD; study testing will provide a unique opportunity to prospectively monitor any newly diagnosed patients to investigate the deficiency prior to symptom development. The inclusion of heterozygous family members may additionally reveal the relationship between minimal plasminogen activity levels and natural history. Inclusion and exclusion criteria are listed in Table 2.
The registry will include a minimum of seven data entry points per subject (baseline and every 6 months for 3 years) with data also collected at other non-scheduled visits (Figure 1B and Table 3). Retrospective baseline data (demographic and clinical history for 1 year prior to enrollment) will be collected at each study site, with prospective follow-up data acquired by telephone if an in-person visit is not required. In-person evaluation will occur in cases of suspected clinical manifestations indica- tive of pseudomembranes or other intermittent medical events including pregnancy. Laboratory evaluation and physical examination will be performed at baseline and at study termination.
To accelerate recruitment and meet the study objectives efficiently, PLGD patients/families/providers held within an IHTC tracking system (~50 probands) will be contacted to determine interest in the study, as will authors of published literature on cases/series of PLGD. Advertisements will be placed in scientific journals that focus on diseases for which clinicians may interface with people with PLGD. Furthermore, an outreach program using social media, a
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