Clinical trial NCT03797495: Study of Individuals Affected With Hypoplasminogenemia
Official title: Hypoplasminogenemia: An International RetroSpecTive and PrOspective CohoRt StudY (HISTORY)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Plasminogen Deficiency
Lead sponsor: Indiana Hemophilia &Thrombosis Center, Inc.
Sponsor class: OTHER
Collaborators: name: Fondazione Angelo Bianchi Bonomi
First posted: 2019-01-09
Enrollment: 100
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: PROBABILITY_SAMPLE
Study population: Study population will include males and females affected with hyposplasminogenemia of any age and their first degree family members (siblings and parents).

Brief summary: This is an Investigator initiated retrospective and prospective single cohort study. The study will utilize an international registry and develop a specimen biobank to provide an improved understanding of the natural history of hyposplasminogenemia, to elucidate the heterogeneity of phenotypic expression, identify markers to predict disease course, and inform improved therapeutic modalities

Detailed description: The aims of this study are to:

1. Define PLGD natural history in a large cohort of individuals with hypoplasminogenemia and their first-degree family members.
2. Identify factors that correlate with disease expression and severity.
3. Create a specimen biobank for further studies, available to other researchers.

The project will be international in scope with two collaborating centers that have created and will collect the subject data and samples. In North/Central/South America, the Indiana Hemophilia \& Thrombosis Center (IHTC) will serve as the primary site while University of Milan will serve as the center for all other sites. The database is housed at the University of Milan, Italy.

Study population will include males and females affected with hyposplasminogenemia of any age. Both one-year retrospective and three-year prospective data will be collected on an international cohort of 100 affected individuals and their first degree family members (parents, siblings; total estimated study population \~500).

Study sample analysis, except for urine analyses, will be centralized and performed in Italy; the plasminogen antibody analysis will be batched for analysis, and the urine analyses will be performed locally. A sample biorepository will be created and ultimately housed in Italy. The study will provide testing for plasminogen activity and antigen, plasminogen genetic analysis, polymorphisms in genes that impact plasminogen expression and fibrinolysis, and global hemostatic assays. In addition, stored samples will be used for further testing and analyses to potentially include whole genome sequencing to further identify plasminogen genetic mutations as needed and to investigate other genetic modifiers of disease expression. An exploratory aim includes investigating the potential relationship with streptococcal strains and altered plasminogen products.

The study period will be 3 years for each enrolled subject. In-person visits will be conducted and samples for analysis will be collected at baseline and at end of study. Interval follow-up will be performed every 6 months by telephone. data will be collected at unscheduled visits that are performed for clinical need at the treating physician's discretion.

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent and assent as applicable (Appendix 1)
2. A. Males or females with type 1 PD diagnosed locally with plasminogen activity levels \<50% OR B. First degree family members of a person diagnosed with type 1 PD (includes parents, siblings, half-siblings)
3. All ages included
4. Available clinical history and treatment for at least 1 year prior to entry except for infants \< 1 year of age
5. Willingness to provide samples for analysis including DNA, plasma etc.
6. Willingness to participate in prospective follow-up for up to 3 years

Exclusion Criteria:

1. Previous organ transplant recipient
2. Any psychiatric disorder, other mental disorder, or any other medical disorder that impairs the subject's ability to give informed consent or to comply with the requirements of the study protocol
3. Refuses to provide informed consent
4. Special patient populations, including prisoners or, are deemed medically or cognitively unsuitable for research by their treating physician
5. Inability to obtain a blood sample due to poor or limited venous access

Primary outcomes:
measure: Define the natural history of plasminogen deficiency
timeFrame: 2 years
measure: Identify factors that contribute to or correlate with disease expression and severity
timeFrame: 5 years
measure: Create a specimen biobank
timeFrame: 15 years
Secondary outcomes:
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Hemophila @Thrombosis Center
state: Indiana
city: East Setauket
country: United States
facility: Stony Brook University | Stony Brook Medicine
state: New York
city: Pittsburgh
country: United States
facility: Hemophilia Center of Western Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Children's Hematology-Oncology
state: Tennessee
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Buenos Aires
country: Argentina
facility: Hospital Britanico Buenos Aires
city: Melbourne
country: Australia
facility: Murdoch Children's Research Institute, The Royal Children's Hospital
state: Victoria
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck, University Clinic for Pediatrics and Adolescent Medicine
city: Montréal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Québec
country: Canada
facility: CHU de Québec Université Laval
city: Saskatoon
country: Canada
facility: University of Saskatchewan
city: Athens
country: Greece
facility: Alexandra Hospital, Athens, Hematology Department
city: Milano
country: Italy
facility: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center,
city: Padua
country: Italy
facility: University Hospital of Padova
city: Chiang Mai
country: Thailand
facility: Faculty of Medicine, Chiang Mai University
city: Izmir
country: Turkey
facility: Dokuz Eylul University pediatric Pulmonology, Allergy and Clinical Immunology
state: Balçova
city: Istanbul
country: Turkey
facility: Istanbul Üniversitesi Onkoloji Enstitüsü
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpsasa, Cerrahpsasa Medical Faculty Pediatric Hematology and Oncology Department
city: Van
country: Turkey
facility: Yuzuncu Yil University Faculty of Medicine Department of Ophthalmology
Study officials:
affiliation: Indiana Hemophilia &Thrombosis Center, Inc.
name: Amy D Shapiro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Univeristy of Milan
name: Flora Peyvandi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shapiro AD, Menegatti M, Palla R, Boscarino M, Roberson C, Lanzi P, Bowen J, Nakar C, Janson IA, Peyvandi F. An international registry of patients with plasminogen deficiency (HISTORY). Haematologica. 2020 Mar;105(3):554-561. doi: 10.3324/haematol.2019.241158. Epub 2020 Jan 30.
citation: Tait RC, Walker ID, Conkie JA, Islam SI, McCall F, Mitchell R, Davidson JF. Plasminogen levels in healthy volunteers--influence of age, sex, smoking and oral contraceptives. Thromb Haemost. 1992 Nov 10;68(5):506-10.
citation: Schuster V, Hugle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007 Dec;5(12):2315-22. doi: 10.1111/j.1538-7836.2007.02776.x. Epub 2007 Sep 26.
citation: Ma Q, Ozel AB, Ramdas S, McGee B, Khoriaty R, Siemieniak D, Li HD, Guan Y, Brody LC, Mills JL, Molloy AM, Ginsburg D, Li JZ, Desch KC. Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels. Blood. 2014 Nov 13;124(20):3155-64. doi: 10.1182/blood-2014-03-560086. Epub 2014 Sep 10.
citation: Celkan T. Plasminogen deficiency. J Thromb Thrombolysis. 2017 Jan;43(1):132-138. doi: 10.1007/s11239-016-1416-6.
citation: Shapiro AD, Nakar C, Parker JM, Albert GR, Moran JE, Thibaudeau K, Thukral N, Hardesty BM, Laurin P, Sandset PM. Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency. Blood. 2018 Mar 22;131(12):1301-1310. doi: 10.1182/blood-2017-09-806729. Epub 2018 Jan 10.