Study of Individuals Affected With Hypoplasminogenemia

Plasminogen Deficiency Clinical Trial

— HISTORY  

Official title:

Hypoplasminogenemia: An International RetroSpecTive and PrOspective CohoRt StudY (HISTORY)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03797495
• Other study ID #: HISTORY
• Status: Recruiting
• Start date: December 18, 2018
• Est. completion date: April 19, 2027

Study information

• Verified date: June 2023
• Source: Indiana Hemophilia &Thrombosis Center, Inc.
• Contact: Amy D Shapiro, MD
• Phone: 317-871-0000
• Email: ashapiro[@]ihtc.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: April 19, 2027
• Est. primary completion date: March 8, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Plasminogen Deficiency

Locations

Country	Name	City	State
Argentina	Hospital Britanico Buenos Aires	Buenos Aires
Australia	Murdoch Children's Research Institute, The Royal Children's Hospital	Melbourne	Victoria
Canada	University of Saskatchewan	Saskatoon
Italy	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center,	Milano
Italy	University Hospital of Padova	Padua
Thailand	Faculty of Medicine, Chiang Mai University	Chiang Mai
Turkey	Istanbul Üniversitesi Onkoloji Enstitüsü	Istanbul
Turkey	Istanbul University Cerrahpsasa, Cerrahpsasa Medical Faculty Pediatric Hematology and Oncology Department	Istanbul
Turkey	Dokuz Eylul University pediatric Pulmonology, Allergy and Clinical Immunology	Izmir	Balçova
Turkey	Yuzuncu Yil University Faculty of Medicine Department of Ophthalmology	Van
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	Indiana Hemophila @Thrombosis Center	Indianapolis	Indiana
United States	Vanderbilt Children's Hematology-Oncology	Nashville	Tennessee
United States	Hemophilia Center of Western Pennsylvania	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Indiana Hemophilia &Thrombosis Center, Inc.	Fondazione Angelo Bianchi Bonomi

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  Italy,  Thailand,  Turkey, 

References & Publications (6)

Celkan T. Plasminogen deficiency. J Thromb Thrombolysis. 2017 Jan;43(1):132-138. doi: 10.1007/s11239-016-1416-6. — View 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 — View 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. — View 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. — View 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):13 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Define the natural history of plasminogen deficiency	Recruit 100 subjects with hypoplasminogenemia and their first-degree family members; Collect up to 1 year retrospective and 3 year prospective data on symptoms, treatment and interventions	2 years
Primary	Identify factors that contribute to or correlate with disease expression and severity	Perform centralized plasminogen activity and antigen analyses; Perform centralized genetic analysis to identify changes in the plasminogen gene; Perform centralized analysis of polymorphisms that affect plasminogen activity levels and impact fibrinolysis; Perform local urine analysis; Collect samples to explore the interaction of altered plasminogen proteins with bacterial strains	5 years
Primary	Create a specimen biobank	Bank plasma, serum and DNA on consenting enrolled subjects	15 years