<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03797495</url>
  </required_header>
  <id_info>
    <org_study_id>HISTORY</org_study_id>
    <nct_id>NCT03797495</nct_id>
  </id_info>
  <brief_title>Study of Individuals Affected With Hypoplasminogenemia</brief_title>
  <acronym>HISTORY</acronym>
  <official_title>Hypoplasminogenemia: An International RetroSpecTive and PrOspective CohoRt StudY (HISTORY)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Indiana Hemophilia &amp;Thrombosis Center, Inc.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fondazione Angelo Bianchi Bonomi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Indiana Hemophilia &amp;Thrombosis Center, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an Investigator initiated retrospective and prospective single cohort study. The&#xD;
      study will utilize an international registry and develop a specimen biobank to provide an&#xD;
      improved understanding of the natural history of hyposplasminogenemia, to elucidate the&#xD;
      heterogeneity of phenotypic expression, identify markers to predict disease course, and&#xD;
      inform improved therapeutic modalities&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The aims of this study are to:&#xD;
&#xD;
        1. Define PLGD natural history in a large cohort of individuals with hypoplasminogenemia&#xD;
           and their first-degree family members.&#xD;
&#xD;
        2. Identify factors that correlate with disease expression and severity.&#xD;
&#xD;
        3. Create a specimen biobank for further studies, available to other researchers.&#xD;
&#xD;
      The project will be international in scope with two collaborating centers that have created&#xD;
      and will collect the subject data and samples. In North/Central/South America, the Indiana&#xD;
      Hemophilia &amp; Thrombosis Center (IHTC) will serve as the primary site while University of&#xD;
      Milan will serve as the center for all other sites. The database is housed at the University&#xD;
      of Milan, Italy.&#xD;
&#xD;
      Study population will include males and females affected with hyposplasminogenemia of any&#xD;
      age. Both one-year retrospective and three-year prospective data will be collected on an&#xD;
      international cohort of 100 affected individuals and their first degree family members&#xD;
      (parents, siblings; total estimated study population ~500).&#xD;
&#xD;
      Study sample analysis, except for urine analyses, will be centralized and performed in Italy;&#xD;
      the plasminogen antibody analysis will be batched for analysis, and the urine analyses will&#xD;
      be performed locally. A sample biorepository will be created and ultimately housed in Italy.&#xD;
      The study will provide testing for plasminogen activity and antigen, plasminogen genetic&#xD;
      analysis, polymorphisms in genes that impact plasminogen expression and fibrinolysis, and&#xD;
      global hemostatic assays. In addition, stored samples will be used for further testing and&#xD;
      analyses to potentially include whole genome sequencing to further identify plasminogen&#xD;
      genetic mutations as needed and to investigate other genetic modifiers of disease expression.&#xD;
      An exploratory aim includes investigating the potential relationship with streptococcal&#xD;
      strains and altered plasminogen products.&#xD;
&#xD;
      The study period will be 3 years for each enrolled subject. In-person visits will be&#xD;
      conducted and samples for analysis will be collected at baseline and at end of study.&#xD;
      Interval follow-up will be performed every 6 months by telephone. data will be collected at&#xD;
      unscheduled visits that are performed for clinical need at the treating physician's&#xD;
      discretion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 18, 2018</start_date>
  <completion_date type="Anticipated">April 19, 2027</completion_date>
  <primary_completion_date type="Anticipated">March 8, 2027</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Other</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Define the natural history of plasminogen deficiency</measure>
    <time_frame>2 years</time_frame>
    <description>Recruit 100 subjects with hypoplasminogenemia and their first-degree family members&#xD;
Collect up to 1 year retrospective and 3 year prospective data on symptoms, treatment and interventions</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Identify factors that contribute to or correlate with disease expression and severity</measure>
    <time_frame>5 years</time_frame>
    <description>Perform centralized plasminogen activity and antigen analyses&#xD;
Perform centralized genetic analysis to identify changes in the plasminogen gene&#xD;
Perform centralized analysis of polymorphisms that affect plasminogen activity levels and impact fibrinolysis&#xD;
Perform local urine analysis&#xD;
Collect samples to explore the interaction of altered plasminogen proteins with bacterial strains</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Create a specimen biobank</measure>
    <time_frame>15 years</time_frame>
    <description>Bank plasma, serum and DNA on consenting enrolled subjects</description>
  </primary_outcome>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Plasminogen Deficiency</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood, serum, and plasma will be retained. Time perspective is retrospective and&#xD;
      prospective.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Study population will include males and females affected with hyposplasminogenemia of any&#xD;
        age and their first degree family members (siblings and parents).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed informed consent and assent as applicable (Appendix 1)&#xD;
&#xD;
          2. A. Males or females with type 1 PD diagnosed locally with plasminogen activity levels&#xD;
             &lt;50% OR B. First degree family members of a person diagnosed with type 1 PD (includes&#xD;
             parents, siblings, half-siblings)&#xD;
&#xD;
          3. All ages included&#xD;
&#xD;
          4. Available clinical history and treatment for at least 1 year prior to entry except for&#xD;
             infants &lt; 1 year of age&#xD;
&#xD;
          5. Willingness to provide samples for analysis including DNA, plasma etc.&#xD;
&#xD;
          6. Willingness to participate in prospective follow-up for up to 3 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous organ transplant recipient&#xD;
&#xD;
          2. Any psychiatric disorder, other mental disorder, or any other medical disorder that&#xD;
             impairs the subject's ability to give informed consent or to comply with the&#xD;
             requirements of the study protocol&#xD;
&#xD;
          3. Refuses to provide informed consent&#xD;
&#xD;
          4. Special patient populations, including prisoners or, are deemed medically or&#xD;
             cognitively unsuitable for research by their treating physician&#xD;
&#xD;
          5. Inability to obtain a blood sample due to poor or limited venous access&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amy D Shapiro, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Indiana Hemophilia &amp;Thrombosis Center, Inc.</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Flora Peyvandi, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Univeristy of Milan</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Amy D Shapiro, MD</last_name>
    <phone>317-871-0000</phone>
    <email>ashapiro@ihtc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Charles Nakar, MD</last_name>
    <phone>317-871-0000</phone>
    <email>cnakar@ihtc.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Indiana Hemophila @Thrombosis Center</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46260</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Neelam Thukral, CCRC</last_name>
      <phone>317-871-0000</phone>
      <phone_ext>373</phone_ext>
      <email>nthukral@ihtc.org</email>
    </contact>
    <contact_backup>
      <last_name>Charles Nakar, MD</last_name>
      <phone>317-871-0000</phone>
      <email>cnakar@ihtc.org</email>
    </contact_backup>
    <investigator>
      <last_name>Amy D Shapiro, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Charles Nakar, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hemophilia Center of Western Pennsylvania</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Frederico Xavier, MD</last_name>
      <phone>412-209-7411</phone>
      <email>fxavier@hmc.psu.edu</email>
    </contact>
    <contact_backup>
      <last_name>Debbie Vehec</last_name>
      <phone>412-209-7564</phone>
      <email>dvehec@vitalant.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Vanderbilt Children's Hematology-Oncology</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Delia Darst</last_name>
      <phone>615-343-7190</phone>
      <email>delia.h.darst@vumc.org</email>
    </contact>
    <contact_backup>
      <last_name>Heather McDaniel, MD, MSCI</last_name>
      <phone>615 936 1762</phone>
      <email>heather.mcdaniel@vumc.org</email>
    </contact_backup>
    <investigator>
      <last_name>Heather McDaniel, MD, MSCI</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Cook Children's Medical Center</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>76104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Heather Urbanek</last_name>
      <phone>682-885-1244</phone>
      <email>Heather.Urbanek@cookchildrens.org</email>
    </contact>
    <contact_backup>
      <last_name>Marcela Torres, MD</last_name>
      <phone>682 885 4007</phone>
      <email>marcela.torres@cookchildrens.org</email>
    </contact_backup>
    <investigator>
      <last_name>Marcela Torres, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The University of Texas Health Science Center at Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Katherine Addy, RN, BSN, MPH</last_name>
      <phone>713-500-8352</phone>
      <email>Katherine.E.Addy@uth.tmc.edu</email>
    </contact>
    <contact_backup>
      <last_name>Nidra Rodriguez, MD</last_name>
      <phone>713 500 8360</phone>
      <email>Nidra.I.Rodriguez@uth.tmc.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Nidra Rodriguez, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hospital Britanico Buenos Aires</name>
      <address>
        <city>Buenos Aires</city>
        <zip>C1280</zip>
        <country>Argentina</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jhon A Avila, MD</last_name>
      <phone>549 114 187 9723</phone>
      <email>jaavilar@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Jose M Ceresetto, MD</last_name>
      <phone>541 143 041 081</phone>
      <email>jceresetto@intramed.net</email>
    </contact_backup>
    <investigator>
      <last_name>Jose M Ceresetto, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jhon A Avila, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Murdoch Children's Research Institute, The Royal Children's Hospital</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3052</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paul Monagle, MD</last_name>
      <phone>61 3 9936-6330</phone>
      <email>paul.monagle@rch.org.au</email>
    </contact>
    <contact_backup>
      <last_name>Jodi Hislop, RN</last_name>
      <phone>61 3 9936-6330</phone>
      <email>jodi.hislop@rch.org.au</email>
    </contact_backup>
    <investigator>
      <last_name>Paul Monagle, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Saskatchewan</name>
      <address>
        <city>Saskatoon</city>
        <zip>SK S7N 0W8</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sarah Tehseen, MBBS, MSc. FRCPC</last_name>
      <phone>639 998 3972</phone>
      <email>Sarah.Tehseen@saskhealthauthority.ca</email>
    </contact>
    <contact_backup>
      <last_name>Rashmi Nagaraj</last_name>
      <phone>306-978-8306</phone>
      <email>rashmi.nagaraj@usask.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Sarah Tehseen, MBBS, MSc. FRCPC</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Angelo Bianchi Bonomi Hemophilia and Thrombosis Center,</name>
      <address>
        <city>Milano</city>
        <zip>20122</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marzia Menegatti, PhD</last_name>
      <phone>+39 - 02/50320727</phone>
      <email>marzia.menegatti@guest.unimi.it</email>
    </contact>
    <investigator>
      <last_name>Flora Peyvandi, MD,PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospital of Padova</name>
      <address>
        <city>Padua</city>
        <zip>35100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maria Teresa Sartori, MD</last_name>
      <phone>3334530450</phone>
      <email>mtsart@unipd.it</email>
    </contact>
    <contact_backup>
      <last_name>C. Dalla Porta, MD</last_name>
      <phone>39 049 821 1111</phone>
      <email>cesare.dallaporta@gmail.com</email>
    </contact_backup>
    <investigator>
      <last_name>Maria Teresa Sartori, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Faculty of Medicine, Chiang Mai University</name>
      <address>
        <city>Chiang Mai</city>
        <zip>50200</zip>
        <country>Thailand</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rungrote Natesirinilkul, MD</last_name>
      <phone>66 2 201 1749</phone>
      <email>rungrote.n@cmu.ac.th</email>
    </contact>
    <investigator>
      <last_name>Rungrote Natesirinilkul, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dokuz Eylul University pediatric Pulmonology, Allergy and Clinical Immunology</name>
      <address>
        <city>Izmir</city>
        <state>Balçova</state>
        <zip>35330</zip>
        <country>Turkey</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Serdar Al, MD</last_name>
      <phone>905336510797</phone>
      <email>drserdaral@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Serdar Al, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Istanbul Üniversitesi Onkoloji Enstitüsü</name>
      <address>
        <city>Istanbul</city>
        <zip>34093</zip>
        <country>Turkey</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Basak Koc, MD</last_name>
      <phone>90 5326003027</phone>
      <email>s_basakkoc@hotmail.com</email>
    </contact>
    <investigator>
      <last_name>Basak Koc, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Istanbul University Cerrahpsasa, Cerrahpsasa Medical Faculty Pediatric Hematology and Oncology Department</name>
      <address>
        <city>Istanbul</city>
        <zip>34098</zip>
        <country>Turkey</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ayse Gonca Kacar, MD</last_name>
      <phone>505 259 1229</phone>
      <email>goncakacar@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Tulin Celkan, MD</last_name>
      <phone>532 57 60723</phone>
      <email>tirajecelkan@yahoo.com</email>
    </contact_backup>
    <investigator>
      <last_name>Tulin Celkan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Yuzuncu Yil University Faculty of Medicine Department of Ophthalmology</name>
      <address>
        <city>Van</city>
        <zip>65040</zip>
        <country>Turkey</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Muhammed Batur, MD</last_name>
      <phone>904 322 150 473</phone>
      <phone_ext>6030</phone_ext>
      <email>muhammedbatur@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Muhammed Batur, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Australia</country>
    <country>Canada</country>
    <country>Italy</country>
    <country>Thailand</country>
    <country>Turkey</country>
    <country>United States</country>
  </location_countries>
  <reference>
    <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>
    <PMID>32001536</PMID>
  </reference>
  <results_reference>
    <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>
    <PMID>1455395</PMID>
  </results_reference>
  <results_reference>
    <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>
    <PMID>17900274</PMID>
  </results_reference>
  <results_reference>
    <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>
    <PMID>25208887</PMID>
  </results_reference>
  <results_reference>
    <citation>Celkan T. Plasminogen deficiency. J Thromb Thrombolysis. 2017 Jan;43(1):132-138. doi: 10.1007/s11239-016-1416-6.</citation>
    <PMID>27629020</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>29321155</PMID>
  </results_reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 28, 2018</study_first_submitted>
  <study_first_submitted_qc>January 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <last_update_submitted>June 16, 2023</last_update_submitted>
  <last_update_submitted_qc>June 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Indiana Hemophilia &amp;Thrombosis Center, Inc.</investigator_affiliation>
    <investigator_full_name>Amy D Shapiro, MD</investigator_full_name>
    <investigator_title>Medical Director</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03797495
org study id: HISTORY
nct id: NCT03797495
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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
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.
observational model: Cohort
time perspective: Other
measure: Define the natural history of plasminogen deficiency
time frame: 2 years
description: 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
measure: Identify factors that contribute to or correlate with disease expression and severity
time frame: 5 years
description: 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
measure: Create a specimen biobank
time frame: 15 years
description: Bank plasma, serum and DNA on consenting enrolled subjects
Whole blood, serum, and plasma will be retained. Time perspective is retrospective and
      prospective.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Amy D Shapiro, MD
role: Principal Investigator
affiliation: Indiana Hemophilia &Thrombosis Center, Inc.
last name: Flora Peyvandi, MD, PhD
role: Principal Investigator
affiliation: Univeristy of Milan
last name: Amy D Shapiro, MD
phone: 317-871-0000
email: ashapiro@ihtc.org
last name: Charles Nakar, MD
phone: 317-871-0000
email: cnakar@ihtc.org
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: Argentina
country: Australia
country: Canada
country: Italy
country: Thailand
country: Turkey
country: United States
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.
PMID: 32001536
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.
PMID: 1455395
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.
PMID: 17900274
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.
PMID: 25208887
citation: Celkan T. Plasminogen deficiency. J Thromb Thrombolysis. 2017 Jan;43(1):132-138. doi: 10.1007/s11239-016-1416-6.
PMID: 27629020
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.
PMID: 29321155
responsible party type: Principal Investigator
investigator affiliation: Indiana Hemophilia &Thrombosis Center, Inc.
investigator full name: Amy D Shapiro, MD
investigator title: Medical Director
sharing ipd: Undecided