Clinical trial: rVWF Pediatric and Adult Study (NCT03879135)

Eligibility criteria:
Inclusion Criteria:

        The participant will not be considered eligible for the study without meeting all of the
        criteria below.

        Participants who have completed Study 071301 or Study 071102 (or participants who have
        completed the surgery in Study 071102 and want to continue to receive on-demand (OD)
        treatment) and are willing to immediately transition into this study, must meet the
        following 2 criteria to be eligible for this study:

          1. If female of childbearing potential, has a negative blood/urine pregnancy test at
             screening and agrees to employ highly effective birth control measures for the
             duration of the study.

          2. Participant and/or legally authorized representative is willing and able to comply
             with the requirements of the protocol.

             New participants (Cohort 4) who meet the above 2 and ALL the following additional
             criteria are eligible for this study:

          3. Participant has a documented diagnosis of severe von Willebrand disease (VWD)
             (baseline von Willebrand factor: Ristocetin cofactor (VWF:RCo) <20 IU/dL) with a
             history of requiring substitution therapy with von Willebrand factor (vWF) concentrate
             to control bleeding:

               1. Type 1 (VWF:RCo <20 IU/dL) or,

               2. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype),
                  Type 2M or,

               3. Type 3 (Von Willebrand factor antigen (VWF:Ag) ≤3 IU/dL). Diagnosis is confirmed
                  by genetic testing and multimer analysis, documented in patient history or at
                  screening.

          4. Participant has been receiving OD therapy with VWF products for at least 12 months,
             and prophylactic treatment is recommended by the investigator.

          5. Participant has ≥3 documented spontaneous bleeds (not including menorrhagia) requiring
             VWF treatment during the past 12 months.

          6. Participant has available records that reliably evaluate type, frequency, and
             treatment of bleeding episodes for at least 12 months preceding enrollment; up to 24
             months of retrospective data should be collected if available.

          7. Participant is ≥12 years old at the time of screening and has a body mass index ≥15
             but <40 kg/m^2.

        Exclusion Criteria:

        The participant will be excluded from the study if any of the following exclusion criteria
        are met.

          1. The participant has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary
             or acquired coagulation disorder other than VWD (eg, qualitative and quantitative
             platelet disorders or elevated prothrombin time (PT)/international normalized ratio
             [INR] >1.4).

          2. The participant has a history or presence of a VWF inhibitor at screening.

          3. The participant has a history or presence of a Factor VIII (FVIII) inhibitor with a
             titer ≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU (by
             Bethesda assay).

          4. The participant has a known hypersensitivity to any of the components of the study
             drugs, such as mouse or hamster proteins.

          5. The participant has a medical history of immunological disorders, excluding seasonal
             allergic rhinitis/conjunctivitis, mild asthma, food allergies, or animal allergies.

          6. The participant has a medical history of a thromboembolic event.

          7. The participant is human immunodeficiency virus (HIV) positive with an absolute Helper
             T cell (CD4) count <200/mm^3.

          8. The participant has been diagnosed with significant liver disease per investigator's
             medical assessment of the participant's current condition or medical history or as
             evidenced by, but not limited to any of the following: serum alanine aminotransferase
             (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; portal vein
             hypertension (eg, presence of otherwise unexplained splenomegaly, history of
             esophageal varices) or liver cirrhosis classified as Child-Pugh class B or C.

          9. The participant has been diagnosed with renal disease, with a serum creatinine (CR)
             level ≥2.5 mg/dL.

         10. The participant has a platelet count <100,000/mL at screening.

         11. The participant has been treated with an immunomodulatory drug, excluding topical
             treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed
             consent (or assent, if appropriate).

         12. The participant is pregnant or lactating at the time of enrollment.

         13. The participant has cervical or uterine conditions causing menorrhagia or metrorrhagia
             (including infection, dysplasia).

         14. The participant has participated in another clinical study involving another
             investigational product (IP) or investigational device within 30 days prior to
             enrollment or is scheduled to participate in another clinical study involving an IP or
             investigational device during the course of this study.

         15. The participant has a progressive fatal disease and/or life expectancy of less than 15
             months.

         16. For new OD subjects, the participant is scheduled for a surgical intervention.

         17. The participant is identified by the investigator as being unable or unwilling to
             cooperate with study procedures.

         18. The participant has a mental condition rendering him/her unable to understand the
             nature, scope and possible consequences of the study and/or evidence of an
             uncooperative attitude.

         19. The participant is member of the study team or in a dependent relationship with one of
             the study team members which includes close relatives (i.e., children, partner/spouse,
             siblings and parents) as well as employees.

        Delay criteria Only for Cohort 4, if the participant presents with an acute bleeding
        episodes or acute illness (eg, influenza, flu-like syndrome, allergic
        rhinitis/conjunctivitis, and non-seasonal asthma) the screening visit will be postponed
        until the participant has recovered. For all other participants, end of study (EOS) visit
        for 071102 or 071301 will be completed per protocol and the completed EOS in Study 071102
        or 071301 will also serve as the screening visit for this continuation study (SHP677-304).
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.



Patient description (medical language): A 23-year-old female has prolonged oral bleeding immediately after a tooth extraction.  Despite several interventions, the bleeding persists for hours and stops only after desmopressin (DDAVP) administration.  The patient has heavy menstrual cycles each month.  She has no other medical problems and takes no medications.  Her mother and grandmother have also had excessive bleeding during menstrual period.  Review of systems is positive for mild bruising on his legs. Laboratory findings reveal a normal platelet count and an abnormal ristocetin cofactor assay, as well as CB <= 0.30 IU/mL and FVIII:C <= 0.40 IU/mL.

Patient description (patient's own words): I'm a 23 woman and I went to the ER because of non-stop bleeding after my tooth extraction. I tried to make the bleeding stop but it just kept going for hours and it finally stopped when I took some medication called DDAVP. I usually have heavy periods, just like my mom and grandma had. I don't have any other medical condition and I don't take any other medication. The doctor noticed the bruises on my legs. I had to do some lab tests. I had a normal platelet count but an abnormal ristocetin cofactor assay. I had low CB and FVIII:C levels.

Does the patient match the trial criteria? Entailment