A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia
Condition: Hypoplasminogenemia; Congenital Plasminogen Deficiency
MeSH terms: Coagulation Protein Disorders
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      This is a Phase 2/3 pivotal study to evaluate pharmacokinetics (PK), efficacy, and safety of
      Prometic Plasminogen (Human) Intravenous Lyophilized Solution, the investigational medicinal
      product (IMP), in pediatric and adult subjects with hypoplasminogenemia.
    

Detailed description: 
      This is a Phase 2/3, open-label, repeat-dose study of the PK, efficacy, and safety of the
      IMP, in pediatric and adult subjects with hypoplasminogenemia. The study consists of a
      screening period and 3 treatment segments (Segment 1,2, and 3). Subjects who have documented
      individual PK profiles do not need to undergo Segment 1 and can proceed directly to Segment
      2. Subjects in Segment 1 will receive a single dose of 6.6 mg/kg IMP infusion. Blood samples
      for PK analysis will be drawn prior to infusion and subsequently through 96 hours after the
      infusion to establish individual PK profiles. The sample drawn prior to infusion will be used
      to measure the subject's baseline anti-plasminogen antibody, plasminogen activity and antigen
      as well as D-dimer levels. The resulting PK profile will be used to determine each subject's
      dosing interval in Segment 2.

      Based on individual PK profiles from Segment 1 subjects will receive 6.6 mg/kg IMP infusion
      every second, third, or fourth day for 12 weeks in Segment 2. For subjects who directly enter
      Segment 2, baseline assessments will be conducted before the first dose of IMP, including a
      blood sample to measure the baseline anti-plasminogen antibody, plasminogen activity and
      antigen as well as D-dimer levels. Subjects will visit the study sites on Week 1 and
      subsequently every 4 weeks, and receive the IMP infusion at the study site. Blood samples
      will be obtained at each study visit at Weeks 4, 8 and 12 and by a home health nurse at Weeks
      2, 6 and 10. Subjects will undergo clinical assessments of the disease, including but not
      limited to: photographic measurements of visible lesions, spirometry for subjects with
      pulmonary involvement, and imaging study of nonvisible lesions, as applicable. Plasma samples
      will be drawn before IMP administration every 2 weeks to measure the trough levels of
      plasminogen activity and antigen, and D-dimer.

      At the end of Segment 2, subjects will have the option to participate in Segment 3 where they
      will continue to receive IMP for an additional 36 weeks in Norway, and until product
      licensing or study termination by the sponsor for subjects in the United States. Subjects
      will return to the study sites for assessments every 3 months to monitor subjects' clinical
      status and plasminogen trough levels. Subjects at the Norway site in Segment 3 should return
      to the study site for a safety follow-up visit 30 days after the final IMP dose. Due to the
      delay in product approval, subjects at the US site in Segment 3 will be allowed to enroll in
      treatment protocol 2002C018G and continue ongoing IMP treatment without any break in
      treatment. If subjects decide to not enter treatment protocol 2002C018G, then they will stop
      IMP and return to the study site for a safety follow-up visit 30 days after the final IMP
      dose.

      The primary objective of this study is to achieve an increase of individual trough
      plasminogen activity by at least an absolute 10% (i.e., 10 U/dL) from baseline during the 12
      weeks of plasminogen replacement therapy in Segment 2; and to evaluate the efficacy of
      plasminogen replacement therapy on clinically evident or visible symptoms of
      hypoplasminogenemia during the 48 weeks of dosing in Segments 2 and 3.
    

Intervention name(s): Plasminogen (Human) intravenous
Intervention type(s): Biological
Intervention description(s): Prometic Plasminogen (Human) intravenous infusion given as single dose of 6.6 mg/kg in Segment 1 and repeat doses in Segments 2 and 3.
Intervention MeSH terms: Plasminogen
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment