a study of prometic plasminogen iv infusion in subjects with hypoplasminogenemia

Conditions: Hypoplasminogenemia; Congenital Plasminogen Deficiency

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.

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.

Eligibility criteria:
inclusion criteria: * subject is a male or female between the ages of 2 and 80 years (inclusive), is able to provide informed consent or assent, and agrees to use contraceptive methods during the study (unless documented as biologically or surgically sterile or has not reached reproductive age). * subject has documented history of hypoplasminogenemia and has plasminogen activity level ≤ 45%. * subject had a documented history of lesions and symptoms consistent with a diagnosis of congenital plasminogen deficiency. * subject has documented vaccination to hepatitis a virus (hav) and hepatitis b virus (hbv), or has received the first dose of hav and hbv vaccine prior to the first dose of imp and is scheduled to receive the second vaccine dose. exclusion criteria: * subject has uncontrolled hypertension; clinical or laboratory evidence of an intercurrent infection; a malignancy within 3 years, except for basal or squamous cell skin cancer; a psychiatric disorder; chronic or acute clinically significant inter-current illness; or evidence of renal and hepatic dysfunction. * subject is pregnant or lactating * subject has a history of anaphylactic reactions to blood or blood products that may interfere with participation in study in the opinion of the investigator. * subject is a previous organ transplant recipient; has received exogenous plasminogen within 2 weeks of the screening; has a history of anaphylactic reactions to blood or blood products; or has received another irb-approved interventional clinical trial of a drug, biologic, or device within 30 days before the first dose of the imp.