A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, Efficacy, and Safety of Prometic Plasminogen Intravenous Infusion in Subjects With Hypoplasminogenemia

Conditions
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Hypoplasminogenemia, Congenital Plasminogen Deficiency

Intervention / Treatment
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* Biological: Plasminogen (Human) intravenous


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 6.6 mg/kg Plasminogen (Human) Intravenous<br>6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30-minute intravenous infusion | Biological: Plasminogen (Human) intravenous<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Clinical Success in Number and Size of Lesions as Measured by Photographic or Other Imaging Modality Depending on the Organ System Affected or Change in Affected Organ Functionality at 48 Weeks. | Overall clinical success was defined as 50% of participants with visible or other measurable lesions achieving at least a 50% improvement in lesion number/size or functionality impact from baseline. Visible lesions were defined as lesions that could be imaged and analyzed with digital photography. Non-visible lesions were defined as lesions whose dimensions could have been assessed by medical imaging studies (eg, computed tomography, magnetic resonance imaging, ultrasound, etc) or functional assessments (eg, spirometry, audiogram, oximetry, etc).Visible lesions that had both a length and width as measured by the 1mm scale, were referred to as measurable lesions, and visible lesions that were too small to measure by the 1mm scale (length and/or width could not have been measured) were referred to as non-measurable lesions. | 48 weeks | 
| Number and Percentage of Particpants Who Achieved the Target Plasminogen Activity Trough Levels for at Least 3 Measurements in 12 Weeks During Segment 2 | Plasminogen activity is a measurement of functional plasminogen levels and is therefore the most accurate and specific method to quantify active Plasminogen (Human) Intravenous concentration in participants' plasma. Primary endpoint success was defined as at least 80% of evaluable participants (ie, 8 or more) achieving the target trough levels for at least 3 measurements in 12 weeks. The target trough level was defined as an increase in plasminogen activity level of at least an absolute 10% (10 U/dL) from the participant's individual baseline level. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Clinical Success in Number and Size of Lesions as Measured by Photographic or Other Imaging Modality Depending on the Organ System Affected or Change in Affected Organ Functionality at 12 Weeks | Overall clinical success was defined as 50% of participants with visible or other measurable lesions achieving at least a 50% improvement in lesion number/size or functionality impact from baseline. Visible lesions were defined as lesions that could be imaged and analyzed with digital photography. Non-visible lesions were defined as lesions whose dimensions could have been assessed by medical imaging studies (eg, computed tomography, magnetic resonance imaging, ultrasound, etc) or functional assessments (eg, spirometry, audiogram, oximetry, etc).Visible lesions that had both a length and width as measured by the 1mm scale, were referred to as measurable lesions, and visible lesions that were too small to measure by the 1mm scale (length and/or width could not have been measured) were referred to as non-measurable lesions. | 12 Weeks | 
| Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI-I scores are measured at 12 and 48 weeks after study drug treatment. The CGI-I Scale is a single, clinician completed scale designed to capture the clinician's impression of the participant's disease improvement over time. For this scale, clinicians were asked to consider their experience in this population and rate the change relative to the participant's state at Baseline using a 7-point scale (1 = very much improved, 7 = very much worse). | 12 weeks | 
| Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI-I scores are measured at 12 and 48 weeks after study drug treatment. The CGI-I Scale is a single, clinician completed scale designed to capture the clinician's impression of the participant's disease improvement over time. For this scale, clinicians were asked to consider their experience in this population and rate the change relative to the participant's state at Baseline using a 7-point scale (1 = very much improved, 7 = very much worse). | 48 Weeks | 
| Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | Quality of life score (QOL) was measured at baseline and at 12 and 48 weeks after study drug treatment. For the QOL assessment, participants were asked to rate their overall QOL using an 11-point scale (0 = non-functioning, 10 = normal; The QOL scale was adapted from a scale developed by the American Chronic Pain Association. | 12 weeks | 
| Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | Quality of life score (QOL) was measured at baseline and at 12 and 48 weeks after study drug treatment. For the QOL assessment, participants were asked to rate their overall QOL using an 11-point scale (0 = non-functioning, 10 = normal; The QOL scale was adapted from a scale developed by the American Chronic Pain Association. | 48 weeks | 
| Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Plasminogen activity trough levels were measured at Weeks 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120. | Week 2 to Week 120 | 
| Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Plasminogen antigen trough levels were measured at Weeks 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120. | Week 2 to Week 120 | 
| Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12 | t1/2 is time required for the plasma concentration of Plasminogen to decrease 50% in the final stage of its elimination | First dose and 12 weeks | 
| AUClast of Plasminogen Activity After the First Dose and at Week 12 | AUCLast is the area under the plasma concentration-curve of Plasminogen from time 0 to the last measured concentration. | First dose and 12 weeks | 
| Cmax of Plasminogen Activity After First Dose and at Week 12 | Cmax is the maximum plasma concentration of Plasminogen | First dose and 12 weeks | 
| Cl of Plasminogen Activity After First Dose and at Week 12 | Cl is the volume of plasma cleared of Plasminogen per unit time | First dose and 12 weeks | 
| AUCinf of Plasminogen Activity After First Dose and at Week 12 | AUCinf is the area under the plasma concentration-curve of Plasminogen from time 0 extrapolated to infinity | First dose and 12 weeks | 
| MRTlast for Plasminogen Activity After First Dose and at Week 12 | MRTLast is the mean residence time of Plasminogen from time 0 to the last measured concentration | First dose and 12 weeks | 
| Vss for Plasminogen Activity After First Dose and at Week 12 | Vss is the apparent volume of distribution at steady state of Plasminogen | First dose and 12 weeks |