Congenital Plasminogen Deficiency, Hypoplasminogenemia
Conditions
Brief 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.
Interventions
BIOLOGICALPlasminogen (Human) intravenous
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.
Sponsors
Prometic Biotherapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
| Number and Percentage of Particpants Who Achieved the Target Plasminogen Activity Trough Levels for at Least 3 Measurements in 12 Weeks During Segment 2 | 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | 48 Weeks | 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). |
| Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | 12 weeks | 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. |
| Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | 48 weeks | 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. |
| Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 2 to 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. |
| Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 2 to 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. |
| Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12 | First dose and 12 weeks | t1/2 is time required for the plasma concentration of Plasminogen to decrease 50% in the final stage of its elimination |
| 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 | 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. |
| Cmax of Plasminogen Activity After First Dose and at Week 12 | First dose and 12 weeks | Cmax is the maximum plasma concentration of Plasminogen |
| Cl of Plasminogen Activity After First Dose and at Week 12 | First dose and 12 weeks | Cl is the volume of plasma cleared of Plasminogen per unit time |
| AUCinf of Plasminogen Activity After First Dose and at Week 12 | First dose and 12 weeks | AUCinf is the area under the plasma concentration-curve of Plasminogen from time 0 extrapolated to infinity |
| MRTlast for Plasminogen Activity After First Dose and at Week 12 | First dose and 12 weeks | MRTLast is the mean residence time of Plasminogen from time 0 to the last measured concentration |
| Vss for Plasminogen Activity After First Dose and at Week 12 | First dose and 12 weeks | Vss is the apparent volume of distribution at steady state of Plasminogen |
| AUClast of Plasminogen Activity After the First Dose and at Week 12 | First dose and 12 weeks | AUCLast is the area under the plasma concentration-curve of Plasminogen from time 0 to the last measured concentration. |
| Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | 12 weeks | 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). |
Countries
Norway, United States
Participant flow
Recruitment details
This study was conducted at 2 sites, 1 in the United States (US) and 1 in Norway. The first participant was screened in May 2016 and the last participant visit was in October 2018.
Participants by arm
| Arm | Count |
|---|---|
| 6.6 mg/kg Plasminogen (Human) Intravenous 6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30-minute intravenous infusion
Plasminogen (Human) intravenous: 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. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Post-Wk 48: Safety Week 48 to EoS Visit | Physician Decision | 1 |
| Post-Wk 48: Safety Week 48 to EoS Visit | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | 6.6 mg/kg Plasminogen (Human) Intravenous |
|---|---|
| Age, Continuous | 23.0 years STANDARD_DEVIATION 13.05 |
| Age, Customized 12-17 years | 2 Participants |
| Age, Customized > 17 years | 9 Participants |
| Age, Customized 2-11 years | 4 Participants |
| Number of Visible and Assesable Non-Visible Lesions Non-visible lesions | 15 Number of lesions |
| Number of Visible and Assesable Non-Visible Lesions Number of lesions analyzed | 47 Number of lesions |
| Number of Visible and Assesable Non-Visible Lesions Visible lesions | 32 Number of lesions |
| Plasminogen Activity Plasminogen activity 11-20% | 4 Participants |
| Plasminogen Activity Plasminogen activity 21-30% | 6 Participants |
| Plasminogen Activity Plasminogen activity 31-40% | 1 Participants |
| Plasminogen Activity Plasminogen activity 41-45% | 1 Participants |
| Plasminogen Activity Plasminogen activity >45% | 0 Participants |
| Plasminogen Activity Plasminogen activity <5-10% | 3 Participants |
| Plasminogen Activity | 21.1 % activity STANDARD_DEVIATION 10.83 |
| Plasminogen antigen Plasminogen antigen <0.5-3.0 mg/dL | 4 Participants |
| Plasminogen antigen Plasminogen antigen >20.0 mg/dL | 0 Participants |
| Plasminogen antigen Plasminogen antigen 3.1-6.0 mg/dL | 10 Participants |
| Plasminogen antigen Plasminogen antigen 6.1-20.0 mg/dL | 1 Participants |
| Plasminogen antigen | 4.7 mg/dL STANDARD_DEVIATION 3.7 |
| Quality of Life Assessment QOL score = 0 | 0 Participants |
| Quality of Life Assessment QOL score = 1 | 0 Participants |
| Quality of Life Assessment QOL score = 10 | 9 Participants |
| Quality of Life Assessment QOL score = 2 | 0 Participants |
| Quality of Life Assessment QOL score = 3 | 0 Participants |
| Quality of Life Assessment QOL score = 4 | 0 Participants |
| Quality of Life Assessment QOL score = 5 | 0 Participants |
| Quality of Life Assessment QOL score = 6 | 1 Participants |
| Quality of Life Assessment QOL score = 7 | 3 Participants |
| Quality of Life Assessment QOL score = 8 | 1 Participants |
| Quality of Life Assessment QOL score = 9 | 1 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 1 Participants |
| Race/Ethnicity, Customized Non-Hispanic/Latino | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment Norway | 3 Participants |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 4 Participants |
| Visible and Non-Visible Lesions by Participant >= 1 Visible or non-visible lesion | 11 Participants |
| Visible and Non-Visible Lesions by Participant None | 4 Participants |
| Weight | 60.37 Kg STANDARD_DEVIATION 26.803 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 3 / 15 |
Outcome results
Primary
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.
Time frame: 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Plasminogen (Human) Intravenous | Number and Percentage of Particpants Who Achieved the Target Plasminogen Activity Trough Levels for at Least 3 Measurements in 12 Weeks During Segment 2 | 15 Participants |
Primary
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.
Time frame: 48 weeks
Population: Efficacy Population Week 48-Segment 3 included all 15 enrolled participants who completed the Week 48 visit at the time of the data cut-off date of 14Dec2017. This analysis included 11 participants with 47 visible and/or non-visible lesions at baseline. All 15 participants were assessed, however only 11 participants had visible and/or non-visible lesions at baseline.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Plasminogen (Human) Intravenous | 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. | Total Visible/Non-Visible lesions resolved (%) | 34 Lesions |
| Plasminogen (Human) Intravenous | 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. | Total Visible/Non-Visible lesions improved (%) | 10 Lesions |
| Plasminogen (Human) Intravenous | 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. | Not applicable (not assessed) | 3 Lesions |
Secondary
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
Time frame: First dose and 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | AUCinf of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) AUCinf of plasminogen after first dose | 3605.8 hr*% | Standard Deviation 1023.88 |
| Plasminogen (Human) Intravenous | AUCinf of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) AUCinf of plasminogen at Week 12 | 5731.8 hr*% | Standard Deviation 1431.7 |
Secondary
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.
Time frame: First dose and 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | AUClast of Plasminogen Activity After the First Dose and at Week 12 | Mean (SD) AUClast after first dose of plasminogen | 3063.6 hr*% | Standard Deviation 778.67 |
| Plasminogen (Human) Intravenous | AUClast of Plasminogen Activity After the First Dose and at Week 12 | Mean (SD) AUClast at Week 12 | 4656.0 hr*% | Standard Deviation 1012.66 |
Secondary
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).
Time frame: 12 weeks
Population: CGI-I population included all 15 enrolled participants who completed the week 12 (and week 48) visit.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 0 = Not assessed: Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 1 = Very much improved: Week 12 | 11 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 2 = Much improved : Week 12 | 4 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 3 = Minimally improved : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 4= No change : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 5 = Minimally worse : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 6 = Much worse : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 | CGI score 7 = Very much worse : Week 12 | 0 Participants |
Secondary
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).
Time frame: 48 Weeks
Population: CGI-I population included all 15 enrolled participants who completed the week 48 (and week 12) visit.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 0= Not assessed: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 1= Very much improved: Week 48 | 13 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 2= Much improved: Week 48 | 2 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 3= Minimally improved: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 4= No change: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 5= Minimally worse: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 6= Much worse: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 | CGI Score 7= Very much worse: Week 48 | 0 Participants |
Secondary
Cl of Plasminogen Activity After First Dose and at Week 12
Cl is the volume of plasma cleared of Plasminogen per unit time
Time frame: First dose and 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | Cl of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) Cl of plasminogen after first dose | 1.44 mL/hr/kg | Standard Deviation 0.46 |
| Plasminogen (Human) Intravenous | Cl of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) Cl of plasminogen at Week 12 | 0.92 mL/hr/kg | Standard Deviation 0.257 |
Secondary
Cmax of Plasminogen Activity After First Dose and at Week 12
Cmax is the maximum plasma concentration of Plasminogen
Time frame: First dose and 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | Cmax of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) Cmax of plasminogen after first dose | 95 % plasminogen activity | Standard Deviation 23.5 |
| Plasminogen (Human) Intravenous | Cmax of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) Cmax of plasminogen at Week 12 | 125 % plasminogen activity | Standard Deviation 23.3 |
Secondary
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
Time frame: First dose and 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) t1/2 of plasminogen after the first dose | 34 Hours | Standard Deviation 11.73 |
| Plasminogen (Human) Intravenous | Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12 | Mean (SD) t1/2 of plasminogen at week 12 | 39.2 Hours | Standard Deviation 6.22 |
Secondary
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
Time frame: First dose and 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | MRTlast for Plasminogen Activity After First Dose and at Week 12 | Mean (SD) MRTlast of plasminogen after first dose | 30.6 hours | Standard Deviation 3.22 |
| Plasminogen (Human) Intravenous | MRTlast for Plasminogen Activity After First Dose and at Week 12 | Mean (SD) MRTlast of plasminogen at Week 12 | 33.5 hours | Standard Deviation 1.6 |
Secondary
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.
Time frame: 12 weeks
Population: Efficacy Population Week 48-Segment 3 included all 15 enrolled participants who completed the Week 48 visit at the time of the data cut-off date of 14Dec2017
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 3 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score 0 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 1 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 2 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 4 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 5 : Week 12 | 1 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 6 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 7 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 8 : Week 12 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 9 : Week 12 | 1 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment | QOL score = 10 : Week 12 | 13 Participants |
Secondary
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.
Time frame: 48 weeks
Population: Efficacy Population Week 48-Segment 3 included all 15 enrolled participants who completed the Week 48 visit at the time of the data cut-off date of 14Dec2017
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 0: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 1: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 2: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 3: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 4: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 5: Week 48 | 1 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 6: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 7: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 8: Week 48 | 0 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 9: Week 48 | 1 Participants |
| Plasminogen (Human) Intravenous | Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment | QOL Score 10: Week 48 | 13 Participants |
Secondary
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.
Time frame: 12 Weeks
Population: Efficacy population week 12 included all 15 enrolled participants who completed the week 12 visit. All 15 participants were assessed, however only 11 participants had visible and/or non-visible lesions at baseline.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Plasminogen (Human) Intravenous | 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 | Total Visible/Non-Visible lesions resolved | 26 Number of Lesions |
| Plasminogen (Human) Intravenous | 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 | Total Visible/Non-Visible lesions improved | 14 Number of Lesions |
| Plasminogen (Human) Intravenous | 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 | Total Visible/Non-visible unchanged | 2 Number of Lesions |
| Plasminogen (Human) Intravenous | 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 | Not applicable/Not assessed | 5 Number of Lesions |
Secondary
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.
Time frame: Week 2 to Week 120
Population: Pharmacokinetic Population included any participant who had completed Segment 2, 3 and post week 48 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 2 | 45.1 percentage of activity | Standard Deviation 15.05 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 4 | 48.9 percentage of activity | Standard Deviation 14.56 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 6 | 52.4 percentage of activity | Standard Deviation 11.45 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 8 | 48.3 percentage of activity | Standard Deviation 17.43 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 10 | 50.2 percentage of activity | Standard Deviation 12.39 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 12 | 51.0 percentage of activity | Standard Deviation 12.01 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 24 | 45.0 percentage of activity | Standard Deviation 12.88 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 36 | 45.5 percentage of activity | Standard Deviation 13.18 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 48 | 41.7 percentage of activity | Standard Deviation 16.99 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 60 | 49.0 percentage of activity | Standard Deviation 8.88 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 72 | 46.7 percentage of activity | Standard Deviation 10.97 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 84 | 51.7 percentage of activity | Standard Deviation 20.76 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 96 | 50.1 percentage of activity | Standard Deviation 20.08 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 108 | 45.0 percentage of activity | Standard Deviation 25.19 |
| Plasminogen (Human) Intravenous | Plasminogen Activity Trough Levels Between Week 2 and Week 120 | Week 120 | 36.5 percentage of activity | Standard Deviation 12.02 |
Secondary
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.
Time frame: Week 2 to Week 120
Population: Pharmacokinetic Population included any participant who had completed Segment 2, 3 and post week 48 dosing and had provided at least 3 blood samples to measure plasminogen antigen trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 2 | 6.550 mg/dL | Standard Deviation 3.0457 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 4 | 7.800 mg/dL | Standard Deviation 3.8813 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 6 | 7.268 mg/dL | Standard Deviation 3.3155 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 8 | 6.607 mg/dL | Standard Deviation 3.0046 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 10 | 9.460 mg/dL | Standard Deviation 7.1543 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 12 | 7.340 mg/dL | Standard Deviation 2.9342 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 24 | 5.913 mg/dL | Standard Deviation 2.2181 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 36 | 6.667 mg/dL | Standard Deviation 2.7336 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 48 | 6.973 mg/dL | Standard Deviation 3.1299 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 60 | 6.415 mg/dL | Standard Deviation 1.7578 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 72 | 6.083 mg/dL | Standard Deviation 2.2851 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 84 | 7.183 mg/dL | Standard Deviation 3.8129 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 96 | 7.656 mg/dL | Standard Deviation 4.203 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 108 | 6.529 mg/dL | Standard Deviation 4.0852 |
| Plasminogen (Human) Intravenous | Plasminogen Antigen Trough Levels Between Week 2 and Week 120 | Week 120 | 6.550 mg/dL | Standard Deviation 6.2933 |
Secondary
Vss for Plasminogen Activity After First Dose and at Week 12
Vss is the apparent volume of distribution at steady state of Plasminogen
Time frame: First dose and 12 weeks
Population: Pharmacokinetic Population included any participant who had completed Segment 2 dosing and had provided at least 3 blood samples to measure plasminogen activity trough levels.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Plasminogen (Human) Intravenous | Vss for Plasminogen Activity After First Dose and at Week 12 | Mean (SD) Vss of plasminogen after first dose | 63.3 mL/kg | Standard Deviation 11.44 |
| Plasminogen (Human) Intravenous | Vss for Plasminogen Activity After First Dose and at Week 12 | Mean (SD) Vss of plasminogen at Week 12 | 49.3 mL/kg | Standard Deviation 10.36 |