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A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia

Primary Purpose

Hypoplasminogenemia, Congenital Plasminogen Deficiency

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Plasminogen (Human) intravenous
Sponsored by
Prometic Biotherapeutics, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoplasminogenemia

Eligibility Criteria

2 Years - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Indiana Hemophilia and Thrombosis Center
  • Oslo University Hospital HF

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

6.6 mg/kg Plasminogen (Human) Intravenous

Arm Description

6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30-minute intravenous infusion

Outcomes

Primary Outcome Measures

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".
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.

Secondary Outcome Measures

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".
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).
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).
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.
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.
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.
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.
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
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.
Cmax of Plasminogen Activity After First Dose and at Week 12
Cmax is the maximum plasma concentration of Plasminogen
Cl of Plasminogen Activity After First Dose and at Week 12
Cl is the volume of plasma cleared of Plasminogen per unit time
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
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
Vss for Plasminogen Activity After First Dose and at Week 12
Vss is the apparent volume of distribution at steady state of Plasminogen

Full Information

First Posted
February 12, 2016
Last Updated
July 30, 2021
Sponsor
Prometic Biotherapeutics, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02690714
Brief Title
A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia
Official Title
A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, Efficacy, and Safety of Prometic Plasminogen Intravenous Infusion in Subjects With Hypoplasminogenemia
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
May 4, 2016 (Actual)
Primary Completion Date
December 17, 2017 (Actual)
Study Completion Date
October 8, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Prometic Biotherapeutics, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoplasminogenemia, Congenital Plasminogen Deficiency

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
6.6 mg/kg Plasminogen (Human) Intravenous
Arm Type
Experimental
Arm Description
6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30-minute intravenous infusion
Intervention Type
Biological
Intervention Name(s)
Plasminogen (Human) intravenous
Intervention Description
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.
Primary Outcome Measure Information:
Title
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.
Description
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
Title
Number and Percentage of Particpants Who Achieved the Target Plasminogen Activity Trough Levels for at Least 3 Measurements in 12 Weeks During Segment 2
Description
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
Secondary Outcome Measure Information:
Title
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
Description
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
Title
Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12
Description
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
Title
Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48
Description
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
Title
Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment
Description
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
Title
Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment
Description
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
Title
Plasminogen Activity Trough Levels Between Week 2 and Week 120
Description
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
Title
Plasminogen Antigen Trough Levels Between Week 2 and Week 120
Description
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
Title
Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12
Description
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
Title
AUClast of Plasminogen Activity After the First Dose and at Week 12
Description
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
Title
Cmax of Plasminogen Activity After First Dose and at Week 12
Description
Cmax is the maximum plasma concentration of Plasminogen
Time Frame
First dose and 12 weeks
Title
Cl of Plasminogen Activity After First Dose and at Week 12
Description
Cl is the volume of plasma cleared of Plasminogen per unit time
Time Frame
First dose and 12 weeks
Title
AUCinf of Plasminogen Activity After First Dose and at Week 12
Description
AUCinf is the area under the plasma concentration-curve of Plasminogen from time 0 extrapolated to infinity
Time Frame
First dose and 12 weeks
Title
MRTlast for Plasminogen Activity After First Dose and at Week 12
Description
MRTLast is the mean residence time of Plasminogen from time 0 to the last measured concentration
Time Frame
First dose and 12 weeks
Title
Vss for Plasminogen Activity After First Dose and at Week 12
Description
Vss is the apparent volume of distribution at steady state of Plasminogen
Time Frame
First dose and 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amy Shapiro, MD
Organizational Affiliation
Indiana Hemophilia & Thrombosis Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Indiana Hemophilia and Thrombosis Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
Oslo University Hospital HF
City
Oslo
State/Province
Sognsvannvejen 20
ZIP/Postal Code
0372
Country
Norway

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
29321155
Citation
Shapiro AD, Nakar C, Parker JM, Albert GR, Moran JE, Thibaudeau K, Thukral N, Hardesty BM, Laurin P, Sandset PM. Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency. Blood. 2018 Mar 22;131(12):1301-1310. doi: 10.1182/blood-2017-09-806729. Epub 2018 Jan 10.
Results Reference
background

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A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia

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