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A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia

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ClinicalTrials.gov Identifier: NCT02690714
Recruitment Status : Completed
First Posted : February 24, 2016
Results First Posted : April 19, 2021
Last Update Posted : August 2, 2021
Sponsor:
Information provided by (Responsible Party):
Prometic Biotherapeutics, Inc.

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.

Condition or disease Intervention/treatment Phase
Hypoplasminogenemia Congenital Plasminogen Deficiency Biological: Plasminogen (Human) intravenous Phase 2 Phase 3

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 4, 2016
Actual Primary Completion Date : December 17, 2017
Actual Study Completion Date : October 8, 2018


Arm Intervention/treatment
Experimental: 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
Biological: 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.




Primary Outcome Measures :
  1. 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. [ Time Frame: 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".

  2. Number and Percentage of Particpants Who Achieved the Target Plasminogen Activity Trough Levels for at Least 3 Measurements in 12 Weeks During Segment 2 [ Time Frame: 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 Outcome Measures :
  1. 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 [ Time Frame: 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".

  2. Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 12 [ Time Frame: 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).


  3. Clinical Global Impression-Global Improvement (CGI-I) Scores at Week 48 [ Time Frame: 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).


  4. Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment [ Time Frame: 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.

  5. Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment [ Time Frame: 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.

  6. Plasminogen Activity Trough Levels Between Week 2 and Week 120 [ Time Frame: 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.

  7. Plasminogen Antigen Trough Levels Between Week 2 and Week 120 [ Time Frame: 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.

  8. Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12 [ Time Frame: 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

  9. AUClast of Plasminogen Activity After the First Dose and at Week 12 [ Time Frame: First dose and 12 weeks ]
    AUCLast is the area under the plasma concentration-curve of Plasminogen from time 0 to the last measured concentration.

  10. Cmax of Plasminogen Activity After First Dose and at Week 12 [ Time Frame: First dose and 12 weeks ]
    Cmax is the maximum plasma concentration of Plasminogen

  11. Cl of Plasminogen Activity After First Dose and at Week 12 [ Time Frame: First dose and 12 weeks ]
    Cl is the volume of plasma cleared of Plasminogen per unit time

  12. AUCinf of Plasminogen Activity After First Dose and at Week 12 [ Time Frame: First dose and 12 weeks ]
    AUCinf is the area under the plasma concentration-curve of Plasminogen from time 0 extrapolated to infinity

  13. MRTlast for Plasminogen Activity After First Dose and at Week 12 [ Time Frame: First dose and 12 weeks ]
    MRTLast is the mean residence time of Plasminogen from time 0 to the last measured concentration

  14. Vss for Plasminogen Activity After First Dose and at Week 12 [ Time Frame: First dose and 12 weeks ]
    Vss is the apparent volume of distribution at steady state of Plasminogen



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02690714


Locations
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United States, Indiana
Indiana Hemophilia and Thrombosis Center
Indianapolis, Indiana, United States, 46260
Norway
Oslo University Hospital HF
Oslo, Sognsvannvejen 20, Norway, 0372
Sponsors and Collaborators
Prometic Biotherapeutics, Inc.
Investigators
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Principal Investigator: Amy Shapiro, MD Indiana Hemophilia & Thrombosis Center
  Study Documents (Full-Text)

Documents provided by Prometic Biotherapeutics, Inc.:
Study Protocol  [PDF] August 8, 2018
Statistical Analysis Plan  [PDF] February 1, 2017

Publications:
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Responsible Party: Prometic Biotherapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02690714    
Other Study ID Numbers: 2002C011G
First Posted: February 24, 2016    Key Record Dates
Results First Posted: April 19, 2021
Last Update Posted: August 2, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Coagulation Protein Disorders
Blood Coagulation Disorders
Hematologic Diseases
Plasminogen
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action