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A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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.

Tracking Information
First Submitted Date  ICMJE February 12, 2016
First Posted Date  ICMJE February 24, 2016
Results First Submitted Date  ICMJE March 22, 2021
Results First Posted Date  ICMJE April 19, 2021
Last Update Posted Date August 2, 2021
Actual Study Start Date  ICMJE May 4, 2016
Actual Primary Completion Date December 17, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 22, 2021)
  • 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".
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 19, 2016)
Plasma plasminogen activity trough levels [ Time Frame: 48 or 72 hours after infusion every 2 weeks for up to 12 weeks ]
Plasma samples will be taken 48 or 72 hours after infusion every 2 weeks to be analyzed for plasminogen activity levels
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2021)
  • 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".
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: February 19, 2016)
  • Size of visible lesions by photographic evidence [ Time Frame: Every 2 weeks up to 12 weeks ]
    Visible lesions will be assessed by measuring the lesions in photographic images at clinic visits
  • Quality of Life survey (10-point scale) [ Time Frame: Every 2 weeks for up to 12 weeks ]
    A short survey using a 10-point scale (0 = non-functioning, 10 = normal) documenting patient reported quality of life will be assessed at clinic visits
  • Physicians Global Clinical Impression (7-point scale) [ Time Frame: Every 2 weeks for up to 12 weeks ]
    A 7-item scale documenting the physicians assessment of subject's disease status will be assessed at clinic visits
  • Treatment emergent adverse events [ Time Frame: Ongoing throughout 12 weeks ]
    Treatment emergent adverse events will be queried and reported continuously
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia
Official Title  ICMJE A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, Efficacy, and Safety of Prometic Plasminogen Intravenous Infusion in Subjects With Hypoplasminogenemia
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hypoplasminogenemia
  • Congenital Plasminogen Deficiency
Intervention  ICMJE 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.
Study Arms  ICMJE 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
Intervention: Biological: Plasminogen (Human) intravenous
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 28, 2017)
15
Original Estimated Enrollment  ICMJE
 (submitted: February 19, 2016)
12
Actual Study Completion Date  ICMJE October 8, 2018
Actual Primary Completion Date December 17, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 80 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Norway,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02690714
Other Study ID Numbers  ICMJE 2002C011G
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Prometic Biotherapeutics, Inc.
Study Sponsor  ICMJE Prometic Biotherapeutics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Amy Shapiro, MD Indiana Hemophilia & Thrombosis Center
PRS Account Prometic Biotherapeutics, Inc.
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP