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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
Last Update Posted : December 10, 2019
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
Last Update Posted Date December 10, 2019
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: April 4, 2019)
  • Trough plasminogen activity levels during 12 weeks of study drug treatment [ Time Frame: 12 weeks ]
    Blood samples are collected before the first dose of the study drug to establish the baseline levels and every 2 weeks thereafter prior to study drug administration through Week 12 to measure trough levels of plasminogen activity.
  • Number of lesions after 48 weeks of study drug treatment [ Time Frame: 48 weeks ]
    Clinical success is defined as 50% of subjects with visible or other measureable lesions achieving at least a 50% improvement in lesion number/size or functionality impact from baseline.
  • Size of lesions after 48 weeks of study drug treatment [ Time Frame: 48 weeks ]
    Clinical success is defined as 50% of subjects with visible or other measurable lesions achieving at least a 50% improvement in lesion size from baseline.
  • Spirometry results after 48 weeks of study drug treatment in subjects with bronchial lesions of hypoplasminogenemia. [ Time Frame: 48 weeks ]
    Clinical success is defined as 50% of subjects with visible or other measurable lesions achieving at least a 50% improvement in affected organ functionality (e.g., spirometry) from baseline.
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: April 4, 2019)
  • Incidence of treatment emergent adverse events (TEAEs) [ Time Frame: Approximately 53 weeks ]
    • The relatedness and severity of all TEAEs will be summarized
    • Numbers of subjects who had changes from baseline in viral tests will be summarized
    • Number of subjects who had changes from baseline in immunogenicity tests will be summarized
  • Trough plasminogen activity levels after 24, 36, and 48 weeks of study drug treatment [ Time Frame: 24-48 weeks ]
    Blood samples are collected before the first dose of the study drug to establish the baseline levels and at 24, 36, and 48 weeks thereafter prior to study drug administration to measure trough levels of plasminogen activity.
  • Number of lesions after 12 weeks of study drug treatment [ Time Frame: 12 weeks ]
    Clinical success is defined as 50% of subjects with visible or other measurable lesions achieving at least a 50% improvement in lesion number from baseline.
  • Size of lesions after 12 weeks of study drug treatment [ Time Frame: 12 weeks ]
    Clinical success is defined as 50% of subjects with visible or other measurable lesions achieving at least a 50% improvement in lesion size from baseline.
  • Change from baseline in spirometry after 12 weeks of study drug treatment [ Time Frame: 12 weeks ]
    Clinical success is defined as 50% of subjects with visible or other measurable lesions achieving at least a 50% improvement in affected organ functionality (e.g., spirometry) from baseline.
  • Clinical Global Impression-Global Improvement (CGI-I) scores after 12 and 48 weeks of study drug treatment [ Time Frame: 12 and 48 weeks ]
    CGI-I scores are measured at baseline and at 12 and 48 weeks after study drug treatment.
  • Quality of life score after 12 and 48 weeks of study treatment [ Time Frame: 12 and 48 weeks ]
    Quality of life scores are measured at baseline and at 12 and 48 weeks after study drug treatment.
  • Mean baseline-adjusted mean plasminogen activity levels after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    Blood samples are collected prior to the first and Week 12 dose and at 0.167, 6, 24, 48, 72, and 96 hours after the first and Week 12 dose of study drug to measure plasminogen activity.
  • Mean area under the concentration-time curve, from time 0 to the last measured time point (AUCLAST) of baseline-adjusted plasminogen activity after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean AUCLAST of baseline-adjusted plasminogen activity in subjects with hypoplasminogenemia
  • Mean extrapolated area under the concentration-time curve, from time 0 to infinity (AUCINF) of baseline-adjusted plasminogen activity after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean AUCINF of baseline-adjusted plasminogen activity in subjects with hypoplasminogenemia
  • Mean clearance (CL) of baseline-adjusted plasminogen activity after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean CL of baseline-adjusted plasminogen activity in subjects with hypoplasminogenemia
  • Mean MRT of baseline-adjusted plasminogen activity after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean MRT of baseline-adjusted plasminogen activity in subjects with hypoplasminogenemia
  • Mean Vd of baseline-adjusted plasminogen activity after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean Vd of baseline-adjusted plasminogen activity in subjects with hypoplasminogenemia
  • Mean terminal half-life (t1/2) of baseline-adjusted plasminogen activity after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean t1/2 of baseline-adjusted plasminogen activity in subjects with hypoplasminogenemia
  • Mean Cmax of baseline-adjusted plasminogen activity after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean t1/2 of baseline-adjusted plasminogen activity in subjects with hypoplasminogenemia
  • Mean baseline-adjusted mean plasminogen antigen levels after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    Blood samples are collected prior to the first and Week 12 dose and at 0.167, 6, 24, 48, 72, and 96 hours after the first and Week 12 dose of study drug to measure plasminogen antigen levels.
  • Mean AUCLAST of baseline-adjusted plasminogen antigen after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean AUCLAST of baseline-adjusted plasminogen antigen in subjects with hypoplasminogenemia
  • Mean AUCINF of baseline-adjusted plasminogen antigen after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean AUCINF of baseline-adjusted plasminogen antigen in subjects with hypoplasminogenemia
  • Mean CL of baseline-adjusted plasminogen antigen after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean CL of baseline-adjusted plasminogen antigen in subjects with hypoplasminogenemia
  • Mean MRT of baseline-adjusted plasminogen antigen after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean MRT of baseline-adjusted plasminogen antigen in subjects with hypoplasminogenemia
  • Mean Vd of baseline-adjusted plasminogen antigen after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean Vd of baseline-adjusted plasminogen antigen in subjects with hypoplasminogenemia
  • Mean t1/2 of baseline-adjusted plasminogen antigen after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean t1/2 of baseline-adjusted plasminogen antigen in subjects with hypoplasminogenemia
  • Mean Cmax of baseline-adjusted plasminogen antigen after the first and Week 12 dose of study drug treatment [ Time Frame: 12 weeks ]
    To determine the mean t1/2 of baseline-adjusted plasminogen antigen in subjects with hypoplasminogenemia
  • Abnormal D-dimer levels after study drug treatment [ Time Frame: 48 weeks ]
    Abnormal D-dimer levels in subjects with hypoplasminogenemia
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
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 for 48 weeks (Norway) and longer until product licensing or study termination by the Sponsor (US).
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 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 December 2019

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