Research Into the Effect of a Clot-dissolving Agent and Its Inhibitor
Phase 1 Trial of Mutant proUK, M5, and Its Inhibitor, C1-inhibitor
2 other identifiers
interventional
8
1 country
1
Brief Summary
Single-chain urokinase-type plasminogen activator (pro-urokinase) is a highly effective thrombolytic drug. At pharmacologic concentrations however, pro-urokinase is converted to urokinase - a non specific thrombolytic, limiting its therapeutic use. Mutant pro-urokinase (M5) is more stable and its conversion to urokinase is inhibited by C1-inhibitor. The primary objectives of the study are:
- To assess the overall safety and tolerability related to systemic plasminogen activation of single doses of M5 over a wide dose range (study part I).
- To assess the effect of single doses of C1-inhibitor on the overall safety and tolerability of single doses of M5 and its effect on M5-induced coagulation changes (study part II).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for early_phase_1
Started Sep 2012
Shorter than P25 for early_phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
September 1, 2012
CompletedFirst Submitted
Initial submission to the registry
September 24, 2012
CompletedFirst Posted
Study publicly available on registry
September 27, 2012
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 1, 2012
CompletedStudy Completion
Last participant's last visit for all outcomes
October 1, 2012
CompletedJanuary 19, 2021
January 1, 2021
1 month
September 24, 2012
January 14, 2021
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Changes to vital signs, routine safety laboratory results, or ECG-findings
-42d, -14h, -15', 15', 30', 45',60', 90', 10h, 24h, 48h, 7d
Study Arms (2)
mutant pro-urokinase (M5) alone
EXPERIMENTALIn the first study part subjects in cohorts of 4 will receive ascending doses of either M5 (3 subjects) or M5-placebo (1 subject) without C1-inhibitor.
Mutant pro-urokinase (M5) and its inhibitor, C1 inhibitor
EXPERIMENTALIn the second study part subjects in cohorts of 5 will receive ascending doses of either M5 or M5-placebo, preceded by a single intravenous dose of C1-inhibitor or C1-inhibitor-placebo. Each subject will randomly be allocated to one of the following treatment arms within one cohort: * C1-inhibitor followed by M5 (3 subjects); * C1-inhibitor followed by M5-placebo (1 subject); * C1-inhibitor-placebo followed by M5-placebo (1 subject). Dose levels of both M5 and C1-inhibitor within each cohort will be chosen based on the available safety, pharmacokinetic and pharmacodynamic data of the preceding cohorts.
Interventions
single point mutant of serine protease prourokinase
a protease inhibitor belonging to the serpin superfamily.
Eligibility Criteria
You may qualify if:
- Be male, aged between 18 and 35 years inclusive, and with a body weight of at least 60 kg and a body mass index (BMI) between 18.5 and 25 kg/m2 inclusive.
- Be without clinical significant abnormalities according to the investigator's judgment, based on a detailed medical history, a complete physical examination (including vital signs), a standard 12-lead electrocardiogram, urinalysis, and routine clinical laboratory tests.
- Have endogenous C1-inhibitor, α2-antiplasmin, fibrinogen, and plasminogen levels within the laboratory's reference range.
- Have a negative serology for HIV, HBsAg, and HCV.
- Have a negative test for alcohol and drugs of abuse at screening and on study day -1.
- Be capable of understanding and willing to comply with the conditions and restrictions of the protocol.
- Have read, understood and provided written informed consent.
You may not qualify if:
- Has a known or suspected inherited, congenital, or acquired disease or condition that affects the haemostatic or coagulation pathways or that is associated with an increased bleeding tendency.
- Has a reasonable chance of developing a clinically significant bleeding event or a bleeding event that may go undetected for a considerable amount of time during the study, for example:
- Has undergone major (internal) surgery or trauma within the last three months of the anticipated dosing day;
- Has an intestinal or cerebral vascular malformation;
- Has participated in high impact contact sports, such as kick-boxing, within two weeks of the anticipated dosing day.
- Has received any systemically absorbed drug or substance (including prescription, over-the-counter, or alternative remedies) that is not permitted by this protocol prior to dosing without undergoing a wash-out period of at least seven times the elimination half-life of the product. For aspirin or other products inhibiting thrombocyte-aggregation the wash-out period must not be less than 28 days.
- Has smoked tobacco in any form within three months of dosing, or has ever smoked more than five cigarettes per day (or equivalent) on average.
- Has received blood or plasma derivatives in the year preceding the administration day.
- Has lost blood or plasma outside the limits of the local blood donation service (i.c. Sanquin) three months prior to dosing.
- Has a known hypersensitivity to any of the investigational material or related compounds.
- Has a history of severe hypersensitivity or of an allergy with severe reactions.
- Has a history of substance abuse, including caffeine, tobacco, and alcohol.
- Has a condition or demonstrates an attitude that in the opinion of the investigator might jeopardise the subject's health or well-being, or the scientific integrity of the study results.
- Is mentally or legally incapacitated to provide informed consent.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- TSI, LLClead
Study Sites (1)
Center for Human Drug Research
Leiden, 2333, Netherlands
Related Publications (4)
Tomasi S, Sarmientos P, Giorda G, Gurewich V, Vercelli A. Mutant prourokinase with adjunctive C1-inhibitor is an effective and safer alternative to tPA in rat stroke. PLoS One. 2011;6(7):e21999. doi: 10.1371/journal.pone.0021999. Epub 2011 Jul 14.
PMID: 21779364BACKGROUNDPannell R, Kung W, Gurewich V. C1-inhibitor prevents non-specific plasminogen activation by a prourokinase mutant without impeding fibrin-specific fibrinolysis. J Thromb Haemost. 2007 May;5(5):1047-54. doi: 10.1111/j.1538-7836.2007.02453.x.
PMID: 17459007BACKGROUNDGurewich V, Pannell R, Simmons-Byrd A, Sarmientos P, Liu JN, Badylak SF. Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator. J Thromb Haemost. 2006 Jul;4(7):1559-65. doi: 10.1111/j.1538-7836.2006.01993.x.
PMID: 16839354BACKGROUNDLiu JN, Liu JX, Liu Bf BF, Sun Z, Zuo JL, Zhang Px PX, Zhang J, Chen Yh YH, Gurewich V. Prourokinase mutant that induces highly effective clot lysis without interfering with hemostasis. Circ Res. 2002 Apr 19;90(7):757-63. doi: 10.1161/01.res.0000014825.71092.bd.
PMID: 11964367BACKGROUND
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Koos Burggraaf, MD, PhD
Center for Human Drug Research
Study Design
- Study Type
- interventional
- Phase
- early phase 1
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Masking Details
- Double-blinded study.
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 24, 2012
First Posted
September 27, 2012
Study Start
September 1, 2012
Primary Completion
October 1, 2012
Study Completion
October 1, 2012
Last Updated
January 19, 2021
Record last verified: 2021-01