Research Into the Effect of a Clot-dissolving Agent and Its Inhibitor

January 14, 2021 updated by: TSI, LLC

Phase 1 Trial of Mutant proUK, M5, and Its Inhibitor, C1-inhibitor

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).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Mutant proUK, M5, was specifically designed to improve the plasma stability of single-chain proUK by reducing its intrinsic catalytic activity and allowing it to retain its proenzyme form until it encounters a thrombus. As an additional consequence of the mutation, its two-chain enzymatic form (tcM5) is sensitive to inhibition by C1-inhibitor (C1INH) a relatively abundant plasma inhibitor.

While it has a negligible effect on urokinase (UK), C1INH inhibits tcM5 irreversibly, preventing non-specific plasminogen activation, responsible for bleeding complications. The effect of endogenous C1INH can be augmented by the addition of exogenous C1INH. In vitro studies in rats and dogs indicated that adding C1INH to plasma prior to clot lysis by M5 prevented bleeding, fibrinogenolysis and plasminogen depletion but did not affect the rate of fibrinolysis. In a recent pilot rat stroke study, at similarly effective doses, M5, preceded by C1INH adjunctive therapy, was equivalent to tPA alone but caused significantly less ICH, was much more effective than tPA preceded by adjunctive C1INH, and was the only group with a significant functional improvement at 24h.

Dose restrictions which limit efficacy of tPA-based thrombolysis are expected to be circumvented by M5 preceded by adjunctive C1INH. C1INH is a commercially available plasma derived product with a well-established safety and efficacy profile and is currently indicated and available for routine prophylaxis of hereditary angioedema (HAE).

Study Type

Interventional

Enrollment (Actual)

8

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Leiden, Netherlands, 2333
        • Center for Human Drug Research

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 35 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: mutant pro-urokinase (M5) alone
In 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.
Drug: M5
single point mutant of serine protease prourokinase
EXPERIMENTAL: Mutant pro-urokinase (M5) and its inhibitor, C1 inhibitor

In 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.
Drug: M5
single point mutant of serine protease prourokinase
Drug: C1-inhibitor
a protease inhibitor belonging to the serpin superfamily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Changes to vital signs, routine safety laboratory results, or ECG-findings
Time Frame: -42d, -14h, -15', 15', 30', 45',60', 90', 10h, 24h, 48h, 7d
-42d, -14h, -15', 15', 30', 45',60', 90', 10h, 24h, 48h, 7d

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

TSI, LLC

Investigators

  • Principal Investigator: Koos Burggraaf, MD, PhD, Center for Human Drug Research

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

September 1, 2012

Primary Completion (ACTUAL)

October 1, 2012

Study Completion (ACTUAL)

October 1, 2012

Study Registration Dates

First Submitted

September 24, 2012

First Submitted That Met QC Criteria

September 24, 2012

First Posted (ESTIMATE)

September 27, 2012

Study Record Updates

Last Update Posted (ACTUAL)

January 19, 2021

Last Update Submitted That Met QC Criteria

January 14, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TS01-01
  • 2012-002225-30 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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