Acute Ischemic StrokeEarly Phase 1NCT01694381
Research Into the Effect of a Clot-dissolving Agent and Its Inhibitor
A Early Phase 1 study testing M5 and C1-inhibitor in people with Acute Ischemic Stroke, run by TSI, LLC at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Acute Ischemic Stroke
- What is being tested?
- M5 and C1-inhibitor
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteNetherlands
- Study dates
- Sep 2012to Oct 2012
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 14Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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).
Read the 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).
- Conditions
- Acute Ischemic Stroke
- Being tested
- M5, C1-inhibitor
- Keywords
- Acute Ischemic Stroke, TS01, Mutant pro-urokinase, M5, C1 inhibitor, Safety, Stroke, Tolerability, Ischemia, Cerebral Infarction, Cerebrovascular Disorders, Vascular Diseases, Cardiovascular Diseases, Brain Infarction, Brain Ischemia, Fibrinolytic Agents, Thrombolytic Agents, Molecular Mechanisms of Pharmacological Action, Pharmacologic Actions, Cardiovascular Agents
- Medical subject headings
- Ischemic Stroke, Angioedemas, Hereditary, Stroke, Ischemia, Cerebral Infarction, Cerebrovascular Disorders, Vascular Diseases, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
M5Drug
single point mutant of serine protease prourokinase
C1-inhibitorDrug
a protease inhibitor belonging to the serpin superfamily.
| Study group | Role | What they receive |
|---|---|---|
| mutant pro-urokinase (M5) alone | Experimental | 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. Receives: Drug: M5 |
| Mutant pro-urokinase (M5) and its inhibitor, C1 inhibitor | Experimental | 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. Receives: Drug: M5; Drug: C1-inhibitor |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes to vital signs, routine safety laboratory results, or ECG-findings
Measured: -42d, -14h, -15', 15', 30', 45',60', 90', 10h, 24h, 48h, 7d
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Sep 2012 (estimated)
- Study startSep 2012
- Primary completionOct 2012
- Study completionOct 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Acute Ischemic StrokeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The trial consists of two study parts in which healthy male volunteers will randomly and in a double-blinded manner receive a single dose of M5 or M5-placebo intravenously, with (part II) or without (part I) a preceding single dose of C1-inhibitor.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- TSI, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Koos Burggraaf, MD, PhD, Principal investigator, Center for Human Drug Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01694381
- Sponsor's protocol ID
- TS01-01
- Other IDs
- 2012-002225-30
- Status last verified
- Jan 2021
- First submitted
- 24 Sep 2012
- Last updated
- 19 Jan 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 21779364Pannell 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.
PubMed 17459007Gurewich 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.
PubMed 16839354Liu 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.
PubMed 11964367
Study at a glance
From the registry record, last updated by the sponsor on 19 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1 Trial of Mutant proUK, M5, and Its Inhibitor, C1-inhibitor
- ClinicalTrials.gov ID
- NCT01694381
- Acronym / sponsor ID
- TS01-01
- Conditions
- Acute Ischemic Stroke
- Keywords
- Acute Ischemic Stroke, TS01, Mutant pro-urokinase, M5, C1 inhibitor, Safety, Stroke, Tolerability
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 8 participants (actual)
- Lead sponsor
- TSI, LLCIndustry (pharma, biotech, devices)
- Study start
- Sep 2012 (actual)
- Primary completion
- Oct 2012 (actual)
- Study completion
- Oct 2012 (actual)
- First posted
- 27 Sep 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- The trial consists of two study parts in which healthy male volunteers will randomly and in a double-blinded manner receive a single dose of M5 or M5-placebo intravenously, with (part II) or without (part I) a preceding single dose of C1-inhibitor.
| Arm | Type | Receives |
|---|---|---|
| mutant pro-urokinase (M5) alone | Experimental | Drug: M5In 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 | Experimental | Drug: M5, Drug: C1-inhibitorIn 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. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| M5single point mutant of serine protease prourokinase | Drug | Mutant pro-urokinase (M5) and its inhibitor, C1 inhibitor, mutant pro-urokinase (M5) alone |
| C1-inhibitora protease inhibitor belonging to the serpin superfamily. | Drug | Mutant pro-urokinase (M5) and its inhibitor, C1 inhibitor |
Primary outcome
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
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jan 2021.
- Background: PubMed 21779364Tomasi 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.
- Background: PubMed 17459007Pannell 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.
- Background: PubMed 16839354Gurewich 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.
- Background: PubMed 11964367Liu 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Koos Burggraaf, MD, PhD principal investigator
Center for Human Drug Research
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing M5 and C1-inhibitor in people with Acute Ischemic Stroke, run by TSI, LLC at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 19 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01694381, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jan 2021.