To test the safety and preliminary efficacy of a dual acute thrombolytic treatment consisting of a small intravenous (IV) bolus of alteplase followed by IV infusion of m-pro-urokinase against usual treatment with IV alteplase in patients presenting…
ID
Source
Brief title
Condition
- Central nervous system vascular disorders
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome is any post-intervention intracranial haemorrhage on MRI
according to the Heidelberg Bleeding Classification within 24-48 hours of study
drug administration.
Secondary outcome
Secondary clinical outcomes
- Score on the National Institute of Health Stroke Scale (NIHSS) assessed at 24
hours and at 5-7 days post-treatment.
- Improvement of at least 4 points on NIHSS at 24 hours compared to baseline,
or (near) complete recovery (NIHSS 0 or 1).
- Score on the modified Rankin Scale (mRS) assessed at 30 days (-7 days to +14
days) post-treatment.
- All possible dichotomizations of the mRS as assessed at 30 days (-7 days to
+14 days) post-treatment. This includes complete recovery (mRS 0 vs 1-6),
excellent functional outcome (mRS 0-1 vs 2-6), good functional outcome (mRS 0-3
vs 4-6), and handicapped survival (mRS 0-4 vs 5-6) and survival in any
condition (mRS 0-5 vs 6).
Secondary neuroimaging outcomes
- Infarct volume measured with MRI (DWI) at 24-48 hours post-treatment.
- Change (pre-treatment vs. post-treatment) in abnormal perfusion volume based
on TTP/MTT maps measured with CT perfusion at baseline and MRI at 24-48 hours
post treatment.
Secondary blood biomarker outcomes
- Secondary blood biomarkers of thrombolysis at 1 hour, 3 hours and 24 hours
after treatment, including d-dimeres and fibrinogen.
- Change in blood biomarkers of thrombolysis from baseline to 24 hours,
including d-dimeres and fibrinogen.
Safety outcomes
- Symptomatic intracranial hemorrhage (sICH) according to the Heidelberg
Bleeding Classification within the follow-up period defined by the last
follow-up contact at 30 days5
- Death from any cause including intracranial hemorrhage within 30 days (-7
days or +14 days) (this is equivalent to handicapped survival (mRS 0-4 vs 5-6)
and survival in any condition (mRS 0-5 vs 6).
- Major extracranial hemorrhage according to the ISTH criteria within 24 hours
of study drug administration.
Background summary
Recombinant tissue plasminogen activator alteplase is the only FDA-approved
thrombolytic agent for thrombolytic treatment of ischemic stroke. Its
effectiveness is limited and the occurrence of intra- and extracerebral
hemorrhage is a major limitation. Dual thrombolytic therapy with low dose
alteplase pre-treatment followed by a mutant pro-urokinase (m-pro-urokinase,
HisproUK), which does not lyse hemostatic fibrin, has a significant potential
to be safer and more efficacious than the FDA-approved regimen of standard dose
alteplase alone.
Study objective
To test the safety and preliminary efficacy of a dual acute thrombolytic
treatment consisting of a small intravenous (IV) bolus of alteplase followed by
IV infusion of m-pro-urokinase against usual treatment with IV alteplase in
patients presenting with ischemic stroke.
Study design
This is a multicentre, phase II, , randomized clinical trial with open-label
treatment, adaptive design for dose optimization and blinded outcome
assessment, comparing low dose IV alteplase + two different dosages of IV
m-pro-urokinase with usual thrombolytic treatment.
Intervention
Bolus of IV alteplase (5 mg) followed by continuous IV infusion of the study
medication: m-pro-urokinase 40 mg/hr during 60 minutes (initial dose).
Depending on results of interim analyses, the alternate dose may be revised to
a lower dose (30 mg/hr during 60 minutes) or a higher dose (50mg/hr during 60
minutes). Usual care consists of a bolus of IV alteplase followed by
continuous infusion of alteplase in a total dose of 0.9 mg/kg with a maximum of
90 mg.
Study burden and risks
M-pro-urokinase has an improved safety profile and similar effectiveness as
alteplase in ex- and in-vivo experimental studies as well as in a clinical
study in myocardial infarction. The informed consent procedure takes on average
one hour, both in proxies and in stroke patients themselves. For every 15
minutes of delay of IV thrombolytic treatment, the likelihood of a good
functional outcome is reduced by 1% (absolute risk difference). We will
therefore defer consent and ask for written informed consent as early as deemed
appropriate according to the treating physician.
Wytemaweg 80
Rotterdam 3015CN
NL
Wytemaweg 80
Rotterdam 3015CN
NL
Listed location countries
Age
Inclusion criteria
- A clinical diagnosis of acute ischemic stroke;
- A score of at least 1 on the NIH Stroke Scale;
- CT or MRI ruling out intracranial hemorrhage;
-Treatment is possible
o within 4.5 hours from symptom onset or last seen well, or
o between 4.5 to 12 hours from symptom onset or last seen well, if the infarct
core is less than 25 mL and a penumbra is at least the same size as the infarct
core (i.e. total ischemic volume/infarct core mismatch >= 2.0),5 or 3)
* In case of lacunar syndrome,25 if there is a diffusion-weighted imaging and
FLAIR mismatch4;*
- Meet the criteria for standard treatment for IV alteplase according to
national guidelines;
- Contra-indication for an MRI scan (e.g., an MRI incompatible pacemaker and
metal foreign bodies)
- Age of 18 years or older;
- Written informed consent (deferred).
Exclusion criteria
- Candidate for endovascular thrombectomy (i.e., no proximal intracranial large
artery occlusion on CTA or MRA)
- Contra-indication for treatment with IValteplase
- Pre-stroke disability which interferes with the assessment of functional
outcome at 30 days, i.e. mRS > 2.
- Known pregnancy or if pregnancy cannot be excluded, i.e. adequate use of any
contraceptive method (e.g. intrauterine devices) or sterilization of the
subject herself
- Participation in medical or surgical intervention trials other than DUMAS (or
MR ASAP/ARTEMIS)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-004448-42-NL |
| CCMO | NL68252.078.18 |
| Other | NL7409 (NTR7634) en NCT04256473 |