Contact information
Type
Scientific
Primary contact
Mrs Claire Macdonald
ORCID ID
Contact details
Newcastle Clinical Trials Unit
Institute of Health and Society
4th Floor William Leech Building
Framlington Place
Newcastle Upon Tyne
NE2 4HH
United Kingdom
-
claire.macdonald@newcastle.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
13646
Study information
Scientific title
ARTSS-2: A pilot, phase IIb, randomised, multi-center trial of Argatroban in combination with recombinant tissue plasminogen activator for acute stroke
Acronym
ARTSS-2
Study hypothesis
A pilot, phase IIb, randomised, multicentre trial of Argatroban in combination with recombinant tissue plasminogen activator for acute stroke.
Recombinant tissue plasminogen activator (rtPA), the only proven treatment for acute ischemic stroke, fails to reperfuse the brain in most patients with large thrombi. In a Phase IIa low dose safety study (n=65), conducted by University of Texas Houston, delivering Argatroban with rtPA indicated that both drugs appear safe when delivered concomitantly and recanalisation rates were greater than with historical controls.
The purpose of the trial is to estimate the overall treatment benefit (improvement in disability) among stroke patients treated with rtPA (Alteplase) who are randomised to receive either lowdose Argatroban, highdose Argatroban or neither.
This study will provide evidence based hypotheses and data needed to design a larger definitive trial. The study will be conducted in six hospitals across the UK and will recruit males and females over 18 years of age with acute ischemic stroke.
Ethics approval
NRES Committee North West Greater Manchester South, 24/07/2012, ref:12/NW/0425
Study design
Pilot phase IIb randomised multicentre trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Stroke
Intervention
Three treatment arms (n=35 each) will be enrolled:
1. Low-dose Argatroban* (1.0µg/kg/min continuous infusion of Argatroban, preceded by a 100 µg/kg bolus administered over 3-5 minutes Infusion will be titrated to achieve an aPTT of 1.75 times baseline - not to exceed 10 µg/kg/min) + usual care IV-rt-PA;
2. High-dose Argatroban* 3.0 µg/kg/min continuous infusion of Argatroban, preceded by a 100 µg/kg bolus administered over 3-5 minutes Infusion will be titrated to achieve an aPTT of 2.25 times baseline - not to exceed 10 µg/kg/min) + usual care IV-rt-PA;
3. Intravenous-rt-PA alone (usual care).
*Argatroban infusions will continue for a maximum of 48 hours.
During the course of the treatment, patients will be evaluated via Computed Tomography (CT) angiogram, CT scans, vital signs, laboratory measurements, and neurological and unctional outcomes. Patients will also be evaluated at 24 hours following the onset of the stroke, Day 7 or discharge (whichever comes first) and at day 90.
Sponsor's EEA representative:
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
email: Trust.R&D@nuth.nhs.uk
Intervention type
Drug
Phase
Phase II
Drug names
Argatroban
Primary outcome measure
Excellent functional outcome as measured by the percentage of patients with a 0 or 1 on the modified Rankin Scale (mRS) at day 90 as assessed by study personnel blinded to treatment
Secondary outcome measures
1. Safety as measured by the incidence of:
1.1. Symptomatic intracranial haemorrhage (sICH)
1.2. Parenchymal Haemorrhage 2 (PH-2)
1.3. Major systemic haemorrhage.
2. Rates and completeness of arterial recanalisation assessed at baseline and 2-3 hours by CT-Angiogram (CTA)
3. Neurological deficits improvement from baseline to 2 hours, 24 hours, end of Argatroban infusion, Day 7/discharge and day 90 as measured by NIHSS
4. Quality of Life obtained by standard gamble, time-trade-off method and visual analogue scale (VAS)
5. Cost and cost-effectiveness analysis
5.1 Medical costs associated with each treatment
5.2 Incremental cost-effectiveness ratio (change in cost divided by quality of life gained)
Overall trial start date
01/03/2013
Overall trial end date
31/07/2014
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Disabling ischemic stroke symptoms with onset < 3 hours treated with IV rtPA (alteplase) by local standards*.
* or <= 4.5 hours according to local standard of care
2. Age >= 18
3. National Institutes of Health Stroke Scale (NIHSS) >= 10* or any NIHSS with an intracranial clot should be demonstrated on neurovascular imaging (TCD or CTA) in any one of the following areas: distal ICA, MCA (M1 or M2), PCA (P1 or P2), distal vertebral or basilar artery
3.1. TCD criteria: TIBI 0, 1, 2 or 3
3.2. CTAngiogram: TIMI 0 or 1
* NIHSS = 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with noncontrast head CT alone), but if performed, a clot must be demonstrated
4. For those patients who will undergo repeat CT Angiogram at 23 hours, estimated glomerular filtration rate (eGFR) must be >= 60 mL/min/1.73m2
5. Females of childbearing potential must have a negative serum pregnancy test prior to the administration of trial medication
6. Signed (written) informed consent by the patient or the patients legal representative and/or guardian
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
UK Sample Size: 50
Participant exclusion criteria
1. Patients whom the treating physician is planning (or could plan) to treat with intraarterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalisation
2. Evidence of intracranial haemorrhage (ICH) on baseline CT scan or diagnosis of a nonvascular cause of neurologic deficit
3. NIHSS Level of Consciousness score (1a) >= 2
4. Preexisting disability with mRS >= 2
5. CT scan findings of hypoattenuation of the xray signal (hypodensity) involving >= 1/3 of the MCA territory
6. Any evidence of clinically significant bleeding, or known coagulopathy
7. INR >1.5
8. Patients with an elevated activated partial thromboplastin time (aPTT) greater than the upper limit of normal
9. Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor
10. Heparin flush required for an IV line. Line flushes with saline only.
11. Any history of intracranial haemorrhage, known arteriovenous malformation or unsecured cerebral aneurysms
12. Significant bleeding episode within the 3 weeks before study enrollment
13. Major surgery or serious trauma in last 2 weeks
14. Patients who have had an arterial puncture at a noncompressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks
15. Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months
16. Uncontrolled hypertension (SBP > 185 mmHg or DBP >110 mmHg) that does not respond to intravenous antihypertensive agents
17. Surgical intervention (any reason) anticipated within the next 48 hours
18. Known history of clinically significant hepatic dysfunction or liver disease including a current history of alcohol abuse
19. Abnormal blood glucose <50 mg/dL (2.7 mmol/L)
20. History of primary or metastatic brain tumor
21. Current platelet count < 100,000/mm3
22. Life expectancy < 3 months
23.Patients who, in the judgment of the investigator, needs to be on concomitant (i.e., during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, GPIIb/IIIa inhibitor or warfarin. [*Caveat: However, if in the judgment of the investigator a patient needs to be anticoagulated, but this can be deferred for 48 hours, then they could be included.]
24. Currently participating or has participated in any investigational drug or device study within 30 days before the first dose of study medication
25. Known hypersensitivity to Argatroban or its agents
26. Additional exclusion criteria if patient presents between 34.5 hours:
26.1. Age >80
26.2. Currently taking oral anticoagulants (regardless of INR)
26.3. A history of stroke and diabetes.
26.4. NIHSS > 25
Recruitment start date
01/03/2013
Recruitment end date
31/07/2014
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Newcastle Clinical Trials Unit
Newcastle Upon Tyne
NE2 4HH
United Kingdom
Sponsor information
Organisation
The University of Texas Health Science Center at Houston (USA)
Sponsor details
7000 Fannin
Suite 1200
Houston
Texas
77030
United States of America
Sponsor type
University/education
Website
Funders
Funder type
Government
Funder name
National Institutes of Health (USA)
Alternative name(s)
NIH
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United States of America
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2015 results in: https://www.ncbi.nlm.nih.gov/pubmed/26278031