Ischemic StrokePhase 2ARTSS-2NCT01464788
Randomized Controlled Trial of Argatroban With Tissue Plasminogen Activator (tPA) for Acute Stroke
A Phase 2 study testing Low Dose Argatroban, High Dose Argatroban and rt-PA (alteplase) in people with Ischemic Stroke, run by Andrew D. Barreto, MD at 1 site in United States.
Trial summary
Randomized controlled clinical trial to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Ischemic Stroke
- What is being tested?
- Low Dose Argatroban, High Dose Argatroban and rt-PA (alteplase)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2011to 11 Jun 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Disabling Ischemic stroke symptoms with onset < 3 hours treated with IV rt-PA by local standards*.
- or ≤ 4.5 hours according to local standard of care.
- 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 internal carotid artery (ICA) carotid artery (CA), middle cerebral artery (MCA - M1 or M2), posterior cerebral artery (PCA - P1 or P2), distal vertebral or basilar artery.
- TCD criteria: Thrombolysis in brain ischemia (TIBI) 0, 1, 2 or 3 - CT-Angiogram: thrombolysis in myocardial ischemia (TIMI) 0 or 1 * NIHSS ≥ 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with non-contrast head CT alone), but if performed, a clot must be demonstrated.
- For those patients who will undergo repeat CT-Angiogram at 2-3 hours, estimated glomerular filtration rate (eGFR) must be ≥ 60 mL/min/1.73m2.
- Females of childbearing potential must have a negative serum pregnancy test (HCG) prior to the administration of trial medication.
- Signed (written) informed consent by the patient or the patient's legal representative and/or guardian.
Who cannot join
- Patients whom the treating physician is planning (or could plan) to treat with intra-arterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalization.
- Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit.
- National institute health stroke scale (NIHSS) Level of Consciousness score (1a) ≥ 2.
- Pre-existing disability with mRS ≥ 2.
- CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory.
- Any evidence of clinically significant bleeding, or known coagulopathy.
Show all 30Show fewer
- INR >1.5.
- Patients with an elevated activated partial thromboplastin time (aPTT) greater than the upper limit of normal
- Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor (i.e., dabigatran).
- Heparin flush required for an IV line. Line flushes with saline only.
- Any history of intra-cranial hemorrhage, known arteriovenous -malformation or unsecured cerebral aneurysms.
- Significant bleeding episode [e.g. gastrointestinal (GI) or urinary tract] within the 3 weeks before study enrollment.
- Major surgery or serious trauma in last 2 weeks.
- Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks.
- Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months.
- Uncontrolled hypertension [Systolic blood pressure (SBP) > 185 mmHg or diastolic blood pressure (DBP) >110 mmHg] that does not respond to intravenous anti-hypertensive agents.
- Surgical intervention (any reason) anticipated within the next 48 hours.
- Known history of clinically significant hepatic dysfunction or liver disease - including a current history of alcohol abuse.
- Abnormal blood glucose <50 mg/dL (2.7 mmol/L).
- History of primary or metastatic brain tumor.
- Current platelet count < 100,000/mm3.
- Life expectancy < 3 months.
- Patient 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, glycoprotein llb/llla (GPIIb/IIIa) inhibitor or warfarin.
- Participated in any investigational study within 30 days before the first dose of study medication.
- Known hypersensitivity to Argatroban or its agents.
- Additional exclusion criteria if patient presents between 3-4.5 hours:
- Age >80
- Currently taking oral anticoagulants (regardless of INR)
- A history of stroke and diabetes.
- NIHSS > 25.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Texas Health Science Center at Houston
Houston, Texas, 77030
About this study
Official title: ARTSS-2: A Pilot, Phase 2b, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke
Randomized controlled clinical trial to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.
Read the detailed description
Recombinant tissue plasminogen activator (rt-PA), the only proven treatment for acute ischemic stroke, fails to reperfuse brain in most patients with large thrombi. In our Phase 2a low-dose safety study (n=65), the two drugs appeared safe when delivered concomitantly and recanalization rates were greater than historical controls. This study will provide evidence-based hypotheses and data needed to design a larger definitive trial.
The purpose of this trial is to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.
- Conditions
- Ischemic Stroke
- Being tested
- Low Dose Argatroban, High Dose Argatroban, rt-PA (alteplase)
- Keywords
- stroke, Argatroban, thrombin-inhibition, thrombolysis, anticoagulation
- Medical subject headings
- Ischemic Stroke, Stroke
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low Dose ArgatrobanDrug
Also called Argatroban
100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
High Dose ArgatrobanDrug
Also called Argatroban
100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
rt-PA (alteplase)Drug
rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
| Study group | Role | What they receive |
|---|---|---|
| Low dose Argatroban + rt-PA (alteplase) | Experimental | 100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours
and
rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour Receives: Drug: Low Dose Argatroban; Drug: rt-PA (alteplase) |
| High dose Argatroban + rt-PA (alteplase) | Experimental | 100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours
and
rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour Receives: Drug: High Dose Argatroban; Drug: rt-PA (alteplase) |
| rt-PA (alteplase) | Active comparator | rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour Receives: Drug: rt-PA (alteplase) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With 0 or 1 on Modified Rankin Scale
Excellent functional outcome as measured by the number of patients with a 0 or 1 on the modified Rankin Scale (mRS) at day 90 as assessed by study personnel blinded to treatment.
Measured: 90 days
Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration
Symptomatic intracranial hemorrhage (sICH) is defined as any evidence of bleeding on CT scan that in the opinion of the treating physician and/or an independent safety monitor is associated with a clinically significant neurological worsening. A four or more point increase in the NIHSS score from baseline (or last score obtained prior to blood found on CT scan) to subsequent CT scan at the time of potential worsening can be used as a guide by the clinical investigator or safety monitor for what represents a significant worsening in neurologic status but sICH can include any worsening deemed significant by the clinical investigator or independent safety monitor.
Measured: 48-hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2011 (estimated)
- Study startOct 2011
- Primary completion11 Jun 2015
- Study completion11 Jun 2015
Why it stopped: The study was halted prematurely at 90 of 105 planned patients due to the beneficial results of embolectomy clinical trials.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for 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
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- Andrew D. Barreto, MD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Andrew D. Barreto, MD, The University of Texas Health Science Center, Houston
- Investigators
- Andrew Barreto, MD, Principal investigator, The University of Texas Health Science Center, Houston
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01464788
- Sponsor's protocol ID
- HSC-MS-11-0464
- Acronym
- ARTSS-2
- Status last verified
- Mar 2017
- First submitted
- 1 Nov 2011
- Last updated
- 11 May 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Sugg RM, Pary JK, Uchino K, Baraniuk S, Shaltoni HM, Gonzales NR, Mikulik R, Garami Z, Shaw SG, Matherne DE, Moye LA, Alexandrov AV, Grotta JC. Argatroban tPA stroke study: study design and results in the first treated cohort. Arch Neurol. 2006 Aug;63(8):1057-62. doi: 10.1001/archneur.63.8.1057.
PubMed 16908730Barreto AD, Alexandrov AV, Lyden P, Lee J, Martin-Schild S, Shen L, Wu TC, Sisson A, Pandurengan R, Chen Z, Rahbar MH, Balucani C, Barlinn K, Sugg RM, Garami Z, Tsivgoulis G, Gonzales NR, Savitz SI, Mikulik R, Demchuk AM, Grotta JC. The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. Stroke. 2012 Mar;43(3):770-5. doi: 10.1161/STROKEAHA.111.625574. Epub 2012 Jan 5.
PubMed 22223235Barreto AD, Ford GA, Shen L, Pedroza C, Tyson J, Cai C, Rahbar MH, Grotta JC; ARTSS-2 Investigators. Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke). Stroke. 2017 Jun;48(6):1608-1616. doi: 10.1161/STROKEAHA.117.016720. Epub 2017 May 15.
PubMed 28507269
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ARTSS-2: A Pilot, Phase 2b, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke
- ClinicalTrials.gov ID
- NCT01464788
- Acronym / sponsor ID
- ARTSS-2 / HSC-MS-11-0464
- Conditions
- Ischemic Stroke
- Keywords
- stroke, Argatroban, thrombin-inhibition, thrombolysis, anticoagulation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was halted prematurely at 90 of 105 planned patients due to the beneficial results of embolectomy clinical trials.
- Enrolment
- 90 participants (actual)
- Lead sponsor
- Andrew D. Barreto, MDUniversity, hospital or other
- Collaborators
- The University of Texas Health Science Center, Houston
- Study start
- Oct 2011
- Primary completion
- 11 Jun 2015 (actual)
- Study completion
- 11 Jun 2015 (actual)
- First posted
- 4 Nov 2011 (estimated)
- Results
- Posted 11 May 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Randomized controlled clinical trial to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.
Detailed description
Recombinant tissue plasminogen activator (rt-PA), the only proven treatment for acute ischemic stroke, fails to reperfuse brain in most patients with large thrombi. In our Phase 2a low-dose safety study (n=65), the two drugs appeared safe when delivered concomitantly and recanalization rates were greater than historical controls. This study will provide evidence-based hypotheses and data needed to design a larger definitive trial.
The purpose of this trial is to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Low dose Argatroban + rt-PA (alteplase) | Experimental | Drug: Low Dose Argatroban, Drug: rt-PA (alteplase)100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour |
| High dose Argatroban + rt-PA (alteplase) | Experimental | Drug: High Dose Argatroban, Drug: rt-PA (alteplase)100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour |
| rt-PA (alteplase) | Active comparator | Drug: rt-PA (alteplase)rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Disabling Ischemic stroke symptoms with onset < 3 hours treated with IV rt-PA by local standards*.
- 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 internal carotid artery (ICA) carotid artery (CA), middle cerebral artery (MCA - M1 or M2), posterior cerebral artery (PCA - P1 or P2), distal vertebral or basilar artery.
- TCD criteria: Thrombolysis in brain ischemia (TIBI) 0, 1, 2 or 3 - CT-Angiogram: thrombolysis in myocardial ischemia (TIMI) 0 or 1 * NIHSS ≥ 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with non-contrast head CT alone), but if performed, a clot must be demonstrated.
- For those patients who will undergo repeat CT-Angiogram at 2-3 hours, estimated glomerular filtration rate (eGFR) must be ≥ 60 mL/min/1.73m2.
- Females of childbearing potential must have a negative serum pregnancy test (HCG) prior to the administration of trial medication.
Key exclusion criteria (30 listed)
- Patients whom the treating physician is planning (or could plan) to treat with intra-arterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalization.
- Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit.
- National institute health stroke scale (NIHSS) Level of Consciousness score (1a) ≥ 2.
- Pre-existing disability with mRS ≥ 2.
- CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory.
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 |
|---|---|---|
| Low Dose ArgatrobanAlso: Argatroban100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour | Drug | Low dose Argatroban + rt-PA (alteplase) |
| High Dose ArgatrobanAlso: Argatroban100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour | Drug | High dose Argatroban + rt-PA (alteplase) |
| rt-PA (alteplase)rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour | Drug | High dose Argatroban + rt-PA (alteplase), Low dose Argatroban + rt-PA (alteplase), rt-PA (alteplase) |
Primary outcome
Number of Participants With 0 or 1 on Modified Rankin Scale
Time frame: 90 days
Excellent functional outcome as measured by the number of patients with a 0 or 1 on the modified Rankin Scale (mRS) at day 90 as assessed by study personnel blinded to treatment.
Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration
Time frame: 48-hours
Symptomatic intracranial hemorrhage (sICH) is defined as any evidence of bleeding on CT scan that in the opinion of the treating physician and/or an independent safety monitor is associated with a clinically significant neurological worsening. A four or more point increase in the NIHSS score from baseline (or last score obtained prior to blood found on CT scan) to subsequent CT scan at the time of potential worsening can be used as a guide by the clinical investigator or safety monitor for what represents a significant worsening in neurologic status but sICH can include any worsening deemed significant by the clinical investigator or independent safety monitor.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 16908730Sugg RM, Pary JK, Uchino K, Baraniuk S, Shaltoni HM, Gonzales NR, Mikulik R, Garami Z, Shaw SG, Matherne DE, Moye LA, Alexandrov AV, Grotta JC. Argatroban tPA stroke study: study design and results in the first treated cohort. Arch Neurol. 2006 Aug;63(8):1057-62. doi: 10.1001/archneur.63.8.1057.
- Background: PubMed 22223235Barreto AD, Alexandrov AV, Lyden P, Lee J, Martin-Schild S, Shen L, Wu TC, Sisson A, Pandurengan R, Chen Z, Rahbar MH, Balucani C, Barlinn K, Sugg RM, Garami Z, Tsivgoulis G, Gonzales NR, Savitz SI, Mikulik R, Demchuk AM, Grotta JC. The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. Stroke. 2012 Mar;43(3):770-5. doi: 10.1161/STROKEAHA.111.625574. Epub 2012 Jan 5.
- Derived from this study: PubMed 28507269Barreto AD, Ford GA, Shen L, Pedroza C, Tyson J, Cai C, Rahbar MH, Grotta JC; ARTSS-2 Investigators. Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke). Stroke. 2017 Jun;48(6):1608-1616. doi: 10.1161/STROKEAHA.117.016720. Epub 2017 May 15.
- University of Texas Houston Stroke Team WebsiteLink provided by the sponsor.
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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.
Andrew Barreto, MD principal investigator
The University of Texas Health Science Center, Houston
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Low Dose Argatroban, High Dose Argatroban and rt-PA (alteplase) in people with Ischemic Stroke, run by Andrew D. Barreto, MD at 1 site in United States.
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 30 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 11 May 2017. 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 United States. 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?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 May 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Number of Participants With 0 or 1 on Modified Rankin Scale (time frame: 90 days). The study lists 2 primary outcomes in all. 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 NCT01464788, which also lists 3 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 11 May 2017.