ARTSS-2: Randomized Controlled Trial of Argatroban With Tissue Plasminogen Activator (tPA) for Acute Stroke

• Sponsor: Andrew D. Barreto, MD (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01464788
• Collaborator: The University of Texas Health Science Center, Houston (Other)
• Enrollment: 90
• Location: 1
• Arms: 3
• Duration (Months): 44.3
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke	Drug: Low Dose Argatroban; Drug: High Dose Argatroban; Drug: rt-PA (alteplase)	Phase 2

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

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: ARTSS-2: A Pilot, Phase 2b, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Jun 11, 2015
• Actual Study Completion Date: Jun 11, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low dose Argatroban + 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	Drug: Low Dose 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; Other Names: Argatroban ; Drug: rt-PA (alteplase); rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Experimental: High dose Argatroban + 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	Drug: High Dose 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; Other Names: Argatroban ; Drug: rt-PA (alteplase); rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Active Comparator: rt-PA (alteplase) rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour	Drug: rt-PA (alteplase); rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour

Outcome Measures

Primary Outcome Measures

1. Number of Participants With 0 or 1 on Modified Rankin Scale [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.

2. Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

• 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:

1. Age >80

2. Currently taking oral anticoagulants (regardless of INR)

3. A history of stroke and diabetes.

4. NIHSS > 25.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Health Science Center at Houston	Houston	Texas	United States	77030

Sponsors and Collaborators

• Andrew D. Barreto, MD
• The University of Texas Health Science Center, Houston

Investigators

• Principal Investigator: Andrew Barreto, MD, The University of Texas Health Science Center, Houston

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas Houston Stroke Team Website

Publications

• Barreto 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.
• Sugg RM, Pary JK, Uchino K, Baraniuk S, Shaltoni HM, Gonzales NR, Mikulik R, Garami Z, Shaw SG, Matherne DE, Moyé 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.

• Responsible Party: Andrew D. Barreto, MD, Assistant Professor of Neurology, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT01464788
• Other Study ID Numbers: HSC-MS-11-0464
• First Posted: Nov 4, 2011
• Last Update Posted: May 11, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Andrew D. Barreto, MD, Assistant Professor of Neurology, The University of Texas Health Science Center, Houston: stroke; Argatroban; thrombin-inhibition; thrombolysis; anticoagulation
• Additional relevant MeSH terms: Stroke; Ischemic Stroke; Tissue Plasminogen Activator; Argatroban

Study Results

Participant Flow

Recruitment Details	Patients who have had an ischemic stroke and admitted to the Accident and Emergency Department or Acute Stroke Unit by their treating physician receive IV Recombinant tissue plasminogen activator as per standard treatment, provided they are able to be treated within 4.5 hours of the onset of their stroke symptoms.
Pre-assignment Detail	Patients who met the inclusion criteria received a head CT scan prior to initiation of rt-PA and the Argatroban infusion. If available, patients also underwent intracranial vessel imaging performed before or immediately after IV-tPA bolus (but before Argatroban bolus). Patients could not be randomized until after the CTA demonstrated an occlusion.

Arm/Group Title	Low-dose Argatroban + Rt-PA (Alteplase)	High Dose Argatroban + Rt-PA (Alteplase)	Rt-PA (Alteplase) Only
Arm/Group Description	100 micrograms/kilogram bolus, followed by 1 micrograms/kilogram/minute IV infusion for 48 hours. and Intravenous rt-PA (alteplase) 0.9mg/kg (max dose 90mg); 10% bolus and remaining over 1 hour.	Argatroban: 100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours. and Intravenous rt-PA (alteplase) 0.9mg/kg (max dose 90mg); 10% bolus and remaining over 1 hour.	Intravenous rt-PA (alteplase) 0.9mg/kg (max dose 90mg); 10% bolus and remaining over 1 hour.
Period Title: Overall Study
STARTED	30	31	29
COMPLETED	30	29	29
NOT COMPLETED	0	2	0

Baseline Characteristics

Arm/Group Title	Low Dose Argatroban + Rt-PA	High Dose Argatroban + Rt-PA	Rt-PA (Alteplase)	Total
Arm/Group Description	100 micrograms/kilogram bolus, followed by 1 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	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) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour	Total of all reporting groups
Overall Participants	30	31	29	90
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	11 36.7%	13 41.9%	13 44.8%	37 41.1%
>=65 years	19 63.3%	18 58.1%	16 55.2%	53 58.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.9 (15.1)	67.1 (13.4)	68.9 (15.4)	68.9 (14.6)
Sex: Female, Male (Count of Participants)
Female	13 43.3%	15 48.4%	12 41.4%	40 44.4%
Male	17 56.7%	16 51.6%	17 58.6%	50 55.6%
Region of Enrollment (participants) [Number]
United States	22 73.3%	22 71%	21 72.4%	65 72.2%
United Kingdom	8 26.7%	9 29%	8 27.6%	25 27.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With 0 or 1 on Modified Rankin Scale
Description	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.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

One patient in the high dose group did not receive Argatroban and another in the high dose group was lost to follow up; however, an intention-to-treat analysis was used and all 31 enrolled patients were included.

Arm/Group Title	Low Dose Argatroban + Rt-PA	High Dose Argatroban + Rt-PA	Rt-PA (Alteplase)
Arm/Group Description	100 micrograms/kilogram bolus, followed by 1 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	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) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Measure Participants	30	31	29
Number [participants]	9 30%	10 32.3%	6 20.7%

2. Primary Outcome

Title	Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration
Description	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.
Time Frame	48-hours

Outcome Measure Data

Analysis Population Description

One patient in the high dose group did not receive Argatroban and another in the high dose group was lost to follow up; however, an intention-to-treat analysis was used and all 31 enrolled patients were included.

Arm/Group Title	Low Dose Argatroban + Rt-PA (Alteplase)	High Dose Argatroban + Rt-PA (Alteplase)	Rt-PA (Alteplase)
Arm/Group Description	100 micrograms/kilogram bolus, followed by 1 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	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) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Measure Participants	30	31	29
Number [participants]	4 13.3%	2 6.5%	3 10.3%

Adverse Events

Time Frame	Baseline to day 90
Adverse Event Reporting Description	AE's regardless of whether thought to be associated with the study or IMP under investigation were graded by the investigator and recorded on the Electronic Case Report Form. An AE form was completed for any intracranial Hemorrhage (ICH). A hemorrhage was labeled as symptomatic by either the local principal investigator of the safety monitor.
Arm/Group Title	Low Dose Argatroban + Rt-PA		High Dose Argatroban + Rt-PA		Rt-PA (Alteplase)
Arm/Group Description	100 micrograms/kilogram bolus, followed by 1 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		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) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
All Cause Mortality
	Low Dose Argatroban + Rt-PA		High Dose Argatroban + Rt-PA		Rt-PA (Alteplase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/30 (16.7%)		3/31 (9.7%)		5/29 (17.2%)
Serious Adverse Events
	Low Dose Argatroban + Rt-PA		High Dose Argatroban + Rt-PA		Rt-PA (Alteplase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/30 (50%)		15/31 (48.4%)		14/29 (48.3%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders	0/30 (0%)	0	0/31 (0%)	0	1/29 (3.4%)	1
Cardiac disorders
Cardiac Disorders	0/30 (0%)	0	2/31 (6.5%)	2	1/29 (3.4%)	1
Gastrointestinal disorders
Gastrointestinal disorders	1/30 (3.3%)	1	1/31 (3.2%)	1	1/29 (3.4%)	1
General disorders
Electrolyte imbalance	5/30 (16.7%)	5	3/31 (9.7%)	3	5/29 (17.2%)	5
Death	5/30 (16.7%)	5	3/31 (9.7%)	3	5/29 (17.2%)	5
Infections and infestations
Infections and Infestations	3/30 (10%)	3	1/31 (3.2%)	1	1/29 (3.4%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue	1/30 (3.3%)	1	0/31 (0%)	0	1/29 (3.4%)	1
Nervous system disorders
Nervous system disorders	11/30 (36.7%)	11	10/31 (32.3%)	10	9/29 (31%)	9
Renal and urinary disorders
Renal and Urinary disorders	0/30 (0%)	0	1/31 (3.2%)	1	0/29 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	5/30 (16.7%)	5	5/31 (16.1%)	5	3/29 (10.3%)	3
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	3/30 (10%)	3	0/31 (0%)	0	0/29 (0%)	0
Other (Not Including Serious) Adverse Events
	Low Dose Argatroban + Rt-PA		High Dose Argatroban + Rt-PA		Rt-PA (Alteplase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/30 (90%)		25/31 (80.6%)		20/29 (69%)
Blood and lymphatic system disorders
Electrolyte imbalance	0/30 (0%)	0	1/31 (3.2%)	1	0/29 (0%)	0
Blood - circulation system	0/30 (0%)	0	2/31 (6.5%)	2	0/29 (0%)	0
Hematologic	3/30 (10%)	3	3/31 (9.7%)	3	4/29 (13.8%)	5
Cardiac disorders
Cardiac disorders	5/30 (16.7%)	5	7/31 (22.6%)	8	9/29 (31%)	9
Ear and labyrinth disorders
Ear, Nose and throat (ENT)	0/30 (0%)	0	1/31 (3.2%)	1	0/29 (0%)	0
Endocrine disorders
Endocrine disorders	1/30 (3.3%)	1	1/31 (3.2%)	1	1/29 (3.4%)	1
Gastrointestinal disorders
Gastrointestinal disorders	5/30 (16.7%)	6	8/31 (25.8%)	9	0/29 (0%)	0
General disorders
Dental	0/30 (0%)	0	1/31 (3.2%)	1	0/29 (0%)	0
Immune system disorders
Immune system disorders	2/30 (6.7%)	2	0/31 (0%)	0	0/29 (0%)	0
Infections and infestations
Infections and infestations	7/30 (23.3%)	9	10/31 (32.3%)	12	6/29 (20.7%)	6
Metabolism and nutrition disorders
Metabolism and nutrition disorders	6/30 (20%)	8	2/31 (6.5%)	2	3/29 (10.3%)	4
Musculoskeletal and connective tissue disorders
Musculoskeletal disorder	6/30 (20%)	7	5/31 (16.1%)	5	3/29 (10.3%)	3
Nervous system disorders
Nervous system disorders	16/30 (53.3%)	18	7/31 (22.6%)	10	4/29 (13.8%)	5
Psychiatric disorders
Psychiatric disorders	1/30 (3.3%)	1	0/31 (0%)	0	0/29 (0%)	0
Renal and urinary disorders
Genitourinary	1/30 (3.3%)	1	1/31 (3.2%)	1	1/29 (3.4%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary	8/30 (26.7%)	11	0/31 (0%)	0	4/29 (13.8%)	4
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	9/30 (30%)	11	6/31 (19.4%)	8	4/29 (13.8%)	5

Limitations/Caveats

Study limitations include the open-label design that was necessary due to prohibitive costs of placebo manufacture and sham aPTT tests. Given that vessel imaging was not mandatory, a meaningful analysis of early recanalization rates was not possible.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.