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

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ClinicalTrials.gov Identifier: NCT01464788
Recruitment Status : Terminated (The study was halted prematurely at 90 of 105 planned patients due to the beneficial results of embolectomy clinical trials.)
First Posted : November 4, 2011
Results First Posted : May 11, 2017
Last Update Posted : May 11, 2017
Sponsor:
Collaborator:
The University of Texas Health Science Center, Houston
Information provided by (Responsible Party):
Andrew D. Barreto, MD, The University of Texas Health Science Center, Houston

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Outcomes Assessor);   Primary Purpose: Treatment
Condition Ischemic Stroke
Interventions Drug: Low Dose Argatroban
Drug: High Dose Argatroban
Drug: rt-PA (alteplase)
Enrollment 90
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 Details 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
Hide 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
Reason Not Completed
Lost to Follow-up             0             1             0
Patient had hemorrhage after tPA started             0             1             0
Arm/Group Title Low Dose Argatroban + Rt-PA High Dose Argatroban + Rt-PA Rt-PA (Alteplase) Total
Hide 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 Number of Baseline Participants 30 31 29 90
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 31 participants 29 participants 90 participants
<=18 years
0
   0.0%
0
   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, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants 31 participants 29 participants 90 participants
70.9  (15.1) 67.1  (13.4) 68.9  (15.4) 68.9  (14.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 31 participants 29 participants 90 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  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 30 participants 31 participants 29 participants 90 participants
United States 22 22 21 65
United Kingdom 8 9 8 25
1.Primary Outcome
Title Number of Participants With 0 or 1 on Modified Rankin Scale
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Overall Number of Participants Analyzed 30 31 29
Measure Type: Number
Unit of Measure: participants
9 10 6
2.Primary Outcome
Title Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Overall Number of Participants Analyzed 30 31 29
Measure Type: Number
Unit of Measure: participants
4 2 3
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)
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/30 (16.67%)      3/31 (9.68%)      5/29 (17.24%)    
Show Serious Adverse Events Hide 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 (50.00%)      15/31 (48.39%)      14/29 (48.28%)    
Blood and lymphatic system disorders       
Blood and lymphatic system disorders  1  0/30 (0.00%)  0 0/31 (0.00%)  0 1/29 (3.45%)  1
Cardiac disorders       
Cardiac Disorders  1  0/30 (0.00%)  0 2/31 (6.45%)  2 1/29 (3.45%)  1
Gastrointestinal disorders       
Gastrointestinal disorders  1  1/30 (3.33%)  1 1/31 (3.23%)  1 1/29 (3.45%)  1
General disorders       
Electrolyte imbalance  1  5/30 (16.67%)  5 3/31 (9.68%)  3 5/29 (17.24%)  5
Death  1  5/30 (16.67%)  5 3/31 (9.68%)  3 5/29 (17.24%)  5
Infections and infestations       
Infections and Infestations  1  3/30 (10.00%)  3 1/31 (3.23%)  1 1/29 (3.45%)  1
Musculoskeletal and connective tissue disorders       
Musculoskeletal and connective tissue  1  1/30 (3.33%)  1 0/31 (0.00%)  0 1/29 (3.45%)  1
Nervous system disorders       
Nervous system disorders  1 [1]  11/30 (36.67%)  11 10/31 (32.26%)  10 9/29 (31.03%)  9
Renal and urinary disorders       
Renal and Urinary disorders  1  0/30 (0.00%)  0 1/31 (3.23%)  1 0/29 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Respiratory, thoracic and mediastinal disorders  1  5/30 (16.67%)  5 5/31 (16.13%)  5 3/29 (10.34%)  3
Skin and subcutaneous tissue disorders       
Skin and subcutaneous tissue disorders  1  3/30 (10.00%)  3 0/31 (0.00%)  0 0/29 (0.00%)  0
1
Term from vocabulary, SNOMED CT
Indicates events were collected by systematic assessment
[1]
includes: symptomatic intracranial hemorrhage, neurological worsening, cerebral edema/ brain herniation, seizures, etc.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
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 (90.00%)      25/31 (80.65%)      20/29 (68.97%)    
Blood and lymphatic system disorders       
Electrolyte imbalance  1  0/30 (0.00%)  0 1/31 (3.23%)  1 0/29 (0.00%)  0
Blood - circulation system  1  0/30 (0.00%)  0 2/31 (6.45%)  2 0/29 (0.00%)  0
Hematologic  1  3/30 (10.00%)  3 3/31 (9.68%)  3 4/29 (13.79%)  5
Cardiac disorders       
Cardiac disorders  1  5/30 (16.67%)  5 7/31 (22.58%)  8 9/29 (31.03%)  9
Ear and labyrinth disorders       
Ear, Nose and throat (ENT)  1  0/30 (0.00%)  0 1/31 (3.23%)  1 0/29 (0.00%)  0
Endocrine disorders       
Endocrine disorders  1  1/30 (3.33%)  1 1/31 (3.23%)  1 1/29 (3.45%)  1
Gastrointestinal disorders       
Gastrointestinal disorders  1  5/30 (16.67%)  6 8/31 (25.81%)  9 0/29 (0.00%)  0
General disorders       
Dental  1  0/30 (0.00%)  0 1/31 (3.23%)  1 0/29 (0.00%)  0
Immune system disorders       
Immune system disorders  1  2/30 (6.67%)  2 0/31 (0.00%)  0 0/29 (0.00%)  0
Infections and infestations       
Infections and infestations  1  7/30 (23.33%)  9 10/31 (32.26%)  12 6/29 (20.69%)  6
Metabolism and nutrition disorders       
Metabolism and nutrition disorders  1  6/30 (20.00%)  8 2/31 (6.45%)  2 3/29 (10.34%)  4
Musculoskeletal and connective tissue disorders       
Musculoskeletal disorder  1  6/30 (20.00%)  7 5/31 (16.13%)  5 3/29 (10.34%)  3
Nervous system disorders       
Nervous system disorders  1  16/30 (53.33%)  18 7/31 (22.58%)  10 4/29 (13.79%)  5
Psychiatric disorders       
Psychiatric disorders  1  1/30 (3.33%)  1 0/31 (0.00%)  0 0/29 (0.00%)  0
Renal and urinary disorders       
Genitourinary  1  1/30 (3.33%)  1 1/31 (3.23%)  1 1/29 (3.45%)  1
Respiratory, thoracic and mediastinal disorders       
Pulmonary  1  8/30 (26.67%)  11 0/31 (0.00%)  0 4/29 (13.79%)  4
Skin and subcutaneous tissue disorders       
Skin and subcutaneous tissue disorders  1  9/30 (30.00%)  11 6/31 (19.35%)  8 4/29 (13.79%)  5
1
Term from vocabulary, SNOMED CT
Indicates events were collected by systematic assessment
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.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Andrew Barreto
Organization: McGovern Medical School UTHealth - Houston
Phone: 713-500-7002
Responsible Party: Andrew D. Barreto, MD, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier: NCT01464788     History of Changes
Other Study ID Numbers: HSC-MS-11-0464
First Submitted: November 1, 2011
First Posted: November 4, 2011
Results First Submitted: January 26, 2017
Results First Posted: May 11, 2017
Last Update Posted: May 11, 2017