Trial Outcomes & Findings for Randomized Controlled Trial of Argatroban With Tissue Plasminogen Activator (tPA) for Acute Stroke (NCT NCT01464788)

Last Updated: 2017-05-11

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

90 participants

Primary outcome timeframe

90 days

Results posted on

2017-05-11

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Low-dose Argatroban + Rt-PA (Alteplase) 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.	High Dose Argatroban + Rt-PA (Alteplase) 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.	Rt-PA (Alteplase) Only Intravenous rt-PA (alteplase) 0.9mg/kg (max dose 90mg); 10% bolus and remaining over 1 hour.
Overall Study STARTED	30	31	29
Overall Study COMPLETED	30	29	29
Overall Study NOT COMPLETED	0	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Low-dose Argatroban + Rt-PA (Alteplase) 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.	High Dose Argatroban + Rt-PA (Alteplase) 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.	Rt-PA (Alteplase) Only Intravenous rt-PA (alteplase) 0.9mg/kg (max dose 90mg); 10% bolus and remaining over 1 hour.
Overall Study Lost to Follow-up	0	1	0
Overall Study Patient had hemorrhage after tPA started	0	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Low Dose Argatroban + Rt-PA n=30 Participants 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	High Dose Argatroban + Rt-PA n=31 Participants 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) n=29 Participants rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour	Total n=90 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	11 Participants n=5 Participants	13 Participants n=7 Participants	13 Participants n=5 Participants	37 Participants n=4 Participants
Age, Categorical >=65 years	19 Participants n=5 Participants	18 Participants n=7 Participants	16 Participants n=5 Participants	53 Participants n=4 Participants
Age, Continuous	70.9 years STANDARD_DEVIATION 15.1 • n=5 Participants	67.1 years STANDARD_DEVIATION 13.4 • n=7 Participants	68.9 years STANDARD_DEVIATION 15.4 • n=5 Participants	68.9 years STANDARD_DEVIATION 14.6 • n=4 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	15 Participants n=7 Participants	12 Participants n=5 Participants	40 Participants n=4 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	16 Participants n=7 Participants	17 Participants n=5 Participants	50 Participants n=4 Participants
Region of Enrollment United States	22 participants n=5 Participants	22 participants n=7 Participants	21 participants n=5 Participants	65 participants n=4 Participants
Region of Enrollment United Kingdom	8 participants n=5 Participants	9 participants n=7 Participants	8 participants n=5 Participants	25 participants n=4 Participants

PRIMARY outcome

Timeframe: 90 days

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Low Dose Argatroban + Rt-PA n=30 Participants 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	High Dose Argatroban + Rt-PA n=31 Participants 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) n=29 Participants rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Number of Participants With 0 or 1 on Modified Rankin Scale	9 participants	10 participants	6 participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Low Dose Argatroban + Rt-PA n=30 Participants 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	High Dose Argatroban + Rt-PA n=31 Participants 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) n=29 Participants rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration	4 participants	2 participants	3 participants

Adverse Events

Low Dose Argatroban + Rt-PA

Serious events: 15 serious events

Other events: 27 other events

Deaths: 5 deaths

High Dose Argatroban + Rt-PA

Serious events: 15 serious events

Other events: 25 other events

Deaths: 3 deaths

Rt-PA (Alteplase)

Serious events: 14 serious events

Other events: 20 other events

Deaths: 5 deaths

Serious adverse events

Serious adverse events
Measure	Low Dose Argatroban + Rt-PA n=30 participants at risk 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	High Dose Argatroban + Rt-PA n=31 participants at risk 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) n=29 participants at risk rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Cardiac disorders Cardiac Disorders	0.00% 0/30 • Baseline to day 90 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.	6.5% 2/31 • Number of events 2 • Baseline to day 90 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.	3.4% 1/29 • Number of events 1 • Baseline to day 90 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.
Blood and lymphatic system disorders Blood and lymphatic system disorders	0.00% 0/30 • Baseline to day 90 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.	0.00% 0/31 • Baseline to day 90 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.	3.4% 1/29 • Number of events 1 • Baseline to day 90 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.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	16.7% 5/30 • Number of events 5 • Baseline to day 90 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.	16.1% 5/31 • Number of events 5 • Baseline to day 90 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.	10.3% 3/29 • Number of events 3 • Baseline to day 90 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.
Nervous system disorders Nervous system disorders	36.7% 11/30 • Number of events 11 • Baseline to day 90 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.	32.3% 10/31 • Number of events 10 • Baseline to day 90 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.	31.0% 9/29 • Number of events 9 • Baseline to day 90 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.
General disorders Electrolyte imbalance	16.7% 5/30 • Number of events 5 • Baseline to day 90 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.	9.7% 3/31 • Number of events 3 • Baseline to day 90 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.	17.2% 5/29 • Number of events 5 • Baseline to day 90 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.
General disorders Death	16.7% 5/30 • Number of events 5 • Baseline to day 90 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.	9.7% 3/31 • Number of events 3 • Baseline to day 90 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.	17.2% 5/29 • Number of events 5 • Baseline to day 90 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.
Gastrointestinal disorders Gastrointestinal disorders	3.3% 1/30 • Number of events 1 • Baseline to day 90 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.	3.2% 1/31 • Number of events 1 • Baseline to day 90 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.	3.4% 1/29 • Number of events 1 • Baseline to day 90 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.
Renal and urinary disorders Renal and Urinary disorders	0.00% 0/30 • Baseline to day 90 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.	3.2% 1/31 • Number of events 1 • Baseline to day 90 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.	0.00% 0/29 • Baseline to day 90 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.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders	10.0% 3/30 • Number of events 3 • Baseline to day 90 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.	0.00% 0/31 • Baseline to day 90 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.	0.00% 0/29 • Baseline to day 90 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.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue	3.3% 1/30 • Number of events 1 • Baseline to day 90 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.	0.00% 0/31 • Baseline to day 90 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.	3.4% 1/29 • Number of events 1 • Baseline to day 90 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.
Infections and infestations Infections and Infestations	10.0% 3/30 • Number of events 3 • Baseline to day 90 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.	3.2% 1/31 • Number of events 1 • Baseline to day 90 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.	3.4% 1/29 • Number of events 1 • Baseline to day 90 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.

Other adverse events

Additional Information

Dr. Andrew Barreto

McGovern Medical School UTHealth - Houston

Phone: 713-500-7002

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place