Safety and Efficacy of Alteplase When Administered in Chinese Patients With Acute Ischemic Hemispheric Stroke Where Thrombolysis is Initiated Between 3 and 4.5 Hours After Stroke Onset

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02930837
• Collaborator: (none)
• Enrollment: 120
• Locations: 11
• Arm: 1
• Actual Duration (Months): 12.8
• Patients Per Site: 10.9
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

To evaluate the safety and efficacy of alteplase when administered between 3 and 4.5 hours after onset of stroke symptoms in Chinese patients with acute ischemic stroke

Condition or Disease	Intervention/Treatment	Phase
Stroke	Drug: alteplase	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Multicenter, Single-arm Trial to Assess Safety and Efficacy of Alteplase (Rt-PA) in Chinese Patients With Acute Ischemic Hemispheric Stroke Where Thrombolysis is Initiated Between 3 and 4.5 Hours After Stroke Onset
• Actual Study Start Date: Nov 15, 2016
• Actual Primary Completion Date: Dec 11, 2017
• Actual Study Completion Date: Dec 11, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: alteplase	Drug: alteplase

Outcome Measures

Primary Outcome Measures

1. The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient [90 days]

   The percentage of patients with modified Rankin Scale (mRS 0-1) (favourable outcome) response at Visit 5 (Day 90) after stroke onset by face-to-face interview with patient. Modified Rankin Scale (mRS): 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead.

2. The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period [90 days]

   The percentage of patients with symptomatic intracranial haemorrhage (sICH) centrally evaluated by data-monitoring committee (DMC) consultants according to European Cooperative Acute Stroke Study (ECASS) III definition within the whole study period. According to the protocol, sICH (ECASS III criteria) was defined as: any apparently extravascular blood in the brain or within the cranium that was associated with clinical deterioration (defined by an increase in the NIHSS score of 4 or more points), or that led to death and that was identified as the predominant cause of the neurological deterioration. sICH event was firstly evaluated by investigator. The DMC consultants evaluated all the patients with NIHSS score increase of at least 4 any time after treatment (including all fatal patients and sICH events evaluated by investigator). Wilson score confidence interval is presented.

Secondary Outcome Measures

1. The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1 [90 days]

   Percentage of global outcome responder at day 90 if he/she obtains the following results at day 90 for the endpoints mRS score of 0 to 1; Barthel Index score >= 95; NIHSS score of 0 to 1; Glasgow Outcome Scale score of 1. mRS: 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead. NIHSS is composed of 11 items, and for each item a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. Glasgow Outcome Score applies to patients with brain damage allowing the objective assessment of their recovery in five categories: 1 Good Recovery, 2 Moderately Disabled, 3 Severely Disabled, 4 Vegetative State, 5 Dead. Barthel Index score to measure performance in activities of daily living with the scale ranging from 0 to 100. Global outcome response is the intersection of above four respective outcomes.

2. Patient Survival Probability at Visit 5 (Censoring at Day 90) [90 days]

   Patient survival probability at visit 5 (censoring at day 90). The percentage of patients who died until Day 1, Day 7, Day 30, Day 90.

3. The Percentage of Patients With Death Related to Stroke or of Neurological Causes [90 days]

   The percentage of patients with death related to stroke or of neurological causes.

4. The Percentage of Patients With Severity of Adverse Events [On-treatment period, that is, within 7 days from the start of bolus]

   The percentage of patients with severity of adverse events (AEs). The percentage of patients with different categories of AEs are presented.

5. The Percentage of Patients With Incidence of Cerebral Herniation and Symptomatic Edema [90 days]

   The percentage of patients with incidence of cerebral herniation and symptomatic edema.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

Age >= 18 years at screening(visit 1A) but <= 80 years Signed and dated written informed consent in accordance with good clinical practice and local legislation prior to admission to the trial Diagnosis of ischemic stroke with a measureable neurological deficit on National Institute of Health Stroke Scale (NIHSS) Thrombolytic therapy can be initiated within 3 to 4.5 hours of stroke onset Further inclusion criteria apply

Exclusion criteria:

Evidence of intracranial haemorrhage (ICH) on the (Computer Tomography) CT/(Magnetic Resonance Imaging)MRI-scan or symptoms suggestive of subarachnoid haemorrhage, even if the CT/MRI-scan is normal Acute bleeding diathesis Severe stroke as assessed clinically( e.g. National Institute of Health Stroke Scale>25) and/ or imaging demonstrates multi-lobar infarction (hypodensity >1/3 cerebral hemisphere) Severe uncontrolled arterial hypertension, e.g. systolic blood pressure>185 mmHg or diastolic blood pressure>110mmHg, or aggressive management (intravenous medication) necessary to reduce blood pressure to these limits Blood glucose <50mg/ dL or >400 mg/dL Any history of prior stroke in previous 3 months, or any history of prior stroke with concomitant diabetes Seizure at stroke onset Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beijing Tiantan Hospital affiliated to Cap Med University	Beijing		China	100050
2	First Hospital of Jilin University	Changchun		China	130031
3	Dongguan People's Hospital	Dongguan		China	523059
4	No.900 Hospital of PLA Joint Logistics Support Force	Fuzhou		China	350025
5	Third Affiliated Hospital of Guangzhou Medical University	Guangzhou		China	510150
6	The First Affiliated Hospital of Jinan University	Guangzhou		China	510630
7	General Hospital of Shenyang Military Region	Shenyang		China	110015
8	Tianjin Medical University General Hospital	Tianjin		China	300052
9	Renmin Hospital of Wuhan University	Wuhan		China	430060
10	Xuzhou Central Hospital	Xuzhou		China	221009
11	Yanbian University Hospital	Yanji		China	133000

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Feb 15, 2017
• Statistical Analysis Plan - Aug 23, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02930837
• Other Study ID Numbers: 135.331
• First Posted: Oct 12, 2016
• Last Update Posted: Aug 5, 2019
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Stroke; Tissue Plasminogen Activator

Study Results

Participant Flow

Recruitment Details	A total of 121 patients were screened from 11 centres across China. Of the screened patients, 1 patient did not meet the study entry criteria. The first patient visit was on 12 December 2016 and the last patient visit was on 11 December 2017.
Pre-assignment Detail	All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they met all strictly implemented inclusion/exclusion criteria. Patients were not to be entered to trial if any one of the specific entry criteria was violated. Rescue medication was allowed for all patients as required.

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Period Title: Overall Study
STARTED	120
COMPLETED	108
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Overall Participants	120
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.1 (10.85)
Sex: Female, Male (Count of Participants)
Female	24 20%
Male	96 80%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	120 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	120 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Baseline NIHSS (Unit on Scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Unit on Scale]	6.9 (4.68)
Baseline NIHSS by class (Count of Participants)
0-3	36 30%
4-9	56 46.7%
10-15	19 15.8%
16-20	7 5.8%
>20	2 1.7%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient
Description	The percentage of patients with modified Rankin Scale (mRS 0-1) (favourable outcome) response at Visit 5 (Day 90) after stroke onset by face-to-face interview with patient. Modified Rankin Scale (mRS): 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Treated Set, worst and last observation carried forward were used for the imputation of efficacy endpoints

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Measure Participants	120
No symptom at all	42.5
No sign. disability	20.8
Slight disability	8.3
Moderate disability	14.2
Moderate Severe disability	1.7
Severe disability	7.5
Dead	5.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alteplase (Rt-PA)
	Comments	A null hypothesis of p ≤40% versus the alternative hypothesis of p >40% was tested using a one sample test at two-sided significance level of 0.05, where p denoted the response rate in Chinese patients who were treated within 3-4.5 h after stroke onset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One-sample test
	Comments
Method of Estimation	Estimation Parameter	Percentage of patients
	Estimated Value	63.3
	Confidence Interval	(2-Sided) 95%; 54.42 to 71.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percentage of patients with Favourable outcome

2. Secondary Outcome

Title	The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1
Description	Percentage of global outcome responder at day 90 if he/she obtains the following results at day 90 for the endpoints mRS score of 0 to 1; Barthel Index score >= 95; NIHSS score of 0 to 1; Glasgow Outcome Scale score of 1. mRS: 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead. NIHSS is composed of 11 items, and for each item a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. Glasgow Outcome Score applies to patients with brain damage allowing the objective assessment of their recovery in five categories: 1 Good Recovery, 2 Moderately Disabled, 3 Severely Disabled, 4 Vegetative State, 5 Dead. Barthel Index score to measure performance in activities of daily living with the scale ranging from 0 to 100. Global outcome response is the intersection of above four respective outcomes.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Treated Set, worst and last observation carried forward were used for the imputation of efficacy endpoints

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Measure Participants	120
Global outcome response	55.0
A response of 0 or 1 on mRS	63.3
A response of least 95 on the Barthel index score	65.8
A response of 0 or 1 on NIHSS	56.7
A Glasgow outcome of 1	69.2

3. Primary Outcome

Title	The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period
Description	The percentage of patients with symptomatic intracranial haemorrhage (sICH) centrally evaluated by data-monitoring committee (DMC) consultants according to European Cooperative Acute Stroke Study (ECASS) III definition within the whole study period. According to the protocol, sICH (ECASS III criteria) was defined as: any apparently extravascular blood in the brain or within the cranium that was associated with clinical deterioration (defined by an increase in the NIHSS score of 4 or more points), or that led to death and that was identified as the predominant cause of the neurological deterioration. sICH event was firstly evaluated by investigator. The DMC consultants evaluated all the patients with NIHSS score increase of at least 4 any time after treatment (including all fatal patients and sICH events evaluated by investigator). Wilson score confidence interval is presented.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Measure Participants	120
Day 0-1	2.5
Day 2-7	0.0
Day 8-30	0.0
Day 31-90	0.0
Day>90	0.0

4. Secondary Outcome

Title	Patient Survival Probability at Visit 5 (Censoring at Day 90)
Description	Patient survival probability at visit 5 (censoring at day 90). The percentage of patients who died until Day 1, Day 7, Day 30, Day 90.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Measure Participants	120
Day 0-1	0.0
Day 2-7	3.3
Day 8-30	1.7
Day 31-90	0.0

5. Secondary Outcome

Title	The Percentage of Patients With Death Related to Stroke or of Neurological Causes
Description	The percentage of patients with death related to stroke or of neurological causes.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Measure Participants	120
Number (95% Confidence Interval) [Percentage of patients]	4.2

6. Secondary Outcome

Title	The Percentage of Patients With Severity of Adverse Events
Description	The percentage of patients with severity of adverse events (AEs). The percentage of patients with different categories of AEs are presented.
Time Frame	On-treatment period, that is, within 7 days from the start of bolus

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Measure Participants	120
Any AE	85.8
Severe AE	20.8
Investigator defined drug-related AEs	12.5
AEs leading to discontinuation of study drug	0.0
Serious AEs	10.0
Results in death	4.2
Immediately life threatening	3.3
Persistent or significant disability/ incapacity	1.7
Required/prolonged hospitalization	5.0
Congenital anomaly/ birth defect	0.0
Other comparable medical criteria	0.0

7. Secondary Outcome

Title	The Percentage of Patients With Incidence of Cerebral Herniation and Symptomatic Edema
Description	The percentage of patients with incidence of cerebral herniation and symptomatic edema.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
Measure Participants	120
Number (95% Confidence Interval) [Percentage of patients]	4.2

Adverse Events

Time Frame	Serious and Other Adverse Events (AEs): From the administration of trial medication until 7 days, up to 7 days. All-Cause Mortality: From the administration of trial medication until 100 days, up to 100 days
Adverse Event Reporting Description	There is 1 patient died during the post-study period (Day 100) which is not relevant to study medication. But this patient has been counted in this table.
Arm/Group Title	Alteplase (Rt-PA)
Arm/Group Description	Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose.
All Cause Mortality
	Alteplase (Rt-PA)
	Affected / at Risk (%)	# Events
Total	7/120 (5.8%)
Serious Adverse Events
	Alteplase (Rt-PA)
	Affected / at Risk (%)	# Events
Total	12/120 (10%)
Cardiac disorders
Acute left ventricular failure	1/120 (0.8%)
Injury, poisoning and procedural complications
Brain herniation	2/120 (1.7%)
Nervous system disorders
Haemorrhage intracranial	3/120 (2.5%)
Cerebral haemorrhage	1/120 (0.8%)
Cerebral infarction	1/120 (0.8%)
Stroke in evolution	1/120 (0.8%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	3/120 (2.5%)
Other (Not Including Serious) Adverse Events
	Alteplase (Rt-PA)
	Affected / at Risk (%)	# Events
Total	72/120 (60%)
Gastrointestinal disorders
Constipation	22/120 (18.3%)
General disorders
Pyrexia	9/120 (7.5%)
Hepatobiliary disorders
Hepatic function abnormal	9/120 (7.5%)
Infections and infestations
Lung infection	10/120 (8.3%)
Pneumonia	10/120 (8.3%)
Metabolism and nutrition disorders
Hypokalaemia	15/120 (12.5%)
Hyperhomocysteinaemia	15/120 (12.5%)
Vitamin B12 deficiency	7/120 (5.8%)
Nervous system disorders
Headache	9/120 (7.5%)
Cerebral artery stenosis	7/120 (5.8%)
Cerebrovascular stenosis	7/120 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.