Post-marketing Clinical Study of Alteplase for Acute Ischemic Stroke （Japan Alteplase Clinical Trial Ⅱ：J-ACT Ⅱ）

• Sponsor: Mitsubishi Tanabe Pharma Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00412867
• Collaborator: Kyowa Kirin Co., Ltd. (Industry)
• Enrollment: 58
• Location: 1
• Arm: 1
• Duration (Months): 18
• Patients Per Site Per Month: 3.2

Study Details

Study Description

Brief Summary

The purpose of this study is to confirm the efficacy and safety of intravenously administered alteplase in patients with acute ischemic stroke based on the rate of recanalization assessed by magnetic resonance angiography (MRA), the rate of patients with a modified Rankin Scale (mRS) score of 0-1, and the incidence of symptomatic intracranial hemorrhage (sICH), in comparison with the data reported in the current literature.

Condition or Disease	Intervention/Treatment	Phase
Stroke	Drug: Alteplase	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Post-marketing Clinical Study of Alteplase for Acute Ischemic Stroke (Phase 4)
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alteplase 0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour	Drug: Alteplase; 0.6 mg/kg of Alteplase is intravenously administered; Other Names: Tissue Plasminogen Activator GRTPA ACTIVACIN

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Valid Recanalization Assessed by Magnetic Resonance Angiography (MRA) [within 6 hours, from 24 to 36 hours after onset]

   Recanalization was evaluated according to the modified Mori grade: Grade 0, no reperfusion; Grade 1, movement of thrombus not associated with any flow improvement; Grade 2, partial (branch) recanalization in <50% of the branches in the occluded-arterial territory; Grade 3, nearly complete recanalization with reperfusion in ≥50% of the branches in the occluded-arterial territory. The recanalization rate was estimated by regarding Grades 2 and 3 as valid recanalization.

2. Number of Patients With a Modified Rankin Scale (mRS) Score of 0-1 a 3 Months [3 months after onset]

   The number of patients with an mRS score of 0-1. The mRS has 6 items, where 0 = No symptoms at all, 1 = No significant disability despite symptoms, 2 = Slight disability, 3 = Moderate disability, 4 = Moderately severe disability, 5 = Severe disability. The higher scores reflect increased disability.

3. Number of Patients With Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours [within 36 hours after starting treatment]

   The number of patients with sICH

Secondary Outcome Measures

1. National Institutes of Health Stroke Scale (NIHSS) Score [within 6 hours, from 24 to 36 hours, 3 months after onset.]

   from 0 (normal) to 40 (most severe)

2. Barthel Index (BI) [the day of discharge within 3 months after onset, and 3 months after onset]

   from 100 (Independent) to 0 (full assistance)

3. Percentage of Participants With Adverse Events and Adverse Drug Reactions [3 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with acute ischemic stroke within 3 hours of onset, with a clearly defined time of onset.

• Patients who have been revealed to have occlusion on one side of the middle cerebral artery (M1 or M2 portion) on MRA before the start of treatment.

• Patients for whom consent has been obtained from either themselves or from their legally acceptable representatives in written form.

Exclusion Criteria:

• Patients with very light neurological symptoms (an NIHSS score of <= 4) or with rapidly improving symptoms before the start of treatment.

• Patients with serious neurological disorders (an NIHSS score of >= 23), or serious consciousness disorders (a Japan Coma Scale score of >= 100) before the start of treatment.

• Patients with functional disorders (a mRS score of >= 2) before stroke onset.

• Patients who have been administered drugs that are not allowed to be administered concomitantly with alteplase (other thrombolytic agents) after the stroke onset.

• Patients who have been revealed to have extensive early ischemic change (an Alberta Stroke Program Early CT score of <= 6) on computed tomography (CT) before treatment.

• Patients who have been revealed to have obvious occlusion in the blood vessel except for the middle cerebral artery on MRA before treatment.

• Patients who are forbidden to undergo magnetic resonance imaging (MRI).

• Patients who are defined as having cerebral hemorrhage or subarachnoid hemorrhage (SAH) on CT before treatment.

• Patients whose symptoms suggest SAH.

• Patients with hemorrhage (gastrointestinal hemorrhage, urinary hemorrhage, retroperitoneal hemorrhage, or hemoptysis).

• Patients with a platelet count below 100,000/mm3.

• Patients with fasting blood glucose levels of < 50 mg/dL or > 400 mg/dL.

• Patients whose activated partial thromboplastin time (APTT) is prolonged due to heparin administration within 48 hours before stroke onset.

• Patients who have been administered oral anticoagulants with values of the international normalized ratio of prothrombin time (PT-INR) of > 1.7.

• Patients who have a systolic blood pressure of > 185 mmHg or a diastolic blood pressure of > 110 mmHg.

• Patients who need antihypertensive therapy (e.g. continuous infusion of antihypertensive drug etc.) to lower blood pressure below those limits under the preceding article.

• Patients who have a history of intracranial hemorrhage, or who have a disease considered to increase the risk of intracranial hemorrhage such as an intracranial tumor, cerebral aneurysm, or intracranial arteriovenous malformation, etc.

• Patients who have a history of stroke within 3 months before onset.

• Patients who were operated on or injured their head or spinal cord within 3 months before onset.

• Patients who have a history of gastrointestinal or urinary tract hemorrhage within 21 days before onset.

• Patients who had a major surgery or serious trauma (except for head or spinal cord trauma) within 14 days before onset.

• Patients who have a history of organ biopsy, arterial puncture, or lumbar puncture within 10 days before onset.

• Patients with severe hepatic dysfunction or severe renal dysfunction.

• Patients with acute pancreatitis.

• Patients who had a seizure at the onset of stroke.

• Patients who have a history of hypersensitivity to protein preparations.

• Patients who are lactating, pregnant, probably pregnant, or menstruating.

• Patients with malignant tumors.

• Patients with acute myocardial infarction (AMI) or pericarditis after AMI.

• Patients with concurrent infectious endocarditis, moyamoya disease (Willis circle occlusion syndrome), aortic dissection, or neck trauma, etc.

• Patients with strong suspicion of ischemic cerebrovascular disorder caused by non-thrombotic occlusion or any other hemodynamic condition.

• Patients judged to be difficult in monitoring for 3 months by their physician.

• Patients who have participated in other clinical trials during the last 3 months.

• In addition to the above exclusion criteria, patients judged to be inadequate to participate in this study by their physician.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational site 01	Hokkaido		Japan

Sponsors and Collaborators

• Mitsubishi Tanabe Pharma Corporation
• Kyowa Kirin Co., Ltd.

Investigators

• Study Chair: Takenori Yamaguchi, M.D., National Cerebral and Cardiovascular Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mitsubishi Tanabe Pharma Corporation
• ClinicalTrials.gov Identifier: NCT00412867
• Other Study ID Numbers: 527-0611; NCT00412945
• First Posted: Dec 19, 2006
• Last Update Posted: Jan 19, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by Mitsubishi Tanabe Pharma Corporation: Cerebral Infarction; acute ischemic stroke; Brain ischemia
• Additional relevant MeSH terms: Stroke; Ischemic Stroke; Tissue Plasminogen Activator; Plasminogen

Study Results

Participant Flow

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Period Title: Overall Study
STARTED	58
COMPLETED	58
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Overall Participants	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.3 (11.5)
Sex: Female, Male (Count of Participants)
Female	23 39.7%
Male	35 60.3%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Valid Recanalization Assessed by Magnetic Resonance Angiography (MRA)
Description	Recanalization was evaluated according to the modified Mori grade: Grade 0, no reperfusion; Grade 1, movement of thrombus not associated with any flow improvement; Grade 2, partial (branch) recanalization in <50% of the branches in the occluded-arterial territory; Grade 3, nearly complete recanalization with reperfusion in ≥50% of the branches in the occluded-arterial territory. The recanalization rate was estimated by regarding Grades 2 and 3 as valid recanalization.
Time Frame	within 6 hours, from 24 to 36 hours after onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Measure Participants	58
within 6 hours after onset	30 51.7%
from 24 to 36 hours after onset	40 69%

2. Primary Outcome

Title	Number of Patients With a Modified Rankin Scale (mRS) Score of 0-1 a 3 Months
Description	The number of patients with an mRS score of 0-1. The mRS has 6 items, where 0 = No symptoms at all, 1 = No significant disability despite symptoms, 2 = Slight disability, 3 = Moderate disability, 4 = Moderately severe disability, 5 = Severe disability. The higher scores reflect increased disability.
Time Frame	3 months after onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Measure Participants	58
Number [participants]	27 46.6%

3. Primary Outcome

Title	Number of Patients With Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours
Description	The number of patients with sICH
Time Frame	within 36 hours after starting treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Measure Participants	58
Number [participants]	0 0%

4. Secondary Outcome

Title	National Institutes of Health Stroke Scale (NIHSS) Score
Description	from 0 (normal) to 40 (most severe)
Time Frame	within 6 hours, from 24 to 36 hours, 3 months after onset.

Outcome Measure Data

Analysis Population Description

Two participants (from 24 to 36 hours) and four participants (3 months after onset) were excluded from analysis because of dropouts or missing data

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Measure Participants	58
within 6 hours	8.5
from 24 to 36 hours	7.0
3 months after onset	1.5

5. Secondary Outcome

Title	Barthel Index (BI)
Description	from 100 (Independent) to 0 (full assistance)
Time Frame	the day of discharge within 3 months after onset, and 3 months after onset

Outcome Measure Data

Analysis Population Description

Eleven participants (the day of discharge within 3 months after onset) and four participants (3 months after onset) were excluded from analysis because of dropouts or missing data

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Measure Participants	58
the day of discharge within 3 months after onset	76.2 (32.4)
3 months after onset	77.8 (33.2)

6. Secondary Outcome

Title	Percentage of Participants With Adverse Events and Adverse Drug Reactions
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alteplase
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
Measure Participants	58
Percentage of Patients with Adverse Events	96.6
Percentage of Patients with Adverse Drug Reactions	41.4

Adverse Events

Time Frame	3 months
Arm/Group Title	Alteplase (Non-Haemorrhage)		Alteplase (Haemorrhage)
Arm/Group Description	0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour		0.6mg/kg intravenous alteplase with 10% being administered as a bolus followed by continuous infusion of the remainder over 1 hour
All Cause Mortality
	Alteplase (Non-Haemorrhage)		Alteplase (Haemorrhage)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Alteplase (Non-Haemorrhage)		Alteplase (Haemorrhage)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/58 (20.7%)		1/58 (1.7%)
Cardiac disorders
Cardiac failure	2/58 (3.4%)		0/58 (0%)
Sick sinus syndrome	2/58 (3.4%)		0/58 (0%)
Acute left ventricular failure	1/58 (1.7%)		0/58 (0%)
Gastrointestinal disorders
Inguinal hernia	1/58 (1.7%)		0/58 (0%)
Melaena	0/58 (0%)		1/58 (1.7%)
Hepatobiliary disorders
Cholecystitis	1/58 (1.7%)		0/58 (0%)
Infections and infestations
Pneumonia	2/58 (3.4%)		0/58 (0%)
Septic shock	1/58 (1.7%)		0/58 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer	1/58 (1.7%)		0/58 (0%)
Uterine leiomyoma	1/58 (1.7%)		0/58 (0%)
Nervous system disorders
Cerebral infarction	4/58 (6.9%)		0/58 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/58 (1.7%)		0/58 (0%)
Other (Not Including Serious) Adverse Events
	Alteplase (Non-Haemorrhage)		Alteplase (Haemorrhage)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/58 (87.9%)		25/58 (43.1%)
Cardiac disorders
Atrial fibrillation	3/58 (5.2%)		0/58 (0%)
Bradycardia	2/58 (3.4%)		0/58 (0%)
Mitral valve incompetence	4/58 (6.9%)		0/58 (0%)
Tachycardia	3/58 (5.2%)		0/58 (0%)
Tricuspid valve incompetence	3/58 (5.2%)		0/58 (0%)
Gastrointestinal disorders
Constipation	27/58 (46.6%)		0/58 (0%)
Diarrhoea	7/58 (12.1%)		0/58 (0%)
Mouth haemorrhage	0/58 (0%)		3/58 (5.2%)
Nausea	2/58 (3.4%)		0/58 (0%)
Vomiting	6/58 (10.3%)		0/58 (0%)
General disorders
Pyrexia	5/58 (8.6%)		0/58 (0%)
Hepatobiliary disorders
Hepatic function abnormal	10/58 (17.2%)		0/58 (0%)
Liver disorder	4/58 (6.9%)		0/58 (0%)
Infections and infestations
Nasopharyngitis	4/58 (6.9%)		0/58 (0%)
Urinary tract infections	10/58 (17.2%)		0/58 (0%)
Investigations
Alanine aminotransferase increased	2/58 (3.4%)		0/58 (0%)
Aspartate aminotransferase increased	2/58 (3.4%)		0/58 (0%)
Blood bilirubin increased	2/58 (3.4%)		0/58 (0%)
Blood creatine phosphokinase increased	7/58 (12.1%)		0/58 (0%)
Blood fibrinogen increased	2/58 (3.4%)		0/58 (0%)
Blood lactate dehydrogenase increased	2/58 (3.4%)		0/58 (0%)
Blood pressure increased	2/58 (3.4%)		0/58 (0%)
Blood urea increased	3/58 (5.2%)		0/58 (0%)
Blood urine present	2/58 (3.4%)		0/58 (0%)
Liver function test abnormal	2/58 (3.4%)		0/58 (0%)
Protein urine present	3/58 (5.2%)		0/58 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	2/58 (3.4%)		0/58 (0%)
Hyponatraemia	3/58 (5.2%)		0/58 (0%)
Hyperlipidaemia	3/58 (5.2%)		0/58 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/58 (3.4%)		0/58 (0%)
Back pain	6/58 (10.3%)		0/58 (0%)
Musculoskeletal pain	5/58 (8.6%)		0/58 (0%)
Osteoarthritis	2/58 (3.4%)		0/58 (0%)
Pain in extremity	3/58 (5.2%)		0/58 (0%)
Periarthritis	2/58 (3.4%)		0/58 (0%)
Nervous system disorders
Cervicobrachial syndrome	2/58 (3.4%)		0/58 (0%)
Haemorrhagic cerebral infarction	0/58 (0%)		21/58 (36.2%)
Headache	5/58 (8.6%)		0/58 (0%)
Psychiatric disorders
Insomnia	13/58 (22.4%)		0/58 (0%)
Restlessness	3/58 (5.2%)		0/58 (0%)
Renal and urinary disorders
Dysuria	2/58 (3.4%)		0/58 (0%)
Haematuria	0/58 (0%)		2/58 (3.4%)
Neurogenic bladder	6/58 (10.3%)		0/58 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/58 (3.4%)		0/58 (0%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	2/58 (3.4%)		0/58 (0%)
Pneumonia aspiration	3/58 (5.2%)		0/58 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	3/58 (5.2%)		0/58 (0%)
Erythema	5/58 (8.6%)		0/58 (0%)
Haemorrhage subcutaneous	0/58 (0%)		5/58 (8.6%)
Skin exfoliation	2/58 (3.4%)		0/58 (0%)
Vascular disorders
Deep vein thrombosis	2/58 (3.4%)		0/58 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Sponsor's consent must be obtained in advance if the investigator or other study-related personnel in the study center intend to publish information obtained via this study at a scientific conference or similar venue.