APCAST: Activated Protein C in Acute Stroke Trial

• Sponsor: University of Rochester (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00533546
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 12
• Locations: 9
• Arm: 1
• Duration (Months): 37
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine the safety and learn more about the dose of Activated Protein C (APC) in reducing the damage from stroke.

Condition or Disease	Intervention/Treatment	Phase
Stroke	Drug: Activated Protein C	Phase 2

Detailed Description

An ischemic stroke occurs when there is damage to the brain caused by blockage in the blood vessels supplying the brain. Approximately 500,000 people in the United States experience this type of stroke each year. The only approved treatment for acute stroke is to attempt to dissolve the blood clot using t-PA (tissue plasminogen activator). This treatment must be given within 3 hours of symptom onset and is associated with a risk of brain hemorrhage (bleeding in the brain) of about 6% (6 in 100 patients).

Activated Protein C (APC) is a protein in the blood that is important in dissolving blood clots and reducing inflammation. Studies in animals suggest that APC may also protect brain cells from injury caused by a stroke. We are doing this study to determine if giving APC to individuals who have had a stroke will be safe and will reduce the damage to brain cells caused by the stroke. APC is currently approved by the Food and Drug Administration (FDA) for use in patients with severe, life-threatening infections.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Activated Protein C in Acute Stroke Trial
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tier One Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one ho.	Drug: Activated Protein C; Intravenous APC (10, 15, 22, 33, 50, and 75 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset; Other Names: Xigris

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Intracranial Hemorrhage [Measured within 36-48 hours of treatment]

   Intracranial Hemorrhage (ICH): Fatal ICH: Death ascribed to ICH confirmed by autopsy or CT imaging. Major non-fatal ICH: Hemorrhage within brain parenchyma associated with neurological deterioration or evidence of subdural, epidural or intraventricular hemorrhage on CT imaging, with or without symptoms. Symptomatic ICH: Hemorrhage within the territory of qualifying infarction with neurological deterioration as measured by > 2 point increase in the National Institutes of Health Stroke Scale (NIHSS) from previous examination; hemorrhage in different vascular territory associated with new neurologic deficit. All symptomatic ICH will be defined as a major ICH. Asymptomatic ICH: Presence of hemorrhage within the territory of qualifying infarction without neurological deterioration ascribed to the hemorrhage or presence of hemorrhage within brain parenchyma outside the territory of qualifying infarction without new neurologic deficit (would not be considered a major ICH)

Secondary Outcome Measures

1. Mean Modified Rankin Scale Score [90 days]

   Measure of disability as determined by categorical assignment on modified Rankin Scale.. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms. - No significant disability. Able to carry out all usual activities, despite some symptoms. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. - Moderate disability. Requires some help, but able to walk unassisted. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. - Dead.

2. Mean Barthel Index Score [90 days]

   Measure of functional recovery using Barthel Index (range 0-100). The Barthel scale or Barthel ADL index is an ordinal scale used to measure performance in activities of daily living (ADL). Each performance item is rated on this scale with a given number of points assigned to each level or ranking. It uses ten variables describing ADL and mobility with 10 points given to each variable for a total of 100 points. A higher number is associated with a greater likelihood of being able to live at home with a degree of independence following discharge from hospital. The ten variables addressed in the Barthel scale are: presence or absence of fecal incontinence presence or absence of urinary incontinence help needed with grooming help needed with toilet use help needed with feeding help needed with transfers (e.g. from chair to bed) help needed with walking help needed with dressing help needed with climbing stairs and help needed with bathing

3. National Institutes of Health Stroke Scale (NIHSS) [90 days]

   The NIHSS is a measure of neurologic deficit on a scale of 0-42, with 0 being normal. The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. 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. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0. The 11 items are: Level of Consciousness Horizontal Eye Movement Visual field test Facial Palsy Motor Arm Motor Leg Limb Ataxia Sensory Language Speech Extinction and Inattention

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Symptoms of acute ischemic stroke; acute ischemic stroke is defined as the sudden onset of a measurable neurological deficit presumably attributable to focal cerebral ischemia, and otherwise not attributable to ICH or other disease process

• Symptom onset within 0-9 hours of administration of study medication Stroke onset is defined as the time of first symptoms or signs of neurologic deficit. If the onset of symptoms/signs is unwitnessed, time of onset is presumed to be the last time the patient was observed to be intact

• Neurologic deficit on examination with NIHSS of greater than 4 and less than 23

• In women of childbearing potential, a negative urine pregnancy test prior to enrollment (to be confirmed later by serum test)

• Signed informed consent by subject or authorized representative

Exclusion Criteria:

• Computed tomography scan of the brain with evidence of intracranial hemorrhage or any finding not consistent with acute ischemic stroke as cause of presenting symptoms

• CT imaging demonstrating hypodensity more than 1/3 of MCA territory or mass effect

• Neurological (other than presenting stroke) or psychiatric condition that may affect the patient's functional status or that may interfere with the patient's assessment

• Clinically relevant pre-existing neurological deficit (historical modified Rankin score greater than 2 regardless of cause)

• Treatment with tissue plasminogen activator or other thrombolytic agent within 3 months, including treatment with tissue plasminogen activator for current stroke

• Need for treatment with anti-platelet agent or anticoagulant within 36 hours

• Previous stroke or serious head trauma within 3 months

• Major surgery within previous 14 days

• History of intracranial hemorrhage

• Rapidly improving or minor symptoms

• Symptoms suggestive of subarachnoid hemorrhage

• Gastrointestinal hemorrhage or urinary tract hemorrhage within previous 21 days

• Arterial puncture at noncompressible site within the previous 7 days

• Seizure at onset of stroke

• Use of oral anticoagulant medications at time of symptom onset or treatment with subcutaneous or intravenous heparin within previous 48 hours with elevated partial thromboplastin time

• INR values greater than 1.5

• Platelet count less than 100,000/μL

• Glucose concentration less than 40 mg/dL or greater than 400mg/dL

• Participation in another clinical trial within the last 30 days, or planned participation in another clinical trial

• Women who are currently breast-feeding

• Known resistance to activated Protein C (Factor V Leiden mutation)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Irvine Medical Center	Orange	California	United States	92868
2	Loyola University Medical Center	Maywood	Illinois	United States	60153
3	Washington University--Barnes-Jewish Hospital	St. Louis	Missouri	United States	63110
4	SUNY Downstate	Brooklyn	New York	United States	11203
5	Maimonides Medical Center	Brooklyn	New York	United States	11219
6	Mt. Sinai School of Medicine	New York	New York	United States	10029
7	Rochester General Hospital	Rochester	New York	United States	14621
8	University of Rochester	Rochester	New York	United States	14642
9	Palmetto Health Richland	Columbia	South Carolina	United States	29203

Sponsors and Collaborators

• University of Rochester
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Chair: Curtis Benesch, MD, MPH, University of Rochester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Curtis Benesch, Associate Professor of Neurology, University of Rochester
• ClinicalTrials.gov Identifier: NCT00533546
• Other Study ID Numbers: 537; 5R01HL080107; 5R01HL080107-05
• First Posted: Sep 21, 2007
• Last Update Posted: Oct 24, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by Curtis Benesch, Associate Professor of Neurology, University of Rochester: Acute Ischemic Stroke
• Additional relevant MeSH terms: Stroke; Drotrecogin alfa activated; Protein C

Study Results

Participant Flow

Recruitment Details	The recruitment period spanned the following dates: October 2007 through July 2010. Location of recruitment and enrollment was in the emergency department of approved sites for patients presenting with acute ischemic stroke. Of the 9 participating sites, 3 actively enrolled.
Pre-assignment Detail	No patients were excluded after enrollment.

Arm/Group Title	Intravenous APC 10 Microgram/kg Dose
Arm/Group Description	Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one hour. Activated Protein C : Intravenous APC (10 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Intravenous APC 10 Microgram/kg Dose
Arm/Group Description	Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one hour. Activated Protein C : Intravenous APC (10, 15, 22, 33, 50, and 75 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset
Overall Participants	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.6 (17.3)
Sex: Female, Male (Count of Participants)
Female	5 41.7%
Male	7 58.3%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Intracranial Hemorrhage
Description	Intracranial Hemorrhage (ICH): Fatal ICH: Death ascribed to ICH confirmed by autopsy or CT imaging. Major non-fatal ICH: Hemorrhage within brain parenchyma associated with neurological deterioration or evidence of subdural, epidural or intraventricular hemorrhage on CT imaging, with or without symptoms. Symptomatic ICH: Hemorrhage within the territory of qualifying infarction with neurological deterioration as measured by > 2 point increase in the National Institutes of Health Stroke Scale (NIHSS) from previous examination; hemorrhage in different vascular territory associated with new neurologic deficit. All symptomatic ICH will be defined as a major ICH. Asymptomatic ICH: Presence of hemorrhage within the territory of qualifying infarction without neurological deterioration ascribed to the hemorrhage or presence of hemorrhage within brain parenchyma outside the territory of qualifying infarction without new neurologic deficit (would not be considered a major ICH)
Time Frame	Measured within 36-48 hours of treatment

Outcome Measure Data

Analysis Population Description

All participants enrolled were analyzed.

Arm/Group Title	Intravenous APC 10 Microgram/kg Dose
Arm/Group Description	Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one hour. Activated Protein C : Intravenous APC (10, 15, 22, 33, 50, and 75 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset
Measure Participants	12
Number [participants]	0 0%

2. Secondary Outcome

Title	Mean Modified Rankin Scale Score
Description	Measure of disability as determined by categorical assignment on modified Rankin Scale.. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms. - No significant disability. Able to carry out all usual activities, despite some symptoms. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. - Moderate disability. Requires some help, but able to walk unassisted. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. - Dead.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous APC 10 Microgram/kg Dose
Arm/Group Description	Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one hour. Activated Protein C: Intravenous APC (10, 15, 22, 33, 50, and 75 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	2.91 (1.58)

3. Secondary Outcome

Title	Mean Barthel Index Score
Description	Measure of functional recovery using Barthel Index (range 0-100). The Barthel scale or Barthel ADL index is an ordinal scale used to measure performance in activities of daily living (ADL). Each performance item is rated on this scale with a given number of points assigned to each level or ranking. It uses ten variables describing ADL and mobility with 10 points given to each variable for a total of 100 points. A higher number is associated with a greater likelihood of being able to live at home with a degree of independence following discharge from hospital. The ten variables addressed in the Barthel scale are: presence or absence of fecal incontinence presence or absence of urinary incontinence help needed with grooming help needed with toilet use help needed with feeding help needed with transfers (e.g. from chair to bed) help needed with walking help needed with dressing help needed with climbing stairs and help needed with bathing
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous APC 10 Microgram/kg Dose
Arm/Group Description	Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one hour. Activated Protein C: Intravenous APC (10, 15, 22, 33, 50, and 75 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	67.7 (34.2)

4. Secondary Outcome

Title	National Institutes of Health Stroke Scale (NIHSS)
Description	The NIHSS is a measure of neurologic deficit on a scale of 0-42, with 0 being normal. The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. 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. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0. The 11 items are: Level of Consciousness Horizontal Eye Movement Visual field test Facial Palsy Motor Arm Motor Leg Limb Ataxia Sensory Language Speech Extinction and Inattention
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous APC 10 Microgram/kg Dose
Arm/Group Description	Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one hour. Activated Protein C: Intravenous APC (10, 15, 22, 33, 50, and 75 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	5.0 (4.2)

Adverse Events

Time Frame	90 days following enrollment
Adverse Event Reporting Description	Serious Adverse Events were collected without regard to the specific Adverse Event Term.
Arm/Group Title	Intravenous APC 10 Microgram/kg Dose
Arm/Group Description	Participants will receive APC by intravenous injection, receiving 50% of dose as a bolus and the remainder as an infusion over one hour. Activated Protein C : Intravenous APC (10, 15, 22, 33, 50, and 75 mcg/kg) administered to patients with acute ischemic stroke within 0 - 9 hours of symptom onset
All Cause Mortality
	Intravenous APC 10 Microgram/kg Dose
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Intravenous APC 10 Microgram/kg Dose
	Affected / at Risk (%)	# Events
Total	5/12 (41.7%)
General disorders
Hospitalization > 24 hours	3/12 (25%)	3
death	1/12 (8.3%)	1
Nervous system disorders
worsening of neurological symptoms	3/12 (25%)	5
Other (Not Including Serious) Adverse Events
	Intravenous APC 10 Microgram/kg Dose
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Anaemia	3/12 (25%)
Leukocytosis	3/12 (25%)
Cardiac disorders
Acute myocardial infarction	1/12 (8.3%)
Cardiac failure congestive	2/12 (16.7%)
Cardiomegaly	1/12 (8.3%)
Oedema peripheral	1/12 (8.3%)
Tachycardia	1/12 (8.3%)
Congenital, familial and genetic disorders
Atrial septal defect	1/12 (8.3%)
Endocrine disorders
Hypoglycaemia	1/12 (8.3%)
Hypothyroidism	1/12 (8.3%)
Eye disorders
Eye discharge	2/12 (16.7%)
Gastrointestinal disorders
Abdominal pain	1/12 (8.3%)
Constipation	1/12 (8.3%)
Diarrhoea	2/12 (16.7%)
Gastrointestinal haemorrhage	1/12 (8.3%)
Haematemesis	1/12 (8.3%)
Nausea	1/12 (8.3%)
Oral candidiasis	1/12 (8.3%)
Oral fungal infection	1/12 (8.3%)
Vomiting	2/12 (16.7%)
General disorders
Catheter site pain	1/12 (8.3%)
Discomfort	1/12 (8.3%)
Implant site pain	1/12 (8.3%)
Lethargy	1/12 (8.3%)
Pain	1/12 (8.3%)
Pyrexia	6/12 (50%)
Infections and infestations
Cellulitis	1/12 (8.3%)
Enterococcal infection	1/12 (8.3%)
Sepsis	1/12 (8.3%)
Tinea pedis	1/12 (8.3%)
Urinary tract infection	7/12 (58.3%)
Injury, poisoning and procedural complications
Contusion	1/12 (8.3%)
Fall	1/12 (8.3%)
Infusion related reaction	1/12 (8.3%)
Renal injury	1/12 (8.3%)
Skin laceration	1/12 (8.3%)
Investigations
Blood cholesterol increased	1/12 (8.3%)
Body temperature increased	1/12 (8.3%)
Electrocardiogram change	1/12 (8.3%)
Neurological examination abnormal	1/12 (8.3%)
Vibration test abnormal	1/12 (8.3%)
White blood cell count increased	1/12 (8.3%)
Metabolism and nutrition disorders
Hyperkalaemia	1/12 (8.3%)
Hyperlipidaemia	1/12 (8.3%)
Hypocalcaemia	1/12 (8.3%)
Hypokalaemia	3/12 (25%)
Hyponatraemia	3/12 (25%)
Ketoacidosis	1/12 (8.3%)
Magnesium deficiency	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/12 (8.3%)
Contusion	1/12 (8.3%)
Groin pain	1/12 (8.3%)
Muscle twitching	1/12 (8.3%)
Musculoskeletal pain	3/12 (25%)
Neck pain	1/12 (8.3%)
Nervous system disorders
Brain oedema	1/12 (8.3%)
Disturbance in attention	1/12 (8.3%)
Headache	3/12 (25%)
Insomnia	3/12 (25%)
Muscle spasticity	3/12 (25%)
Neurological symptom	2/12 (16.7%)
Status epilepticus	1/12 (8.3%)
Psychiatric disorders
Agitation	2/12 (16.7%)
Anxiety	2/12 (16.7%)
Confusional state	1/12 (8.3%)
Delirium	1/12 (8.3%)
Depression	5/12 (41.7%)
Insomnia	3/12 (25%)
Suicidal ideation	1/12 (8.3%)
Renal and urinary disorders
Haematuria	1/12 (8.3%)
Renal cyst	1/12 (8.3%)
Urinary retention	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/12 (8.3%)
Cough	1/12 (8.3%)
Dyspnoea	1/12 (8.3%)
Increased upper airway secretion	1/12 (8.3%)
Pharyngolaryngeal pain	1/12 (8.3%)
Pleural effusion	1/12 (8.3%)
Pneumonia	2/12 (16.7%)
Pulmonary hypertension	1/12 (8.3%)
Respiratory distress	1/12 (8.3%)
Small cell lung cancer stage unspecified	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Lipoma	1/12 (8.3%)
Decubitus ulcer	1/12 (8.3%)
Petechiae	1/12 (8.3%)
Pruritus	1/12 (8.3%)
Rash	1/12 (8.3%)
Skin disorder	2/12 (16.7%)
Urticaria	1/12 (8.3%)
Surgical and medical procedures
Gastrointestinal tube insertion	3/12 (25%)
Vascular disorders
Deep vein thrombosis	2/12 (16.7%)
Hypertension	2/12 (16.7%)

Limitations/Caveats

Study was terminated after completion of Tier One dosing level (n=12 subjects) due to lack of recruitment.

More Information

Certain Agreements

Principal Investigators are NOT 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.