CLEAR-ER: Study of the Combination Therapy of Rt-PA and Eptifibatide to Treat Acute Ischemic Stroke

• Sponsor: University of Cincinnati (Other)
• Overall Status: Completed
• CT.gov ID: NCT00894803
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 126
• Locations: 20
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary goal of this trial is to determine if individuals with acute ischemic stroke treated with a medium dose of IV rt-PA plus IV eptifibatide started within 3 hours of symptom onset are more likely to have a better outcome than individuals treated with standard IV rt-PA alone.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke; Stroke; Brain Infarction	Drug: Eptifibatide; Drug: rt-PA	Phase 2

Detailed Description

The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA (recombinant tissue plasminogen activator) in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER Stroke) trial is a Phase II trial and part of the Specialized Program on Translational Research in Acute Stroke (SPOTRIAS). The overall goals of SPOTRIAS are to enhance delivery of acute stroke patient care and train acute stroke translational researchers.

Stroke most often occurs when blood flow to the brain stops because it is blocked by a blood clot. When a blood clot blocks the blood supply to the brain, parts of the brain may not get enough blood and oxygen to survive. As a result, permanent brain damage can occur, which can affect a person's ability to walk, talk, and function independently. In order to reduce the risk of permanent damage, it is important to restore blood flow to the brain as quickly as possible.

rt-PA, used alone, is already approved by the Food and Drug Administration (FDA) as treatment for patients with a stroke caused by blockage of an artery in the brain and when given within 3 hours of the onset of stroke symptoms. Eptifibatide is also already FDA-approved as a treatment for blood clots causing heart attack. The investigational aspect of this study is the use of eptifibatide for a stroke victim in combination with rt-PA.

The CLEAR Stroke Trial (NCT00250991) demonstrated that the combination of low dose rt-PA plus eptifibatide can be safely given to acute ischemic stroke patients within 3 hours of symptom onset.

The CLEAR-ER Stroke Trial is designed to provide data concerning the risks and benefits of combining eptifibatide with medium dose intravenous rt-PA in 126 acute ischemic stroke patients within 3 hours of symptom onset. Patients will be randomized to a combined intravenous medium-dose rt-PA and eptifibatide regimen, or standard dose rt-PA in a 5 to 1 ratio. This will result in a total of 105 patients treated with a combined regimen, and 21 patients treated with standard dose IV rt-PA alone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The "Combined Approach to Lysis Utilizing Eptifibatide and Rt-PA in Acute Ischemic Stroke-Enhanced Regimen" (CLEAR-ER Stroke Trial)
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: rt-PA only Subject will receive the standard dose (0.9mg/kg) of IV rt-PA given over 60 minutes. One out of 6 subjects will be in this group.	Drug: rt-PA; Intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy.; Other Names: Activase
Experimental: rt-PA and Eptifibatide Subject will receive the standard dose (0.9mg/kg) of IV rt-PA. This IV dose will be discontinued at 40 minutes. The subject will immediately receive an IV bolus of 135mcg/kg eptifibatide followed by an IV infusion of 0.75 mcg/kg/min eptifibatide for 2 hours. Five out of six subjects will be in this group.	Drug: Eptifibatide; IV Eptifibatide is an approved drug by the Food and Drug Administration as a treatment for blood clots causing heart attack and chest pain.Eptifibatide inhibits platelet aggregation by blocking activated platelets from binding fibrinogen.; Other Names: Integrilin ; Drug: rt-PA; Intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy.; Other Names: Activase

Outcome Measures

Primary Outcome Measures

1. Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours of Treatment Onset [Within 36 hours of initiation of therapy]

   Primary safety outcome measure - Any ICH related to a decline in neurologic status or the development of new neurologic symptoms which in the judgment of the clinical investigator was related to the ICH. Judgment of significant neurological decline was made by the local clinical investigator

2. Modified Rankin Scale (mRS) Score <1 or Return to mRS Baseline [90 days from treatment onset]

   Primary efficacy outcome measure - Modified Rankin Scale of 0 or 1 or return to the pre-stroke value at baseline or better. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days were given a value of '6', and assigned the "bad" outcome. Also those lost to follow-up were assigned the "bad" outcome. The Modified Rankin Score (mRS) is a 6 point ordinal scale, measuring functional status. 0 (no symptoms at all), 5 (severe disability; bedridden, incontinent, and requiring constant nursing care).

Secondary Outcome Measures

1. Barthel Index ≥ 95 [90 days from treatment onset]

   Barthel index score of ≥ 95. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days and those lost to follow-up were assigned the "bad" outcome. The Barthel index is a score comprised of 10 individual items. Each item may be scored 0, 5, 10 or 15; not all items use the full range of 4 possible values. The individual items are summed to produce a total score between 0 and 100; where 0 is inferior performance and 100 is optimal. A score of ≥ 95 is usually considered excellent.

2. Glasgow Outcome Scale (GOS) of 1 [90 days from treatment onset]

   Glasgow outcome scale score of 1 versus greater than 1. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days and those lost to follow-up were assigned the "bad" outcome. The Glasgow Outcome Scale is scored; 1=good recovery, 2=moderately disabled, 3=severely disabled, 4=vegetative survival, 5=dead.

Other Outcome Measures

1. Serious Systemic Bleeding [Within 7 days of treatment onset]

   Incidence of serious systemic bleeding defined as requiring transfusion of 2 or more units of packed red blood cells.

2. Symptomatic Intracranial Hemorrhage (sICH) Within 7 Days of Treatment Onset [Within 7 days of treatment onset]

   Any ICH related to a decline in neurologic status or the development of new neurologic symptoms which in the judgment of the clinical investigator was related to the ICH. Judgment of significant neurological decline was made by the local clinical investigator

3. Asymptomatic Intracranial Hemorrhage (asICH) Within 7 Days of Treatment Onset [Within 7 days of treatment onset]

   Any ICH observed on CT by the study site neuroradiologist and the independent study neuroradiologist; the central reader. The ICH would not be related to a decline in neurologic status or the development of new neurologic symptoms which in the judgment of the clinical investigator was related to the ICH,where judgment of significant neurological decline was made by the local clinical investigator. A third independent reader will make the final determination if there is disagreement between the treating investigator and the central reader

4. Death Within 7 Days of Treatment Onset [Within 7 days of treatment onset]

   Death due to any cause within 7 days of treatment onset

5. Death Due to Stroke Within 7 Days of Treatment Onset [Within 7 days of treatment onset]

   Death due to stroke within 7 days of treatment onset. Classified by blinded clinical investigators

6. NIH Stroke Scale Score (NIHSS) ≤ 5 [Within 2 hours of treatment onset]

   Study subjects with an NIH stroke scale score of ≤ 5 at 2 hours from treatment onset, those sedated and unable to be evaluated by the NIHSS were assigned the "bad" outcome (n=1). The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.

7. NIH Stroke Scale Score (NIHSS) ≤ 2 [Within 24 hours of treatment onset]

   Study subjects with an NIH stroke scale score of ≤ 2 at 24 hours from treatment onset, those dead (n=1) or sedated and unable to be evaluated by the NIHSS were assigned the "bad" outcome (n=5). The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.

8. NIH Stroke Scale Score (NIHSS) ≤2 at 90 Days [90 days from treatment onset]

   Study subjects with an NIH stroke scale score ≤ 2 points at 90 days from treatment onset compared to baseline value, those dead or unable to be evaluated by the NIHSS were assigned the "bad" outcome. The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a serious measurable neurological deficit on the NIH Stroke Scale due to focal brain ischemia.

• An NIH Stroke Scale score >5 at the time the rt-PA is begun.

• Age: 18 through 85 years (i.e. candidates must have had their 18th birthday, but not had their 86th birthday).

• Intravenous rt-PA therapy must be initiated within 3 hours of onset of stroke symptoms.

Exclusion Criteria:

• History of stroke in the past 3 months.

• Previous intra-cranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation.

• Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT scan is normal.

• Hypertension at time of treatment; systolic BP > 185 or diastolic > 110 mmHg or aggressive measures to lower blood pressure to below these limits are needed.

• Presumed septic embolus.

• Presumed pericarditis including pericarditis after acute myocardial infarction.

• Recent (within 30 days) surgery or biopsy of parenchymal organ.

• Recent (within 30 days) trauma, with internal injuries or ulcerative wounds.

• Recent (within 90 days) severe head trauma or head trauma with loss of consciousness.

• Any active or recent (within 30 days) serious systemic hemorrhage.

• Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; or oral anticoagulant therapy with Iinternational Normalized Ratio (INR) > 1.7.

• Baseline lab values: positive urine pregnancy test, glucose < 50 or > 400 mg/dl, platelets <100,000 /mm3, Hct (hematocrit) <25 %, or creatinine > 4 mg/dl.

• Ongoing renal dialysis, regardless of creatinine.

• If heparin has been administered within 48 hours, the patient must have a normal partial thromboplastin time (PTT).

• Arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days.

• Seizure at onset of stroke.

• Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations.

• Other serious, advanced, or terminal illness or any other condition that the investigator feels would pose a significant hazard to the patient if rt-PA or eptifibatide therapy were initiated.

• Patients whose peripheral venous access is so poor that they are unable to have two standard peripheral intravenous lines started.

• Current participation in another research drug treatment protocol. Patient cannot start another experimental agent until after 90 days.

• Informed consent is not or cannot be obtained.

• Any known history of amyloid angiopathy.

• High density lesion consistent with hemorrhage of any degree.

• Significant mass effect with midline shift.

• Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT scan. Sulcal effacement and/or loss of grey-white differentiation alone are not contraindications for treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Ronald Reagan Medical Center	Los Angeles	California	United States	90024
2	University of California San Diego	San Diego	California	United States	92103
3	UCLA Medical Center Santa Monica	Santa Monica	California	United States	90404
4	Washington Hospital Center	Washington	District of Columbia	United States	20010
5	St. Elizabeth Healthcare Edgewood	Edgewood	Kentucky	United States	41017
6	St. Elizabeth Healthcare Florence	Florence	Kentucky	United States	41042
7	St. Elizabeth Healthcare Ft. Thomas	Ft. Thomas	Kentucky	United States	41075
8	Suburban Hospital	Bethesda	Maryland	United States	20814
9	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
10	Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
11	Mission Hospital, Inc.	Asheville	North Carolina	United States	28801
12	The Christ Hospital	Cincinnati	Ohio	United States	45219
13	University Hospital	Cincinnati	Ohio	United States	45219
14	Good Samaritan Hospital	Cincinnati	Ohio	United States	45220-2489
15	The Jewish Hospital	Cincinnati	Ohio	United States	45236
16	Mercy Hospital, Western Hills	Cincinnati	Ohio	United States	45238
17	Mercy Hospital Mt Airy	Cincinnati	Ohio	United States	45239
18	Bethesda North Hospital	Cincinnati	Ohio	United States	45242
19	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
20	West Virginia University Hospital	Morgantown	West Virginia	United States	26506

Sponsors and Collaborators

• University of Cincinnati
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Arthur M Pancioli, MD, University of Cincinnati College of Medicine Department of Emergency Medicine
• Principal Investigator: Opeolu M Adeoye, MD, University of Cincinnati College of Medicine Department of Emergency Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Barreto AD, Pedroza C, Grotta JC. Adjunctive medical therapies for acute stroke thrombolysis: is there a CLEAR-ER choice? Stroke. 2013 Sep;44(9):2377-9. doi: 10.1161/STROKEAHA.113.001830. Epub 2013 Jul 25.

• Responsible Party: Arthur Pancioli, Dir Academic Med, University of Cincinnati
• ClinicalTrials.gov Identifier: NCT00894803
• Other Study ID Numbers: P50NS04483-06; 00894803
• First Posted: May 7, 2009
• Last Update Posted: Apr 17, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Arthur Pancioli, Dir Academic Med, University of Cincinnati: acute ischemic stroke; stroke; rt-PA, thrombolytic; t-PA; recombinant tissue plasminogen activator; Activase; eptifibatide; Integrilin; fibrinolytic agents; clot dissolving; blood clot
• Additional relevant MeSH terms: Stroke; Ischemic Stroke; Cerebral Infarction; Brain Infarction; Ischemia; Infarction; Eptifibatide

Study Results

Participant Flow

Recruitment Details	The trial was conducted in emergency departments at 9 US medical centers comprised of 21 hospitals. Subjects were recruited between July 2009 and October 2012.
Pre-assignment Detail	No enrolled participants were excluded from the trial before assignment to groups.

Arm/Group Title	Rt-PA and Eptifibatide	Rt-PA Only
Arm/Group Description	recombinant tissue Plasminogen Activator (rt-PA; 0.6 mg/kg) and Epifibatide (225 mcg/kg)	recombinant tissue Plasminogen Activator (rt-PA; 0.9 mg/kg)
Period Title: Overall Study
STARTED	101	25
COMPLETED	81	20
NOT COMPLETED	20	5

Baseline Characteristics

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide	Total
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)	Total of all reporting groups
Overall Participants	25	101	126
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 28%	37 36.6%	44 34.9%
>=65 years	18 72%	64 63.4%	82 65.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.9 (13.0)	69.0 (13.6)	69.3 (13.4)
Age (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	75.5	71.6	74.2
Sex: Female, Male (Count of Participants)
Female	12 48%	48 47.5%	60 47.6%
Male	13 52%	53 52.5%	66 52.4%
Region of Enrollment (participants) [Number]
United States	25 100%	101 100%	126 100%
National Institutes of Health Stroke Scale Score (NIHSS) (Number) [Number]
NIHSS <=12	10 40%	56 55.4%	66 52.4%
NIHSS >12	15 60%	45 44.6%	60 47.6%
National Institutes of Health Stroke Scale Score (NIHSS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	16.4 (6.7)	14.1 (6.9)	14.6 (6.9)
National Institutes of Health Stroke Scale Score (NIHSS) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	17	12	12
Stroke symptom onset to intravenous rt-PA start (Number) [Number]
< 1 hour	0 0%	1 1%	1 0.8%
1 to 2 hours	11 44%	56 55.4%	67 53.2%
>2 to 3 hours	13 52%	42 41.6%	55 43.7%
> 3 hours	1 4%	2 2%	3 2.4%
Stroke symptom onset to intravenous rt-PA start (minutes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [minutes]	129	113	116
Modified Rankin Score (mRS) (participants) [Number]
0	16 64%	74 73.3%	90 71.4%
1	2 8%	11 10.9%	13 10.3%
2	3 12%	7 6.9%	10 7.9%
3	4 16%	4 4%	8 6.3%
4	0 0%	5 5%	5 4%
5	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours of Treatment Onset
Description	Primary safety outcome measure - Any ICH related to a decline in neurologic status or the development of new neurologic symptoms which in the judgment of the clinical investigator was related to the ICH. Judgment of significant neurological decline was made by the local clinical investigator
Time Frame	Within 36 hours of initiation of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
sICH within 36 hours of treatment onset	3 12%	2 2%
No sICH within 36 hours of treatment onset	22 88%	99 98%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	Regression, Logistic
	Comments	an exact logistic regression was used due to the number of events
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; 0.01 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

2. Primary Outcome

Title	Modified Rankin Scale (mRS) Score <1 or Return to mRS Baseline
Description	Primary efficacy outcome measure - Modified Rankin Scale of 0 or 1 or return to the pre-stroke value at baseline or better. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days were given a value of '6', and assigned the "bad" outcome. Also those lost to follow-up were assigned the "bad" outcome. The Modified Rankin Score (mRS) is a 6 point ordinal scale, measuring functional status. 0 (no symptoms at all), 5 (severe disability; bedridden, incontinent, and requiring constant nursing care).
Time Frame	90 days from treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
mRS of 0-1 or return to baseline	9 36%	50 49.5%
mRS >1 and > baseline	16 64%	51 50.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; 0.70 to 4.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Regression, Logistic
	Comments	adjusting for age, baseline NIHSS score and time to IV rt-PA
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.51 to 3.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

3. Other Pre-specified Outcome

Title	Serious Systemic Bleeding
Description	Incidence of serious systemic bleeding defined as requiring transfusion of 2 or more units of packed red blood cells.
Time Frame	Within 7 days of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
Serious systemic bleeding	0 0%	1 1%
No Serious systemic bleeding	25 100%	100 99%

4. Other Pre-specified Outcome

Title	Symptomatic Intracranial Hemorrhage (sICH) Within 7 Days of Treatment Onset
Description	Any ICH related to a decline in neurologic status or the development of new neurologic symptoms which in the judgment of the clinical investigator was related to the ICH. Judgment of significant neurological decline was made by the local clinical investigator
Time Frame	Within 7 days of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
sICH within 7 days of treatment onset	3 12%	2 2%
No sICH within 7 days of treatment onset	22 88%	99 98%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	Regression, Logistic
	Comments	Exact method used due to number of responses
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; 0.01 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

5. Other Pre-specified Outcome

Title	Asymptomatic Intracranial Hemorrhage (asICH) Within 7 Days of Treatment Onset
Description	Any ICH observed on CT by the study site neuroradiologist and the independent study neuroradiologist; the central reader. The ICH would not be related to a decline in neurologic status or the development of new neurologic symptoms which in the judgment of the clinical investigator was related to the ICH,where judgment of significant neurological decline was made by the local clinical investigator. A third independent reader will make the final determination if there is disagreement between the treating investigator and the central reader
Time Frame	Within 7 days of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
asICH within 7 days of treatment onset	3 12%	16 15.8%
No asICH within 7 days of treatment onset	22 88%	85 84.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.38
	Confidence Interval	() 95%; 0.35 to 8.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

6. Other Pre-specified Outcome

Title	Death Within 7 Days of Treatment Onset
Description	Death due to any cause within 7 days of treatment onset
Time Frame	Within 7 days of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
Death within 7 days of treatment onset	3 12%	12 11.9%
No death within 7 days of treatment onset	22 88%	89 88.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.99999
	Comments
	Method	Regression, Logistic
	Comments	Exact method used due to small number of responses
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.24 to 5.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

7. Other Pre-specified Outcome

Title	Death Due to Stroke Within 7 Days of Treatment Onset
Description	Death due to stroke within 7 days of treatment onset. Classified by blinded clinical investigators
Time Frame	Within 7 days of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
Death due to stroke within 7 days of treatment ons	3 12%	12 11.9%
No Death due to stroke within 7 days of treatment	22 88%	89 88.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.99999
	Comments
	Method	Regression, Logistic
	Comments	Exact method used due to number of responses
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.24 to 5.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

8. Post-Hoc Outcome

Title	Death Within 90 Days of Treatment Onset
Description	Death due to any cause within 90 days of treatment onset
Time Frame	Within 90 days of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
Death within 90 days of treatment onset	4 16%	20 19.8%
No death within 90 days of treatment onset	21 84%	81 80.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Regression, Logistic
	Comments	Exact methods used due t number of responses
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.38 to 5.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

9. Post-Hoc Outcome

Title	Death Due to Stroke Within 90 Days of Treatment Onset
Description	Death due to stroke within 90 days of treatment onset. Classified by blinded clinical investigators
Time Frame	Within 90 days of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
Death due to stroke within 90 days of treatment on	4 16%	15 14.9%
No Death due to stroke within 90 days of treatment	21 84%	86 85.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.99999
	Comments
	Method	Regression, Logistic
	Comments	Exact method used due to number of responses
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	.92
	Confidence Interval	(2-Sided) 95%; 0.26 to 4.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

10. Secondary Outcome

Title	Barthel Index ≥ 95
Description	Barthel index score of ≥ 95. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days and those lost to follow-up were assigned the "bad" outcome. The Barthel index is a score comprised of 10 individual items. Each item may be scored 0, 5, 10 or 15; not all items use the full range of 4 possible values. The individual items are summed to produce a total score between 0 and 100; where 0 is inferior performance and 100 is optimal. A score of ≥ 95 is usually considered excellent.
Time Frame	90 days from treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
Barthel Index ≥ 95	11 44%	55 54.5%
Barthel Index < 95	14 56%	46 45.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.63 to 3.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	Regression, Logistic
	Comments	adjusting for age, baseline NIHSS and time to IV rt-PA
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.40 to 3.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

11. Secondary Outcome

Title	Glasgow Outcome Scale (GOS) of 1
Description	Glasgow outcome scale score of 1 versus greater than 1. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days and those lost to follow-up were assigned the "bad" outcome. The Glasgow Outcome Scale is scored; 1=good recovery, 2=moderately disabled, 3=severely disabled, 4=vegetative survival, 5=dead.
Time Frame	90 days from treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
GOS =1	10 40%	52 51.5%
GOS > 1	15 60%	49 48.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.59
	Confidence Interval	(2-Sided) 95%; 0.65 to 3.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments
	Method	Regression, Logistic
	Comments	adjusting for age, baseline NIHSS and time to IV rt-PA
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.44 to 3.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

12. Other Pre-specified Outcome

Title	NIH Stroke Scale Score (NIHSS) ≤ 5
Description	Study subjects with an NIH stroke scale score of ≤ 5 at 2 hours from treatment onset, those sedated and unable to be evaluated by the NIHSS were assigned the "bad" outcome (n=1). The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.
Time Frame	Within 2 hours of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
NIHSS ≤ 5	6 24%	35 34.7%
NIHSS > 5	19 76%	66 65.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 95%; 0.61 to 4.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

13. Other Pre-specified Outcome

Title	NIH Stroke Scale Score (NIHSS) ≤ 2
Description	Study subjects with an NIH stroke scale score of ≤ 2 at 24 hours from treatment onset, those dead (n=1) or sedated and unable to be evaluated by the NIHSS were assigned the "bad" outcome (n=5). The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.
Time Frame	Within 24 hours of treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
NIHSS ≤ 2	5 20%	27 26.7%
NIHSS > 2	20 80%	74 73.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.39
	Confidence Interval	(2-Sided) 95%; 0.47 to 4.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

14. Other Pre-specified Outcome

Title	NIH Stroke Scale Score (NIHSS) ≤2 at 90 Days
Description	Study subjects with an NIH stroke scale score ≤ 2 points at 90 days from treatment onset compared to baseline value, those dead or unable to be evaluated by the NIHSS were assigned the "bad" outcome. The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.
Time Frame	90 days from treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
NIHSS ≤ 2	11 44%	45 44.6%
NIHSS > 2	14 56%	56 55.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.46 to 2.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

15. Post-Hoc Outcome

Title	Modified Rankin Scale (mRS) of 0-1
Description	Modified Rankin Scale of 0 or 1. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days were given a value of '6', and assigned the "bad" outcome. Also those lost to follow-up were assigned the "bad" outcome. The Modified Rankin Score (mRS) is a 6 point ordinal scale, measuring functional status. 0 (no symptoms at all), 5 (severe disability; bedridden, incontinent, and requiring constant nursing care).
Time Frame	90 days from treatment onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rt-PA Only	Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)	rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
Measure Participants	25	101
mRS of 0-1	6 24%	44 43.6%
mRS > 1	19 76%	57 56.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.44
	Confidence Interval	(2-Sided) 95%; 0.90 to 6.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rt-PA Only, Rt-PA and Eptifibatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Regression, Logistic
	Comments	adjusting for age, baseline NIHSS and time to IV rt-PA
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.98
	Confidence Interval	(2-Sided) 95%; 0.67 to 5.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Arm 2 (rt-PA and Eptifibitide) represents the numerator, Arm 1 (rt-PA only) the denominator

Adverse Events

Time Frame	Up to 90 days from initiation of therapy
Adverse Event Reporting Description	Adverse events were documented as recorded in the medical record until discharge. The occurrence of adverse events from the time of hospital discharge to the 90 day visit was collected at the time of the 90 day visit.
Arm/Group Title	Rt-PA Only		Rt-PA and Eptifibatide
Arm/Group Description	rt-PA (0.9 mg/kg)		rt-PA (0.6 mg/kg) and Epifibatide (225 mcg/kg)
All Cause Mortality
	Rt-PA Only		Rt-PA and Eptifibatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rt-PA Only		Rt-PA and Eptifibatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/25 (28%)		26/101 (25.7%)
Blood and lymphatic system disorders
Anaemias nonhaemolytic and marrow depression	0/25 (0%)	0	1/101 (1%)	1
Cardiac disorders
Coronary artery disorders	0/25 (0%)	0	3/101 (3%)	3
Heart failures	0/25 (0%)	0	1/101 (1%)	1
Gastrointestinal disorders
Gastrointestinal haemorrhages NEC	1/25 (4%)	1	3/101 (3%)	3
Gastrointestinal inflammatory conditions	0/25 (0%)	0	1/101 (1%)	1
Gastrointestinal signs and symptoms	1/25 (4%)	1	0/101 (0%)	0
General disorders
General system disorders NEC	0/25 (0%)	0	1/101 (1%)	1
Hepatobiliary disorders
Gallbladder disorders	0/25 (0%)	0	2/101 (2%)	2
Infections and infestations
Infections - pathogen unspecified	0/25 (0%)	0	5/101 (5%)	5
Injury, poisoning and procedural complications
Injuries NEC	0/25 (0%)	0	5/101 (5%)	5
Musculoskeletal and connective tissue disorders
Muscle disorders	1/25 (4%)	1	0/101 (0%)	0
Nervous system disorders
Central nervous system vascular disorders	1/25 (4%)	1	1/101 (1%)	1
Increased intracranial pressure and hydrocephalus	0/25 (0%)	0	5/101 (5%)	5
Neurological disorders NEC	2/25 (8%)	3	3/101 (3%)	3
Neuromuscular disorders	1/25 (4%)	1	0/101 (0%)	0
Seizures (incl subtypes)	0/25 (0%)	0	1/101 (1%)	1
Psychiatric disorders
Communication disorders and disturbances	1/25 (4%)	1	0/101 (0%)	0
Deliria (incl confusion)	0/25 (0%)	0	1/101 (1%)	1
Renal and urinary disorders
Genitourinary tract disorders NEC	0/25 (0%)	0	1/101 (1%)	1
Renal disorders (excl nephropathies)	0/25 (0%)	0	1/101 (1%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary vascular disorders	1/25 (4%)	1	1/101 (1%)	1
Respiratory disorders NEC	1/25 (4%)	1	3/101 (3%)	3
Respiratory tract infections	0/25 (0%)	0	3/101 (3%)	3
Surgical and medical procedures
Cardiac therapeutic procedures	0/25 (0%)	0	1/101 (1%)	1
Vascular therapeutic procedures	0/25 (0%)	0	2/101 (2%)	2
Vascular disorders
Arteriosclerosis, stenosis, vascular insufficiency and necrosis	1/25 (4%)	1	3/101 (3%)	3
Embolism and thrombosis	2/25 (8%)	2	2/101 (2%)	2
Vascular haemorrhagic disorders	1/25 (4%)	1	3/101 (3%)	3
Other (Not Including Serious) Adverse Events
	Rt-PA Only		Rt-PA and Eptifibatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/25 (68%)		80/101 (79.2%)
Blood and lymphatic system disorders
Anaemias nonhaemolytic and marrow depression	0/25 (0%)	0	2/101 (2%)	2
White blood cell disorders	1/25 (4%)	1	0/101 (0%)	0
Cardiac disorders
Cardiac arrhythmias	5/25 (20%)	5	8/101 (7.9%)	9
Cardiac disorder signs and symptoms	0/25 (0%)	0	3/101 (3%)	4
Coronary artery disorders	1/25 (4%)	1	1/101 (1%)	1
Heart failures	2/25 (8%)	2	0/101 (0%)	0
Endocrine disorders
Glucose metabolism disorders (incl diabetes mellitus)	0/25 (0%)	0	4/101 (4%)	4
Eye disorders
Eye disorders NEC	0/25 (0%)	0	1/101 (1%)	1
Gastrointestinal disorders
Dental and gingival conditions	0/25 (0%)	0	3/101 (3%)	3
Gastrointestinal motility and defaecation conditions	1/25 (4%)	1	9/101 (8.9%)	9
Tongue conditions	0/25 (0%)	0	1/101 (1%)	1
General disorders
Administration site reactions	0/25 (0%)	0	5/101 (5%)	6
Body temperature conditions	3/25 (12%)	3	7/101 (6.9%)	7
Device issues	0/25 (0%)	0	1/101 (1%)	1
Gastrointestinal signs and symptoms	7/25 (28%)	7	15/101 (14.9%)	22
General system disorders NEC	4/25 (16%)	4	5/101 (5%)	5
Immune system disorders
Allergic conditions	0/25 (0%)	0	5/101 (5%)	5
Infections and infestations
Bacterial infectious disorders	1/25 (4%)	2	0/101 (0%)	0
Fungal infectious disorders	0/25 (0%)	0	1/101 (1%)	1
Infections - pathogen unspecified	3/25 (12%)	3	10/101 (9.9%)	10
Injury, poisoning and procedural complications
Administration site reactions	0/25 (0%)	0	5/101 (5%)	5
Injuries NEC	0/25 (0%)	0	2/101 (2%)	2
Procedural related injuries and complications NEC	1/25 (4%)	1	0/101 (0%)	0
Investigations
Enzyme investigations NEC	1/25 (4%)	1	0/101 (0%)	0
Haematology investigations (incl blood groups)	1/25 (4%)	1	1/101 (1%)	1
Physical examination and organ system status topics	0/25 (0%)	0	1/101 (1%)	1
Water, electrolyte and mineral investigations	0/25 (0%)	0	1/101 (1%)	1
Metabolism and nutrition disorders
Bone, calcium, magnesium and phosphorus metabolism disorders	1/25 (4%)	2	2/101 (2%)	2
Electrolyte and fluid balance conditions	3/25 (12%)	3	16/101 (15.8%)	16
Glucose metabolism disorders (incl diabetes mellitus)	0/25 (0%)	0	4/101 (4%)	4
Musculoskeletal and connective tissue disorders
Joint disorders	1/25 (4%)	1	1/101 (1%)	1
Muscle disorders	1/25 (4%)	1	2/101 (2%)	2
Musculoskeletal and connective tissue disorders NEC	1/25 (4%)	1	12/101 (11.9%)	14
Nervous system disorders
Central nervous system vascular disorders	0/25 (0%)	0	2/101 (2%)	2
Headaches	4/25 (16%)	4	21/101 (20.8%)	21
Increased intracranial pressure and hydrocephalus	0/25 (0%)	0	1/101 (1%)	1
Neurological disorders NEC	5/25 (20%)	5	11/101 (10.9%)	11
Neuromuscular disorders	0/25 (0%)	0	3/101 (3%)	3
Seizures (incl subtypes)	1/25 (4%)	1	1/101 (1%)	1
Sleep disturbances (incl subtypes)	0/25 (0%)	0	2/101 (2%)	2
Psychiatric disorders
Anxiety disorders and symptoms	2/25 (8%)	2	4/101 (4%)	4
Changes in physical activity	0/25 (0%)	0	1/101 (1%)	1
Cognitive and attention disorders and disturbances	0/25 (0%)	0	1/101 (1%)	1
Depressed mood disorders and disturbances	0/25 (0%)	0	1/101 (1%)	1
Sleep disorders and disturbances	0/25 (0%)	0	2/101 (2%)	2
Renal and urinary disorders
Genitourinary tract disorders NEC	4/25 (16%)	4	7/101 (6.9%)	7
Renal disorders (excl nephropathies)	0/25 (0%)	0	1/101 (1%)	1
Urinary tract signs and symptoms	2/25 (8%)	2	5/101 (5%)	5
Urolithiases	0/25 (0%)	0	1/101 (1%)	1
Reproductive system and breast disorders
Penile and scrotal disorders (excl infections and inflammations)	0/25 (0%)	0	2/101 (2%)	2
Respiratory, thoracic and mediastinal disorders
Bronchial disorders (excl neoplasms)	0/25 (0%)	0	1/101 (1%)	1
Lower respiratory tract disorders (excl obstruction and infection)	1/25 (4%)	1	2/101 (2%)	2
Pleural disorders	0/25 (0%)	0	1/101 (1%)	1
Respiratory disorders NEC	2/25 (8%)	2	7/101 (6.9%)	10
Respiratory tract infections	0/25 (0%)	0	2/101 (2%)	2
Upper respiratory tract disorders (excl infections)	0/25 (0%)	0	1/101 (1%)	1
Skin and subcutaneous tissue disorders
Angioedema and urticaria	0/25 (0%)	0	5/101 (5%)	5
Epidermal and dermal conditions	1/25 (4%)	1	5/101 (5%)	5
Vascular disorders
Arteriosclerosis, stenosis, vascular insufficiency and necrosis	0/25 (0%)	0	2/101 (2%)	2
Decreased and nonspecific blood pressure disorders and shock	2/25 (8%)	2	4/101 (4%)	4
Embolism and thrombosis	0/25 (0%)	0	1/101 (1%)	1
Vascular haemorrhagic disorders	0/25 (0%)	0	12/101 (11.9%)	16

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.