ICTuS2/3: The Intravascular Cooling in the Treatment of Stroke 2/3 Trial

• Sponsor: University of California, San Diego (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01123161
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH), The University of Texas Health Science Center, Houston (Other)
• Enrollment: 120
• Locations: 31
• Arms: 2
• Duration (Months): 59
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial is to determine whether the combination of thrombolysis and hypothermia is superior to thrombolysis alone for the treatment of acute ischemic stroke.

Condition or Disease	Intervention/Treatment	Phase
Stroke, Acute	Device: hypothermia and anti-shivering treatment; Drug: Group1: IV t-PA and normothermia	Phase 2/Phase 3

Detailed Description

A stroke is usually caused by a blockage in one of the arteries that carries blood to the brain. Research has shown that tissue plasminogen activator (tPA)-a naturally occurring protein that opens blocked arteries by dissolving blood clots - activates the body's ability to dissolve recently formed blood clots and reduces or prevents the brain damage caused by a stroke.

The Food and Drug Administration (FDA) has approved the use of tPA for people having a stroke when taken within 3 hours of stroke onset.

Researchers believe that a lower body temperature (hypothermia) may be beneficial while a stroke is happening because hypothermia may prevent further brain injury, or may make the stroke less damaging.

Patients will receive a standard stroke evaluation, which includes blood tests, a computed tomography (CT) scan, complete physical and neurological examinations, and an electrocardiogram (EKG) to determine eligibility for the study.

There are two study groups - tPA alone or tPA with cooling (hypothermia). Participants will be randomly assigned to one of the two study groups. Length of participation (including observation after the patient leaves the hospital) is 90 days.

This study is part of the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS), which allows researchers to enhance and initiate translational research that ultimately will benefit stroke patients by treating more patients in less than 2 hours, and finding ways to treat additional patients later.

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Intervention Model Description: Randomized to normothermia or hypothermiaRandomized to normothermia or hypothermia
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group1: IV t-PA and normothermia IV tpa and normothermia	Drug: Group1: IV t-PA and normothermia; Group 1 will t-PA as standard of care and normothermia
Active Comparator: Group 2 : IV t-PA and hypothermia and anti-shivering treatment IV tpa and hypothermia and anti-shivering treatment	Device: hypothermia and anti-shivering treatment; Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine and surface warming; Other Names: cooling

Outcome Measures

Primary Outcome Measures

1. The Primary Outcome is the Proportion of Patients Achieving a Favorable Outcome Defined as Modified Rankin Scale Score of 0 or 1, Assessed 90 Days After Treatment. [90 days]

   Modified Rankin describes disability: 0 is free of any disability or symptoms, 6 is death, and higher grades between 0 and 6 reflect progressively greater disability

2. Incidence of Any Intracranial Hemorrhage (ICH) Within 48 Hours of Stroke Onset [48 hours]

   Incidence (number) of any intracranial hemorrhage (ICH) (whether or not symptomatic) within 48 hours of stroke onset will be presented by treatment group and overall.

3. Incidence of Any Symptomatic Intracranial Hemorrhage (sICH) Within 48 Hours of Stroke Onset [48 hours]

   Incidence (number) of Symptomatic ICH (sICH) within 48 hours of stroke onset will be presented by treatment group and overall. Patients with neuroworsening (4 or more point increase in NIHSS , or a decline in the NIHSS consciousness item 1A score of more than 1 point, or a motor deterioration lasting more than 8 hours, all not due to iatrogenic cause) and hemorrhage seen on brain images in whom the investigator attributes the clinical change to the hemorrhage.

4. Incidence of Pneumonia [7 days or discharge whichever comes first]

   Number subjects diagnosed with pneumonia according to CDC criteria will be presented by treatment group and overall, regardless of seriousness

5. 90 Day Mortality [90 days]

   Mortality prior to the 90-day evaluation.

Secondary Outcome Measures

1. The Barthel Index Measure of Activities of Daily Living; [90 days]

   The Barthel index measures independence in activities of daily living from 0 (worst) to 100 (best) in 5 point increments. Higher scores between 0 and 100 reflect progressively greater levels of independence. Scores were dichotomized at 90 so that a score of 95 or 100 was considered a successful treatment.

2. NIHSS Scores at 90 Days [90 days]

   The National Institutes of Health Stroke Scale (NIHSS) is used to quantify neurological deficit. The scale ranges from 0 (best) to 42 points (worst). Between scores of 0 to 42, higher values reflect progressively greater deficit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 22 Years to 82 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age 22 to 82 years old inclusive

2. Patient receiving IV rt-PA using standard guidelines

3. NIHSS score ≥ 7 and ≤ 20 (right hemisphere) or ≥ 7 and ≤ 24 (left hemisphere) at the time of randomization

4. Pre-stroke mRS 0-1

5. Able to begin endovascular phase of hypothermia within 2 hours of tPA completion

6. Written Informed Consent, signed and dated by the patient (or patient's authorized representative)

Exclusion Criteria:

1. Etiology other than ischemic stroke

2. Item 1a on NIHSS > 1 at the time of randomization

3. Clinical symptoms consistent with brainstem or cerebellar stroke

4. Classic lacunar syndrome with imaging confirmation of small deep ischemia, but randomization will not be delayed for neuroimaging other than initial scan to exclude hemorrhage

5. Known contraindications to hypothermia, such as known hematologic dyscrasias that affect thrombosis (cryoglobulinemia, Sickle cell disease, serum cold agglutinins), or vasospastic disorders such as Raynaud's or thromboangiitis obliterans

6. Known co-morbid conditions that are likely to complicate therapy in the opinion of the investigator, e.g., i. Heart failure (NYHA class III and IV)* ii. Uncompensated arrhythmia iii. Severe Liver disease iv. History of pelvic or abdominal mass likely to compress inferior vena cava v. IVC filters vi. HIV positive vii. Clinically active hypo or hyperthyroidism viii. Renal insufficiency likely to impair meperidine clearance ix. Chronic ethanol abuse x. History of HIT (heparin induced thrombocytopenia)

7. Pregnancy (All women of child-bearing potential must have a negative pregnancy test, urine or blood, prior to therapy.)

8. Medical conditions likely to interfere with patient assessment.

9. Known allergy to meperidine or buspirone

10. Currently taking or used within previous 14 days MAO-I class of medication.

11. Life expectancy < 6 months

12. Not likely to be available for long-term follow-up

13. Use, or planned use, of intra-arterial thrombolysis, mechanical clot removal, or other experimental or approved acute therapy for this stroke event

14. Chest radiograph or clinical presentation suggestive of pneumonia or clinically significant pulmonary edema at baseline.

15. Temperature upon admission greater than or equal to 38°C

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Hospital	Birmingham	Alabama	United States	35249
2	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
3	Hoag Memorial Hospital Presbyterian	Newport Beach	California	United States	92658
4	University of California San Diego Health System	San Diego	California	United States	92093
5	Scripps Mercy Medical Center	San Diego	California	United States	92103
6	University of Colorado Hospital	Aurora	Colorado	United States	80045
7	Swedish Medical Center	Englewood	Colorado	United States	80113
8	Hartford Hospital	Hartford	Connecticut	United States	06102
9	Yale University	New Haven	Connecticut	United States	06510
10	Gulf Coast Medical Center	Fort Myers	Florida	United States	33912
11	University of Florida	Gainesville	Florida	United States	32608
12	University of Miami, Jackson Memorial Hospital	Miami	Florida	United States	33136
13	Intercoastal Medical Group	Sarasota	Florida	United States	34232
14	St. Joseph's Hospital	Tampa	Florida	United States	33607
15	Alexian Brothers Medical Center	Elk Grove Village	Illinois	United States	60007
16	Parkview Hospital	Fort Wayne	Indiana	United States	46805
17	Ruan Neurology Clinic and Research Center	Des Moines	Iowa	United States	50314
18	University of Louisville	Louisville	Kentucky	United States	40202
19	Henry Ford Health System	Detroit	Michigan	United States	48202
20	Michigan State University	East Lansing	Michigan	United States	48824
21	North Memorial Medical Center	Robbinsdale	Minnesota	United States	55422
22	Saint Louis University Medical Center	St. Louis	Missouri	United States	63110
23	Columbia University Medical Center	New York	New York	United States	10032
24	University of Toledo Medical Center	Toledo	Ohio	United States	43614
25	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
26	Lehigh Valley Health Network	Allentown	Pennsylvania	United States	18103
27	Seton Medical Center Austin	Austin	Texas	United States	78705
28	UT Southwestern	Dallas	Texas	United States	75390
29	University of Texas Health Science Center	Houston	Texas	United States	77030
30	Medical University Innsbruck	Innsbruck		Austria
31	CHUV	Lausanne		Switzerland

Sponsors and Collaborators

• University of California, San Diego
• National Institute of Neurological Disorders and Stroke (NINDS)
• The University of Texas Health Science Center, Houston

Investigators

• Principal Investigator: Patrick D. Lyden, MD, Cedars-Sinai Medical Center
• Study Director: Thomas M. Hemmen, MD, PhD, University of California, San Diego
• Study Director: James C. Grotta, MD, The University of Texas Health Science Center, Houston

Study Documents (Full-Text)

None provided.

More Information

Publications

• Guluma KZ, Hemmen TM, Olsen SE, Rapp KS, Lyden PD. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad Emerg Med. 2006 Aug;13(8):820-7. Epub 2006 Jun 9.
• Guluma KZ, Liu L, Hemmen TM, Acharya AB, Rapp KS, Raman R, Lyden PD. Therapeutic hypothermia is associated with a decrease in urine output in acute stroke patients. Resuscitation. 2010 Dec;81(12):1642-7. doi: 10.1016/j.resuscitation.2010.08.003.
• Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD; ICTuS-L Investigators. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010 Oct;41(10):2265-70. doi: 10.1161/STROKEAHA.110.592295. Epub 2010 Aug 19.
• Lyden P, Ernstrom K, Cruz-Flores S, Gomes J, Grotta J, Mullin A, Rapp K, Raman R, Wijman C, Hemmen T. Determinants of effective cooling during endovascular hypothermia. Neurocrit Care. 2012 Jun;16(3):413-20. doi: 10.1007/s12028-012-9688-y.
• Lyden P, Ernstrom K, Raman R. Determinants of Pneumonia Risk During Endovascular Hypothermia. Ther Hypothermia Temp Manag. 2013 Mar;3(1):24-27.
• Lyden PD, Allgren RL, Ng K, Akins P, Meyer B, Al-Sanani F, Lutsep H, Dobak J, Matsubara BS, Zivin J. Intravascular Cooling in the Treatment of Stroke (ICTuS): early clinical experience. J Stroke Cerebrovasc Dis. 2005 May-Jun;14(3):107-14.

• Responsible Party: Patrick Lyden, Principal Investigator, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT01123161
• Other Study ID Numbers: ICTuS2/3; P50NS044148; P50NS044227
• First Posted: May 14, 2010
• Last Update Posted: Apr 5, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Patrick Lyden, Principal Investigator, Cedars-Sinai Medical Center: Hypothermia; Molecular Mechanisms of Pharmacological Action; Cerebral Infarction; Hematologic Agents; Stroke; Nervous System Diseases; Vascular Diseases; Tissue Plasminogen Activator; Central Nervous System Diseases; Fibrinolytic Agents; Cardiovascular Agents; Body Temperature Changes; Brain Diseases; Cerebrovascular Disorders; Pharmacologic Actions; Signs and Symptoms; Fibrin Modulating Agents; Therapeutic Uses; Brain Ischemia; Cardiovascular Diseases; Brain Infarction; Plasminogen; cooling; tPA; thrombolysis
• Additional relevant MeSH terms: Stroke

Study Results

Participant Flow

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine, and surface warming.
Period Title: Overall Study
STARTED	57	63
COMPLETED	55	63
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment	Total
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine, and surface warming	Total of all reporting groups
Overall Participants	57	63	120
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.5 (11.1)	65.5 (10.3)	66.4 (10.7)
Sex: Female, Male (Count of Participants)
Female	22 38.6%	29 46%	51 42.5%
Male	35 61.4%	34 54%	69 57.5%
Baseline NIHSS (points) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [points]	14.5 (4.9)	14.1 (4.8)	14.3 (4.8)
Baseline temperature (degrees (C)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [degrees (C)]	36.4 (0.50)	36.6 (0.46)	36.5 (0.48)

Outcome Measures

1. Primary Outcome

Title	The Primary Outcome is the Proportion of Patients Achieving a Favorable Outcome Defined as Modified Rankin Scale Score of 0 or 1, Assessed 90 Days After Treatment.
Description	Modified Rankin describes disability: 0 is free of any disability or symptoms, 6 is death, and higher grades between 0 and 6 reflect progressively greater disability
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Intention to Treat Population

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia hypothermia: Hypothermia is induced using the Celsius Control™ System
Measure Participants	55	63
Number [participants]	21 36.8%	21 33.3%

2. Primary Outcome

Title	Incidence of Any Intracranial Hemorrhage (ICH) Within 48 Hours of Stroke Onset
Description	Incidence (number) of any intracranial hemorrhage (ICH) (whether or not symptomatic) within 48 hours of stroke onset will be presented by treatment group and overall.
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Intention to treat patients with imaging obtained 36 to 48 hours after treatment

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine, and surface warming
Measure Participants	57	63
Number [participants]	13 22.8%	9 14.3%

3. Primary Outcome

Title	Incidence of Any Symptomatic Intracranial Hemorrhage (sICH) Within 48 Hours of Stroke Onset
Description	Incidence (number) of Symptomatic ICH (sICH) within 48 hours of stroke onset will be presented by treatment group and overall. Patients with neuroworsening (4 or more point increase in NIHSS , or a decline in the NIHSS consciousness item 1A score of more than 1 point, or a motor deterioration lasting more than 8 hours, all not due to iatrogenic cause) and hemorrhage seen on brain images in whom the investigator attributes the clinical change to the hemorrhage.
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

ITT patients in whom a brain image was obtained 36 yo 48 hours after treatment

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine, and surface warming
Measure Participants	57	63
Number [participants]	2 3.5%	1 1.6%

4. Primary Outcome

Title	Incidence of Pneumonia
Description	Number subjects diagnosed with pneumonia according to CDC criteria will be presented by treatment group and overall, regardless of seriousness
Time Frame	7 days or discharge whichever comes first

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine, and surface warming
Measure Participants	57	63
Number [participants]	6 10.5%	12 19%

5. Primary Outcome

Title	90 Day Mortality
Description	Mortality prior to the 90-day evaluation.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine, and surface warming.
Measure Participants	57	63
Number [participants]	5 8.8%	10 15.9%

6. Secondary Outcome

Title	The Barthel Index Measure of Activities of Daily Living;
Description	The Barthel index measures independence in activities of daily living from 0 (worst) to 100 (best) in 5 point increments. Higher scores between 0 and 100 reflect progressively greater levels of independence. Scores were dichotomized at 90 so that a score of 95 or 100 was considered a successful treatment.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

The intention to treat population with a 90-day Barthel index available was used, therefore the numbers are fewer than in the total population.

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering treatment includes buspirone, meperidine, and surface warming.
Measure Participants	46	49
Number [participants]	25 43.9%	24 38.1%

7. Secondary Outcome

Title	NIHSS Scores at 90 Days
Description	The National Institutes of Health Stroke Scale (NIHSS) is used to quantify neurological deficit. The scale ranges from 0 (best) to 42 points (worst). Between scores of 0 to 42, higher values reflect progressively greater deficit.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Intention to treat patients with an available 90-day NIHSS values therefore the total numbers available are fewer than the total ITT population.

Arm/Group Title	Group1: IV t-PA and Normothermia	Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia	IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine, and surface warming
Measure Participants	44	43
Mean (Standard Deviation) [units on a scale]	6.1 (6.6)	4.8 (5.4)

Adverse Events

Time Frame	Adverse events were collected for 7 days or discharge whichever came first. Serious adverse events were collected for 90 days.
Adverse Event Reporting Description	Adverse events and Other (not including serious) events are summarized by system organ class, rather than Adverse Event Terms, due to the small number of subjects and infrequency of adverse events.
Arm/Group Title	Group1: IV t-PA and Normothermia		Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
Arm/Group Description	IV tpa and normothermia Group1: IV t-PA and normothermia: Group 1 will t-PA as standard of care and normothermia		IV tpa and hypothermia and anti-shivering treatment hypothermia: Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine and surface warming.
All Cause Mortality
	Group1: IV t-PA and Normothermia		Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group1: IV t-PA and Normothermia		Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/57 (35.1%)		26/63 (41.3%)
Cardiac disorders
Cardiac Disorders	3/57 (5.3%)	3	2/63 (3.2%)	2
Infections and infestations
Infections	0/57 (0%)	0	4/63 (6.3%)	4
Injury, poisoning and procedural complications
injury	3/57 (5.3%)	3	0/63 (0%)	0
Metabolism and nutrition disorders
Metabolism	0/57 (0%)	0	2/63 (3.2%)	2
Musculoskeletal and connective tissue disorders
muskuloskeletal	0/57 (0%)	0	1/63 (1.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm	1/57 (1.8%)	1	0/63 (0%)	0
Nervous system disorders
Nervous System Disorders	13/57 (22.8%)	17	13/63 (20.6%)	13
Psychiatric disorders
psychiatric disorders	0/57 (0%)	0	1/63 (1.6%)	1
Renal and urinary disorders
renal	0/57 (0%)	0	1/63 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory	2/57 (3.5%)	3	9/63 (14.3%)	10
Vascular disorders
vascular	3/57 (5.3%)	4	1/63 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Group1: IV t-PA and Normothermia		Group 2 : IV t-PA and Hypothermia and Anti-shivering Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/57 (93%)		63/63 (100%)
Blood and lymphatic system disorders
Blood and lymphatic	7/57 (12.3%)	7	4/63 (6.3%)	4
Cardiac disorders
Cardiac	15/57 (26.3%)	16	19/63 (30.2%)	33
Endocrine disorders
Endocrine	0/57 (0%)	0	6/63 (9.5%)	6
Eye disorders
Eye	2/57 (3.5%)	2	2/63 (3.2%)	2
Gastrointestinal disorders
GI	23/57 (40.4%)	30	36/63 (57.1%)	50
General disorders
General	17/57 (29.8%)	21	34/63 (54%)	38
Immune system disorders
immune	1/57 (1.8%)	1	2/63 (3.2%)	2
Infections and infestations
Infection	10/57 (17.5%)	11	14/63 (22.2%)	14
Injury, poisoning and procedural complications
injury	6/57 (10.5%)	6	7/63 (11.1%)	7
Investigations
investigations	34/57 (59.6%)	83	52/63 (82.5%)	139
Metabolism and nutrition disorders
Metabolism	6/57 (10.5%)	6	11/63 (17.5%)	11
Musculoskeletal and connective tissue disorders
Muskuloskeletal	7/57 (12.3%)	8	11/63 (17.5%)	12
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms	1/57 (1.8%)	1	0/63 (0%)	0
Nervous system disorders
Nervous Systen	33/57 (57.9%)	54	37/63 (58.7%)	46
Psychiatric disorders
Psychiatric	8/57 (14%)	8	8/63 (12.7%)	8
Renal and urinary disorders
Renal	6/57 (10.5%)	6	5/63 (7.9%)	6
Reproductive system and breast disorders
Reproductive	1/57 (1.8%)	1	0/63 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory	15/57 (26.3%)	21	31/63 (49.2%)	44
Skin and subcutaneous tissue disorders
Skin	2/57 (3.5%)	2	1/63 (1.6%)	1
Vascular disorders
Vascular	19/57 (33.3%)	23	28/63 (44.4%)	33

Limitations/Caveats

[Not Specified]

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.