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Interventional Management of Stroke (IMS) III Trial (IMSIII)

This study has been terminated.
(NINDS/NIH-DSMB recommended halting trial due to futility, no safety concerns.)
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Medical University of South Carolina
University of Calgary
Information provided by (Responsible Party):
Joseph Broderick, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT00359424
First received: July 31, 2006
Last updated: November 19, 2013
Last verified: November 2013
History of Changes
Results First Received: July 4, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Stroke
Interventions: Drug: IV rt-PA alone
Other: endovascular therapy

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

A total of 656 participants underwent randomization

  • participants to endovascular therapy >> and 222 to intravenous t-PA alone) at 58 study >> centers between August 25, 2006, and April 17, >> 2012 in the United States (41 sites), Canada (7), >> Australia (4), and Europe (6)

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Endovascular Therapy Endovascular therapy (group two) received a lower dose (0.09mg per kg bolus and 0.54mg/kilogram infusion over 40 minutes, maximum dose 53.6mg) or after Amendment #5, a standard dose of IV rt-PA (.9mg/kg with 10% as a bolus and the remainder over one hour) and then underwent an angiogram test (cerebral angiography) right after the medicine was given to check for blood clots. If a clot was not seen, then no more treatment was given. If a clot was seen, the neurointerventionalist chose (based on the location and extent of the blood clot) a protocol approved endovascular treatment given directly in the brain artery that would be most effective in reopening the blocked artery.
IV Rt-PA Alone IV rt-PA alone (group one) received the standard dose (.9mg per kilogram with 10% as a bolus and the remainder as an infusion over 1 hour -maximum dose 90mg) of intravenous (IV) rt-PA alone.

Participant Flow:   Overall Study
    Endovascular Therapy     IV Rt-PA Alone  
STARTED     434     222  
90 Day Follow up     343     172  
180 Day Follow up     325     167  
270 Day Follow up     313     159  
COMPLETED     304     155  
NOT COMPLETED     130     67  
Death                 99                 58  
Lost to Follow-up                 19                 7  
Withdrawal by Subject                 10                 2  
follow up not conducted                 2                 0  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
A sample of 900 was calculated to provide an effect size of 10 percentage points assuming that 40% of the patients had a good outcome in the IV t-PA group, as noted in patients in the NINDS rt-PA Stroke Study who had age and baseline stroke severity similar to the eligibility criteria for the IMS3 trial. The trial was halted at 656 subjects.

Reporting Groups
  Description
Endovascular Therapy Group two will receive a lower dose or a standard dose of IV rt-PA and then undergo an angiogram test (cerebral angiography) right after the medicine is given to check for blood clots. If a clot is not seen then no more treatment will be given. If a clot is seen, the neurointerventionalist will then choose (based on the location and extent of the blood clot) a protocol approved endovascular treatment given directly in the brain artery that will be most effective in reopening the blocked artery.
IV Rt-PA Alone Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour.
Total Total of all reporting groups

Baseline Measures
    Endovascular Therapy     IV Rt-PA Alone     Total  
Number of Participants  
[units: participants]
 		  434     222     656  
Age  
[units: years]
Median ( Full Range ) 		  69  
  ( 23 to 89 )   		  68  
  ( 23 to 84 )   		  69  
  ( 23 to 89 )  
Gender  
[units: participants]
 		     
Female     216     100     316  
Male     218     122     340  
NIHSS Score [1]
[units: Score on a scale]
Median ( Full Range ) 		  17  
  ( 7 to 40 )   		  16  
  ( 8 to 30 )   		  17  
  ( 7 to 40 )  
Time from stroke onset to initiation of IV rt-PA [2]
[units: minutes]
Mean ± Standard Deviation 		  122.4  ± 33.7     121.2  ± 33.8     122.0  ± 33.7  
NIHSS Score Strata  
[units: participants]
 		     
NIHSS Score <20     302     150     452  
NIHSS Score > = 20     132     72     204  
[1]

The National Institutes of Health Stroke Scale (NIHSS), a serial measure of neurologic deficit, is a 42-point scale that >> quantifies neurologic deficits in 11 categories, with 0 indicating normal function without neurologic deficit and higher

>> scores indicating greater severity of deficit.
[2] Time from stroke onset to initiation of intravenous (IV) rt-PA in minutes.



  Outcome Measures
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1.  Primary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2.   [ Time Frame: at 90 days post randomization ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2.
Measure Description The modified Rankin Scale (mRS) runs from 0-6 running from perfect health without symptoms to death. 0 - No symptoms at all. 1 - No significant disability. Able to carry out all usual duties and activities. 2 - Slight disability. Unable to carry out all previous activities but able to look after own affairs without assistance. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to walk unassisted and unable to attend to own bodily needs without assistance. 5 - Severe disability. Bedridden, incontinent, and requires constant nursing care and attention. 6 - Dead. Persons with a Rankin of 0-2 are considered functionally independent.
Time Frame at 90 days post randomization  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The primary analysis was conducted according to intention to treat. All subjects were analyzed in the treatment group to which they were randomized. Subjects with missing mRS (n=9 in group two; n=4 in group one) or mRS assessed <60 days or >120 days post-randomization (n=10 in group two; n=4 in group one) are assigned an unfavorable outcome(mRS >2)

Reporting Groups
  Description
Endovascular Therapy Group two will receive a lower dose or a standard dose of IV rt-PA and then undergo an angiogram test (cerebral angiography) right after the medicine is given to check for blood clots. If a clot is not seen then no more treatment will be given. If a clot is seen, the neurointerventionalist will then choose (based on the location and extent of the blood clot) a protocol approved endovascular treatment given directly in the brain artery that will be most effective in reopening the blocked artery.
IV Rt-PA Alone Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour.

Measured Values
    Endovascular Therapy     IV Rt-PA Alone  
Number of Participants Analyzed  
[units: participants]
 		  434     222  
Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2.  
[units: participants]
 		   
mRS 0-2     177     86  
mRS 3-6     257     136  


Statistical Analysis 1 for Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2.
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] .7031
Risk Difference (RD) [4] 1.5
95% Confidence Interval ( -6.1 to 9.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Test of null hypothesis (equal proportions of subjects with mRS of 0-2 at 90 days post-randomization in IV Only and Endovascular treatment arms) versus alternative hypothesis (unequal proportions of subjects with mRS of 0-2 at 90 days post-randomization in IV Only and Endovascular treatment arms).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Cochran-Mantel-Haenszel (CMH) test adjusting for the dichotomized baseline NIHSS score (<20 or ≥20).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The CMH statistic is tested at the two-sided alpha level of 0.05. For the interim analyses of the primary efficacy analysis, the alpha spending function method (Lan and DeMets, 1987) with O'Brien and Fleming (1979) stopping boundaries were adopted.
[4] Other relevant estimation information:
  Positive adjusted risk difference indicates greater risk in the Endovascular group, while negative adjusted risk difference indicates greater risk in the IV Only group.



2.  Primary:   Death Due to Any Cause   [ Time Frame: within 90 days post randomization ]
  Show Outcome Measure 2

3.  Primary:   Symptomatic Intracranial Hemorrhage   [ Time Frame: within the first 30 hours post IV rt-PA ]
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4.  Secondary:   Incidence of Parenchymal Type II (PH2) Hematomas   [ Time Frame: within 30 hours post IV rt-PA ]
  Show Outcome Measure 4

5.  Secondary:   Asymptomatic Intracranial Hemorrhage   [ Time Frame: within 30 hours post IV rt-PA ]
  Show Outcome Measure 5

6.  Secondary:   National Institutes of Health Stroke Scale Score (NIHSS) >> Dichotomized 0-1 Versus 2 or Greater.   [ Time Frame: at 24 hours post randomization ]
  Show Outcome Measure 6

7.  Secondary:   National Institutes of Health Stroke Scale Score (NIHSS) Dichotomized 0-1 Versus 2 or Greater.   [ Time Frame: at 90 days post randomization ]
  Show Outcome Measure 7

8.  Secondary:   Barthel Index (BI) Dichotomized 0-90 Versus 95-100   [ Time Frame: at 90 days post randomization ]
  Show Outcome Measure 8

9.  Secondary:   Trail Making Test Part A Time   [ Time Frame: 90 days post randomization ]
  Show Outcome Measure 9

10.  Secondary:   Trail Making Test Part B Time   [ Time Frame: at 90 days post randomization ]
  Show Outcome Measure 10

11.  Secondary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2   [ Time Frame: at 180 days ]
  Show Outcome Measure 11

12.  Secondary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2   [ Time Frame: 270 days ]
  Show Outcome Measure 12

13.  Secondary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2   [ Time Frame: 360 days post randomization ]
  Show Outcome Measure 13


  Serious Adverse Events
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  Other Adverse Events
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  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The IMS III trial was stopped early because of futility, according to the prespecified rules. A limitation of our trial is that it did not compare the efficacy of the new stent retrievers with that of intravenous t-PA alone.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Joseph P. Broderick
Organization: University of Cincinnati Academic Health Center
phone: 513-558-5429
e-mail: broderjp@ucmail.uc.edu


No publications provided by University of Cincinnati

Publications automatically indexed to this study:


Responsible Party: Joseph Broderick, University of Cincinnati
ClinicalTrials.gov Identifier: NCT00359424     History of Changes
Other Study ID Numbers: U01NS052220, U01NS052220, U01NS054630, 2009-017454-12
Study First Received: July 31, 2006
Results First Received: July 4, 2013
Last Updated: November 19, 2013
Health Authority: United States: Food and Drug Administration
United States: Federal Government
Canada: Health Canada
Australia: Department of Health and Ageing Therapeutic Goods Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Ethics Commission
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Spain: Ministry of Health
Switzerland: Swissmedic