CLUE: Evaluation of Intravenous Cardene(Nicardipine)and Labetalol Use in the Emergency Department

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00765648
• Collaborator: EKR Therapeutics, Inc (Industry)
• Enrollment: 226
• Locations: 2
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 113
• Patients Per Site Per Month: 7.5

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the safety and efficacy of Cardene I.V. to labetalol administered intravenously for the management of hypertension in the emergency department setting.

Condition or Disease	Intervention/Treatment	Phase
Hypertensive Urgency	Drug: nicardipine intravenous; Drug: Labetalol	Phase 4

Detailed Description

More than 3 million patients yearly receive an intravenous antihypertensive agent in the US. Despite this large number of critically ill patients treated annually, little research exists in the area of acute severe hypertension, specifically hypertensive emergency, a serious condition that contributes to morbidity and mortality.

Two agents that are commonly used to treat acute hypertensive crisis include labetalol and nicardipine. Cardene may provide benefits in titration and has shown to have lower dosage adjustments compared to labetalol. Nicardipine has also shown a decreased need for additional antihypertensives when compared to labetalol in patients with stroke in a neurological ICU.

Study Design

• Study Type: Interventional
• Actual Enrollment: 226 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IV, Randomized Trial to Determine the Efficacy and Safety of Cardene Intravenous (I.V.) Versus Labetalol for Management of Hypertensive Emergencies in the Emergency Department Setting
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 nicardipine intravenous	Drug: nicardipine intravenous; nicardipine intravenous 5 mg/hour titrated every 5 minutes by 2.5 mg/hour until target systolic blood pressure range (TSBPR) is reached or maximum dose of 15 mg/hour is achieved.Following achievement of target systolic blood pressure range the infusion rate should be decreased to 3 mg/hour; Other Names: Nicardipine hydrochloride
Active Comparator: 2 Labetalol	Drug: Labetalol; Labetalol: bolus therapy to start at 20 mg intravenous injection over 2 minutes, may repeat 20mg, 40mg or 80mg injections every 10 minutes until target systolic blood pressure range(TSBPR)is reached or a maximum of 300 mg is injected.

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects Achieving a Pre-defined Target Systolic Blood Pressure (BP) Within 30 Minutes. [30 minutes after initiation of therapy]

   Percentage of subjects achieving a pre-defined target systolic blood pressure (BP) range defined as a systolic blood pressure that is within +/- 20 mmHg of the target as established by the investigator.

Secondary Outcome Measures

1. Average Number of Dose Titrations Within 30 Minutes [30 minutes]

   Calculated as the mean (± standard deviation) number of titrations over 30 minutes for each treatment group

2. Emergency Department(ED)Time to Disposition Decision [6 hours]

   Median number of hours from hospital admission until Emergency Department(ED)disposition

3. Treatment Failure [6 hours]

   Treatment failure is defined as admission to the hospital or observation unit for BP management

4. Subjects Requiring the Use of Intravenous Rescue Medications [6 hours]

   The percent of subjects requiring the use of intravenous rescue medications

5. Transition Time to Oral Medication [6 hours]

   The median transition time (in hours) to oral medication

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 18 years of age or older

• Systolic blood pressure ≥180 mm Hg on 2 consecutive readings(10 minutes apart)presenting in the emergency department (ED)

Exclusion Criteria:

• Use of any investigational drug within 1 month prior to emergency department (ED)

• Pregnant or breast-feeding females

• Contraindications or allergy to beta-blockers and calcium channel blockers (see FDA approved labeling for nicardipine intravenous and labetalol)

• Subjects with decompensated congestive heart failure (CHF) or with a known left ventricular ejection fraction (LVEF) <35%

• History of stroke within 30 days

• Known liver failure

• Suspected myocardial infarction

• Suspected aortic dissection

• Suspected cocaine overdose

• Concurrently receiving other intravenous (I.V.) hypertensive medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic	Cleveland	Ohio	United States	44122
2	University of Texas Health Science Center	Houston	Texas	United States

Sponsors and Collaborators

• The Cleveland Clinic
• EKR Therapeutics, Inc

Investigators

• Principal Investigator: W. Frank Peacock, MD, The Cleveland Clinic
• Principal Investigator: Joseph Varon, MD, The University of Texas Health Science Center, Houston

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT00765648
• Other Study ID Numbers: 2008-001
• First Posted: Oct 3, 2008
• Last Update Posted: Jan 6, 2015
• Last Verified: Jul 1, 2011

• Keywords provided by The Cleveland Clinic: hypertension; emergency department; Nicardipine; Labetalol; hypertensive emergency; hypertensive urgency
• Additional relevant MeSH terms: Emergencies; Labetalol; Nicardipine

Study Results

Participant Flow

Recruitment Details	Eligible patients had 2 systolic blood pressures(BP) measures > 180 mmHg at least 10 minutes apart, and no contraindications.Emergency room setting.

Arm/Group Title	Nicardipine Dosing Was 5 mg/Hour	Bolus Labetalol Began at 20 mg Over 2 Minutes
Arm/Group Description	nicardipine intravenous	Labetalol
Period Title: Overall Study
STARTED	110	116
COMPLETED	109	114
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Nicardipine Dosing Was 5 mg/Hour	Bolus Labetalol Began at 20 mg Over 2 Minutes	Total
Arm/Group Description	nicardipine intravenous	Labetalol	Total of all reporting groups
Overall Participants	110	116	226
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	81 73.6%	98 84.5%	179 79.2%
>=65 years	29 26.4%	18 15.5%	47 20.8%
Sex: Female, Male (Count of Participants)
Female	60 54.5%	59 50.9%	119 52.7%
Male	50 45.5%	57 49.1%	107 47.3%
Region of Enrollment (participants) [Number]
United States	110 100%	116 100%	226 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects Achieving a Pre-defined Target Systolic Blood Pressure (BP) Within 30 Minutes.
Description	Percentage of subjects achieving a pre-defined target systolic blood pressure (BP) range defined as a systolic blood pressure that is within +/- 20 mmHg of the target as established by the investigator.
Time Frame	30 minutes after initiation of therapy

Outcome Measure Data

Analysis Population Description

Intent to treat cohort.

Arm/Group Title	Nicardipine	Labetalol
Arm/Group Description	Nicardipine was administered at 5mg/hour and increased every 5 minutes by 2.5 mg/hour until the target systolic blood pressure (SBP) range is reached or maximum of 15mg/hour is achieved.	Labetalol is given intravenous bolus starting with 20mg over 2 minutes, which is repeated at 20, 40, or 80mg injections every 10 minutes until the target systolic blood pressure (SBP) range is reached or a maximum of 300mg is administered.
Measure Participants	109	114
Number [percentage of participants]	91.7 83.4%	82.5 71.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nicardipine, Labetalol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-9.3
	Confidence Interval	(2-Sided) 95%; -18.0 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Average Number of Dose Titrations Within 30 Minutes
Description	Calculated as the mean (± standard deviation) number of titrations over 30 minutes for each treatment group
Time Frame	30 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicardipine	Labetalol
Arm/Group Description	Nicardipine was administered at 5mg/hour and increased every 5 minutes by 2.5 mg/hour until the target systolic blood pressure (SBP) range is reached or maximum of 15mg/hour is achieved.	Labetalol is given intravenous bolus starting with 20mg over 2 minutes, which is repeated at 20, 40, or 80mg injections every 10 minutes until the target systolic blood pressure (SBP) range is reached or a maximum of 300mg is administered.
Measure Participants	109	114
Mean (Standard Deviation) [number of titrations]	2.2 (1)	1.3 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nicardipine, Labetalol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Emergency Department(ED)Time to Disposition Decision
Description	Median number of hours from hospital admission until Emergency Department(ED)disposition
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

these are the correct participant numbers for this secondary analysis

Arm/Group Title	Nicardipine	Labetalol
Arm/Group Description	Nicardipine was administered at 5mg/hour and increased every 5 minutes by 2.5 mg/hour until the target systolic blood pressure (SBP) range is reached or maximum of 15mg/hour is achieved.	Labetalol is given intravenous bolus starting with 20mg over 2 minutes, which is repeated at 20, 40, or 80mg injections every 10 minutes until the target systolic blood pressure (SBP) range is reached or a maximum of 300mg is administered.
Measure Participants	109	115
Median (Inter-Quartile Range) [hours]	4.6	4.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nicardipine, Labetalol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Treatment Failure
Description	Treatment failure is defined as admission to the hospital or observation unit for BP management
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

these are the correct participant numbers for this secondary analysis

Arm/Group Title	Nicardipine	Labetalol
Arm/Group Description	Nicardipine was administered at 5mg/hour and increased every 5 minutes by 2.5 mg/hour until the target systolic blood pressure (SBP) range is reached or maximum of 15mg/hour is achieved.	Labetalol is given intravenous bolus starting with 20mg over 2 minutes, which is repeated at 20, 40, or 80mg injections every 10 minutes until the target systolic blood pressure (SBP) range is reached or a maximum of 300mg is administered.
Measure Participants	109	115
Number [percentage of participants]	43.1 39.2%	37.4 32.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nicardipine, Labetalol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Subjects Requiring the Use of Intravenous Rescue Medications
Description	The percent of subjects requiring the use of intravenous rescue medications
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicardipine	Labetalol
Arm/Group Description	Nicardipine was administered at 5mg/hour and increased every 5 minutes by 2.5 mg/hour until the target systolic blood pressure (SBP) range is reached or maximum of 15mg/hour is achieved.	Labetalol is given intravenous bolus starting with 20mg over 2 minutes, which is repeated at 20, 40, or 80mg injections every 10 minutes until the target systolic blood pressure (SBP) range is reached or a maximum of 300mg is administered.
Measure Participants	110	116
Number [percentage of participants]	15.5 14.1%	22.4 19.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nicardipine, Labetalol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Transition Time to Oral Medication
Description	The median transition time (in hours) to oral medication
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

these are the correct participant numbers for this secondary analysis

Arm/Group Title	Nicardipine	Labetalol
Arm/Group Description	Nicardipine was administered at 5mg/hour and increased every 5 minutes by 2.5 mg/hour until the target systolic blood pressure (SBP) range is reached or maximum of 15mg/hour is achieved.	Labetalol is given intravenous bolus starting with 20mg over 2 minutes, which is repeated at 20, 40, or 80mg injections every 10 minutes until the target systolic blood pressure (SBP) range is reached or a maximum of 300mg is administered.
Measure Participants	96	85
Median (Inter-Quartile Range) [hours]	4.9	6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nicardipine, Labetalol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Emergency Room visit
Adverse Event Reporting Description	Elevated cardiac markers
Arm/Group Title	Nicardipine		Labetalol
Arm/Group Description	Nicardipine dosing was 5 mg/hour		Bolus Labetalol began at 20 mg over 2 minutes
All Cause Mortality
	Nicardipine		Labetalol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nicardipine		Labetalol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/110 (0%)		0/116 (0%)
Other (Not Including Serious) Adverse Events
	Nicardipine		Labetalol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/110 (0.9%)		0/116 (0%)
Cardiac disorders
Elevated cardiac biomarkers	1/110 (0.9%)	1	0/116 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.