ICE T-TIMI 49: A Safety/Efficacy Study of Intra-coronary Tenecteplase During Balloon Angioplasty to Treat Heart Attacks

• Sponsor: C. Michael Gibson, MS, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00604695
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 40
• Locations: 8
• Arms: 2
• Duration (Months): 40
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study is to gather preliminary data regarding the angiographic efficacy of the administration of low-dose adjunctive intracoronary (IC) tenecteplase during balloon angioplasty for heart attacks.

We hypothesize that low-dose IC tenecteplase will enhance the breakdown of blood clots at the site of the culprit lesion leading to reduced damage to the heart muscle.

Condition or Disease	Intervention/Treatment	Phase
Acute Myocardial Infarction	Drug: Tenecteplase; Drug: Sterile Saline	Phase 2

Detailed Description

The primary objective of this study is to gather preliminary data regarding the angiographic efficacy of the administration of low-dose adjunctive intracoronary (IC) tenecteplase during primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Efficacy will be assessed by measurements of both the angiographic characteristics of the culprit lesion as well as by measurements of epicardial flow and myocardial perfusion in the territory of the infarct-related artery. This study will also evaluate the safety of administering low-dose IC tenecteplase to subjects undergoing primary PCI for STEMI treated with standard therapy (aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors). Safety endpoints include the incidence of death, recurrent myocardial infarction (MI), abrupt vessel closure, subacute stent thrombosis, and TIMI major and minor bleeding events.

Prompt reperfusion therapy with primary PCI in patients with STEMI improves clinical outcomes through salvage of myocardial tissue. The proposed pilot trial is a randomized, placebo-controlled trial to evaluate the effectiveness and safety of adjunctive low-dose IC tenecteplase in conjunction with standard medical therapy during primary PCI for STEMI. We hypothesized that low-dose IC tenecteplase will enhance fibrinolysis at the site of the culprit lesion leading to reduced microvascular dysfunction. As reduced dose tenecteplase will be injected directly into the coronary artery increasing local concentration of the drug with minor systemic effects, an improved safety profile is also expected from this mode of administration.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial Evaluating Low-Dose IntraCoronary AdjunctivE Tenecteplase During Primary PCI for ST-Elevation Myocardial Infarction (ICE T)
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Two (4mg) doses of tenecteplase	Drug: Tenecteplase; Intracoronary injection of IV tenecteplase.
Placebo Comparator: 2 Two (4mL) doses of sterile saline	Drug: Sterile Saline; Intracoronary injection of IV sterile saline

Outcome Measures

Primary Outcome Measures

1. Percent Diameter Stenosis of the Culprit Lesion Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention [Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention]

Secondary Outcome Measures

1. Number of Patients With Decrease in Thrombus Grade in the Culprit Artery Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention [Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention]

2. Number of Patients With Thrombolysis In Myocardial Infarction (TIMI) Myocardial Perfusion Grade (TMPG) of 2 or 3 in the Territory of the Culprit Artery Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug [Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug]

   Thrombolysis In Myocardial Infarction (TIMI) Myocardial Perfusion Grade (TMPG) of 2 or 3 in the territory of the culprit artery

3. Measurements of Flow Velocity in the Culprit Artery in Terms of Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC) [Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug]

   Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC) in the culprit artery

4. Number of Patients With Hyperemic Flow in the Culprit Artery. That is Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC) of Less Than 14 [Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug]

   Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC) of less than 14

5. Safety Endpoint: Number of Patients Who Developed Thrombolysis In Myocardial Infarction (TIMI) Minor Bleeding [Through 30days following PPCI]

6. Safety Endpoint: Number of Patients Who Developed Thrombolysis In Myocardial Infarction (TIMI) Minimal Bleeding [Through 30days following primary percutaneous coronary intervention]

7. Safety Endpoint: Number of Patients Who Developed Cardiac Arrhythmias [Through 30days following primary percutaneous coronary intervention]

8. Safety Endpoint: Number of Deaths [Through 30days following primary percutaneous coronary intervention]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects (men or women) at least 18 years and less than 75 years of age and

• Ischemic discomfort ≥20 minutes and ≤6 hours of duration and

• ST elevation ≥1mm (≥0.1mV) in two contiguous limb leads OR ≥2mm (≥0.2mV) in two contiguous precordial leads and

• Occluded infarct-related artery (TIMI Flow Grade 0 or 1) at the time of coronary angiography and

• Planned primary PCI within 2 hours of hospital presentation and

• Planned or concomitant use of aspirin, clopidogrel, unfractionated heparin, and Glycoprotein IIb/IIIa inhibition with intent to stent the infarct-related artery and

• Informed consent able to be obtained

Exclusion Criteria:

CLINICAL

• Age ≥75 years

• Maximal systolic blood pressure <80 mmHg AFTER initial fluid and/or pressor resuscitation.

• Uncontrolled hypertension (SBP >180 OR DBP >110) at time of enrollment.

• Cardiac arrest or arrhythmia requiring chest compressions or cardiopulmonary resuscitation.

• Known pregnancy.

BIOCHEMICAL

• Known thrombocytopenia (platelet count <100,000)

• Known severe renal insufficiency (creatinine >4.0 mg/dL).

INCREASED BLEEDING RISK

• Active internal bleeding

• Recent (<3 months) gastrointestinal hemorrhage

• Recent intracranial or intraspinal surgery, trauma, major surgery, or biopsy of a parenchymal organ (< 1 month)

• Known coagulopathy, platelet disorder, or history of thrombocytopenia

• Current warfarin therapy

• Known neoplasm

• Any known history of transient ischemic attack, cerebrovascular accident, or active intracranial pathology including arteriovenous malformation or aneurysm

MEDICATIONS

• Administration of a fibrinolytic agent within 72 hours

• Known allergy or contraindication to fibrinolytics OR aspirin OR heparin OR clopidogrel

ANGIOGRAPHIC

• Left Main Coronary artery culprit lesion

• Ostial culprit lesion (ostium of LAD, LCX, or RCA).

• Lesion in non-native coronary artery (e.g. saphenous vein graft, arterial conduit graft)

• Subjects requiring urgent coronary artery bypass grafting

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northeast Georgia Heart Center, PC	Gainesville	Florida	United States	30501
2	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
3	Atlanta VA Medical Center	Decatur	Georgia	United States	30033
4	Emory University	Decatur	Georgia	United States	30033
5	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
6	Crittenton Hospital Medical Center	Rochester	Michigan	United States	48307
7	Heart Consultants, PC	Freemont	Nebraska	United States	68025
8	University of North Carolina	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• C. Michael Gibson, MS, MD
• Genentech, Inc.

Investigators

• Principal Investigator: C. Michael Gibson, MS, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: C. Michael Gibson, MS, MD, Sponsor-Investigator, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT00604695
• Other Study ID Numbers: N3770S
• First Posted: Jan 30, 2008
• Last Update Posted: Sep 7, 2012
• Last Verified: Aug 1, 2012

• Keywords provided by C. Michael Gibson, MS, MD, Sponsor-Investigator, Brigham and Women's Hospital: ST-Elevation Myocardial Infarction; Acute Myocardial Infarction; No Reflow
• Additional relevant MeSH terms: Myocardial Infarction; ST Elevation Myocardial Infarction; Infarction; Tenecteplase

Study Results

Participant Flow

Recruitment Details	The study randomized 40 primary percutaneous coronary intervention (PPCI) patients from 6 hospitals in the United States. The patients were given either a volume matched bolus of intracoronary (IC) tenecteplase (TNK) (4 mg; n=20) or IC saline placebo (4 mg; n=16) before and following PPCI. 4 subjects were randomized but did not receive 1st bolus.

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Period Title: Overall Study
STARTED	20	20
COMPLETED	20	16
NOT COMPLETED	0	4

Baseline Characteristics

Arm/Group Title	Active Treatment	Placebo Control	Total
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline	Total of all reporting groups
Overall Participants	20	20	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 85%	18 90%	35 87.5%
>=65 years	3 15%	2 10%	5 12.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (7.6)	55.6 (8.9)	55.4 (8.2)
Sex: Female, Male (Count of Participants)
Female	5 25%	3 15%	8 20%
Male	15 75%	17 85%	32 80%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Percent Diameter Stenosis of the Culprit Lesion Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention
Time Frame	Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention

Outcome Measure Data

Analysis Population Description

Of the 20 patients randomized to the treatment arm, 4 patients did not meet the inclusion criteria of Thrombolysis In Myocardial Infarction (TIMI) Flow Grade(TFG) 0/1. Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo) and 3 patients did not meet the inclusion criteria of TFG 0/1.

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	16	13
Median (Inter-Quartile Range) [Percent diameter stenosis]	100	100

2. Secondary Outcome

Title	Number of Patients With Decrease in Thrombus Grade in the Culprit Artery Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention
Time Frame	Following the First Bolus of Study Drug Prior to Primary Percutaneous Coronary Intervention

Outcome Measure Data

Analysis Population Description

Of the 20 patients randomized to the treatment arm, 4 patients did not meet the inclusion criteria of Thrombolysis In Myocardial Infarction (TIMI) Flow Grade(TFG) 0/1. Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo) and 3 patients did not meet the inclusion criteria of TFG 0/1.

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	16	13
Number [participants]	7 35%	2 10%

3. Secondary Outcome

Title	Number of Patients With Thrombolysis In Myocardial Infarction (TIMI) Myocardial Perfusion Grade (TMPG) of 2 or 3 in the Territory of the Culprit Artery Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug
Description	Thrombolysis In Myocardial Infarction (TIMI) Myocardial Perfusion Grade (TMPG) of 2 or 3 in the territory of the culprit artery
Time Frame	Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug

Outcome Measure Data

Analysis Population Description

Of the 20 patients randomized to the treatment arm, 4 patients did not meet the inclusion criteria of Thrombolysis In Myocardial Infarction (TIMI) Flow Grade(TFG) 0/1. Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo) and 3 patients did not meet the inclusion criteria of TFG 0/1.

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	16	13
Number [participants]	8 40%	8 40%

4. Secondary Outcome

Title	Measurements of Flow Velocity in the Culprit Artery in Terms of Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC)
Description	Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC) in the culprit artery
Time Frame	Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug

Outcome Measure Data

Analysis Population Description

Of the 20 patients in treatment arm, 4 did not meet the inclusion criteria of TIMI Flow Grade(TFG) 0/1 and cTFC could not be obtained in 4 patients Of the 20 patients in placebo arm, 4 did not receive the first bolus (drug or placebo) and 3 patients did not meet the inclusion criteria of TFG 0/1. cTFC could not be obtained in 3 patients

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	12	10
Median (Inter-Quartile Range) [Corrected TIMI Frame Count (cTFC)]	26	14

5. Secondary Outcome

Title	Number of Patients With Hyperemic Flow in the Culprit Artery. That is Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC) of Less Than 14
Description	Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (cTFC) of less than 14
Time Frame	Following Primary Percutaneous Coronary Intervention Prior to Second Bolus of the Study Drug

Outcome Measure Data

Analysis Population Description

Of the 20 patients in treatment arm, 4 did not meet the inclusion criteria of TIMI Flow Grade(TFG) 0/1 and cTFC could not be obtained in 4 patients Of the 20 patients in placebo arm, 4 did not receive the first bolus (drug or placebo) and 3 patients did not meet the inclusion criteria of TFG 0/1. cTFC could not be obtained in 3 patients

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	12	10
Number [participants]	1 5%	5 25%

6. Secondary Outcome

Title	Safety Endpoint: Number of Patients Who Developed Thrombolysis In Myocardial Infarction (TIMI) Minor Bleeding
Time Frame	Through 30days following PPCI

Outcome Measure Data

Analysis Population Description

Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo)

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	20	16
Number [participants]	1 5%	0 0%

7. Secondary Outcome

Title	Safety Endpoint: Number of Patients Who Developed Thrombolysis In Myocardial Infarction (TIMI) Minimal Bleeding
Time Frame	Through 30days following primary percutaneous coronary intervention

Outcome Measure Data

Analysis Population Description

Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo)

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	20	16
Number [participants]	4 20%	2 10%

8. Secondary Outcome

Title	Safety Endpoint: Number of Patients Who Developed Cardiac Arrhythmias
Time Frame	Through 30days following primary percutaneous coronary intervention

Outcome Measure Data

Analysis Population Description

Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo)

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	20	16
Number [participants]	1 5%	2 10%

9. Secondary Outcome

Title	Safety Endpoint: Number of Deaths
Time Frame	Through 30days following primary percutaneous coronary intervention

Outcome Measure Data

Analysis Population Description

Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo)

Arm/Group Title	Active Treatment	Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase	Two (4mL) doses of sterile saline
Measure Participants	20	16
Number [participants]	1 5%	0 0%

Adverse Events

Time Frame	30-days following primary percutaneous coronary intervention
Adverse Event Reporting Description	Of the 20 patients randomized to the placebo arm, 4 patients did not receive the first bolus (drug or placebo).
Arm/Group Title	Active Treatment		Placebo Control
Arm/Group Description	Two (4mg) doses of tenecteplase		Two (4mL) doses of sterile saline
All Cause Mortality
	Active Treatment		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Active Treatment		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		1/16 (6.3%)
Cardiac disorders
Dressler's syndrome	0/20 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Erosive Gastritis	1/20 (5%)		0/16 (0%)
General disorders
Death	1/20 (5%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Active Treatment		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/20 (70%)		11/16 (68.8%)
Blood and lymphatic system disorders
Anemia	1/20 (5%)		0/16 (0%)
Cardiac disorders
Ventricular Tachycardia	1/20 (5%)		1/16 (6.3%)
Hypotension	1/20 (5%)		0/16 (0%)
Chest pain	1/20 (5%)		1/16 (6.3%)
High grade Atrio-Ventricular Block	1/20 (5%)		1/16 (6.3%)
Gastrointestinal disorders
Pancreatitis	1/20 (5%)		0/16 (0%)
General disorders
Back pain	0/20 (0%)		1/16 (6.3%)
Immune system disorders
Allergic reaction to Bactrim	0/20 (0%)		1/16 (6.3%)
Allergic reaction to Lisinopril	0/20 (0%)		1/16 (6.3%)
Infections and infestations
Clostridium difficile infection	1/20 (5%)		0/16 (0%)
Urinary tract infection	1/20 (5%)		0/16 (0%)
Injury, poisoning and procedural complications
Incision site pain	1/20 (5%)		0/16 (0%)
Right hand and finger numbness	0/20 (0%)		1/16 (6.3%)
Right groin cellulitis	0/20 (0%)		1/16 (6.3%)
Bleeding	5/20 (25%)		2/16 (12.5%)
Respiratory, thoracic and mediastinal disorders
Wheezing	0/20 (0%)		1/16 (6.3%)

Limitations/Caveats

This pilot study was not adequately powered to exclude a modest increase in bleeding events. Study drug could not be administered to 4 patients and 7 patients were excluded for not meeting the inclusion criteria of TIMI Flow Grade 0/1 at enrollment.

More Information

Certain Agreements

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

Principal Investigator shall furnish Sponsor with copy of any proposed publication for review/comment prior to submission for publication, at least thirty (30) days prior to submission for manuscripts and at least fifteen (15) days prior to submission for abstracts. Institution agrees to delete information identified by Sponsor as Confidential Information prior to submission for publication.