Low-Dose Alteplase to Treat Blood Clots in Deep Leg Veins

• ClinicalTrials.gov Identifier: NCT00082355
• Recruitment Status: Completed
• First Posted: May 6, 2004
• Results First Posted: December 19, 2012
• Last Update Posted: November 6, 2014
• Sponsor: Richard Chang, M.D.
• Collaborator: National Institutes of Health Clinical Center (CC)
• Information provided by (Responsible Party): Richard Chang, M.D., National Institutes of Health Clinical Center (CC)

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Deep Venous Thrombosis of the Lower Extremity
• Intervention: Drug: Alteplase (Activase, Genentech)
• Enrollment: 30

Participant Flow

Recruitment Details	Recruitment began in 2004 and was completed by 2009. All patients were treated at NIH Clinical Center.
Pre-assignment Details	2 patients who were incorrectly diagnosed with Deep Vein Thrombosis (DVT) were excluded from the protocol after a preliminary ultrasound exam at NIH indicated they did not have DVT.

Arm/Group Title	Alteplase
Arm/Group Description	Dose of Alteplase will not exceed 10 mg/d/leg and is delivered in a concentration of 100ug/mL. The actual dose delivered is based upon the length of the thrombosed vein and 1 mL is injected directly into each centimeter of a thrombosed vein in a lower extremity. The treatment will be repeated up to 4 times over a 5 day period.
Period Title: Initial Results of Thrombolytic Therapy
Started	30
Completed	28
Not Completed	2
Reason Not Completed
died of causes unrelated to protocol	1
Withdrawal by Subject	1
Period Title: 5 Year Recurrent Thromboembolism Rate
Started	28
Completed	0 [1]
Not Completed	28
Reason Not Completed
will be completed 2014	28
[1] data will not be complied until 2014

Baseline Characteristics

Arm/Group Title		Alteplase
Arm/Group Description		Dose of Alteplase will not exceed 10 mg/d/leg and is delivered in a concentration of 100ug/mL. The actual dose delivered is based upon the length of the thrombosed vein and 1 mL is injected directly into each centimeter of a thrombosed vein in a lower extremity. The treatment will be repeated up to 4 times over a 5 day period.
Overall Number of Baseline Participants		30
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	30 100.0%
	>=65 years	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	30 participants
		46.7 (12)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	Female	12 40.0%
	Male	18 60.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	30 participants
		30

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Restored Venous Function
Description	The outcome measures the ability of Alteplase to lyse acute and subacute deep venous thrombosis (DVT) of the lower extremities and/or pelvis and restore venous function, or blood flow, to these areas. Restored venous function is also known as patency. Patency is measured by venography and ultrasound exams.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The number of participants analyzed is an Intent-to-Treat (ITT) population. The initial goal was to be able to evaluate outcomes of treatment of DVT with alteplase over a 6 month period in 25 patients. 30 patients were treated but two participants did not complete the study before being assessed for this outcome measure.

Arm/Group Title	Alteplase
Arm/Group Description:	Dose of Alteplase will not exceed 10 mg/d/leg and is delivered in a concentration of 100ug/mL. The actual dose delivered is based upon the length of the thrombosed vein and 1 mL is injected directly into each centimeter of a thrombosed vein in a lower extremity. The treatment will be repeated up to 4 times over a 5 day period.
Overall Number of Participants Analyzed	30
Measure Type: Number; Unit of Measure: participants
	28

2. Secondary Outcome

Title	Number of Participants That Developed Hemorrhage
Description	The outcome measures the number of participants who developed hemorrhage after receiving up to 4 days of Alteplase treatment for DVT.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

The number of participants analyzed is an Intent-to-Treat (ITT) population. The accrual target was to analyze outcomes(immediate, at 6 weeks, and at 6months) after treatment of DVT with alteplase in 25 patients. 30 patients were treated but two participants did not complete the study for 6 week and 6 month outcome assessments.

Arm/Group Title	Alteplase
Arm/Group Description:	Dose of Alteplase will not exceed 10 mg/d/leg and is delivered in a concentration of 100ug/mL. The actual dose delivered is based upon the length of the thrombosed vein and 1 mL is injected directly into each centimeter of a thrombosed vein in a lower extremity. The treatment will be repeated up to 4 times over a 5 day period.
Overall Number of Participants Analyzed	30
Measure Type: Number; Unit of Measure: participants
	0

Adverse Events

Time Frame	Data accumulated during 5 year study.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Alteplase
Arm/Group Description	Dose of Alteplase will not exceed 10 mg/d/leg and is delivered in a concentration of 100ug/mL. The actual dose delivered is based upon the length of the thrombosed vein and 1 mL is injected directly into each centimeter of a thrombosed vein in a lower extremity. The treatment will be repeated up to 4 times over a 5 day period.
All-Cause Mortality
	Alteplase
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Alteplase
	Affected / at Risk (%)	# Events
Total	0/30 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Alteplase
	Affected / at Risk (%)	# Events
Total	2/30 (6.67%)
Vascular disorders
catheter insertion site hematoma *	2/30 (6.67%)	2
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

Small trial of 30 patients does not have statistical power to prove clinical safety (expected to be <1 %)

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr Richard Chang
• Organization: NIHCC
• Phone: 301-402-0256
• EMail: rchang@cc.nih.gov

Publications of Results:

Chang R, Horne MK 3rd, Shawker TH, Kam AW, Chen EA, Joe GO, Ching WL, Mao E, Wyrick DA Jr, Lozier JN. Low-dose, once-daily, intraclot injections of alteplase for treatment of acute deep venous thrombosis. J Vasc Interv Radiol. 2011 Aug;22(8):1107-16. doi: 10.1016/j.jvir.2011.03.023. Epub 2011 Jun 12.

Lozier JN, Cullinane AM, Nghiem K, Chang R, Horne MK 3rd. Biochemical dynamics relevant to the safety of low-dose, intraclot alteplase for deep vein thrombosis. Transl Res. 2012 Sep;160(3):217-22. doi: 10.1016/j.trsl.2012.01.025. Epub 2012 Feb 23.

Chang R, Butman JA, Lonser RR, Sherry RM, Pandalai PK, Horne MK 3rd, Lozier JN. Treatment of high-risk venous thrombosis patients using low-dose intraclot injections of recombinant tissue plasminogen activator and regional anticoagulation. J Vasc Interv Radiol. 2013 Jan;24(1):27-34.e1. doi: 10.1016/j.jvir.2012.09.017.

Other Publications:

Schafer AI. Venous thrombosis as a chronic disease. N Engl J Med. 1999 Mar 25;340(12):955-6.

Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996 Jul 1;125(1):1-7.

Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Turpie AG, Gent M. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest. 1990 Dec;98(6):1473-9.

Horne MK 3rd, Mayo DJ, Cannon RO 3rd, Chen CC, Shawker TH, Chang R. Intraclot recombinant tissue plasminogen activator in the treatment of deep venous thrombosis of the lower and upper extremities. Am J Med. 2000 Feb 15;108(3):251-5.

Chang R, Cannon RO 3rd, Chen CC, Doppman JL, Shawker TH, Mayo DJ, Wood B, Horne MK 3rd. Daily catheter-directed single dosing of t-PA in treatment of acute deep venous thrombosis of the lower extremity. J Vasc Interv Radiol. 2001 Feb;12(2):247-52.

• Responsible Party: Richard Chang, M.D., National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00082355
• Other Study ID Numbers: 040178; 04-CC-0178 ( Other Identifier: NIH Clinical Center )
• First Submitted: May 6, 2004
• First Posted: May 6, 2004
• Results First Submitted: February 8, 2011
• Results First Posted: December 19, 2012
• Last Update Posted: November 6, 2014