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Acute Deep Venous Thrombosis of the Lower ExtremityPhase 2NCT00082355

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

A Phase 2 study testing Alteplase (Activase, Genentech) in people with Acute Deep Venous Thrombosis of the Lower Extremity, run by Richard Chang, M.D. at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study will test the effectiveness of low-dose recombinant tissue plasminogen activator (rtPA, or alteplase) in dissolving blood clots in deep leg veins. Alteplase is used to clear blood clots in coronary arteries in patients having heart attacks. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Alteplase (Activase, Genentech)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteUnited States
Study dates
May 2004to Oct 2014
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Only adult patients (18 years old or older) are included.
  • Patients must have thrombosis documented by ultrasound or venography to involve the deep veins of the pelvis and/or a lower extremity proximal to the calf veins, i.e., the popliteal vein or above.
  • The thrombosis must be the patient's first DVT.
  • The thrombosis must have been symptomatic for no more than 14 days.
  • Patients must be able to give informed consent and be able to follow the prescribed anticoagulation regimen.
  • Patients on concurrent NIH protocols will be eligible as well as patients from the community and the rest of the U.S. who are not already on NIH protocols.

Who cannot join

  • Pregnant patients are not eligible, although postpartum mothers over 10 days from delivery are eligible if they refrain from breast feeding their infants for 24 hours after each study with x-ray contrast material.
  • Serum creatinine greater than than 2 mg/dL.
  • Any current bleeding diathesis not attributable to heparin or warfarin. Fibrinogen less than 150 mg/dL. Any patient with a prothrombin time (PTT) greater than 15 s, an activated partial thromboplastin time (aPTT) greater than 35 s, or a platelet count less than 100,000/microliter must be evaluated by the Hematology Service for a coagulopathy before being included.
  • Within the previous 10 days: major surgery or trauma, puncture of a noncompressible vessel, organ biopsy, or cardiopulmonary resuscitation.
  • Within the previous 2 months: cerebrovascular infarction or hemorrhage, or intracranial or intraspinal surgery or trauma.
  • Within the previous 6 months: major internal bleeding.
Show all 16Show fewer
  • Active intracranial disease (aneurysm, vascular malformation, neoplasm).
  • Life expectancy less than 6 months.
  • Patients with hemoglobin concentration less than 9g/dL will not participate in the pharmacokinetic portion of the protocol.
  • Uncontrolled systolic blood pressure greater than 180 mm Hg or diastolic greater than 100 mm Hg.
  • Atrial fibrillation, unless a cardiac echocardiogram excludes the presence of intracardiac thrombus.
  • Known right-to-left intracardiac shunt.
  • Pericarditis, infective endocarditis.
  • History of heparin-induced thrombocytopenia within 6 months or the presence of persistent anti-heparin antibodies by ELISA.
  • History of anaphylactic reactions to x-ray contrast media.
  • Known retinopathy unless cleared by an ophthalmologist at NIH.Evidence of uncontrolled congestive heart failure or a history of diabetes mellitus.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: The Treatment of Deep Vein Thrombosis (DVT) of the Lower Extremities With "Low-Dose" Alteplase: a Pilot Study

This study will test the effectiveness of low-dose recombinant tissue plasminogen activator (rtPA, or alteplase) in dissolving blood clots in deep leg veins. Alteplase is used to clear blood clots in coronary arteries in patients having heart attacks. Blood clots can develop in the deep leg veins causing pain and swelling and may break loose and lodge in the lungs. Current routine treatments use anticoagulants such as heparin stop the clots from enlarging and prevent clots from moving to the lung but do not reliably dissolve clots in the leg.In an earlier study we showed that rtPA could be used to actually dissolve the clots. This study will determine whether lower doses of rtPA can dissolve clots with fewer bleeding complications than the current higher-dose regimens.

Patients 18 years of age and older who have blood clots in a deep vein of the pelvis or leg may be eligible for this study if they have had symptoms for 14 days or less and if they have never had clots in their deep veins before.

Read more

Participants are admitted to hospital for up to 5 days. On the first treatment day, the patient has a venogram to show the location of the clots. The radiologist injects an x-ray contrast material into a small vein in the foot and watches the dye by x-ray as it moves up the leg, revealing the clot(s). A catheter (plastic tube) is then inserted into a vein either behind the knee, in the groin, or in the neck, and advanced until it reaches the clots. When the catheter is in place, rtPA is injected while the radiologist watches the vein under the x-ray image. The amount of rtPa needed will depends on the size of the clot. Up to five venograms may be done if the clot requires the maximum four rtPA treatments allowed in this study. During the treatments, patients receive standard doses of heparin, given continuously by vein, After completion of treatments, anticoagulation is continued through use of a low molecular weight heparin (usually enoxaparin) given by subcutaneous injection as a transition medication during conversion to anticoagulation with warfarin ( also known as coumadin), another blood thinner, taken by mouth. Patients continue taking warfarin for 6 months.

During thrombolytic therapy, blood samples are drawn shortly before the first dose of rtPA and at five time points afterward to measure the rtPA in the circulation and other factors that indicate whether the rtPA is affecting clotting ability. Blood also is drawn at least once a day to monitor heparin levels.

To evaluate the impact of treatment on the function of the leg, patients return to the Rehabilitation Medicine Department and Radiology department at about 6 weeks (4 to 8 week ) and 6 months for clinical and imaging evaluation of impact of therapy on venous function.

The objectives are to determine how well this treatment will restore venous function and whether this can be done safely- without causing bleeding complications, which have been the main risks of previous thrombolytic treatments.

Read the detailed description

Deep venous thrombosis (DVT) of the lower extremities is routinely treated with anticoagulants, which is very effective in preventing pulmonary embolism, but does not reliably restore venous function in the leg affected by DVT,often leaving permanent vein damage that leads to chronic disability known as post thrombotic syndromes. There is evidence that this may be prevented, and therefore long-term sequelae avoided, if the thrombi are dissolved quickly with thrombolytic agents. In a previous protocol we developed a method using intra-clot injections of alteplase (recombinant tissue plasminogen activator, rtPA) for the treatment of lower extremity DVT. Although the treatment was very successful with few complications, pharmacokinetic data obtained suggest that the regimen can be made safer and perhaps even more effective by using a substantially lower dose of alteplase. The current protocol is a pilot study to test this hypothesis by treating 25 patients with first-time DVT symptomatic for less than or equal to 14 days, accepted from referring physicians both within and outside the National Institutes of Health (NIH). They will be treated with less than or equal to 10 mg alteplase per day for up to four days. Depending on location and extent of the blood clot, catheters are introduced into jugular, femoral, popliteal, and/or posterior tibial vein at the ankle so as to inject alteplase (diluted with normal saline to 0.1mg/ml, throughout the entire length of the clot) once a day with each total daily dose limited to 10mg alteplase per day.The protocol is designed so that if the low-dose regimen is unsuccessful, the patient will subsequently receive the higher-dose regimen that has previously been shown to be effective. During thrombolytic therapy, catheters left in the vein to maintain venous access are also used to infuse unfractionated heparin to provide regional and therapeutic systemic anticoagulation. After completing thrombolytic therapy, the patients will be anticoagulated for approximately 6 months after treatment by conversion from intravenous infusions of unfractionated heparin during thrombolytic therapy to low molecular weight heparin (enoxaparin) and subsequent conversion to oral warfarin anticoagulation for 6 months.

Efficacy of treatments will be evaluated at 3 time points (pre- and 1 day post-thrombolytic therapy for initial outcome; at about 6 weeks for short term outcome; and at about 6 months for durability of outcome) by clinical examination (department of Rehabilitation Medicine) and medical imaging through venography and duplex ultrasound sans in department of Radiology. The protocol is also monitored for safety. Safety monitoring is focused on bleeding complications which is the primary risk of all forms of thrombolytic and anticoagulation regimens. As an adverse event, bleeding complications can be classified as either expected (for example, at vascular puncture or access sites as where treatment catheters have been inserted); or unexpected as at remote sites where no instrumentation has been conducted (for example, Intracranial or retroperitoneal bleeding).The latter form of bleeding has been reported and attributed to use of thrombolytic and anticoagulant therapies and is usually much more serious than the former. A second classification is for severity of adverse events. For this protocol a serious adverse event is an event that is life or quality of life threatening, requires additional hospitalization, or surgical intervention, or in the case of thrombolytic therapy requires blood transfusions. A minor adverse event is one that does not have any of above features and will resolve without sequelae with conservative management and without need for invasive interventions.

A secondary objective (added to this protocol through an amendment) is to study the rate of recurrent DVT during the 5 year period after treatment. Historical studies show a recurrent venothromboembolism rate of 30% in patients treated with anticoagulation alone. Thrombolytic therapy should improve preservation of venous function which may reduce recurrence rate of venothromboembolism and although the protocol cannot accrue any new patients, the protocol remains active to allow data compilation testing this hypothesis in patients already treated which will be completed by 2014, the expected date of protocol termination.

Being tested
Alteplase (Activase, Genentech)
Keywords
r-tPA, Thrombolysis, Clot, Anticoagulation, Fibrinolysis, Deep Vein Thrombosis, DVT
Medical subject headings
Venous Thrombosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Alteplase (Activase, Genentech)Drug

    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 4 day period.

Study groups in NCT00082355
Study groupRoleWhat they receive
Alteplase (r-tPA)ExperimentalPatients with DVT of lower extremity will receive up to 4 treatments low dose (<10 mg/day) intraclot injections of alteplase. Intention is to evaluate safety and efficacy of this treatment, and durability of outcomes (for 6 months)in 25 patients.
Receives: Drug: Alteplase (Activase, Genentech)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Restored Venous Function

    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.

    Measured: 6 months

Secondary outcomes (1)
  1. Number of Participants That Developed Hemorrhage

    The outcome measures the number of participants who developed hemorrhage after receiving up to 4 days of Alteplase treatment for DVT.

    Measured: 5 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 May 2004 (estimated)
  2. Study startMay 2004
  3. Primary completionMar 2010
  4. Study completionOct 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00082355
Sponsor's protocol ID
040178
Other IDs
04-CC-0178
Status last verified
Oct 2014
First submitted
6 May 2004
Last updated
6 Nov 2014
Data monitoring committee
No

Publications

  • Schafer AI. Venous thrombosis as a chronic disease. N Engl J Med. 1999 Mar 25;340(12):955-6. doi: 10.1056/NEJM199903253401209. No abstract available.

    PubMed 10089190
  • 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. doi: 10.7326/0003-4819-125-1-199607010-00001.

    PubMed 8644983
  • 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. doi: 10.1378/chest.98.6.1473.

    PubMed 2123152
  • 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. doi: 10.1016/s0002-9343(99)00407-6. No abstract available.

    PubMed 10723981
  • 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. doi: 10.1016/s1051-0443(07)61832-6.

    PubMed 11265890
  • 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.

    PubMed 21664144
  • 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.

    PubMed 22683421
  • 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.

    PubMed 23273695

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Alteplase (Activase, Genentech) in people with Acute Deep Venous Thrombosis of the Lower Extremity, run by Richard Chang, M.D. at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Nov 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Dec 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Restored Venous Function (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00082355, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2014.

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