Clinical trial NCT02898051: Anti Xa Activity in Cancer Patients Receiving Low-molecular-weight Heparin for Venous Thromboembolism
Official title: Anti Xa Activity in Cancer Patients Receiving Low-molecular-weight Heparin for Venous Thromboembolism
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Neoplasms
Venous Thromboembolism
Keywords: heparin low-molecular-weight;pharmacokinetics
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
name: National Cancer Institute, France
First posted: 2016-09-13
Enrollment: 370
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Hospitalized patients in tertiary care hospitals participating to the study and treated with curative dose of low molecular weight heparins (LMWH) for venous thromboembolism (VTE).

Brief summary: Low molecular weight heparins (LMWH) are the reference molecule for the long term treatment of venous thromboembolism (VTE) in cancer patients but remains, however, associated with a high risk of recurrent thromboembolism. The high rate of recurrence may result from alterations in the pharmacokinetics of LMWH. The primary purpose of the study is to compare the pharmacokinetics of anti-Xa activity in patients with cancer and patients without cancer treated with curative dose of low molecular weight heparins (LMWH) for venous thromboembolism (VTE). The secondary purposes are 1/ to study the correlation between anti-Xa LMWH and concentration of plasma heparanase and 2/ to evaluate the predictive nature of the anti-Xa activity on the occurrence of thromboembolic recurrence in cancer patients treated with LMWH for VTE.

Detailed description: Purpose of the study:

The primary purpose of the study is to compare the pharmacokinetics of anti-Xa activity in patients with cancer and patients without cancer treated with curative dose of low molecular weight heparins (LMWH) for venous thromboembolism (VTE).

The secondary purposes are 1/ to study the correlation between anti-Xa LMWH and concentration of plasma heparanase and 2/ to evaluate the predictive nature of the anti-Xa activity on the occurrence of thromboembolic recurrence in cancer patients treated with LMWH for VTE.

Study design:

Multicentre cohort study of patients hospitalized with VTE:

1. Observational case-control study to compare the pharmacodynamics of anti-Xa activity between patients cancer patients (n = 50) and non-cancer patients (n = 50) matched (1-1) for age, renal function and LMWH
2. A prospective cohort study including 320 cancer patients with a 6 months follow-up.

Study hypothesis:

Venous thrombosis and pulmonary embolism are a common complication of cancer. They complicate up to 10% of cancers and are the cause of fatality, morbidity and significant impaired quality of life. The treatment of these diseases is difficult in this context. Low molecular weight heparins (LMWH) are the reference molecule for the long term treatment of venous thromboembolism (VTE) in cancer patients. Outside this context, their pharmacological properties allow to administer a fixed dose without measuring anti-Xa activity. In the presence of cancer, their use remains, however, associated with a high risk of recurrent thromboembolism up to 9% after 6 months of treatment.

This high rate of recurrence may result from alterations in the pharmacokinetics of LMWH in the presence of a cancer. The synthesis of heparanase by tumor cells might cause a decrease in anti-Xa activity of LMWH and reduce their effectiveness. If this hypothesis is verified, it could result in a change in the management of thrombosis in cancer patients and lead to a dose adjustment of LMWH through the measurement of anti-Xa activity, which may allow reduce the incidence of thromboembolic relapses during treatment.

Enrollment (Target or Actual Number of Subjects):

1. Pharmacokinetics study In a preliminary unpublished study of 37 cancer and non-cancer subjects with the highest concentration of anti-Xa activity was measured. Included 100 subjects (50 cancer patients and 50 non-cancer) would detect a maximum level difference of anti-Xa activity in plasma of 0.20 between cancer patients and cancer-with a power of 90% and a risk of the first kind 5%.

   A difference of 0.20 seems relevant from these preliminary data (median 0.46 vs 0.65), and returns to show that a cancer patient has over 70% chance of having a maximum concentration of anti-Xa activity below that of a free cancer patient (nonparametric Wilcoxon test).
2. Cohort study (cancer patients) The risk of recurrent thromboembolism was estimated between 5 and 10% in cancer patients. By including 200 subjects, around twenty events would be observed and corresponds to a reasonable number of subjects can be recruited over 18 months (50 would already enroll in the pharmacodynamic study). The event rate will be assessed on the first 100 patients that will have been followed for 6 months, if event rate is lower than expected, the number of participants will be reassessed.

After over 2 years of inclusion, the event rate is lower than expected (7%). The number of subjects required was therefore reassessed. To reach the number of 20 events necessary to our analysis, a total of 320 cancer subjects must therefore be included.

Target Follow-Up, duration :

Study duration: 5 years and 6 months (inclusion: 5 years follow-up: 6 months). Duration of participation: 3 a 10 days for non-cancer patients, 6 months for cancer patient.

Performance of the study:

1. Pharmacokinetics study Inclusion (as soon as the diagnosis is confirmed VTE): 1 tube of blood taken before the start of treatment (at the time of another blood sample) for determination of heparanase. After the start of treatment: 3 tubes of blood drawn for determination of anti-Xa activity.

   Assays will be centrally performed, blinded from the clinical data and from the group knowledge of the group patient.
2. Prospective cohort study of cancer patients Followed for 6 months with consultation at 1, 3, and 6 months (normal monitoring).

Follow-up visits: Collection of clinical data (recurrent thromboembolism, hemorrhage, death, tumor progression, cancer treatment since last visit, interruption of treatment with LMWH, thrombocytopenia, anemia), and removal of 1 tube of blood (at the time of a another sample) for determination of anti-Xa activity.

Thromboembolic recurrences will be validated centrally by an independent committee.

Prospects:

Reduce the incidence of thromboembolic recurrence in cancer patients treated with LMWH for VTE by adapting the dose of LMWH with anti-Xa activity in this population if the hypothesis is verified.

Eligibility criteria: Inclusion Criteria:

Case:

* Being affiliated to a social security scheme
* Having an active solid or hematological cancer (myeloma or lymphoma), histologically or cytologically confirmed, for which the active state will be defined by the existence of a tumoral active disease or an incomplete tumoral resection or the persistence of high tumor markers after complete resection of the tumor.
* The venous thromboembolism disease has to be:
* A deep vein thrombosis of lower extremity (proximal or distal) confirmed by the lack of compressibility of a venous segment under the ultrasound probe or the presence of a venous gap in CT venography or phlebography;
* or a thrombosis of the vena cava or the iliac vein confirmed by an abdominal CT scan with contrast or a venous ultrasound or an ilio-cavography;
* or a pulmonary embolism confirmed according to the guidelines of the European Society of Cardiology : through a gap in a pulmonary artery, at least segmental or multiple gaps sub-segmental on spiral CT angiography of the pulmonary arteries or by a high appearance probability on a lung radionuclide imaging, or by clinical symptoms of pulmonary embolism accompanying symptomatic proximal vein thrombosis confirmed by a venous ultrasound or by an unexplained echocardiography acute pulmonary heart in presence of a high clinical probability and for patients who are unfit for transport and with cardiogenic shock
* The venous thromboembolism disease can be asymptomatic or incidentally discovered but is confirmed objectively.
* No cons-indication to low molecular weight heparin treatment at therapeutic dose.
* Prescription in the last 72 hours of a low molecular weight heparin treatment or fondaparinux at therapeutic dose.

Control:

* Being affiliated to a social security scheme.
* Being free from malignant tumor pathology detectable at the time of inclusion.
* Being afflicted with venous thromboembolism defined by the same criteria of cancer subjects.
* The venous thromboembolism disease can be asymptomatic or incidentally discovered but is confirmed objectively.
* No cons-indication to low molecular weight heparin treatment at therapeutic dose.
* Prescription in the last 72 hours of a low molecular weight heparin treatment or fondaparinux at therapeutic dose.

Exclusion Criteria:

Case:

* Visceral vein thrombosis of the upper limb or venous thrombosis of the superior vena cava system because their scalability under treatment, including the risk of embolic recurrence is less known that pulmonary embolism and thrombosis of the lower limbs and their diagnostic modalities are less formalized.
* Tumor disease not confirmed histologically or cytologically.
* Follow-up after complete tumor resection without elevated tumor markers.
* Cons-indication to low molecular weight heparin treatment at therapeutic dose.
* Initial treatment with another anticoagulant molecule than LMWH or fondaparinux (thrombin inhibitor, direct factor Xa inhibitors)
* Severe renal impairment defined by a creatinine clearance below than 30 ml / min at baseline.
* Known pregnancy or lack of effective contraception for women of childbearing age or breastfeeding.
* Patient previously included in the study.
* Impossible follow-up.
* Life expectancy less than 6 months.
* Patient whose weight is greater than 100 Kg.

Control:

* Not yet confirmed suspected malignant tumor pathology associated with the venous thromboembolism disease.
* Active cancer in the last 2 years.
* Cons-indication to low molecular weight heparin treatment at therapeutic dose.
* Initial treatment with another anticoagulant molecule than LMWH or fondaparinux (thrombin inhibitor, direct factor Xa inhibitors)
* Severe renal impairment defined by a creatinine clearance below than 30 ml / min at baseline.

Primary outcomes:
measure: anti-Xa activity
timeFrame: 10 days
Secondary outcomes:
measure: hemorrhage
timeFrame: 6 months
measure: all cause mortality
timeFrame: 6 months
measure: thromboembolic recurrences
timeFrame: 6 months
Other outcomes:
Locations:
city: Lyon
country: France
facility: Hôpital d'instruction des armees Desgenettes
state: Auvergne-Rhône-Alpes
city: Saint-Priest-en-Jarez
country: France
facility: CHU de Saint-Etienne Hôpital Nord
state: Auvergne-Rhône-Alpes
city: Dijon
country: France
facility: CHU de Dijon
state: Bourgogne-Franche-Comte
city: Brest
country: France
facility: Hôpital La Cavale Blanche
state: Bretagne
city: Colombes
country: France
facility: Hôpital Louis Mourier
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Saint-Louis
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Europeen Georges Pompidou
state: Ile-de-France
city: Amiens
country: France
facility: CHU Amiens - Hôpital Sud
state: Picardie
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Guy Meyer, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006 Feb 27;166(4):458-64. doi: 10.1001/archinte.166.4.458.
citation: Khorana AA, Streiff MB, Farge D, Mandala M, Debourdeau P, Cajfinger F, Marty M, Falanga A, Lyman GH. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. J Clin Oncol. 2009 Oct 10;27(29):4919-26. doi: 10.1200/JCO.2009.22.3214. Epub 2009 Aug 31.
citation: Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S-545S. doi: 10.1378/chest.08-0658.
citation: Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. doi: 10.1056/NEJMoa025313.
citation: Katz BZ, Muhl L, Zwang E, Ilan N, Herishanu Y, Deutsch V, Naparstek E, Vlodavsky I, Preissner KT. Heparanase modulates heparinoids anticoagulant activities via non-enzymatic mechanisms. Thromb Haemost. 2007 Dec;98(6):1193-9.