Randomized Controlled Trial of Anticoagulation vs. Placebo for a First Symptomatic Isolated Distal Deep-vein Thrombosis (IDDVT)

Study Overview
=================
Brief Summary
-----------------
CACTUS-PTS is a randomized, placebo-controlled, double-blind study which aims primarily to determine the effectiveness of a 6 week course of therapeutic-dose LMWH (nadroparine) injections vs. placebo in patients with a first symptomatic isolated distal (calf) deep-vein thrombosis (IDDVT), as measured by rate of proximal DVT and symptomatic PE at 6 weeks. Additionally, the study aims to determine if the 6 week course of treatment with therapeutic-dose LMWH (nadroparine) injections, compared to placebo, decreases the frequency of post-thrombotic syndrome (PTS) at 1 year.

Detailed Description
-----------------
The CACTUS-PTS study will compare anticoagulant treatment for 6 weeks versus placebo in acute, symptomatic distal DVT. Patients will be randomized to receive either a six-week period of LMWH at therapeutic dosage or a six-week period of placebo. All patients will be treated with elastic compression stockings and followed-up with a standardized ultrasonography protocol. Strict ultrasonographic diagnostic criteria for distal DVT have been defined. Control compression ultrasonography will be performed between days 3 and 7 and at six weeks after inclusion. The primary outcome will be a composite of the proportion of patients with extension of the thrombus to the proximal veins (detected by the programmed ultrasound examinations or by an ultrasound performed because of recurrent symptoms) or symptomatic PE in both arms of the study during the 6-weeks study period. Patients with such an outcome will be anticoagulated as currently admitted in presence of a proximal DVT. Secondary outcomes will be the individual components of the composite endpoint (distal DVT extension to proximal veins; symptomatic PE), major bleeding, serious adverse events and death reported at 6 weeks and 90 days. To answer the research question of the PTS add-on study, patients will self-assess and be assessed for PTS by a clinician using the Villalta scale, 1 year following their enrolment into the trial. In addition, patients will complete a Quality of Life (QOL) questionnaire. The QOL questionnaire will be comprised of both the VEINES-QOL and SF-36. The primary outcome is the rate of PTS, with secondary outcomes of QOL scores and PTS severity.

Official Title
-----------------
Contention Alone Versus Anticoagulation for Symptomatic Calf Vein Thrombosis Diagnosed by Ultrasonography

Conditions
-----------------
Distal (Calf) Deep-vein Thrombosis

Intervention / Treatment
-----------------
* Drug: nadroparine calcium
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All outpatients with an acute, symptomatic, distal DVT will be included in the study, provided they correspond to the following diagnostic and exclusion criteria, and they have signed an informed consent form. Exclusion Criteria: Age less than 18 years Previously objectively diagnosed DVT or PE Distal DVT involving the tibioperoneal trunk (i.e. calf trifurcation) Clinically suspected pulmonary embolism Active cancer, receiving cancer treatment or cancer considered cured for <6 months Ipsilateral or contralateral proximal DVT Indication for long-term anticoagulation (e.g. atrial fibrillation, mechanical heart valve...) Pregnancy Thrombocytopenia (platelet count < 100 g/l) Impaired renal function (serum creatinine > 180 micromol/l or clearance to creatinine less than 30 ml/min) Known hypersensitivity to heparin Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (gastric ulcer, cerebral malignant disease...) Treatment with daily NSAIDs (aspirin ≤160 mg/day permitted) Body weight >115 kg or <40 kg Treatment with therapeutic doses of anticoagulants for >2 days, corresponding to: 2 injections of LMWH if once daily therapeutic LMWH used; 3 injections of LMWH if twice-daily therapeutic LMWH used; 1 dose of oral vitamin K antagonist (e.g. warfarin) Ongoing requirement for prophylactic dose thromboprophylaxis (e.g. acute post-op patient receiving thromboprophylaxis) Enrolled in another clinical trial within previous 30 days Inability or refusal to provide informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LMWH<br>Therapeutic dose of Nadroparin | Drug: nadroparine calcium<br>* Once-daily injection of 171 U/Kg/day of nadroparine calcium for 6 weeks.<br>|
| Placebo Comparator: Placebo<br>Injectable placebo | Drug: Placebo<br>* Once-daily injectable placebo (sterilized NaCL 0.9%) for 6 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of rate of extension of distal DVT to proximal deep veins (includes ipsilateral extension or new contralateral proximal DVT) or symptomatic PE at 6 weeks |  | 6 weeks | 
| Rate of post-thrombotic syndrome (PTS) | Rate of post-thrombotic syndrome (PTS) diagnosed using the Villalta scale. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual components of the composite endpoint: distal DVT extension to proximal veins at 6 weeks and 90 days; PE at 6 weeks and 90 days |  | 6 weeks and 3 months | 
| Major bleeding at 6 weeks and 90 days |  | 6 weeks and 3 months | 
| Death at 6 weeks and 90 days |  | 6 weeks and 3 months | 
| Serious adverse events at 6 weeks and 90 days |  | 6 weeks and 3 months | 
| Generic and venous disease-specific Quality of Life scores |  | 1 year | 
| PTS severity category | Can either be mild, intermediate, severe | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Deep vein Thrombosis, Calf vein thrombosis, Low-molecular weight heparin, Placebo, Elastic contention, Compression Ultrasonography