Prophylaxis of Thromboembolic Complications Trial: Thromboprophylaxis Needed in Below Knee Plaster Cast Immobilization for Ankle and Foot Fractures (PROTECT)

Prophylaxis of Venous Thromboembolism in Patients With a Nonsurgical Fracture of the Lower Extremity Immobilised in a Below-Knee Plaster Cast

Objective:

The purpose of this study is to determine the need for thromboprophylaxis in patients with a fracture of the lower extremity being treated conservatively in a below-knee plaster cast and to assess if both of the two tested prophylactic treatments are effective for this indication.

Hypothesis:

Nadroparine and Fondaparinux are both effective in preventing a thromboembolic event in patients with a nonsurgical fracture of a lower extremity immobilised in a below-knee plaster cast.

Study Overview

• Status: Unknown
• Conditions: Deep Vein Thrombosis; Pulmonary Embolism
• Intervention / Treatment: Drug: Nadroparin; Drug: Fondaparinux

Detailed Description

Study Design:

A prospective, randomised, controlled, single blinded, multi-centre trial.

Intervention:

After meeting the inclusion criteria stated above and obtaining informed consent, patients will be randomly assigned to three groups: one receiving Nadroparine (2850 IE anti-Xa = 0,3 ml, given once daily), one receiving Fondaparinux (2,5 mg = 0,5 ml, given once daily) and one receiving no prophylaxis. These dosages are standard for the use in thromboprophylaxis. The first two groups will be instructed by a trained nurse in subcutaneous self-injection of the medicine and will be given pre-filled disposable syringes for once-daily administration for the duration of immobilisation.

In the light of current scientific knowledge a placebo effect of subcutaneous injections of saline in the control group is implausible since the outcome measure (colour duplex sonography) is an objective one.

Patients further will receive a letter explaining the symptoms suggesting the development of deep-vein thrombosis, pulmonary embolism and adverse events and will be asked to contact the emergency room when any of these would occur.

All patient-information will be coded so that it cannot be traced back to the individual patient. This coded information can be used for publication.

Outcome:

At the time of removal of the plaster cast symptoms or signs suggestive of DVT will be noted and a colour duplex ultrasonography of the treated limb will be performed in all patients by an experienced technician according to a strict diagnostic test protocol (see enclosure 1). When there is incompressibility of a vein or lack of flow the diagnosis of DVT is made. The technician will be blinded to treatment.

In case of a suspected pulmonary embolism pulmonary angiography will be performed.

The following risk-factors for DVT will be recorded: age, sex, body mass index (BMI), current smoking, use of estrogen-containing hormonal replacement therapy or oral contraception, active cancer (treatment on going or stopped for less than one year), congenital or acquired hypercoagulable state, previous deep venous thromboembolism and varicose veins.

Safety will be assessed as a secondary outcome. Adverse events such as haematomas, bleeding and allergic reactions will be recorded.

• Study Type: Interventional
• Enrollment (Anticipated): 669
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Robert J Derksen, MD, PhD; Phone Number: +31 6 24748122; Email: rjderksen@hotmail.com
• Study Contact Backup: Name: Roelf S Breederveld, MD, PhD; Phone Number: +31 251 264920; Email: breed@kpnplanet.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands
      • Recruiting
      • University Medical Center Nijmegen
      • Contact: Jan Paul Frolke, MD, PhD
  • N-Holland
    • Amsterdam, N-Holland, Netherlands, 1117 MB
      • Recruiting
      • VU University Medical Center
      • Contact: Fred C Bakker, MD, PhD; Phone Number: 097 +31 20 4444444; Email: fc.bakker@vumc.nl
      • Contact: Jels Fongers, MD; Phone Number: +31 20 4443636; Email: J.Fongers@vumc.nl
    • Beverwijk, N-Holland, Netherlands, 1942 LE
      • Recruiting
      • Red Cross Hospital
      • Contact: Robert J Derksen, MD, PhD; Phone Number: +31 6 24748122; Email: rjderksen@hotmail.com
      • Contact: Roelf S Breederveld, MD, PhD; Phone Number: +31251264920
  • North Holland
    • Alkmaar, North Holland, Netherlands, 1815 JD
      • Recruiting
      • Medical Center Alkmaar
      • Contact: J H van der Brand, MD, PhD
    • Hoofddorp, North Holland, Netherlands, 2134 TM
      • Recruiting
      • Spaarne Hospital
      • Contact: Nico Sosef, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• at least 18 years
• with a nonsurgical fracture of the lower extremity requiring immobilisation in a below-knee plaster cast for a minimum of 4 weeks.

Exclusion Criteria:

• Delay between injury and Emergency Department visit greater than three days
• Pregnancy/ lactation
• Body weight < 50 kg
• Severe hepatic impairment
• Severe renal impairment (creatinin-clearance < 30 ml/min)
• Known hypersensitivity to nadroparine or fondaparinux
• Pre-existing venous thromboembolism
• Pre-existing post-thrombotic syndrome
• Documented congenital or acquired bleeding tendency/disorder(s)
• Active, clinically significant bleeding
• Clinically significant bleeding within the past six months
• Previous or active bleeding from the digestive tract by peptic ulcer, tumours, hiatus hernia or diverticulosis
• Severe hypertension (systolic blood pressure above 180 mmHg or diastolic blood pressure above 110 mmHg)
• Bacterial endocarditis
• Haemorrhagic stroke within the previous two months
• Severe head injury within the previous three months
• Intraocular, spinal, and/or brain surgery within the previous twelve months
• Major surgery within the previous two months
• Treatment with LMWH or other anticoagulants
• Anticoagulant therapy required or likely to be required during the study period (e.g. planned surgery justifying pharmacological thromboprophylaxis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: 1; Patients randomized to the no intervention group
Experimental: Nadroparin; Subjects randomized to group receiving nadroparin 0,3 cc daily during immobilization	Drug: Nadroparin; nadroparin 0,3 cc once daily during immobilization period; Other Names: Fraxiparin
Experimental: Fondaparinux; Subjects randomized to fondaparinux 2,5 mg daily group during immobilization	Drug: Fondaparinux; Fondaparinux 2,5 mg daily during immobilization period; Other Names: Arixtra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Primary outcome measure is deep vein trombosis as detected by venous duplex	subjects are assessed after 6 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Bleeding complications	6 weeks

Collaborators and Investigators

• Sponsor: Red Cross Hospital Beverwijk
• Investigators: Study Director: Roelf S Breederveld, MD, PhD, Red Cross Hospital Beverwijk; Principal Investigator: Yannick M Groutars, MD, Red Cross Hospital Beverwijk

Publications and helpful links

General Publications

• Bruntink MM, Groutars YME, Schipper IB, Breederveld RS, Tuinebreijer WE, Derksen RJ; PROTECT studygroup. Nadroparin or fondaparinux versus no thromboprophylaxis in patients immobilised in a below-knee plaster cast (PROTECT): A randomised controlled trial. Injury. 2017 Apr;48(4):936-940. doi: 10.1016/j.injury.2017.02.018. Epub 2017 Feb 22.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Anticipated): April 1, 2013
• Study Completion (Anticipated): April 1, 2013

Study Registration Dates

• First Submitted: April 13, 2009
• First Submitted That Met QC Criteria: April 14, 2009
• First Posted (Estimate): April 15, 2009

Study Record Updates

• Last Update Posted (Estimate): December 18, 2012
• Last Update Submitted That Met QC Criteria: December 15, 2012
• Last Verified: May 1, 2009

More Information

Terms related to this study

• Keywords: Ankle fracture; Deep vein trombosis; Profylaxis; Below knee plaster cast
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Venous Thrombosis; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Fondaparinux; PENTA; Nadroparin
• Other Study ID Numbers: PROTEcT