Thromboprophylaxis in Lower Limb Immobilisation

Thrombosis Clinical Trial

— TiLLI  

Official title:

Thromboprophylaxis in Lower Limb Immobilisation (TiLLI): a Multicentre Study Comprising Two Linked Open Label Phase III Randomised Controlled Trials Evaluating the Effectiveness and Cost Effectiveness of Different Methods of Pharmacological Prophylaxis for Patients With Temporary Lower Limb Immobilisation.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06370273
• Other study ID #: 1009305
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: May 2024
• Est. completion date: February 2028

Study information

• Verified date: April 2024
• Source: Queen Mary University of London
• Contact: Trial Manager
• Phone: +44 (0) 20 7882 5555
• Email: tilli-bjh[@]qmul.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to find out the clinical and cost effectiveness of Thromboprophylaxis in participants who have been placed in a plaster cast or splint after injury. The main questions it aims to answer are: - whether giving tablets to people at high risks of clots after a leg injury is as good as injections (standard care) - whether giving any medication after a leg injury is better than standard care (advice only) for people at low risk of clots. Participants will be assessed to be high risk (TiLLI High) or low risk (TiLLI Low). People who are at high risk of clots will have either tablets or injections to reduce their risk. People at low risk will receive tablets, injections or no medication. Drug treatments will be provided for the duration of immobilisation or up to 42 days (whichever is earlier), in accordance with current NICE guidelines. The participants will be followed up for 90 days following randomisation.

Description:

People have an increased risk of blood clots when they have a leg injury treated with a plaster cast or a splint, which happens to over 70,000 people every year in the UK. Blood clots can cause long term problems in the legs and can also move to the lungs, causing serious illness and occasionally death. Medicines are available to reduce the risk of blood clots, but they can also increase the risk of bleeding. In people at high risk of clots, most hospitals use the recommended daily injections which can be uncomfortable and sometimes difficult to give. Tablets are available that reduce the risk of blood clots in other groups, but it is not known if tablets work as well as the injections for people with a leg injury. It is also not known whether people at low risk of blood clots may benefit from any medication. As such, a national research body has identified the need for further study on this topic. The TiLLI study has two aims - to determine whether giving tablets to people at high risk of clots after a leg injury is as good as injections, and whether giving any medication is better than standard care (advice only) for people at low risk of clots. The TiLLI study consists of two linked trials: TiLLI-High and TiLLI-Low. People who have been placed in a plaster cast or splint after a leg injury will be invited to participate. Those who agree and are at high risk of clots will enter TiLLI-High and be randomised to receive either tablets or injections to reduce their risk of blood clots; those at low risk will enter TiLLI-Low and will be randomised to receive tablets, injections, or no medication. Patients and doctors will know what medication they are taking. All patients will be provided with written guidance on the signs and symptoms of blood clots and advice on managing their medication. Information will be collected from study participants up to 90 days after joining the study to find out whether anyone suffers blood clots or complications from the medication. This data will be collected by reviewing medical records and contacting participants as needed. To encourage people from different backgrounds to take part, the study will run from lots of different hospitals across the UK. Study materials will be translated into different languages for those who do not speak English. The investigators will collect as much information as possible from people without extra hospital visits. An independent panel will look at the data as the study progresses to decide whether it is safe to continue. The study will cost approximately £300 per patient, which is excellent value for money. If these trials show that tablets are as effective as injections, approximately 20,000 patients will be able to avoid injections and >£1.5 million will be released back to NHS resources, every year. When the study is finished, the investigators will share the findings with staff in the NHS, patient charities and national guideline bodies. They will also publish the findings in the medical press and work with international research groups to answer further research questions on this topic.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10044
• Est. completion date: February 2028
• Est. primary completion date: February 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

• Age >/= 16 years
• Placed in temporary lower limb immobilisation (rigid cast or brace) as a result an injury that occurred within the last 7 days

Exclusion Criteria:

• Hospital admission is required immediately with an expected length of stay >48h.
• Absolute contraindication or known hypersensitivity to anticoagulants, including history of end stage renal failure (eGFR <15ml/min/1.73m2), hepatic failure or use of concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g. ritonavir) or active substances strongly inhibiting elimination pathways such as CYP3A4 or P-gp (such as clarithromycin, erythromycin or dronaderone) or a history of heparin induced thrombocytopenia.
• Pregnancy, actively seeking conception, or active breastfeeding.
• Ongoing use of anticoagulant treatment at prophylactic or therapeutic dose for alternate reason.
• Prior enrolment in the study.
• Non-rigid immobilisation (crepe bandage, tubigrip support, strapping).
• Time since prescription of rigid immobilisation >72h.

Related Conditions & MeSH terms

• Injury Leg
• Thrombosis

Intervention

Drug:
• Rivaroxaban
10mg once daily via oral ingestion
• Apixaban
2.5mg twice daily via oral ingestion
• Enoxaparin Injectable Solution
40mg once daily via subcutaneous injection
• Tinzaparin Injectable Solution
4500 IU once daily via subcutaneous injection
• Dalteparin Injectable Solution
5000 IU once daily via subcutaneous injection
• Fondaparinux Injectable Product
2.5 mg once daily via subcutaneous injection

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Queen Mary University of London

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of net clinical benefit comprising clinical VTE event, major bleeding, and cause-specific mortality	To estimate and draw inferences on the difference in a composite outcome of net clinical benefit between treatment groups. A composite primary outcome of net clinical benefit, comprising symptomatic VTE events (any deep vein thrombosis or pulmonary embolism), major bleeding or cause-specific mortality (death from either pulmonary embolus or major bleeding) used as a binary variable ('1' is any event occurred, '0' if none of the events occurred).	Within 90 days of randomisation
Secondary	Symptomatic VTE event occurrence	To compare symptomatic VTE events (any deep vein thrombosis or pulmonary embolism) (an individual component of primary composite outcome) between treatment groups as a binary variable ('1' if any event occurred, '0' if no event occurred). Symptomatic VTE events objectively defined by ISTH criteria.	Within 90 days from randomisation
Secondary	Major bleeding occurrence	To compare major bleeding events (an individual component of primary composite outcome) between treatment groups as a binary variable ('1' if any event occurred, '0' if no event occurred). Major bleeding events objectively defined by ISTH criteria.	Within 42 days from randomisation
Secondary	Cause-specific mortality occurrence	To compare cause-specific mortality events (an individual component of primary composite outcome) between treatment groups as a binary variable ('1' if any event occurred, '0' if no event occurred).	Within 90 days from randomisation
Secondary	Adverse and Serious adverse events	To estimate and draw inferences on the difference in complications (including clinically relevant non-major bleeding and surgical site bleeding) objectively defined by ISTH criteria, between treatment groups.	Within 90 days from randomisation.
Secondary	Medication adherence	To report participant adherence to allocated anticoagulant verified through digital response system.	Up to 42 days from randomisation
Secondary	Health utility (EQ-5D-5L)	To estimate and draw inferences on differences in quality-of-life measures between treatment groups. Using the EuroQol 5 Dimensions 5 Level (EQ-5D-5L), a validated instrument comprising a self-rated health VAS and a five-domain health status questionnaire related to daily activities. Will collect for 4 timepoints: pre injury (completed retrospectively within 7 days following randomisation), 7 days following randomisation, 42 days following randomisation, and 90 days following randomisation	Up to 90 days post randomisation.
Secondary	Patient satisfaction regarding the burdens and benefits of anticoagulation	To estimate and draw inferences on the acceptability of different prophylactic anticoagulants using the validated Anti Clot Treatment Scale (ACTS) for patients allocated to drug treatments. The scale is a 15-item patient-reported instrument of satisfaction with anticoagulation treatment, with separate internal measures of burden and benefits.	Collected within 42 days following randomisation when the participants stops study treatment.
Secondary	Hospital readmission/reattendance	To estimate and draw inferences on the difference in resource use (including hospital readmission/reattendance), cost, quality of life-adjusted survival and relative cost effectiveness between treatment groups. Using bespoke Case Report Forms and review of EHR, research staff to collect information on resources required to deliver subsequent care reviews (including scheduled clinic and unscheduled hospital attendance), and investigations.	Within the first 90 days.
Secondary	Health and social care resource use	To estimate the health and social care resource use and costs and the relative cost effectiveness between treatment groups. Using bespoke Case Report Forms and review of EHR, research staff to collect information on health and social care resource use.	Within the first 90 days
Secondary	Patient longer term outcome VTE and bleeding data	To estimate longer term outcomes, such as post thrombotic syndrome, chronic thromboembolic pulmonary hypertension and bleeding complications and draw inferences on cost effectiveness, by using an existing VTE model with risk-adjusted, population specific effect estimates from this study. This will allow efficient, value for money inferences to made about long-term sequelae of VTE events and determine whether detailed long-term follow-up of participants would be worthwhile. Clinically relevant non-major bleeding events, major bleeding events and symptomatic bleeding events objectively defined by ISTH criteria.	Informed by directly measured events up to 90 days.