Thromboprophylaxis in Lower Limb Immobilisation

NCT06370273 | Recruiting Phase 3 DMC

• 1 other identifier: 1009305
• Study Type: interventional
• Target: 10,044
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Thrombosis; Injury Leg

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Symptomatic VTE event occurrence

  Within 90 days from randomisation

• Major bleeding occurrence

  Within 42 days from randomisation

• Cause-specific mortality occurrence

  Within 90 days from randomisation

• Adverse and Serious adverse events

  Within 90 days from randomisation.

• Medication adherence

  Up to 42 days from randomisation

Study Arms (5)

TiLLI-High Intervention

ACTIVE COMPARATOR

A non-inferiority trial in people with temporary lower limb immobilisation at high risk of VTE comparing Direct Oral AntiCoagulants (DOACs) (intervention) to parenteral prophylaxis (routine care). Drug treatments will be provided for the duration of immobilisation or up to 42 days (whichever is earlier), in accordance with current NICE guidance. Intervention medications: Rivaroxaban 10mg once daily via oral ingestion. OR Apixaban 2.5mg twice daily via oral ingestion.

Drug: Rivaroxaban; Drug: Apixaban

TiLLI-High Routine Care

ACTIVE COMPARATOR

A non-inferiority trial in people with temporary lower limb immobilisation at high risk of VTE comparing Direct Oral AntiCoagulants (DOACs) (intervention) to parenteral prophylaxis (routine care). Drug treatments will be provided for the duration of immobilisation or up to 42 days (whichever is earlier), in accordance with current NICE guidance. Routine Care: Enoxaparin 40mg once daily via subcutaneous injection OR Tinzaparin 4500 IU once daily via subcutaneous injection OR Dalteparin 5000 IU once daily via subcutaneous injection OR Fondaparinux 2.5mg once daily via subcutaneous injection

Drug: Enoxaparin Injectable Solution; Drug: Tinzaparin Injectable Solution; Drug: Dalteparin Injectable Solution; Drug: Fondaparinux Injectable Product

TiLLI-Low Intervention 1 (DOAC)

ACTIVE COMPARATOR

A superiority trial in people with temporary lower limb immobilisation at low risk of VTE comparing parenteral prophylaxis (intervention) or Direct Oral AntiCoagulants (DOACs) (intervention) to no pharmacological prophylaxis (routine care). Drug treatments will be provided for the duration of immobilisation or up to 42 days (whichever is earlier), in accordance with current NICE guidance. Intervention medication: DOACs: Rivaroxaban 10mg once daily via oral ingestion. OR Apixaban 2.5mg twice daily via oral ingestion.

Drug: Rivaroxaban; Drug: Apixaban

TiLLI-Low Intervention 2 (Parenteral prophylaxis)

ACTIVE COMPARATOR

A superiority trial in people with temporary lower limb immobilisation at low risk of VTE comparing parenteral prophylaxis (intervention) or Direct Oral AntiCoagulants (DOACs) (intervention) to no pharmacological prophylaxis (routine care). Drug treatments will be provided for the duration of immobilisation or up to 42 days (whichever is earlier), in accordance with current NICE guidance. Parenteral prophylaxis: Enoxaparin 40mg once daily via subcutaneous injection OR Tinzaparin 4500 IU once daily via subcutaneous injection OR Dalteparin 5000 IU once daily via subcutaneous injection OR Fondaparinux 2.5mg once daily via subcutaneous injection

Drug: Enoxaparin Injectable Solution; Drug: Tinzaparin Injectable Solution; Drug: Dalteparin Injectable Solution; Drug: Fondaparinux Injectable Product

TiLLI-Low Routine Care

NO INTERVENTION

A superiority trial in people with temporary lower limb immobilisation at low risk of VTE comparing parenteral prophylaxis (intervention) or Direct Oral AntiCoagulants (DOACs) (intervention) to no pharmacological prophylaxis (routine care). Drug treatments will be provided for the duration of immobilisation or up to 42 days (whichever is earlier), in accordance with current NICE guidance. Routine care: No pharmacological prophylaxis

Interventions

Rivaroxaban DRUG

10mg once daily via oral ingestion

TiLLI-High Intervention; TiLLI-Low Intervention 1 (DOAC)

Apixaban DRUG

2.5mg twice daily via oral ingestion

TiLLI-High Intervention; TiLLI-Low Intervention 1 (DOAC)

Enoxaparin Injectable Solution DRUG

40mg once daily via subcutaneous injection

TiLLI-High Routine Care; TiLLI-Low Intervention 2 (Parenteral prophylaxis)

Tinzaparin Injectable Solution DRUG

4500 IU once daily via subcutaneous injection

TiLLI-High Routine Care; TiLLI-Low Intervention 2 (Parenteral prophylaxis)

Dalteparin Injectable Solution DRUG

5000 IU once daily via subcutaneous injection

TiLLI-High Routine Care; TiLLI-Low Intervention 2 (Parenteral prophylaxis)

Fondaparinux Injectable Product DRUG

2.5 mg once daily via subcutaneous injection

TiLLI-High Routine Care; TiLLI-Low Intervention 2 (Parenteral prophylaxis)

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Hospital admission is required direct from the emergency department, minor injuries unit, or fracture clinic setting with an expected length of stay \>2 calendar days.
• Absolute contraindication or known hypersensitivity to anticoagulants, including history of end stage renal failure (eGFR \<20ml/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.
• Preceding use of anticoagulant treatment for \>3 calendar days at prophylactic or therapeutic dose.
• Prior enrolment in the TiLLI study.
• Non-rigid immobilisation (crepe bandage, tubigrip support, strapping).
• Time since prescription of rigid immobilisation \>3 calendar days
• Co-enrolment onto a CTIMP where an anticoagulant is administered
• People lacking the capacity to consent
• Inability or refusal to use acceptable contraception up until after the last administration of IMP. Only applicable for women of childbearing potential who have been randomised to receive apixaban or rivaroxaban

Sponsors & Collaborators

• Queen Mary University of London: lead

Study Sites (3)

Epsom and St Helier University Hospitals NHS Trust

Carshalton, Surrey, United Kingdom

RECRUITING

Barts Health NHS Trust

London, United Kingdom

RECRUITING

Northern Care Alliance NHS Foundation Trust

Manchester, United Kingdom

RECRUITING

MeSH Terms

Conditions

Thrombosis; Leg Injuries

Interventions

Rivaroxaban; apixaban

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Trial Manager

CONTACT

+44 (0) 20 7882 5555; tilli-bjh@qmul.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Open-label study. Trial Statistician and Health Economist to be blinded for analysis
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A pragmatic, open-label, linked pair of randomised controlled trials with common outcomes and parallel economic analysis each with internal pilot phases, conducted across 30 NHS sites

Study Record Dates

• First Submitted: March 21, 2024
• First Posted: April 17, 2024
• Study Start: November 12, 2024
• Primary Completion (Estimated): August 31, 2028
• Study Completion (Estimated): August 31, 2028
• Last Updated: January 6, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)