Trial of Nebulized Heparin Versus Placebo for Inhalation Trauma (Hepburn)

Randomized Controlled Trial Investigating the Efficacy and Safety of Nebulized Heparin Versus Placebo in Burn Patients With Inhalation Trauma (Hepburn)

The purpose of this international multi-center double-blind randomized placebo-controlled trial is to determine the effect of nebulized heparin, compared to placebo, on the number of ventilator-free days at day 28, in burn patients with confirmed inhalation trauma requiring mechanical ventilation.

Study Overview

• Status: Terminated
• Conditions: Burn Injury; Inhalation Injury
• Intervention / Treatment: Drug: unfractionated heparin; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3065
      • St Vincent's Hospital
• Belgium
  • Antwerpen, Belgium, 2000
    • Ziekenhuis Netwerk Antwerpen- Stuivenberg
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium, 9000
      • University Hospital, Gent
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • University Hospital Gasthuisberg - Leuven
• Netherlands
  • Groningen, Netherlands, 9728 NT
    • Martini Hospital
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
      • Academic Medical Center
    • Beverwijk, Noord-Holland, Netherlands, 1942 LE
      • Red Cross Hospital, Beverwijk, the Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3079 DZ
      • Maasstad Hospital

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:

• Informed consent
• Age > 18 years
• Need for invasive mechanical ventilation
• Confirmed inhalation trauma (bronchoscopically)

Exclusion Criteria:

• > 36 hours after trauma
• Receiving invasive ventilation > 24 hours
• Expected duration of mechanical ventilation < 24 hours
• Chronic obstructive pulmonary disease GOLD stage III and IV
• Any history of pulmonary hemorrhage in the past 3 months
• Any history of significant bleeding disorder
• Known allergy to heparin, including heparin-induced thrombocytopenia
• Pregnancy or breast feeding
• Unlikely to survive for > 72 hours
• Total body surface area (TBSA) > 60%
• Witnessed or proven aspiration (i.e., confirmed by bronchoscopy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: unfractionated heparin; 25.000 IU/5 ml, will be nebulized 4 hourly (i.e. 6 times daily)	Drug: unfractionated heparin; nebulized 6 times daily, daily dose 150.000 IU for the maximum duration of 14 days; Other Names: unfractionated heparin sodium, EV Product Code: SUB02475MIG,; Marketing Authorisation number: RVG 01372; ATC codes: B01AB01
PLACEBO_COMPARATOR: placebo; Sterile sodium chloride (NaCl 0.9%, Pfizer), in 5 ml, will be nebulized every 4 hours (i.e. 6 times daily)	Drug: placebo; Placebo: Sterile saline nebulized 6 times daily for the maximum duration of 14 days; Other Names: sterile sodium chloride (NaCl 0.9%)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of ventilator-free days at day 28	The number of ventilator-free days is defined as the number of days a patient is breathing without assist of a ventilator during the first 28 days; thus, the patient must be free of mechanical ventilation for 24 hours to have one ventilator-free day; if after successful detubation the patient requires a reintubation due to a surgical procedure, this reintubation will not count as a ventilator day - however, the day(s) will be counted as ventilator day(s) if mechanical ventilation is prolonged after surgery due to respiratory insufficiency.	at day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical outcome parameters	Clinical outcome parameters will include but not be restricted to: (a) length of stay (ICU and hospital); (b) mortality (28- and 90 days); (c) mortality (ICU and hospital); (d) daily Lung Injury Score (LIS); (e) daily Oxygenation Index (OI) ; (f) daily Sequential Organ Failure Assessment (SOFA)-scores ; (g) cumulative dosages of sedatives; (h) incidence of Ventilator-associated Pneumonia (VAP); (i) total number of bronchoscopy-guided cleaning of the larger airway	daily or at day 28 and day 90
Laboratory outcome parameters	Levels of markers of coagulation and fibrinolysis in blood and lung lavage fluid, Levels of markers of inflammation in blood and lung lavage fluid, Biomarkers of lung injury in blood and lung lavage fluid	Blood and lavage samples: on admission day and every other day for a maximum period of 14 days
Safety parameters	Safety parameters will include but not be restricted to: Occurrence of serious bleedings, any other transfusion of blood products - red cells and/or platelets and/or plasma, Confirmed Heparin induced thrombocytopenia, prolonged activated partial thromboplastin time (aPTT > 150 seconds)	daily, for a maximum period of 28 days

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Dutch Burns Foundation
• Investigators: Principal Investigator: Marcus J Schultz, MD-PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Glas GJ, Muller J, Binnekade JM, Cleffken B, Colpaert K, Dixon B, Juffermans NP, Knape P, Levi MM, Loef BG, Mackie DP, Malbrain M, Schultz MJ, van der Sluijs KF. HEPBURN - investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial. Trials. 2014 Mar 25;15:91. doi: 10.1186/1745-6215-15-91.

Helpful Links

• HEPBURN website

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (ACTUAL): October 1, 2016
• Study Completion (ACTUAL): December 1, 2017

Study Registration Dates

• First Submitted: January 16, 2013
• First Submitted That Met QC Criteria: January 18, 2013
• First Posted (ESTIMATE): January 23, 2013

Study Record Updates

• Last Update Posted (ACTUAL): February 16, 2022
• Last Update Submitted That Met QC Criteria: February 14, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: mechanical ventilation; Inhalation trauma; pulmonary coagulopathy; heparin nebulization
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Respiratory Aspiration; Wounds and Injuries; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: HepBurn; 2012-003289-42 (EUDRACT_NUMBER)