Heparin Anticoagulation in Septic Shock (HALO)

May 17, 2022 updated by: University of Manitoba

Heparin AnticoaguLation to Improve Outcomes in Septic Shock: The HALO International Phase II RCT

This study is a pragmatic open-label international randomized trial comparing therapeutic dose intravenous unfractionated heparin (UFH) to standard care venous thromboprophylaxis in patients diagnosed with septic shock.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Background and significance: Sepsis and septic shock account for 10% of admissions to the intensive care unit and constitute the second most frequent cause of death among admitted patients. The mortality rate associated with septic shock ranges from 30% to 50% and death is often due to multiple organ dysfunction coupled with systemic inflammation. Given the pathobiological relationship between coagulation and inflammation in sepsis, treatment with anticoagulants has been investigated in this population. Multiple lines of evidence suggest that heparin, a widely available, inexpensive anticoagulant, may improve clinical outcomes in sepsis, but high quality evidence to guide practice is lacking.

Hypothesis: Intravenous (IV) unfractionated heparin (UFH) reduces mortality and morbidity when administered to patients with suspected septic shock.

Study Design: A pragmatic open-label international randomized trial comparing therapeutic dose intravenous unfractionated heparin (UFH) to standard care venous thromboprophylaxis in patients diagnosed with septic shock.

Setting: To increase the external validity/generalizability of the trial results, 20 sites in 4 countries will participate.

Study Population: Patients with systemic inflammation, vasopressor dependent shock, and signs of organ dysfunction.

Interventions: IV infusion of UFH at 18 IU/kg/hr, dosed according to total body weight and pragmatically adjusted according to usual care to achieve an activated partial thromboplastin time (aPTT) of 1.5-2.5x that of the reference aPTT value (approximately 59-99 seconds). Alternately, therapeutic anti-Xa values (ie. values typically targeted for the treatment of venous thromboembolism) can be targeted based on local practice. Duration of heparin infusion is for a maximum of 5 days (120 hours) or until death, ICU discharge or discontinuation of vasopressors. The dose of UFH has been informed by our observational study and meta-analysis that showed a benefit of UFH in patients receiving therapeutic doses.

Control group: Local standard care for venous thromboprophylaxis (i.e. not therapeutic) which may include SC LMWH, SC UFH, sequential compression devices or graduated compression stockings.

Outcomes: At the end of the HALO international phase II trial, an international DSMB will be presented with by-group efficacy (vasopressor-free days) data in the context of 90-day mortality, and safety (bleeding and transfusion). With these data the DSMB will suggest: a) terminating enrollment for futility (lack of efficacy) or harm, or b) continuing to the phase III trial along with a recommended sample size to detect a clinically relevant difference in 90-day mortality. Patients will be analyzed according to the treatment group to which they are allocated. By-group data will remain blinded to study investigators so that these patients may be included in the HALO international phase III RCT. Our analytic approach provides a rationale to either stop, or to justify further investment in a large international phase III trial.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
178

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Brazil
      • Altamira, Brazil
        • Hospital São José
      • Atibaia, Brazil
        • Hospital Novo Atibaia
      • Barretos, Brazil
        • Hospital de Amor (Barretos)
      • Belo Horizonte, Brazil
        • Santa Casa de Misericórdia de Belo Horizonte
      • Bento Gonçalves, Brazil
        • Hospital Tacchini
      • Brasilia, Brazil
        • Hospital de Brasília
      • Brasília, Brazil
        • Hospital Ortopedico e Medicina Especializada ltda. - HOME
      • Brasília, Brazil
        • Instituto de Cardiologia do Distrito Federal
      • Colatina, Brazil
        • Hospital Maternidade São José
      • Florianópolis, Brazil
        • Hospital Baia Sul
      • Florianópolis, Brazil
        • Hospital Nereu Ramos
      • Jales, Brazil
        • Hospital de Amor Jales
      • Juazeiro Do Norte, Brazil
        • Unimed Cariri Hospital
      • Porto Alegre, Brazil
        • Irmandade da Santa Casa de Misericordia de Porto Alegre
      • Porto Alegre, Brazil
        • Hospital de Clínicas de Porto Alegre
      • Ribeirão Preto, Brazil
        • Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
      • Rio Grande, Brazil
        • Hospital Bruno Born
      • Salvador, Brazil
        • Hospital da Cidade
      • São João Del Rei, Brazil
        • Santa Casa de São João Del Rei
      • São Paulo, Brazil
        • Hospital Santa Paula
      • São Paulo, Brazil
        • Hospital Beneficência Portuguesa
      • São Paulo, Brazil
        • Hospital AC Camargo
      • São Paulo, Brazil
        • Hospital da Luz
      • São Paulo, Brazil
        • Hospital das Clinicas da faculdade de Medicina de Universidade de São Paulo
      • São Paulo, Brazil
        • Hospital e Maternidade Sao Vicente
      • São Paulo, Brazil
        • Hospital SEPACO
      • São Paulo, Brazil
        • Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo
      • São Paulo, Brazil
        • Universidade Federal de São Paulo - UNIFESP
      • Taguatinga, Brazil
        • Hospital Ana Nery
  • Canada
      • Quebec, Canada, G1J 1Z4
        • Hôpital de l'Enfant-Jésus
    • Alberta
      • Calgary, Alberta, Canada, T2N 2T9
        • Foothills Medical Centre
    • British Columbia
      • Victoria, British Columbia, Canada, V8R 1J8
        • Vancouver Island Health Authority
    • Manitoba
      • Winnipeg, Manitoba, Canada, R3A 1R9
        • Health Sciences Centre Winnipeg
      • Winnipeg, Manitoba, Canada, R2H 2A6
        • St Boniface General Hospital
    • Ontario
      • Ottawa, Ontario, Canada, K1H 8L6
        • The Ottawa Hospital - General Campus
      • Ottawa, Ontario, Canada, K1Y 4E9
        • The Ottawa Hospital - Civic Campus
      • St. Catherines, Ontario, Canada, L2S 0A9
        • Niagara Health System - St Catharines Site
      • Toronto, Ontario, Canada, M5B 1W8
        • St Michael's Hospital
    • Quebec
      • Montréal, Quebec, Canada, H2X 0A9
        • Centre Hospitalier de l'Universite de Montreal (CHUM)
      • Québec, Quebec, Canada, G1V 4G5
        • Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval
  • Greece
      • Athens, Greece
        • Attikon University Hospital
      • Athens, Greece
        • Korgialeneion Benakeion Hospital
  • India
      • Kolkata, India
        • AMRI Hospital Kolkata
  • Pakistan
      • Karachi, Pakistan
        • Dr Ruth K.M. PFAU Civil Hospital
      • Karachi, Pakistan
        • Shaheed Mohtarma Benazir Bhutto Trauma Center
      • Karachi, Pakistan
        • The Indus Hospital
      • Lahore, Pakistan
        • Mayo Hospital Lahore
  • Philippines
      • Manila, Philippines
        • The Asian Hospital
      • Manila, Philippines
        • The Medical City
      • Manila, Philippines
        • The Philippines General Hospital
  • United States
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Froedtert Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • ≥ 18 years of age
  • Refractory hypotension documented within 18 hours prior to enrolment that requires the institution and ongoing use of vasopressor agents, (phenylephrine, norepinephrine, vasopressin, epinephrine, midodrine or dopamine >5 mcg/kg/min) at the time of enrolment. Refractory hypotension is defined as a systolic blood pressure (SBP) less than 90 mm Hg, or a systolic blood pressure more than 30 mm Hg below baseline, or a mean arterial pressure (MAP) less than 65 mm Hg and receipt of ≥ 2 litres of intravenous fluid for the treatment of hypotension (≥ 1 litre if dialysis dependent end-stage renal disease or if the patient is felt to be in congestive heart failure).

  • At least 1 other new organ dysfunction (in addition to refractory hypotension), defined by the following:

    1. Creatinine ≥1.5x the known baseline creatinine, or ≥ 26.5 µmol/L increase or <0.5 mL/kg of urine output for 6-12 hours according to the KDIGO [Kidney Disease improving Global Outcomes (KDiGO)] guideline definition of acute kidney injury.
    2. Need for invasive mechanical ventilation or a P/F ratio <250
    3. Platelets <100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrolment
    4. Arterial pH < 7.30 or base deficit > 5 mmol/L in association with a lactate > 4.0 mmol/L

Exclusion Criteria:

  • Other forms of shock including cardiogenic, hemorrhagic, hypovolemic, neurogenic, or obstructive shock.
  • Clinical suspicion or confirmation of a viral hemorrhagic shock syndrome including, but not limited to, dengue fever
  • Rapid clinical improvement; vasopressors likely to be discontinued in the next 6 hours
  • Received vasopressor therapy for greater than 18 hours prior to enrolment

  • Bleeding Risk:

    1. Clinical: Active bleeding; head trauma; intracranial surgery or stroke within 3 months; history of intracerebral arteriovenous malformation, cerebral aneurysm or mass lesions of the central nervous system; history of a bleeding diatheses; gastrointestinal bleeding within 6 weeks; presence of an epidural or spinal catheter; selected cases of recent surgery where IV therapeutic UFH is considered contraindicated
    2. Laboratory: Platelet count <50 x109/L, INR >2.0, or baseline aPTT >50 seconds prior to enrolment
  • Known or suspected adverse reaction to UFH including heparin induced thrombocytopenia (HIT).
  • Use of any of the following treatments: UFH to treat a thrombotic event within 12 hours before enrolment; LMWH at a higher dose than recommended for prophylactic use within 12 hours before the infusion; warfarin (if used within 7 days before study entry AND if the INR exceeds 2.0 at enrolment); thrombolytic therapy within 3 previous days; use of IIb/IIIa inhibitors within the previous 7 days.
  • Need for therapeutic anticoagulation
  • Terminal illness with a life expectancy of less than 3 months, or no commitment to aggressive care.
  • Consent declined from patient or authorized 3rd party
  • Physician refusal

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Unfractionated Heparin (UFH)
UFH initiated at 18 IU/kg/hr
Drug: Unfractionated heparin
UFH initiated at 18 IU/kg/hr, dosed according to total body weight and pragmatically adjusted according to local institutional policy to achieve an activated partial thromboplastin (aPTT) of 1.5 to 2.5 times that of the reference aPTT value or anti-Xa values targeted to local practice levels. Duration of study intervention will be a maximum of 5 days (120 hours) or until vasopressors have been discontinued for 24 continuous hours. All participants will then receive venous thromboprophylaxis according to local practice.
Other Names:
  • Heparin
Other: Venous thromboprophylaxis (VTE)
as per local standard
Other: Venous thromboprophylaxis (VTE)
May include subcutaneous heparin or dalteparin, sequential compression device or graduated compression stockings

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Vasopressor-free days.
Time Frame: 30 days
The goal of phase II trial is to provide the international Data Safety Monitoring Committee (DSMC) with a sensible estimate to justify continued enrollment in an adaptive (sample size) trial. Vasopressor use, reflecting cardiovascular collapse due to overwhelming systematic inflammation, is a key inclusion criterion for the trial and durable discontinuation of such drugs and meaningful clinical improvement. Vasopressor-free days has been recommended as a preferred clinical outcome in phase II trials in critical illness.
30 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Clinical Outcome #1 - ICU mortality
Time Frame: From date of randomization until the first documentation of death from any cause or ICU discharge date or 90 days, whichever came first
Survival
From date of randomization until the first documentation of death from any cause or ICU discharge date or 90 days, whichever came first
Clinical Outcome #2 - Hospital mortality
Time Frame: From date of randomization to the first documentation of death from any cause or hospital discharge date or 90 days, whichever came first.
Survival
From date of randomization to the first documentation of death from any cause or hospital discharge date or 90 days, whichever came first.
Clinical Outcome #3 - 90-day mortality
Time Frame: Up to day 90
Survival
Up to day 90
Clinical Outcome # 4 - ∆SOFA score (Sequential Organ Failure Assessment)
Time Frame: Daily from randomization to ICU discharge or hospital discharge or time of death or to study day 9 if still in ICU or hospital.
Organ failure assessment using the SOFA scoring tool
Daily from randomization to ICU discharge or hospital discharge or time of death or to study day 9 if still in ICU or hospital.
Clinical Outcome # 5 - Hospital-free days to day 90
Time Frame: from hospital admission to hospital discharge or time of death to day 90
Hospital admission duration in the context of survival
from hospital admission to hospital discharge or time of death to day 90
Clinical Outcome #6 - Renal replacement therapy-free days to day 28
Time Frame: from start of renal replacement therapy to study day 28
Renal replacement therapy duration in the context of survival
from start of renal replacement therapy to study day 28
Safety Outcome #1 - Major Bleeding
Time Frame: Assessed daily to day 8
Rates of major bleeding using a validated bleeding assessment tool
Assessed daily to day 8
Safety Outcome #2 - Minor Bleeding
Time Frame: Assessed daily to day 8
Rates of minor bleeding using a validated bleeding assessment tool
Assessed daily to day 8
Safety Outcome #3 - Suspected HIT (Heparin induced thrombocytopenia)
Time Frame: Assessed daily to day 8
Incidence of any laboratory testing for HIT including screening or confirmatory tests
Assessed daily to day 8
Safety Outcome #4 - Confirmed HIT (Heparin induced thrombocytopenia)
Time Frame: Assessed daily to day 8
Postive confirmatory HIT test (one of Serotonin release assay (SRA) or Heparin induced platelet aggregation (HIPA))
Assessed daily to day 8
Rate of enrolment
Time Frame: Monthly starting at individual site initiation through to end of enrollment, estimated two years
average number of patients enrolled per site per month
Monthly starting at individual site initiation through to end of enrollment, estimated two years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Manitoba

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Canadian Institutes of Health Research (CIHR)
CancerCare Manitoba

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ryan Zarychanski, MD MSc, University of Manitoba
  • Principal Investigator: Anand Kumar, MD, University of Manitoba
  • Principal Investigator: Dean A Fergusson, PhD MHA, University of Ottawa

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 12, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 9, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 18, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 19, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 24, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 17, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HCA2017

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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