Heparin Anticoagulation to Improve Outcomes in Septic Shock: The HALO Pilot

July 9, 2014 updated by: Dr. Ryan Zarychanski, University of Manitoba
Life-threatening infections account for 10% of all intensive care unit admissions and constitute the second more frequent cause of death in the ICU after heart diseases. The most common cause of death in patients admitted with life-threatening infections is multi-organ failure that is mediated by severe inflammation. Given the relationship between inflammation and blood clotting, blood-thinners (also called anticoagulants) have been used to decrease inflammation and the formation of small clots. Several lines of evidence suggest that heparin, a proven and inexpensive blood-thinner, may reduce improve survival in patients diagnosed with life-threatening infection. The primary objective of this study is to demonstrate the feasibility of enrolling patients in a large randomized controlled trial investigating heparin in patients with severe infections. In this study, patients with life-threatening infections will have an equal chance of receiving an intravenous infusion of heparin, or a low dose of a similar drug to prevent of blood clots while patients are immobile. The primary purpose of the study is to demonstrate that an average of 2 patients per site, per month, can be enrolled. Other measures of feasibility include the consent rate, the number of protocol violations that occur during the trial, and the number of dose reductions needed due to excessive anticoagulation. To study the biologic effects of heparin in patients with severe infection, specific laboratory markers will be measured and analyzed. If the feasibility of the trial is confirmed, a large randomized trial designed to tell if heparin can safely improve survival will be conducted. Given its low cost and availability, if heparin is shown to improve survival in patients with severe infection, adoption of this therapy on a global scale is anticipated.

Study Overview

Status

Status

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

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.

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.
76

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

  • Canada
      • Quebec, Canada, G1J 1Z4
        • Hôpital de l'Enfant-Jésus
    • Manitoba
      • Winnipeg, Manitoba, Canada, R2H 2A6
        • St. Boniface Hospital
      • Winnipeg, Manitoba, Canada, R3A 1R9
        • Winnipeg Health Sciences Centre
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 3A7 and B3H 2Y9
        • Capital Health - Queen Elizabeth II Health Sciences Centre
    • Ontario
      • Hamilton, Ontario, Canada, L8L 2X2
        • Hamilton General Hospital
      • Hamilton, Ontario, Canada, L8N 4A6
        • St Joseph's Healthcare Hamilton
      • Ottawa, Ontario, Canada, K1H 8L6
        • Ottawa Hospital General Campus
      • Ottawa, Ontario, Canada, K1Y 4E9
        • Ottawa Hospital Civic Campus
      • Toronto, Ontario, Canada, M5B 1W8
        • St Michael's 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:

  1. ≥ 18 years of age
  2. Refractory hypotension documented within 36 hours prior to enrolment that requires institution and ongoing use of vasopressor agents (phenylephrine, norepinephrine, vasopressin, epinephrine, or dopamine > 5 mcg/kg/min) at the time of enrolment. Refractory hypotension is defined as a systolic blood pressure < 90 mmHG or a systolic blood pressure more than 30 mmHg below baseline, or a mean arterial pressure less than 65 mmHG and receipt of greater than or equal to 2 litres of intravenous fluid for the treatment of hypotension.

  3. At least 1 other new organ dysfunction defined by the following:

    • Creatinine ≥ 150 µmol/L, or ≥ 1.5x the upper limit of normal or the known baseline creatinine, or < 0.5 ml/kg or urine output for 2 hours(Patients on chronic hemodialysis or peritoneal dialysis must meet one of the following criteria)
    • Need for invasive mechanical ventilation or a P/F ratio < 250
    • Platelets < 100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrollment
    • Arterial pH < 7.30 or base deficit > 5 mmol/L in association with a lactate >/= to 3.0 mmol/L

Exclusion Criteria:

  1. Consent declined
  2. Clinically apparent other forms of shock including cardiogenic, obstructive (massive pulmonary embolism, cardiac tamponnade, tension pneumothorax), hemorrhagic, neurogenic, or anaphylactic
  3. Received vasopressor therapy for greater than 36 hours prior to enrollment

  4. Have a significant risk of bleeding as evidenced by one of the following:

    • Clinical: Surgery requiring general or spinal anesthesia within 24 hours prior to enrollment, or the potential need for such surgery in the next 24 hours; evidence of active bleeding; a history of severe head trauma requiring hospitalization; intracranial surgery, or stroke within 3 months before the study or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or mass lesions of the central nervous system; a history of congenital bleeding diatheses; gastrointestinal bleeding within 6 weeks before the study unless corrective surgery had been performed; trauma considered to increase the risk of bleeding; presence of an epidural catheter
    • Laboratory: Platelet count < 30 x109/L, INR > 2.0, or baseline aPTT > 50 sec prior to enrollment.
  5. Have an indication for therapeutic anticoagulation (e.g. ACS, acute VTE, mechanical valve, etc)
  6. Intent of the most responsible physician to prescribe rhAPC
  7. Have had a known or suspected adverse reaction to UFH including HIT
  8. Are currently enrolled in related trial
  9. Known or suspected cirrhosis, or chronic ascites
  10. Use of any of the following medications or treatment regimens: unfractionated heparin to treat an active thrombotic event within 12 hours before the infusion enrollment; low-molecular-weight heparin at a higher dose than recommended for prophylactic use (as specified in the package insert) within 12 hours before the infusion; warfarin (if used within 7 days before study entry AND if the INR time exceeded the upper limit of the normal range for the institution); thrombolytic therapy within 3 days before the study, glycoprotein IIb/IIIa antagonists within 7 days before study entry; protein C or rhAPC within 24 hours before enrollment.
  11. Terminal illness with a life expectancy of less than 3 months
  12. Are pregnant

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: Triple

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
Drug: Unfractionated heparin
Dose: 18 IU/kg/hr, continuous intravenous infusion. Duration: up to 7 days or until ICU discharge or death
Active Comparator: Dalteparin
Standard of care
Drug: Dalteparin
Dose 5000 IU, subcutaneous, daily
Other Names:
  • Fragmin

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
Feasibility of enrollment - to enrol an average of 2 patients per site per month over the duration of the study
Time Frame: 1 year
The primary measure of feasibility is the ability of participating sites to enroll an average of 2 patients per month.
1 year

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
Feasibility(1) - Consent rate - will be considered adequate if 60% of eligible patients are enrolled in the HALO pilot
Time Frame: 1 year
1 year
Safety - Rate of major and minor bleeding events
Time Frame: Duration of ICU admission, or up to day +9
a.) Rates of major and minor bleeding will be adjudicated and will be considered in the context of monitored aPTTs: 1) in the context of aPTTs ≤95 seconds, the rate of major bleeding will be deemed acceptable if major bleeding occurs in ≤10% of patients; and 2) if >20% of patients require an initial (6 hour aPTT) dose reduction of the study drug due to an aPTT >95 seconds, this dose will be deemed infeasible as an initiation dose.
Duration of ICU admission, or up to day +9
Activation of coagulation - Thrombin-antithrombin (TAT) complexes
Time Frame: Day 1, 2, 3, 5, 7, and 9 (or ICU discharge)
Day 1, 2, 3, 5, 7, and 9 (or ICU discharge)
Feasibility(2): Protocol Deviations - The investigators believe that an acceptable rate of protocol violations resulting in a non-scheduled dose reduction or interruption of the study drug to be less than 10% of all study drug dose adjustments
Time Frame: Duration of study drug infusion or up to a maximum of 7 days
Duration of study drug infusion or up to a maximum of 7 days
Feasibility(3) - Time from randomization to initiation of study drug
Time Frame: the outcome will be assessed during the first 24 hours of enrollment
The investigators will consider the time from randomization to study treatment initiation to be satisfactory if this interval is less than 4 hours.
the outcome will be assessed during the first 24 hours of enrollment
Activation of coagulation - Protein C concentration
Time Frame: Day 1, 2, 3, 5, 7, and 9 (or ICU discharge)
Day 1, 2, 3, 5, 7, and 9 (or ICU discharge)
Activation of Coagulation - Quantitative d-dimer
Time Frame: Days 1, 2, 3, 5, 7, and 9 (or ICU discharge)
Days 1, 2, 3, 5, 7, and 9 (or ICU discharge)
Markers of Inflammation (IL-6, IL-8, IL-10, and IL-17)
Time Frame: Days 1, 2, 3, 5, 7, and 9 (or ICU discharge)
Days 1, 2, 3, 5, 7, and 9 (or ICU discharge)
ICU Mortality (Tertiary, descriptive outcome only)
Time Frame: Will be assessed at the time of ICU discharge or death; expected average length of ICU admission is 5.7 days
Will be assessed at the time of ICU discharge or death; expected average length of ICU admission is 5.7 days
Hospital Mortality (Tertiary, descriptive outcome only)
Time Frame: Will be assessed at the time of hospital discharge or death; expected average length of hospital admission is 14 days
Will be assessed at the time of hospital discharge or death; expected average length of hospital admission is 14 days
Change in MODS score (Tertiary, descriptive outcome only)
Time Frame: Will be assessed daily during admission to the ICU; expected average length of ICU admission is 5.7 days
Will be assessed daily during admission to the ICU; expected average length of ICU admission is 5.7 days

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

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: Dean Fergusson, PhD MHA, Ottawa Hospital Research Institute

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

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.
July 1, 2012

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.
January 1, 2014

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.
February 1, 2014

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).
July 14, 2012

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.
July 19, 2012

First Posted (Estimate)

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.
July 24, 2012

Study Record Updates

Last Update Posted (Estimate)

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.
July 10, 2014

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.
July 9, 2014

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.
July 1, 2014

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.
  • HCA2011/001

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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