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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Dr. Ryan Zarychanski, University of Manitoba
ClinicalTrials.gov Identifier:
NCT01648036
First received: July 14, 2012
Last updated: January 17, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Septic Shock
Drug: Unfractionated heparin
Drug: Dalteparin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Heparin Anticoagulation to Improve Outcomes in Septic Shock: The HALO Pilot

Resource links provided by NLM:


Further study details as provided by University of Manitoba:

Primary Outcome Measures:
  • Feasibility of enrollment - to enrol an average of 2 patients per site per month over the duration of the study [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    The primary measure of feasibility is the ability of participating sites to enroll an average of 2 patients per month.


Secondary Outcome Measures:
  • Feasibility(1) - Consent rate - will be considered adequate if 60% of eligible patients are enrolled in the HALO pilot [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Safety - Rate of major and minor bleeding events [ Time Frame: Duration of ICU admission, or up to day +9 ] [ Designated as safety issue: Yes ]
    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.

  • Activation of coagulation - Thrombin-antithrombin (TAT) complexes [ Time Frame: Day 1, 2, 3, 5, 7, and 9 (or ICU discharge) ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Feasibility(3) - Time from randomization to initiation of study drug [ Time Frame: the outcome will be assessed during the first 24 hours of enrollment ] [ Designated as safety issue: No ]
    The investigators will consider the time from randomization to study treatment initiation to be satisfactory if this interval is less than 4 hours.

  • Activation of coagulation - Protein C concentration [ Time Frame: Day 1, 2, 3, 5, 7, and 9 (or ICU discharge) ] [ Designated as safety issue: No ]
  • Activation of Coagulation - Quantitative d-dimer [ Time Frame: Days 1, 2, 3, 5, 7, and 9 (or ICU discharge) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 76
Study Start Date: July 2012
Estimated Study Completion Date: February 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Fragmin

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01648036

Locations
Canada, Manitoba
St. Boniface Hospital
Winnipeg, Manitoba, Canada, R2H 2A6
Winnipeg Health Sciences Centre
Winnipeg, Manitoba, Canada, R3A 1R9
Canada, Nova Scotia
Capital Health - Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, Canada, B3H 3A7 and B3H 2Y9
Canada, Ontario
Hamilton General Hospital
Hamilton, Ontario, Canada, L8L 2X2
St Joseph's Healthcare Hamilton
Hamilton, Ontario, Canada, L8N 4A6
Ottawa Hospital Civic Campus
Ottawa, Ontario, Canada, K1Y 4E9
Ottawa Hospital General Campus
Ottawa, Ontario, Canada, K1H 8L6
St Michael's Hospital
Toronto, Ontario, Canada, M5B 1W8
Canada
Hopital de l'Enfant-Jesus
Quebec, Canada, G1J 1Z4
Sponsors and Collaborators
University of Manitoba
Investigators
Principal Investigator: Ryan Zarychanski, MD MSc University of Manitoba
Principal Investigator: Dean Fergusson, PhD MHA Ottawa Hospital Research Institute
  More Information

No publications provided

Responsible Party: Dr. Ryan Zarychanski, MD MSc. FRCPC, University of Manitoba
ClinicalTrials.gov Identifier: NCT01648036     History of Changes
Other Study ID Numbers: HCA2011/001
Study First Received: July 14, 2012
Last Updated: January 17, 2014
Health Authority: Canada: Health Canada

Additional relevant MeSH terms:
Shock
Shock, Septic
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Calcium heparin
Heparin
Dalteparin
Heparin, Low-Molecular-Weight
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents

ClinicalTrials.gov processed this record on April 20, 2014