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

NCT01648036 | Completed Phase 2 DMC

• 1 other identifier: HCA2011/001
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 9

Brief Summary

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.

Conditions

Septic Shock

Outcome Measures

Primary Outcomes (1)

• Feasibility of enrollment - to enrol an average of 2 patients per site per month over the duration of the study

  The primary measure of feasibility is the ability of participating sites to enroll an average of 2 patients per month.

  1 year

Secondary Outcomes (11)

• Feasibility(1) - Consent rate - will be considered adequate if 60% of eligible patients are enrolled in the HALO pilot

  1 year

• Safety - Rate of major and minor bleeding events

  Duration of ICU admission, or up to day +9

• Activation of coagulation - Thrombin-antithrombin (TAT) complexes

  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

  Duration of study drug infusion or up to a maximum of 7 days

• Feasibility(3) - Time from randomization to initiation of study drug

  the outcome will be assessed during the first 24 hours of enrollment

Study Arms (2)

Unfractionated Heparin

EXPERIMENTAL

Drug: Unfractionated heparin

Dalteparin

ACTIVE COMPARATOR

Standard of care

Drug: Dalteparin

Interventions

Unfractionated heparin DRUG

Dose: 18 IU/kg/hr, continuous intravenous infusion. Duration: up to 7 days or until ICU discharge or death

Unfractionated Heparin

Dalteparin DRUG

Dose 5000 IU, subcutaneous, daily

Also known as: Fragmin

Dalteparin

Eligibility Criteria

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

You may qualify if:

• ≥ 18 years of age
• 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.
• 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

You may not qualify if:

• Consent declined
• Clinically apparent other forms of shock including cardiogenic, obstructive (massive pulmonary embolism, cardiac tamponnade, tension pneumothorax), hemorrhagic, neurogenic, or anaphylactic
• Received vasopressor therapy for greater than 36 hours prior to enrollment
• 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.
• Have an indication for therapeutic anticoagulation (e.g. ACS, acute VTE, mechanical valve, etc)
• Intent of the most responsible physician to prescribe rhAPC
• Have had a known or suspected adverse reaction to UFH including HIT
• Are currently enrolled in related trial
• Known or suspected cirrhosis, or chronic ascites
• 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.
• Terminal illness with a life expectancy of less than 3 months
• Are pregnant

Sponsors & Collaborators

• University of Manitoba: lead

Study Sites (9)

St. Boniface Hospital

Winnipeg, Manitoba, R2H 2A6, Canada

Location

Winnipeg Health Sciences Centre

Winnipeg, Manitoba, R3A 1R9, Canada

Location

Capital Health - Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, B3H 3A7 and B3H 2Y9, Canada

Location

Hamilton General Hospital

Hamilton, Ontario, L8L 2X2, Canada

Location

St Joseph's Healthcare Hamilton

Hamilton, Ontario, L8N 4A6, Canada

Location

Ottawa Hospital General Campus

Ottawa, Ontario, K1H 8L6, Canada

Location

Ottawa Hospital Civic Campus

Ottawa, Ontario, K1Y 4E9, Canada

Location

St Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Hopital de l'Enfant-Jesus

Québec, Quebec, G1J 1Z4, Canada

Location

MeSH Terms

Conditions

Shock, Septic

Interventions

Heparin; Dalteparin

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates; Heparin, Low-Molecular-Weight

Study Officials

• Ryan Zarychanski, MD MSc

  University of Manitoba

  PRINCIPAL INVESTIGATOR

• Dean Fergusson, PhD MHA

  Ottawa Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD MSc. FRCPC

Study Record Dates

• First Submitted: July 14, 2012
• First Posted: July 24, 2012
• Study Start: July 1, 2012
• Primary Completion: January 1, 2014
• Study Completion: February 1, 2014
• Last Updated: July 10, 2014

Record last verified: 2014-07

Locations

CA (9)