Heparin Anticoagulation in Septic Shock

NCT03378466 | Terminated Phase 2 DMC FDA Drug

• 1 other identifier: HCA2017
• Study Type: interventional
• Target: 178
• Locations: 7 countries
• Sites: 51

Brief Summary

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.

Conditions

Septic Shock; Vasodilatory Shock

Outcome Measures

Primary Outcomes (1)

• Vasopressor-free 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 Outcomes (11)

• Clinical Outcome #1 - ICU mortality

  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

  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

  Up to day 90

• Clinical Outcome # 4 - ∆SOFA score (Sequential Organ Failure Assessment)

  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

  from hospital admission to hospital discharge or time of death to day 90

Study Arms (2)

Unfractionated Heparin (UFH)

EXPERIMENTAL

UFH initiated at 18 IU/kg/hr

Drug: Unfractionated heparin

Venous thromboprophylaxis (VTE)

OTHER

as per local standard

Other: Venous thromboprophylaxis (VTE)

Interventions

Unfractionated heparin DRUG

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.

Also known as: Heparin

Unfractionated Heparin (UFH)

Venous thromboprophylaxis (VTE) OTHER

May include subcutaneous heparin or dalteparin, sequential compression device or graduated compression stockings

Venous thromboprophylaxis (VTE)

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 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:
• 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.
• 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 enrolment
• Arterial pH \< 7.30 or base deficit \> 5 mmol/L in association with a lactate \> 4.0 mmol/L

You may not qualify if:

• 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:
• 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
• 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

Sponsors & Collaborators

• University of Manitoba: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• CancerCare Manitoba: collaborator

Study Sites (51)

Froedtert Hospital

Milwaukee, Wisconsin, 53226, United States

Location

Hospital Sao Jose

Altamira, Brazil

Location

Hospital Novo Atibaia

Atibaia, Brazil

Location

Hospital de Amor (Barretos)

Barretos, Brazil

Location

Santa Casa de Misericórdia de Belo Horizonte

Belo Horizonte, Brazil

Location

Hospital Tacchini

Bento Gonçalves, Brazil

Location

Hospital de Brasília

Brasília, Brazil

Location

Hospital Ortopedico e Medicina Especializada ltda. - HOME

Brasília, Brazil

Location

Instituto de Cardiologia do Distrito Federal

Brasília, Brazil

Location

Hospital Maternidade São José

Colatina, Brazil

Location

Hospital Baía Sul

Florianópolis, Brazil

Location

Hospital Nereu Ramos

Florianópolis, Brazil

Location

Hospital de Amor Jales

Jales, Brazil

Location

Unimed Cariri Hospital

Juazeiro do Norte, Brazil

Location

Hospital de Clínicas de Porto Alegre

Porto Alegre, Brazil

Location

Irmandade da Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Brazil

Location

Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto

Ribeirão Preto, Brazil

Location

Hospital Bruno Born

Rio Grande, Brazil

Location

Hospital da Cidade

Salvador, Brazil

Location

Santa Casa de São João Del Rei

São João del Rei, Brazil

Location

Hospital AC Camargo

São Paulo, Brazil

Location

Hospital Beneficência Portuguesa

São Paulo, Brazil

Location

Hospital da Luz

São Paulo, Brazil

Location

Hospital das Clinicas da faculdade de Medicina de Universidade de São Paulo

São Paulo, Brazil

Location

Hospital e Maternidade Sao Vicente

São Paulo, Brazil

Location

Hospital Santa Paula

São Paulo, Brazil

Location

Hospital Sepaco

São Paulo, Brazil

Location

Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo

São Paulo, Brazil

Location

Universidade Federal de Sao Paulo - UNIFESP

São Paulo, Brazil

Location

Hospital Ana Nery

Taguatinga, Brazil

Location

Foothills Medical Centre

Calgary, Alberta, T2N 2T9, Canada

Location

Vancouver Island Health Authority

Victoria, British Columbia, V8R 1J8, Canada

Location

St Boniface General Hospital

Winnipeg, Manitoba, R2H 2A6, Canada

Location

Health Sciences Centre Winnipeg

Winnipeg, Manitoba, R3A 1R9, Canada

Location

The Ottawa Hospital - General Campus

Ottawa, Ontario, K1H 8L6, Canada

Location

The Ottawa Hospital - Civic Campus

Ottawa, Ontario, K1Y 4E9, Canada

Location

Niagara Health System - St Catharines Site

Saint Catherines, Ontario, L2S 0A9, Canada

Location

St Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, H2X 0A9, Canada

Location

Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Universite Laval

Québec, Quebec, G1V 4G5, Canada

Location

Hopital de l'Enfant-Jesus

Québec, G1J 1Z4, Canada

Location

ATTIKON University Hospital

Athens, Greece

Location

Korgialeneion Benakeion Hospital

Athens, Greece

Location

AMRI Hospital Kolkata

Kolkata, India

Location

Dr Ruth K.M. PFAU Civil Hospital

Karachi, Pakistan

Location

Shaheed Mohtarma Benazir Bhutto Trauma Center

Karachi, Pakistan

Location

The Indus Hospital

Karachi, Pakistan

Location

Mayo Hospital Lahore

Lahore, Pakistan

Location

The Asian Hospital

Manila, Philippines

Location

The Medical City

Manila, Philippines

Location

The Philippines General Hospital

Manila, Philippines

Location

MeSH Terms

Conditions

Shock, Septic

Interventions

Heparin; vinyltriethoxysilane

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2017
• First Posted: December 19, 2017
• Study Start: March 12, 2018
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: May 24, 2022

Record last verified: 2021-01

Locations

US (1); CA (11); GR (2); IN (1); PA (4); BR (29); PH (3)