Septic ShockPhase 2HALONCT03378466
Heparin Anticoagulation in Septic Shock
A Phase 2 study testing Unfractionated heparin and Venous thromboprophylaxis (VTE) in people with Septic Shock and Vasodilatory Shock, run by University of Manitoba at 51 sites in 7 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Septic Shock, Vasodilatory Shock
- What is being tested?
- Unfractionated heparin and Venous thromboprophylaxis (VTE)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 178 participants
- Where
- 51 sitesin 7 countries
- Study dates
- 12 Mar 2018to 31 Dec 2021
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- ≥ 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
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
51 sites in 7 countries.
51 sites in 7 countries
Brazil29 sites
Hospital Sao Jose
Altamira
Hospital Novo Atibaia
Atibaia
Hospital de Amor (Barretos)
Barretos
Santa Casa de Misericórdia de Belo Horizonte
Belo Horizonte
Hospital Tacchini
Bento Gonçalves
Hospital de Brasília
Brasília
Hospital Ortopedico e Medicina Especializada ltda. - HOME
Brasília
Instituto de Cardiologia do Distrito Federal
Brasília
Hospital Maternidade São José
Colatina
Hospital Baía Sul
Florianópolis
Hospital Nereu Ramos
Florianópolis
Hospital de Amor Jales
Jales
Unimed Cariri Hospital
Juazeiro do Norte
Hospital de Clínicas de Porto Alegre
Porto Alegre
Irmandade da Santa Casa de Misericordia de Porto Alegre
Porto Alegre
Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto
Ribeirão Preto
Hospital Bruno Born
Rio Grande
Hospital da Cidade
Salvador
Santa Casa de São João Del Rei
São João del Rei
Hospital AC Camargo
São Paulo
Hospital Beneficência Portuguesa
São Paulo
Hospital da Luz
São Paulo
Hospital das Clinicas da faculdade de Medicina de Universidade de São Paulo
São Paulo
Hospital e Maternidade Sao Vicente
São Paulo
Hospital Santa Paula
São Paulo
Hospital Sepaco
São Paulo
Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo
São Paulo
Universidade Federal de Sao Paulo - UNIFESP
São Paulo
Hospital Ana Nery
Taguatinga
Canada11 sites
Foothills Medical Centre
Calgary, Alberta, T2N 2T9
Centre Hospitalier de l'Universite de Montreal (CHUM)
Montreal, Quebec, H2X 0A9
The Ottawa Hospital - General Campus
Ottawa, Ontario, K1H 8L6
The Ottawa Hospital - Civic Campus
Ottawa, Ontario, K1Y 4E9
Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Universite Laval
Québec, Quebec, G1V 4G5
Hopital de l'Enfant-Jesus
Québec, G1J 1Z4
Niagara Health System - St Catharines Site
Saint Catherines, Ontario, L2S 0A9
St Michael's Hospital
Toronto, Ontario, M5B 1W8
Vancouver Island Health Authority
Victoria, British Columbia, V8R 1J8
St Boniface General Hospital
Winnipeg, Manitoba, R2H 2A6
Health Sciences Centre Winnipeg
Winnipeg, Manitoba, R3A 1R9
Pakistan4 sites
Dr Ruth K.M. PFAU Civil Hospital
Karachi
Shaheed Mohtarma Benazir Bhutto Trauma Center
Karachi
The Indus Hospital
Karachi
Mayo Hospital Lahore
Lahore
Philippines3 sites
The Asian Hospital
Manila
The Medical City
Manila
The Philippines General Hospital
Manila
Greece2 sites
ATTIKON University Hospital
Athens
Korgialeneion Benakeion Hospital
Athens
About this study
Official title: 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.
Read the 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.
- Conditions
- Septic Shock, Vasodilatory Shock
- Being tested
- Unfractionated heparin, Venous thromboprophylaxis (VTE)
- Medical subject headings
- Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Unfractionated heparinDrug
Also called 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.
Venous thromboprophylaxis (VTE)Other
May include subcutaneous heparin or dalteparin, sequential compression device or graduated compression stockings
| Study group | Role | What they receive |
|---|---|---|
| Unfractionated Heparin (UFH) | Experimental | UFH initiated at 18 IU/kg/hr Receives: Drug: Unfractionated heparin |
| Venous thromboprophylaxis (VTE) | Other | as per local standard Receives: Other: Venous thromboprophylaxis (VTE) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 days
Secondary outcomes (11)
Clinical Outcome #1 - ICU mortality
Survival
Measured: 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
Survival
Measured: 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
Survival
Measured: Up to day 90
Clinical Outcome # 4 - ∆SOFA score (Sequential Organ Failure Assessment)
Organ failure assessment using the SOFA scoring tool
Measured: 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
Hospital admission duration in the context of survival
Measured: from hospital admission to hospital discharge or time of death to day 90
Clinical Outcome #6 - Renal replacement therapy-free days to day 28
Renal replacement therapy duration in the context of survival
Measured: from start of renal replacement therapy to study day 28
Safety Outcome #1 - Major Bleeding
Rates of major bleeding using a validated bleeding assessment tool
Measured: Assessed daily to day 8
Safety Outcome #2 - Minor Bleeding
Rates of minor bleeding using a validated bleeding assessment tool
Measured: Assessed daily to day 8
Safety Outcome #3 - Suspected HIT (Heparin induced thrombocytopenia)
Incidence of any laboratory testing for HIT including screening or confirmatory tests
Measured: Assessed daily to day 8
Safety Outcome #4 - Confirmed HIT (Heparin induced thrombocytopenia)
Postive confirmatory HIT test (one of Serotonin release assay (SRA) or Heparin induced platelet aggregation (HIPA))
Measured: Assessed daily to day 8
Rate of enrolment
average number of patients enrolled per site per month
Measured: Monthly starting at individual site initiation through to end of enrollment, estimated two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Dec 2017
- Study start12 Mar 2018
- Primary completion31 Dec 2021
- Study completion31 Dec 2021
Why it stopped: infeasible to continue due-to inability to recruit during the COVID-19 pandemic and grants coming to an end.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 178 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Manitoba
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR), CancerCare Manitoba
- Responsible party
- Sponsor
- Investigators
- Ryan Zarychanski, MD MSc, Principal investigator, University of ManitobaAnand Kumar, MD, Principal investigator, University of ManitobaDean A Fergusson, PhD MHA, Principal investigator, University of Ottawa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03378466
- Sponsor's protocol ID
- HCA2017
- Acronym
- HALO
- Status last verified
- Jan 2021
- First submitted
- 9 Nov 2017
- Last updated
- 24 May 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No