Back to results

Therapeutic Plasma Exchange in Septic Shock: A Pilot Study (PLEXSIS)

Primary Purpose

Septic Shock

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Therapeutic Plasma Exchange

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring Sepsis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Eligible patients must be admitted to an ICU and must meet all of the following inclusion criteria:

≥ 18 years of age
Refractory hypotension documented within 18 hours prior to enrolment requiring the institution and ongoing use of vasopressor agents (phenylephrine, norepinephrine, vasopressin, epinephrine, midodrine or dopamine >5 mcg/kg/min) at enrolment. Refractory hypotension is defined as a systolic blood pressure (SBP) less than 90 mmHg, or a SBP more than 30 mmHg below baseline, or a mean arterial blood pressure less than 65 mmHg, plus the receipt of ≥ 2 litres of intravenous fluid for the treatment of hypotension.
At least 1 other new organ dysfunction (in addition to refractory hypotension), defined by the following at the time of enrollment:
1. 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) guideline definition of acute kidney injury.
2. Need for invasive mechanical ventilation or a P/F ratio <250
3. Platelets <100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrolment
4. Arterial pH < 7.30 or base deficit > 5 mmol/L in association with a lactate >/= to 4.0 mmol/L

Exclusion Criteria:

We will exclude patients who have any one of the following criteria at the time of enrolment:

Consent declined (refusal from patient, SDM, or physician)
Clinically apparent other forms of shock including cardiogenic, obstructive (e.g. massive pulmonary embolism, cardiac tamponade, tension pneumothorax), hemorrhagic, neurogenic, or anaphylactic
Received vasopressor therapy for greater than 24 hours prior to enrolment
Are currently enrolled in related trial
Terminal illness with a life expectancy of less than 3 months
Are pregnant

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Treatment Arm

Standard of Care Arm

Arm Description

Participants randomized to treatment will received 1.0 plasma volume exchanges daily until discontinuation of vasopressors, death or to a maximum of 5 treatments. The management of septic shock, including but not limited to, antibiotic therapy, infection source control, fluid therapy, mechanical ventilation, and nutrition, will be at the discretion of the treating medical team, and will be recorded and reported.

Participants randomized to Standard-of-Care will be treated at the discretion of the treating medical team. The management of septic shock, including but not limited to, antibiotic therapy, infection source control, fluid therapy, mechanical ventilation, and nutrition, will be at the discretion of the treating medical team, and will be recorded and reported.

Outcomes

Primary Outcome Measures

Assess the feasibility of a large, multicenter trial of TPE in patients with septic shock

Assessing the feasibility of a large, multicenter trial of TPE in patients with septic shock will be the primary outcome. Our primary measure of feasibility will be the ability to enroll an average of 2 patients per site per month.

Secondary Outcome Measures

Assess the rate of enrollment and adherence to the protocol of those enrolled

We will consider the consent rate to be adequate if 30% of eligible patients are enrolled, an acceptable rate of protocol adherence to be 90% of all study participants; and we will consider the time from randomization to study treatment initiation to be satisfactory if this interval is less than 6 hours.

Number of participants that develop adverse reactions to TPE

The following will be recorded: a) plasma transfusion reactions b) occurrence of transfusion related acute lung injury (TRALI) c) development of coagulopathy (INR >1.4) d) complications related to central venous access devices including bleeding or pneumothorax post-insertion, thrombosis, and line infection.

Further understand the biological impact of TPE in sepsis

To further our understanding of the biologic impact of TPE in sepsis, we will collect plasma samples at randomization (day 1), and prior to TPE treatments on days 2, 3 and 5 to evaluate coagulation markers, and ADAMTS13. We will perform activity-based protein profiling of serine hydrolases on patients treated with TPE compared to controls. We will observe changes in the protein profile over time in the same patients to determine associated with septic shock(controls) and compare to those who are treated with TPE. We will attempt to identify key enzymes that may be affected by TPE in septic shock.

Full Information

NCT ID

NCT05093075

First Posted

July 19, 2021

Last Updated

October 12, 2021

Sponsor

University of Manitoba

Collaborators

Canadian Institutes of Health Research (CIHR), Health Sciences Centre Foundation, Manitoba, McMaster University, University of Toronto

1. Study Identification

Unique Protocol Identification Number

NCT05093075

Brief Title

Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

Acronym

PLEXSIS

Official Title

Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Not yet recruiting

Study Start Date

October 2021 (Anticipated)

Primary Completion Date

December 2023 (Anticipated)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Manitoba

Collaborators

Canadian Institutes of Health Research (CIHR), Health Sciences Centre Foundation, Manitoba, McMaster University, University of Toronto

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

At the Health Sciences Centre and St. Boniface Hospital in Winnipeg, Manitoba, the investigators propose to conduct a two-center randomized trial comparing therapeutic plasma exchange to standard of care in patients diagnosed with septic shock.

Detailed Description

The intervention arm consists of an exchange of one volume of plasma equivalent to the patient's total calculated blood volume (1.0 plasma volume plasma exchange) performed daily until discontinuation of vasopressors, death or up to a maximum of 5 days. Frozen plasma (FP) will be used as the replacement fluid. The control group will receive standard of care for the treatment of septic shock in accordance with local practice and informed by national and international guidelines. The management of septic shock, including but not limited to, antibiotic therapy, infection source control, fluid therapy, mechanical ventilation, and nutrition, will be at the discretion of the treating PLEXSIS medical team, and will be recorded and reported. The investigators will monitor for development of coagulopathy by measure the INR and fibrinogen levels daily. These are expected to normalize with the use of plasma as replacement fluid. The investigators will monitor for adverse reactions related to central venous access devices (insertion related complications, infection, thrombosis), TPE (including reaction to plasma, allergic reactions and hypotension). Venous access devices will be inserted by trained, experienced personnel using real-time ultrasound guidance. To further our understanding of the biologic impact of TPE in sepsis, the investigators will collect plasma and whole blood samples at randomization (day 1), post TPE on day 1, prior to TPE treatment on day 3, and 48 hours after completion of TPE to evaluate markers of coagulation (D-dimer, thrombin-antithrombin (TAT) complexes, protein C levels, plasminogen-activator inhibitor 1) and ADAMTS13.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Septic Shock

Keywords

Sepsis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

A web-based randomization system maintained at the Center for Healthcare Innovation (CHI) (Winnipeg, Manitoba) will be used to allocate treatment assignments. The randomization process will consist of a computer-generated random listing of the treatment allocations in variable permuted blocks of 2 and 4. Participants will be randomized to Treatment (5 Therapeutic Plasma Exchanges) or Standard of Care.

Masking

InvestigatorOutcomes Assessor

Masking Description

All investigators and research staff will be blinded to the allocation schedules. The PLEXSIS pilot trial is designed as a prospective randomized open, blinded endpoint (PROBE) trial. This pragmatic design is necessary given impractical nature of blinding the TPE intervention.

Allocation

Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment Arm

Arm Type

Experimental

Arm Description

Arm Title

Standard of Care Arm

Arm Type

No Intervention

Arm Description

Intervention Type

Other

Intervention Name(s)

Therapeutic Plasma Exchange

Intervention Description

TPE procedures will be performed using a Spectra Optia ® apheresis machine (Terumo BCT, Lakewood, USA) according to usual-care procedures for apheresis. Venous access for the TPE procedures will be obtained through a double lumen dialysis catheter to provide adequate flow rates required for TPE. Regional citrate anticoagulation will be used for anticoagulation within the apheresis circuit. One to two grams of calcium chloride will be infused as per standard during TPE to prevent symptomatic hypocalcemia. Plasma volume will be calculated as per a standard formula whereby estimated plasma volume (in liters) = 0.07 x weight (kg) x (1 - hematocrit). In patients on dialysis, dialysis will be interrupted for the duration of the procedure. Antibiotics will be given after TPE to avoid clearance of the antibiotics. On the first day of TPE, a repeat dose of antibiotics will be administered after completion of TPE. Nurse clinicians trained in TPE will perform the TPE procedures.

Primary Outcome Measure Information:

Title

Assess the feasibility of a large, multicenter trial of TPE in patients with septic shock

Description

Time Frame

18 months for enrollment

Secondary Outcome Measure Information:

Title

Assess the rate of enrollment and adherence to the protocol of those enrolled

Description

Time Frame

18 months

Title

Number of participants that develop adverse reactions to TPE

Description

Time Frame

18 months

Title

Further understand the biological impact of TPE in sepsis

Description

Time Frame

18 months

Other Pre-specified Outcome Measures:

Title

Mortality and organ failure outcomes

Description

Our pilot trial is not designed to detect differences in clinical outcomes. However, we will measure and describe the rate of new organ failure and mortality.

Time Frame

18 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Eligible patients must be admitted to an ICU and must meet all of the following inclusion criteria: ≥ 18 years of age Refractory hypotension documented within 18 hours prior to enrolment requiring the institution and ongoing use of vasopressor agents (phenylephrine, norepinephrine, vasopressin, epinephrine, midodrine or dopamine >5 mcg/kg/min) at enrolment. Refractory hypotension is defined as a systolic blood pressure (SBP) less than 90 mmHg, or a SBP more than 30 mmHg below baseline, or a mean arterial blood pressure less than 65 mmHg, plus the receipt of ≥ 2 litres of intravenous fluid for the treatment of hypotension. At least 1 other new organ dysfunction (in addition to refractory hypotension), defined by the following at the time of enrollment: 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) 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 >/= to 4.0 mmol/L Exclusion Criteria: We will exclude patients who have any one of the following criteria at the time of enrolment: Consent declined (refusal from patient, SDM, or physician) Clinically apparent other forms of shock including cardiogenic, obstructive (e.g. massive pulmonary embolism, cardiac tamponade, tension pneumothorax), hemorrhagic, neurogenic, or anaphylactic Received vasopressor therapy for greater than 24 hours prior to enrolment Are currently enrolled in related trial Terminal illness with a life expectancy of less than 3 months Are pregnant

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Emily Rimmer, MD, MSc

Phone

204-787-2128

erimmer@cancercare.mb.ca

First Name & Middle Initial & Last Name or Official Title & Degree

Lisa Albensi, BSN, MSN

Phone

204-260-9139

lalbensi2@hsc.mb.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ryan Zarychanski, MD, MSc

Organizational Affiliation

University of Manitoba

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Emily Rimmer, MD, MSc

Organizational Affiliation

University of Manitoba

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

We do not plan to make individual participant data available to other researchers.

Citations:

PubMed Identifier

27322218

Citation

Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, Dunbar NM, Witt V, Wu Y, Shaz BH. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. 2016 Jun;31(3):149-62. doi: 10.1002/jca.21470.

Results Reference

background

PubMed Identifier

25527094

Citation

Rimmer E, Houston BL, Kumar A, Abou-Setta AM, Friesen C, Marshall JC, Rock G, Turgeon AF, Cook DJ, Houston DS, Zarychanski R. The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis. Crit Care. 2014 Dec 20;18(6):699. doi: 10.1186/s13054-014-0699-2.

Results Reference

background

PubMed Identifier

12373468

Citation

Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med. 2002 Oct;28(10):1434-9. doi: 10.1007/s00134-002-1410-7. Epub 2002 Jul 23.

Results Reference

background

PubMed Identifier

30515242

Citation

Davies R, O'Dea K, Gordon A. Immune therapy in sepsis: Are we ready to try again? J Intensive Care Soc. 2018 Nov;19(4):326-344. doi: 10.1177/1751143718765407. Epub 2018 Apr 4.

Results Reference

background

PubMed Identifier

18158437

Citation

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296-327. doi: 10.1097/01.CCM.0000298158.12101.41. Erratum In: Crit Care Med. 2008 Apr;36(4):1394-6.

Results Reference

background

PubMed Identifier

23659614

Citation

Lega JC, Mismetti P, Cucherat M, Fassier T, Bertoletti L, Chapelle C, Laporte S. Impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta-analysis. J Thromb Haemost. 2013 Jul;11(7):1240-50. doi: 10.1111/jth.12294.

Results Reference

background

PubMed Identifier

31939781

Citation

Binnie A, Walsh CJ, Hu P, Dwivedi DJ, Fox-Robichaud A, Liaw PC, Tsang JLY, Batt J, Carrasqueiro G, Gupta S, Marshall JC, Castelo-Branco P, Dos Santos CC; Epigenetic Profiling in Severe Sepsis (EPSIS) Study of the Canadian Critical Care Translational Biology Group (CCCTBG). Epigenetic Profiling in Severe Sepsis: A Pilot Study of DNA Methylation Profiles in Critical Illness. Crit Care Med. 2020 Feb;48(2):142-150. doi: 10.1097/CCM.0000000000004097.

Results Reference

background

Learn more about this trial

Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

We'll reach out to this number within 24 hrs