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Terlipressin for Refractory Septic Shock (TERESEP)

Primary Purpose

Septic Shock, Refractory Shock, Norepinephrine Adverse Reaction

Status
Recruiting
Phase
Phase 2
Locations
Thailand
Study Type
Interventional
Intervention
Terlipressin
Placebo
Sponsored by
Mahidol University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Septic Shock

Eligibility Criteria

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

Inclusion Criteria:

  • Septic shock according to Sepsis-3 definition
  • Evidence of adequate fluid
  • Received norepinephrine 0.2 mcg/kg/min or more
  • Received norepinephrine plus epinephrine (any dose)
  • Mean arterial lower than 65 mmHg or lactate > 2 mmol/liter

Exclusion Criteria:

  1. Septic shock diagnosis > 48 hours before
  2. Receive intravenous fluid < 30 mL/kg before enrollment
  3. Do-not-resuscitation and terminally ill
  4. Refractory to treatment malignancy
  5. Pregnancy

7. Chronic renal failure stage 5 with no plan for long term renal replacement therapy 8. Cirrhosis child C 9. Cardiogenic shock 10. Acute decompensated heart failure 11. Evidence of left ventricular ejection fraction (LVEF) < 35% 12. Acute coronary syndrome within 72 hours 13. Severe valvular heart disease 14. Documented life-threatening tachyarrhythmia before enrollment 15. Diagnosis of acute mesenteric ischemia before enrollment 16. Previous diagnosis of Raynaud's phenomenon 17. Known peripheral arterial disease 18. Refuse to sign the informed consent by patient or representative

Sites / Locations

  • Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Terlipressin group

Placebo group

Arm Description

Terlipressin acetate 1 mg in 0.9% normal saline (NaCl) 50 mL (0.02 mg/mL) Initial dose 20 mcg/hr (1 mL/hr) titrate increase 1 mL/hr every 30 min to 100 mcg/hr (5 mg/hr) to keep mean arterial blood pressure (MAP) > 65 mmHg If MAP > 75 mmHg for > 30 min, decrease epinephrine and norepinephrine until < 0.15 mcg/kg/min, then decrease terlipressin until stop

Placebo 0.9% NaCl 50 mL Initial dose 1 mL/hr titrate increase 1 mL/hr every 30 min to 5 mg/hr to keep mean arterial blood pressure (MAP) > 65 mmHg If MAP > 75 mmHg for > 30 min, decrease epinephrine and norepinephrine until < 0.15 mcg/kg/min, then decrease placebo until stop

Outcomes

Primary Outcome Measures

Achieve target blood pressure with low dose adrenergic agents
Achieve target mean arterial blood pressure 65 millimeter mercury or more with norepinephrine and/or epinephrine dose 0.2 mcg/kg/min or lower

Secondary Outcome Measures

28 day mortality
Proportion of patient who dead before 28 days after enrollment
Mean arterial blood pressure
Mean arterial blood pressure after initiate study drug
Hospital mortality
Proportion of patient who dead before hospital discharge after enrollment
ICU mortality
Proportion of patient who dead before ICU discharge after enrollment

Full Information

First Posted
April 7, 2020
Last Updated
September 23, 2021
Sponsor
Mahidol University
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1. Study Identification

Unique Protocol Identification Number
NCT04339868
Brief Title
Terlipressin for Refractory Septic Shock
Acronym
TERESEP
Official Title
Terlipressin Versus Placebo for Septic Shock Refractory to High Doses Catecholamine Vasopressors: A Randomized-controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Recruiting
Study Start Date
April 3, 2020 (Actual)
Primary Completion Date
March 31, 2025 (Anticipated)
Study Completion Date
July 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mahidol University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Norepinephrine was recommended as the first vasopressor for septic shock resuscitation. For the patient who did not response to high dose norepinephrine, epinephrine was recommended. Vasopressin was also recommended as an alternative vasopressor, in case patient did not response to norepinephrine and or epinephrine. Terlipressin, a selective V1 receptor binding with long half life, was reported that it main action is to increase blood pressure via the different mechanism from norepinephrine and epinephrine. To use terlipressin, combine with norepinephrine and or epinephrine among refractory septic shock, could decrease the usage dose of norepinephrine and epinephrine as well as lower the side effects of too high adrenergic stimuli.
Detailed Description
Norepinephrine was recommended as the first vasopressor for septic shock resuscitation. For the patient who did not response to high dose norepinephrine, epinephrine was recommended. Both norepinephrine and epinephrine action via the alpha adrenergic stimuli to increase vascular smooth muscle contraction, induced vasoconstriction and increase arterial blood pressure. It also action via beta adrenergic stimuli, to increase heart rate and myocardial contractility, then increase stroke volume and cardiac output. Too much alpha and beta adrenergic stimulation, especially during received high dose norepinephrine and or epinephrine associated with vasoconstriction induce organs ischemia. The most common organ ischemia included myocardial ischemia, bowel ischemia and limbs ischemia. Cardiac arrhythmia was also the most common complication associated with high dose norepinephrine and or epinephrine. Atrial fibrillation was the most common reported arrhythmia, however, fatal arrhythmia included ventricular fibrillation and tachycardia were also reported. Vasopressin was recommended as an alternative vasopressor, in case patient did not response to norepinephrine and or epinephrine. Terlipressin, a selective V1 receptor binding with long half life, was reported that it main action is to increase blood pressure via the different mechanism from norepinephrine and epinephrine. To use terlipressin, combine with norepinephrine and or epinephrine among refractory septic shock, could decrease the usage dose of norepinephrine and epinephrine as well as lower the side effects of too high adrenergic stimuli. The benefit effect of terlipressin could be demonstrated when prescribe among the septic shock patients who required high dose of adrenergic vasoactive agents. Terlipressin plus norepinephrine and or epinephrine could maintain or even improve blood pressure and tissue perfusion with lower fatal side effects than norepinephrine and or epinephrine without terlipressin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Septic Shock, Refractory Shock, Norepinephrine Adverse Reaction

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Intervention arm: Terlipressin plus Norepinephrine and/or Epinephrine Controlled arm: Placebo plus Norepinephrine and/or Epinephrine for Treatment Refractory Septic Shock
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Performed a randomization table before enrollment. Prepare the study drug receiving or placebo receiving according to sequential number derived from the randomization table and keep it in a conceal envelop. Prepare study drug and placebo by a pharmacist or an investigation nurse, according to the randomization table number, and keep both study drug and placebo in the identical containment which labeled by a sequential number. Once a patient was enrolled and informed was signed, then study drug or placebo was start according to sequential number.
Allocation
Randomized
Enrollment
130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Terlipressin group
Arm Type
Active Comparator
Arm Description
Terlipressin acetate 1 mg in 0.9% normal saline (NaCl) 50 mL (0.02 mg/mL) Initial dose 20 mcg/hr (1 mL/hr) titrate increase 1 mL/hr every 30 min to 100 mcg/hr (5 mg/hr) to keep mean arterial blood pressure (MAP) > 65 mmHg If MAP > 75 mmHg for > 30 min, decrease epinephrine and norepinephrine until < 0.15 mcg/kg/min, then decrease terlipressin until stop
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
Placebo 0.9% NaCl 50 mL Initial dose 1 mL/hr titrate increase 1 mL/hr every 30 min to 5 mg/hr to keep mean arterial blood pressure (MAP) > 65 mmHg If MAP > 75 mmHg for > 30 min, decrease epinephrine and norepinephrine until < 0.15 mcg/kg/min, then decrease placebo until stop
Intervention Type
Drug
Intervention Name(s)
Terlipressin
Intervention Description
Terlipressin (20-100 mcg/hr) plus norepinephrine and/or epinephrine
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
0.9% NaCl plus norepinephrine and/or epinephrine
Primary Outcome Measure Information:
Title
Achieve target blood pressure with low dose adrenergic agents
Description
Achieve target mean arterial blood pressure 65 millimeter mercury or more with norepinephrine and/or epinephrine dose 0.2 mcg/kg/min or lower
Time Frame
6 hours after initiate study drug
Secondary Outcome Measure Information:
Title
28 day mortality
Description
Proportion of patient who dead before 28 days after enrollment
Time Frame
28 days
Title
Mean arterial blood pressure
Description
Mean arterial blood pressure after initiate study drug
Time Frame
72 hours
Title
Hospital mortality
Description
Proportion of patient who dead before hospital discharge after enrollment
Time Frame
90 days
Title
ICU mortality
Description
Proportion of patient who dead before ICU discharge after enrollment
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Septic shock according to Sepsis-3 definition Evidence of adequate fluid Received norepinephrine 0.2 mcg/kg/min or more Received norepinephrine plus epinephrine (any dose) Mean arterial lower than 65 mmHg or lactate > 2 mmol/liter Exclusion Criteria: Septic shock diagnosis > 48 hours before Receive intravenous fluid < 30 mL/kg before enrollment Do-not-resuscitation and terminally ill Refractory to treatment malignancy Pregnancy 7. Chronic renal failure stage 5 with no plan for long term renal replacement therapy 8. Cirrhosis child C 9. Cardiogenic shock 10. Acute decompensated heart failure 11. Evidence of left ventricular ejection fraction (LVEF) < 35% 12. Acute coronary syndrome within 72 hours 13. Severe valvular heart disease 14. Documented life-threatening tachyarrhythmia before enrollment 15. Diagnosis of acute mesenteric ischemia before enrollment 16. Previous diagnosis of Raynaud's phenomenon 17. Known peripheral arterial disease 18. Refuse to sign the informed consent by patient or representative
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Surat Tongyoo, MD
Phone
0820137771
Email
surat.ton@mahidol.ac.th
First Name & Middle Initial & Last Name or Official Title & Degree
Chawanee Chayakul, MD
Phone
080-440-1137
Email
jingjaring@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Surat Tongyoo, MD
Organizational Affiliation
Mahidol University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Surat Tongyoo, MD
Phone
6624198534
Email
surat.ton@mahidol.ac.th
First Name & Middle Initial & Last Name & Degree
Chawanee Chayakul, MD
Phone
080-440-1137
Email
jingjaring@gmail.com
First Name & Middle Initial & Last Name & Degree
Tanuwong Vialasilpa, Dr
First Name & Middle Initial & Last Name & Degree
Chawanee Chayakul, Dr
First Name & Middle Initial & Last Name & Degree
Chairat Permpikul, Dr

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The data set and analysis are available from the corresponding author on reasonable request.
IPD Sharing Time Frame
After complete enrollment and for 24 months
IPD Sharing Access Criteria
Please direct contact to the principle investigator
Citations:
PubMed Identifier
28101605
Citation
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.
Results Reference
result
PubMed Identifier
26903338
Citation
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
Results Reference
result
PubMed Identifier
30704260
Citation
Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):1097-1105. doi: 10.1164/rccm.201806-1034OC.
Results Reference
result

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Terlipressin for Refractory Septic Shock

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