Terlipressin for Refractory Septic Shock (TERESEP)

Terlipressin Versus Placebo for Septic Shock Refractory to High Doses Catecholamine Vasopressors: A Randomized-controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Refractory Shock; Norepinephrine Adverse Reaction
• Intervention / Treatment: Drug: Terlipressin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 130
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Surat Tongyoo, MD; Phone Number: 0820137771; Email: surat.ton@mahidol.ac.th
• Study Contact Backup: Name: Chawanee Chayakul, MD; Phone Number: 080-440-1137; Email: jingjaring@hotmail.com

Study Locations

• Thailand
  • Bangkok, Thailand, 10700
    • Recruiting
    • Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University
    • Contact: Surat Tongyoo, MD; Phone Number: 6624198534; Email: surat.ton@mahidol.ac.th
    • Contact: Chawanee Chayakul, MD; Phone Number: 080-440-1137; Email: jingjaring@gmail.com
    • Sub-Investigator: Tanuwong Vialasilpa, Dr
    • Sub-Investigator: Chawanee Chayakul, Dr
    • Sub-Investigator: Chairat Permpikul, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Terlipressin group; 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	Drug: Terlipressin; Terlipressin (20-100 mcg/hr) plus norepinephrine and/or epinephrine
Placebo Comparator: Placebo group; 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	Drug: Placebo; 0.9% NaCl plus norepinephrine and/or epinephrine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	6 hours after initiate study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 day mortality	Proportion of patient who dead before 28 days after enrollment	28 days
Mean arterial blood pressure	Mean arterial blood pressure after initiate study drug	72 hours
Hospital mortality	Proportion of patient who dead before hospital discharge after enrollment	90 days
ICU mortality	Proportion of patient who dead before ICU discharge after enrollment	90 days

Collaborators and Investigators

• Sponsor: Mahidol University
• Investigators: Principal Investigator: Surat Tongyoo, MD, Mahidol University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2020
• Primary Completion (Anticipated): March 31, 2025
• Study Completion (Anticipated): July 31, 2025

Study Registration Dates

• First Submitted: April 7, 2020
• First Submitted That Met QC Criteria: April 7, 2020
• First Posted (Actual): April 9, 2020

Study Record Updates

• Last Update Posted (Actual): September 24, 2021
• Last Update Submitted That Met QC Criteria: September 23, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Antihypertensive Agents; Vasoconstrictor Agents; Terlipressin
• Other Study ID Numbers: Si 049/2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No