Shock, SepticPhase 2/3NCT06155812
Multimodal Vasopressor Strategy in Septic Shock
A Phase 2/3 study testing Simultaneous administration of vasopressors and Successive administration of vasopressors in people with Shock, Septic, run by University Medical Centre Maribor at 2 sites in 2 countries.
Trial summary
The goal of this prospective randomized controlled trial is to compare the effects of classic stepwise vs. early balanced multimodal vasopressor strategies in septic shock. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Shock, Septic
- What is being tested?
- Simultaneous administration of vasopressors and Successive administration of vasopressors
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 79 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 23 Dec 2023to 1 Feb 2026
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
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
- Adult patients (≥18 years).
- Sepsis (an acute change in total Sequential Organ Failure Assessment (SOFA) score ≥2 points consequent to infection) with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L despite adequate volume resuscitation (20-30ml/kg in 3 hours).
- Vasopressor requirement of ≥0,15 μg/kg/min equivalent of norepinephrine base.
- Patients are required to have central venous access and an arterial line present, and these are expected to remain present for at least the initial 72 hours of study.
- Patients are required to have an urinary catheter present, and it is expected to remain present for at least the initial 72 hours of study.
- Patients must have cardiac index (CI) >2.3 L/min/m2 (measured by bedside echocardiography, pulse contour cardiac output (PiCCO) or Swan-Ganz catheter).
Who cannot join
- Death expected <24 hours.
- Pregnancy (suspected or confirmed).
- Surgery expected for source of infection.
- Inter-hospital transfer expected during first 72 hours of hospitalization.
- Liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥30.
- Patients with acute mesenteric ischemia or a history of mesenteric ischemic.
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- Patients with Raynaud's phenomenon, systemic sclerosis or vasospastic disease.
- Patients with active bleeding and an anticipated need (within 48 hours of initiation of the study) for transfusion of >4 units of packed red blood cells.
- Patients with a known allergy to mannitol.
- Patients on veno-arterial (VA) ECMO.
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
About this study
Official title: Simultaneous Administration of Norepinephrine, Angiotensin II, and Vasopressin in Septic Shock Patients
The goal of this prospective randomized controlled trial is to compare the effects of classic stepwise vs. early balanced multimodal vasopressor strategies in septic shock.
Read the detailed description
CONTROL GROUP(Classic stepwise vasopressor administration):
Patients will be started on norepinephrine with increases of 0.05-0.1 mcg/kg/min up to 0.5 mcg/kg/min, followed by vasopressin (administered at a fixed dose of 0.03 IE/min). If MAP remains < 65 mmHg, norepinephrine will be titrated above dose of 0.5 mcg/kg/min until MAP ≥ 65 mmHg. Initiation of additional vasoactive drugs (epinephrine, Ang II, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamine, milrinone, levosimendan) as per clinical team decision.
EXPERIMENTAL GROUP(Balanced multimodal vasopressor administration):
Early, simultaneous start of norepinephrine, angiotensin II and vasopressin at equivalent starting doses (equivalent to approximately 0.05 mcg/kg/min of norepinephrine). Increments of 0.05 mcg/kg/min of equivalent doses of all three vasopressors every 3-5 min until MAP ≥ 65 mmHg is reached (vasopressin will be administered at a maximum dose of 0.03 IE/min, Ang II will be administered at maximum dose of 100ng/kg/min). Initiation of additional vasoactive drugs (epinephrine, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamine, milrinone, levosimendan) as per clinical team decision.
- Conditions
- Shock, Septic
- Being tested
- Simultaneous administration of vasopressors, Successive administration of vasopressors
- Keywords
- Vasopressor agents, Angiotensin II, Vasopressin, Norepinephrine, Renin, Lactate
- Medical subject headings
- Shock, Septic, Diabetes Insipidus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Simultaneous administration of vasopressorsOther
Early, simultaneous administration of norepinephrine, angiotensin II, and vasopressin.
Successive administration of vasopressorsOther
Administration and titration of norepinephrine and vasopressin. Administration of additional vasoactive drugs (epinephrine, methylene blue, angiotensin II or dopamine) as per clinical team. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision.
| Study group | Role | What they receive |
|---|---|---|
| STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT | Active comparator | Regimen: Norepinephrine increases of 0.05-0.1 mcg/kg/min up to 0.5 mcg/kg/min, followed by vasopressin (administered at a fixed dose of 0.03 IE/min). If MAP remains < 65 mmHg, norepinephrine will be titrated above dose of 0.5 mcg/kg/min until MAP ≥ 65 mmHg. Maximum norepinephrine dose as per clinical team decision. Initiation of additional vasoactive drugs (epinephrine, Ang II methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision. Receives: Other: Successive administration of vasopressors |
| BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT | Experimental | Regimen: Simultaneous administration of norepinephrine, angiotensin II and vasopressin at equivalent starting doses (equivalent to approximately 0.05 mcg/kg/min of norepinephrine). Increments of 0.05 mcg/kg/min of equivalent doses of all three vasopressors every 3-5 min until MAP ≥ 65 mmHg is reached (vasopressin will be administered at a maximum dose of 0.03 IE/min, AT II will be administered at a maximum dose of 100 ng/kg/min). Initiation of additional vasoactive drugs (epinephrine, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision. Receives: Other: Simultaneous administration of vasopressors |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of change in renin levels
There is an increasing amount of data that renin is the best marker of tissue hypoperfusion and predictor of ICU mortality in patients with sepsis and septic shock, even outperforming lactate. Renin increased between the first and third day in non-survivors, but dropped in survivors. The rate of change in renin concentration but not lactate concentration in ICU patients over first 72 hours is associated with in hospital mortality.
Measured: 72 hours
Secondary outcomes (3)
Compare lactate levels
In critically ill patients, plasma lactate is commonly used to guide hemodynamic resuscitation. Hyperlactatemia has been widely recognized as a marker of tissue hypoxia/hypoperfusion but it can also result from increased or accelerated aerobic glycolysis during the stress response and may represent an important energy source in critically ill patients. Resuscitation to normalize lactate levels could worsen physiological status.
Measured: 72h
Compare Δ Sequential Organ Failure Assessment (SOFA) score
The purpose is to monitor the rate of organ dysfunction. Score ranges from 0 (best) to 24 (worst) points.
Measured: 72 hours
Compare acute kidney injury rate
The purpose is to monitor acute kidney injury based on Improving Global Outcomes (KDIGO) definition and staging system.
Measured: 72 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2023
- Study start23 Dec 2023
- Primary completion31 Dec 2025
- Study completion1 Feb 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Shock, SepticStudies 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Vasopressors will be administered successively in the control group. In the experimental group norepinephrine, angiotensin II, and vasopressin will be administered simultaneously.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 79 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Centre Maribor
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ziga Kalamar, University Medical Centre Maribor
- Investigators
- Žiga Kalamar, MD, Principal investigator, University Medical Centre Maribor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06155812
- Sponsor's protocol ID
- IRP-2023/01-03
- Status last verified
- Mar 2026
- First submitted
- 9 Nov 2023
- Last updated
- 31 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All of the individual participant data collected during the trial, after deidentification.
Publications
Kalamar Z, Landoni G, Gorenjak M, Cestar I, Fluher J, Horvat M, Jerenec K, Kit B, Marinsek M, Puklavec N, Svensek F, Radonic R, Sundalic S, Brajkovic AV, Vujevic A, Erjavc N, Petek D, Kosir AS, Homsak E, Knehtl MC, Markota A. Early multimodal vasopressor strategy in septic shock: results of the TRICYCLE randomized controlled trial. Crit Care. 2026 Sep 7;30(1):508. doi: 10.1186/s13054-026-06323-z.
PubMed 42827265Kalamar Z, Gorenjak M, Landoni G, Markota A. Early multimodal vasopressor strategy in septic shock (TRICYCLE)-Study protocol for a randomized controlled clinical trial. PLoS One. 2025 Aug 29;20(8):e0331304. doi: 10.1371/journal.pone.0331304. eCollection 2025.
PubMed 40880376
Study at a glance
From the registry record, last updated by the sponsor on 31 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Simultaneous Administration of Norepinephrine, Angiotensin II, and Vasopressin in Septic Shock Patients
- ClinicalTrials.gov ID
- NCT06155812
- Acronym / sponsor ID
- IRP-2023/01-03
- Conditions
- Shock, Septic
- Keywords
- Vasopressor agents, Angiotensin II, Vasopressin, Norepinephrine, Renin, Lactate
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 79 participants (actual)
- Lead sponsor
- University Medical Centre MariborUniversity, hospital or other
- Study start
- 23 Dec 2023 (actual)
- Primary completion
- 31 Dec 2025 (actual)
- Study completion
- 1 Feb 2026 (actual)
- First posted
- 4 Dec 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this prospective randomized controlled trial is to compare the effects of classic stepwise vs. early balanced multimodal vasopressor strategies in septic shock.
Detailed description
CONTROL GROUP(Classic stepwise vasopressor administration):
Patients will be started on norepinephrine with increases of 0.05-0.1 mcg/kg/min up to 0.5 mcg/kg/min, followed by vasopressin (administered at a fixed dose of 0.03 IE/min). If MAP remains < 65 mmHg, norepinephrine will be titrated above dose of 0.5 mcg/kg/min until MAP ≥ 65 mmHg. Initiation of additional vasoactive drugs (epinephrine, Ang II, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamine, milrinone, levosimendan) as per clinical team decision.
EXPERIMENTAL GROUP(Balanced multimodal vasopressor administration):
Early, simultaneous start of norepinephrine, angiotensin II and vasopressin at equivalent starting doses (equivalent to approximately 0.05 mcg/kg/min of norepinephrine). Increments of 0.05 mcg/kg/min of equivalent doses of all three vasopressors every 3-5 min until MAP ≥ 65 mmHg is reached (vasopressin will be administered at a maximum dose of 0.03 IE/min, Ang II will be administered at maximum dose of 100ng/kg/min). Initiation of additional vasoactive drugs (epinephrine, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamine, milrinone, levosimendan) as per clinical team decision.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Vasopressors will be administered successively in the control group. In the experimental group norepinephrine, angiotensin II, and vasopressin will be administered simultaneously.
| Arm | Type | Receives |
|---|---|---|
| STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT | Active comparator | Other: Successive administration of vasopressorsRegimen: Norepinephrine increases of 0.05-0.1 mcg/kg/min up to 0.5 mcg/kg/min, followed by vasopressin (administered at a fixed dose of 0.03 IE/min). If MAP remains < 65 mmHg, norepinephrine will be titrated above dose of 0.5 mcg/kg/min until MAP ≥ 65 mmHg. Maximum norepinephrine dose as per clinical team decision. Initiation of additional vasoactive drugs (epinephrine, Ang II methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision. |
| BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT | Experimental | Other: Simultaneous administration of vasopressorsRegimen: Simultaneous administration of norepinephrine, angiotensin II and vasopressin at equivalent starting doses (equivalent to approximately 0.05 mcg/kg/min of norepinephrine). Increments of 0.05 mcg/kg/min of equivalent doses of all three vasopressors every 3-5 min until MAP ≥ 65 mmHg is reached (vasopressin will be administered at a maximum dose of 0.03 IE/min, AT II will be administered at a maximum dose of 100 ng/kg/min). Initiation of additional vasoactive drugs (epinephrine, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Adult patients (≥18 years).
- Sepsis (an acute change in total Sequential Organ Failure Assessment (SOFA) score ≥2 points consequent to infection) with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L despite adequate volume resuscitation (20-30ml/kg in 3 hours).
- Vasopressor requirement of ≥0,15 μg/kg/min equivalent of norepinephrine base.
- Patients are required to have central venous access and an arterial line present, and these are expected to remain present for at least the initial 72 hours of study.
- Patients are required to have an urinary catheter present, and it is expected to remain present for at least the initial 72 hours of study.
Key exclusion criteria (10 listed)
- Death expected <24 hours.
- Pregnancy (suspected or confirmed).
- Surgery expected for source of infection.
- Inter-hospital transfer expected during first 72 hours of hospitalization.
- Liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥30.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Simultaneous administration of vasopressorsEarly, simultaneous administration of norepinephrine, angiotensin II, and vasopressin. | Other | BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT |
| Successive administration of vasopressorsAdministration and titration of norepinephrine and vasopressin. Administration of additional vasoactive drugs (epinephrine, methylene blue, angiotensin II or dopamine) as per clinical team. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision. | Other | STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT |
Primary outcome
Rate of change in renin levels
Time frame: 72 hours
There is an increasing amount of data that renin is the best marker of tissue hypoperfusion and predictor of ICU mortality in patients with sepsis and septic shock, even outperforming lactate. Renin increased between the first and third day in non-survivors, but dropped in survivors. The rate of change in renin concentration but not lactate concentration in ICU patients over first 72 hours is associated with in hospital mortality.
3 secondary outcomes
Compare lactate levels
Time frame: 72h
Compare Δ Sequential Organ Failure Assessment (SOFA) score
Time frame: 72 hours
Compare acute kidney injury rate
Time frame: 72 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Mar 2026.
- Derived from this study: PubMed 42827265Kalamar Z, Landoni G, Gorenjak M, Cestar I, Fluher J, Horvat M, Jerenec K, Kit B, Marinsek M, Puklavec N, Svensek F, Radonic R, Sundalic S, Brajkovic AV, Vujevic A, Erjavc N, Petek D, Kosir AS, Homsak E, Knehtl MC, Markota A. Early multimodal vasopressor strategy in septic shock: results of the TRICYCLE randomized controlled trial. Crit Care. 2026 Sep 7;30(1):508. doi: 10.1186/s13054-026-06323-z.
- Derived from this study: PubMed 40880376Kalamar Z, Gorenjak M, Landoni G, Markota A. Early multimodal vasopressor strategy in septic shock (TRICYCLE)-Study protocol for a randomized controlled clinical trial. PLoS One. 2025 Aug 29;20(8):e0331304. doi: 10.1371/journal.pone.0331304. eCollection 2025.
- Individual participant dataSharing planned: Yes. All of the individual participant data collected during the trial, after deidentification.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Žiga Kalamar, MD principal investigator
University Medical Centre Maribor
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Simultaneous administration of vasopressors and Successive administration of vasopressors in people with Shock, Septic, run by University Medical Centre Maribor at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Croatia, Slovenia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of change in renin levels (time frame: 72 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06155812, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Mar 2026.