Efficacy and Safety of Angiotensin II Injection Versus Placebo in Patients With Refractory Distributed Shock

Official title

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial to Evaluate the Efficacy and Safety of Angiotensin II Injection in the Background Treatment of Catecholamines and Other Vasopressors in Chinese Adult Patients With Refractory Distributive Shock

Overview

A randomized, double-blind, placebo-controlled study on the treatment of refractory distributed shock with angiotensin II injection, with a random ratio of 1:1. Assuming a success rate of 25% for the main therapeutic endpoint in the control group and 50% for the experimental group, a total of 214 subjects will be enrolled, including 107 in the experimental group and 107 in the control group.

Interventions

• Drug Angiotensin II Injection
  1、Angiotensin II injection is a naturally occurring octapeptide hormone in the human renin angiotensin aldosterone system (RAAS). It is the main effector molecule of the RAAS system and one of the strongest known vasoconstrictors, involved in neurohumoral regulation.
• Drug 0.9% sodium chloride injection
  0.9% sodium chloride injection, not containing active ingredients.

Primary outcome measures

• Proportion of subjects with blood pressure response at 3 hours after administration of study drug [Time frame: 3 hours after dose]

Secondary outcome measures (12)

• Sequential Organ Failure Assessment (SOFA) total score [Time frame: 48 hours after dose]
• Cardiovascular SOFA subscore [Time frame: 48 hours after dose]
• Mortality at Day 7 [Time frame: Day 7 after dose]
• Mortality at Day 28 [Time frame: Day 28 after dose]
• Proportion of subjects with blood pressure response at 1 hour after administration [Time frame: 1 hour after dose]
• Proportion of subjects with blood pressure response at 2 hours after administration [Time frame: 2 hours after dose]
• Change in background vasoactive agent dose from 0 to 48 hours [Time frame: 48 hours after dose]
• Absolute change in blood lactate from 0 to 3 hours [Time frame: 3 hours after dose]
• Absolute change in blood lactate from 3 to 48 hours [Time frame: 3 to 48 hours after dose]
• Absolute change in heart rate from 0 to 3 hours [Time frame: 3 hours after dose]
• Absolute change in heart rate from 3 to 48 hours [Time frame: 3 to 48 hours after dose]
• Adverse events (AE) [Time frame: From drug administration to the end of the study, a total of 28 days]

Eligibility criteria

Inclusion criteria

• age: 18 years to 75 years old, male or female;
• diagnosis of distributive shock;
• on the basis of the treatment of total vasoactive drugs dose > 0.2 μg/kg/min norepinephrine (or equivalent dose of another vasoactive drug: such as epinephrine > 0.2 μg/kg/min, dopamine > 30 μg/kg/min, phenylephrine > 2 μg/kg/min, vasopressin > 0.08 U/min) and continuous treatment for at least 6 hours and no more than 48 hours, the patient's mean arterial pressure can still only be maintained between 55 and 70 mmHg, or do not reach the target MAP assessed by clinicians, it can be diagnosed as refractory distributive shock.
• have central venous access and arterial catheters, and are expected to be present for at least the first 48 hours of the study.
• indwelling catheter, and expected to be present for at least the first 48 hours of the study.
• patient has received at least 30 mL/kg of crystalloid or colloid volume in the previous 24 hours or has undergone adequate volume resuscitation in the opinion of the investigator.
• patients must have one of the following criteria with clinical features of high-output shock

• Central venous oxygen saturation (ScVO2) > 70% (via saturation catheter or central venous blood gas) and central venous pressure (CVP) > 8 mmHg.
• cardiac index (CI) > 2.3 L/min/m2.
• the patient or legal representative is willing and able to provide written informed consent and comply with all protocol requirements.

Exclusion criteria

• Patients with burns > 20% of total body surface area;
• Patients with cardiovascular (CV) SOFA score ≤ 3;
• Patients with acute coronary syndrome requiring interventional therapy;
• Patients treated with Extracorporeal Membrane Oxygenation (ECMO);
• Patients with end-stage liver failure (Model for end-stage liver disease score (MELD) > 30).
• Patients with a diagnosis of asthma or bronchospasm.
• Patients with a diagnosis of acute mesenteric ischemia, or patients with suspected acute mesenteric ischemia.
• Patients with a history, presence, or high suspicion of aortic dissection or abdominal aortic aneurysm, or patients diagnosed with aortic dissection or abdominal aortic aneurysm.
• Patients who have been diagnosed with malignant tumor within the past 2 years, except for early malignant tumors (carcinoma in situ or stage I tumor) that have been radically treated or expected to recover after treatment, such as adequately treated thyroid cancer, cervical carcinoma in situ, basal cell or squamous cell carcinoma.
• Patients with Raynaud's phenomenon, systemic sclerosis or vasospastic disease.
• Patients with life expectancy ≤ 24 hours as assessed by the study physician.
• Patients with active bleeding who are expected to require transfusion of > 4 units of packed red blood cells within 48 hours of study start.
• Patients with active bleeding and hemoglobin < 7 g/dL or any other condition that contraindicates serial blood sampling.
• Patients with absolute neutrophil count (ANC) < 1000 cells/mm3.
• Patients with known hypersensitivity to angiotensin II injection and its excipients.
• Patients who are currently participating in another interventional clinical trial.
• Blood/urine pregnancy test should be performed for patients with known pregnancy at screening and those with clinical suspicion of pregnancy.
• Patients who are considered unstable by the investigator or have any condition that would affect the safety of the study or the interpretation of the study results, or that would prevent the patient from completing the study, including but not limited to cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical disorders. For example: patients with arrhythmia, uncontrolled hyperglycemia, cerebrovascular disease, uncontrolled hypertension, autoimmune disease requiring daily use of ≥ 500 mg hydrocortisone or equivalent glucocorticoids, etc.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 42 centers

• The Second People's Hospital of Hefei — Hefei
• The Frist Affiliated Hospital of Wannan Medical College — Wuhu
• Beijing Tiantan Hospital,Capital Medical University — Beijing
• Peking Union Medical College Hospital — Beijing
• The Frist Affiliated Hospital of Chongqing Medical University — Chongqing
• The people's Hospital of the University of traditional Chinese medicine in Fujian — Fuzhou
• Gansu Provincial Hospital — Lanzhou
• The First Affiliated Hospital of Sun Yat sen University — Guangzhou
• … and 34 more centers

Identifiers

NCT: NCT06351150 · TQG3902-III-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗