Angiotensin II for Refractory Hypotension in Paediatric Patients With Distributive Shock: A Phase III Randomised Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of angiotensin II compared to placebo on the required dose of standard-of-care vasopressors. This investigation is conducted in paediatric patients aged 0 to 17 years presenting with refractory hypotension in distributive shock receiving fluid resuscitation. The study aims to assess the efficacy and safety of the intervention in managing hemodynamic instability. Secondary objectives include the evaluation of:

• Mean arterial pressure;
• Dose of standard-of-care vasopressors;
• Time until maintenance of infusion maintenance dose and the dose at that time;
• Organ dysfunction.

The sponsor did not provide information regarding the total number of participants. The study population consists of pediatric patients aged 0 to 17 years of any gender. Participants must present with refractory hypotension in distributive shock. Inclusion requires the administration of adequate fluid resuscitation and a norepinephrine base equivalent dose exceeding 0.2 µg/kg/min. The study population is considered vulnerable. Necessary protocols include obtaining informed consent from legal representatives and, where possible, patient assent. For individuals of childbearing potential, a negative pregnancy test is required. Additionally, venous thromboembolism prophylaxis must be implemented prior to the administration of the investigational medicinal product if indicated by local guidelines.

This Phase III, randomised, double-blind, placebo-controlled, multicentre clinical trial is designed to evaluate the efficacy and safety of angiotensin II compared to a placebo in paediatric patients aged 0 to 17 years presenting with refractory hypotension in distributive shock. Eligible participants must be receiving fluid resuscitation and standard-of-care vasopressors, specifically maintaining a norepinephrine base equivalent dose greater than 0.2 µg/kg/min. The study aims to assess the change in the dose of standard-of-care vasopressors from baseline to the first 6 hours of administration of the investigational medicinal product. Secondary endpoints include changes in mean arterial pressure, the paediatric logistic organ dysfunction score, and blood lactate levels over a defined period. The trial involves a screening process to confirm eligibility, followed by the administration of the study intervention via intravenous infusion and subsequent monitoring during follow-up periods. The total estimated duration of the trial is expected to span from April 2026 to April 2028.

The investigational product is Giapreza, which contains the active substance angiotensin II. It is supplied as a 2.5 mg/ml concentrate for solution for infusion. The administered dose is 80 ng via intravenous infusion.

The control group receives a placebo consisting of sodium chloride solution 0.9%. This is administered via intravenous infusion at a dose of 0.11 mg/kg.

Participants in the study are receiving fluid resuscitation and standard-of-care vasopressors for the management of refractory hypotension associated with distributive shock.

The efficacy of angiotensin II in pediatric patients with refractory hypotension in distributive shock will be assessed using several predefined endpoints. The primary endpoint is the change in the dose of standard-of-care vasopressors, expressed as the norepinephrine base equivalent dose (NED) sum per hour, from baseline to the first 6 hours of investigational medicinal product administration.

Secondary efficacy parameters include:

• Change in mean arterial pressure (MAP) from baseline at intervals of 3 hours, 3–6 hours, 6–12 hours, 12–24 hours, and 24–48 hours.
• Change in the dose of standard-of-care vasopressors, expressed as NED sum per hour, from baseline at intervals of 3 hours, 3–6 hours, 6–12 hours, 12–24 hours, and 24–48 hours.
• Time from the start of administration to the first maintenance dose sustained at the same dose for at least 1 hour, including the dose at that time.
• Change in the paediatric logistic organ dysfunction (PELOD-2) score from baseline to 48 hours and to day 7 for participants remaining in the pediatric intensive care unit.
• Change in blood lactate levels from baseline to 6, 12, 24, and 48 hours.
• Proportion of participants achieving a reduction of ≥ 25%, ≥ 50%, or ≥ 75% in the dose of standard-of-care vasopressors from baseline to 6 hours, among those who are alive, blinded, and not withdrawn at 6 hours.