Angiotensin II Antagonist in Severe Sepsis (SartSep)

University of Salerno

Status and phase: Unknown; Phase 3

Conditions: Severe Sepsis

Treatments: Drug: Irbesartan

Study type: Interventional

Funder types: Other

Identifiers

NCT01992796

FARM97AJNN

Details and patient eligibility

About

The investigators propose a clinical study of irbersartan for the early treatment of severe sepsis patients with elevated predicted risk of death between. This study will evaluate whether early administration of the the angiotensin receptor blocker irbersartan provides significant reduction of 28 days mortality and multi organ failure incidence to patients with severe sepsis.

Full description

Background: Angiotensin II (ANG II) is a potent vasoconstrictor and diminishes vasodilator responses in arteries. In addition to direct effects on vascular tone, ANG II affects multiple aspects of microvascular function through promotion of leukostasis, induction of capillary permeability and depletion of glutathione. Binding of ANG II to its receptors (in particular AT1) mediates intracellular free radical generation that contributes to tissue damage by promoting mitochondrial dysfunction.

Angiotensin receptor blockers (ARBs) interrupt renin-angiotensin system (RAS) overactivity by blocking a specific receptor that mediates the pathogenic activity of angiotensin II. Objectives: The clinical question objective of this study is if the antiinflammatory effect of ARBs is relevant in sepsis management and in particular if ARBs are able to improve survival and reduce the incidence of Multi Organ Failure in septic patients.

Methods:

STUDY DESIGN: Experimental; prospective, randomized, multicenter, phase III trial.

STUDY POPULATION: Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80% are eligible.

Settings: 5 Italian Intensive Care Units. Oral irbesartan (total dose of 75 mg) or placebo administered every 24 hrs for 15 days. Analysis of data performed by a blind operator. Expected results: about 25% reduction in 28-day mortality rate and incidence of multi organ failure in the study population.

Enrollment: 300 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria: adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80% are eligible.

Exclusion Criteria:Patients already treated with ACE inhibitors or ARBs will be excluded. Patients admitted in shock conditions (systolic blood pressure lower than 90 mmHg) will be excluded. Patients with severe renal failure (serum creatinine of 2.0 mg/dL or dialysis) will be excluded.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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300 participants in 2 patient groups, including a placebo group

irbesartan

Experimental group

Description:

Irbesartan (total dose of 75 mg) or placebo administered every 24 hrs for 15 days. Moreover, the sepsis management will follow standard international guidelines (Crit Care Med.2008 Jan;36(1):296-327. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock). Duration of treatment: Irbesartan 75 mg daily for 15 days; only one cycle. Follow up will last 90 days both for treatment and control arm. * Route of administration : oral by nasogastric tube. * Medication permitted and not permitted during the trial: all the therapeutic interventions for sepsis management as indicated by international guidelines are admitted. During the trial are not permitted: ACE inhibitors, ARBs different from Irbersartan, angiotensin I synthesis inhibitors

Treatment:

Drug: Irbesartan

Placebo

Placebo Comparator group

Description:

Packaging and labelling for blinding purposes: tablets of placebo looking like the study drug