Angiotensin II Antagonist in Severe Sepsis (SartSep)

Phase III Study of Irbersartan for the Early Treatment of Severe Sepsis Patients

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.

Study Overview

• Status: Unknown
• Conditions: Severe Sepsis
• Intervention / Treatment: Drug: Irbesartan

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Salerno, Italy
    • Università di Salerno

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: irbesartan; 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	Drug: Irbesartan; 75 mg/per os/for 15 days; Other Names: Aprovel; Candesartan.; Telmisartan.; Olmesartan.; Lortaan; Losaprex; Neolotan; Tevetenz; Rixil; Tareg; Valpression; Karvea.
PLACEBO_COMPARATOR: Placebo; Packaging and labelling for blinding purposes: tablets of placebo looking like the study drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
mortality	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of altered organ function in sepsis patients measured by SOFA score (Sequential Organ Failure Assessment score)	Incidence of altered organ function in sepsis patients measured by SOFA score (Sequential Organ Failure Assessment score). It is known that respiratory failure is more common in the first 72 hours after the original insult, hepatic failure after 5-7 days, gastrointestinal bleeding within 10-15 days and renal failure in 11-17 days: the SOFA score will be checked every day for 28 days. The SOFA score is a scoring system to determine the extent of a person's organ function or rate of failure. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. Creatinine serum levels, bilirubin, coagulation tests, blood gases and neurological clinical evaluation will be performed every day for the first 15 days; they will be retested at least once a week and at the end of the study protocol (28-day).	28 day

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of renal failure	Creatinine (mg/dl) (SOFA score) 1.2 - 1.9 (1) 2.0 - 3.4 (2) 3.5 - 4.9 (or urine output< 500 ml/d) (3) > 5.0 (or urine output< 200 ml/d) (4)	28 days

Collaborators and Investigators

• Sponsor: University of Salerno
• Collaborators: Federico II University
• Investigators: Study Director: Rosalba Tufano, MD, Federico II University

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (ANTICIPATED): January 1, 2017
• Study Completion (ANTICIPATED): January 1, 2017

Study Registration Dates

• First Submitted: November 11, 2013
• First Submitted That Met QC Criteria: November 19, 2013
• First Posted (ESTIMATE): November 25, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): November 25, 2013
• Last Update Submitted That Met QC Criteria: November 19, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: irbesartan, angiotensin, sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Olmesartan; Candesartan; Telmisartan; Irbesartan
• Other Study ID Numbers: FARM97AJNN