SartSep: Angiotensin II Antagonist in Severe Sepsis

Sponsor

University of Salerno (Other)

Overall Status

Unknown status

CT.gov ID

NCT01992796

Collaborator

Federico II University (Other)

300

Enrollment

Location

Arms

Duration (Months)

8.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Severe Sepsis	Drug: Irbesartan	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2014

Anticipated Primary Completion Date :

Jan 1, 2017

Anticipated Study Completion Date :

Jan 1, 2017

Arms and Interventions

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: Candesartan. Telmisartan. Olmesartan. Lortaan Losaprex Neolotan Tevetenz Rixil Tareg Valpression Aprovel Karvea.
Placebo Comparator: Placebo Packaging and labelling for blinding purposes: tablets of placebo looking like the study drug

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:

Candesartan.

Telmisartan.

Olmesartan.

Lortaan

Losaprex

Neolotan

Tevetenz

Rixil

Tareg

Valpression

Aprovel

Karvea.

Placebo Comparator: Placebo

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

Outcome Measures

Primary Outcome Measures

mortality [28 days]

Secondary Outcome Measures

Incidence of altered organ function in sepsis patients measured by SOFA score (Sequential Organ Failure Assessment score) [28 day]
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).

Other Outcome Measures

Incidence of renal failure [28 days]
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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.