Clinical trial NCT03654001: ALBumin Italian Outcome Septic Shock-BALANCED Trial (ALBIOSS-BALANCED)
Official title: Efficacy of Albumin Replacement and Balanced Solution in Patients with Septic Shock (the ALBIOSS-BALANCED Trial): a 2-by-2 Factorial, Investigator-initiated, Open- Label, Multicenter, Randomized, Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Septic Shock
Keywords: Septic Shock
Albumin
Balanced crystalloids
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sponsor class: OTHER
Collaborators: name: Istituto Di Ricerche Farmacologiche Mario Negri
First posted: 2018-08-31
Enrollment: 1319
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: 2-by-2 factorial design, open-label, multicenter, randomized, controlled trial, in patients with septic shock, as defined according to clinical criteria. Patients will be randomized in a 1:1:1:1 ratio to one of the 4 groups (Albumin + BAL, Albumin + NS, BAL, NS).
Primary purpose: TREATMENT

Brief summary: Septic shock is a devastating condition often observed in ICU. It is characterized by pro-inflammatory and immune responses, organ failures, high incidence of AKI and lethality. Fluid resuscitation is pivotal as supportive therapy. At present, there are no effective therapies to improve survival of such clinical condition, often characterized by a mortality as high as 40% during the first 90 days from diagnosis.

This project proposes a large 2-by-2 factorial randomized clinical trial testing the efficacy of albumin and the low- chloride balanced crystalloid solutions (either Ringer Lactate, Ringer Acetate, or Crystalsol - BAL) in septic shock.

The investigators have recently concluded a multicenter, randomized trial, the ALBIOS trial, in which, in a post-hoc analysis, albumin, in addition to crystalloids, reduced 90-day mortality in patients with septic shock, as compared to crystalloids alone (Caironi P et al, 2014). Crystalloids with supra-physiological chloride content may deteriorate renal perfusion, increasing the risk of acute kidney injury (AKI) and mortality.

Detailed description: The project will consist of a 2-by-2 factorial, investigator-initiated, open-label, multicenter, randomized, controlled trial, with PROBE design (Prospective Randomized Open Trial with Blinded Evaluation of Outcomes), in patients with septic shock, as defined according to clinical criteria.

Patients will be randomized in a 1:1:1:1 ratio to one of the 4 study groups (Albumin + BAL, Albumin + NS, BAL, NS).

Both the primary endpoints will include events evaluated objectively: 90-day mortality and incidence of AKI, as assessed by KDIGO criteria (KDIGO Acute Kidney Injury Work Group, 2012).

Eligibility criteria: Inclusion Criteria:

Patients with septic shock if they meet the two following criteria:

1. Presence of an infection (known or suspected) in at least one site:

   1. Lung
   2. Abdomen
   3. Urinary tract
   4. Others (blood, skin and soft tissues, central nervous system, bones and joints, cardiac system, reproductive organs).
2. Presence of a severe and acute, sepsis-related cardiovascular failure (as assessed by the SOFA score - see Annex 1), requiring vasopressor to maintain mean arterial pressure \>=65 mmHg, despite adequate volume resuscitation a) Cardiovascular SOFA score \> 2 (3 or 4) If the patient is unable to provide informed consent, she/he can be included in the trial provided that the requirements of ongoing laws are fulfilled; details on this approach are provided in the protocol, par 11.1 and related Annex 3. The patient will be informed about having been included in a clinical trial, as soon as she/he will regain consciousness.

Exclusion Criteria:

1. Age \< 18 years
2. Moribund state
3. Known or suspected adverse reaction to albumin administration
4. Septic shock in patients with traumatic brain injury or a clinically active cerebral lesion (known or suspected)
5. Severe congestive heart failure (NYHA III and IV classes)
6. Clinical situations in which the use of albumin is known or supposed to be clinically beneficial (hepatic cirrhosis with ascites, malabsorption syndrome or protein-losing enteropathy, nephrotic syndrome, burns)
7. More than 24 hours after the onset of septic shock
8. Religious objection to the administration of human blood products
9. Presence of chronic end-stage renal disease
10. Severe hyperkalemia (\> 6 mmol/L)
11. Known or suspected pregnancy based on patient information
12. Enrollment in other experimental interventional studies
13. Laboratory confirmation for SARS-CoV-2 infection

Primary outcomes:
measure: All-cause 90-day mortality
timeFrame: Up to 90 days
measure: Combined co-primary endpoint
timeFrame: Up to 90 days
Secondary outcomes:
measure: ICU mortality
timeFrame: Up to ICU discharge, a median of 9 days
measure: In-hospital mortality
timeFrame: Up to hospital discharge, a median of 20 days
measure: 1-year mortality
timeFrame: Up to 1 year
measure: SOFA score
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
measure: Incidence of AKI during ICU stay
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
measure: RRT
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
measure: Need for vasopressors
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
measure: Mechanical ventilation
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
measure: Secondary infections in ICU
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
measure: Duration of stay in ICU
timeFrame: Up to ICU discharge, a median of 9 days
measure: Duration of stay in hospital
timeFrame: Up to hospital discharge, a median of 20 days
measure: 1-year functional and physical disability
timeFrame: Up to 1 year
Other outcomes:
measure: Severe metabolic acidosis
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
measure: Severe hyperkalemia
timeFrame: Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
Locations:
city: Ancona
country: Italy
facility: Ospedali Riuniti di Ancona
state: AN
city: Bari
country: Italy
facility: AOU Policlinico di Bari
state: BA
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
state: BG
city: Seriate
country: Italy
facility: ASST BG Est - Ospedale Bolognini
state: BG
city: Treviglio
country: Italy
facility: AST BG Ovest - PO Treviglio
state: BG
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola-Malpighi
state: BO
city: Cona
country: Italy
facility: Azienda Ospedaliero - Universitaria di Ferrara - Arcispedale Sant'Anna
state: FE
city: Borgo San Lorenzo
country: Italy
facility: Ospedale del Mugello
state: FI
city: Empoli
country: Italy
facility: Ospedale San Giuseppe
state: FI
city: Firenze
country: Italy
facility: AOU Careggi
state: FI
city: Orbetello
country: Italy
facility: Ospedale Colline dell'Albegna
state: GR
city: Desio
country: Italy
facility: Presidio Ospedaliero di Desio
state: MB
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
state: MB
city: Cinisello Balsamo
country: Italy
facility: ASST Nord Milano - Ospedale Bassini
state: MI
city: Legnano
country: Italy
facility: ASST Ovest Milano
state: MI
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
state: MI
city: Milano
country: Italy
facility: ASST Fatebenefratelli - Sacco P.O. Sacco
state: MI
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
state: MI
city: San Donato Milanese
country: Italy
facility: IRCCS Policlinico San Donato
state: MI
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria di Modena, Policlinico di Modena
state: MO
city: Palermo
country: Italy
facility: AOU Policlinico Paolo Giaccone
state: PA
city: Palermo
country: Italy
facility: ISMETT
state: PA
city: Pisa
country: Italy
facility: AOU Pisana
state: PI
city: Pordenone
country: Italy
facility: As FO Azienda sanitaria Friuli Occidentale
state: PN
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
state: PV
city: Reggio Emilia
country: Italy
facility: IRCCS ASMN Reggio Emilia
state: RE
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore
state: RM
city: Trento
country: Italy
facility: Ospedale Santa Chiara
state: TN
city: Moncalieri
country: Italy
facility: Ospedale Santa Croce
state: TO
city: Orbassano
country: Italy
facility: Azienda Ospedaliero - Universitaria S. Luigi Gonzaga
state: TO
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino
state: TO
city: Trieste
country: Italy
facility: ASU Giuliano Isontina
state: TS
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Integrata di Udine
state: UD
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi
state: VA
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata di Verona
state: VR
city: Alessandria
country: Italy
facility: Ospedale SS. Antonio e Biagio e Cesare Arrigo
city: Rimini
country: Italy
facility: Ospedale Infermi di Rimini
Study officials:
affiliation: AOU S. Luigi Gonzaga, Orbassano
name: Pietro Caironi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Policlinico di Milano Ospedale Maggiore | Fondazione IRCCS Ca' Granda
name: Giacomo Grasselli, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L; ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727. Epub 2014 Mar 18.
citation: SAFE Study Investigators; Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, Norton R. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011 Jan;37(1):86-96. doi: 10.1007/s00134-010-2039-6. Epub 2010 Oct 6.
citation: Mehlman DJ, Bulkley BH, Wiernik PH. Serum alpha-1-fetoglobulin with gastric and prostatic carcinomas. N Engl J Med. 1971 Nov 4;285(19):1060-1. doi: 10.1056/NEJM197111042851907. No abstract available.
citation: Semler MW, Self WH, Rice TW. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 May 17;378(20):1951. doi: 10.1056/NEJMc1804294.
citation: Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. No abstract available.