Clinical trial NCT02317549: Treatment of Septic Shock by Inhibiting Autodigestion and Preserving Gut Integrity With Enteric LB1148
Official title: Treatment of Septic Shock by Inhibiting Autodigestion and Preserving Gut Integrity With Enteric LB1148 (SSAIL Trial)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Septic Shock
Keywords: sepsis
septic shock
vasodilatory shock
circulatory shock
Systemic Inflammatory Response Syndrome
SIRS
infection
toxemia
gut barrier breakdown
autodigestion
multiorgan failure
MOF
multiorgain dysfunction syndrome
MODS
hyperlactatemia
tissue hypoxia
Lead sponsor: Palisade Bio
Sponsor class: INDUSTRY
First posted: 2014-12-16
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Septic shock is a potentially life-threatening condition that can result in multi-organ dysfunction syndrome (MODS) and mortality. LB1148 was formulated to preserve gut integrity during physiological shock and ameliorate the subsequent autodigestion leading to MODS and mortality. The purpose of this study in septic shock patients is to determine if enteral administration of LB1148 will increase the number of days alive without cardiovascular, pulmonary or renal replacement therapy through Day 28.

Detailed description: Primary Objective(s):

The primary objective of this study is to determine if enteral administration of LB1148 will increase the number of days alive without cardiovascular, renal or pulmonary organ support through Day 28.

The secondary objectives of this study are to determine if LB1148 will:

* Reduce mortality at Day 7, Day 28 and Day 90;
* Reduce the number of days to organ dysfunction resolution as evidenced by Sequential Organ Failure Assessment (SOFA) score ≤2 in patients alive on Day 28;
* Reduce the daily organ dysfunction as evidenced by average SOFA score through Day 14 and Day 28;
* Reduce the number of patients with new-onset organ dysfunction at Day 8;
* Increase the number of days alive and free from renal replacement therapy through Day 28;
* Increase the number of days alive and free from renal dysfunction through Day 28;
* Increase the number of days alive and ventilator free through Day 28;
* Increase the number of days alive and free of vasopressors through Day 14 and Day 28;
* Increase the numbers of days alive and free from liver dysfunction through Day 28;
* Increase the number of days alive and not in the Intensive Care Unit (ICU) through Day 28;
* Increase the number of days alive and not in the hospital through Day 28, and
* Improve patient functional outcomes through Day 28 as evidenced by the EuroQoL EQ 5D questionnaire.

In addition, the study will assess the safety and tolerability of LB1148 in patients with septic shock.

The exploratory objectives of this study are to determine if LB1148 will:

* Reduce the number of patients with new-onset organ dysfunction from Day 9 through Day 16;
* Decrease the number of days to normalize serum lactate (≤2.2 mmol/L) through Day 28;
* Reduce the average daily serum lactate levels through Day 8;
* Increase the number of days alive and free from ileus through Day 8 and Day 28.

Eligibility criteria: Inclusion Criteria:

1. First episode (during the current hospitalization) of documented or suspected sepsis of peritoneum/abdomen, soft tissue, blood, or non-hospital acquired lung origin.
2. Must be receiving antimicrobial therapy for documented or suspected infection.
3. Must have septic shock requiring vasopressors despite adequate fluid resuscitation of 30 mL/kg crystalloid or colloid equivalent, for either an SBP ≤90 mmHg or a MAP ≤65 mmHg (i.e. must have been unable to maintain adequate blood pressure despite adequate fluid resuscitation without the use of vasopressors). Note: 30 mL/kg crystalloid is equivalent to 15 mL/kg colloids.
4. Must have a requirement for vasopressor support after adequate fluid resuscitation, and, at randomization, must require a minimum dose of at least 1 of the following vasopressors:

   * Norepinephrine ≥5 µg/min;
   * Dopamine ≥10 µg/kg/min;
   * Phenylephrine ≥25 µg/min;
   * Epinephrine ≥5 µg/min, or
   * Vasopressin ≥0.03 units/min.

Exclusion Criteria

Patients will not be eligible for participation in the study if they meet ANY of the following criteria:

1. Age \<18 or age ≥76 years.
2. Time elapsed since onset of shock is \>24 hours. Onset of shock is defined as the first administration of a vasopressor given by continuous infusion (i.e. not a single bolus of norepinephrine, phenylephrine, or ephedrine).
3. Septic shock episode is the second or greater episode in current hospitalization.

   Note: patients transferred from another healthcare facility that are still within the first 24 hours of the first episode of shock are eligible.
4. Have hospital acquired pneumonia.
5. Have genitourinary infections as the cause of septic shock.
6. Unable to maintain a minimum MAP of 60 mmHg despite the presence of vasopressors and IV fluids.

   Note: brief transient BPs below 60 mmHg are not disqualifying.
7. Have a serum lactate measurement \<2.5 mmol/L after adequate fluid resuscitation (refer to Inclusion Criteria #3).
8. Not expected to survive for at least 28 days due to a preexisting, non-shock related medical condition.
9. Highest total SOFA score (known to staff at the time of randomization) during the screening period \<6.

   Note: each individual organ component sub-score is calculated from the highest (worst) score obtained for that organ during the screening period, up until randomization.
10. Highest total SOFA score (known to staff at the time of randomization) during the screening period \>18.

    Note: each individual organ component sub-score is calculated from the highest (worst) score obtained for that organ during the screening period.
11. Lack of commitment to aggressive source control of infection.
12. The patient or patient's surrogate fails to voluntarily sign an informed consent form (ICF).
13. Ineligible for feeding tube placement.
14. Chronic renal insufficiency requiring hemodialysis not associated with the current episode of sepsis.
15. Chronic pulmonary dysfunction requiring mechanical ventilation unrelated to the current episode of sepsis.
16. Undergoing active radiation or cytotoxic chemotherapy treatment for uncontrolled malignancy.

    Note: hormonal and surgical therapies are permitted.
17. Presence of third degree burns involving \>20% body surface area in the 7 days prior to study entry.
18. Known inability to take the study medication (i.e. complete small bowel obstruction).
19. Has acute meningitis.
20. Have any of the following medical conditions:

    * HIV-positive patients whose most recent CD4 count was ≤50/mm3;
    * Neutrophils \<1000/mm3 unless due to sepsis;
    * Received chest compressions as part of CPR during this hospitalization without neurologic recovery;
    * Poorly controlled neoplasm;
    * End-stage lung disease or Cystic Fibrosis;
    * End-stage liver disease (Child-Pugh Class C \[score \>10\], evidence of portal hypertension or esophageal varices);
    * Severe congestive heart failure (New York Heart Association \[NYHA\] Class IV or pre-sepsis ejection fraction \<30%);
    * Undergone organ transplant (including bone marrow, heart, lung, liver, pancreas, or small bowel transplantation), or
    * Primary ICU admitting diagnosis of acute myocardial infarction (MI).
21. Have relative contraindications to taking TXA or have a believed adverse risk/benefit ratio for taking the drug. These include patients with:

    * Known sensitivity to TXA;
    * Recent craniotomy (past 28 days);
    * Active cerebrovascular bleed;
    * Active thromboembolic disease, (such as deep vein thrombosis, pulmonary embolism \[PE\], cerebral thrombosis, ischemic stroke, or acute coronary syndrome \[ACS\]);
    * Acute promyelocytic leukemia taking all-trans retinoic acid for remission induction or;
    * Continuing use of a combined hormonal contraceptive (including combined hormonal pill, patch or vaginal ring).
22. Exclusion for any other condition that, in the opinion of the investigator or coordinating center, would preclude the subject from being an appropriate candidate for the study.
23. Received any other investigational therapy or device within 4 weeks prior to Screening.
24. Female patients of childbearing potential with a positive urine or serum pregnancy test or who are not taking (or not willing to take) acceptable birth control measures (abstinence, intrauterine devices, contraceptive implants or barrier methods) through Day 28. Additionally, those women who are lactating and insist on breast feeding within 5 days of the last dose of study drug if their sepsis resolves.

Note: post-partum patients who have a persistent positive pregnancy test (human chorionic gonadotropin \[HCG\] values which have not had time to decrease) will be allowed in the study.

Primary outcomes:
measure: Number of Days Alive Without Cardiovascular, Renal or Pulmonary Organ Support
timeFrame: Through day 28.
Secondary outcomes:
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Providence Hospital
state: Alabama
city: Fresno
country: United States
facility: Community Regional Medical Center, Fresno
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Hazard
country: United States
facility: ARH Regional Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville Hospital Laboratory
state: Kentucky
city: Burlington
country: United States
facility: Lahey Hospital and Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Labs - Rochester Campus
state: Minnesota
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: Missoula
country: United States
facility: St. Patrick Hospital
state: Montana
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Brooklyn
country: United States
facility: New York Methodist Hospital
state: New York
city: Chapel Hill
country: United States
facility: UNC Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Toledo
country: United States
facility: Mercy St. Vincent Medical Center, Clinical Research Offices
state: Ohio
city: Oklahoma City
country: United States
facility: OU Medical Center
state: Oklahoma
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Ben Taub Hospital
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Milwaukee
country: United States
facility: Froedtert Hospital and Medial College of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Royal Jubilee Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Victoria General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St Boniface Hospital
state: Manitoba
city: Winnipeg
country: Canada
facility: WHRA Winnipeg Health Sciences
state: Manitoba
city: Halifax
country: Canada
facility: Nova Scotia Health Authority
state: Nova Scotia
Study officials:
affiliation: Vice President
name: Tom Hallam, PhD
role: STUDY_CHAIR
References: