Treatment of Septic Shock by Inhibiting Autodigestion and Preserving Gut Integrity With Enteric LB1148

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.

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.