Treatment of Septic Shock by Inhibiting Autodigestion and Preserving Gut Integrity With Enteric LB1148
Condition: Septic Shock
MeSH terms: Shock, Septic; Shock
Intervention: LB1148; Placebo
Intervention MeSH terms: Tranexamic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
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

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.
    

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.