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

Treatment of Septic Shock by Inhibiting Autodigestion and Preserving Gut Integrity With Enteric LB1148 (SSAIL Trial)

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.

Study Overview

• Status: Terminated
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Placebo; Drug: LB1148

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Centre
    • Calgary, Alberta, Canada, T1Y6J4
      • Peter Lougheed Centre
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z1Y6
      • St. Paul's Hospital
    • Victoria, British Columbia, Canada, V8R 1J8
      • Royal Jubilee Hospital
    • Victoria, British Columbia, Canada, V8Z 6R5
      • Victoria General Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • St Boniface Hospital
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • WHRA Winnipeg Health Sciences
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Nova Scotia Health Authority
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Providence Hospital
  • California
    • Fresno, California, United States, 93721
      • Community Regional Medical Center, Fresno
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
  • Illinois
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Hazard, Kentucky, United States, 41701
      • ARH Regional Medical Center
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Hospital Laboratory
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Labs - Rochester Campus
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes Jewish Hospital
  • Montana
    • Missoula, Montana, United States, 59802
      • St. Patrick Hospital
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper University Hospital
  • New York
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Chapel Hill
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Toledo, Ohio, United States, 43608
      • Mercy St. Vincent Medical Center, Clinical Research Offices
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • OU Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Ben Taub Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital and Medial College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tranexemic Acid; Daily a total of 700 mL of LB1148 solution containing 7.5 g of tranexemic acid will be administered orally or via NG/OG/NJ/ND/PEG tube	Drug: LB1148; Other Names: Tranexamic Acid
Placebo Comparator: Placebo; Daily a total of 700 mL of Placebo solution will be administered orally or via NG/OG/NJ/ND/PEG tube	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Days Alive Without Cardiovascular, Renal or Pulmonary Organ Support	The patient will be classified as having organ support if organ support is required through the use of: Mechanical ventilation;; Vasopressors to maintain adequate blood pressure (BP), or; Renal replacement therapy.	Through day 28.

Collaborators and Investigators

• Sponsor: Leading BioSciences, Inc
• Investigators: Study Chair: Tom Hallam, PhD, Vice President

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: December 11, 2014
• First Submitted That Met QC Criteria: December 11, 2014
• First Posted (Estimate): December 16, 2014

Study Record Updates

• Last Update Posted (Actual): June 1, 2020
• Last Update Submitted That Met QC Criteria: May 14, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: septic shock; infection; sepsis; SIRS; Systemic Inflammatory Response Syndrome; MOF; hyperlactatemia; tissue hypoxia; vasodilatory shock; circulatory shock; toxemia; gut barrier breakdown; autodigestion; multiorgan failure; multiorgain dysfunction syndrome; MODS
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: LBS-SS201