A Phase 2 Study Evaluating Efficacy, Safety and Tolerability of Different Doses and Regimens of Allocetra-OTS for the Treatment of Organ Failure in Adult Sepsis Patients

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Brief Title

A Phase 2 Study Evaluating Efficacy, Safety and Tolerability of Different Doses and Regimens of Allocetra-OTS for the Treatment of Organ Failure in Adult Sepsis Patients

Official Title

A Phase 2, Multi-Center, Randomized, Placebo-Controlled, Dose-Finding Study Evaluating Efficacy, Safety and Tolerability of Different Doses and Regimens of Allocetra-OTS for the Treatment of Organ Failure in Adult Sepsis Patients

Brief Summary

      A phase II, multi-center (approximately 35 sites), randomized, placebo-controlled, dose-
      finding study comparing the efficacy, safety and tolerability of different dosing regimens of
      Allocetra-OTS, in up to 160 adult patients with sepsis.
    

Detailed Description

      Up to 160 patients will be allocated in a 1:1:1:1 ratio between the 4 cohorts (up to 40
      patients in each cohort). Randomization will be in a double blinding fashion which will be
      kept until Day 4. On day 4, the investigator will become unblinded to Cohort 4 patients in
      order to assess patient eligibility for second dose. Cohort 4 patients may also become
      unblinded as a result of second dose administration. The remaining Cohorts 1-3 will be kept
      blinded throughout the entire study period unless requested and justified by the
      investigator.

      Randomization will be stratified by screening Sequential Organ Failure Assessment (SOFA)
      score (2-6 vs. 7-9).

      Safety data will be reviewed by the Data Safety Monitoring Board (DSMB). Patients will be
      followed over 28 days for efficacy and continue safety follow up of 12 months from IP
      administration.

      Patients participating in this study, regardless if hospitalized or discharged, will be
      followed daily through Day 7 (inclusive, short-term follow-up), then on Days 10 (only for
      patients receiving 2nd dose), Day 14, and Day 28 (medium-term follow-up), and then at 3
      months, 6 months and 12 months (long-term safety follow-up).
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

To compare the safety of different doses and regimens of Allocetra-OTS to that of Placebo in the treatment of organ failure in adult sepsis patients

Secondary Outcome

 compare other clinical manifestations of different doses and regimens of Allocetra-OTS associated with organ failure in sepsis patients

Condition

Sepsis

Intervention

ALLOCETRA-OTS

Study Arms / Comparison Groups

 Cohort 1
Description:  375 ml Ringer's lactate solution

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

160

Start Date

November 30, 2020

Completion Date

September 1, 2024

Primary Completion Date

July 1, 2023

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female ≥18 years and ≤90 years of age.

          2. Meets Sepsis 3 criteria: the presence of organ dysfunction as identified by a total
             SOFA score ≥2 points above pre-admission SOFA. Patients in septic shock with SOFA
             score up to 9 may be included.

          3. Initiation of antibiotics treatment for the suspected infection.

          4. Sepsis due to infection in at least one of the below organs:

             4.1. Suspected, presumed or documented Community-Acquired Pneumonia (CAP). CAP
             diagnosis or suspicion will be based on clinical signs (cough, purulent sputum, chest
             pain, fever and dyspnea) and radiological results, and can also be supported by
             microbiological results.

             4.2. Urinary tract infection diagnosed by:

               -  Two of the following signs and symptoms of UTI: urinary frequency, urinary
                  urgency, pain or burning on micturition, flank pain or suprapubic pain or
                  costovertebral angle (CVA) tenderness, gross hematuria. AND,

               -  A Mid-Stream Clean-Catch (MSCC) or catheterized urine specimen with a dipstick
                  analysis positive for nitrite OR, in the same urine specimen evidence of pyuria
                  as defined by either:

                    -  a dipstick analysis positive for leukocyte esterase, AND/OR

                    -  at least 10 white blood cells per cubic millimeter on microscopic analysis
                       of unspun urine, AND/OR

                    -  White blood cell count ≥5 cells/HPF in the sediment of a spun urine.

             4.3. Acute cholecystitis diagnosed by the below Tokyo criteria:

             • At least one of the following local signs of inflammation:

               -  Murphy's sign, AND/OR

               -  RUQ mass/pain/tenderness

             AND

             • At least one of the following systemic signs of inflammation:

               -  Fever (body temperature > 38°), AND/OR

               -  Elevated CRP (CRP > 1 mg/dL), AND/OR

               -  Elevated WBC count (WBC > 10 x 103 /µL).

             AND

             • Imaging findings characteristic of acute cholecystitis.

             4.4. Acute cholangitis diagnosed by the below Tokyo criteria:

             • At least one of the following systemic signs of inflammation:

               -  Fever (body temperature > 38°)/or shaking chills, AND/OR

               -  Laboratory data: evidence of inflammatory response [Abnormal white blood cell
                  counts (WBC < 4 or > 10 x 103 /µL) OR increased serum C-reactive protein levels
                  (CRP ≥1 mg/dL), and other changes indicating inflammation]

             AND

             • At least one of the following signs of cholestasis:

               -  Jaundice (total bilirubin ≥ 2mg/dL), AND/OR

               -  Laboratory data: abnormal liver function tests > 1.5 ULN [Increased serum ALP,
                  γ-GTP (GGT), AST, and ALT levels]

             AND

             • At least one of the following imaging findings:

               -  Biliary dilatation, AND/OR

               -  Evidence of the etiology on imaging (stricture, stone, stent etc.)

             4.5. Other intra-abdominal infections (IAI), diagnosed by at least one of the below
             documented, following adequate source control by surgical intervention (including open
             laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery:

             4.5.1. Diverticular disease with perforation or abscess.

             4.5.2. Cholecystitis with gangrenous rupture or perforation or progression of the
             infection beyond the gallbladder wall.

             4.5.3. Appendiceal perforation or peri-appendiceal abscess.

             4.5.4. Acute gastric and duodenal perforations, only if operated on <24 hours after
             perforation is diagnosed.

             4.5.5. Traumatic perforation of the intestines, only if operated on <12 hours after
             perforation is diagnosed.

             4.5.6. Secondary peritonitis (but not spontaneous bacterial peritonitis associated
             with cirrhosis and chronic ascites).

             4.5.7. Intra-abdominal abscess (including of liver and spleen provided that there is
             extension beyond the organ with evidence of intraperitoneal involvement).

          5. Adequate source control, if necessary, as determined by the investigator or source
             control is scheduled to be completed prior to IP administration. In case source
             control will not be completed prior to IP administration, Sponsor pre-approval is
             required for IP administration.

          6. Signed written informed consent by the patient, or consent obtained according to local
             regulations if the patient is unable to provide informed consent.

          7. Women of childbearing potential and all men must agree to use 2 methods of an adequate
             contraception: One barrier method (e.g. diaphragm, or condom or sponge, each of which
             are to be combined with a spermicide) and one hormonal method (e.g. oral, transdermal
             patch, implanted contraceptives or intrauterine device) prior to study entry and for
             the duration of study participation through 4 weeks following IP administration.
             Subjects that are highly unlikely to conceive (e.g. surgically sterile,
             postmenopausal, or not heterosexually active) are exempt. Non-childbearing potential
             is defined as (by other than medical reasons):

               -  ≥45 years of age and has not had menses for over 2 years.

               -  <45 years of age and amenorrhoeic for > 2 years without a hysterectomy and
                  oophorectomy and a Follicle Stimulating Hormone (FSH) value in the postmenopausal
                  range upon pre-trial (screening) evaluation.

        For women, post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or bilateral
        tubal ligation and vasectomy for men at least 6 weeks prior to screening. Documented
        hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure
        or confirmed by ultrasound. Tubal ligation must be confirmed with medical records of the
        actual procedure.

        Exclusion Criteria:

          1. Sepsis due to infection other than lung infection, UTI or IAI, or sepsis patients
             where site of infection is unclear or unknown.

          2. On chronic dialysis.

          3. Patients with acute pancreatitis (serum amylase > 3 ULN with clinical abdominal pain).

          4. Invasive ventilated patient and PaO2/FiO2 < 100 mmHg

          5. Weight <50 kg or >120 kg or BMI >40 kg/m2.

          6. SOFA score ≥ 10 at screening (Day -1).

          7. Patients with risk of nosocomial infection due to hospitalization or surgery within 30
             days prior to diagnosis of sepsis.

          8. A known malignancy that is progressing or has required active treatment within the
             past 3 months.

          9. Patients with end-stage disease (unrelated to sepsis) defined as patients who prior to
             the current hospitalization are expected to live < 6 months (as assessed by the study
             physician).

         10. Known active symptomatic SARS-CoV-2 or chronic viral infections, such as HBV or HCV,
             HIV or other chronic infections.

         11. Chronic respiratory disease requiring home oxygen therapy on a regular basis for > 6
             h/day.

         12. Known active upper GI tract ulceration or hepatic dysfunction including but not
             limited to biopsy-proven cirrhosis; End-stage cirrhosis (Child Pugh Class C); portal
             hypertension; episodes of past upper GI bleeding attributed to portal hypertension; or
             prior episodes of hepatic failure, encephalopathy, or coma.

         13. Known NYHA class IV heart failure or unstable angina, ventricular arrhythmias, acute
             coronary disease or myocardial infarction within six months prior to diagnosis of
             sepsis.

         14. Known immunocompromised state or medications known to be immunosuppressive.

               -  Hydrocortisone (for the treatment of septic shock) > 300 mg /d Prednisone or
                  equivalent to a dose ≥10 mg/day, for more than 14 days within the last 28 days.

               -  Methotrexate, cyclophosphamide, cyclosporine A (unless as ophthalmic
                  formulation), leflunomide/teriflunomide (unless as monotherapy), tacrolimus
                  (unless as a topical formulation), sirolimus, everolimus, temsirolimus,
                  mycophenolate mofetil or azathioprine, in the last 60 days;

               -  Chemotherapy in the last 3 months;

               -  Mycophenolate mofetil (MMF) or sirolimus for solid organ transplant or bone
                  marrow transplant with no time limitation.

               -  Thalidomide within the last 72 hours.

               -  Anti-tumor necrosis factor (TNF) agents, interleukin (IL)-1 receptor antagonists
                  (IL-1-RA), CTLA-4 fusion proteins, anti-CD20, anti-CD52, anti-IL-2, anti-IL-6R,
                  anti-IL-12/23, anti-B-cell activation factor (BAFF) or integrin inhibitor agents
                  within the last 8 weeks.

         15. Organ allograft or previous history of stem cell transplantation.

         16. Women who are pregnant or breastfeeding. Child-bearing potential females must have a
             negative serum ß-hCG or hCG blood test at screening. Pregnancy testing is not required
             for postmenopausal or surgically sterilized women.

         17. Known hypersensitivity to any component of study treatment or excipients.

         18. Participation in an interventional investigational study within 30 days prior to
             diagnosis of sepsis.

         19. Likely to be non-compliant or uncooperative during the study (e.g. substance abuse
             such as drug or alcohol abuse, uncontrolled psychiatric disorder or any chronic
             condition that may interfere with study conduct).
      

Gender

All

Ages

18 Years - 90 Years

Accepts Healthy Volunteers

No

Contacts

Pierre Singer, MD, 972-548887609, [email protected]

Location Countries

Greece

Location Countries

Greece

Administrative Informations


NCT ID

NCT04612413

Organization ID

ENX-CL-02-002


Responsible Party

Sponsor

Study Sponsor

Enlivex Therapeutics Ltd.

Collaborators

 Cato Research

Study Sponsor

Pierre Singer, MD, Principal Investigator, Rabin medical center, Belinson Campus, Petah Tiqwa Isarel


Verification Date

May 2022