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
Study Details
Study Description
Brief Summary
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This is a multi-center, 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. Potential patients will be identified and recruited in the Emergency Room (ER), scheduled to be admitted to Intensive Care Unit (ICU) or Intermediate Care Unit (IMU) or patients already admitted to the ICU or IMU.
After the patient or his/her legal guardian has signed the informed consent form (ICF), or following a delayed consent process, and after confirmation that the patient meets all eligibility criteria, the patient will be randomized to one of the 4 treatment groups:
-
Placebo
-
Single Intravenous (IV) dose of Allocetra-OTS, 5x10^9 cells
-
Single IV dose of Allocetra-OTS, 10x10^9 cells
-
Single or two IV doses of Allocetra-OTS, 10x10^9 cells in each dose
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 be unblinded for Cohort 4, 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 over 28 days of the first 16 dosed patients (approximately 4 patients in each Cohort) will be submitted for review by the Data Safety Monitoring Board (DSMB).
Prior to Investigational Product (IP) administration (as specified in Schedule of Assessments [SOA]), the patient will be assessed to exclude:
-
Septic shock; requiring persisting hypotension treated with vasopressors to maintain mean arterial pressure (MAP) ≥ 65 mmHg AND having serum lactate >4 mmol/L (36 mg/dL) despite adequate volume resuscitation.
-
SOFA score improvement, i.e., total score below 2 points. Patients who developed septic shock, according to the above criteria, or had their SOFA score improved below the score of 2 points will not be administered with the IP and will be counted as randomization failure.
IP handling (Cohort 1-3 and first dose of Cohort 4), from receipt at the site through administration and until destruction will be done by unblinded delegated personnel.
Note: The time of initial sepsis diagnosis will be captured as time 0 (prior to screening), IP administration will occur on Day 1 within 24±12 hours from the time of sepsis diagnosis at admission to the hospital.
Up to four hours pre-administration (or as specified SOA), patient's SOFA parameters will be measured to determine baseline SOFA.
All patients will receive at least one course of IV antibiotics and as soon as possible after diagnosis.
Patients who have been assigned to Cohort 4 may be eligible for a second dose treatment if no detrimental drug related effect was indicated following first dose administration and if their screening SOFA of 2-6 deteriorates (Day 4 SOFA> Screening SOFA), or screening SOFA of 7-9 has no improvement (Day 4 SOFA ≥ Screening SOFA). To determine eligibility for a second dose, investigator will be unblinded on Day 4 and prompted to evaluate SOFA score in the morning of Day 4. Patients who will be found eligible, will receive the second dose treatment on Day 5 (24+6) hours from the eligibility determination (on Day 4).
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 of whether 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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Cohort 1 375 ml Ringer's lactate solution |
Other: Placebo
Ringer's Lactate Solution
|
| Experimental: Cohort 2 Single IV dose of Allocetra-OTS contain 5x10^9 cells |
Drug: ALLOCETRA-OTS
The product contains allogeneic donor mononuclear enriched cells in the form of a liquid suspension containing early apoptotic cells.
Other Names:
|
| Experimental: Cohort 3 Single IV dose of Allocetra-OTS contain 10x10^9 cells |
Drug: ALLOCETRA-OTS
The product contains allogeneic donor mononuclear enriched cells in the form of a liquid suspension containing early apoptotic cells.
Other Names:
|
| Experimental: Cohort 4 Single or two IV doses of Allocetra-OTS contain 10x10^9 cells in each dose |
Drug: ALLOCETRA-OTS
The product contains allogeneic donor mononuclear enriched cells in the form of a liquid suspension containing early apoptotic cells.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Efficacy: Change from baseline in SOFA score [28 days]
Change from baseline in SOFA score throughout 28 days
- Safety: Number and severity of AEs and SAEs [28 days]
Number and severity of AEs and SAEs throughout 28 days follow up period
Secondary Outcome Measures
- Ventilator-free days [28 days]
Ventilator-free days over 28 days
- Vasopressor-free days [28 days]
Vasopressor-free days over 28 days.
- Days without renal replacement therapy (dialysis). [28 days]
Days without renal replacement therapy (dialysis).
- Time in ICU and time in hospital [28 days]
Time in ICU and time in hospital
- Number of days with creatinine ≤ Baseline levels +20% [28 days]
Number of days with creatinine ≤ Baseline levels +20%
- All-cause mortality [28 days]
All-cause mortality at Day 28 following first dose
- Changes from baseline in CRP levels [28 days]
Changes from baseline in CRP levels
- Number and severity of AEs and Serious Adverse Events (SAEs) [12 months]
Number and severity of AEs and Serious Adverse Events (SAEs) throughout 12 months follow up period
- Detection of autoimmune and HLA antibodies [12 months]
Detection of autoimmune and HLA antibodies
Eligibility Criteria
Criteria
Inclusion criteria:
-
Male or female ≥18 years and ≤90 years of age.
-
Suspected, presumed or documented community-acquired pneumonia by imaging.
-
Treatment with antibiotics after at least one course for the suspected infection.
-
Meets Sepsis 3 criteria: the presence of organ dysfunction as identified by a total SOFA score ≥2 points above pre-admission SOFA.
-
Signed written informed consent by the patient, or his/her legal guardian or delayed patient consent (based on local regulations).
-
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:
-
Sepsis due to infection other than lung infection, or sepsis Patients where site of infection is unclear or unknown.
-
On chronic dialysis.
-
Invasive ventilated patient and PaO2/FiO2 < 100 mmHg
-
Weight <50 kg or >120 kg or BMI >40 kg/m2.
-
SOFA score ≥ 10 at screening (Day -1).
-
Patients with Septic shock; requiring persisting hypotension treated with vasopressors to maintain MAP≥65 mmHg AND having a serum lactate level >4 mmol/L (36 mg/dL) despite adequate volume resuscitation on Screening and on Day 1 prior to IP administration.
-
Surgical intervention within 30 days prior to diagnosis of sepsis, plan for surgical intervention (not including percutaneous procedure needed for the current treatment of the sepsis and its complications such as chest drain, PICC line or central line insertion among others).
-
Patients with risk of nosocomial infection due to hospitalization within 30 days prior to diagnosis of sepsis.
-
A known malignancy that is progressing or has required active treatment within the past 3 months.
-
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).
-
Known active SARS-CoV-2) or chronic viral infections, such as HBV or HCV, HIV or other chronic infections.
-
Chronic respiratory disease requiring home oxygen therapy on a regular basis for > 6 h/day.
-
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.
-
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.
-
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.
-
Organ allograft or previous history of stem cell transplantation.
-
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.
-
Participation in an interventional investigational study within 30 days prior to diagnosis of sepsis.
-
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).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Attikon | Athens | Greece | ||
| 2 | Evaggelismos | Athens | Greece | ||
| 3 | Barzilai Medical Center | Ashkelon | Israel | ||
| 4 | Soroka Medical Center | Be'er Sheva | Israel | ||
| 5 | Hillel Yaffe Medical Center | Hadera | Israel | ||
| 6 | Bnai Zion Medical Center | Haifa | Israel | ||
| 7 | Carmel Medical Center | Haifa | Israel | ||
| 8 | Rambam Medical Center | Haifa | Israel | ||
| 9 | Hadassah Ein Kerem Medical Center | Jerusalem | Israel | ||
| 10 | Beilinson Medical Center | Petah tikva | Israel | ||
| 11 | Kaplan Medical Center | Reẖovot | Israel | ||
| 12 | Poriya Medical Center | Tverya | Israel | ||
| 13 | Ziv Medical Center | Zefat | Israel | ||
| 14 | Clinic Barcelona University Hospital | Barcelona | Spain | ||
| 15 | Mutua Terrassa | Barcelona | Spain | ||
| 16 | Vall d'Hebron | Barcelona | Spain |
Sponsors and Collaborators
- Enlivex Therapeutics Ltd.
- Cato Research
- Accelsiors CRO & Consultancy Services
Investigators
- Principal Investigator: Pierre Singer, MD, Rabin medical center, Belinson Campus, Petah Tiqwa Isarel
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ENX-CL-02-002