Advanced Mesenchymal Enhanced Cell THerapY for SepTic Patients

Study Overview
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Brief Summary
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Bacterial sepsis occurs in patients with severe infections. The condition is caused by toxic substances (toxins) released from bacteria and the patient's elevated inflammatory response to those toxins. In preclinical studies, human mesenchymal stromal cells (MSCs) have been proven to modulate host inflammation in infections, including sepsis. The purpose of the Phase I, open label, dose escalation safety trial is to determine whether escalating doses of enhanced MSCs (GEM00220) are safe and well tolerated in patients with septic shock.

Detailed Description
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This trial consists of 2 sequential parts using the same trial infrastructure: Phase 1a: A dose escalating and safety trial with pre-defined stopping rules for safety. Up to 12 participants will receive a single infusion of GEM00220. If no safety issues are identified, we will continue to the Phase 1b trial at the maximum feasible tolerated dose. Phase 1b: A single-arm, open-label extension of the Phase 1a trial to assess early signs of efficacy (major morbidity and mortality). The Phase 1b trial will enroll up to 9 participants to assess early signals of benefit on mortality and major morbidity in a high risk, high mortality population.

Official Title
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Advanced Mesenchymal Enhanced Cell THerapY for SepTic Patients

Conditions
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Septic Shock

Intervention / Treatment
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* Biological: GEM00220


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients age 18 years and older Receipt of appropriate antibiotics for the suspected/confirmed bacterial sepsis as the main diagnosis according to the opinion of the treating staff physician. Hypotension documented within 48 hours prior to enrolment that requires the institution and ongoing use of vasopressor agents (phenylephrine, norepinephrine, vasopressin, epinephrine, or dopamine >5 mcg/kg/min) for at least 3 hours within 24 hours prior to infusion, despite adequate fluid resuscitation in the opinion of the qualified investigator. At least 1 other new organ dysfunction defined by the following: Renal: Acute kidney injury with creatinine ≥ 150 µmol/L, or ≥ 1.5x the upper limit of normal or the known baseline creatinine, or < 0.5 ml/kg/hr urine output for 6 hours despite adequate fluid resuscitation or requirement for new renal replacement therapy (patients on chronic hemodialysis or peritoneal dialysis must meet one of the other organ dysfunction criteria) Respiratory: Need for invasive mechanical ventilation or a P/F ratio < 250 Hematological: Platelets < 100 x10^9/L, or a drop of 50 x10^9/L in the 3 days prior to enrollment Metabolic Acidosis: Arterial pH < 7.30 in association with base deficit > 5 mmol/L OR a lactate >/= to 3.0 mmol/L Exclusion Criteria: Pregnant or lactating Currently receiving extracorporeal life support Major surgery within this hospitalization and not prophylactically anticoagulated Documented history of a hypercoagulable state (eg Factor V Leiden) or heparin-induced thrombocytopenia (HIT) Body Mass Index (BMI) > 35 Documented COVID-19 (SARS-CoV2) within 30 days Documentation of viral lung infection as the primary diagnosis (e.g. influenza infection, respiratory syncytial virus (RSV) infection, or other laboratory-confirmed viral lung infection) Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the past year Documented history of severe heart failure with a New York Heart Association Functional Class of III or IV, or severe ischemic heart disease with a Canadian Cardiovascular Society angina class score of III or IV Documented history of moderate to severe chronic liver disease (Childs-Pugh Score > 12) Documented history of peripheral vascular disease with a Rutherford classification greater than Grade I, Category 2: moderate claudication Severe chronic respiratory disease with a baseline PaCO2 > 50 mm Hg or the use of home oxygen Documented deep venous thrombosis or pulmonary embolism Chronic immunosuppression (any chronic immunotherapy including daily oral steroid use >6months) Documented, uncontrolled HIV infection or end stage HIV/AIDS with CD4+ T-cell counts <50 cells/mm^3, history of hepatitis B, untreated hepatitis C, or active tuberculosis Concurrent use of immunomodulatory biologic drugs or TNF-α inhibitors Participation in another interventional study involving an investigational new drug within 30 days prior to enrolment Moribund patient not expected to survive 24 hours Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A dose-escalation study evaluating GEM00220 cell therapy in 4 cohorts with 3 subjects per cohort. Study will proceed from lower dose to next higher dose if no safety concerns are observed in each cohort. If no safety issues are identified, we will continue to the Phase 1b trial. Phase 1b: A single-arm, open-label extension of the Phase 1a trial to assess early signs of efficacy (major morbidity and mortality). The Phase 1b trial will enroll up to 9 participants.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm - Dose Cohort 1<br>Participants will receive a single dose of GEM00220 at 15 million cells | Biological: GEM00220<br>* Cryopreserved allogeneic, enhanced MSCs administered as a single intravenous infusion<br>|
| Experimental: Treatment arm - Dose Cohort 2<br>Participants will receive a single dose of GEM00220 at 60 million cells | Biological: GEM00220<br>* Cryopreserved allogeneic, enhanced MSCs administered as a single intravenous infusion<br>|
| Experimental: Treatment arm - Dose Cohort 3<br>Participants will receive a single dose of GEM00220 at 150 million cells | Biological: GEM00220<br>* Cryopreserved allogeneic, enhanced MSCs administered as a single intravenous infusion<br>|
| Experimental: Treatment arm - Dose Cohort 4<br>Participants will receive two doses of GEM00220 at 150 million cells each, seperated by 24 hours | Biological: GEM00220<br>* Cryopreserved allogeneic, enhanced MSCs administered as a single intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of GEM00220 will be assessed by monitoring adverse events |  | Baseline to 28 days | 
| Maximum Feasible Tolerated Dose | The highest dose which does not meet any of the pre-defined stopping criteria | Baseline to 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Bacteria, Septic Shock, Mesenchymal Stromal Cells, Inflammation, Mesenchymal Stem Cells, Infection