Cx611-0204 SEPCELL Study

Study Overview
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Brief Summary
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The purpose of this randomised, multicentre, double-blind, placebo-controlled, phase Ib/IIa study is to assess the safety, tolerability and efficacy of eASCs (Cx611) administered intravenously as adjunctive therapy, therefore in addition to standard of care (SoC) therapy, to patients with severe community-acquired bacterial pneumonia (sCABP). The completion of this study will contribute to the basic knowledge on stem cells and their mode-of-action, and has a large translational character, i.e. to document the safety and explore the efficacy of Cx611 in patients with sCABP.

Detailed Description
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The purpose of this randomised, multicentre, double-blind, placebo-controlled, phase Ib/IIa study is to assess the safety, tolerability and efficacy of eASCs (Cx611) administered intravenously as adjunctive therapy, therefore in addition to standard of care (SoC) therapy, to patients with severe community-acquired bacterial pneumonia (sCABP). The key objectives of this study are to: Primary objective: Investigate the safety profile of two allogeneic Cx611 80 mL infusions administered through a central line within 3 days (on days 1 and 3) at a dose of 160 million cells each (320 million cells total) and to monitor any adverse event and potential immunological host responses against the administered cells during 90 days of follow-up after the first infusion. Secondary objective: Explore the clinical efficacy of Cx611 in terms of a reduction of the duration of mechanical ventilation and/or need for vasopressors and/or improved survival, and/or clinical cure of the sCABP, and other efficacy-related endpoints.

Official Title
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A Phase Ib/IIa, Randomised, Double Blind, Parallel Group, Placebo Controlled, Multicentre Study to Assess the Safety and Efficacy of Expanded Cx611 Allogeneic Adipose-derived Stem Cells (eASCs) for the Intravenous Treatment of Adult Patients With Severe Community-acquired Bacterial Pneumonia and Admitted to the Intensive Care Unit

Conditions
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Bacterial Pneumonia

Intervention / Treatment
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* Biological: Cx611
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Adult subjects of either gender (aged ≥18 years and ≤80 years old.) Body weight between 50 kg and 100 kg. Clinical diagnosis of acute (developed within ≤21 past days) community acquired bacterial pneumonia based on the presence of two relevant signs (fever, tachypnoea, leukocytosis, or hypoxemia) and radiographic findings of new pulmonary infiltrate/s. Subjects with pneumonia of sufficient severity requiring ICU management and with at least one of the two following major criteria of severity present for less than 18 hours: Requiring invasive mechanical ventilation for respiratory failure due to pneumonia, or Requiring treatment with vasopressors (i.e., dopamine >5 mcg/kg/min or any dose of epinephrine, norepinephrine, phenylephrine or vasopressin) for at least 2 hours to maintain or attempt to maintain systolic blood pressure (SBP) >90 mm Hg (or mean arterial pressure [MAP] >70 mm Hg) after adequate fluid resuscitation (i.e. for shock). NOTE: Patients that are for 18 hours or more under high flow nasal cannula (HFNC) at ≥50 liters per minute and FiO2 ≥0.6 or under non-mechanical ventilation (NMV) are not eligible for the study Female subject of no childbearing potential i.e. non-fertile, pre-menarche, permanently sterile (i.e. underwent hysterectomy, bilateral salpingectomy or bilateral ovariectomy) or post-menopausal (history of no menses for at least 12 months without an alternative medical cause) or Woman of childbearing potential* with a negative serum or urine pregnancy test (sensitive to 25 IU human chorionic gonadotropin [hCG]) and agree to use an adequate method of contraception for three months after the last dose of the IMP according to her preferred and usual life style. Adequate methods of female contraception for this study are: sexual abstinence (refraining from heterosexual intercourse), hormonal contraception (both progesterone-only or combined oestrogen and progesterone; both with inhibition of ovulation or where inhibition of ovulation is not the primary mechanism of action), intra-uterine device, bilateral tubal occlusion, condom use by male sexual partner(s) or medically-assessed successfully vasectomized male sexual partner(s). *A woman of childbearing potential is a woman between menarche and post-menopause (history of no menses for at least 12 months without an alternative medical cause) unless she has undergone hysterectomy, bilateral salpingectomy or bilateral ovariectomy Male subject agreeing to use one of the following methods of birth control according to his preferred and usual life style for three months after the last dose of the IMP: sexual abstinence (refraining from heterosexual intercourse), use of condoms or medically-assessed successful vasectomy , or having a female sexual partner(s) who is using an adequate method of contraception as described above. Signed informed consent provided by the participant, the relatives or the designated legal representative according to local guidelines. Exclusion criteria A patient will not be included in the study if he/she meets ANY of the following criteria: Subjects with Hospital acquired (HAP)-, Health Care acquired (HCAP)- or Ventilator associated-pneumonia (VAP). Subjects with pneumonia exclusively of viral or fungal origin*. Subjects with bacterial pneumonia co-infected with viruses and/or other microorganisms may be entered into the study. *Due to the short time window (up to 18 hours) between fulfillment of severity criteria (i.e. initiation of invasive mechanical ventilation or vasopressors administration, whichever comes first) and the start of the first dose of study treatment, patients with a pneumonia of suspected bacterial origin by any established standard diagnostic method routinely applied at the study site (e.g. urinary antigen test, rt-PCR) can be entered into the study (confirmation of bacterial origin must be obtained afterwards). Subjects with known or suspected Pneumocystis jirovecii (formerly known as Pneumocystis carinii) pneumonia. Subjects with an aspiration pneumonia. Subjects with known active tuberculosis. Subjects with a history of post-obstructive pneumonia. Subjects with cystic fibrosis. Subjects with any chronic lung disease requiring oxygen therapy at home. Presence of infection in another organ location caused by same pathogen (e.g. pneumococcal meningitis in the context of pneumococcal pneumonia). Subjects expected to have rapidly fatal disease within 72 hours after randomisation. Inability to maintain a mean arterial pressure ≥50 mmHg prior to screening despite the presence of vasopressors and intravenous fluids. Subjects not expected to survive for 3 months due to other pre-existing medical conditions such as end-stage neoplasm or other diseases. Subjects with a history of malignancy in the 5 years prior to screening, except for successfully surgically treated non-melanoma skin malignancies. Subjects with known primary immunodeficiency disorder or with HIV infection and acquired immune deficiency syndrome (AIDS) with CD4 count <200 cells/mm^3 or not receiving highly active antiretroviral therapy (HAART) for HIV. Subjects receiving immunosuppressant therapy (including chronic treatment with anti-tumour necrosis factor alpha (TNFα ) or on chronic high doses of steroids (single administration of ≥2 mg/kg body weight or 20 mg/day of prednisone or equivalent for ≥2 weeks). Chronic granulocytopenia, not thought to be due to sepsis, as evidenced by an absolute neutrophil count <500 per µL>21 days prior to onset of pneumonia symptoms. Subjects who received stem cell therapy, or allogenic transplantation (organ or bone marrow transplant) within the past 6 months. Subjects receiving treatment with a biological agent (e.g. antibodies, cells), immunotherapy or plasma exchange treatment within the last 8 weeks. Subjects currently receiving, or having received another investigational medication within 90 days prior to start of the study (or 5 half-lives of the investigational compound, whichever is longer). Known allergies or hypersensitivity to Penicillin or Streptomycin and/or any component of CryoStor® CS10. Subjects with a known liver function impairment associated with liver cirrhosis (Child Pugh C) or known oesophageal varices. Subjects hospitalised within the previous 15 days. Conditions resulting in a New York Heart Association or Canadian Cardiovascular Society Class IV functional status. End-stage neuromuscular disorders (e.g. motor neuron diseases, myasthenia gravis, etc.) or cerebral disorders that impair weaning. Patients with quadriplegia (traumatic or otherwise).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cx611<br>Subjects treated in an intensive care unit for sCABP, but that may be screened at the emergency department, will receive SoC therapy according to local guidelines plus two intravenous central line infusions of Cx611 at a fixed dose of 160 million expanded allogeneic adipose-derived stem cells (eASCs) each. | Biological: Cx611<br>* Two intravenous infusions, one on day 1 and another one on day 3.<br>|
| Placebo Comparator: Placebo<br>Subjects treated in an intensive care unit for sCABP, but that may be screened at the emergency department, will receive SoC therapy according to local guidelines plus two intravenous central line infusions of Ringer Lactate. | Other: Placebo<br>* Two intravenous infusions, one on day 1 and another one on day 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) |  | Baseline up to Day 90 | 
| Number of Participants With Adverse Events of Special Interest (AESI) | AESIs are predefined adverse events (AEs) that required close monitoring and prompt reporting to the sponsor. Protocol-specific AEs considered as AESI for this study are thromboembolic events and hypersensitivity reactions such as anaphylaxis. | Baseline up to Day 90 | 
| Number of Participants With Hypersensitivity Reactions | Hypersensitivity reactions included anaphylaxis (changes in systolic and diastolic blood pressure, core temperature, respiratory rate [non-ventilated participants], heart rate), episodes of skin reactions and signs and symptoms of respiratory distress, which require therapeutic intervention including drugs and/or changes in mechanical ventilation setting. Number of participants with hypersensitivity reactions were reported for this outcome measure. | Baseline up to Day 90 | 
| Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 1 |  | Day 1 | 
| Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 3 |  | Day 3 | 
| Number of Participants With Markedly Abnormal Laboratory Values |  | Baseline up to Day 90 | 
| Number of Participants With Anti-human Leukocyte Antigen Complex (Anti-HLA)/Donor Antibodies At Day 1, 14, and 90 |  | At Days 1, 14, and 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mechanical Ventilation and Vasopressors Treatment-free Days | Participants with sCABP suffer either a respiratory failure that requires invasive mechanical ventilation and/or a severe hypotension that requires vasopressors. Number of days when participants were alive and free from mechanical ventilation and vasopressors were reported. | Baseline up to Day 28 | 
| Percentage of Participants Alive and Free of Both Mechanical Ventilation and Vasopressors at Day 29 | Participants with sCABP suffer either a respiratory failure that requires invasive mechanical ventilation and/or a severe hypotension that requires vasopressors. Percentage of participants who were alive and free of both mechanical ventilation and vasopressors at Day 29 were reported. | Day 29 | 
| Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 |  | Day 29 | 
| Number of Ventilator Free Days (VeFD) | VeFD are defined as one point for each day during the measurement period that participants are both alive and free from mechanical ventilation. | Baseline up to Day 28 | 
| Percentage of Participants Alive and Free of Vasopressors at Day 29 |  | Day 29 | 
| Number of Vasopressor Treatment-free Days (VaFD) | VaFD over 28 days defined as one point for each day during the measurement period that participants are both alive and free of vasopressors. | Baseline up to Day 28 | 
| Time to End of Invasive Mechanical Ventilation | Time in days, from the start date of invasive mechanical ventilation to the first stop date of invasive mechanical ventilation (that is, first time the participant ends mechanical ventilation), or death. Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 29 | 
| Time to End of Invasive and/or Non-invasive Mechanical Ventilation | Time in days, from the start date of invasive or non-invasive mechanical ventilation to the first stop date of invasive or non-invasive mechanical ventilation (that is, first time the participant ends mechanical ventilation), or death. Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 29 | 
| Time to End of Vasopressors Treatment | Time in days, from the start date of vasopressors treatment to the first stop date of vasopressors treatment (that is, first time the participant ends vasopressors treatment), or death. Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 29 | 
| Number of Participants With sCABP Clinical Response Visit at Days 8-10, 14, and 29 | Cure:complete pneumonia resolution at baseline(BL),no new pneumonia symptoms/complications attributable.Non-response:failure related/unrelated to pneumonia:persistence/progression of BL signs/symptoms of pneumonia;BL radiographic abnormalities after atleast 2 days of treatment;development of new pulmonary/extra pulmonary findings consistent with active infection/development of new pulmonary infection/extrapulmonary infection requiring antimicrobial therapy;persistence/progression of BL signs/symptoms of severe sepsis;development of new signs/symptoms of severe sepsis;death due to sepsis.Non-response-failure unrelated to pneumonia:any cause of clinical response failure that in investigator's judgement is unrelated to index pneumonia(e.g.myocardial infarction, pulmonary thromboembolism, sepsis of urinary origin etc).Indeterminate:extenuating circumstances precluding classification to one of the above. | Days 8 to 10, 14, and 29 | 
| Time to sCABP Clinical Cure | Cure is defined as complete resolution of pneumonia signs and symptoms present at baseline, no new symptoms or complications attributable to the pneumonia. Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 29 | 
| Duration of Antibiotic Treatment |  | Baseline up to Day 29 | 
| Percentage of Participants With Pneumonia Recurrence or Reinfection After Clinical Cure | Pneumonia recurrence is defined as a new acute clinical episode of pneumonia, after clinical cure of the episode that qualified the participant for the study, based on the presence of two relevant signs (fever, tachypnoea, leukocytosis, or hypoxemia) and radiographic findings of new pulmonary infiltrate/s or clinically significant worsening of previous ones. If a bacterial pathogen isolated in the recurrent episode is phenotypically different from the one isolated in the previous episode this will be considered as reinfection. | Days 14, 29, and 90 | 
| Time to Recurrence or Reinfection of Pneumonia After Clinical Cure at sCABP Clinical Response Assessments | Pneumonia recurrence is defined as a new acute clinical episode of pneumonia, after clinical cure of the episode that qualified the participant for the study, based on the presence of two relevant signs (fever, tachypnoea, leukocytosis, or hypoxemia) and radiographic findings of new pulmonary infiltrates or clinically significant worsening of previous ones. If a bacterial pathogen isolated in the recurrent episode is phenotypically different from the one isolated in the previous episode this will be considered as reinfection. Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 90 | 
| 28-day All-cause Mortality |  | Day 28 | 
| 28-day sCABP-associated Mortality |  | Day 28 | 
| Survival at Baseline, Days 10, 20, 30, 40, 50, 60, 70, 80, and 90 | Survival data for percentage of participants at Baseline and at Days 10, 20, 30, 40, 50, 60, 70, 80, and 90 was assessed and reported. | At Baseline, Days 10, 20, 30, 40, 50, 60, 70, 80, and 90 | 
| Time to Death | Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 90 | 
| Time to Discharge From Intensive Care Unit (ICU) | Time to discharge from ICU was defined, in days, as the time between informed consent date and the date of discharge from the ICU. Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 730 | 
| Time to Discharge From Hospital | Time to discharge from hospital was defined, in days, as the time between informed consent date and the date of discharge from the hospital. Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported. | Baseline up to Day 730 | 
| Length of Stay (LOS) in ICU and Hospital After Randomization |  | Baseline up to Day 730 | 
| Number of ICU-free Days | ICU-free days will be defined as the number of days during which the participant was not in ICU, starting from the randomization date, to Day 29, or day of discontinuation. | Baseline up to Day 29 | 
| Change From Baseline in Sepsis-related Organ Failure Assessment (SOFA) Score During Stay at ICU | The total SOFA Score is a composite of six sub scores representing the degree of dysfunction of six organ systems: Respiratory, Cardiovascular, Liver, Renal, Coagulation and Central Nervous System. Each organ system sub score ranges from 0 to 4 points. The total SOFA Score is the sum of the six-organ system sub scores. Accordingly, the total SOFA Score may range from a minimum score of 0 to a maximum score of 24. Higher scores indicate greater degree of dysfunction. | Baseline up to Day 29 | 
| Number of Participants Categorized Based on the Chest X-ray Assessments Compared to Previous Chest X-ray Assessment | Number of participants with chest X-ray assessment compared to the previous assessment were assessed and reported. Number of participants which showed improvement, remission, stabilization, and worsening compared to previous CXR were reported. Cumulative data is reported only for participants who were assessed from Day 8-10. | Days 1, 2, 3, 4, 5, 6, 7, 8-10, 14, and 29 | 
| Change in the Ratio of the Partial Pressure of Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio) |  | Baseline up to Day 7 | 
| Number of Participants Requiring Mechanical Ventilation or Non-invasive Ventilation Twelve Hours After the Second Investigational Medicinal Product (IMP) Infusion |  | Day 3: 0 to 12 hours post-IMP infusion | 
| Number Participants Using Rescue Antibiotics | Any new intravenous antibiotic for CABP indication that was started after Day 1 and before Day 29 was considered a rescue antibiotic. | Baseline up to Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biologic Therapy