Cx611-0204 SEPCELL Study

Tigenix S.A.U.84 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Bacterial Pneumonia

Interventions

Cx611BIOLOGICAL

Two intravenous infusions, one on day 1 and another one on day 3.

PlaceboOTHER

Two intravenous infusions, one on day 1 and another one on day 3.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion criteria 1. Adult subjects of either gender (aged ≥18 years and ≤80 years old.) 2. Body weight between 50 kg and 100 kg. 3. 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. 4. 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: 1. Requiring invasive mechanical ventilation for respiratory failure due to pneumonia, or 2. 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 5. 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. 6. 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: 1. Subjects with Hospital acquired (HAP)-, Health Care acquired (HCAP)- or Ventilator associated-pneumonia (VAP). 2. 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). 3. Subjects with known or suspected Pneumocystis jirovecii (formerly known as Pneumocystis carinii) pneumonia. 4. Subjects with an aspiration pneumonia. 5. Subjects with known active tuberculosis. 6. Subjects with a history of post-obstructive pneumonia. 7. Subjects with cystic fibrosis. 8. Subjects with any chronic lung disease requiring oxygen therapy at home. 9. Presence of infection in another organ location caused by same pathogen (e.g. pneumococcal meningitis in the context of pneumococcal pneumonia). 10. Subjects expected to have rapidly fatal disease within 72 hours after randomisation. 11. Inability to maintain a mean arterial pressure ≥50 mmHg prior to screening despite the presence of vasopressors and intravenous fluids. 12. Subjects not expected to survive for 3 months due to other pre-existing medical conditions such as end-stage neoplasm or other diseases. 13. Subjects with a history of malignancy in the 5 years prior to screening, except for successfully surgically treated non-melanoma skin malignancies. 14. 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. 15. 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). 16. 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. 17. Subjects who received stem cell therapy, or allogenic transplantation (organ or bone marrow transplant) within the past 6 months. 18. Subjects receiving treatment with a biological agent (e.g. antibodies, cells), immunotherapy or plasma exchange treatment within the last 8 weeks. 19. 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). 20. Known allergies or hypersensitivity to Penicillin or Streptomycin and/or any component of CryoStor® CS10. 21. Subjects with a known liver function impairment associated with liver cirrhosis (Child Pugh C) or known oesophageal varices. 22. Subjects hospitalised within the previous 15 days. 23. Conditions resulting in a New York Heart Association or Canadian Cardiovascular Society Class IV functional status. 24. End-stage neuromuscular disorders (e.g. motor neuron diseases, myasthenia gravis, etc.) or cerebral disorders that impair weaning. 25. Patients with quadriplegia (traumatic or otherwise).

Locations (33)

Outcomes

Primary Outcomes

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)

Time frame: 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.

Time frame: 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.

Time frame: Baseline up to Day 90

Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 1

Time frame: Day 1

Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 3

Time frame: Day 3

Number of Participants With Markedly Abnormal Laboratory Values

Time frame: Baseline up to Day 90

Number of Participants With Anti-human Leukocyte Antigen Complex (Anti-HLA)/Donor Antibodies At Day 1, 14, and 90

Time frame: At Days 1, 14, and 90

Secondary Outcomes

Data from ClinicalTrials.gov

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Clinique Universitaire Saint-Luc

Brussels, Brussels Capital, Belgium

UZ Brussel

Brussels, Belgium

CHU Sart Tilman

Liège, Belgium

Clinique Saint-Pierre

Ottignies, Belgium

Centre Hospitalier d'Angoulême

Angoulême, France

Centre Hospitalier Victor Dupouy

Argenteuil, France

Centre Hospitalier Universitaire de Clermont Ferrand

Clermont-Ferrand, France

CHU Bocage

Dijon, France

Centre Hospitalier Departemental les Ouidairies

La Roche-sur-Yon, France

Centre Hospitalier Départemental les Oudairies

La Roche-sur-Yon, France

...and 23 more locations

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.

Time frame: 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.

Time frame: Day 29

Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29

Time frame: 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.

Time frame: Baseline up to Day 28

Percentage of Participants Alive and Free of Vasopressors at Day 29

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline up to Day 29

Duration of Antibiotic Treatment

Time frame: 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.

Time frame: 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.

Time frame: Baseline up to Day 90

28-day All-cause Mortality

Time frame: Day 28

28-day sCABP-associated Mortality

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline up to Day 730

Length of Stay (LOS) in ICU and Hospital After Randomization

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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

Time frame: 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.

Time frame: Baseline up to Day 29