Cx611-0204 SEPCELL Study

Bacterial Pneumonia Clinical Trial

— SEPCELL  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03158727
• Other study ID #: Cx611-0204
• Secondary ID: 2015-002994-39
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 30, 2017
• Est. completion date: July 7, 2020

Study information

• Verified date: February 2022
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 84
• Est. completion date: July 7, 2020
• Est. primary completion date: July 7, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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 (TNFa ) 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).

Related Conditions & MeSH terms

• Bacterial Pneumonia
• Pneumonia
• Pneumonia, Bacterial

Intervention

Biological:
• Cx611
Two intravenous infusions, one on day 1 and another one on day 3.

Other:
• Placebo
Two intravenous infusions, one on day 1 and another one on day 3.

Locations

Country	Name	City	State
Belgium	Clinique Universitaire Saint-Luc	Brussels	Bruxelles
Belgium	UZ Brussel	Brussels
Belgium	CHU Sart Tilman	Liège
Belgium	Clinique Saint-Pierre	Ottignies
France	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 Regional Universitaire de Lille	Lille
France	Centre Hospitalier Universitaire de Limoges - CHU Dupuytren	Limoges
France	Centre Hospitalier Universitaire de Nantes	Nantes
France	Centre Hospitalier Regional d'Orleans	Orléans
France	Centre Hospitalier Départemental les Oudairies	Roche Sur Yon
France	Centre Hospitalier Departemental les Ouidairies	Roche sur Yon Cedex 9
France	CHRU de Strasbourg	Strasbourg
France	CHU TOURS - Hôpital Bretonneau	Tours
Italy	Azienda Ospedaliera San'Andrea. UOC Anestesia e Terapia Intensiva	Roma
Lithuania	Klaipeda Republican Hospital, The Pulmonology and Allergology Department	Klaipeda
Norway	St. Olavs Hospital, Department of Intensive care Clinical Immunology and Infectious Disease	Trondheim
Spain	Hospital Clínic I Provincial de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario de Getafe	Getafe	Madrid
Spain	Hospital Universitari Bellvitge	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitari Arnau de Vilanova de Lleida	Lleida
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Marqués de Valdecilla	Santander
Spain	Hospital Universitari de Tarragona Joan XXIII	Tarragona
Spain	Hospital Mútua de Terrassa	Terrassa	Barcelona
Spain	Hospital Virgen de la Salud	Toledo
Spain	Hospital Universitario y Politécnico La Fe	Valencia

Sponsors (6)

Lead Sponsor	Collaborator
Tigenix S.A.U.	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Centre Hospital Regional Universitaire de Limoges, Cliniques universitaires Saint-Luc- Université Catholique de Louvain, European Commission, Hospital San Carlos, Madrid

Countries where clinical trial is conducted

Belgium,  France,  Italy,  Lithuania,  Norway,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)		Baseline up to Day 90
Primary	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
Primary	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
Primary	Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 1		Day 1
Primary	Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 3		Day 3
Primary	Number of Participants With Markedly Abnormal Laboratory Values		Baseline up to Day 90
Primary	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	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
Secondary	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
Secondary	Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29		Day 29
Secondary	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
Secondary	Percentage of Participants Alive and Free of Vasopressors at Day 29		Day 29
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Duration of Antibiotic Treatment		Baseline up to Day 29
Secondary	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
Secondary	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
Secondary	28-day All-cause Mortality		Day 28
Secondary	28-day sCABP-associated Mortality		Day 28
Secondary	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
Secondary	Time to Death	Median survival time and the associated 95% confidence interval based on Kaplan-Meier estimation are reported.	Baseline up to Day 90
Secondary	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
Secondary	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
Secondary	Length of Stay (LOS) in ICU and Hospital After Randomization		Baseline up to Day 730
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in the Ratio of the Partial Pressure of Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio)		Baseline up to Day 7
Secondary	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
Secondary	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