Clinical trial NCT03158727: Cx611-0204 SEPCELL Study
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Bacterial Pneumonia
Keywords: Biologic Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: European Commission
name: Centre Hospital Regional Universitaire de Limoges
name: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Hospital San Carlos, Madrid
First posted: 2017-05-18
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
timeFrame: Baseline up to Day 90
measure: Number of Participants With Adverse Events of Special Interest (AESI)
timeFrame: Baseline up to Day 90
measure: Number of Participants With Hypersensitivity Reactions
timeFrame: Baseline up to Day 90
measure: Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 1
timeFrame: Day 1
measure: Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 3
timeFrame: Day 3
measure: Number of Participants With Markedly Abnormal Laboratory Values
timeFrame: Baseline up to Day 90
measure: Number of Participants With Anti-human Leukocyte Antigen Complex (Anti-HLA)/Donor Antibodies At Day 1, 14, and 90
timeFrame: At Days 1, 14, and 90
Secondary outcomes:
measure: Mechanical Ventilation and Vasopressors Treatment-free Days
timeFrame: Baseline up to Day 28
measure: Percentage of Participants Alive and Free of Both Mechanical Ventilation and Vasopressors at Day 29
timeFrame: Day 29
measure: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29
timeFrame: Day 29
measure: Number of Ventilator Free Days (VeFD)
timeFrame: Baseline up to Day 28
measure: Percentage of Participants Alive and Free of Vasopressors at Day 29
timeFrame: Day 29
measure: Number of Vasopressor Treatment-free Days (VaFD)
timeFrame: Baseline up to Day 28
measure: Time to End of Invasive Mechanical Ventilation
timeFrame: Baseline up to Day 29
measure: Time to End of Invasive and/or Non-invasive Mechanical Ventilation
timeFrame: Baseline up to Day 29
measure: Time to End of Vasopressors Treatment
timeFrame: Baseline up to Day 29
measure: Number of Participants With sCABP Clinical Response Visit at Days 8-10, 14, and 29
timeFrame: Days 8 to 10, 14, and 29
measure: Time to sCABP Clinical Cure
timeFrame: Baseline up to Day 29
measure: Duration of Antibiotic Treatment
timeFrame: Baseline up to Day 29
measure: Percentage of Participants With Pneumonia Recurrence or Reinfection After Clinical Cure
timeFrame: Days 14, 29, and 90
measure: Time to Recurrence or Reinfection of Pneumonia After Clinical Cure at sCABP Clinical Response Assessments
timeFrame: Baseline up to Day 90
measure: 28-day All-cause Mortality
timeFrame: Day 28
measure: 28-day sCABP-associated Mortality
timeFrame: Day 28
measure: Survival at Baseline, Days 10, 20, 30, 40, 50, 60, 70, 80, and 90
timeFrame: At Baseline, Days 10, 20, 30, 40, 50, 60, 70, 80, and 90
measure: Time to Death
timeFrame: Baseline up to Day 90
measure: Time to Discharge From Intensive Care Unit (ICU)
timeFrame: Baseline up to Day 730
measure: Time to Discharge From Hospital
timeFrame: Baseline up to Day 730
measure: Length of Stay (LOS) in ICU and Hospital After Randomization
timeFrame: Baseline up to Day 730
measure: Number of ICU-free Days
timeFrame: Baseline up to Day 29
measure: Change From Baseline in Sepsis-related Organ Failure Assessment (SOFA) Score During Stay at ICU
timeFrame: Baseline up to Day 29
measure: Number of Participants Categorized Based on the Chest X-ray Assessments Compared to Previous Chest X-ray Assessment
timeFrame: Days 1, 2, 3, 4, 5, 6, 7, 8-10, 14, and 29
measure: Change in the Ratio of the Partial Pressure of Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio)
timeFrame: Baseline up to Day 7
measure: Number of Participants Requiring Mechanical Ventilation or Non-invasive Ventilation Twelve Hours After the Second Investigational Medicinal Product (IMP) Infusion
timeFrame: Day 3: 0 to 12 hours post-IMP infusion
measure: Number Participants Using Rescue Antibiotics
timeFrame: Baseline up to Day 29
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Clinique Universitaire Saint-Luc
state: Bruxelles
city: Brussels
country: Belgium
facility: UZ Brussel
city: Liège
country: Belgium
facility: CHU Sart Tilman
city: Ottignies
country: Belgium
facility: Clinique Saint-Pierre
city: Angoulême
country: France
facility: Centre Hospitalier d'Angoulême
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupouy
city: Clermont-Ferrand
country: France
facility: Centre Hospitalier Universitaire de Clermont Ferrand
city: Dijon
country: France
facility: CHU Bocage
city: Lille
country: France
facility: Centre Hospitalier Regional Universitaire de Lille
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges - CHU Dupuytren
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Orléans
country: France
facility: Centre Hospitalier Regional d'Orleans
city: Roche sur Yon Cedex 9
country: France
facility: Centre Hospitalier Departemental les Ouidairies
city: Roche Sur Yon
country: France
facility: Centre Hospitalier Départemental les Oudairies
city: Strasbourg
country: France
facility: CHRU de Strasbourg
city: Tours
country: France
facility: CHU TOURS - Hôpital Bretonneau
city: Roma
country: Italy
facility: Azienda Ospedaliera San'Andrea. UOC Anestesia e Terapia Intensiva
city: Klaipeda
country: Lithuania
facility: Klaipėda Republican Hospital, The Pulmonology and Allergology Department
city: Trondheim
country: Norway
facility: St. Olavs Hospital, Department of Intensive care Clinical Immunology and Infectious Disease
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari Bellvitge
state: Barcelona
city: Terrassa
country: Spain
facility: Hospital Mútua de Terrassa
state: Barcelona
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic I Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Santander
country: Spain
facility: Hospital Marqués de Valdecilla
city: Tarragona
country: Spain
facility: Hospital Universitari de Tarragona Joan XXIII
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Laterre PF, Sanchez-Garcia M, van der Poll T, de la Rosa O, Cadogan KA, Lombardo E, Francois B. A phase Ib/IIa, randomised, double-blind, multicentre trial to assess the safety and efficacy of expanded Cx611 allogeneic adipose-derived stem cells (eASCs) for the treatment of patients with community-acquired bacterial pneumonia admitted to the intensive care unit. BMC Pulm Med. 2020 Nov 25;20(1):309. doi: 10.1186/s12890-020-01324-2.