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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 84
- 试验地点
- 65
- 主要终点
- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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® CS
- •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).
结局指标
主要结局
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
时间窗: Baseline up to Day 90
Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 3
时间窗: Day 3
Number of Participants With Adverse Events of Special Interest (AESI)
时间窗: Baseline up to Day 90
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.
Number of Participants With Hypersensitivity Reactions
时间窗: Baseline up to Day 90
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.
Number of Participants With Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters on Day 1
时间窗: Day 1
Number of Participants With Markedly Abnormal Laboratory Values
时间窗: Baseline up to Day 90
Number of Participants With Anti-human Leukocyte Antigen Complex (Anti-HLA)/Donor Antibodies At Day 1, 14, and 90
时间窗: At Days 1, 14, and 90
次要结局
- 28-day sCABP-associated Mortality(Day 28)
- Mechanical Ventilation and Vasopressors Treatment-free Days(Baseline up to Day 28)
- Percentage of Participants Alive and Free of Both Mechanical Ventilation and Vasopressors at Day 29(Day 29)
- Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29(Day 29)
- Duration of Antibiotic Treatment(Baseline up to Day 29)
- 28-day All-cause Mortality(Day 28)
- Number of Ventilator Free Days (VeFD)(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)(Baseline up to Day 28)
- Time to Recurrence or Reinfection of Pneumonia After Clinical Cure at sCABP Clinical Response Assessments(Baseline up to Day 90)
- Time to Death(Baseline up to Day 90)
- Time to End of Invasive Mechanical Ventilation(Baseline up to Day 29)
- Time to End of Vasopressors Treatment(Baseline up to Day 29)
- Number of Participants With sCABP Clinical Response Visit at Days 8-10, 14, and 29(Days 8 to 10, 14, and 29)
- Time to sCABP Clinical Cure(Baseline up to Day 29)
- Time to End of Invasive and/or Non-invasive Mechanical Ventilation(Baseline up to Day 29)
- Percentage of Participants With Pneumonia Recurrence or Reinfection After Clinical Cure(Days 14, 29, and 90)
- Survival at Baseline, Days 10, 20, 30, 40, 50, 60, 70, 80, and 90(At Baseline, Days 10, 20, 30, 40, 50, 60, 70, 80, and 90)
- Time to Discharge From Intensive Care Unit (ICU)(Baseline up to Day 730)
- Time to Discharge From Hospital(Baseline up to Day 730)
- Number Participants Using Rescue Antibiotics(Baseline up to Day 29)
- Length of Stay (LOS) in ICU and Hospital After Randomization(Baseline up to Day 730)
- Number of ICU-free Days(Baseline up to Day 29)
- Change From Baseline in Sepsis-related Organ Failure Assessment (SOFA) Score During Stay at ICU(Baseline up to Day 29)
- Number of Participants Categorized Based on the Chest X-ray Assessments Compared to Previous Chest X-ray Assessment(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)