| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe community-acquired bacterial pneumonia requiring mechanical ventilation and/or vasopressors. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Severe bacterial pneumonia acquired in the community which makes the patient require assistance in breathing and/or medication that raises the blood pressure. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051739 |
| E.1.2 | Term | Pulmonary sepsis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Investigate the safety profile of two allogeneic Cx611 80 mL infusions administered through a central line Cx611 central line within 3 days (on days 1 and 3) at a dose of 160 million cells each (320 million cells total). To monitor any adverse event and potential immunological host responses against the administered cells during 90 days of follow-up after the first infusion. |
|
| E.2.2 | Secondary objectives of the trial |
1. 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 CABP, and other efficay-related endpoints
2. Understand the mode-of-action of Cx611 in patients with sCABP by identifying the pro-inflammatory and anti- inflammatory pathways through which Cx611 may affect the underlying processes of sepsis.
3. Follow-up safety (only SAEs) at months 6 and 12 after the first IMP dose administration (Day 1).
Exploratory objective:
Safety data collection at months 18 and 24.
The study will contribute to the basic knowledge on mesenchymal 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. The results will be critical for the design of further confirmatory clinical trials in terms of definition of endpoints, key biomarkers and sample size determination. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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, tachypnea, 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:
a) Requiring invasive mechanical ventilation for respiratory failure due to pneumonia or
b) Requiring treatment with vasopressors (i.e., dopamine >5 µg/mg/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
menarchic,
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 investigational medicinal product 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 progestron
only
or combined oestrogen and progestron; 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 vasectomised
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 investigational medicinal product: sexual
abstinence (refraining from heterosexual intercourse), use of condoms
or medically-assessed successfull 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 subject, the relatives or the designated legal representative according to local guidelines.
|
|
| E.4 | Principal exclusion criteria |
1. Subjects with Hospital acquired (HAP)-, Health Care Associated (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 fulfilment of severity criteria (i.e. initiation of invasive mechanical ventilation or vasopressors, whichever comes first) and the start of the first dose of study treatment, patients with a pneumonia of suspected bacterial origin 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 dementia 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/mm3 or not receiving highly active antiretroviral therapy (HAART)for HIV.
15. Subjects receiving immunosuppressant therapy (including chronic treatment with any anti-tumour necrosis factor alpha (TNFa) or on chronic high doses of steroids (single administration of ≥2 mg/kg body weight for ≥2 weeks or 20 mg/day of prednisone or equivalent for ≥2 weeks).
16. Chronic granulocytopenia, not thought to be due to sepsis, as evidenced by leukocyte 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 hypersensivity to Penicillin or Streptomycin and/or any component of CryoStor (please refer to section 9.1.2)
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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Safety Endpoints by Day 90
Safety measured throughout the study by the incidence of treatment emergent adverse events (TEAEs) judged related or not to study treatment. Safety analyses will be performed based on the Safety Population.
An independent Data Monitoring Committee (DMC) will review safety data on a regular basis and ad hoc if needed. This DMC will be composed by a Chairman, expert in stem cells and former Chair of the Safety Committee of the completed CELLULA phase I trial, at least two Intensivists and an Independent Statistician. Membership, roles, responsibilities and operating procedures for the DMC will be specified in a separate independent DMC charter.
Subjects will be continuously monitored during and after treatment for:
· Frequency, duration, severity, seriousness, relatedness to study treatment, actions taken and outcome of adverse events (AEs), from time of signature of informed consent until visit 11 (Day 90) or study discontinuation. AEs will start being recorded after signing the informed consent. AEs occurring from the beginning of the administration of study medication and until visit 11 (Day 90) or study discontinuation will be analysed as treatment-emergent AEs
(TEAEs).
· Adverse events of special interest (see Sections 5.10 and 11.1.6 and also refer to the Investigators’ Brochure (1)).
· Signs for hypersensitivity reactions such as anaphylaxis (changes in systolic and diastolic blood pressure, core temperature [tympanic, rectal or bladder], respiratory rate [nonventilated patients], heart rate), at Days 1 and 3 (at Pre-dose and at 0.5h (±5 min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24 h (±1 h) post each IMP infusion.
Episodes of skin reactions and respiratory distress requiring therapeutic intervention and their description during the first 24 hours after the infusion of IMP.
· Changes in vital signs (daily: systolic and diastolic blood pressure, heart rate, core temperature [tympanic, rectal or bladder], respiratory rate [in non-ventilated patients]) as follows:
Screening, Day 1 (at Pre-dose, and at 0.5h (±5 min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24 h (±1 h) post each IMP infusion), Day 2 (at least 4 times), Day 3 (at Predose, and at 0.5h (±5 min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24 h (±1 h) post each IMP infusion), then at least 4 times daily while in the ICU or, if discharged from ICU at least once on Days 4, 5, 6, 7, 8-10, 14, 29, 90 or study discontinuation.
· Changes in 12-lead electrocardiogram (ECG) from Screening, Day 1 and Day 3 both 5 hours ± 1h post-study treatment administration.
· Changes in haematology and coagulation, clinical chemistry (at least including renal, liver, cholesterol and triglycerides profiles), and urine analysis at Screening, Day 1 Pre-dose, and then at least on Days 2, 3 (only haematology and coagulation), 4, 7, 14, 29, 90, 180 and 365 or study discontinuation.
· Anti-human leukocyte antigen complex (HLA)/donor antibodies (Abs) on Day 1 Pre-dose, Day 14 and Day 90 or study discontinuation.
Secondary Safety Endpoints from Day 90 to Day 365
· Anti-human leukocyte antigen complex (HLA)/donor antibodies (Abs) on Day 180, Day 365 or study discontinuation.
· Frequency, duration, severity, relatedness to study treatment, actions taken and outcome of treatment emergent serious adverse events (TESAEs), from Day 90 to Day 180 and to Day 365 or study discontinuation.
Exploratory Safety Endpoints by Months 18 and 24 (phone calls)
· Frequency, duration, severity, relatedness to study treatment, actions taken and outcome of spontaneous serious adverse events (SAEs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints
1. Mechanical ventilator and vasopressors treatment-free days (number of days that a patient is alive and free from mechanical ventilation and vasopressors) over 28 days.
2. Percentage of patients alive and free of mechanical ventilation and free of vasopressors at Day 29.
3. Percentage of patients alive and free of mechanical ventilation at Day 29.
4. Ventilator free days (VFD) over 28 days. VFD are defined as one point for each day during the measurement period that are both alive and free of mechanical ventilation.
5. Percentage of patients alive and free of vasopressors at Day 29.
6. Vasopressors-free days over 28 days defined as one point for each day during the measurement period that subjects are both alive and free of vasopressors.
7. Time to end of invasive mechanical ventilation.
8. Time to end of invasive and/or non-invasive mechanical ventilation.
9. Time to end of vasopressors treatment.
sCABP Clinical Response visit at Day 14±2 assessed as follows:
o Cure: complete resolution of pneumonia signs and symptoms present at baseline, no new symptoms or complications attributable to the pneumonia.
o Non Response: any of the following:
Failure related to pneumonia: persistence/progression of baseline signs/symptoms of pneumonia; or baseline radiographic abnormalities after
at least 2 days of treatment; or development of new pulmonary/extra
pulmonary findings consistent with active infection, or development of new
pulmonary infection or extrapulmonary infection requiring antimicrobial
therapy; or persistence/progression of baseline signs/symptoms of severe
sepsis; or development of new signs/symptoms of severe sepsis; or death
due to sepsis.
Failure unrelated to pneumonia: any other cause of clinical response failure
than in the investigator’s judgement is unrelated to the index pneumonia
(myocardial infarction, pulmonary thromboembolism, sepsis of urinary
origin, etc.).
o Indeterminate: extenuating circumstances precluding classification to one of the above.
· Clinical response visits at Day 8-10 and Day 29 or early discontinuation.
· Time to clinical sCABP cure.
· Duration of antibiotic treatment.
· Rate of pneumonia recurrence/reinfection after clinical cure. Pneumonia recurrence is defined as a new acute clinical episode of pneumonia, after clinical cure of the episode which qualified the patient for the study, based on the presence of two relevant signs (fever,tachypnea, 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 to recurrence/reinfection of pneumonia after clinical cure at sCABP clinical response assessments.
Survival
· 28-day all-cause mortality.
· 28-day sCABP-associated mortality.
· Survival at Day 7, 14, 29, and 90 visits.
· Time to death.
Other efficacy endpoints
· Time to discharge from ICU.
· Time to discharge from hospital.
· Length of stay in ICU and hospital after randomisation.
· Number of ICU-free days over 28 days.
· Changes in Sepsis-related Organ Failure Assessment score daily during stay at ICU.
· Changes on chest X-ray assessed at Screening, and then as medically required with at least one CXR per sCABP clinical response assessment until clinical cure from Day 1 to Day 29 and for pneumonia recurrence/reinfection assessment.
· Evolution of PaO2/FiO2 daily until Day 7.
· Need of mechanical ventilation or need of non-invasive ventilation 12 hours after the second IMP infusion.
· Use of rescue antibiotics i.e. addition or change of antibiotic treatments due to the occurrence of antibiotic resistance posterior to microbiology results at baseline or insufficient efficacy during the course of the study.
Secondary Biological Endpoints
· T cell responses on Day 1 Pre-dose and Days 7, 14 and 29 or early discontinuation:
o Cell proliferative capacity in the presence and absence of stimulation
o Cell activation status (phenotype pro/anti-inflammatory monocytes, pro/antiinflammatory T cells, HLADR, CD69)
o Secretion assay of peripheral blood mononuclear cells in response to
stimulation
· Evaluation of RNA expression profiles of blood leukocytes Screening, Day 1 Post-dose, Day 2, Day 3 Post-dose and Days 7 and 14 or early discontinuation.
· Evolution of plasma concentrations of biomarkers* on Screening, Day 1 Post-dose, Day 2, Day 3 Post-dose, and Days 7 and 14 or early discontinuation.
*Protein biomarkers: TNF-α, IL-1β, IL-6, IL-8, IL-10, soluble triggering
receptor expressed on myeloid cells 1, C-reactive protein, procalcitonin, pro-adrenomedullin, D-dimer, plasminogen activator inhibitor-1, protein C, sE selectin, angiopoietin-1, angiopoietin-2, International Normalised Ratio, thrombin-antithrombin complexes, copeptin, B-type natriuretic peptide |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Assess safety in patients with sepsis (already provided to human vols and RA patients) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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