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
Phase: PHASE1
Conditions: Bacterial Pneumonia
Sponsor: Tigenix S.A.U.




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
NCT Number: NCT03158727
Protocol Approve Date: 19 December 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.
A protocol clarification letter for the final protocol, dated 19-December-2019, explaining the discrepancies within the 
protocol is appended to the back of the protocol.

CLINICAL STUDY PROTOCOL
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
SEPCELL Study
Study Code: 
Cx611-0204
EudraCT Number: 
2015-002994-39
Version: 
Final, Version 7 incorporating Amendment 5
Date:
19 December 2019
Coordinating Investigators: 
Overall Study Coordinator: 
Clinical Project Coordinators:
Coordinator Host Biomarkers: 
Sponsor:
TIGENIX, S.A.U. 
A Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited
C/ Marconi, 1
Parque Tecnológico de Madrid
28760, Tres Cantos, Madrid
Please Note: TIGENIX S.A.U., is a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, and may be referred to in this protocol 
as ‘TiGenix,’ ‘sponsor,’ or ‘Takeda.’
Sponsor Signatory: 
Property of Takeda: For Non-Com
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
EudraCT No.: 2015-002994-39
Page 2 of 130
PROTOCOL AMENDMENT 05 SUMMARY OF CHANGES
Rationale for Amendment 05
This document describes the changes to the protocol incorporating Amendment 05. The 
primary reason for this amendment is the early closure of enrolment. This decision was the 
result of persistent enrolment challenges throughout the study and the high risk of not meeting 
study enrolment goals in a sufficient period of time. Of note, TiGenix has not observed any 
new safety concerns related to Cx611 in this study.
Changes in Amendment 05
1. Study enrolment will be closed early, at which time the projected enrolment will be
approximately 85 subjects.
a.
The number of study centres across Europe was updated to reflect the revised
enrolment, and a statement was added regarding distribution of subjects across sites.
2. The secondary objective of identifying pro-inflammatory and anti-inflammatory pathways
through which Cx611 may affect the underlying processes of sepsis was made into an
exploratory objective. Data analysis with the reduced number of subjects will not be
powered to detect a statistical difference but may provide useful information on trends.
3. Unblinding of the study will occur after the Day 90 data have been collected and analysed
for all subjects (including the primary safety and secondary efficacy variables). The
Day 180 (Visit 12) and Day 365 (Visit 13) visits will be replaced with follow-up safety
phone calls for reporting of serious adverse events (SAEs), similar to the Month 18 and
Month 24 safety phone calls. No additional efficacy data will be collected beyond Day 90
(Visit 11).
a.
Removal of the secondary objective: Follow-up safety (only SAEs) at Months 6 and
12 after the first investigational medicinal product (IMP) dose administration (Day 1).
b. Removal of the secondary safety endpoints from Day 180 and Day 365, including
collection of anti-human leukocyte antigen complex/donor antibodies, treatment
emergent SAEs, and changes in haematology and coagulation, clinical chemistry, and
urine analysis.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 3 of 130
•
Removal of blood volume estimates for Day 180 (Visit 12) and Day 365 
(Visit 13). 
•
Removal of Day 180 and Day 365 planned analyses for collected samples (e.g.
shift tables for each assessed laboratory parameter).
c.
End of Study redefined to the date of the subject’s last scheduled visit (Day 90 
±4 days) or early withdrawal from study prior to Day 90 ±4 days.
d. Premature discontinuation redefined to patients who withdraw from the study before 
Day 90. These subjects will complete the Early Termination (ET) visit assessments. 
4. All safety and efficacy data will be summarized using descriptive statistics only, without 
any statistical inference or sensitivity analyses based on different patient populations. Due 
to the early closure of enrolment, the total number of enrolled subjects will be too low to 
detect any safety and efficacy signals; therefore any statistical inference including 95% 
confidence intervals and p-values may be misleading, and any sensitivity analyses based 
on different patient populations will be unnecessary. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only. Updates 
to the Schedule of Study Assessments and the Study Design have been implemented to reflect 
the changes outlined above.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 4 of 130
1
SYNOPSIS
Name of the Sponsor/Company:
TiGenix S.A.U
Study Code:
Cx611-0204
Name of Investigational Product:
Cx611 (eASCs)
EudraCT No.:
2015-002994-39
Development Phase of the Study: Ib/IIa
Trial under an IND: Not applicable
TITLE OF THE STUDY:
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 a severe community-acquired bacterial pneumonia and 
admitted to the intensive care unit. SEPCELL study.
OBJECTIVES:
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). 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.
Exploratory objectives:
The completion of this 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 study results will be informative for the 
potential design of further confirmatory clinical trials in terms of definition of endpoints, key 
biomarkers and sample size determination. 
OVERALL STUDY DESIGN:
Phase Ib/IIa, randomised, double blind, parallel groups, placebo controlled, and multicentre trial.
Subjects treated in an intensive care unit (ICU) for sCABP, but that may be screened at the 
emergency department, will receive SoC therapy according to local guidelines plus two 80 mL 
intravenous (IV) central line infusions (on Days 1 and 3) at 240 mL/h of Cx611 at a fixed dose of 
160 million cells per infusion (total 320 million cells), or placebo. The administration of the first 
infusion of Cx611 or placebo will be performed as early as possible in the ICU within the first 18 
hours of patients fulfilling at least one of the two major criteria of severity for community-acquired 
pneumonia (CAP) (i.e. from the initiation of invasive mechanical ventilation or vasopressors, 
whichever comes first), after patient’s eligibility is confirmed. The calendar day of administration 
of the first dose of Cx611 will be considered Day 1 of the study. From Day 1 onwards study days 
will be considered as calendar days.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 5 of 130
This study will enrol approximately 85 male and female subjects, who will be treated with Cx611 
or placebo in a 1:1 ratio. Each subject will receive two 80 ml IV central line infusions (active or 
placebo) in 20-30 minutes on Day 1 and Day 3 respectively according to a pre-defined 
randomisation list.
The Screening duration will be about 18 hours, treatment duration will be three days and the total 
study duration per subject will be two years. There will be a total of 12 visits per subject: Screening 
visit and on Days 1, 2, 3, 4, 5, 6, 7, 8-10, 14, 29 and 90. Four safety follow-up phone calls will be 
made to the patient, or otherwise to the patient’s General Practitioner (GP) or family doctor, at 
Months 6 (Day 180), 12 (Day 365), 18 (Day 545) and 24 (Day 730) to collect spontaneous report of 
health status, and eventually to investigate any SAE with the GP.
The double blind design will be maintained by a specific blinding of study treatments, which
will be described in the study operations manual and site blinding plan to ensure an unbiased
safety and efficacy evaluation. The double blind design will be maintained until the primary safety 
and secondary efficacy endpoints have been assessed (i.e. at Day 90). The study participants 
(Sponsor, investigators and site team members) will be unblinded after all Day 90 data have been 
collected.
The study will permit concomitant SoC treatment of the sCABP including antibiotic and standard
therapy in the ICU, in an add-on design.
Stratification will be considered based on CABP severity criteria at inclusion:
- shock requiring vasopressors, or 
- respiratory failure requiring invasive mechanical ventilation, or 
- both.
In each stratum, patients will be randomised 1:1 to Cx611 or placebo.
INVESTIGATIONAL PRODUCT:
Cx611, two 80 mL Ringer lactate dilutions of adult eASCs at one fixed dose of 160 million cells each 
(total 320 million cells per patient) and excipient, provided at 240 mL/h via IV central line on Days 1 
and 3 or placebo as two 80 mL IV central lines infusions of excipient and Ringer lactate solution alone 
(on Days 1 and 3).
Subjects will also receive SoC therapy as per local guidelines, with IV and/or oral antibiotics or other 
drugs, either alone or in combination. Details for dose and frequency of administration of SoC therapy 
(as well as warnings, precautions, and contraindications) can be found in the referenced summaries of 
product characteristics for the specific drugs selected by the investigator as SoC. Investigators will be 
instructed to select only country-approved therapies.
NUMBER OF PATIENTS:
This study will enrol approximately 85 subjects in total. 
NUMBER OF STUDY CENTRES:
The study will be conducted in approximately 20 centres across Belgium, France, Lithuania, and 
Spain.
DISEASE UNDER STUDY
sCABP requiring mechanical ventilation and/or vasopressors.
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 start of administration of 
the first dose of study treatment, patients with a sCABP, either suspected and/or later confirmed of 
bacterial origin by any established standard diagnostic method routinely applied at the study site 
(please refer to section 7.2.2.1), can be entered into the study.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 6 of 130
PATHOGEN IDENTIFICATION AND SUSCEPTIBILITY TESTING
For the confirmation of the causative pathogen of the bacterial pneumonia, pulmonary, pleural, blood 
and urine samples will be collected and analysed by any established standard diagnostic method 
routinely applied at the study site including classical microbiology and/or any other methods.
Pulmonary samples can be obtained by bronchoalveolar lavage (BAL) and/or mini-BAL/protected 
specimen brush (PSB) and/or by endotracheal aspiration (ETA) for intubated patients, and sputum 
production for non-ventilated patients. Samples will be rapidly proccessed for Gram stain and culture 
and/or other established standard rapid diagnostic system, e.g. peptide nucleic acid fluorescent in situ 
hybridization (PNA FISH) or Cepheid GeneXpert for S. aureus, urinary antigen test for S. pneumoniae 
or Legionella, or real-time polymerase chain reaction (rt-PCR). Should a bacterial pathogen grow in 
culture, susceptibility testing against the standard local antibiotic panel for the pathogen will be 
performed according to the site´s practice. Pathogen identification and susceptibility testing will be 
collected from follow-up pulmonary/blood/respiratory/pleural cultures performed as per investigator´s 
decision as well. Pathogen identification and susceptibility testing will also be performed in case of 
clinical suspicion of pneumonia recurrence.
INCLUSION AND EXCLUSION CRITERIA
The reference population will consist of adult patients with a sCABP, admitted to the ICU.
A patient will be included in the study if he/she meets ALL the following 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: 
a) Requiring invasive mechanical ventilation for respiratory failure due to pneumonia, or
b) Requiring treatment with vasopressors (i.e., dopamine >5 µg/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 
litres 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 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 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 7 of 130
product: 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 subject, 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 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 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 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 (TNFα) 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 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.
 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms o
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 8 of 130
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).
ENDPOINTS:
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, focussing on any adverse event of special 
interests (AESIs). 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 of 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 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 [non-
ventilated 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 24h (±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 24h [±1 h] post each IMP infusion), Day 2 (at least 4 times), Day 3 (at Pre-
dose, and at 0.5h [±5 min], 1h [±10 min], 2h [±10 min], 4h [±20 min], 12h [±30 min] and 24h 
[±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, Days 1 and 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, and 90 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.
Exploratory Safety Endpoints by Months 6 (Day 180), 12 (Day 365), 18 (Day 545) and 24
(Day 730) (phone calls)
!
Relatedness to study treatment, actions taken and outcome of spontaneous SAEs will be 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Term
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 9 of 130
captured after Day 90.
Secondary Efficacy Clinical Endpoints
Efficacy analyses will be performed based on the Modified Intention-to-treat (mITT), Intention-to-
treat (ITT), Clinically Evaluable (CE), Microbiological ITT (micro-ITT) and Microbiologically 
Evaluable (ME) populations.
Efficacy endpoints
1.
Mechanical ventilator and vasopressor 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 subjects are both alive and free of mechanical ventilation (e.g., 
a patient who is extubated on Day 2 of the study and remains alive and free of the ventilator 
for the remainder of the 28-day study period would receive a VFD score of 26, whereas the 
patient who is ventilated until death on Day 2 would receive a score of zero).
5.
Percentage of patients alive and free of vasopressors at Day 29.
6.
Vasopressor treatment-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
!
!
Clinical response visits at Day 8-10 and Day 29 or early discontinuation.
!
Time to sCABP clinical 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 that
qualified the patient 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.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 10 of 130
!
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 Days 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 (LOS) in ICU and hospital after randomisation.
!
Number of ICU-free days over 28 days.
!
Changes in Sepsis-related Organ Failure Assessment (SOFA) score daily during stay at ICU.
!
Changes on chest X-ray (CXR) assessed at Screening, and then as medically required with 
at least one CXR per sCABP clinical response assessment until clinical cure from Days 1 to 
29 and for pneumonia recurrence/reinfection assessment.
!
Evolution of partial pressure of oxygen /fraction inspire oxygen (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.
Property of 
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 11 of 130
STATISTICAL METHODS: 
In general, data will be summarised by means of summary statistics. Continuous data will be 
presented with the number of observations, mean value, standard deviation, minimum, median and 
maximum value. Categorical data will be presented as counts and percentages. Individual patient 
data will be listed.
Safety analyses
All safety analyses will be only descriptive. 
Adverse events (AEs) will be collected throughout the study duration. All AEs (recorded after the 
signature of the informed consent) and TEAEs (those recorded from the beginning of study 
medication administration) will be tabulated. The number and percentage of subjects in each 
treatment group reporting at least 1 occurrence of an AE/TEAE for each unique System Organ 
Class (SOC) and Preferred Term (PT) will be tabulated. TEAEs will also be tabulated by severity 
and by the relationship to study medication in treatment groups as assessed by the Investigator. The 
number and percentage of subjects in each treatment group reporting at least 1 occurrence of a SAE 
for each unique SOC and PT will be tabulated. SAEs will also be tabulated by severity and by 
relationship to study medication in treatment groups as assessed by the Investigator. The number 
and percentage of subjects (in each treatment group) prematurely discontinuing study treatment due 
to a TEAE will be tabulated by SOC and PT. Safety laboratory data will be presented by absolute 
and changes from baseline values by visit. Shift tables for each assessed laboratory parameter will 
be presented to summarise the change from Low, Normal, High values at baseline to ‘on treatment’ 
visit (Day 2) and post-treatment visits (Days 4, 7, 14, 29 and 90). The number and percentage of 
subjects with laboratory, vital signs, ECG, or physical examination abnormalities at baseline, 
subsequent visits, or ET from the study will be tabulated by treatment group. The results of all 
laboratory test results, physical examination findings, ECGs, and vital signs will be presented in 
data listings. All abnormalities will be assessed for being clinically significant or not as per 
investigator.
Efficacy analyses
Efficacy and biomarker analyses will be descriptive summaries in the safety population at the 
scheduled visits. 
The change from baseline in SOFA scores and all other secondary efficacy and biological 
variables will be summarised using descriptive statistics.
All data, including derived values that are computed for use in summaries or analyses, will be
listed.
Baseline values will be defined as the last value obtained prior to first dosing and the value
used in the baseline summary will also be used as the baseline value for purposes of computing
change from baseline.
Data might be treated or transformed, as appropriate (e.g. log- transformed or ranked). Details 
of any transformed data will be specified on the Statistical Analysis Plan (SAP).
Summary tables will indicate the number of patients with complete data for each measurement,
event, or outcome. In general, no imputation of missing data will be made, and any exception on 
efficacy data would be detailed on the SAP. 
The following subgroup analyses will be performed but not limited to: severity score, bacterial 
load, initial adequate or inadequate antibiotic treatment, concomitant treatment, sCABP clinical 
response (cure or non-response i.e. failure) or indeterminate, antimicrobial resistance profile, 
previous vaccination, and presence or not of bacteraemia. A thorough review will be performed 
when data for the primary endpoint are available and before database lock and unblinding, by a 
blinded Adjudication Committee (AC) of experts to assess subject evaluability and agree on 
sCABP clinical response assessment and patient assignment process e.g. validation based on the 
dose, the bacterial susceptibility profile to administered antibiotics and duration of antibiotics, 
molecular identification data, etc. Membership, roles and responsibilities and operating procedures 
for the AC as well as the subject evaluability criteria to be followed will be specified in a separate 
AC charter.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 12 of 130
Data set to be analysed
The following analysis set will be defined:
•
Safety: Includes all randomised patients who have received at least one dose of the study 
treatment irrespective of randomisation. The safety population will be the primary population for 
all the safety and efficacy analyses.
ANTICIPATED STUDY PERIOD:
October 2015:
Ethics Committee (EC) / Health Authorities Cx611-0204 submission
December 2015: First Approval EC/Health Authorities
January 2017:
First Patient In
December 2019: Last Patient In
March 2020:
Last Patient Out (3 months follow-up)
June 2020:
Database Lock Day 90 (3 months follow-up)
September 2020: Clinical Study Report Day 90 (3 months follow-up)
December 2021:  Last Patient Out (2 years follow-up)
October 2022:
Clinical Study Report Addendum (2 years follow-up)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
EudraCT No.: 2015-002994-39
Confidential
Page 13 of 130
Table 1. Schedule of Study Assessments
VISITS
Screening
Visit 1
(V1)
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Early
Termination 
(ET)
Safety12 phone calls
Study days (allowed
deviation days in
brackets)
Day 1 (D1)
D2
D3
D4
D5
D6
D7
D8-D10 D14 (±2)
D29 (±2)
D90 (±4)
D180 (±30) D365 (±30) D545 (±30) D730 (±30)
Informed consent
X
Inclusion and exclusion
criteria
X*
X*
Medical history
X
Physical
examination
X
X*
X
X*
X
X
X
X
X
X
X
X
X
Vital signs1
X
X1
X
X1
X
X
X
X
X
X
X
X
X
Urine and Serum 
pregnancy tests
X6
Pa02/Fi02
X
X*
X
X*
X
X
X
X
X***
CURB-65
X
APACHE II 
X
X*
SOFA score2
X
X*
X
X
X
X
X***
ECG
X
X**
X**
Chest X-ray
X
As per investigator’s decision, at least 1 chest X-ray per sCABP clinical response assessment until clinical cure and for 
pneumonia recurrence/reinfections assessment
Randomisation
X
Study Treatment
administration
X7
X
Signs of 
hypersensitivity 
reactions 
X8
X8
sCABP clinical 
response assessments
X
X
X
X***
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
EudraCT No.: 2015-002994-39
Confidential
Page 14 of 130
VISITS
Screening
Visit 1
(V1)
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Early
Termination 
(ET)
Safety12 phone calls
Study days (allowed
deviation days in
brackets)
Day 1 (D1)
D2
D3
D4
D5
D6
D7
D8-D10 D14 (±2)
D29 (±2)
D90 (±4)
D180 (±30) D365 (±30) D545 (±30) D730 (±30)
Pneumonia recurrence / 
reinfection
X
X
X
X
Pathogen identification 
and susceptibility 
testing 
X9
As per investigator’s decision from D1 to D299. Pathogen identification and susceptibility 
testing will be collected from follow-up pulmonary/blood/respiratory/pleural cultures 
performed as per investigator´s decision as well.
X***
Pneumococcal 
urine antigen
X
Haematological & 
Coagulation / 
Biochemical tests / 
Urinalysis
X
X*
X
X* (only 
haematol. 
& coag.)
X
X
X
X
X
X
Proximal Lower Limb 
Compression 
Ultrasonography.
X11
X11
Adverse events
←-------------------------throughout the study (starting from the signature of the informed consent)---------------→
X
Only SAEs
Prior/Concomitant
treatments****
X
←-----------------------------------throughout the study-----------------------------------------→
X
* Pre-study treatment administration ** 5 hours ± 1h post-study treatment administration *** If applicable **** Fluids excluded
+ 
++ Only anti-HLA/Donor Abs +++ If ET is after V11 (Day 90) only anti-HLA/Donor Abs +++ + Only if ET is before V9 (Day 14)
1.
Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, rectal or bladder), respiratory rate (in non-ventilated patients) will be measured 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 24h [±1 h] post IMP dose), Day 2 (at least 4 times i.e. every 6h±1h), Day 3 (at Pre-dose, and at 0.5h [±5 min], 1h [±10 
min], 2h [±10 min], 4h [±20 min], 12h [±30 min] and 24h [±1 h] post IMP dose), Days 4, 5, 6, 7, 8-10, 14, 29, 90 or study discontinuation. If in the ICU at least 4 times daily i.e. every 6h±1h, if discharged 
Property o
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al Use Only and Subject to the Applicable Terms of Use
Genix S.A
Genix S.
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No.:
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
EudraCT No.: 2015-002994-39
Confidential
Page 15 of 130
from ICU at least once. When more than one measurement is available for screening, Day 2 and Day 4 onwards only the highest and the lowest value measured for each vital sign for that time period will be 
recorded in the CRF for that timepoint.
2.
Full SOFA: Cardio-vascular, Respiration, Coagulation, Liver, CNS and Renal.
3.
 
4.
5.
6.
A rapid diagnosis using urine pregnancy test may be performed for inclusion, awaiting the serum pregnancy test for confirmation.
7.
Start of first infusion of IMP must be within the first 18h of patients fulfilling at least one of the two major criteria of severity for CABP (i.e. initiation of ventilation support or vasopressors, whichever comes 
first). 
8.
Signs of hypersensitivity reactions or anaphylaxis: vital signs (systolic and diastolic blood pressure, heart rate, core temperature and respiratory rate in non-ventilated patients) will be assessed at 0.5h (±5 
min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24h (±1 h) after the start of the infusion, in addition the patient will be monitored for skin reactions and episodes of respiratory distress 
requiring therapeutic intervention during the first 24 hours after the infusion.
9.
Pathogen identification and susceptibility testing: During Screening (if possible within a timeframe that allows to keep the 18 hour window between fulfilment of the severity criteria for the pneumonia and 
start of treatment with Cx611) and as medically required afterwards (at least one further pulmonary sample). For the confirmation of the causative pathogen of the bacterial pneumonia, pulmonary, pleural, 
blood and urine samples will be collected and analysed by any established standard diagnostic method routinely applied at the study site including classical microbiology and/or any other methods (please refer 
to Section 7.2.2.1). Pathogen identification and susceptibility testing will be collected from follow-up pulmonary/blood/respiratory/pleural cultures performed as per investigator´s decision as well. Pathogen 
identification and susceptibility testing will also be performed in case of clinical suspicion of pneumonia recurrence.
10. At 8-12 hours post-administration.
11. Can be performed on Day 5 or Day 6.
12. Long-term safety follow-up: four follow-up phone calls will be made to the patient, at Months 6 (Day 180), 12 (Day 365), 18 (Day 545) and 24 (Day 730), by the investigational staff to investigate 
any spontaneous report on his/her health status. Up to three phone call attempts will be done and if not successful, a contact will be established with the patient’s GP. The investigator will report any
SAE and will liaise with the patient’s GP for obtaining further documentation on the investigation of the SAE.
Abs=antibodies, APACHE=Acute Physiology and Chronic Health Evaluation, CABP=Community-acquired bacterial pneumonia, CNS=central nervous system, coag=coagulation, CRF=case report form, 
 CURB-65=Confusion, elevated blood urea nitrogen level, respiratory rate, and blood pressure plus age ≥65 years score, D=Day, eASCs=Adipose-derived Stem Cells, 
ECG=Electrocardiogram, 
, ET= Early Termination, FiO2=Fraction of inspired Oxygen, GP=general practitioner, haematol=haematology, 
 
h= hour, ICU=Intensive care unit, 
, IMP=investigational medicinal product, Min= minute; 
 PaO2=Partial pressure of Oxygen, 
 
 
sCABP=severe community-acquired bacterial pneumonia, SAE=serious adverse event, SOFA=Sequential Organ Failure Assessment, 
 
, V=Visit
Property of Takeda:
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Genix S.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
EudraCT No.: 2015-002994-39
Page 16 of 130
2
TABLE OF CONTENTS
Section
Page
PROTOCOL AMENDMENT 05 SUMMARY OF CHANGES......................................................2
1
SYNOPSIS ..............................................................................................................................4
2
TABLE OF CONTENTS......................................................................................................16
3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................................19
3.1
List of Abbreviations...................................................................................................19
3.2
Definition of Terms .....................................................................................................20
4
STUDY ADMINISTRATIVE STRUCTURE ......................................................................21
5
INTRODUCTION.................................................................................................................23
5.1
Background: Severe Community-acquired Bacterial Pneumonia.............................23
5.2
Current Treatment of sCABP and Sepsis...................................................................25
5.3
Cell Therapies Based on Adult Stem Cells .................................................................26
5.4
Advantages and Potential Risks of Expanded Adipose-derived Stem Cells 
(eASCs)........................................................................................................................27
5.5
Mechanism of Action of eASCs: Immunomodulatory properties..............................28
5.6
Safety of Cx611............................................................................................................29
5.7
Efficacy of Cx611 in Animal Sepsis Models ...............................................................31
5.8
Phase I Results With Cx611 in Healthy Volunteers ...................................................31
5.9
Rationale......................................................................................................................33
5.10
Risk Assessment ..........................................................................................................35
6
STUDY OBJECTIVES.........................................................................................................37
6.1
Primary Objective.......................................................................................................37
6.2
Secondary Objective ...................................................................................................37
6.3
Exploratory Objectives ...............................................................................................37
7
INVESTIGATIONAL PLAN ...............................................................................................38
7.1
Overall Study Design ..................................................................................................38
7.2
Study Procedures ........................................................................................................40
7.2.1
Schedule of Study Assessments...................................................................40
7.2.2
Study Flow Chart ......................................................................................41
7.3
Discussion of Study Design, Including the Choice of Control Groups.......................55
7.4
Study Period................................................................................................................55
7.5
End of Study................................................................................................................56
8
SELECTION OF STUDY POPULATION ..........................................................................57
8.1
Number of Subjects.....................................................................................................57
8.2
Screening Log..............................................................................................................57
8.3
Inclusion Criteria ........................................................................................................58
8.4
Exclusion Criteria .......................................................................................................59
8.5
Removal of Patients From Therapy or Assessment ...................................................61
8.6
Handling and Replacement of Withdrawals ..............................................................62
8.7
Premature Termination of the Study .........................................................................62
9
TREATMENT OF SUBJECTS............................................................................................64
9.1
Investigational Products..............................................................................................64
9.1.1
Treatment Regimens..................................................................................64
9.1.2
Identity of Investigational Product(s): Dosage Form, Dose and 
Administration Route.................................................................................64
9.1.3
Packaging and Labelling...........................................................................66
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 17 of 130
9.1.4
Storage and Disposition of Study Medication.............................................67
9.1.5
Handling of Study Medication ...................................................................67
9.2
Method of Assigning Patients to Treatment Groups..................................................67
9.3
Selection of Doses in the Study....................................................................................68
9.4
Blinding .......................................................................................................................69
9.5
Prior and Concomitant Therapy ................................................................................70
9.6
Prohibited Medications...............................................................................................70
9.7
Treatment Adherence .................................................................................................71
9.8
Drug Accountability....................................................................................................71
9.9
Treatment Compliance ...............................................................................................71
10
STUDY ASSESSMENTS......................................................................................................72
10.1
Safety, Efficacy and Additional Endpoints.................................................................72
10.1.1
Primary Safety Endpoints by Day 90..........................................................72
10.1.2
Exploratory Safety Endpoint by Months 6 (Day 180), 12 (Day 365), 18 
(Day 545) and 24 (Day 730) (Phone Calls)................................................73
10.1.3
Secondary Efficacy Clinical Endpoints ......................................................73
10.1.4
10.2
Demographic and Other Baseline Characteristics .....................................................75
10.2.1
Demographic Characteristics....................................................................75
10.2.2
Other Baseline Data..................................................................................76
10.2.3
Medical History, Prior and Concomitant Medications and Procedures ......76
10.3
Safety Assessments......................................................................................................77
10.3.1
Safety Variables ........................................................................................77
10.3.2
Adverse Events ..........................................................................................77
10.3.3
Physical Examination................................................................................77
10.3.4
Assessment of Clinical Signs and Symptoms of Pneumonia ........................77
10.3.5
Signs for Hypersensitivity Reactions or Anaphylaxis..................................78
10.3.6
Vital Signs.................................................................................................78
10.3.7
Electrocardiogram (ECG) .........................................................................79
10.3.8
Laboratory Safety Assessments..................................................................79
10.3.9
Anti-HLA/donor Antibodies .......................................................................81
10.4
Efficacy Assessments...................................................................................................81
10.4.1
Ventilator-free Days ..................................................................................81
10.4.2
sCABP Clinical Response..........................................................................82
10.4.3
APACHE II and SOFA Scores ...................................................................82
10.5
Immunological Assessments........................................................................................82
10.5.1
..........................................................................................83
10.5.2
...84
10.6
Total Blood Volume ....................................................................................................85
10.7
Appropriateness of Measurements .............................................................................85
11
ADVERSE EVENTS.............................................................................................................86
11.1
Definitions ...................................................................................................................86
11.1.1
Adverse Event (AE)....................................................................................86
11.1.2
Adverse Reaction (AR)...............................................................................87
11.1.3
Unexpected Adverse Reaction (uAR)..........................................................87
11.1.4
Serious Adverse Event (SAE) .....................................................................87
11.1.5
Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................89
11.1.6
Adverse Event of Special Interest (AESI)....................................................89
11.2
Adverse Event Severity Assessment ...........................................................................90
11.3
Adverse Event Relatedness Assessment (Causality Assessment)...............................90
11.4
Adverse Event Collection Period ................................................................................93
11.5
Adverse Event Reporting............................................................................................93
11.5.1
Recording of Adverse Events .....................................................................93
Property of Takeda: For Non-Commercial Use Only and Subject to t
pplicable Terms of Use
1
..71
71
........ 71
7
..........
.....
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..........
......
.........
.....
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ay 365
.........
.....
.........
.........
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.........
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11.1
CCI
CCI
CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 18 of 130
11.5.2
Immediately Reportable Events (IRE) ........................................................94
11.5.3
Immediately Reportable Event Reporting...................................................95
11.5.4
Pregnancy Reporting.................................................................................96
12
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ....................98
12.1
Statistical and Analytical Plans ..................................................................................98
12.1.1
Data Set to be Analysed.............................................................................98
12.1.2
Summary Statistics ....................................................................................98
12.1.3
Demographic and Other Baseline Characteristics .....................................98
12.1.4
Safety Analysis ..........................................................................................98
12.1.5
Efficacy and Biomarkers Analyses...........................................................100
12.2
Determination of Sample Size...................................................................................101
12.3
Interim Analysis ........................................................................................................101
13
INVESTIGATOR/SPONSOR RESPONSIBILITIES........................................................102
13.1
Ethics .........................................................................................................................102
13.1.1
Independent Ethics Committee (IEC).......................................................102
13.1.2
Ethical Conduct of the Study....................................................................102
13.1.3
Patient Information and Consent .............................................................103
13.2
Patient Records and Source Data .............................................................................105
13.3
Access to Source Data and Documentation ..............................................................106
13.4
Monitoring.................................................................................................................106
13.5
Sponsor’s Obligations ...............................................................................................107
13.6
Investigator's Obligations .........................................................................................108
13.7
Data Management.....................................................................................................108
13.8
Quality Assurance and Audit....................................................................................108
13.9
Traceability of the Study Product.............................................................................109
13.10 Record Retention.......................................................................................................110
13.11 Protocol Deviations ...................................................................................................110
13.12 Amendment of Protocol ............................................................................................111
13.13 Insurance...................................................................................................................112
13.14 Confidentiality...........................................................................................................112
13.15 Report and Publication.............................................................................................113
14
REFERENCE LIST............................................................................................................114
15
SIGNATURES ....................................................................................................................120
16
CLINICAL STUDY PROTOCOL AGREEMENT FORM...............................................121
17
APPENDICES.....................................................................................................................122
APPENDIX A
Corticosteroid Conversion Table .......................................................123
APPENDIX B
CURB-65 Score (Confusion, Elevated Blood Urea Nitrogen Level, 
Respiratory Rate, and Blood Pressure Plus Age ≥65 Years).....................124
APPENDIX C
APACHE II (Acute Physiology And Chronic Health Evaluation) 
Score.......................................................................................................125
APPENDIX D
SOFA Score ......................................................................................129
APPENDIX E
Conversion Table SO2 (%) to PaO2 (mmHg) and O2 (l/min) to FiO2
(%)..........................................................................................................130
LIST OF TABLES
Table 1. Schedule of study assessments.............................................................................................12
LIST OF FIGURES
Figure 1. Study design ......................................................................................................................41
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3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
3.1
List of Abbreviations
Abs
Antibodies
AC
AE
Adjudication committee
Adverse event
AESI
Adverse event of special interest
AIDS
Acquired immune deficiency syndrome
APACHE
APTT
Acute Physiology and Chronic Health Evaluation
Activated partial thromboplastin time
ATIMP
Advanced therapy investigational medicinal product
BAL
BL
Broncho Alveolar Lavage
Baseline
CA
Competent authority
CABP
Community-acquired bacterial pneumonia
CAP
Community-acquired pneumonia
CI
Confidence interval
CRF
Case report form
CRO
Contract research organization
CTA
Clinical Trials Authorisation
CURB
Confusion, elevated blood urea nitrogen level, respiratory rate, and blood pressure
(score)
CURB-65
Confusion, elevated blood urea nitrogen level, respiratory rate, and blood pressure
plus age ≥65 years score
CXR
Chest X-ray
DMC
Data Monitoring Committee
DMSO
Dimethyl sulfoxide
eASCs
Expanded Adipose-derived Stem Cells
EC
European commission
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EEA
European Economic Area
EOS
End Of Study
ETA
Endotracheal Aspiration
EU
European Union
FiO2 
Fraction of inspired Oxygen
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GP
General Practitioner
HAART
Highly active antiretroviral therapy
HAP
Hospital acquired pneumonia
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen complex
ICH
International Conference on Harmonization
ICU
Intensive care unit
IEC
Independent ethics committee
IFN
Interferon
IL
Interleukin
IMP
Investigational medicinal product
IMPD
Investigational medicinal product dossier
IRT
Interactive Response Technology
IV
Intravenous
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rogen lev
gen le
ea nitrog
ea nitro
mmittee
mitt
e
pose
ose-deri
d
ommissio
mmissi
rdiogram
diogra
onic case
nic cas
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CG
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HIV
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Clinical Study Protocol
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Study Code: Cx611-0204
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kg
Kilogram
LOS
Length of stay
LPS
Lipopolysaccharide
MAP
Mean Arterial Pressure
MedDRA
Medical Dictionary for Regulatory Activities
MIP-2
Macrophage inflammatory protein-2
PaO2
Partial pressure of Oxygen
PBMC
Peripheral blood mononuclear cells
PNA FISH
Peptide nucleic acid fluorescent in situ hybridization
PSB
Protected specimen brush
PT
RANTES
Preferred term; prothrombin time
Regulated on activation normal T cell expressed and secreted
RBC
REB
Red blood cell count
Regional Ethics Board
RNA
Ribonucleic acid
rt-PCR
Real-time polymerase chain reaction
SAE
SAP
Serious adverse event
Statistical Analysis Plan
SAS
Statistical analysis systems
SBP
Systolic blood pressure
SUSAR
Suspected unexpected serious adverse reaction
sCABP
Severe community-acquired bacterial pneumonia
SD
Standard deviation
SoC
Standard of Care
SOC
SOFA
System organ class
Sequential Organ Failure Assessment
SOM
Study Operations Manual
SOP
Standard operating procedure
TEAE
Treatment – emergent adverse events
TLR
Toll-like receptor
TNF
Tumour necrosis factor
VAP
Ventilator associated-pneumonia
VFD
Ventilator free days
WBC
White blood cell count
3.2
Definition of Terms
Competent Authority
A government body or government appointed body that has legal authority to 
approve or disapprove clinical studies
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ction
tion
neumoni
neumoni
Assessm
Assessm
nual
ual
procedur
proced
ergent ad
gent 
eceptor
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entilator 
Ventilat
Vent
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CCI
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4
STUDY ADMINISTRATIVE STRUCTURE
COORDINATING INVESTIGATORS
OVERALL STUDY COORDINATOR
Name:
Address: 
Phone:
Fax: 
E-mail:
CLINICAL PROJECT COORDINATORS
Name:
Address: 
Phone:
Fax: 
E-mail:
Name:
Address: 
Phone:
Fax: 
E-mail:
Name:
Address: 
Phone:
Fax: 
E-mail:
COORDINATOR HOST BIOMARKERS
Name:
Address: 
Phone:
Fax: 
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l:
OORD
OORD
Nam
Nam
A
 Use
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PPD
PPD

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E-mail:
NAME AND ADDRESS OF THE SPONSOR
Name:
TIGENIX, S.A.U.
Address:
C/ Marconi, 1. Parque Tecnológico de Madrid 28760, Tres Cantos, Madrid, 
Spain
Phone:
+34 91 804 92 64
Fax:
+34 91 804 92 63
SPONSOR’S STUDY RESPONSIBLE 
Name:
Address:
Phone : 
E-mail:
MEDICAL MONITOR
Name:
Address:
Phone:
Fax:
DRUG SAFETY OFFICER
Name:
Address:
Phone:
E-mail:
CONTRACT RESEARCH ORGANISATION (CRO)
Name:
Address:
Phone:
Fax:
ly
Terms of Use
PPD
PPD
PPD
PPD
PPD

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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5
INTRODUCTION
5.1
Background: Severe Community-acquired Bacterial Pneumonia
Community-acquired pneumonia (CAP) is the most common cause of death associated with 
infectious disease and the sixth most common cause of death in the United States (2,3). When 
CAP is caused by bacterial pathogens, it is named a community-acquired bacterial pneumonia 
(CABP). It has been defined by the Infectious Diseases Society of America as an acute 
infection of the pulmonary parenchyma that is associated with at least some symptoms of 
acute infection (i.e., chest pain, cough, sputum production, difficulty of breathing, chills, 
rigors, and fever), accompanied by the presence of a new infiltrate on a chest radiograph or 
auscultatory findings consistent with pneumonia, in a patient not hospitalised or residing in a 
long-term– care facility for ≥14 days before onset of symptoms (4). 
Around one third of cases with severe CABP (sCABP) are caused by Streptococcus 
pneumoniae. Other common pathogens are Haemophilus influenzae, Staphylococcus aureus
and Moraxella catarrhalis. Atypical cases are caused by Mycoplasma pneumoniae, 
Chlamydophila pneumonia and Legionella species (5). In about one third of subjects, the 
organism remains unidentified (6). 
CABP represents a public health problem of substantial magnitude, with an overall annual 
incidence ranging 1.6-10.6/1,000 adult population in Europe (7). This incidence increases 
with age, from 18.2 cases per 1,000 patient-years in patients aged 60 to 69 years up to 52.3 
cases per 1,000 patient-years in those older than 85 years (8). The number of cases requiring 
hospitalisation is around 267 per 100,000 people (9). More than fifty percent of hospitalised
patients with CABP develop severe sepsis during the course of the disease (10), and around 
10% are admitted to the intensive care unit (ICU) (2). The incidence of sCAP has increased in 
the last decade by 128%, from 12.8 admissions per ICU in 1996 to 29.2 admissions in 2004,
compared to a 24% rise in total ICU admissions (11).
A CABP leading to organ dysfunction (severe sepsis) is considered severe (sCABP). Patients 
with sCABP suffer either a respiratory failure that requires invasive mechanical ventilation 
and/or a severe hypotension that requires vasopressors. Approximately fifty percent of 
patients that initiate mechanical ventilation require vasopressors later on, and fifty percent of 
patients requiring vasopressors are intubated afterwards (12). The presence of at least three of 
other minor criteria (respiratory rate >30 breaths/min; arterial oxygen pressure/fraction of 
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inspired oxygen (PaO2/FiO2) ratio <250; multilobar infiltrates; confusion; blood urea 
nitrogen level >20 mg/dL; leukopenia; thrombocytopenia; hypothermia; or hypotension
requiring aggressive fluid resuscitation) may also suggest a severe CABP (4). To aid in 
deciding whether a given patient can be treated as an outpatient or should be admitted to the 
hospital, severity scores (such as the Pneumonia Severity Index [PSI]; the confusion, elevated 
blood urea nitrogen level, respiratory rate, and blood pressure [CURB] score; and the CURB 
plus age ≥65 years [CURB 65] score) have been described; these scores stratify patients with 
CABP into mortality risk groups (4,13).
Despite effective antibiotic therapy, the mortality rate remains unacceptably high.
Outpatients’ CABP has a mortality rate of <5% (14). However, when hospitalisation is 
required, the mortality of CABP reaches 12% and increases to 22% if the patient is admitted 
to the ICU (14). In patients requiring mechanical ventilation, mortality may be as high as 
25%, and increases up to 50% in patients also requiring vasopressor support (15,16). Among 
elderly (≥65 years) ICU patients with sCAP requiring mechanical ventilation, the mortality 
rate reaches 55% (17). 
Irrespective of severity of initial presentation, the development of sepsis-related complications 
(delayed septic shock, adult respiratory distress syndrome [ARDS], and extrapulmonary organ 
dysfunction) during ICU stay is associated with a significantly higher ICU mortality: 57–
100% (18). sCABP in patients admitted to the ICU has shown little improvement during the 
last 20 years, with an all-cause 28-day mortality rate up to 43% in subjects with a baseline 
Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥25 (19). Septic 
shock is associated with the highest mortality, approaching 50% (20). Despite advances in 
antibiotic treatment and ICU care, these high rates demonstrate the need for additional 
interventions, even in patients who receive adequate antimicrobial therapy (4,21). 
Severe sepsis is a life-threatening syndrome characterised by an infection-induced organ 
dysfunction and/or hypoperfusion abnormalities, caused by a dysregulated host response (22). 
Sepsis occurs when the response of the immune system to fight the infection triggers a 
systemic inflammation that damages multiple organ systems, causing them to fail. 
Inflammatory molecules, such as tissue factor (TF) (23), are pathologically expressed and 
released into the bloodstream, with consequent activation of coagulation and inflammatory 
processes. Septic shock is diagnosed when hypotension persists despite adequate fluid 
resuscitation or when perfusion abnormalities occur, which may lead to death. Although 
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severe sepsis may be associated to all types of infections (genitourinary, abdominal, skin and 
soft tissue, device-related, central nervous system or endocarditis), CABP is the most 
common source of infection (around 40% of cases) (24), and it is associated with the highest 
mortality (31-40%) (25). Several studies have shown increased pulmonary and circulating 
inflammatory cytokine levels in patients with sCABP (26,27). Among patients admitted to the 
ICU, higher circulating inflammatory cytokine levels correlated with the presence of bilateral 
pneumonia, bacteraemia, need for mechanical ventilation, and higher APACHE II and 
multiple organ dysfunction syndrome (MODS) scores (26,27). Taken as a whole, the findings 
of these studies indicate that degree and duration of the systemic inflammation have a strong 
effect on final outcome in patients with sCABP. In other words, in sCABP, deaths are not due 
to failure to eradicate the microorganism causing pneumonia, but are closely related to 
inadequate host response. Excessive cytokine response in patients with sCAP has been linked 
in many studies with deleterious effects and poor prognosis (18,28).
5.2
Current Treatment of sCABP and Sepsis
According to current guidelines, all patients with sCABP and severe sepsis or septic shock 
require close monitoring and must be admitted to the ICU (4,22). Drug therapy is complex, 
and includes broad-spectrum antibiotics, corticosteroids, inotropic agents, and vasopressors, 
as well as oxygen and volume resuscitation with large amounts of intravenous fluids. The 
antimicrobial therapy must start in the first hour and, after 6 hours, the patient must be re-
evaluated (4). A β-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either 
azithromycin or a fluoroquinolone is the most common antibiotic combination in ICU patients 
(4). If a combined pneumococcal and Pseudomonas
infection is suspected, an 
antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) 
plus either ciprofloxacin, levofloxacin, an aminoglycoside and azithromycin, or an 
aminoglycoside and an antipneumococcal fluoroquinolone are recommended. For 
community-acquired methicillin-resistant Staphylococcus aureus infection, vancomycin or 
linezolid are usually added (4). The treatment lasts for a minimum of 5 days, or until the 
patient is afebrile for 48-72 hours and does not have more than one CABP-associated sign of 
clinical instability (4).
The treatment of severe sepsis and septic shock has been recently reviewed (22). Overall, it is 
based on the following recommendations (summarised):
1. Initial resuscitation: goals during the first 6 hours of resuscitation:
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a) Central venous pressure 8–12 mm Hg
b) Mean arterial pressure (MAP) ≥65 mm Hg
c) Urine output ≥0.5 mL/kg/hr
d) In patients with elevated lactate levels (≥4 mmol/L) targeting resuscitation to 
normalise lactate.
2. Diagnosis
a) Cultures as clinically appropriate before antimicrobial therapy
b) Imaging studies to confirm a potential source of infection
3. Antimicrobial Therapy
a) Administration of effective intravenous antimicrobials within the first hour of 
septic shock and severe sepsis
b) Empiric anti-infective therapy active against likely pathogens 
c) Antimicrobial regimen reassessed daily for potential de-escalation
d) Use of biomarkers to assist in the discontinuation of empiric antibiotics 
e) Combination empirical therapy for neutropenic patients with severe sepsis and 
for patients with difficult-to-treat, multi drug resistant bacterial pathogens
Despite all these interventions, patients with sCABP and sepsis have a low survival rate, 
reflecting the limited effectiveness of current therapy (20). There is an unmet medical need, 
but the number of new drugs currently in development is small.
5.3
Cell Therapies Based on Adult Stem Cells
Stem cells are unspecialised cells capable of dividing and regenerating for long periods of 
time (29). Due to their unique properties, they are being investigated for treating many 
diseases. Until the discovery of adult stem cells, research was limited due to ethical concerns 
over the use of embryonic stem cells. Adult stem cells are found in various parts of the body, 
such as the brain, bone marrow, blood, skin, heart and adipose tissue, but not all of them can 
be easily cultured in vitro (30). 
Adult mesenchymal stem cells (MSCs) are a stem cell population that can be isolated, 
expanded in culture, and characterised in vitro and in vivo, according to the criteria of the 
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International Society for Cellular Therapy (29). In the recent years, adult MSCs have emerged 
as potent therapeutic tools based not only on their differentiation potential, but also on their 
capacity to modulate immune responses and their low immunogenicity. Compared with other 
cell types, MSCs have lower levels of Major Histocompatibility Complex (MHC) Class I 
antigens, and do not express MHC Class II or co-stimulatory molecules (CD40, CD80 or 
CD86) (29). Short persistence of allogeneic MSCs in vivo and little rejection by T cells allow 
their potential use as allogeneic treatment (31–34). They also express high levels of protectors 
of complement-associated lysis (CD55 and CD59), and show strong indoleamine 2,3-
dioxygenase (IDO) induction. This enzyme is one of the key regulators of tryptophan 
catabolism and may inhibit activated T cells proliferation and cause halted growth of 
microorganisms. In vitro, MSCs may differentiate into mesenchymal-type cells (trilineage 
differentiation into adipocytes, osteoblasts, and chondrocytes) (35). MSCs are negative for 
CD45, CD34, CD14, or CD11b, CD79a, or CD19 and HLA-DR, and positive for a variety of 
other markers, including CD73, CD90, and CD105 (29).
5.4
Advantages and Potential Risks of Expanded Adipose-derived Stem Cells (eASCs)
MSCs have been isolated from multiple tissues of mesodermal origin, such as bone marrow, 
adipose tissue, umbilical cord or placenta (30). Expanded adipose-derived stem cells (eASCs) 
can be obtained in a technically simple way from human lipoaspirates containing subdermal 
adipose tissue, and constitute an easily accessible and exceptionally abundant source of stem 
cells (36). Progenitor cells represent 2% of the total cells of the Stromal Vascular Fraction 
(SVF) of the fat tissue, whereas the equivalent cell type on bone marrow only represents 
0.002% of total cells. 
Although their immunosuppressive properties are the same as those described for bone 
marrow-derived MSCs, their ribonucleic acid (RNA) and protein expression profiles are 
different (37). eASCs lack the expression of ligands for natural killer (NK) activation
receptors. The eASCs display a lower susceptibility to NK cell-mediated lysis when 
compared with bone marrow-MSCs (38). Thus, eASCs may remain in the tissue long enough 
to balance the immune response before being cleared (38).
The potential benefit and relative lack of acute safety issues of MSCs administration has been 
suggested by a growing number of non-clinical and uncontrolled clinical studies in a large 
number of pathologies (39). Potential risks associated with the administration of eASCs may 
include ectopic tissue or tumour formation, unwanted local or systemic immune response and 
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transmission of adventitious agents (40,41). Moreover, the intravenous (IV) infusion of such 
cells may result in events of thromboembolism (40,42–44). These risks may be considered as 
adverse events of special interest (AESI) by investigators (please refer to the Investigators’ 
brochure (1)).
5.5
Mechanism of Action of eASCs: Immunomodulatory properties
Data from in vitro and animal studies suggest that the possible mechanisms of action of 
eASCs are multiple. They have immunomodulatory properties, with both local and systemic 
effects. At short term, they modulate the inflammation status, shifting from Th1 to Th2 
immune response. At long term, they may restore homeostasis through generation of immune 
cells with regulatory phenotype like regulatory T cells (Treg), regulatory B cells and M2 
macrophages (45–47).
In in vitro studies, eASCs inhibited peripheral blood mononuclear cells (PBMCs), and more 
concretely CD4 + and CD8 + T cell proliferation in a dose dependent manner (ratio 
1:25-1:200), both by cell contact-dependent mechanisms (48) and by releasing soluble factors 
(49), which was accompanied by a reduction of proinflammatory cytokines. Among the 
soluble factors, the following molecules have been described: hepatocyte growth factor 
(HGF), prostanglandin-E2 (PGE2), transforming growth factor (TGF)-β1, IDO, nitric oxide 
(NO), interleukin(IL)-10, hemeoxygenase-1 (HO-1) and HLA-G5 (45). Many of these factors 
are released into small membranous vesicles called exosomes. In vitro studies demonstrated 
that exosomes from eASCs display similar immunosuppressive effects than eASCs, inhibiting 
the differentiation and activation of T cells (50).
An antiproliferative effect was observed on activated PBMCs and in an allogeneic way (i.e. it 
does not need human leukocyte antigen complex [HLA] matching) (51,52). The generation of 
Tregs has been also observed in vitro (53–55), although it is unknown if they are created 
de novo or expanded from pre-existing Tregs (56). eASC activity in vivo can be modulated 
through toll-like receptors (TLRs) signalling (57). These receptors have been linked to 
rejection and inflammatory diseases (e.g. Crohn’s disease, rheumatoid arthritis or sepsis), 
because they may recognise pathogen components or self-antigens similar to pathogen-
derived components or tissue danger signals produced upon injury. However, activation of 
eASCs by TLR ligands in vitro has not been reported to interfere with their low 
immunogenicity. eASCs also promoted B-cell migration through the secretion of chemotactic 
factors (38). 
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Due to all these properties, eASCs are being investigated for the treatment of human 
autoimmune, acute and chronic inflammatory pathologies and healing disorders. In a study in 
patients with Crohn´s disease, they have already demonstrated efficacy in the repair and 
regeneration of damaged tissue (58). In the local treatment of inflammatory diseases with 
tissue damage and/or wounds, the eASCs establish an environment that accelerates healing
(59). In the systemic treatment of diseases with an acute inflammatory component (patients 
with acute myocardial infarction), the eASCs migrate to the inflammatory environment and 
suppress inflammation, avoiding tissue damage (60).
eASCs can be administered locally (Cx601, cell suspension, being investigated for the 
treatment of complex perianal fistulas in Crohn’s disease patients), intravenously (Cx611, in 
development for early rheumatoid arthritis and severe sepsis) or by intra-lymphatic 
administration (Cx621, candidate for the treatment of autoimmune diseases) (1).
5.6
Safety of Cx611
TiGenix has conducted a full spectrum of studies of eASCs in 6 animal models, 3 indications 
and 5 routes of administration (1). With the IV formulation Cx611, the results from the 
pharmacokinetics and biodistribution studies demonstrated very limited migration and 
reduced persistence (61). Toxicology single and repeat dose studies with the IV route found 
no toxicological findings, except from some cases of pulmonary embolism in rat studies. 
Tumorigenicity (in vitro and in vivo) studies comprised cytogenetic analyses, growth kinetics 
and senescence studies, telomerase activity studies, c-myc expression studies and anchorage 
independent growth. None of them showed any sign of tumorigenicity (1). 
The key safety findings from the preclinical studies are the following:
Distribution studies in animal models indicate that Cx611 administered intravenously 
accumulate mainly in the lung and can be detected to a lesser extent in some other 
tissues: heart, liver, kidney, jejunum, ileum, colon and cecum. The persistence of the 
cells was limited as cells were detected at Days 2 and 14 after injection but not at later 
time points;
Cx611 administered intraperitoneally in mice with colitis accumulated preferentially 
in the inflamed areas of colon and secondary lymphoid organs (mesenteric lymph 
nodes and spleen), indicating that eASCs have a potential to migrate to the site of 
inflammation;
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Tumorigenicity and transformation: 
oKaryotype: No aberration could be detected in any clinical sample. 
oC-myc expression, telomerase activity and test of soft agar: No concerns arose 
from those tests. 
oTumour formation: In vivo tumorigenicity studies clearly demonstrate the lack of 
any tumour formation. 
oSenescence: The growth of all eASCs used in the preclinical program was 
monitored and doubling populations were established, showing a linear growth. 
Doubling populations upper limit has been established within the routine 
manufacturing process in order to avoid any potential senescence phase of the 
cells. 
Differentiation: eASCs do not differentiate spontaneously into a certain lineage. 
Differentiation processes require inductive signals and permissive environment. The in 
vitro differentiation assays have demonstrated that differentiation is highly reduced 
with expansion. 
TiGenix studies demonstrate the lack of tumours and opportunistic infections. This fact is 
demonstrating on one side that eASCs are not tumorigenic and well tolerated and on another 
side that the potential over suppression of eASCs which might subsequently lead to 
spontaneous tumours or opportunistic infections is not occurring. Therefore there is no 
concern on potential tumorigenicity from allogeneic eASCs. This is in agreement with recent 
review on the risks of mesenchymal stromal cell therapy in which it is stated that 
tumorigenesis is likely to be an extremely uncommon event (62).
With regard to the IV administration route, when a very high number of eASCs were 
administered in animals by IV route, manually or by a high infusion rate, respiratory problems 
immediately after eASCs infusion were observed, likely due to eASC aggregation and bolus 
formation in the lungs. These adverse events observed in small animals have not been 
reported in the phase Ib/IIa clinical trial in rheumatoid arthritis (Cx611-0101, EudraCT 
Number: 2010-021602-37) when up to 4 million cells/kg were administered at an infusion 
rate of 4 mL/min (62), nor in the phase I trial in healthy volunteers injected with 
lipopolysaccharide, whose results are presented below (see Section 5.8) (1). However, in 
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order to control this potential risk associated to the IV administration route, the respiratory 
function will be controlled during and shortly after the IV administration of Cx611.
5.7
Efficacy of Cx611 in Animal Sepsis Models
Current treatments inadequately address the complex immune-modulatory pathways that 
intervene in the pathogenesis of sepsis secondary to sCABP. Cx611 is an intravenously-
administered product of allogeneic eASCs in development for early rheumatoid arthritis and 
severe sepsis. Cx611 offers a novel mechanism of action that is potentially able to address the 
underlying immune dysregulation through multiple pathways. It has demonstrated its efficacy 
in several studies with mainly two animal models of sepsis (endotoxemia caused by 
lipopolysaccharide (LPS) administration and caecal ligation followed by puncture) by 
significantly reducing mortality through a combination of reduced inflammation, production 
of anti-microbial effectors, and increased phagocytosis (45).
In a mouse model of sepsis, Cx611 infusion to septic animals decreased the levels of 
inflammatory mediators (TNF-α), IL 6, IL1b, IL12, interferon gamma (IFN-γ), regulated on 
activation normal T cell expressed and secreted (RANTES) and macrophage inflammatory 
protein-2 (MIP-2)) and increased IL-10 in the major affected organs, and diminished the 
inflammatory infiltration into the peritoneal cavity, lung, liver and intestine, and showed anti-
microbial effects reducing bacterial burden in major affected organs (63). In another pre-
clinical study in mice, treatment with eASCs (1×106 cells/animal) decreased the mortality to 
40% within 26 h, compared to the 100% in the untreated septic group, decreased 
inflammatory cytokines, increased IL-10 and inhibited splenocytes apoptosis (64). In an 
endotoxemic rat model, treatment with eASCs decreased the level of inflammatory cytokines 
in the lung and serum, reduced inflammatory changes in the lung, prevented apoptosis in the 
kidney and improved multi-organ injury (65). In a pneumonia mouse model, treatment with 
MSCs showed reduced bacterial counts as a consequence of the release of the anti-microbial 
peptide LL-37 by the cells (66).
5.8
Phase I Results With Cx611 in Healthy Volunteers
The results from a Phase I, single centre, and placebo controlled clinical trial to investigate 
safety, tolerability and to assess the effect of Cx611 on the human response to 
lipopolysaccharide in healthy male volunteers are presented below (1).
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 32 of 130
This trial, codenamed CELLULA, was designed to confirm the safety and demonstrate the 
anti-inflammatory effect of Cx611 on the sepsis-like clinical symptoms and immunological 
response elicited by an IV administration in healthy volunteers of a bacterial endotoxin 
(lipopolysaccharide), a potent pro-inflammatory constituent of the outer membrane of 
Gram-negative bacteria, which elicits an inflammatory response inducing sepsis-like clinical 
symptoms. The trial was a placebo controlled, parallel group study (3 doses of Cx611: 
250,000 cells/kg, 1 and 4 million cells/kg, and placebo groups) in 32 healthy male volunteers. 
Primary endpoints were vital signs and symptoms, laboratory measurements and functional 
assays of innate immunity (1).
No serious adverse events (SAEs) or respiratory problems were reported (1). Few adverse 
events (AEs) were observed in 5 subjects, resolved on the same day, all with mild intensity 
and not related to the study medication, except from one episode of itching throat and legs, 
self-resolving and not due to angioedema or allergy. It was considered of a moderate severity 
and probably related to eASCs effect (1).
The analysis of vital signs and symptoms revealed a lack of effect of eASCs infusion 
compared to placebo, except for an enhanced febrile response with the highest tested dose of 
4 million cells/kg. The laboratory measurements and functional assays of innate immunity 
analysed on the blood samples of the subjects at different time points up to 24 hours after LPS 
injection revealed, in addition to the expected and transient activations of cytokines, 
endothelial cells and neutrophils, and coagulation and fibrinolysis factors in all groups, some 
significant differences between eASCs and placebo groups, mainly caused by the highest 
tested dose of 4 million cells/kg. Indeed the cytokine analysis showed that the 4 million 
cells/kg dose was associated with an enhanced response (higher levels compared to placebo 
within the first hours after LPS administration) of the pro-inflammatory interleukins IL-6, IL-
8 and the anti-inflammatory IL-10 and tumour growth factor β (TGF-β). Although none of the 
administered doses had a significant effect on the release of the pro-inflammatory cytokines 
TNF-α, IL-1β and IL-12p40 compared to placebo, a trend towards lower levels of IL-12p40 
was observed in the 4 million cells/kg dose group. Some procoagulant effects (higher levels 
of D-dimer and thrombin-antithrombin complexes [TATc]) and an attenuated release of 
tissue-type plasminogen activator (tPA) were also observed in this group compared to 
placebo, as well as an enhanced nucleosome release (1).
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 33 of 130
The eASCs infusion did not influence the neutrophil activation (elastase, MPO, LL-37), nor 
the endothelial cell activation (E-selectin, ICAM-1, VCAM-1), nor the reduced 
responsiveness of blood leukocytes upon stimulation with bacterial agonists and T cell 
stimulation induced after IV LPS injection (1).
In conclusion, although some effects on cytokine release and coagulation factors were 
observed with the highest tested dose, the Phase I study could not demonstrate a significant 
effect of eASCs infusion in many of the evaluated variables. One possible explanation is that 
the LPS model may not be suitable for evaluating the efficacy of eASCs, because the brief 
effect of a low dose of LPS on the immune system may be insufficient to detect the activity of 
Cx611 (67). Another hypothesis that could explain these results is that the anti-inflammatory 
effect of Cx611 requires preactivation of immune cells by an infectious agent (like in sepsis) 
(67). The phase Ib/IIa study in patients with sCABP will allow understanding the mechanism 
of action of eASCs in this inflammatory underlying disease. Although there was no safety 
concern in this phase I study in 32 healthy volunteers, an independent Data Monitoring 
Committee (DMC) will closely and regularly monitor the safety along the study. The DMC 
members’ responsibilities, the timing and purpose of DMC meetings, the Early Safety/Trial 
Integrity Reviews of DMC meetings will be described in a DMC charter, signed by all DMC 
members.
5.9
Rationale
A program of non-clinical pharmacology, biodistribution and safety studies has been 
conducted with Cx611. Preclinical data from the investigational medicinal product dossier 
(IMPD) indicate that allogeneic eASCs show anti-inflammatory and immunomodulatory 
effects in vitro and in vivo, providing therapeutic benefit when administered in experimental 
models of acute inflammatory diseases such as sepsis. These anti-inflammatory and 
immunomodulatory capacities rely on the expression of IDO (indoleamine 2, 3-dioxygenase) 
and the generation of immune cells with regulatory role such as Tregs or regulatory 
macrophages. In addition, eASCs have anti-microbial effects as they release peptides with 
antimicrobial properties (LL-37) and increase the phagocytic capacity of monocytes, 
macrophages and neutrophils (45). eASCs can sense inflammation and therefore can migrate 
to the site of inflammation and also to lymphoid organs.
Toxicology and biodistribution studies using different routes of administration demonstrated a 
limited distribution and viability of human Cx611 in immunodeficient animals with no 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 34 of 130
indication of extensive migration of Cx611 after IV administration. Moreover, no toxicity or 
specific adverse effects upon administration were found, including ectopic growth tissue, 
neoplasia, tumour development (no tumour development was found in mice tested 
subcutaneously with a dose of 10 million cells/mouse) or appearance of opportunistic 
infections. No tumorigenic behaviour after long term ex vivo culture of eASCs has been 
found. In addition, a decreased differentiation capacity of the cells with extended expansion of 
eASCs has been observed.
From an allogeneic point of view, TiGenix research indicates that allogeneic Cx611 do not 
trigger immune response by the host immune system by using PBMCs from healthy donors 
cultured several times in vitro with autologous or allogeneic eASCs. Studies performed in 
intravenously treated patients with rheumatoid arthritis indicated that three administrations 
generated allo-antibodies in 16.9% of the patient population. In comparison, the IV 
administration of allogeneic eASCs could be similar as a blood transfusion in terms of 
generation of allo-antibodies that might reject the product in a further administration.
Therefore, our preclinical understanding of the allogeneic eASCs shows that these cells are 
well tolerated and have therapeutic capacities (in experimental models and in samples from 
patients) which make them an excellent source of cells for cell therapy. Based on the clinical 
experience up to now, there are no known specific adverse events that can be attributed to the 
use of allogeneic eASCs.
Based on this, the potential indication developed by TiGenix for allogeneic eASCs 
administered intravenously is severe sepsis.
In summary, available preclinical and clinical results on cellular therapy with Cx611 have 
shown that the overall benefit-risk balance is acceptable, and suggest that it may be well 
tolerated treatment for sCABP associated with severe sepsis. The limited possible risks 
associated with the administration of Cx611 may include tumour formation, unwanted local 
or systemic immune response and transmission of adventitious agents. There is also a 
potential risk associated with the mode of administration of cells clustering as demonstrated 
in small animals, possibly leading to embolisms after IV administration. Although all ICU 
patients present with coagulation disorders due to various factors, this risk will be considered 
as an AESI (please refer to the Investigators’ Brochure (1)).
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 35 of 130
The current phase Ib/IIa study is proposed to assess the safety of two 80 mL allogeneic Cx611 
central line infusions (from a single, healthy donor) on Days 1 and 3 at a dose of 160 million 
cells per infusion (320 million cells total), in an add-on therapy design compared to a placebo
control group, for the treatment of sCABP and sepsis. As a secondary objective, the study will 
explore the efficacy of Cx611 for treating sCABP. An immunological monitoring will be also 
done to further understand the absence of relevant alloreactivity in these patients and how the 
allogeneic treatment is affecting the patient. The immunological follow up will include: the 
pattern of pro- and anti- inflammatory cytokines before and after treatment in serum, to 
demonstrate immunological signals of efficacy; the measurement of anti-donor specific 
antibodies, to ensure that the treatment is safe and does not induce a significant antibody 
response; the profile of circulating cells, to address the patient inflammatory status; the 
response of PBMCs in response to stimulation and the control of the changes on the T cell 
proliferation caused by the Cx611 treatment, to understand the mode-of-action of Cx611.
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. The study results will be critical for 
the design of further confirmatory clinical trials in terms of definition of endpoints, key 
biomarkers and sample size determination.
5.10 Risk Assessment
The preclinical (pharmacology, pharmacokinetic and toxicology) profile of Cx611 supports its 
development as a potential treatment for sCABP. The current study is being conducted to 
investigate safety and tolerability and to explore the efficacy of Cx611 co-administered with 
standard of care (SoC) in patients with sCABP, as outlined in the rationale for the study 
(Section 5.9). The preclinical and clinical safety findings are summarised as part of the 
background information (Sections 5.5-5.8) and are described in detail in the Investigators 
Brochure (1).
Important potential risks of allogeneic stem cell administration might include tumour
formation, unwanted local and systemic immune response, transmission of adventitious 
agents and, when administered intravenously, thromboembolism (40,42–44) and local 
pulmonary inflammation from immunologic origin (reported in a literature report after IV 
injection of stem cells in dogs (68)). Also, sustained engraftment of eASCs with an ability to 
differentiate into various cell types could potentially lead to ectopic tissue formation in the 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 36 of 130
recipient, although analysis of tissues following mesenchymal stromal cell therapy in humans 
indicated limited long-term engraftment and no ectopic tissue formation (69).
During the clinical trial programs of Cx611, Cx601 or Cx621, no important risks have been 
identified so far. No dose-dependent safety concern or toxicity could be identified, no ectopic 
tumour formation, nor hypersensitivity reaction, and no thromboembolic event to the lungs 
were reported. In clinical study Cx611-0101 doses up to 4 million eASC cells per kg body 
weight were injected intravenously on 3 consecutive occasions with a 1-week interval without 
any report of pulmonary embolism (1). The production of allogeneic antibodies in some 
patients has not been reported to be associated to any adverse events so far (1).
This was observed in the phase I study of Cx611 in healthy human volunteers. In this study no 
clinically relevant electrocardiogram (ECG) findings or corresponding AEs were reported, 
where 32 subjects were exposed to single doses of Cx611 up to 4 million eASC cells per kg
body weight.
The potential safety concerns were carefully assessed for their relevance to application of the 
medication in clinical settings. A 240 mL/h infusion rate has been established to prevent any 
risk of thromboembolism, and lung function will be continuously monitored during and after 
the infusion.
In spite of the above, the low number of subjects treated so far does not permit any conclusion 
of safety. Investigators should especially be alerted to the potential risks described above and 
any sign or symptom that could be suspicious for such an event should be carefully assessed.
The Sponsor will immediately notify the Investigators and responsible Ethics Committees if 
any additional safety or toxicology information becomes available during the study after 
review by the DMC.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 37 of 130
6
STUDY OBJECTIVES
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 SoC therapy, to patients with 
sCABP.
The key objectives of this study are to:
6.1
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). To monitor any adverse event and potential 
immunological host responses against the administered cells during 90 days of follow-
up after the first infusion.
6.2
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 (see section 10.1.3)
6.3
Exploratory Objectives
Prope
-Commercial Use Only and Subject to the Applicable Terms of Use
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infusio
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a a dose
dos
adver
adv
stered c
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ctiv
CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 38 of 130
7
INVESTIGATIONAL PLAN
7.1
Overall Study Design
This will be a Phase Ib/IIa, randomised, double blind, parallel groups, placebo controlled and 
multicentre trial to assess the safety and efficacy of a new therapy with eASCs (Cx611) for 
the treatment of sCABP. 
The study will permit concomitant SoC treatment of the sCABP (including antibiotic and 
standard therapy in the ICU) and Cx611, in an add-on design. Subjects will receive SoC
therapy according to local guidelines plus two 80 mL central line infusions at 240 mL/h (on 
Days 1 and 3) of IV allogeneic treatment administration of Cx611, at a fixed dose of 160 
million cells per infusion, or placebo.
This study will enrol approximately 85 adult male and female subjects with sCABP, who will 
be randomised to receive Cx611 or placebo in a 1:1 design. It is expected to have equal 
distribution between the Cx611 and placebo treatments due to the 1:1 randomization design.
Each subject will receive two 20-30 minute central line infusions (active or placebo) 
according to a pre-defined randomisation list. 
In order to balance mechanical ventilation and vasopressors requirement between groups, a 
stratified allocation will be considered based on CABP severity criteria at inclusion:
-
Shock requiring vasopressors, or
-
Respiratory failure requiring invasive mechanical ventilation, or 
-
Both.
In each stratum, patients will be randomised 1:1 to Cx611 or placebo.
The Screening duration will be around 18 hours, treatment duration will be three days and the 
total study duration per subject will be two years.
There will be a total of 12 visits per subject: Screening visit and on Days 1, 2, 3, 4, 5, 6, 7, 
8-10, 14, 29 and 90. For all visits scheduled after hospital discharge, costs of travel to hospital 
(such as taxi) will be reimbursed by the Sponsor.
The double blind design will be maintained until the primary safety and secondary efficacy
endpoints have been assessed (i.e. at Day 90). The study participants (Sponsor, investigators 
and site team members) will be unblinded after all Day 90 data have been collected.
Long-term follow-up: Study site personnel will give four follow-up phone calls to the 
patient, at Months 6 (Day 180 ±30 days), 12 (Day 365 ±30 days), 18 (Day 545 ±30 days) and 
24 (Day 730 ±30 days), to assess any spontaneous report of a health event from him/her. Up 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 39 of 130
to three phone call attempts will be done and if not successful, a contact will be established 
with the patient’s General Practitioner (GP) or family doctor. The investigator will report any 
SAE and will liaise with the patient’s GP or family doctor for obtaining further 
documentation to appropriately assess the SAE.
An approximate 18-hour Screening period is scheduled to determine a patient’s eligibility for 
inclusion in the study. Subjects may be screened at the emergency department, but will be 
treated and receive the study medication (Cx611 or placebo) in the ICU.
The start of the first infusion of Cx611 or placebo will occur as early as possible in ICU 
within the first 18 hours of patients fulfilling at least one of the two major criteria of 
severity for CAP (i.e. from the initiation of invasive ventilation support or vasopressors,
whichever comes first), after patient’s eligibility is confirmed. The day of administration 
of the first dose will be considered the Day 1 of the study and study days are considered as 
calendar days, not as 24-hour days.
If the patient is unable to comprehend the scope of the trial prior to enrolment due to altered 
mental status associated with the underlying pneumonia or any other disease: written 
informed consent to participate in the study must be obtained from the patient’s legally 
acceptable representative, as required by national laws, respective regulations and 
Institutional Review Boards/Independent Ethics Committees/Regional Ethics Boards 
(IRB/IEC/REB). Written informed consent should be sought from the patient as soon as 
he/she becomes capable of comprehending the scope of the trial.
administration. Safety and efficacy assessments will also be performed at different time points 
during the study period.
The study consists of the following periods:
!
Screening visit (around 18 hours) starts, when not exempted according to local 
legislation, with signature of informed consent. Screening procedures will be 
performed so that first infusion of Cx611/placebo can be started as early as possible
within the first 18 hours of patients fulfilling at least one of the two major criteria of 
severity for CAP (i.e. from the initiation of mechanical ventilation support or 
vasopressors, whichever comes first), after patient’s eligibility is confirmed.
!
Baseline (BL) (Day 1) data is the last assessment prior to initiation of study treatment.
Property of Takeda: F
on. Sa
. S
he study
e stud
e study
study c
y
!
ercial Use Only and Subject to the Applicable Terms of Use
l be
be
sible
sible in
i
b
major
ajor c
pli
port or 
ort or
Ap
The
he day
da
study
study
tri
trialal pr
neumo
neumo
must
us b
by 
by na
endent 
endent 
ed d cons
con
rehe
reh
CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 40 of 130

Treatment period (Days 1 and 3) starts with the administration of first dose (Day 1)
and ends with the second dose administration of Cx611/placebo (Day 3).

Clinical Response visit (Day 14 ± 2) is the time of the assessment of the clinical 
response at 14 ± 2 days after the first dose of Cx611/placebo. Clinical response will be 
also assessed at visits on Days 8-10 and 29 ± 2.

Primary Safety Endpoint visit (Day 90 ± 4) is performed at 90 ± 4 days after the 
first dose of Cx611/placebo. 

Premature discontinuation can occur if the patient withdraws from the study before 
Day 90, and leads to ET visit.

Long-term safety follow-up: phone calls are performed at Month 6 ±30 days, 
Month 12 ±30 days, Month 18 ± 30 days and Month 24 ± 30 days after the first 
dose of Cx611/placebo.
7.2
Study Procedures
7.2.1
Schedule of Study Assessments
The study assessments described in the sections below are presented in detail in Section 10
(safety, efficacy and immunological assessments and demographic data and baseline 
characteristics). Recording and reporting of AEs is described in detail in Section 11.
The timing of all study assessments is shown in Table 1 in Section 1.
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Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
EudraCT No.: 2015-002994-39
Confidential
Page 41 of 130
7.2.2
Study Flow Chart
Table 1 in Section 1 shows a schematic representation of the assessments during the study. The overall study design is depicted in Figure 1
below.
Apart from the Screening visit, there will be 11 scheduled visits plus four phone calls at Month 6 ± 30 days, Month 12 ± 30 days, Month 18 ± 30 
days and Month 24 ± 30 days for long-term safety follow-up. If there is a premature discontinuation for any reason before Day 90, the patient 
will undergo an ET Visit.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
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Confidential
Page 42 of 130
Figure 1. Study Design
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Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 43 of 130
7.2.2.1
Screening Period
Screening visit will take place promptly once the patient presents clinical evidence that one of 
the two major criteria of severity for CABP are being met (i.e. need for mechanical ventilation 
or vasopressors, whichever comes first) and after informed consent is obtained, unless 
exempted by applicable local legislation. 
Before any study procedure, as soon as sCABP is clinically diagnosed and indication for 
initiating mechanical ventilation and/or treatment with vasopressors is met, written 
informed consent to participate in the study must be obtained from the patient’s legally 
acceptable representative, as required by local laws and guidelines (written informed consent
should be sought from the patient as soon as he/she becomes capable of comprehending the 
scope of the trial).
Screening period will last around 18 hours. Throughout this period, the patient’s eligibility for 
study entry will be assessed based on the inclusion and exclusion criteria (Section 8). 
Note: The start of the first administration of the Cx611/placebo will occur within 18 hours of 
patient fulfilling at least one of the two major criteria of severity for CABP (i.e. from the 
initiation of invasive mechanical ventilation support or vasopressors, whichever comes first). 
Screening and randomisation procedures should be built into the patient recruitment process 
to allow for this to happen.
The following procedures will be performed and recorded and/or data collected from the 
patient´s clinical records during the Screening period:

Informed consent.

Assessment of inclusion/exclusion criteria.

Demographic data and complete medical history including previous and current diseases
and allergies, immunological status (i.e. previous pregnancies and/or transplants and/or 
blood transfusions), previous anti-pneumococcal vaccination and risk factors for 
pulmonary embolism as applicable by inclusion and exclusion criteria (history of previous 
deep venous thrombosis or pulmonary embolism; history of chronic congestive heart 
failure; hormone replacement therapy or oral contraceptive therapy; antiphospholipid 
antibody syndrome; hereditary thrombotic risk [antithrombin deficiency, protein C and 
protein S deficiencies, activated protein C resistance; factor II –prothrombin- G20210A 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 44 of 130
mutation, hyperhomocysteinemia], thrombophilia; fracture of pelvis, hip or long bones; 
lower limb orthopaedic surgery; malignancy; major general surgery).

Prior antibiotic and non-antibiotic treatments for CABP and treatments for other diseases
(within the last 2 weeks); concomitant treatments for sCABP and other diseases
(concomitant medication page will be completed, including all medication taken by the 
patient at the time of the visit).

Physical examination including weight and height.

Assessment of clinical signs and symptoms of pneumonia.

Vital signs measurement (systolic and diastolic blood pressure, heart rate, core 
temperature (tympanic, rectal or bladder) and, in non-ventilated patients, respiratory rate).
If more than one measurement is available during screening period, only the highest and 
lowest values measured for each vital sign will be recorded in the case report form (CRF).

Serum pregnancy test in women of childbearing age (a rapid diagnosis using urine 
pregnancy test may be performed for inclusion, awaiting the serum pregnancy test for 
confirmation).

PaO2/FiO2 (if more than one reading is available during the screening period then the 
lowest value will be recorded). A conversion table (SO2 % to PaO2 mmHg and O2 l/min to 
FiO2 % is provided in Appendix E).

CURB-65 (Confusion, Urea >7 mmol/L, respiratory rate ≥30 breaths/min, low systolic 
(<90 mm Hg) or diastolic (≤60 mm Hg) blood pressure), age ≥65 years) score when 
severity criteria are met and before mechanical ventilation is applied (see Appendix B).

APACHE II score assessment at admission to ICU.

Sequential Organ Failure Assessment (SOFA) score at admission to ICU.

12-lead ECG.

Chest X-ray (CXR).

Pathogen identification and susceptibility testing: For the confirmation of the causative 
pathogen of the bacterial pneumonia, pulmonary, pleural, blood and urine samples will be 
collected and analysed by any established standard diagnostic method routinely applied at 
the study site including classical microbiology and/or any other methods. Pulmonary 
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Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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samples can be obtained by bronchoalveolar lavage (BAL) and/or mini-BAL/protected 
specimen brush (PSB) and/or by endotracheal aspiration (ETA) for intubated patients, and 
sputum production for non-ventilated patients. Samples will be rapidly processed for 
Gram stain and culture and/or other established standard rapid diagnostic system, e.g. 
peptide nucleic acid fluorescent in situ hybridization (PNA FISH) or Cepheid GeneXpert 
for S. aureus, urinary antigen test for S. pneumoniae or Legionella, or real-time 
polymerase chain reaction (rt-PCR). Should a bacterial pathogen grow in culture, 
susceptibility testing against the standard local antibiotic panel for the pathogen will be 
performed according to the site´s practice. Pathogen identification and susceptibility 
testing will be collected from follow-up pulmonary/blood/respiratory/pleural cultures 
performed as per investigator´s decision as well. Pathogen identification and susceptibility 
testing will also be performed in case of clinical suspicion of pneumonia recurrence.

Blood samples for haematological, coagulation and biochemical tests (according to local 
laboratory requirements),
 
 
 
 
 
 
 
 
 
.

Urine samples for urinalysis
(according to local laboratory requirements)
and 
pneumococcal urine antigen (according to local laboratory requirements).

Assessment of eligibility criteria and approval call to 
 
 See Section 8.2.

Randomisation of the patient.

AEs assessment and recording (from the time of signing the informed consent).
7.2.2.2
Visit 1: Study Day 1 (BL)
Day 1 is considered to be the calendar day in which first dose of study medication is 
administered.
1) If the first dose of study medication starts on the same calendar day of Screening,
after having performed all the assessments of Screening period above (7.2.2.1) please proceed 
with the following:
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accordin
ccord
cording
cordi
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criteria
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f the pa
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Visit 
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admin
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
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
Pre-study product administration:
o
Blood samples for anti-HLA/donor antibodies (Abs)
 
o
Vital signs: systolic and diastolic blood pressure, heart rate, core temperature 
(tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients).

Start IV administration of study product (Cx611 or placebo) as early as possible and 
within the first 18 hours of patient fulfilling at least one of the two major criteria of 
severity for CABP (i.e. from the initiation of invasive mechanical ventilation support 
or vasopressors, whichever comes first).

During and post-study product administration: 
o
Duration of infusion.
o
Vital signs: systolic and diastolic blood pressure, heart rate, core temperature 
(tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients) at 
0.5h (±5 min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24h 
(±1 h) post investigational medicinal product (IMP) infusion.
o
Signs of hypersensitivity reactions or anaphylaxis (the patient will be monitored 
for skin reactions and episodes of respiratory distress requiring therapeutic 
intervention during the first 24 hours after the infusion of IMP).

Post-study product administration (only): 
o
12 lead ECG. 5 hours ± 1h post IMP infusion
o

Pre, during and post-study medication administration: AEs/ treatment emergent adverse 
events (TEAEs) assessment and recording including any AESI.
2) If the first dose of study medication starts the calendar day after the Screening 
procedures, then the following assessments will be performed:

Pre-study medication administration:
o
Review of inclusion/exclusion criteria.
Property of Tak
 Non-Commercial Use Only and Subject to the Applicable Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 47 of 130
o
Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.
o
Physical examination including assessment of clinical signs and symptoms of 
pneumonia.
o
Vital signs: systolic and diastolic blood pressure, heart rate, core temperature 
(tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients).
o
PaO2/FiO2 (if more than one reading is available on the same day then the lowest 
value will be recorded).
o
APACHE II score assessment.
o
SOFA score assessment and recording.
o
If applicable (and as per investigator´s decision): CXR, pulmonary and blood 
samples for culture (results will be recorded in the CRF).
o
Blood samples for haematological, coagulation and biochemical tests (according to 
local laboratory requirements), anti-HLA/donor Abs 
 
o
Urine samples for urinalysis (according to local laboratory requirements).

Start IV administration of study medication (Cx611 or placebo) as early as possible and
within the first 18 hours of patient fulfilling at least one of the two major criteria of 
severity for CABP (i.e. from the initiation of invasive mechanical ventilation support 
or vasopressors, whichever comes first).

During and post-study medication administration: 
o
Duration of infusion.
o
Vital signs: systolic and diastolic blood pressure, heart rate, core temperature 
(tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients) at 
0.5h (±5 min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24h 
(±1 h) post IMP.
o
Signs of hypersensitivity reactions or anaphylaxis (the patient will be monitored 
for skin reactions and episodes of respiratory distress requiring therapeutic 
intervention during the first 24 hours after the infusion of IMP).
Property of Takeda: For Non-Commercial U
 Only and Subject to the Applicable Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 48 of 130

Post-study medication administration: 
o
12 lead ECG. 5 hours ± 1h post IMP infusion.
o

Pre, during and post-study medication administration: AEs/TEAEs assessment and 
recording including any AESI.
7.2.2.3
Visit 2: Study Day 2

Concomitant treatments for sCABP and other diseases. Concomitant medication page will 
be updated.

Physical examination including assessment of clinical signs and symptoms of pneumonia.

Vital signs at least 4 times (i.e. every 6 hours±1h): systolic and diastolic blood pressure, 
heart rate, core temperature (tympanic, rectal or bladder) and respiratory rate (in 
non-ventilated patients). When more than one measurement is available for Day 2, only 
the highest and the lowest value measured for each vital sign for that time period will be 
recorded in the CRF for that time point.

PaO2/FiO2 (if more than one reading is available on the same day then the lowest value 
will be recorded).

If applicable (and as per investigator´s decision): CXR, pulmonary and blood samples for 
culture (results will be recorded in the CRF).


Urine samples for urinalysis (according to local laboratory requirements).

TEAEs assessment and recording including any AESI.
7.2.2.4
Visit 3: Study Day 3

Pre-study product administration:
o
Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

U
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CCI
CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 49 of 130
o
Physical examination including assessment of clinical signs and symptoms of 
pneumonia.
o
Vital signs: systolic and diastolic blood pressure, heart rate, core temperature 
(tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients).
When more than one measurement is available for Day 3, only the highest and the 
lowest value measured for each vital sign for that time period will be recorded in 
the CRF for that timepoint.
o
PaO2/FiO2 (if more than one reading is available on the same day then the lowest 
value will be recorded).
o
Blood samples for haematological and coagulation tests (according to local 
laboratory requirements).
o
If applicable (and as per investigator´s decision): CXR, pulmonary and blood 
samples for culture (results will be recorded in the CRF).

IV administration of study product (Cx611 or placebo) (48 hours ± 2 hours after the start 
of infusion of the first IMP dose).

Post-study product administration: 
o
Duration of infusion.
o
Vital signs: systolic and diastolic blood pressure, heart rate, core temperature 
(tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients) at 
0.5h (±5 min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24h 
(±1 h) post IMP infusion.
o
Signs of hypersensitivity reactions or anaphylaxis (the patient will be monitored 
for skin reactions and episodes of respiratory distress requiring therapeutic 
intervention during the first 24 hours after the infusion of IMP).
o
12 lead ECG. 5h±1h post IMP infusion.
o
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 50 of 130

Pre, during and post-study product administration: TEAEs assessment and recording
including any AESI.
7.2.2.5
Visits 4-7 (Study Days 4, 5, 6 and 7):

Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

Physical examination including assessment of clinical signs and symptoms of pneumonia.

Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, 
rectal or bladder) and respiratory rate (in non-ventilated patients,). On Days 4, 5, 6, 7 if 
patient is in the ICU at least 4 times daily (i.e. every 6h±1h), if discharged from ICU at 
least once. When more than one measurement is available for Days 4, 5, 6 or 7 only the 
highest and the lowest value measured for each vital sign for that time period will be 
recorded in the CRF for that timepoint.

PaO2/FiO2 (if more than one reading is available on the same day then the lowest value 
will be recorded).

If applicable (and as per investigator´s decision): CXR, pulmonary and blood samples for 
culture (results will be recorded in the CRF).

Only at Days 4 and 7:
o
Blood samples for haematological, coagulation and biochemical tests (according to 
local laboratory requirements).
o
SOFA score assessment and recording.
o
Urine samples for urinalysis (according to local laboratory requirements).

Only at Days 5 or 6:
o
Proximal lower limb compression ultrasonography.

Only at Day 7:

TEAEs assessment and recording including any AESI.
y
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
um
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Days 4
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 51 of 130
7.2.2.6
Visit 8: Study Days 8-10

Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

Physical examination including assessment of clinical signs and symptoms of pneumonia.

Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, 
rectal or bladder) and respiratory rate (in non-ventilated patients). On Days 8-10 if patient 
is in the ICU at least 4 times daily (i.e. every 6h±1h), if discharged from ICU at least 
once. When more than one measurement is available only the highest and the lowest 
value measured for each vital sign for that time period will be recorded in the CRF for 
that timepoint.

If applicable (and as per investigator´s decision): pulmonary and blood samples for 
culture (results will be recorded in the CRF).

CXR

sCABP Clinical Response assessment.

TEAEs assessment and recording, including any AESI.
7.2.2.7
Visit 9: Study Day 14 ± 2

Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

Physical examination including assessment of clinical signs and symptoms of pneumonia.

Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, 
rectal or bladder) and respiratory rate (in non-ventilated patients). On Visit 9 if patient is 
in the ICU at least 4 times daily (i.e. every 6h±1h), if discharged from ICU at least once. 
When more than one measurement is available only the highest and the lowest value 
measured for each vital sign for that time period will be recorded in the CRF for that 
timepoint.

SOFA score assessment and recording.

If applicable (and as per investigator´s decision): pulmonary and blood samples for 
culture (results will be recorded in the CRF).

CXR.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 52 of 130

sCABP Clinical Response assessment and recording.

Pneumonia recurrence / reinfection assessment and recording (see page 8 for definition).
Pathogen identification and susceptibility testing will also be performed in case of clinical 
suspicion of pneumonia recurrence. Pathogen identification and susceptibility testing data 
will 
also 
be 
collected 
from 
pneumonia 
recurrence 
follow-up 
pulmonary/blood/respiratory/pleural cultures performed as per investigator´s decision as 
well.

Blood samples for haematological, coagulation and biochemical tests (according to local 
laboratory requirements), anti-HLA/donor Abs &
 
 

Urine samples for urinalysis (according to local laboratory requirements).

TEAEs assessment and recording, including any AESI.
7.2.2.8
Visit 10: Study Day 29 ± 2

Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

Physical examination including assessment of clinical signs and symptoms of pneumonia.

Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, 
rectal or bladder) and respiratory rate (in non-ventilated patients). On Visit 10 if patient is 
in the ICU at least 4 times daily (i.e. every 6h±1h), if discharged from ICU at least once. 
When more than one measurement is available, only the highest and the lowest value 
measured for each vital sign for that time period will be recorded in the CRF for that 
timepoint.

SOFA score assessment and recording.

If applicable (and as per investigator´s decision): pulmonary and blood samples for 
culture (results will be recorded in the CRF).

CXR.

sCABP Clinical Response assessment and recording.
ry requi
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able Terms of Use
up 
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 53 of 130

Pneumonia recurrence/reinfection assessment and recording (see page 8 for definition). 
Pathogen identification and susceptibility testing will also be performed in case of clinical 
suspicion of pneumonia recurrence. Pathogen identification and susceptibility testing data 
will 
also 
be 
collected 
from 
pneumonia 
recurrence 
follow-up 
pulmonary/blood/respiratory/pleural cultures performed as per investigator´s decision as 
well.

Blood samples for haematological, coagulation and biochemical tests (according to local 
laboratory requirements

Urine samples for urinalysis (according to local laboratory requirements).

TEAEs assessment and recording, including any AESI.
7.2.2.9
Visit 11: Study Day 90 ± 4

Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

Physical examination including assessment of clinical signs and symptoms of pneumonia.

Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, 
rectal or bladder) and respiratory rate (in non-ventilated patients). On visit 11 if patient is 
in the ICU at least 4 times daily (i.e. every 6h±1h), if discharged from ICU at least once. 
When more than one measurement is available only the highest and the lowest value 
measured for each vital sign for that time period will be recorded in the CRF for that 
timepoint.

If applicable and as per investigator´s decision (e.g. clinical suspicion of pneumonia 
recurrence): CXR, pulmonary and blood samples for culture (results will be recorded in 
the CRF).

Pneumonia recurrence / reinfection assessment and recording (see page 8 for definition).
Pathogen identification and susceptibility testing will also be performed in case of clinical 
suspicion of pneumonia recurrence. Pathogen identification and susceptibility testing data 
will 
also 
be 
collected 
from 
pneumonia 
recurrence 
follow-up 
pulmonary/blood/respiratory/pleural cultures performed as per investigator´s decision as 
well.
Property of Takeda: For Non-Commercial Use Only and Subject to the Appli
le Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 54 of 130

Blood samples for haematological, coagulation and biochemical tests (according to local 
laboratory requirements) and anti-HLA/donor Abs (4.5 mL EDTA).

Urine samples for urinalysis (according to local laboratory requirements).

TEAEs assessment and recording, including any AESI.
7.2.2.10 Long-term safety follow-up (phone calls at Month 6 [Day 180 ± 30 days], Month 
12 [Day 365 ± 30 days], Month 18 [Day 545 ± 30 days] and Month 24 [Day 730 ± 
30 days]

Patients will be contacted via a phone contact and SAE data will be collected via the 
Safety Follow Up Form and reported in the SAE Report Form.
7.2.2.11 Early Termination
If the patient discontinues the study for any reason before Day 90, perform the following: 

ET date and reason.

Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

Physical examination including assessment of clinical signs and symptoms of pneumonia.

Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, 
rectal or bladder) and respiratory rate (in non-ventilated patients). When more than one 
measurement is available, only the highest and the lowest value measured for each vital 
sign for that time period will be recorded in the CRF for that timepoint.

If applicable (and as per investigator´s decision): PaO2/FiO2 and SOFA score assessment 
and recording, sCABP Clinical Response assessment and recording, pneumonia 
recurrence / reinfection assessment and recording, CXR, pulmonary and blood samples for 
culture (results will be recorded in the CRF.

Blood samples for haematological, coagulation and biochemical tests (according to local 
laboratory requirements), anti-HLA/donor Abs 
 

Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
onth 
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CCI
CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 55 of 130

Urine samples for urinalysis (according to local laboratory requirements).

AEs/TEAEs assessment and recording, including any AESI.
7.2.2.12 Unscheduled Phone-call Follow-up (If Applicable)
Unscheduled phone-calls are proposed for safety follow-up in case the patient cannot attend to 
any visits (e.g. due to a bone fracture) or for any contact requested by the patient between 
scheduled visits. In these phone calls, perform the following:

Unscheduled phone-call follow-up date and reason.

AEs assessment and recording, including any AESI.

Concomitant medication page will be updated with treatment for sCABP and other 
diseases as it applies.

Remind the patient to visit the investigator at the next scheduled visit or for an end of 
study (EOS) visit as soon as possible (if applicable).
7.3
Discussion of Study Design, Including the Choice of Control Groups
This is a multicentre, randomised, double blind, parallel-group, placebo controlled, 
exploratory concept study. The selected dose of the experimental medication has been chosen 
on the basis of the safety results obtained in the Phase Ia/IIb in rheumatoid arthritis and Phase 
I in healthy male volunteers challenged with LPS, studies previously performed by TiGenix. 
The double blind design is needed to ensure unbiased data collection. The study will be
unblinded (Sponsor, investigators and site team members) after the analyses at Day 90 of the 
primary safety and secondary efficacy variables for all subjects. The two-year follow-up will 
allow long-term safety data collection.
7.4
Study Period
Screening period will last around of 18 hours. Treatment period will be 3 days (administration 
on Days 1 and 3). During and after the treatment period, efficacy assessments will be 
performed at different time points until Day 90 ±4 after the first dose of study medication 
(Day 1); safety assessments will be performed at different timepoints until Day 90 ±4 after the 
first dose of study medication (Day 1). 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 56 of 130
Long-term safety follow-up will include four safety follow-up phone calls made to the patient 
at Day 180 ±30 days, Day 365 ±30 days, Day 545 ±30 days and Day 730 ±30 days.
7.5
End of Study
The EOS is defined as the date of the subject’s last scheduled visit (Day 90 ±4 days) or early 
withdrawal from study prior to Day 90 ±4 days. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 57 of 130
8
SELECTION OF STUDY POPULATION
8.1
Number of Subjects
The number of 180 patients in total (i.e. 90 patients per group) was deemed to be sufficient to 
fulfil the objectives of this exploratory study.
The study will be conducted in approximately 20 centres across Belgium, France, Lithuania, 
and Spain. Subject enrolment distribution across sites is expected to fluctuate throughout the 
duration of the study, but no single centre is expected to enrol >20% of the study subject total.
The specific inclusion and exclusion criteria for enrolling patients in this study are described
below (Section 8.3, Inclusion Criteria and Section 8.4, Exclusion Criteria). All the inclusion 
and exclusion criteria should be fulfilled before including a patient into the study.
8.2
Screening Log
Each participating centre will keep a log of all screened patients with sCABP. The 
investigator is requested to record the reason(s) for not including patients who were screened 
but not enrolled.
Due to the short time window (up to 18 hours) between fulfilment of severity criteria (i.e. 
from the initiation of invasive mechanical ventilation support or vasopressors, whichever
comes first) and start of administration of the first dose of study treatment, patients with a 
sCABP, either suspected and/or later confirmed its 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.
After performing the screening visit and verifying inclusion (see Section 8.3) and exclusion 
(see Section 8.4) criteria and subject´s eligibility, the investigator will place a screening and 
approval call to the 
 physicians to be provided with a randomisation authorisation 
number. No patient will be randomised without this authorisation number.
personnel will also be available for consultation in case of screening doubts and for medical 
advice of subject´s management. The 
 will keep record of the conversations with 
investigators in a dedicated database and available for review by the sponsor on a monthly 
basis at least.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ith
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CCI
CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 58 of 130
8.3
Inclusion Criteria
The reference population will consist of adult patients with a sCABP, admitted to the ICU.
All of them must comply with the following 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:
a.
Requiring invasive mechanical ventilation for respiratory failure due to 
pneumonia, or
b. Requiring treatment with vasopressors (i.e. dopamine >5 µg/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 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 litres 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 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 59 of 130
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 
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 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 subject, the relatives or the designated legal 
representative according to local guidelines.
8.4
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 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 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).
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 60 of 130
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 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
human 
immunodeficiency virus (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-TNFα) 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 equivalent1 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.
                                                  
1 See appendix A for dose equivalence between different types of corticosteroids
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 61 of 130
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
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).
8.5
Removal of Patients From Therapy or Assessment
In accordance with the Declaration of Helsinki, patients, or upon their legally authorised
representatives’ decision, will be free to withdraw from the study at any time if they wish so, 
for any reason specified or unspecified. Withdrawal from the study will not affect or 
detriment the patient’s further care or treatment.
In addition, patients may be withdrawn from study treatment and assessments at any time, if 
deemed necessary by the Investigator or the study sponsor. 
Potential reasons for withdrawal of patients from this study are: 
!
Occurrence of adverse events that justify the withdrawal from the study.
!
The decision of a subject to withdraw from the study.
!
Major protocol deviations.
Property of T
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f Takeda: For Non-Commercial Use Only and Subject to the
e Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 62 of 130
A patient may also discontinue the treatment and/or study assessment prematurely, before the 
90 days of scheduled follow-up, for several reasons. Potential reasons for premature 
discontinuation of patients from therapy and/or study assessments are: 

Pregnancy: Pregnant subjects will be withdrawn from further study treatment but not 
from the study (all assessments will continue until EOS visit). In addition, the 
pregnant subject will be followed for safety reasons until the end of the pregnancy.

Subject is lost to follow-up.
The reason and date the subject early terminates or is withdrawn from the study will be 
documented in the CRF (e.g. lost to follow-up, consent withdrawn, AEs, etc.). If a subject is 
withdrawn from further treatment with the study product, the Investigator will attempt to 
complete all study assessments. If a subject is withdrawn from further assessments, the 
Investigator will attempt to complete all ET procedures (see Section 7.2.2.10). All AEs 
occurring 30 days after the last IMP infusion will be recorded and should be followed up 
according to Section 11.2. 
Patients have the right to withdraw their consent at any time; in that case all data collected 
until the time of withdrawal will be used in the analyses, unless it is otherwise required by the 
patient or local regulations.
8.6
Handling and Replacement of Withdrawals
Randomised subjects who withdraw their consent or are removed should undergo the ET visit. 
These data will be registered in the CRF in the ET section. 
Subjects who receive any dose of study treatment and who subsequently withdraw, or are 
withdrawn, from the study, regardless of the reason, will not be replaced.
8.7
Premature Termination of the Study
The Investigator or TiGenix may terminate this study prematurely for any reasonable cause. 
The IECs and Competent Authority (ies) (CAs) should be informed promptly. 
Conditions that may warrant termination include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study or to potential study patients.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 63 of 130

A decision on the part of TiGenix to suspend or discontinue the development of the 
IMP.

The inability to enroll participants in the study in a reasonable timeframe.
If the CA obtains information that raises doubts about the safety or scientific validity of the 
clinical study, the CA can suspend or prohibit the study. Before the CA reaches its decision it 
shall, except where there is an imminent risk, ask the Sponsor and/or the Investigator for their 
opinion, to be delivered within one week (Directive 2001/20/European Commission (EC), 
Article 12, Section 1). 
If the study is prematurely terminated or suspended for any reason, the Investigator/institution 
should promptly inform the study patients or their legally authorised representatives and 
should assure appropriate therapy and follow-up for the patients. 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 64 of 130
9
TREATMENT OF SUBJECTS
9.1
Investigational Products
9.1.1
Treatment Regimens
Cx611 is a suspension of human eASCs of allogeneic origin, containing CryoStor® CS10
(sterile buffered solution) as excipient, dispensed in disposable vials, with no microbial 
preservative agents. The cells will be given on Days 1 and 3 at a dose of 160 million cells 
(2 million cells / mL, total volume 80 mL) each day through a 20-30 minute (240 mL/hr) IV 
central line infusion after dilution with Ringer Lactate solution. Total dose 320 million cells.
Placebo (CryoStor® CS10 and Ringer Lactate) will be given also through a 20-30 minute 
(240 mL/hr) IV central line infusion at the same quantity (total volume of 80 mL) and 
following the same schedule than the active treatment.
To ensure the double blinding, the primary packaging of Cx611 and placebo will be identical 
and the administration of the medication will be masked. In addition, a specific blinding plan 
at each site will document all personnel involved in the trial and their responsibilities as per 
the assignment with regard to the blind (see section 9.4).
9.1.2
Identity of Investigational Product(s): Dosage Form, Dose and Administration 
Route
Investigational product (Advanced Therapy Investigational Medicinal Product 
[ATIMP])
Drug substance
Expanded human viable allogeneic mesenchymal adult stem cells extracted from adipose 
tissue (eASCs).
eASCs is presented as a frozen cell suspension of expanded human viable allogeneic 
mesenchymal adult stem cells, derived from adipose tissue of subdermal origin.
The subdermal adipose tissue is obtained from an allogeneic selected healthy donor through 
liposuction. Donation procurement and testing are carried out according to the applicable 
regulation, in particular Directive 2004/23/EC and therefore under the implementation of
Directives 2006/17/EC, 2006/86/EC and Royal Decree 1301/2006.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 65 of 130
Excipients
CryoStor® CS10, animal-free and protein-free, defined cryopreservation medium containing 
10% (v/v) dimethyl sulfoxide (DMSO) (70).
Physicochemical and biological properties
The IMP consists of an allogeneic stem cell suspension in sterile buffered solution containing 
CryoStor® CS10 as excipient. This excipient constitutes an optimised biopreservation media 
for cells and tissues to preserve cells in ultra-low temperature environments (-80ºC to -
196ºC), which enables to maintain the characteristics of the drug substance, eASCs during the 
freezing, storage, and thawing process. CryoStor® CS10 contains 10% of DMSO in the 
formulation as cryopreservant.
At the time of administration, the frozen product is thawed by adding an isotonic solution, i.e. 
Ringer lactate, to obtain an individual cell suspension that, afterwards, can be injected in 
humans.
Frozen product appearance is a white homogeneous solid, which becomes a clear yellowish 
suspension when thawed. The product is supplied as a frozen cell suspension for infusion containing 
16 million cells/mL in single-use vials. The vials are tightly closed with rubber stoppers and 
sealed with a cap.
The product had an initial re-test period of 18 months if stored at -140°C or below. This re-
test period has been extended and updated expiry dates are reflected in the Interactive 
Response Technology (IRT).
For administration eASCs will be thawed and diluted in Ringer Lactate. The material 
contained in the vials will be transferred to infusion bags for further dilution prior to IV 
administration. Detailed instructions on preparation of the medication will be provided to 
sites.
It is recommended that the administration of the reconstituted product starts not later than 
45 minutes once the product is removed from the cryopreservation chamber to ensure the 
administration is completed within 75 minutes. 
Placebo
The study placebo will consist of vials containing CryoStor® CS10 that will have similar 
external appearance to that of the verum product and will be thawed, diluted and prepared for 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 66 of 130
IV administration with Ringer Lactate as described for the eASCs, following the same 
administration schema.
9.1.3
Packaging and Labelling
Packaging and labelling of the Cx611 will be performed by TiGenix according to Good 
Manufacturing Practice (GMP) principles and local regulation. Products' labelling will report 
the following information:

Name and address and contact phone of the Sponsor.

The reference of the trial: code.

Pharmaceutical dosage form and administration route.

The number and units of the dosage form, batch number and expiry date.

The statement “clinical research sample”.

Storage conditions.

The investigator’s name and the site name.

The statement “This medicine may contain cells of human origin”.

Use according to the instruction manual included.
Container
The product is supplied as a frozen cell suspension for infusion containing 16 million 
cells/mL in single-use vials. The vials are tightly closed with rubber stoppers and sealed with 
a cap.
The packaging material is made up by:

Primary package: polyolefin plastic sterile vials with sterile rubber stopper and 
seal.

Labels printed in black ink by thermal transfer printer.
Secondary packaging: cardboard box with external labelling, containing two vials duly 
labelled.
The diluent buffer (Ringer’s lactate solution) is supplied in plastic bags (the same packaging 
from the manufacturer).
A stock of diluents together with the ancillary materials for the preparation and the 
administration of the IMP will be supplied duly labelled to the participating sites.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 67 of 130
9.1.4
Storage and Disposition of Study Medication
Both Cx611 and placebo vials will be shipped under temperature controlled conditions, using 
appropriate transport for biological samples. Shipping material is also duly labelled and will 
contain the package content list.
The IMP must be stored at -140ºC or below (liquid nitrogen or cryogenic freezers). 
Specific instructions will be provided within a separate Study Operations Manual (SOM).
9.1.5
Handling of Study Medication
Study medication will be shipped by specialised courier to the hospital pharmacy or 
designated site storage facility, according to local practice and/or regulations. 
The Drug Administrator or Designee will maintain adequate records of the receipt and 
disposition of shipment to the site, temperature excursion as well as the corresponding 
accountability. All used and unused vials of Cx611 and placebo should be destroyed at site as 
per the local standards. 
The administration must be performed by authorised personnel with appropriate protocol 
training. 
The SOM that will be provided to the site will ensure an appropriate training.
9.2
Method of Assigning Patients to Treatment Groups
Treatments will be allocated following a pre-established randomisation list, which will take 
into account, in order to balance different factors between the study treatments, a stratified 
allocation using the following criteria:
!
shock, or
!
invasive mechanical ventilation, or 
!
both
In each stratum, patients will be randomised 1:1 to Cx611 or placebo.
During Screening, after confirmation of inclusion/exclusion criteria, all eligible patients will 
be randomised via IRT to one of the treatment arms. After performing the screening visit and 
verifying inclusion and exclusion criteria and subject´s eligibility, the investigator will place a 
screening and approval call to the 
 physicians to be provided with a randomisation 
authorisation number. No patient will be randomised without this authorisation number. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
).
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 68 of 130
 personnel will also be available for consultation in case of screening doubts and for 
medical advice of subject´s management. The 
 will keep record of the conversations 
with investigators in a dedicated database and available for review on a monthly basis at least. 
The investigator or his/her delegate will contact the IRT after confirming that the patient 
fulfils all the inclusion/exclusion criteria. The IRT will assign a randomisation number to the 
patient, which will be used to link the patient to a treatment arm and will specify a unique 
medication number for the package of IMP to be dispensed to the patient at each 
administration date. The package of IMP will include 2 vials of Cx611 or placebo properly 
labelled.
Prior to assigning the randomisation number, the site will inform the IRT provider about the 
stratum of the patient. The randomisation numbers will be generated using the following 
procedure to ensure that treatment assignment is unbiased and concealed from patients and 
investigator staff. A patient randomisation list will be produced by the IRT provider using a 
validated system that automates the random assignment of patient numbers, taking into 
account the stratum, to randomisation numbers. These randomisation numbers are linked to 
the different treatment arms, which in turn are linked to medication numbers. A separate 
medication list will be produced by or under the responsibility of the IRT provider using a 
validated system that automates the random assignment of medication numbers to packs 
containing the IMP. 
The randomisation scheme for patients will be reviewed and approved by clinical team or a 
member of the Biostatistics Quality Assurance Group.
9.3
Selection of Doses in the Study
Dose identification for the clinical trial in cell therapy does not follow the same models used 
for traditional drugs. The models used to determine the dose of a drug are based on the studies 
in Phase I, in which different aspects are assessed such as the metabolism up to the excretion 
of the product. A cell therapy medicinal product consists of cells and not of isolated 
molecules. Therefore, cell products are not subject to commonly defined laws in 
pharmacokinetics and pharmacodynamics of traditional products. An example is the absence 
of metabolism in hepatic cytochromes that obviously should not happen. For these reasons, 
the decision related to a dose administration in cell therapy, even though based on scientific 
data, does not follow traditional diagram.
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nt
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CCI
CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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Page 69 of 130
The safety and feasibility of IV eASC administration has been demonstrated in earlier phase I 
studies: a phase Ia/IIb in rheumatoid arthritis (1) where repeat doses (3 administrations one 
week apart) of 1, 2 and 4 million cells /kg were tested in 46 patients, and a phase I study in 
healthy volunteers in a LPS challenge trial, where a single dose of 0.25, 1 and 4 million cells 
/kg were tested in 24 healthy volunteers.
The dose schedule in the present study consists of two IV administrations of 160 million cells 
two days apart (Days 1 and 3). This dose is equivalent to a dose of 2 million cells/kg in a 
subject of 80 kg. No safety concerns have been detected under any of the tested doses, 
nevertheless in the latest phase I LPS response study in healthy volunteers , the highest dose, 
showed some proinflammatory and procoagulant effect. Thus, the 2 million cells/kg was 
selected by a Clinical Advisory Board as thought to better fulfil the safety requirements. 
9.4
Blinding
Treatments will be prepared (by unblinded personnel) for administration in a blinded location. 
The infusion can be started (bag and system connected to pump and to central catheter and 
pump started) by blinded or unblinded personnel, however follow-up of infusion and 
assessments pre-, during and post-infusion will be done by blinded personnel. Once 
reconstituted, the IMP will be masked to prevent any potential breach of the double blind 
design. 
In addition, the double blind will be preserved by having unblinded and blinded team at the 
site. There will be a specific blinding plan at every site, which will document all personnel
involved in the trial and their responsibilities as per the assignment with regard to the blind. 
This blinding plan will be agreed and signed by TiGenix and the corresponding site 
responsible(s), before any inclusion at that site.
In particular, the study nurse (or designated personnel) who will prepare the treatment for 
administration will remain unblinded but the investigator/s (or designated personnel) will 
administer the treatment, collect the AEs and evaluate the clinical outcomes of sCABP in a 
blinded fashion. The unblinded study nurse or unblinded designated personnel will NOT be 
allowed to participate in any efficacy or clinical assessment during the study.
The unblinded personnel are not allowed to share information about the treatment with any 
member of the blinded team.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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Page 70 of 130
If the investigator deems that unblinding is necessary for the appropriate clinical care of the 
participant, he or she will be able to perform an emergency unblinding at any time via the IRT
used for patient randomization. In this case the investigator will promptly document and 
explain the unblinding to the sponsor.
9.5
Prior and Concomitant Therapy
All additional treatment(s) being taken by the patients on entry into the study (prior to study 
treatment) or any time during the study (concomitant treatment) must be documented on the 
appropriate pages of the CRF (trade name and/or generic name).
Subjects will also receive SoC therapy as per local guidelines, with IV and/or oral antibiotics 
or other drugs, either alone or in combination. Details for dose and frequency of 
administration of SoC therapy (as well as warnings, precautions, and contraindications) can 
be found in the referenced summaries of product characteristics for the specific drugs selected 
by the investigator as SoC therapy. Investigators will be instructed to select only country-
approved therapies.
9.6
Prohibited Medications
The following medications and therapies will be prohibited during the study. In the event of a 
question, the 
should be contacted.
!
Chemotherapy for neoplasms or other diseases.
!
Immunosuppressant therapy (including chronic treatment with any anti-TNFα) 
or chronic high doses of steroids (single administration of ≥2 mg/kg body weight 
or 20 mg/day of prednisone or equivalent for ≥2 weeks)*.
*Concomitant steroids for septic shock are allowed; the doses recommended by 
current guidelines (22) (hydrocortisone 200–300 mg/day, for 7 days) do not
exceed ≥2 mg/kg of equivalent prednisone units (see Appendix A for 
corticosteroid conversion table).
!
Stem cell, organ or bone marrow transplant.
!
Treatment with biological agents (e.g. antibodies, cells) or with plasma
exchange treatment.
!
Other investigational medicinal products.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
or 
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 71 of 130
9.7
Treatment Adherence
Treatment adherence will be ensured because treatment will be injected by trained clinical 
staff at Visit 1 (Day 1) and Visit 3 (Day 3).
9.8
Drug Accountability
Drug accountability will be performed at the site by the unblinded personnel trained and 
designated for this task.
9.9
Treatment Compliance
Cx611 (eASCs) and placebo will be administered under the supervision of the study nurse, or 
delegated professional, thus ensuring treatment compliance for all patients.
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Version: Final, Version 7, incorporating Amendment 5
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10 STUDY ASSESSMENTS
10.1 Safety, Efficacy and Additional Endpoints
10.1.1 Primary Safety Endpoints by Day 90
Safety measured throughout the study by the incidence of TEAEs judged related or not 
to study treatment, focusing on any AESI. Safety analyses will be performed based on the 
Safety Population.
The independent 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 AEs, from time of signature of inform 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 
TEAEs.

AESI (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 [non-ventilated 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 24h [±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 
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min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24h (±1 h) post each IMP 
infusion), Day 2 (at least 4 times), Day 3 (at Pre-dose, and at 0.5h (±5 min), 1h (±10 
min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24h (±1 h) post each IMP 
infusion), then at least 4 times daily while in the ICU or, if discharged from ICU,
then at least once on Days 4, 5, 6, 7, 8-10, 14, 29, 90 or study discontinuation.

Changes in 12-lead ECG from Screening, Days 1 and 3 both 5 hours ± 1 hour
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, and 90 or study discontinuation.

Anti-HLA/donor Abs on Day 1 Pre-dose, Days 14 and 90 or study discontinuation.
10.1.2 Exploratory Safety Endpoint by Months 6 (Day 180), 12 (Day 365), 18 (Day 545) 
and 24 (Day 730) (Phone Calls)

Relatedness to study treatment, actions taken and outcome of spontaneous SAEs will 
be captured after Day 90.
10.1.3 Secondary Efficacy Clinical Endpoints
Efficacy analyses will be performed based on the safety population.
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 subjects are both alive and free of mechanical 
ventilation (e.g., a patient who is extubated on Day 2 of the study and remains alive 
and free of the ventilator for the remainder of the 28-day study period would receive 
a VFD score of 26, whereas the patient who is ventilated until death on Day 2 would 
receive a score of zero).
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5. Percentage of patients alive and free of vasopressors at Day 29.
6. Vasopressor treatment-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

Clinical response visit at Day 14±2.

Clinical response visits at Day 8-10 and Day 29 or early discontinuation.

Time to sCABP clinical 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 that qualified the patient 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 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 Days 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 (LOS) in ICU and hospital after randomisation. 
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!
Number of ICU-free days over 28 days.
!
Changes in SOFA score daily during stay at ICU.
!
Changes on CXR 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.
10.1.4 Exploratory Biological Endpoints
10.2 Demographic and Other Baseline Characteristics
10.2.1 Demographic Characteristics
The following demographic will be collected at the Screening visit:
!
Date of birth/age
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urs af
atm
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
Gender

Race (if applicable)
10.2.2 Other Baseline Data
The following baseline data will be collected at the Screening visit:

CURB 65

Streptococcus pneumoniae antigen in urine

Pathogen identification and susceptibility testing. Pulmonary samples can be obtained 
by BAL and/or mini-BAL/PSB and/or by ETA for intubated patients, and by sputum 
production for non-ventilated patients. Samples will be rapidly processed for Gram 
stain and culture and/or other established standard rapid diagnostic system, e.g. PNA 
FISH or Cepheid GeneXpert for S. aureus, urinary antigen test for S. pneumoniae or 
Legionella, or rt-PCR. Should a bacterial pathogen grow in culture, susceptibility 
testing against the standard local antibiotic panel for the pathogen will be performed 
according to the site´s practice. Pathogen identification and susceptibility testing will 
also be performed in case of clinical suspicion of pneumonia recurrence.

CXR will be 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 29 and 
for recurrence/reinfection assessment. Text from radiologist or ICU physician study 
CXRs reports will be printed signed and dated. CXRs images will be kept by the 
investigator in the patient´s clinical record and available for review by Adjudication 
Committee (AC) or DMC.
10.2.3 Medical History, Prior and Concomitant Medications and Procedures
Medical history will be recorded at the Screening visit including immunological status (i.e.
previous pregnancies and/or transplants and/or blood transfusions). Prior medication taken 
within 2 weeks before the inclusion in the study will be recorded at the Screening visit. 
Concomitant medication and procedures (e.g. tracheostomy) will be recorded on the 
concomitant medication log/page of the CRF throughout the study.
The duration of each infusion of study medication will be recorded on the CRF.
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10.3 Safety Assessments
10.3.1 Safety Variables
The following safety variables will be measured:

All AEs (including TEAEs).

Physical examination including signs and symptoms of pneumonia.

Signs for hypersensitivity reactions or anaphylaxis.

Vital Signs.

12-lead ECG

Laboratory Safety Assessments.

Anti-HLA/donor antibodies.
The timing of the assessments is described in Table 1, Section 1.
10.3.2 Adverse Events
AEs will be recorded from the time of signing the informed consent to Visit 11 (Day 90). AEs 
occurring from the beginning of the administration of study medication and until Visit 11 
(Day 90) or study discontinuation will be analysed as TEAEs. From Day 90 and up to two 
years after Day 1, the investigator will report any SAE. For further information of definitions 
and reporting of AEs, SAEs, and AESIs see Section 11 below.
10.3.3 Physical Examination
All patients will undergo a complete physical examination at Screening, Day 1 (Pre-dose), 
Days 2, 3 (Pre-dose), Days 4, 5, 6, 7, 8-10, 14, 29, 90, or study discontinuation, including the 
following parameters:

Height (only at Screening).

Weight (only at Screening, Days 3, 14, 29, or study discontinuation).

A systematic physical examination covering all body systems.

A clinical assessment (presence of signs and symptoms) of AESI,
i.e. 
thromboembolic events and hypersensitivity.
10.3.4 Assessment of Clinical Signs and Symptoms of Pneumonia
The following symptoms will be carefully checked during the physical examination:

Difficulty breathing.

Cough.
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
Production of purulent sputum.

Fever.

Wheezing.

Chest discomfort.

Chest pain.

Hypotension.

Tachycardia.

Tachypnoea.

Hypoxemia.

Clinical evidence of pulmonary consolidation (if CXR available).

Elevated total white blood cell (WBC) count or leukopenia (if available).

New infiltrates in a lobar or multilobar distribution (if CXR available).
10.3.5 Signs for Hypersensitivity Reactions or Anaphylaxis
In addition to the vital signs described in Section 10.3.6, all patients will be examined for 
signs and symptoms of skin reactions and respiratory distress requiring therapeutic 
intervention during the first 24 hours after the infusion, including the following parameters:

Skin reactions such as rashes, hives, etc.

Signs and symptoms of respiratory distress which require therapeutic intervention 
including drugs and/or changes in mechanical ventilation settings.
10.3.6 Vital Signs
The following vital signs will be assessed at 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 24h (±1 h) post each 
IMP infusion), Day 2 (at least 4 times i.e. every 6h ± 1h), Day 3 (at Pre-dose, and at 0.5h (±5 
min), 1h (±10 min), 2h (±10 min), 4h (±20 min), 12h (±30 min) and 24h (±1 h) post each IMP
infusion). At Days 4, 5, 6, 7, 8-10, 14, 29, 90, or study discontinuation: if in the ICU at least 
4 times daily i.e. every 6h±1h, if discharged from ICU at least once:

Systolic and diastolic blood pressures.

Heart rate.

Core temperature (tympanic, rectal or bladder).

Respiratory rate (in non-ventilated patients).
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When more than one measurement is available for screening, Day 2 and Day 4 onwards only 
the highest and the lowest value measured for each vital sign for that time period will be 
recorded in the CRF for that timepoint.
10.3.7 Electrocardiogram (ECG)
A 12-lead ECG used as part of the SoC in ICU will be performed during Screening and at 
Days 1 and 3 (Post-dose).
The following parameters will be recorded: rhythm, ventricular rate, PR interval, QRS 
duration, QT, QTcB and QTcF. Pathological changes in ECG tracing will be recorded as well.
All ECG tracings are to be printed, signed/dated and their assessment added to the patient’s 
CRF. Print outs will be kept as source documentation and available for review by AC or 
DMC until the end of the study.
Additional ECGs may be performed in case of findings/need at investigators’ discretion.
10.3.8 Laboratory Safety Assessments
Laboratory safety assessments will be performed locally, in each centre’s laboratory. The
tubes for blood and urine samples will be collected according to local laboratory 
requirements.
The samples for laboratory safety assessment will be taken at the following time points:
- During the Screening period.
- On Day 1 before the first infusion (as close as possible to the administration of the 
first dose; if first infusion is administered the same day of extraction of the Screening
sample, there is no need to repeat the assessment).
- On study Days 2, 3 (only haematology and coagulation), 4, 7, 14 (±2), 29 (±2), 90 
(±4) and at ET (if applicable).
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The following laboratory safety parameters will be measured: 
Haematology and Coagulation Parameters
Haematology and coagulation (tubes according to local laboratory requirements)
WBC count
Monocytes absolute value and %
Red blood cell (RBC) count
Eosinophils absolute value and %
Haemoglobin (Hb)
Basophils absolute value and %
Haematocrit (HCT)
Platelets
Mean corpuscular volume (MCV)
Reticulocytes absolute value and %
Mean corpuscular haemoglobin (MCH)
D-dimer
Mean corpuscular haemoglobin concentration 
(MCHC)
Activated partial thromboplastin time
(APTT). Partial Thromboplastin Time 
(PTT) only in case APTT is not 
performed locally.
Neutrophils absolute value and %
Prothrombin time (PT) and International 
Normalised Ratio (INR)
Lymphocytes absolute value and %
Serum Biochemistry Parameters
Serum Biochemistry (tubes according to local laboratory requirements)
Sodium
Alkaline phosphatase (ALP)
Potassium
Alanine aminotransferase (ALT)
Calcium
Aspartate aminotransferase (AST)
Urea
Creatine kinase (CK)
Creatinine
Gamma glutamyl transpeptidase (GGT)
Albumin
Lactate dehydrogenase (LDH)
Phosphate
Total Bilirubin
Glucose
Uric acid
Cholesterol
Chloride
Triglycerides
Conjugated bilirubin
Magnesium
Unconjugated bilirubin
Bicarbonate
Amylase
Total protein
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Urinalysis Parameters
Urinalysis (tubes according to local laboratory requirements)
Leucocytes
RBCs
Protein
pH
Bilirubin
Nitrite
Urobilinogen
Specific gravity
Ketones
Glucose
Microscopy (as required upon anomalies in Urinalysis)
Additional and repeat testing may be performed at the discretion of the Investigator.
10.3.9 Anti-HLA/donor Antibodies
For the analysis of anti-HLA donor-specific Abs, the tubes collected for evaluating 
 
will be used. On Day 90 (±4), where the T cell response sampling does not occur, 
the following tubes will be needed: 4.5 mL EDTA.
The assessment of anti-HLA/donor Abs will be performed at the following time points:
- On Day 1 before the first infusion.
- On study Days 14 (±2) and 90 (±4) and at ET visit (if applicable)
10.4 Efficacy Assessments
10.4.1 Ventilator-free Days
VFD over 28 days are defined as one point for each day during the measurement period that 
subjects are both alive and free of mechanical ventilation (71).
For example, a patient who is extubated on Day 2 of the study and remains alive and free of 
the ventilator for the remainder of the 28-day study period would receive a VFD score of 26, 
whereas the patient who is ventilated until death on Day 2 would receive a score of zero.
In patients with a tracheostomy, the last day of ventilator support will be considered the day 
of extubation.
The variables “Ventilator and vasopressors treatment-free days” and “vasopressors 
treatment-free days” will be calculated in a similar way (i.e. number of days that a patient 
is alive and both mechanical ventilation and vasopressors free days over 28 days; number 
stigator
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whereas
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In
In
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of days that a patient is alive and vasopressors free days over 28 days, respectively).
10.4.2 sCABP Clinical Response 
Clinical Response will be assessed at Days 8-10, 14 (±2), 29 (±2) and at ET visit (if 
applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.4.3 APACHE II and SOFA Scores
See appendices C and D.
10.5 Immunological Assessments
The analyses of the immunological parameters will be performed in the following central 
laboratories:
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CHE II 
HE I
ndidices
es C
5 Imm
Im
The
Th
PPD
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Pro
 Use
PPD
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Pro
f Use
CCI
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10.6 Total Blood Volume
The total estimated volume of blood specifically collected for the study will be around 
222.2 mL spread over 90 Days (4 mL x 1 = 4 for anti-donor antibodies; 40 mL x 4 = 160 mL 
for 
and 9.7 mL x 6 = 58.2 mL for 
).
For the calculation of this volume, routine determinations performed at local laboratories
(blood culture at Screening, haematology, coagulation and blood chemistry at Screening and 
on Days 1, 2, 3 [only haematology and coagulation], 4, 7, 14, 29, 90 or study discontinuation) 
have not been taken into account.
10.7 Appropriateness of Measurements
Standardised methods for measurements of efficacy and safety will be used. The laboratory 
analyses of 
, anti-HLA/donor Abs, 
 
will be performed by the respective central laboratories using 
validated assays.
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L
laborato
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Scre
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saf
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CCI
CCI
CCI
CCI
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11 ADVERSE EVENTS
The development of the IMP is under the “Detailed guidelines on good clinical practice 
specific to advanced therapy medicinal products” [Dec 2009 ENTR/F/2/SF/dn D (2009) 
35810] and it implies that relationship to the procedure of administration of IMP (i.e. through 
intravenous central catheter) is also to be assessed for any adverse event reported among other 
obligations for specific reporting related to IMP administration and use.
All definitions listed below follow ICH E2A and apply for either IMP, its administration or 
procedure related to IMP administration.
11.1 Definitions
11.1.1 Adverse Event (AE)
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an (IMP, whether or not considered related to the IMP. 

Medical disorders, including concomitant diseases present at the time of signing the 
informed consent are only considered AEs if they worsen after this time. All baseline 
conditions should be recorded as part of Medical History.

Changes in laboratory parameters (biochemistry, haematology, urinalysis), as well as 
abnormal results of other tests (worsening results), that are detected after the 
administration of study medication and that the investigator considers to be clinically 
relevant should be recorded as AEs or SAEs, provided that the definitions given in 
this section and in the 11.1.4 section (“Serious Adverse Event”) are met, respectively. 
In contrast, clinically significant changes in laboratory parameters or other tests that 
are associated to the disease under study will not be rated as AEs or SAEs, unless the 
investigator judges them to be more serious than expected based on the patient 
condition.
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For the purpose of this study, any clinical failure related to pneumonia or severe sepsis
(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 clinical 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) will not be reported as an AEs as they will be captured 
as sCABP failures.
11.1.2 Adverse Reaction (AR)
All untoward and unintended responses to an IMP related to any dose administered. All AEs 
judged by either the reporting Investigator or the Sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse reactions. The expression reasonable 
causal relationship means that a relationship between the IMP and the adverse event cannot be 
ruled out. In this study, AEs for which no investigator assessment is available (missing or 
unknown) are considered as adverse reactions.
11.1.3 Unexpected Adverse Reaction (uAR)
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure for an unapproved IMP or the SmPC/ 
Product Information for a marketed drug).
Reports which add significant information on specificity or severity of a known, already 
documented Serious Adverse Reaction (SAR) constitute unexpected events. In the same way, 
when the outcome of the AR is not consistent with the applicable product information, this 
AR should be considered unexpected.
11.1.4 Serious Adverse Event (SAE)
A SAE is defined as any untoward medical occurrence that, at any dose: 

Results in death, or

Is life-threatening, or

Requires inpatient hospitalisation or prolongation of existing hospitalisation, or

Results in persistent or significant disability/incapacity, or
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
Is a congenital abnormality/birth defect, or

Is a medically significant event or requires intervention to prevent at least one of the 
outcomes listed above, or

Is a suspected transmission of an infectious agent
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situation, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation, but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. These 
events should also usually be considered serious. Examples of such adverse events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalisation; or development of drug 
dependency (addiction) or drug abuse.
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
Hospital admission means that the patient has stayed at least 24 hours at the hospital or an 
emergency department for observation and/or treatment that could not have been 
made/administered at the physician’s office or in an outpatient setting. 
Prolongation of hospitalisation is defined as any extension of an in-patient hospitalisation 
beyond the stay required in relation to the original reason for the initial admission, as 
determined by the investigator or treating physician. Complications occurring during 
hospitalisation are AEs. If a complication extends a hospitalisation or meets any other 
seriousness criteria, the event will be considered a SAE.
The following reasons for hospitalisation or prolongation of hospitalisation are not considered 
AEs, and therefore not SAEs:

Hospitalisation for administration of IMPs. Exception: Hospitalisation or prolonged 
hospitalisation for a complication of study treatment administration will be reported 
as a SAE.

Hospitalisation to perform an elective treatment of a condition prior to subject entry 
into the study without worsening from its pre-existing condition.
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
Hospitalisation for diagnostic investigations (e.g., scans, endoscopy, sampling for 
laboratory tests, etc.) that are not related to an adverse event.

Hospitalisation for standard monitoring of a pre-existing disease or medical condition 
that has not worsened (e.g. hospitalisation for coronary angiography in a patient with 
stable angina pectoris).

Hospitalisation for ≤ 24 hours (attendance at the Emergencies).

Other reasons may include: hospitalisations for elective cosmetic surgery; due to 
social reasons or due to convenience reasons.
11.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR)
All Suspected Adverse Reactions which occur in the trial and that are both unexpected and 
serious.
11.1.6 Adverse Event of Special Interest (AESI)
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the Sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterise and understand it. Depending on the nature of the event, 
rapid communication by the trial Sponsor to other parties (e.g. DMC) might also be warranted 
(based on Council for International Organizations of Medical Sciences [CIOMS] VI).
The specific AEs considered as AESI for this study are:
1.-Thromboembolic events
2.- Hypersensitivity reactions such as anaphylaxis
The specific and systematic evaluation of these AESI by the investigator at study visits and 
time-points is documented in the physical examination section of the protocol (see 
section 10.3.3) and pre-infusion, during, and post-infusion of IMP (see section 10.3.5). 
Additional information will be required (as applicable).
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11.2 Adverse Event Severity Assessment
Seriousness and Severity should not be confounded. 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). 
This is not the same as "serious," which is based on patient/event outcome or action criteria 
usually associated with events that pose a threat to a patient's life or functioning (see 
Section 11.1.4). Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations.
Severity of the adverse events will be recorded at the time they occur and will be rated 
according to the following criteria: 

Mild (asymptomatic), an event easily tolerated by the patient, causing minimal 
discomfort that does not prevent the patient from fulfilling daily activities

Moderate, symptomatic, but does not significantly interfere with function

Severe, causes a significant interference with function 
If severity of one event evolves over time only the worst severity category will be recorded.
Death itself is not an adverse event, but rather the outcome of a previously reported event, 
which should be described using medical terminology. Only in those cases where either no 
cause for death is known (e.g. sudden death, Death NOS) the event “death” should be 
reported. 
The terms death/death of unknown cause and sudden death are clearly distinct and must not 
be used interchangeably.
11.3 Adverse Event Relatedness Assessment (Causality Assessment)
The investigator must establish, based on his clinical judgment and the information on IMP 
provided by the sponsor the causal relationship between the investigational product, its 
administration and the occurrence of the AE/SAE. 
The expression: “reasonable causal relationship” means to convey in general that there is 
evidence or argument to suggest a causal relationship. In this study, AEs that are considered 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 91 of 130
as related to IMP, including for which no investigator assessment is available (missing or 
unknown) are considered as adverse reactions. For AEs considered as not related to study 
treatment it is assumed that there is no reasonable causal relationship. 
Detailed considerations to be taken into account on causality assessment include: 
-
associative connections (time or place: plausibility), 
-
pharmacological explanations, 
-
previous knowledge of the drug, 
-
presence of characteristic clinical or pathological phenomena, 
-
exclusion of other causes and/or absence of alternative explanations.
Other causes, such as: the natural history of other underlying diseases, including and namely 
the disease under study, concomitant treatments, other risk factors like surgical procedures, 
and time relationship of the event to the IMP need to be taken into account for the assessment.
Causal relationship to the IMP (Cx611 or Placebo) will be classified:

RELATED NO: if the following circumstances apply,
o
Not related: if there is no reasonable temporal association between event or 
laboratory test abnormality onset and administration of the IMP or that can be 
reasonably explained by other factors, including underlying disease, 
complications, or concomitant medications. Clearly due to extraneous causes.
o
Unlikely: event or laboratory test abnormality, with a time to IMP 
administration that makes a relationship improbable (but not impossible). 
Diseases or other drugs provide plausible explanations.

RELATED YES: if the following circumstances apply,
o
Possible:
Event or laboratory tests abnormality, with reasonable time 
relationship to drug intake. Could also be explained by disease or other drugs. 
Information on drug withdrawal is lacking or unclear.
o
Probable: Event or lab tests abnormality, with reasonable time relationship to 
drug intake. Unlikely to be attributed to disease or other drugs. Response to 
withdrawal clinically reasonable. Rechallenge not necessary.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 92 of 130
o
Definitive: Event or laboratory test abnormality, with plausible time relationship 
to drug intake. Cannot be explained by disease or other drugs. Response to 
withdrawal plausible (pharmacologically, pathologically). Event definitive 
pharmacologically or phenomenologically (an objective and specific medical 
disorder or a recognised pharmacological phenomenon). Rechallenge (if 
necessary).
Causal relationship to the IMP administration process will be classified:

RELATED NO: if the following circumstances apply,
o
Not related: if there is no reasonable temporal association between event and 
IMP administration process or that can be reasonably explained by other factors, 
including underlying disease, complications, or concomitant medications. 
Clearly due to extraneous causes.
o
Unlikely: event with a time to IMP administration process that makes a 
relationship improbable (but not impossible). Diseases or other drugs or 
administration processes provide plausible explanations.

RELATED YES: if the following circumstances apply,
o
Possible: Event with reasonable time relationship to IMP administration process. 
Could also be explained by disease or other drugs or administration processes. 
Information on drug withdrawal (not re-administered) is lacking or unclear.
o
Probable: Event with reasonable time relationship to IMP administration 
process. Unlikely to be attributed to disease or other drugs or administration 
processes. Response to withdrawal (not re-administered) clinically reasonable.
o
Definitive: Event with plausible time relationship to IMP administration process. 
Cannot be explained by disease or other drugs or processes. Response to 
withdrawal 
plausible 
(not 
re-administration). 
Event 
definitive 
phenomenologically (an objective and specific medical disorder).
The relatedness of the event to the IMP administration process as well as the study drug 
will be assessed for all events (AEs and SAEs).
All unexpected SAEs related to the IMP will be considered for regulatory reporting 
purpose (SUSARs).
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
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11.4 Adverse Event Collection Period
All AEs that occur from signature of the informed consent will be recorded, regardless of the 
intensity, seriousness or relationship to study drug, to visit 11 (Day 90) and in case of 
withdrawal up to 30 days after the last IMP administration. AEs occurring from the beginning 
of the administration of study medication and until EOS or study discontinuation will be 
analysed as TEAEs. After Day 90 or 30 days after last IMP administration for early 
discontinuation only SAEs will be reported by the investigator until Month 24 + 30 days.

Pre-existing conditions will be collected on the baseline “Medical History” electronic 
case report form (eCRF)
module and will include, among others, active 
(symptomatic) diseases, diseases under treatment, chronic diseases and long term 
effects of past events present at the time of baseline assessment.

Events that firstly occur within signature of the Informed Consent and administration 
of the study treatment [Non-Treatment Emergent Adverse Events (NTEAEs)] will be 
recorded. Any worsening of Medical History events along study treatment period will 
be subsequently recorded as AEs/SAEs as detailed in Section 11.1.1).

Any AE that is ongoing at the last visit of the subject, either completed or withdrawn 
(as defined per protocol), should be followed up until the AE is resolved or stabilized 
or at least up to 30 days after the last protocol scheduled visit or last IMP dose 
administration (whatever is applicable).

From Day 90 through Month 24, the follow-up incidental SAEs will be captured by 
phone contact with the patient and/or his/her GP (or family doctor) every 6 months.
All AEs elicited by the investigator during the defined AE collection period must be recorded 
in the eCRF as per detailed instructions in the corresponding section. When an AE meets the 
criteria of seriousness (SAE), it must also be recorded on the Immediately Reportable Event 
form and in the eCRF.
11.5 Adverse Event Reporting
11.5.1 Recording of Adverse Events
All adverse events occurring through Day 90 of the trial must be documented in the eCRF. 
This applies not only to those AEs supposedly related to the IMPs, but also to the 
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Clinical Study Protocol
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Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
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Page 94 of 130
administration procedure or to any undesired experience, whether or not a causal relationship 
is suspected. SAEs captured by phone contact at Months 6 (Day 180), 12 (Day 365), 18 (Day 
545), and 24 (Day 730) will be recorded in the SAE report form.
Whenever possible, attempts should be made by the Investigator to provide a specific 
“Diagnosis” or “Syndrome” in addition to a description of the reported signs and symptoms. 
AEs should be reported as separate individual events. 
All AEs and Immediately Reportable Events (IREs) will be followed until they are resolved 
or until a stable situation has been reached. Depending on the event, follow up may require 
additional tests or medical procedures as indicated, and/or referral to a medical specialist.
Follow-up can be wavered in specific cases after consultation with the Sponsor. This 
permission must be documented per case and retained in the Sponsor File.
Each follow up should be reported in a different Safety/IRE Report or Pregnancy Report 
Form as applicable. The final outcome of the IRE or pregnancy should be reported on a final 
Safety/IRE Report or Pregnancy Report Form.
All AEs must be reported regardless of whether or not they are considered related to IMP 
administration or administration procedure, with the exception of:

A pre-existing condition that does not increase in severity; the pre-existing condition 
should be reported on the baseline “Medical History” eCRF module.

Abnormal laboratory values that have been recorded as being not clinically 
significant by the investigator in the source documents.

Medical or surgical procedures (e.g. endoscopy, appendectomy); however, the 
condition leading to these procedures, rather than the procedure itself, should be 
considered as AE.

The expected fluctuations of any disease(s) pre-existent, ongoing, or detected at study 
start (e.g. worsening of rheumatoid arthritis).
11.5.2 Immediately Reportable Events (IRE)
Events subject to immediate notification (within 24 hours), include but are not limited to:

Serious Adverse Events (SAEs),

Pregnancy of study subject (or female partner of a study subject),
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Clinical Study Protocol
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Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 95 of 130
!
Medication errors, namely overdose, leading to a suspected adverse reaction, 
!
Accidental exposure,
!
AE which leads to study drug discontinuation,
!
AESI.
For these events the applicable Safety/IRE Report or Pregnancy Report Form will be used for 
reporting accordingly.
11.5.3 Immediately Reportable Event Reporting
All IREs will be reported by the investigator to the monitor responsible for the clinical trial 
and to Takeda PV Operations (i.e., 
Such report will be made by e-mail (or fax)
using the Safety/IRE Report or the Pregnancy Report Form as applicable.
The completed form should be made available to Takeda PV Operations (i.e., 
)
within 24 hours by sending it to the following e-mail address:
If electronic reporting of IREs is not possible, the form may be submitted via fax to:
Reporting of IREs by using the Safety/IRE Report Form does not exempt from the need to 
complete all information relating to such AEs in the specific CRF section.
Initial minimum information for reporting an adverse event should include the following:
!
AE and onset date
!
Patient identification, sex, and age (or date of birth)
!
Information on IMP administration (dates of IMP infusions)
!
Information on treatment for unexpected and reportable SUSAR (see below)
!
Name and address of the reporting physician
!
Causal relationship to the study treatment or IMP application process.
The complete Safety/IRE Report Form containing all information will be made available to 
the Sponsor (or designee) within the next 2 calendar days. If the SAE or IRE is still active at 
Property of Takeda: For Non-Commercia
e Onl
d Subject to the Applicable Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 96 of 130
the time of reporting or further information is obtained after initial communication, this 
information must be updated accordingly.
The Sponsor is the last responsible for appropriate qualification and reporting of safety 
information to the competent authorities, to the ECs/IRBs and to the investigators.
When a SAE is both unexpected and related to the IMPs (SUSAR) will require expedited 
reporting to the competent authorities and ECs:
!
Fatal or life threatening SUSARs will be reported within 7 calendar days of the 
sponsor awareness of the event. Important additional information should be submitted 
within the following 8 calendar days. All follow-up information later received will be 
reported within 15 calendar days.
!
All other SUSARs will be reported within 15 calendar days of the sponsor becoming 
aware of the event.
In order to comply with Good Clinical Practice (GCP) requirements, all information provided 
by and to the investigator will be kept in the Investigator File at the centre.
11.5.4 Pregnancy Reporting 
Pregnancies of a female subject or the female partner of a male subject, occurring at least, 
while the subject is on protocol treatment or along the follow-up period, will be notified to the 
investigator and immediately communicated to the Sponsor (within 24 hours) using the 
Pregnancy Report Form and including the information in the eCRF.
In order to comply with this requirement, the completed form should be made available to the 
Sponsor (or designee) within 24 hours by sending it to the following e-mail address:
All pregnancies initiated during the patient´s participation in the trial (or up to 30 days after 
last IMP dose administration) which come to the knowledge of the investigator, after the 
closure of the clinical data base should be reported. A pregnancy as such is not an AE per se
but it is important enough to be reported in 24 hours like SAEs/IREs to the Sponsor (or 
designee) to be recorded in the safety data base. 
The pregnant subject or the subject´s consenting pregnant partner will be followed until the 
end of the pregnancy and the outcome of the pregnancy will be notified to the Sponsor (or 
designee) within 5 calendar days using a Pregnancy Report Form. 
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 97 of 130
Any complication during the pregnancy, spontaneous or therapeutic abortion, stillbirth, 
neonatal death, birth defect/congenital anomaly, other serious infant condition must be 
reported and followed up as an SAE and reported using the Safety/IRE Report Form.
In the case of a live “normal” birth, the Sponsor (or designee) should be informed as soon as 
the information is available. All neonatal deaths that occur within 30 days of birth should be 
reported, without regard to causality, as SAEs, using the Safety/IRE Report Form.
In addition, any infant death after 30 days that the Investigator suspects to be related to the 
in utero exposure to the investigational medicinal product should also be reported.
Infants should be followed until 3 months after delivery to detect any complication or 
developmental impairment.
The Investigator is encouraged to provide outcome information of the pregnancy of the 
female partner of a male subject, if this information is available to the Investigator and the 
female partner gives her permission.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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Page 98 of 130
12 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
12.1 Statistical and Analytical Plans
The statistical analysis will be performed by the Department of Biostatistics of
 using 
SAS® Version 9.3 or later. A summary of the analysis to be detailed in the Statistical Analysis 
Plan (SAP) is presented here. A complete SAP will be written and finalized before data base
closure.
12.1.1 Data Set to be Analysed
The following analysis set will be defined:
!
Safety: Includes all randomised patients who have received at least one dose of the study 
treatment irrespective of randomisation. The safety population will be the primary 
population for all the safety and efficacy analyses.
12.1.2 Summary Statistics
In general, data will be summarised by means of summary statistics. Continuous data will be 
presented with the number of observations, mean value, standard deviation, minimum,
median and maximum value. Categorical data will be presented as counts and percentages. 
Individual patient data will be listed.
12.1.3 Demographic and Other Baseline Characteristics
Patient disposition, demographic and other baseline data will be presented using summary 
statistics.
12.1.4 Safety Analysis
All safety analyses will be only descriptive. 
Adverse events will be collected throughout the study duration. All AEs (recorded after the 
signature of the informed consent) and TEAEs (those recorded from the beginning of study 
medication administration) will be tabulated. Specific tables will be provided for AESI
(thromboembolic events and hypersensitivity reactions).
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA v15.0) 
and tabulated by system organ class (SOC) and by preferred term (PT).
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ysis
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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Page 99 of 130
The number and percentage of subjects in each treatment group reporting at least 1 occurrence 
of an AE/TEAE for each unique SOC and PT will be tabulated. TEAEs will also be tabulated 
by severity and by the relationship to study medication in treatment groups as assessed by the 
Investigator. 
Subjects who experienced multiple adverse events within the same PT will be counted once 
for the summaries, using the worst severity.
The number and percentage of subjects in each treatment group reporting at least 1 occurrence 
of a SAE for each unique SOC and PT will be tabulated. SAEs will also be tabulated by 
severity and by the relationship to study medication in treatment groups as assessed by the 
Investigator. Listings of patients with SAEs, Deaths and AEs leading to discontinuation and 
individual narrative summaries for these cases will be provided.
The number and percentage of subjects (in each treatment group) prematurely discontinuing 
study treatment due to a TEAE will be tabulated by SOC and PT. 
Safety laboratory data will be presented by absolute and change from baseline values by visit.
Shift tables for each assessed laboratory parameter will be presented to summarise the change 
from Low, Normal, High values at baseline to ‘on treatment’ visit (Day 2) and post-treatment 
visits (Days 4, 7, 14, 29 and 90).
The number and percentage of subjects with laboratory, vital sign, ECG, or physical 
examination abnormalities at baseline, subsequent visits, or ET from the study will be 
tabulated by treatment group. The results of all laboratory test results, physical examination 
findings, ECGs, and vital signs will be presented in data listings. All abnormalities will be 
assessed for being clinically significant or not as per investigator.
Physical Examination and signs of hypersensitivity reactions
Physical examination data and observed signs of hypersensitivity reactions will be 
summarised in tables.
Vital Signs, Electrocardiogram, haematology, coagulation, blood chemistry and 
urinalysis
All vital signs, haematology, coagulation, blood chemistry, urinalysis and ECG data will be 
listed by subject. All values outside the normal reference ranges will be flagged in this listing. 
In addition all subjects with clinically significant abnormal values will be flagged as well in 
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this listing and also summarised in separate listings. The number of subjects with at least one 
clinically significant abnormal value will be summarised. For ECG data, qualitative results 
will also be listed by time windows. The significant abnormal values will be pre-defined in 
the SAP before the database closure.
12.1.5 Efficacy and Biomarkers Analyses
The efficacy and biomarkers analyses will be descriptive summaries in the safety population 
at the scheduled visits. 
The change from baseline in SOFA scores and all other secondary efficacy and biological 
variables will be summarised using descriptive statistics.
All data, including derived values that are computed for use in summaries or analyses, will be 
listed.
Baseline values will be defined as the last value obtained prior to first dosing and the value 
used in the baseline summary will also be used as the baseline value for purposes of 
computing change from baseline.
Data might be treated or transformed, as appropriate (e.g., log- transformed or ranked).
Details of any transformed data will be specified on the SAP.
Summary tables will indicate the number of patients with complete data for each 
measurement, event, or outcome. In general, no imputation of missing data will be made, and 
any exception on efficacy data would be detailed on the SAP.
The following subgroup analyses will be performed but not limited to: severity score, 
bacterial load, initial adequate or inadequate antibiotic treatment, concomitant treatment, 
sCABP clinical response (cure or non response i.e. failure) or indeterminate, antimicrobial 
resistance profile, previous vaccination, and presence or not of bacteraemia. A thorough 
review will be performed by the AC when data for the primary endpoint are available to agree 
on patient assignment process e.g. validation based on the dose, the bacterial susceptibility
profile to administered antibiotics and duration of antibiotics, molecular identification data, 
etc. Membership, roles and responsibilities and operating procedures for the AC as well as the 
subject evaluability criteria to be followed will be specified in a separate AC charter.
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12.2 Determination of Sample Size
The results from this study are exploratory in nature, hence there is no hypothesis testing 
comparing outcomes between treatment arms.
Confidence intervals will be constructed to assess between-group differences in treatment 
effect. As little is known at present about the outcome measures used in the study for stem 
cells, this study will provide the initial dataset necessary for determining endpoints and 
making a preliminary estimate of effect size for the design of future efficacy-finding studies 
of Cx611 for the add-on therapy of severe community-acquired bacterial pneumonia in 
patients requiring mechanical ventilation and/or vasopressors administration.
The number of 180 patients in total (i.e. 90 patients per group) was deemed to be sufficient to 
fulfil the objectives of this exploratory study.
For safety endpoints (between-group difference in percentage of patients with at least one 
adverse experience): the precision of the estimate (1/2 width of the 95% confidence interval 
[CI]) is equal to 15%. The calculation assumes a percentage of patients with at least one 
adverse experience approximately equal to 50% (conservative assumption).
For the main efficacy endpoint “Between-group difference in number of ventilator-free days”,
the precision of the estimate (1/2 width of the 95% CI) is equal to 3, assuming a SD equal to 
10 for the variable number of ventilator-free.
12.3 Interim Analysis
An interim analysis of the primary endpoint is not planned for this study. The primary safety 
analysis at Day 90 will be performed as scheduled.
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Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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Page 102 of 130
13 INVESTIGATOR/SPONSOR RESPONSIBILITIES
13.1 Ethics
13.1.1 Independent Ethics Committee (IEC)
This protocol and any amendments will be submitted to a properly constituted IEC, in 
accordance with the International Conference on Harmonization (ICH) guidelines, the 
applicable European Directives and local legal requirements, for approval of the study. 
Approval must be obtained in writing before the first patient can be recruited.
The Sponsor must receive the letter or certificate of approval from each IEC prior to delivery 
of ATIMP. A list of members participating in the meeting must be provided, including the 
functions of these members. If study staff were present in the IEC, it must be clear that none 
of these persons voted.
If there are any changes to the approved protocol (with the exception of emergency 
modifications required for the patient's safety), a protocol amendment will be issued by 
mutual agreement of the Co-ordinating Investigator and the Sponsor. The IECs must give 
their written approval of any substantial amendments likely to affect the safety of the patients 
or the conduct of the study. All other changes must be notified to them.
The Investigator will maintain records of all correspondence with the IEC.
13.1.2 Ethical Conduct of the Study
This investigation will only be performed after the appropriate regulatory authorities have 
issued a Clinical Trials Authorisation (CTA) for this study, which will be sought in parallel 
with the IEC approvals.
The appropriate regulatory authorities must give their written approval of any substantial 
amendments to the approved protocol or IMPD that are likely to affect the safety of the 
patients or the conduct of the study (with the exception of emergency modifications required 
for the patient's safety).
The body responsible for making the CTA submission will maintain records of all 
correspondence with the regulatory agencies.
The study will be conducted in compliance with the protocol, regulatory requirements, GCP, 
consolidated guidelines Committee for Proprietary Medicinal Products (CPMP)/ICH/135/95 
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Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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(July 1996), adopted in the European Union (EU) by CPMP EU Commission Directive 
2005/28/EC (GCP, April 2005) and the ethical principles of the latest revision of the 
Declaration of Helsinki as adopted by the World Medical Association.
13.1.3 Patient Information and Consent
All patients or their legally authorised representatives will receive written and verbal 
information regarding the study at a prior interview. This information will emphasize that 
participation in the study is voluntary and that the patient may withdraw from the study at any 
time and for any reason. All patients or legally authorised representatives will be given the 
opportunity to ask questions about the study and will be given ample time to decide whether 
to participate in the study.
Before any study-related procedures, the informed consent form will be signed and personally 
dated by the patient (or their legally authorised representative and/or relative and/or witness, 
as applicable) and by the person who conducted the informed consent discussion unless 
exempted under the conditions described in “Approval of inclusion by an independent 
physician in a case of emergency” below. A legally authorised representative and/or relative 
is required only if patient is unconscious or incapable to understand the nature of the study. A 
witness is required only if the participant is unable to write (such as blind or illiterate). If the 
consent has been given by the legally authorised representative or relative, the patient should 
be informed about their participation in the study and should have the opportunity to confirm 
or revoke their consent once they regain consciousness.
The consent includes information that data will be recorded, collected, processed and may be 
transferred to European Economic Area (EEA) or non-EEA countries in accordance with the 
Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on 
the protection of natural persons with regard to the processing of personal data and on the free 
movement of such data, and repealing Directive 95/46/EC (General Data Protection 
Regulation).
The Informed Consent and Patient Information will be provided in the local language.
A copy of the patient information sheet including the signed consent form will be provided to 
the patient or their legally authorised representative and/or relative.
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Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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Approval of inclusion by an independent physician in a case of emergency 
Many patients with sCABP cannot give their consent because they are not in the condition to 
understand or express an opinion and/or they are often unconscious or very confused.
However, for the present study, only patients with sCABP may be included, because the study 
medication is targeted for this type of patients and may not work on patients that are just in 
the early stages of pneumonia or sepsis. Also, there is the need to do research within this area, 
since there are not many trials done in this type of patients.
The study cannot guarantee that the patient will benefit from his/her participation (because 
there is a placebo as comparator) but, based on the data from animal trials and on the data 
from prior safety trials in humans, the overall benefit-risk balance of Cx611 remains 
acceptable and low considering the high rate of death among these patients.
For all these reasons, if the informed consent cannot be obtained so that first dose of study 
medication cannot be started within 18 hours from the fulfilment of the severity criteria that 
suppose an immediate risk to the physical health of the patient (i.e. requirement of invasive 
mechanical ventilation and/or vasopressors treatment) because it is impossible to 
communicate with the patient and there is insufficient time to obtain informed consent from 
the patient’s legal representative or relative, despite all reasonable efforts made by the 
investigator, the patient can participate in the study (if allowed by local regulations) when (i) 
the inclusion is approved, apart from the decision of the principal investigator, also by another 
independent physician and, where possible, (ii) a person linked to the patient by family or 
similar ties has been previously consulted. As soon as the patient recovers he/she should be 
informed about his/her participation in the study and should have the opportunity to sign the 
informed consent form for continued participation in the clinical trial.
In any case, no treatment will be given as part of the clinical trial if any of the people involved 
know that the patient or his legal representative is opposed to receiving the treatment.
The researcher will ensure that at the first opportunity, the patient or his/her legal 
representative is given detailed information about the treatment, as it would have been given 
to obtain informed consent, and signs the consent form for continuing participation in the 
clinical trial. The patient or his/her legal representative will be told that study participation 
can be stopped at any time, and this will not affect their rights or future treatment.
If a patient who is included in the study without signing the consent form (because they were
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 105 of 130
unconscious) dies before such signature and before their legal representative can be contacted, 
the researcher must try to locate the patient´s legal representative and give him/her
information about the trial.
13.2 Patient Records and Source Data
It is the responsibility of the Investigator to record essential information in the medical 
records in accordance with national regulations and requirements. The following information 
should be included as a minimum:

A statement that the patient is in a clinical study

The identity of the study e.g. Study code

Patient number

That informed consent was obtained and the date and time

Diagnosis

Dates of all visits during the study period

Any information relating to AEs

Treatment with investigational product

All prior, concomitant treatments and medications prescribed/administered (including 
dosage)

All study-related procedures

All information requested to be collected as specified in the protocol

Date of study completion/termination
The Investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the CRFs. Data reported in the CRF that are derived from 
source documents should be consistent with the source documents or the discrepancies should 
be explained. Signed sections of CRFs will be monitored and collected on a regular basis.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 106 of 130
13.3 Access to Source Data and Documentation
The Investigator should guarantee access to source documents for the monitor and auditors as 
well as for inspection by appropriate regulatory agencies, and the IEC, if required. The 
Investigator will keep files of essential documents as defined by the ICH guidelines on GCP 
and local requirements. 
will provide a suitable structure for the Investigator’s site file, 
which the Investigator may update as and when necessary. The Investigator’s site file must be 
available at monitoring visits and during an audit or inspection. The investigator site file 
should clearly record where the different source documents can be found.
13.4 Monitoring
The monitor will visit the study site on a regular basis to ensure that the study is conducted 
and documented in accordance with this protocol, ICH GCP guidelines, regulatory 
requirements, CROs’ procedures and any study specific documents such as CRF completion 
guidelines.
The monitor must be permitted to have access to all source documents needed to verify the 
entries on the CRF and other protocol-related documents, provided that patient confidentiality 
is maintained in accordance with local regulations. It will be the monitor’s responsibility to 
inspect the CRFs at regular intervals throughout the study, to verify adherence to the protocol 
and the completeness, consistency and accuracy of the data being entered on the CRFs.
Monitoring visits will be conducted to confirm that e.g.:
!
The investigational team is adhering to the study protocol
!
Informed consent has been obtained for all participants
!
AEs have been reported as required
!
Data are being accurately recorded in the CRFs
!
IMP is being stored correctly, administered as per protocol and medication
accountability is being performed on an on-going basis
!
Facilities are, and remain, acceptable throughout the study
!
The Investigator and the site are receiving sufficient information and support 
throughout the study.
Property of Takeda: For N
t
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 107 of 130
Moreover, during monitoring visits the data recorded in the CRFs, source documents and 
other study-related records will be compared against each other in order to ensure accurate 
data that reflect the actual existence of the patient in the study i.e. source data verification.
The investigator must ensure that patient codification is maintained. On CRFs or other 
documents submitted to the Sponsor, patients must be identified only by number, and never 
by name. Documents identifying the patients (e.g., signed Informed Consent Forms) should 
not be sent to the Sponsor and CRO, and must be kept in strict confidence by the investigator.
The investigator and co-investigators agree to cooperate with the monitor(s) to ensure that any 
issues detected in the course of these monitoring visits are resolved. If the patient is 
hospitalised or dies in a hospital other than the study centre, the investigator is responsible for 
contacting that hospital in order to document the SAE.
The investigator must on request supply the sponsor/CRO with any required background data 
from the study documentation or clinical records. This is particularly important when CRFs 
are illegible or when errors in data transcription are suspected. In the case of special problems 
and/or government queries, it is also necessary to have access to the complete study records, 
provided that patient confidentiality is protected.
A close-out visit will be performed after study closure.
13.5 Sponsor’s Obligations
The Sponsor must provide an Investigator’s Brochure and, where appropriate, a IMPD, giving 
information about the chemistry, manufacture and controls, and the pharmacological and 
toxicological properties of the ATIMP and summarising any clinical experience of the 
compound. Additional information regarding the IMP should be provided to the Investigator 
when it becomes available. The Sponsor must also provide appropriate documentation on the 
clinical study supplies, including Certificates of Analyses and confirmation of GMP
compliance in their manufacture.
A designated professional representative of the Sponsor will conduct visits at suitable 
intervals throughout the study. These visits will be for the purposes of verifying adherence to
the protocol and the accurate and complete recording of data in the CRFs and medication 
inventory forms.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 108 of 130
13.6 Investigator's Obligations
Prior to initiation of this study, the Investigator (or designee) at each study site will approve 
this protocol by signing the approval signature page. These signatures confirm that the study 
will be performed in compliance with the protocol. The Investigator (or designee) at each site 
must review the CRFs for completeness and accuracy and must sign and date the appropriate 
CRFs as indicated.
13.7 Data Management
Data management and handling will be conducted according to the study specific Data 
Management Plan in accordance with ICH guidelines and 
standard operating procedures 
(SOPs), which will be prepared and approved before the end of the experimental phase of the 
study.
Data entry, validation, and data queries will be handled by the 
Data Management Team.
The data will be subjected to validation according to
SOPs in order to ensure accuracy in 
the collected CRF data.
Before database closure reconciliation will be performed between the SAEs entered in the 
safety database and the study database.
Any deviations, i.e. discrepancies and additions from the process defined in the Data 
Management Plan, will be described in a study specific Data Management Report.
13.8 Quality Assurance and Audit
The sponsor has ethical, legal and scientific obligations to follow-up the trial progress in 
accordance with clinical research principles and regulations.
Audits or inspections, including source data verification, may be performed by representatives 
of 
 the Sponsor, a CA and/or an IEC. Therefore, direct access to source data and 
documentation will be provided for audit, for review by IEC and for any regulatory 
inspection.
The clinical protocol, clinical study report and the experimental phase may be audited to 
assure the integrity of the data and to comply with the Good Clinical Practice regulation.
Property of Takeda: For Non-Commercial Use Only 
 Subject to the Applicable Terms of Use
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 109 of 130
The investigator is required to inform the sponsor immediately of an inspection requested by a 
regulatory authority. The sponsor will advise and help the investigator for an inspection.
13.9 Traceability of the Study Product
As the treatment of this study is qualified as an “ATIMP” (advanced therapy investigational 
medicinal product) it is subject to, among others, (i) Regulation (EC) No 1394/2007 of the 
European Parliament and of the Council of 13 November 2007 on advanced therapy 
medicinal products and amended Directive 2001/83/EC and Regulation (EC) No 726/2004, 
and (ii) the 3 December 2009 EC GCP Guidelines.
TiGenix, the study site and the Investigator are each responsible for their respective duties and 
obligations in ensuring the traceability of the IMP in accordance with the EC GCP Guidelines 
and any other applicable legislation or regulation.
TiGenix shall ensure compliance with European and local legislation in relation to the 
donation and the donors of human cells (including consent, eligibility of donors, data 
protection and confidentiality, selection, evaluation and procurement) as laid down in 
Directive 2004/23/EC and its implementing Directives and local implementation.
TiGenix, as sponsor of the study and as manufacturer of the IMP, shall retain all donor related 
documentation of the starting material of the IMP, including all critical substances coming 
into contact with the cells or tissues it may contain, as well as all data relevant for the 
manufacturing of the IMP, and archive these until thirty (30) years after the expiry date of the 
resulting IMP.
To that effect, TiGenix shall set up a unique coding system whereby each IMP that is 
manufactured receives a unique code, based on the donor identification code, the master cell 
bank and the frozen medication product (the “Unique Code”).
The study site shall establish and maintain a system of subject and product traceability that 
contains sufficient detail to allow linking of each Product delivered to the study site to the 
Study subject who received the Product and vice versa and the Unique Code, it being 
understood that the [study site] is not allowed to provide any personal data to any third party, 
including TiGenix, except as otherwise provided by law.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 110 of 130
13.10 Record Retention
The sponsor and the Investigator/institution must maintain adequate and accurate records to 
enable the conduct of the study to be fully documented and the study data to be subsequently 
verified. These documents are to be classified into two different categories: investigator’s file, 
and patient clinical source documents.
The sponsor’s and/or investigator’s file will contain the protocol and all protocol 
amendments, a financial disclosure form, the CRFs and data clarification and query forms, 
IEC/Institutional Review Board (IRB) and Health Authority approval with correspondence, 
informed consent, medication records, staff curricula vitae and authorisation forms, and other 
appropriate documents/correspondence in accordance with ICH GCP and local regulations.
Patient clinical source documents include, but are not limited to, hospital/clinic records, 
physicians’ and nurses’ notes, appointment book, original laboratory reports, ECG, X-ray, 
MRI, pathology and special assessment reports, consultant letters, etc.
Irrespectively of traceability obligations, these two categories of documents must be kept on 
file by the investigator for as long as is necessary to comply with applicable national and 
international regulations.
When source documents are required for the continued care of the patient, appropriate copies 
must be made for storing off site.
13.11
Protocol Deviations
Deviations to the study protocol will be documented in a Protocol Deviation Log and entered 
into the study-specific protocol violation database.
The classification of patients into protocol violators will be made during a meeting before 
database lock. The classification will be mutually agreed between the Sponsor and 
before 
the database lock. Listings will indicate the allocation of patients by analysis set and the 
number of patients per analysis set will be recorded in the clinical study report.
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 111 of 130
13.12
Amendment of Protocol 
Any change to a protocol must be considered to be an amendment if the documents have 
already been submitted to ECs/IRBs or Health Authorities. An amendment could therefore 
occur before or after the approval of these documents by ECs/IRBs or Health Authorities. 
The amended protocol will be signed by the relevant personnel at TiGenix, 
 and the 
Investigator(s). 
Depending on the contents of the amendment and local legal requirements, the amendment 
will be submitted to the relevant ECs and, where necessary, to the relevant competent 
authorities.
The Investigator should not implement any changes of the protocol, without agreement by 
TiGenix, 
and prior review and documented approval/favourable opinion of the 
appropriate EC and, if legally required, competent authorities, except where necessary to 
eliminate an immediate hazard to the subjects, or when the change(s) involve only logistical 
or administrative aspects of the trial. 
If an amendment substantially alters the trial design, increases the potential risk to the subjects 
or affects the treatment of the subject, then the information sheet must be revised and 
submitted to the relevant EC and, where necessary, to the relevant competent authorities, for 
review and approval. When a subject is currently undergoing trial procedures and is affected 
by the amendment, then the subject must be asked to consent again using the new information 
sheet. The new information sheet must be used to obtain consent from new subjects before 
enrolment.
Non-substantial amendment
Purely administrative or minor logistical changes require only a non-substantial amendment. 
Such changes include but are not limited to changes in study staff or contact details (e.g., 
CRO monitors), or minor changes in the packaging or labelling of study product. The 
implementation of a non-substantial amendment may be undertaken with or without 
notification to the appropriate ECs/IRBs and Health Authorities (subject to national 
regulations).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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CCI

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 112 of 130
Substantial amendment
A substantial amendment is required for significant changes. These include, but are not 
limited to, new data affecting the safety of subjects, and changes to the objectives or 
endpoints of the study, eligibility criteria, dose regimen, study assessments/procedures, or 
treatment or study duration, with or without the need to modify the Core Subject Information 
and Informed Consent. Substantial amendments must be approved by the appropriate 
ECs/IRBs, and in some jurisdictions by the Health Authorities. The implementation of a 
substantial amendment may only occur after formal approval by the appropriate ECs/IRBs 
and/or Health Authorities, and must be signed by the investigators.
13.13
Insurance
The Sponsor will provide insurance or indemnify (legal and financial coverage) the 
Investigator/the institution against claims arising from the study, except for claims that arise 
from malpractice, negligence or non-compliance with the protocol. 
The compensation of the patient in the event of study-related injuries will comply with 
applicable regulations.
13.14
Confidentiality
All study information provided by TiGenix in relation to this study and not previously 
published is considered confidential information. Such information comprises the clinical 
protocol, any workbooks if applicable, CRFs, assessment methods, sponsor technical 
methods, and basic scientific data. This confidential information will be the property of 
TiGenix, must not be disclosed to third parties without prior written consent from the sponsor, 
and must only be used for the study purposes.
Information collected during the conduct of this clinical study is also considered to be 
confidential. Such information can be disclosed to the extent considered necessary by
TiGenix.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 113 of 130
13.15
Report and Publication
In order to allow use of information derived from this study and to ensure compliance with 
the applicable regulations, the investigator is committed to provide TiGenix all examination 
results and all data collected in this study. Except as required by law, information obtained 
during the study can only be provided to physicians and regulatory authorities by TiGenix.
TiGenix undertakes publishing the study results and report them at scientific meetings. The 
list of authors of the publication will be defined based on the authorship criteria by the 
International Committee of Medical Journal Editors (ICMJE), involvement in trial design, 
oversight, number of evaluable patients enrolled, analysis and interpretation of data and 
preparation of manuscript. The study will only be published once it has been completed and 
the final analysis is completed.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 114 of 130
14 REFERENCE LIST
1. 
TIGENIX. Cx611/Investigator´s brochure. 
2. 
Neuhaus T, Ewig S. Defining severe community-acquired pneumonia. Med Clin North 
Am. 2001 Nov;85(6):1413–25. 
3. 
Restrepo MI, Jorgensen JH, Mortensen EM, Anzueto A. Severe community-acquired 
pneumonia: current outcomes, epidemiology, etiology, and therapy. Curr Opin Infect 
Dis. 2001 Dec;14(6):703–9. 
4. 
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. 
Infectious Diseases Society of America/American Thoracic Society consensus 
guidelines on the management of community-acquired pneumonia in adults. Clin Infect 
Dis Off Publ Infect Dis Soc Am. 2007 Mar 1;44 Suppl 2:S27-72. 
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Watkins RR, Lemonovich TL. Diagnosis and management of community-acquired 
pneumonia in adults. Am Fam Physician. 2011 Jun 1;83(11):1299–306. 
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Walden AP, Clarke GM, McKechnie S, Hutton P, Gordon AC, Rello J, et al. Patients 
with community acquired pneumonia admitted to European intensive care units: an 
epidemiological survey of the GenOSept cohort. Crit Care Lond Engl. 2014;18(2):R58. 
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Liapikou A, Cilloniz C. Severe community-acquired pneumonia: Severity and 
management. Community Acquir Infect. 2015;2(1):3. 
8. 
Jackson ML, Neuzil KM, Thompson WW, Shay DK, Yu O, Hanson CA, et al. The 
burden of community-acquired pneumonia in seniors: results of a population-based 
study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2004 Dec 1;39(11):1642–50. 
9. 
Marston BJ, Plouffe JF, File TM, Hackman BA, Salstrom SJ, Lipman HB, et al. 
Incidence of community-acquired pneumonia requiring hospitalization. Results of a 
population-based active surveillance Study in Ohio. The Community-Based Pneumonia 
Incidence Study Group. Arch Intern Med. 1997 Aug 11;157(15):1709–18. 
10. Dremsizov T, Clermont G, Kellum JA, Kalassian KG, Fine MJ, Angus DC. Severe 
sepsis in community-acquired pneumonia*: When does it happen, and do systemic 
inflammatory response syndrome criteria help predict course? Chest. 2006 Apr 
1;129(4):968–78. 
11. Woodhead M, Welch CA, Harrison DA, Bellingan G, Ayres JG. Community-acquired 
pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the 
ICNARC Case Mix Programme Database. Crit Care. 2006;10(Suppl 2):S1. 
12. Wunderink RG, Laterre P-F, Francois B, Perrotin D, Artigas A, Vidal LO, et al. 
Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: 
a randomized trial. Am J Respir Crit Care Med. 2011 Jun 1;183(11):1561–8. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 115 of 130
13. Liapikou A, Ferrer M, Polverino E, Balasso V, Esperatti M, Piñer R, et al. Severe 
community-acquired pneumonia: validation of the Infectious Diseases Society of 
America/American Thoracic Society guidelines to predict an intensive care unit 
admission. Clin Infect Dis Off Publ Infect Dis Soc Am. 2009 Feb 15;48(4):377–85. 
14. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A 
prediction rule to identify low-risk patients with community-acquired pneumonia. N 
Engl J Med. 1997 Jan 23;336(4):243–50. 
15. Angus DC, Marrie TJ, Obrosky DS, Clermont G, Dremsizov TT, Coley C, et al. Severe 
community-acquired pneumonia: use of intensive care services and evaluation of 
American and British Thoracic Society Diagnostic criteria. Am J Respir Crit Care Med. 
2002 Sep 1;166(5):717–23. 
16. Rodríguez A, Mendia A, Sirvent J-M, Barcenilla F, de la Torre-Prados MV, Solé-Violán 
J, et al. Combination antibiotic therapy improves survival in patients with community-
acquired pneumonia and shock. Crit Care Med. 2007 Jun;35(6):1493–8. 
17. Kothe H, Bauer T, Marre R, Suttorp N, Welte T, Dalhoff K, et al. Outcome of 
community-acquired pneumonia: influence of age, residence status and antimicrobial 
treatment. Eur Respir J. 2008 Jul;32(1):139–46. 
18. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al. 
Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary 
randomized study. Am J Respir Crit Care Med. 2005 Feb 1;171(3):242–8. 
19. Richards G, Levy H, Laterre P-F, Feldman C, Woodward B, Bates BM, et al. CURB-65, 
PSI, and APACHE II to assess mortality risk in patients with severe sepsis and 
community acquired pneumonia in PROWESS. J Intensive Care Med. 2011 
Feb;26(1):34–40. 
20. Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014 Jan 
1;5(1):4–11. 
21. Laterre P-F, Garber G, Levy H, Wunderink R, Kinasewitz GT, Sollet J-P, et al. Severe 
community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS 
study. Crit Care Med. 2005 May;33(5):952–61. 
22. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving 
Sepsis Campaign: international guidelines for management of severe sepsis and septic 
shock, 2012. Intensive Care Med. 2013 Feb;39(2):165–228. 
23. Laterre P-F. Beyond antibiotics in severe community-acquired pneumonia: the role and 
rationale for tissue factor pathway inhibition. Crit Care. 2008;12(Suppl 6):S4. 
24. Esper AM, Moss M, Lewis CA, Nisbet R, Mannino DM, Martin GS. The role of 
infection and comorbidity: Factors that influence disparities in sepsis. Crit Care Med.
2006 Oct;34(10):2576–82. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 116 of 130
25. Kumar A, Zarychanski R, Light B, Parrillo J, Maki D, Simon D, et al. Early combination 
antibiotic therapy yields improved survival compared with monotherapy in septic shock: 
a propensity-matched analysis. Crit Care Med. 2010 Sep;38(9):1773–85. 
26. Puren AJ, Feldman C, Savage N, Becker PJ, Smith C. Patterns of cytokine expression in 
community-acquired pneumonia. Chest. 1995 May;107(5):1342–9. 
27. Montón C, Torres A, El-Ebiary M, Filella X, Xaubet A, de la Bellacasa JP. Cytokine 
expression in severe pneumonia: a bronchoalveolar lavage study. Crit Care Med. 1999 
Sep;27(9):1745–53. 
28. Fernández-Serrano S, Dorca J, Garcia-Vidal C, Fernández-Sabé N, Carratalà J, 
Fernández-Agüera A, et al. Effect of corticosteroids on the clinical course of 
community-acquired pneumonia: a randomized controlled trial. Crit Care Lond Engl. 
2011;15(2):R96. 
29. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. 
Minimal criteria for defining multipotent mesenchymal stromal cells. The International 
Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. 
30. Sousa BR, Parreira RC, Fonseca EA, Amaya MJ, Tonelli FMP, Lacerda SMSN, et al. 
Human adult stem cells from diverse origins: an overview from multiparametric 
immunophenotyping to clinical applications. Cytom Part J Int Soc Anal Cytol. 2014 
Jan;85(1):43–77. 
31. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and 
immunologic properties of differentiated and undifferentiated mesenchymal stem cells. 
Exp Hematol. 2003 Oct;31(10):890–6. 
32. Majumdar MK, Keane-Moore M, Buyaner D, Hardy WB, Moorman MA, McIntosh KR, 
et al. Characterization and functionality of cell surface molecules on human 
mesenchymal stem cells. J Biomed Sci. 2003 Apr;10(2):228–41. 
33. Rasmusson I, Ringdén O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit the 
formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or 
natural killer cells. Transplantation. 2003 Oct 27;76(8):1208–13. 
34. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: 
their phenotype, differentiation capacity, immunological features, and potential for 
homing. Stem Cells Dayt Ohio. 2007 Nov;25(11):2739–49. 
35. Pittenger MF, Mackay AM, Beck SC,iswal RK, Douglas R, Mosca JD, et al. 
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and Regenerative Potential. Clin Plast Surg. 2015 Apr;42(2):169–79. 
37. DelaRosa O, Lombardo E, Beraza A, Mancheño-Corvo P, Ramirez C, Menta R, et al. 
Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the 
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Sponsor: TiGenix S.A.U.
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modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue 
Eng Part A. 2009 Oct;15(10):2795–806. 
38. Barrio L, Cuevas VD, Menta R, Mancheño-Corvo P, delaRosa O, Dalemans W, et al. 
Human adipose tissue-derived mesenchymal stromal cells promote B-cell motility and 
chemoattraction. Cytotherapy. 2014 Dec;16(12):1692–9. 
39. Tyndall A. Mesenchymal stem cell treatments in rheumatology: a glass half full? Nat 
Rev Rheumatol. 2014 Feb;10(2):117–24. 
40. Herberts CA, Kwa MSG, Hermsen HPH. Risk factors in the development of stem cell 
therapy. J Transl Med. 2011;9:29. 
41. Heslop JA, Hammond TG, Santeramo I, Tort Piella A, Hopp I, Zhou J, et al. Concise 
review: workshop review: understanding and assessing the risks of stem cell-based 
therapies. Stem Cells Transl Med. 2015 Apr;4(4):389–400. 
42. Tatsumi K, Ohashi K, Matsubara Y, Kohori A, Ohno T, Kakidachi H, et al. Tissue factor 
triggers procoagulation in transplanted mesenchymal stem cells leading to 
thromboembolism. Biochem Biophys Res Commun. 2013 Feb 8;431(2):203–9. 
43. Jung JW, Kwon M, Choi JC, Shin JW, Park IW, Choi BW, et al. Familial occurrence of 
pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei 
Med J. 2013 Sep;54(5):1293–6. 
44. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. 
Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary 
first-pass effect. Stem Cells Dev. 2009 Jun;18(5):683–92. 
45. Lombardo E, van der Poll T, DelaRosa O, Dalemans W. Mesenchymal stem cells as a 
therapeutic tool to treat sepsis. World J Stem Cells. 2015 Mar 26;7(2):368–79. 
46. Franquesa M, Mensah FK, Huizinga R, Strini T, Boon L, Lombardo E, et al. Human 
Adipose Tissue-Derived Mesenchymal Stem Cells Abrogate Plasmablast Formation and 
Induce Regulatory B Cells Independently of T Helper Cells. STEM CELLS. 2015 Mar 
1;33(3):880–91. 
47. Eggenhofer E, Hoogduijn MJ. Mesenchymal stem cell-educated macrophages. 
Transplant Res. 2012;1(1):12. 
48. Liotta F, Angeli R, Cosmi L, Filì L, Manuelli C, Frosali F, et al. Toll-like receptors 3 
and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can 
inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells Dayt 
Ohio. 2008 Jan;26(1):279–89. 
49. Doorn J, Moll G, Le Blanc K, van Blitterswijk C, de Boer J. Therapeutic Applications of 
Mesenchymal Stromal Cells: Paracrine Effects and Potential Improvements. Tissue Eng 
Part B Rev. 2011 Oct 13;18(2):101–15. 
50. Blazquez R, Sanchez-Margallo FM, de la Rosa O, Dalemans W, Álvarez V, Tarazona R, 
et al. Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 118 of 130
Derived Exosomes on in vitro Stimulated T Cells. Front Immunol [Internet]. 2014 Nov 4 
[cited 
2015 
Apr 
20];5. 
Available 
from: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220146/
51. Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, et al. Mesenchymal 
stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci U S A. 
2011 Oct 18;108(42):17384–9. 
52. DelaRosa O, Sánchez-Correa B, Morgado S, Ramírez C, del Río B, Menta R, et al. 
Human Adipose-Derived Stem Cells Impair Natural Killer Cell Function and Exhibit 
Low Susceptibility to Natural Killer-Mediated Lysis. Stem Cells Dev. 2012 May 
20;21(8):1333–43. 
53. Krampera M. Mesenchymal stromal cell “licensing”: a multistep process. Leukemia. 
2011 Sep;25(9):1408–14. 
54. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem 
cells inhibit generation and function of both CD34+-derived and monocyte-derived 
dendritic cells. J Immunol Baltim Md 1950. 2006 Aug 15;177(4):2080–7. 
55. Maccario R, Podesta M, Moretta A, Cometa A, Comoli P, Montagna D, et al. Interaction 
of human mesenchymal stem cells with cells involved in alloantigen-specific immune 
response 
favors 
the 
differentiation 
of 
CD4+ 
T-cell 
subsets 
expressing 
a 
regulatory/suppressive phenotype. Haematologica. 2005 Jan 1;90(4):516–25. 
56. DelaRosa O, Dalemans W, Lombardo E. Toll-Like Receptors as Modulators of 
Mesenchymal Stem Cells. Front Immunol [Internet]. 2012 Jul 2 [cited 2015 Apr 20];3. 
Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387651/
57. DelaRosa O, Lombardo E. Modulation of Adult Mesenchymal Stem Cells Activity by 
Toll-Like Receptors: Implications on Therapeutic Potential. Mediators Inflamm 
[Internet]. 
2010 
[cited 
2015 
Apr 
20];2010. 
Available 
from: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902124/
58. Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. 
Autologous bone marrow-derived mesenchymal stromal cells in the treatment of 
fistulising Crohn’s disease. Gut. 2011 Jun;60(6):788–98. 
59. Herreros MD, Garcia-Arranz M, Guadalajara H, De-La-Quintana P, Garcia-Olmo D, 
FATT Collaborative Group. Autologous expanded adipose-derived stem cells for the 
treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical 
trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis Colon 
Rectum. 2012 Jul;55(7):762–72. 
60. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A 
randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult 
human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am 
Coll Cardiol. 2009 Dec 8;54(24):2277–86. 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 119 of 130
61. Toupet K, Maumus M, Luz-Crawford P, Lombardo E, Lopez-Belmonte J, van Lent P, et 
al. Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not 
affected by the degree of inflammation in arthritis. PloS One. 2015;10(1):e0114962. 
62. Prockop DJ, Brenner M, Fibbe WE, Horwitz E, Le Blanc K, Phinney DG, et al. Defining 
the risks of mesenchymal stromal cell therapy. Cytotherapy. 2010 Sep;12(5):576–8. 
63. Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M. Human 
adult stem cells derived from adipose tissue protect against experimental colitis and 
sepsis. Gut. 2009 Jul 1;58(7):929–39. 
64. Pedrazza L, Lunardelli A, Luft C, Cruz CU, de Mesquita FC, Bitencourt S, et al. 
Mesenchymal stem cells decrease splenocytes apoptosis in a sepsis experimental model. 
Inflamm Res Off J Eur Histamine Res Soc Al. 2014 Sep;63(9):719–28. 
65.
Shin S, Kim Y, Jeong S, Hong S, Kim I, Lee W, et al. The therapeutic effect of human 
adult stem cells derived from adipose tissue in endotoxemic rat model. Int J Med Sci. 
2013;10(1):8–18. 
66. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee J-W, et al. Antibacterial 
Effect of Human Mesenchymal Stem Cells Is Mediated in Part from Secretion of the 
Antimicrobial Peptide LL-37. Stem Cells Dayt Ohio. 2010 Dec;28(12):2229–38. 
67. Schultz MJ, van der Poll T. Animal and human models for sepsis. Ann Med. 2002;34(7–
8):573–81. 
68. Kang MH, Park HM. Evaluation of adverse reactions in dogs following intravenous 
mesenchymal stem cell transplantation. Acta Vet Scand. 2014;56:16. 
69. von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, et al. Analysis of tissues 
following mesenchymal stromal cell therapy in humans indicates limited long-term 
engraftment and no ectopic tissue formation. Stem Cells Dayt Ohio. 2012 
Jul;30(7):1575–8. 
70. CryoStor®
CS10
MSDS. 
https://cdn.stemcell.com/media/files/msds/07930-
MSDS.pdf:Accessed 20 July 2017. 
71. Contentin L, Ehrmann S, Giraudeau B. Heterogeneity in the Definition of Mechanical 
Ventilation Duration and Ventilator-Free Days. Am J Respir Crit Care Med. 2014 Apr 
15;189(8):998–1002. 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 120 of 130
15 SIGNATURES
See separate protocol signature page.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
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16 CLINICAL STUDY PROTOCOL AGREEMENT FORM
I have read the clinical study protocol entitled: “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. 
SEPCELL study” and verified that it contains all necessary information for conducting the study.
I hereby confirm that:

I have carefully read and understood this clinical study protocol

My staff and I will conduct the study according to the study protocol and will comply with its 
requirements, including ethical and safety considerations.
I understand that, should the Sponsor decide to prematurely terminate or suspend the study for whatever 
reason, such decision will be communicated to me in writing. Conversely, if I decide to withdraw from 
execution of the study I will immediately communicate such a decision to the Sponsor.
I agree not to publish any part of the results of the study carried out under this clinical study protocol 
without consulting the Sponsor.
Principal Investigator:
Date:
Signature: 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 122 of 130
17 APPENDICES
Appendix A: Corticosteroid Conversion Table
Appendix B: CURB-65 score
Appendix C: APACHE II (Acute Physiology And Chronic Health Evaluation) Score
Appendix D: Sequential Organ Failure Assessment (SOFA) Score
Appendix E: Conversion Table SO2 (%) to PaO2 (mmHg) and O2 (l/min) to FiO2 (%) 
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 123 of 130
APPENDIX A
Corticosteroid Conversion Table
1. Dixon JS. Second-line Agents in the Treatment of Rheumatic Diseases. Informa Health Care, 1991. 
(456).
2. Meikle AW and Tyler FH. Potency and duration of action of glucocorticoids. Am J of Med 
1977;63;200.
3. Webb R, Singer M. Oxford Handbook of Critical Care. Oxford ; New York : Oxford University Press, 
2005. 
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Clinical Study Protocol
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Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 124 of 130
APPENDIX B
CURB-65 Score (Confusion, Elevated Blood Urea Nitrogen Level, 
Respiratory Rate, and Blood Pressure Plus Age ≥65 Years)
“CURB-65” severity score is calculated and one point is given for each of the following features present 
(range 0–5 points):
Clinical Factor
Points
C Confusion
1
U Blood urea nitrogen > 19 mg/dL or > 7 mmol/L
1
R Respiratory rate ≥ 30 breaths/min
1
B
Systolic blood pressure < 90 mm Hg or Diastolic blood pressure ≤60 mm Hg
1
65 Age ≥65
1
Source: Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, 
Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an 
international derivation and validation study. Thorax. 2003;58(5):377-82.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 125 of 130
APPENDIX C
APACHE II (Acute Physiology And Chronic Health Evaluation) 
Score
Age
POINTS
under 45
0
45-54
2
55-64
3
65-74
5
over 74
6
History of severe organ insufficiency or immunocompromised
Yes, and non-operative or emergency post-operative patient
5
Yes, and elective post-operative patient
2
No
0
Temperature °C
over 40.9
4
39-40.9
3
38.5-38.9
1
36-38.4
0
34-35.9
1
32-33.9
2
30-31.9
3
below 30
4
Mean arterial pressure (mm Hg)
over 159
4
130-159
3
110-129
2
70-109
0
50-69
2
below 50
4
Heart rate (ventricular response)
over 179
4
140-179
3
110-139
2
70-109
0
55-69
2
40-54
3
below 40
4
Respiratory Rate (non-ventilated or ventilated
over 49
4
35-49
3
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Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 126 of 130
25-34
1
12-24
0
10-11
1
6-9
2
below 6
4
Oxygenation (use A-a gradient if FiO2 ≥ 50%, use PaO2 if 
FiO2 <50%)
A-a gradient over 499
4
A-a gradient 350-499
3
A-a gradient 200-349
2
A-a below 200 
0
pO2 > 70
0
pO2 = 61-70
1
pO2 = 55-60
3
pO2 below 55
4
Arterial pH
over 7.69
4
7.60-7.69
3
7.50-7.59
1
7.33-7.49
0
7.25-7.32
2
7.15-7.24
3
below 7.15
4
Serum sodium (mMol/L)
over 179
4
160-179
3
155-159
2
150-154
1
130-149
0
120-129
2
111-119
3
below 111
4
Serum potassium (mMol/L)
over 6.9
4
6-6.9
3
5.5-5.9
1
3.5-5.4
0
3-3.4
1
2.5-2.9
2
below 2.5
4
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 127 of 130
Serum creatinine (mg/ dL)
over 3.4 and ACUTE renal failure
8
2.0-3.4 and ACUTE renal failure
6
over 3.4 and chronic renal failure
4
1.5-1.9 and ACUTE renal failure
4
2.0-3.4 and chronic renal failure
3
1.5-1.9
2
0.6-1.4
0
below 0.6
2
Hematocrit (%)
over 59.9
4
50-59.9
2
46-49.9
1
30-45.9
0
20-29.9
2
below 20
4
White blood count (total/cubic mm in 1000’s)
over 39.9
4
20-39.9
2
15-19.9
1
3.0-14.9
0
1.0-2.9
2
below 1.0
4
Glasgow Coma scale
Eyes open
Spontaneous
4
To speech
3
To pain
2
Absent
1
Verbal
Converses / Oriented
5
Converses / Disoriented
4
Inappropriate
3
Incomprehensible
2
Absent
1
Motor
Obeys
6
Localises pain
5
Withdraws (flexion)
4
Decorticate (flexion) rigidity
3
Decerebrate (flexion) rigidity
2
Absent
1
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7, incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Page 128 of 130
Score relative to GCS: 15 – (minus) Actual GCS
Source: Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985;13(10):818-29.
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Clinical Study Protocol
Sponsor: TiGenix S.A.U.
Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
     
EudraCT No.: 2015-002994-39
Confidential
Page 129 of 130
APPENDIX D
SOFA Score
Source: Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the SOFA score to assess the incidence of organ 
dysfunction/failure in intensive care units: results of a multicentre, prospective study. Working group on “sepsis-related problems” of the European Society of 
Intensive Care Medicine. Crit Care Med 1998;26:1793-800.
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Clinical Study Protocol
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Version: Final, Version 7 incorporating Amendment 5
Study Code: Cx611-0204
Date: 19 December 2019
EudraCT No.: 2015-002994-39
Page 130 of 130
APPENDIX E Conversion Table SO2 (%) to PaO2 (mmHg) and O2 (l/min) to FiO2 (%)
O2 SATURATION AND FiO2 SYSTEM CONVERSIONS
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 Protocol Cx611-0204 – Note to File 
Page 1 of 2 
 
 
NOTE-TO-FILE 
 
From: 
Date: 
04 May 2020 
Sponsor: 
TiGenix, S.A.U. 
A Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited 
Protocol: 
Clinical Study Protocol Cx611-0204, Version 7, dated 19-Dec-2019. (SEPCELL) 
Subject: 
Clarification regarding the recent protocol amendment - Clinical Study Protocol Cx611-
0204, Version 7, dated 19-Dec-2019 
CC: 
eTMF/ Site folder 
 
 
Dear Site Investigator/ Study Coordinator, 
 
The purpose of this Note-to-File is to provide some clarification regarding the recent protocol 
amendment - Clinical Study Protocol Cx611-0204, Version 7, dated 19-Dec-2019. 
 
Efficacy Analyses 
As you are aware, the statistical analysis was revised during the protocol amendment. Accordingly, all 
safety and efficacy data will be summarized using descriptive statistics only, (described in Protocol 
Section 12.1.2), without any statistical inference or sensitivity analyses based on different patient 
populations. Due to the early closure of enrolment, the total number of enrolled subjects is likely to be 
too low to detect any safety and efficacy signals; therefore, traditional statistical analysis including 95% 
confidence intervals and p-values may be misleading, and any sensitivity analyses based on different 
patient populations will be unnecessary.   
 
As such, the description of the Secondary Efficacy Clinical Endpoints in the Synopsis, (page 9), needs to 
be corrected.  The language below in blue font strikethrough is no longer applicable; the language in 
blue font underlined is the correction. Protocol Section 10.1.3 correctly describes the analyses. 
 
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 Anti-HLA Antibodies 
Additionally, the protocol was amended to remove clinic visits and the accompanying physical 
examinations and laboratory testing at the Day 180 (Visit 12) and Day 365 (Visit 13) time points.  As part 
of this, there will no longer be any protocol requirement for collection of lab samples after the subject 
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 Protocol Cx611-0204 – Note to File 
Page 2 of 2 
 
 
has completed Day 90 (Visit 11) on the study.  This also applies to
anti-HLA donor 
antibodies – these will only be collected up to Day 90. There was an oversight in making this update to 
the Schedule of Assessments (Table 1) during the amendment. To clarify, here is the required schedule 
for these samples: 
 
 
Visit 1 
Day 1 (pre-dose) 
Visit 7 
Day 7 
Visit 9 
Day 14 
Visit 10 
Day 29 
Visit 11 
Day 90 
Early Termination  
(only if prior to D90)
 
X 
X 
X 
X 
 
 
Anti-HLA/ 
Donor Abs 
X 
 
X 
 
X 
X 
 
An excerpt of the Schedule of Assessments table is shown below with corrected footnote instructions 
indicating lab sample collection for 
 and anti-HLA donor antibodies up to Day 90 only. 
The language in blue font strikethrough is no longer applicable; the language in blue font underlined is 
the correction: 
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If you have any questions about these clarifications, or any of the other study procedures, please do not 
hesitate to contact your 
 Clinical Research Associate and/or me. 
 
 
 
 
 
 
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