A Phase I, Single Center, Open Label, Single Dose, Dose Escalation Study Assessing the Safety and Tolerability of AllogeneiC MEsenchymAl Stem CEll Infusion in Adults With Cystic Fibrosis-CEASE CF
Phase: PHASE1
Conditions: Cystic Fibrosis
Sponsor: University Hospitals Cleveland Medical Center

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Clinical Research Protocol
A PHASE I, SINGLE CENTER, OPEN LABEL, SINGLE DOSE, DOSE ESCALATION STUDY 
ASSESSING THE SAFETY AND TOLERABILITY OF ALLOGENEIC MESENCHYMAL STEM CELL 
INFUSION IN ADULTS WITH CYSTIC FIBROSIS-CEASE CF
Protocol Number:
CF-MSC-01 
Version Number:
Version 1.13
Version Date:
17Dec2019
Investigational Product:
Mesenchymal Stem Cells
IND Number:
16822
Development Phase:
I
Funding Source:
Cystic Fibrosis Foundation Therapeutics
6931 Arlington Road, 2nd floor
Bethesda, MD 20814
Sponsor- Investigator:
Erica A. Roesch, M.D.
Telephone: 216-844-3267
Fax: 216-844-5916
E-mail: erica.roesch@uhhospitals.org U3 
Medical Monitor:
TDNCC Medical Monitoring Group
Pager: (800) 341-0961
Fax:(206) 985-3278
Coordinating Center:
Rainbow Babies and Children’s Hospital/Case Western 
Reserve University School of Medicine
Cleveland, OH 44106
Telephone: 216-844-3267
Fax: 216-844-1841 

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Approval:
Erica A. Roesch, M.D.
Date
Participating 
Laboratories:
University Hospital Cleveland Medical Center Laboratories 
11100 Euclid Avenue
Cleveland, OH 44106
Center for Interpretive Cytology at Case Western Reserve 
University
11100 Euclid Avenue, Wearn 611
Cleveland, OH 44106
Bioanalyte Core
Department of Pediatric Pulmonology 
Case Western Reserve University
Biomedical Research Building 
10900 Euclid Avenue
Cleveland, OH 44106
Center for Human Genetics Laboratory of University 
Hospitals Cleveland Medical Center
W.O. Walker Center, 6th floor
10524 Euclid Avenue
Cleveland, OH 44106
Indiana Blood Center
Testing Laboratory
3450 N. Meridian Street
Indianapolis, IN 46208
National Center for Regenerative Medicine (NCRM) 
Cellular Therapy Laboratory
2103 Cornell Road, WRB 6-303
Cleveland, OH 44106
Charles River Laboratory
358 Technology Drive
Malvern, PA 19355

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This confidential information about an investigational drug is provided for the 
exclusive use of investigators of this drug and is subject to recall at any time.  The 
information in this document may not be disclosed unless federal or state law or 
regulations require such disclosure.  Subject to the foregoing, this information may 
be disclosed only to those persons involved in the study who have a need to know, 
with the obligation not to further disseminate this information.  These restrictions 
on disclosure will apply equally to all future oral or written information, supplied to 
you by the Cystic Fibrosis Foundation, which is designated as "privileged" or 
"confidential".

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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties include ensuring the 
safety of the study subjects enrolled under my supervision and providing the Cystic Fibrosis Foundation with 
complete and timely information, as outlined in the protocol.  It is understood that all information pertaining to 
the study will be held strictly confidential and that this confidentiality requirement applies to all study staff at 
this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures required to 
carry out the study in accordance with accepted GCP principles and to abide by the terms of this protocol.
Protocol Number:  CF-MSC-01 
Protocol Title:  A Phase I, Single Center, Open Label, Single Dose, Dose Escalation Study Assessing the Safety 
and Tolerability of AllogeneiC MEsenchymAl Stem CEll Infusion in Adults with Cystic 
Fibrosis-CEASE CF
Protocol Version: Version 1.13
Protocol Date:  December 17, 2019
Investigator Signature 
Date
Print Name and Title

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TABLE OF CONTENTS
31TLIST OF ABBREVIATIONS31T
7
31TPROTOCOL SYNOPSIS31T
9
31T131T
31TBACKGROUND31T
15
31T1.131T
31TIntroduction31T .......................................................................................................................15
31T1.231T
31TSpecific Aim31T......................................................................................................................15
31T1.331T
31TSignificance31T.......................................................................................................................15
31T231T
31TSTUDY RATIONALE31T
25
31T2.131T
31TRisk / Benefit Assessment31T.................................................................................................26
31T331T
31TSTUDY OBJECTIVES31T
27
31T3.131T
31TPrimary Objective31T..............................................................................................................27
31T3.231T
31TSecondary Objectives31T ........................................................................................................27
31T3.331T
31TImplications for Future Studies31T .........................................................................................28
31T431T
31TSTUDY DESIGN31T
28
31T4.131T
31TStudy Overview31T.................................................................................................................28
31T531T
31TCRITERIA FOR EVALUATION31T
29
31T5.131T
31TPrimary Endpoint31T...............................................................................................................29
31T5.231T
31TSecondary Endpoints31T.........................................................................................................30
31T631T
31TSUBJECT SELECTION31T
30
31T6.131T
31TStudy Population31T ...............................................................................................................30
31T6.231T
31TInclusion Criteria31T...............................................................................................................30
31T6.331T
31TExclusion Criteria31T..............................................................................................................31
31T731T
31TCONCURRENT MEDICATIONS31T
32
31T7.131T
31TAllowed31T .............................................................................................................................32
31T7.231T
31TProhibited31T ..........................................................................................................................32
31T831T
31TSTUDY TREATMENTS31T
33
31T8.131T
31TMethod of Assigning Subjects to Treatment Groups31T ........................................................33
31T8.231T
31TBlinding31T.............................................................................................................................33
31T8.331T
31TTest and Control Formulation31T ...........................................................................................33
31T8.431T
31TSupply of Investigational Product at the Site31T ....................................................................36
31T8.531T
31TInvestigational Product Accountability31T .............................................................................36
31T8.631T
31TMeasures of Treatment Compliance31T..................................................................................36
31T931T
31TSTUDY PROCEDURES AND GUIDELINES31T
36
31T9.131T
31TClinical Assessments31T.........................................................................................................37
31T9.231T
31TClinical Laboratory Measurements31T ...................................................................................40
31T9.331T
31TResearch Assessments31T.......................................................................................................40
31T9.431T
31TScreening Assessments for Bone Marrow Collection31T.......................................................41
31T1031T
31TEVALUATIONS BY VISIT31T
42
31T10.131T
31TVisit 1 (Screening Visit: Day -42 to -10)31T ..........................................................................42
31T10.231T
31TVisit 1A (if applicable, Optional Bone Marrow Aspiration)31T.............................................43

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31T10.331T
31TFollow-up Phone Call (if applicable, 24 (± 12) hours after Optional Bone Marrow 
Aspiration)31T ...................................................................................................................................43
31T10.431T
31TVisit 2 (Baseline Visit: Day 1)31T ..........................................................................................44
31T10.531T
31TVisit 2 (Baseline Visit: Day 2)31T ..........................................................................................45
31T10.631T
31TTelephone Call 1 (Day 4 or 5)31T...........................................................................................45
31T10.731T
31TVisit 3 (Day 7 ± 2)31T.............................................................................................................45
31T10.831T
31TVisit 4 (Day 14 ± 2)31T...........................................................................................................46
31T10.931T
31TTelephone Call 2 (Day 21 ± 2)31T..........................................................................................47
31T10.1031T........................................................................................................................................... 31TVisit 5 (Day 28 ± 2)31T
47
31T10.1131T........................................................................................................................................... 31TTelephone Call 3 (Day 
56 ± 2)31T..........................................................................................................................................47
31T10.1231T........................................................................................................................................... 31TVisit 6 (Month 3 ± 14 
days)31T48
31T10.1331T........................................................................................................................................... 31TVisit 7 (Month 6 ± 14 
days)31T48
31T10.1431T........................................................................................................................................... 31TTelephone Call 4 
(Month 12 ± 1)31T.............................................................................................................................49
31T10.1531T........................................................................................................................................... 31TAcute Illness/Early 
Termination Visit31T.........................................................................................................................49
31T10.1631T........................................................................................................................................... 31TVisit 1 (Screening 
Visit: Day -30 to -7)31T.....................................................................................................................49
31T10.1731T........................................................................................................................................... 31TVisit 2 (Bone Marrow 
Aspiration)31T ...................................................................................................................................50
31T10.1831T........................................................................................................................................... 31TFollow-up Phone Call 
(24 (± 12) hours after Bone Marrow Aspiration)31T.........................................................................50
31T1131T
31TADVERSE EXPERIENCE REPORTING AND DOCUMENTATION31T
50
31T11.131T
31TAdverse Events31T..................................................................................................................50
31T11.231T
31TSerious Adverse Events (SAE)31T..........................................................................................52
31T11.331T
31TMedical Monitoring31T...........................................................................................................53
31T1231T
31TDISCONTINUATION AND REPLACEMENT OF SUBJECTS31T
53
31T12.131T
31TWithdrawal of Subjects and Drop-outs31T .............................................................................53
31T1331T
31TPROTOCOL VIOLATIONS31T
53
31T1431T
31TDATA SAFETY MONITORING31T
54
31T1531T
31TSTATISTICAL METHODS AND CONSIDERATIONS (BASED UPON PRIMARY 
AND SECONDARY ENDPOINTS)31T
54
31T15.131T
31TData Sets Analyzed31T............................................................................................................54
31T15.231T
31TDemographic and Baseline Characteristics 31T.......................................................................54
31T15.331T
31TAnalysis of Primary Endpoint31T ...........................................................................................54
31T15.431T
31TAnalysis of Secondary/Exploratory Endpoints31T .................................................................55
31T15.531T
31TInterim Analysis31T ................................................................................................................55
31T15.631T
31TSample Size31T .......................................................................................................................55
31T1631T
31TDATA COLLECTION, RETENTION AND MONITORING31T
55
31T16.131T
31TData Collection Instruments31T..............................................................................................55

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31T16.231T
31TData Management Procedures31T...........................................................................................55
31T16.331T
31TData Quality Control and Reporting31T..................................................................................55
31T16.431T
31TArchival of Data31T ................................................................................................................56
31T16.531T
31TAvailability and Retention of Investigational Records31T .....................................................56
31T16.631T
31TMonitoring31T.........................................................................................................................56
31T16.731T
31TSubject Confidentiality31T......................................................................................................56
31T1731T
31TADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS31T
56
31T17.131T
31TProtocol Amendments31T .......................................................................................................56
31T17.231T
31TInstitutional Review Board31T................................................................................................57
31T17.331T
31TInformed Consent Form31T ....................................................................................................57
31T17.431T
31TPublications31T .......................................................................................................................58
31T17.531T
31TInvestigator Responsibilities31T .............................................................................................58
31T1831T
31TAPPENDIX I: DEFINITION OF A PULMONARY EXACERBATION (MODIFIED 
FUCHS CRITERIA)P95
P31T
59
31T1931T
31TAPPENDIX II.  SCHEDULE OF STUDY VISITS31T
60
31TAPPENDIX IIA.  SCHEDULE OF STUDY VISITS FOR OPTIONAL STEM CELL 
COLLECTION FROM CF SUBJECT DONORS31T
63
31TAPPENDIX IIB.  SCHEDULE OF STUDY VISITS FOR STEM CELL 
COLLECTION FROM HEALTHY VOLUNTEER DONORS31T
64
31T2031T
31TREFERENCES31T
65

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LIST OF ABBREVIATIONS
ADL
Activities of daily living
AE
Adverse experience
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BAL
Bronchoalveolar lavage
BM
BMM
BPD
Bone marrow
Bone marrow macrophages
Bronchopulmonary dysplasia
BUN
Blood urea nitrogen
CBC
Complete blood count
CCC
Comprehensive Cancer Center
CF
Cystic fibrosis
CFR
Code of Federal Regulations
CFRSD
Cystic Fibrosis Respiratory Symptom Diary
CFTR
Cystic fibrosis transmembrane conductance regulator
COPD
Chronic obstructive pulmonary disease
CRF
Case report form
CRP
C-reactive protein
CTCAE
Common terminology criteria for adverse events
CWRU
Case Western Reserve University
DCRU
Dahms Clinical Research Unit
DHQ
Donor History Questionnaire
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DMSO
Dimethylsulfoxide
DSMB
Data Safety Monitoring Board
ESR
Erythrocyte sedimentation rate
FBS
Fetal bovine serum
FDA
Food and Drug Administration
FEFR25%-75%
Forced expiratory flow
FEVR1
Forced expiratory volume over one second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GM-CSF
Granulocyte-macrophage colony-stimulating factor

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GVHD
Graft versus host disease
HIPAA
Health Insurance Portability and Accountability Act of 1996
HIV
Human immunodeficiency virus
hMSC
Human mesenchymal stem cell
hs-CRP
High sensitivity C-reactive protein
ICF
Informed consent form
ICH
International Conference on Harmonization
IL
Interleukin
IRB
Institutional Review Board
IV
Intravenous
LDH
Lactate dehydrogenase
LPS
Lipopolysaccharide
mEq
Milliequivalent
MHC
Major histocompatability complex
MIP-3
Macrophage inflammatory protein-3 alpha
MMP-9
Matrix metalloproteinase-9
MPO
Myeloperoxidase
MRSA
Methicillin-resistant Staphylococcus aureus
MSC
Mesenchymal stem cell
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NCRM
National Center for Regenerative Medicine
PBSC
Peripheral blood stem cell
PI
Principal Investigator
QPIT
Quantitative pilocarpine iontophoresis test
RC
Research Coordinator
RSSQ
Respiratory and Systemic Symptoms Questionnaire
SAE
Serious adverse experience
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
SOP
Serum glutamate pyruvate transaminase
Standard operating procedure
TDNCC
TGF-
Therapeutics Development Network Coordinating Center
Transforming growth factor-beta
TNF-
Tumor necrosis factor-alpha

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PROTOCOL SYNOPSIS
TITLE
A Phase I, Single Center, Open Label, Single Dose, Dose Escalation 
Study Assessing the Safety and Tolerability of AllogeneiC 
MEsenchymAl Stem CEll Infusion in Adults with Cystic Fibrosis-
CEASE CF
SPONSOR-
INVESTIGATOR
Erica A. Roesch, M.D.
NUMBER OF SITES
1
RATIONALE
Cystic fibrosis (CF) is a genetically inherited disease which impacts 
sodium and chloride transport across the epithelium leading to viscous 
mucus retention, chronic bacterial infection and relentless inflammation 
in the lung; the main cause of morbidity and mortality in this disease.  
Although new therapeutics have been promising, new and innovative 
approaches to controlling inflammation and bacterial burden in the lungs 
of these patients is important towards minimizing the consequences of 
the disease and improving survival.  We have published pre-clinical 
studies demonstrating that human allogeneic bone marrow derived 
human mesenchymal stem cells (hMSCs) may provide a new therapeutic 
treatment for CF lung disease, attenuating pulmonary inflammation 
while decreasing bacterial growth and enhancing antibiotic efficiency.
STUDY DESIGN
This will be a prospective, single-center, dose-escalation, open-label 
interventional study to evaluate the safety and tolerability of allogeneic 
hMSCs in 15 clinically stable subjects with CF age ≥ 18 years. After a 
two to six week screening period, subjects will have a Baseline visit 
(Days 1-2) where they will undergo a single intravenous infusion of up 
to 5 x 10P6
P allogeneic hMSCs/kg of body weight. Infusions will be 
performed in the Dahms Clinical Research Unit (DCRU) of University 
Hospitals Cleveland Medical Center.  Subjects will be monitored for any 
infusion related toxicities for 24 hours after the infusion.  Subsequent 
study visits will occur on Days 7, 14, 28, Months 3 and 6 and telephone 
calls will occur on Days 4 (or 5), 21, 56 and Month 12.  Subject safety 
and tolerability of a single dose of hMSCs will be evaluated at study 
visits by review of subject diaries, interval history, pulmonary 
exacerbations (standardized definition in Appendix I), physical 
examination, spirometry, and analysis of safety laboratories. Special 
attention will be placed upon detecting pulmonary exacerbations 
because anti-inflammatory therapies theoretically could suppress the 
immune system to the point where it leads to increased infectious 
complications, although MSC therapeutics are proposed to be 
antimicrobial.  In addition to evaluating safety, this study will also 
explore efficacy end-points for future clinical trials of MSCs in CF 
including inflammatory biomarkers from blood and sputum.  Serum 
markers  (calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL8, IL-17, and 
TNF-) and sputum markers (white cell counts and differentials, IL-1β, 

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IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-3, TNF-, and active 
proteases including neutrophil elastase, R1
R-anti-trypsin, and MMP-9) 
will be determined at Baseline and on Days 7 and 28 for with-in subject 
comparison.  All subject samples will be archived for future projects.  
Finally, a diagnostic bone marrow exam will be performed on subjects 
with CF who consent to undergo the procedure.  Bone marrow samples 
will be banked and used for future translational studies. Study-related 
procedures are outlined in Appendix II.
PRIMARY 
OBJECTIVE
To evaluate the infusion-related safety and tolerability of a single 
allogeneic hMSC infusion in adults with CF. 
SECONDARY 
OBJECTIVES

To explore preliminary evidence for the potential efficacy of 
MSCs as a new therapeutic to treat CF pulmonary infection and 
inflammation as measured by
o
Change in sputum inflammatory markers
o
Change in serum inflammatory markers

To compare allogeneic MSCs to autologous MSCs in a 
preclinical model.  The potential efficacy of MSCs obtained from 
CF subjects who agree to undergo the optional bone marrow 
aspiration will be evaluated in validated animal models. 
NUMBER OF 
SUBJECTS
15 subjects with cystic fibrosis for main study
1-2 healthy volunteer subjects for bone marrow donation only
Throughout protocol, “subject” refers to subject with cystic fibrosis 
unless otherwise specified.
SUBJECT 
SELECTION
CRITERIA
Inclusion Criteria: 
1. Male or female 18 years of age and above
2. Confirmed diagnosis of CF as evidenced by 1 or more clinical features 
consistent with the CF phenotype and 1 or more of the following 
criteria:
a.
Sweat chloride equal to or greater than 60 mEq/L by 
quantitative pilocarpine iontophoresis test (QPIT) 
b. 2 well-characterized, disease causing mutations in the 
CFTR gene 
3. Clinically stable with no significant changes in health status within 2 
weeks prior to screening 
4. FEVR1 
R≥ 40% predicted for age based on the global lung function 
initiative equations at the screening visit 
5. Weight ≥ 40 kg at the screening visit
6. Able to perform repeatable, consistent efforts in pulmonary function 
testing
7. Written informed consent obtained from the subject

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Exclusion Criteria: 
1. Use of an investigational agent within the 4-week period prior to Visit 
1 (Day -42 to -10)
2. Chronic daily (>10 mg) or alternate daily (>20 mg on alternate days) 
use of systemic corticosteroids within the 4 weeks prior to Visit 1 (Day 
-42 to -10) or initiation of any dosage of systemic corticosteroids 
within 72 hours prior to Visit 2 (Day 1) 
3. Use of hydroxychloroquine or immunosuppressants 
4. Initiation of a new antibiotic (oral, IV, and/or inhaled) that is  not part 
of the subject’s maintenance regimen for treatment of acute 
respiratory symptoms within 2 weeks prior to screening through Visit 
2 (Day 1)
5. Initiation of any new chronic therapy (e.g., PulmozymeP®
P, hypertonic 
saline, KalydecoP®
P, OrkambiP®
P, high-dose ibuprofen, azithromycin, 
TOBIP®
P, CaystonP®
P, nebulized colistin, bronchodilators, inhaled 
corticosteroids, etc.) within 4 weeks prior to screening
6. Active treatment for non-tuberculous Mycobacteria 
7. History of a sputum culture positive for a Burkholderia cepacia 
complex organism in the previous 12 months 
8. Current tobacco smoker
9. Oxygen saturation < 92% on room air at Visit 1 (Day -42 to -10)
10. History of pulmonary hypertension
11. SGOT (ALT) or SGPT (AST) > 2.5 times the upper limit of normal at 
screening, documented biliary cirrhosis, or portal hypertension 
12. Total bilirubin concentration > 1.2 mg/dL at screening
13. Creatinine > 1.8 mg/dL at screening
14. Pregnant, breastfeeding, or unwilling to practice birth control between 
Visit 2 (Day 1) and Telephone Call 3 (Day 56) (acceptable forms of 
contraception: abstinence, hormonal birth control, intrauterine device, 
or barrier method plus a spermicidal agent), unless surgically 
sterilized or postmenopausal
15. Screening hematology with white blood cell count < 4.5 x 10P9
P cells/L, 
hematocrit < 30%, and platelets < 150 x 10P9
P platelets/L 
16. History of invasive cancer requiring systemic therapy 
17. History of organ transplantation
18. Currently listed for lung transplantation or having potential to be listed 
for lung transplantation in the succeeding 12 calendar months from 
screening
19. Subject unlikely to complete the study as determined by the 
Investigator
TEST PRODUCT, 
Single Infusion of up to 5 x 10P6
P allogeneic MSCs/kg of body weight.  A 

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DOSE AND MODE OF 
ADMINISTRATION
dose escalation using the “3+3” designP1
P will be employed. The three 
doses are 1 x 106, 3 x 106, and 5 x 106 hMSCs/kg. 
Allogeneic MSCs will be derived from bone marrow aspirates from a 
healthy donor whose serum tests negative for cytomegalovirus (CMV) 
antibodies.   Healthy donors will undergo tests for infectious disease and 
screening for 41 common CFTR mutations.  In addition, the MSCs will 
be validated for in vitro and in vivo efficacy and potency using the in 
vivo murine pre-clinical model of CF lung infection and inflammation.
CONTROL 
PRODUCT, DOSE 
AND MODE OF 
ADMINISTRATION
NA
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY
Subjects will be studied for approximately 13 months
Screening:  between 10 and 42 days
Treatment:  1 day 
Follow-up: 12 months
We anticipate 15 months to recruit subjects (due to the 3+3 safety study 
design). The last subject in each cohort must finish Visit 5 before 
enrolling the first subject in the next cohort. 
CONCOMITANT 
MEDICATIONS
For those on alternate month TOBI® or Cayston® therapy, on/off cycles 
must be timed such that a subject is at the same phase of a cycle at Visits 
2-5.
Allowed: All routine chronic CF medications. 

Prohibited: Anti-inflammatory medications (hydroxychloroquine, 
corticosteroids >10mg daily or >20 mg on alternate days) and 
immunosuppressants between Visits 1 and 5. Changes in chronic 
treatment of CF (e.g., introduction, dose escalation, or elimination of 
chronic therapies) between Visits 1 and 5.
SAFETY 
EVALUATIONS
Dose-limiting toxicities, adverse events, including pulmonary 
exacerbations; Cystic Fibrosis Respiratory Symptom Diary (CFRSD); 
Respiratory and Systemic Symptoms Questionnaire (RSSQ); physical 
examination; assessment of vital signs, including oxygen saturation; 
spirometry, sputum bacterial culture (quantitative and qualitative); 
hematology, comprehensive chemistry, erythrocyte sedimentation rate 
(ESR), high-sensitivity C-reactive protein (hs-CRP), and urinalysis 
PRIMARY ENDPOINT
To evaluate safety and tolerability of a single infusion of allogeneic 
hMSCs as determined by: 

Dose limiting toxicity (DLT): A DLT is triggered by occurrence 
in the first 24 hours after hMSC infusion of grade ≥3 infusion-
related allergic toxicities, which include rash, flushing, urticaria, 
dyspnea, fever >40°C (>104.0°F) as scored according to the 
National Cancer Institute (NCI) Common Terminology Criteria 

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for Adverse Events (CTCAE) version 4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf).

Incidence and severity of adverse events 

Number of pulmonary exacerbations (modified Fuch’s criteria95)

Diary reports (Cystic Fibrosis Respiratory Symptom Diary 
(CFRSD))

Changes in subject reported symptoms as captured by the 
Respiratory and Systemic Symptoms Questionnaire (RSSQ) from 
Baseline (Visit 2) Day 1 to Baseline (Visit 2) Day 2, Visits 3, 4, 5, 
6 and 7 and at times when a pulmonary exacerbation is being 
considered 

Changes in physical examination 

Changes in vital signs including oxygen saturation checked 
throughout infusion

Changes in spirometry (FEVR1
R %, FEVR1
R (Liters), FEFR25-75
R) 
determined 30 minutes, 4 hours, and 24 hours after completion of 
infusion and from Baseline (Visit 2) Day 1 to Visits 3, 4, 5, 6 and 
7

Change in sputum quantitative microbiology (bacterial colony 
forming units between Baseline to Day 7 and Day 28)

Changes in hematology, comprehensive chemistry, ESR, hs-CRP, 
and urinalysis results
SECONDARY 
ENDPOINTS

Change in blood inflammatory biomarkers from Baseline to Day 7 
and Day 28

Change in sputum inflammatory biomarkers from Baseline to Day 
7 and Day 28
OTHER 
EVALUATIONS
Bone marrow aspiration is optional.  CF bone marrow aspirates will be 
used to assess autologous approaches to MSC therapeutics. 
Any sputum or serum remaining after the study will be archived for 
future translational projects.
SAFETY 
MONITORING
The Therapeutics Development Network Coordinating Center (TDNCC) 
Medical Monitoring Group will serve as the medical monitor for this 
clinical trial.  In addition, the Cystic Fibrosis Foundation Data Safety 
Monitoring Board (DSMB) will establish a Data Monitoring Committee 
(DMC) to review data relating to safety and efficacy, to conduct and 
review interim analyses, and to ensure the continued scientific validity 
and merit of the study, according to the Cystic Fibrosis Foundation Data 
Safety Monitoring Board Operations Manual and a DMC Charter 
established for this protocol. There will be 3 interim review(s) conducted 
by the DMC for the purpose of monitoring study conduct and assessing 
subject safety.  

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RATIONALE FOR 
NUMBER OF 
SUBJECTS
This is a single center Phase I study.  Enrollment of 15 subjects will be 
feasible and allow us to ascertain if there are any clinically meaningful 
infusion-related adverse effects. 

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1
BACKGROUND
1.1
Introduction
Cystic fibrosis (CF) lung disease begins at birth and continues throughout life2.  While the pathogenesis 
of CF lung disease is complex, excessive inflammation is a key component of disease pathology2.   The vicious 
cycle of airway obstruction, chronic bacterial infection, and excessive inflammation eventually leads to 
irreversible lung damage3.  It is possible that gene modifying agents will eliminate the downstream 
pathophysiologic consequences of defective cystic fibrosis transmembrane conductance regulator (CFTR).  
However, it is more likely that gene modifying agents will reduce the pathophysiologic consequences in the 
airway, particularly the exaggerated inflammatory response and decrease the frequency of pulmonary 
exacerbations, but not eliminate them completely. Therefore, future treatment regimens for CF lung disease will 
likely employ the administration of one or more CFTR disease modifying drugs in combination with an anti-
inflammatory drug.  Unfortunately, previously evaluated anti-inflammatory therapeutics, such as systemic 
corticosteroids and BIIL 284 BS, have been associated with side effects or have not shown to be efficacious, 
and dosing and monitoring of high-dose ibuprofen has precluded its widespread use4,5.     
Mesenchymal stem cell (MSC) based therapies have generated much interest due to their anti-
inflammatory, anti-microbial, immunomodulatory, and regenerative properties6.  MSCs are multipotent cells 
that secrete a variety of bioactive factors, which actively contribute favorably to their environment within 
damaged tissues.  Furthermore, MSCs exert immunomodulatory effects by direct cell to cell contact7,8.  Finally, 
these cells are also capable of changing in response to cues from their environment. MSCs have been evaluated 
in clinical trials of diseases involving multiple organ systems including bone, cartilage, lungs, pancreas, 
neurons, intestines, and the heart and blood vessels6.  The medicinal potency and efficacy of the MSCs are 
particularly useful in scenarios of tissue damage, inflammation, and infection in the lung and gut; implicating 
the power of MSCs therapeutic potential in CF. 
1.2
Specific Aim
To determine the safety and tolerability of a single infusion of human MSCs (hMSCs) and to explore secondary 
efficacy endpoints to determine if hMSCs reduce inflammation in subjects with CF. Markers of inflammation 
will be measured in blood and sputum before and 7 and 28 days after a single infusion of  hMSCs in clinically 
stable adults with CF.  
1.3
Significance
1.3.1
Mesenchymal stem cells mechanism of action: Anti-inflammatory, immunomodulatory, and anti-
bacterial
The immunomodulatory properties of MSCs and their ability to secrete anti-inflammatory cytokines 
make them ideal for allogeneic infusion because immunosuppressants are not required. For this study, 
allogeneic hMSCs are being utilized because autologous MSCs will contain the subject’s CFTR mutations, 
which would offset any potential benefit. MSCs are relatively immunoevasive; they express low levels of major 
histocompatibility complex I (MHC-I) molecules and do not express MHC-II molecules or costimulatory 
molecules such as CD80, CD86, or CD409, suggesting that allogeneic MSCs can be used in the clinical setting. 
MSCs home specifically to injured tissue and exert their immunomodulatory activity through the secretion of 
angiogenic (e.g., vascular endothelial growth factor)10, anti-apoptotic (Bcl-2)11, and inflammatory factors 
[tumor necrosis factor- (TNF-, interferon-γ (IFN-), interleukin (IL)-1, -6, and -10, VEGF, hepatocyte 

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growth factor]10,12-15, stimulation of angiogenesis, promotion of a secure environment for host cell recovery, and 
repair and regeneration of injured tissue. Exogenously administered MSCs modulate the function of host cells at 
the site of injury, both by cell contact-dependent and paracrine mechanisms which involve secretion of specific 
mediators or transfer of cellular materials such as proteins, nucleic acids, and cell organelles (including 
mitochondria) to injured host cells via microvesicles16,17.  MSCs also have antibacterial properties and inhibit 
bacterial growth by secretion of the antimicrobial peptide LL-3718,19.  
1.3.2
Mesenchymal stem cells are safe
Autologous MSCs cannot be used in this clinical trial because the MSCs will contain two mutations in 
CFTR. Therefore subjects with CF who will be enrolled in this trial will receive infusions of allogeneic MSCs. 
Infusions with allogeneic hMSCs has been shown to be safe in follow-up periods lasting several years in 
patients with pulmonary disease and patients with other inflammatory diseases including Crohn’s disease, graft-
vs.-host disease, multiple sclerosis, and type 1 diabetes20. Up to 1 x 107 allogeneic hMSCs/kg (twice the 
maximum dose that will be used in this study) have been infused safely.  There have not been any issues with 
infusion-related toxicities or tumor development. Autopsy studies reveal limited residual MSCs up to 18 months 
after administration21.  A meta-analysis of clinical trials of MSC infusions to evaluate safety identified 1012 
participants with varying clinical conditions and identified eight randomized controlled trials with 321 
subjects22.  The authors did not detect an association between acute infusion-related toxicity, organ system 
complications, infection, death or malignancy, but there was a significant association between MSCs and 
transient fever22.  
A significant concern in CF patients receiving strong anti-inflammatory therapies is the increased risk of 
pulmonary exacerbations.  Weiss and colleagues performed a placebo-controlled, randomized trial of 
mesenchymal stem cells in chronic obstructive pulmonary disease (COPD) where 31 subjects received four 
monthly stem cell infusions and there was no difference in hospitalizations for COPD exacerbations during the 
study (six in the MSC group and five in the placebo group)23.  A recent meta-analysis did not detect an 
association between MSC treatment and the development of infection22.  Preliminary data in CF animals 
suggests improvement in infection related outcomes, not worsening18,19. 
Another concern is the potential for increased risk of cancer.  Again, this has not been detected in 
clinical trials22,24. However, the potential for malignant transformation would not be unexpected given some of 
the biologic similarities between stem cells and cancer cells.  However, the risk of tumorigenesis is likely to be 
an extremely uncommon event with current culture conditions where cells are harvested for therapy well before 
the cultures reach senescence20.  Another potential risk would be if hMSCs engraft for long periods of time 
which would result in ectopic tissue formation and increase the risk of malignant transformation  Autopsy 
studies have not detected hMSCs in MSC recipients, thus suggesting that hMSCs appear to work through a “hit 
and run” mechanism21.  There have been no reports of de novo tumor formation complicating MSC infusion in 
humans22,24.  Nevertheless, in our protocol, cells will be passaged the minimum number of times to obtain 
sufficient cell yield, thereby lessening the potential for cytogenetic abnormalities.  In addition, CF subjects with 
a history of invasive cancer requiring systemic therapy will be excluded from the study.
There have been no published clinical trials of MSCs in CF.  A search of PubMed “Mesenchymal Stem 
Cells” limited to humans and clinical trials returns over 200 citations, including several pulmonary studies.  
Chang and colleagues recently published a phase 1 dose-escalation study in 9 preterm infants at risk for 
bronchopulmonary dysplasia and found MSC infusion to be safe and without associated serious adverse events 
(SAEs) or dose limiting toxicities25.  A human trial of a commercial hUCB-MSC product (PNEUMOSTEMTM) 
for neonatal bronchopulmonary dysplasia has been performed in South Korea and demonstrated decreased 

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levels of inflammatory markers in tracheal secretions and less severe respiratory disease; no long-term data are 
available yet25. A Phase I/II clinical trial of PNEUMOSTEMTM is currently enrolling in the United States. 
Stem cell infusion has also been shown to be safe in 30 adults with multidrug-resistant tuberculosis26, 87 
subjects with drug refractory systemic lupus erythematosus27, and 15 subjects with Crohn’s disease28 and has 
been found to have clinical benefit in pediatric patients with other diseases29-31. 
1.3.3
Overview of pre-clinical data of MSCs in cystic fibrosis
Dr. Bonfield’s (Co-I) laboratory carries out studies using in vivo modeling of acute and chronic 
Pseudomonas aeruginosa (clinical isolate: M5715) infection in mice deficient in Cftr32-34.  This murine model 
was used to evaluate hMSCs.  Importantly, hMSCs attenuated weight loss, clinical score and lung pathology 
associated with chronic infection with P. aeruginosa in comparison to CF mice not treated with hMSCs19.  In 
addition to benefits in weight gain and overall health of the animals, there was a significant decrease in lung 
inflammation (Figure 1A).  CF mice treated with hMSCs had a significant reduction in BAL neutrophils (Figure 
1A) and bacterial burden (Figure 1B). MSC administration also was associated with decreased KC (a neutrophil 
chemoattractant), IL-6 and IL-1 concentrations (p<.05).  These studies also demonstrated that MSC infusion 
was not associated with increased infectious complications despite attenuating inflammation.
 
A. Percent PMNs
B. Bacterial CFUs
Figure 1: hMSCs are Anti-inflammatory and Antimicrobial in vivo.  Cftr deficient mice and WT controls were infected with P aeruginosa and 
followed for up to 10 days.  Mice received hMSCs one day after infection.  Animals were euthanized and evaluated for BAL neutrophils(A), and P. 
aeruginosa CFUs (B). Treatment was associated with a decrease in neutrophils (A, P<0.05) and bacterial CFUs (B, P<0.05).  
 
Bacterial infection with microorganisms, like P. aeruginosa contribute to the lung pathophysiology in 
CF. The challenge clinically, is to attenuate the inflammatory response that is responsible for damaging the lung 
architecture while at the same time not increasing infectious complications.   Figure 2 shows an example of 
how hMSCs impact bacterial growth and kinetics over time. These studies demonstrate that hMSC have 
antimicrobial potential by decreasing the overall growth of the bacteria.  Interestingly, hMSCs in combination 
with gentamicin was even more efficient, thus suggesting the potential to use MSC to enhance antibiotic 
regimens for acute and/or chronic infections.

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Figure 2: hMSC Supernatants are Antimicrobial. Supernatants from 4 different MSC donors were cultured with 
a clinical strain of P. aeruginosa for 5 minutes.  Bacteria were then streaked onto TSA plates and cultured 
overnight and analyzed for CFUs (A) or ATP for determination of growth kinetics (B).  Gentamicin was used as a 
positive control.  Both gentamicin and MSC supernatants decreased CFUs (P<0.05) and rate of growth 
(P<0.05).The largest effect was seen with the combination of supernatants from hMSCs and gentamicin.
In addition to P. aeruginosa, Dr. Bonfield’s lab has also shown that hMSCs have antibacterial effects on 
Staphylococcus aureus.  Given that almost 25% of CF patients are infected with methicillin-resistant S. aureus 
(MRSA), which is associated with worse survival35, these findings are particularly noteworthy.   Dr. Bonfield 
began by evaluating the ability of hMSC supernatants to change the growth potential of S. aureus. Supernatants 
harvested from hMSCs in culture were associated with significantly fewer S. aureus CFUs.  Bacterial CFUs 
were decreased further when the hMSC supernatants were given in combination with antibiotics. Our laboratory 
now consistently screens different donor preparations for their antimicrobial potency.  These potency assays are 
unique and were developed here at Case Western Reserve University by Dr. Bonfield.  In these in vitro potency 
and efficacy assays, MSC preparations are cultured with pathogens such as P. aeruginosa, S. aureus (including 
MRSA), and Streptococcus pneumoniae.
Cytokines are essential in the process of leukocyte recruitment and define the cell type and 
inflammatory response.  Wild-type and Cftr deficient epithelial cell lines were stimulated to produce pro-
inflammatory cytokines and co-cultured with human MSCs and then stimulated with lipopolysaccharide (LPS). 
Figure 3 shows the results obtained when hMSCs were cultured in cell culture conditions with and without 
stimulation with E. coli LPS. In both model systems the hMSC suppressed the production of LPS induced pro-
inflammatory mediators. These cell lines are now part of our in vitro system for monitoring MSC donor efficacy 
and potency in terms of inflammation and leukocyte recruitment.

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Figure 3: hMSCs are Anti-Inflammatory. MSCs from 4 different bone marrow donors were cultured with either LPS, 
stimulated macrophages (A and B), or epithelial cells (C and D) from either CFTR-deficient or WT sources.  After 24 
hours, cells were harvested and processed for cDNA and real-time PCR.  LPS-induced IL-6 and TNF-a gene expression 
in the in macrophages was suppressed by the addition of hMSC supernatants (P<0.05).  LPS-induced IL-6 and IL-8 gene 
expression in the epithelial cells was also suppressed by the addition of hMSC (P<0.05). BMM=bone marrow 
macrophages
1.3.4
Overview of Clinical Studies
1.3.4.1
Mesenchymal stem cells in pulmonary disease
COPD is a heterogeneous systemic disease that is characterized by significant inflammation.  The only 
published study of hMSC infusion in COPD is the study by Weiss and colleagues in which the infusions were 
well tolerated23.  The design was a placebo-controlled, randomized trial of mesenchymal stem cells in COPD 
where 30 subjects received four monthly stem cell infusions (100 x 106 cells) and 32 subjects received placebo.  
We propose using a weight based approach rather than administering a fixed dose of hMSCs.  The dose of 
MSCs that will be used in this trial, 1 to 5 x 106 hMSCs/kg, would be approximately 70 to 350 x 106 hMSCs.  It 
is also important to emphasize that these COPD subjects had more fixed lung disease compared to CF subjects 
with mild to moderate CF lung disease, the target population that will be recruited into this clinical trial.  In 
addition, subjects with COPD were older (average age 68), had moderate to severe COPD, and had multiple co-
morbidities.  In this population of subjects with COPD, the infusion of hMSCs was well tolerated with no 
differences between the groups in adverse events (AEs). No infusion-related toxicities and no SAEs occurred 
that were related to study drug.  The study did not detect any differences in pulmonary function test results or 
quality of life indicators.  The subjects with the highest levels of inflammation at baseline had significant 
improvements in inflammatory markers compared to the placebo group, and the authors hypothesize that 
chronic immune based inflammatory diseases, such as CF, may be more likely to respond than what was seen in 
this COPD study. In addition, the dosing was the same for every subject, regardless of weight.  In another 
clinical trial of hMSC infusion in pulmonary disease, there was significant efficacy seen in the phase 1 dose-

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escalation study of preterm infants with bronchopulmonary dysplasia (BPD)25.  In this study, concentrations of 
IL-6, IL-8, MMP-9, TNF-, and transforming growth factor (TGF)-1 in tracheal aspirates at day 7 were 
significantly decreased compared to baseline and 3 days post-infusion.  Furthermore, the severity of BPD was 
reduced in MSC recipients, while AEs did not differ between the study groups. Human studies are ongoing in 
acute respiratory distress syndrome and idiopathic pulmonary fibrosis, but have not been completed or 
published. 
1.3.4.2
Infusion of Mesenchymal Stem Cells in Humans
MSCs have been tested as treatment for a variety of clinical indications, and in some settings, dramatic 
benefit has been reported.  Hillard Lazarus, M.D. and Arnold Caplan, Ph.D. designed and executed the very first 
in-human MSC trial, which was conducted here at Case Western Reserve University 36.  Since that very first-in-
human MSC study, it is estimated that tens of thousands of subjects have received MSCs in over 500 trials22. 
1.3.4.3
Mesenchymal Stem Cell Trials at University Hospitals Cleveland Medical Center
1.3.4.3.1 CWRU 1494 Autologous Mesenchymal Stem Cell Infusion at the Time of Autologous 
Peripheral Blood Stem Cell Transplantation
We evaluated the feasibility and safety of autologous MSC infusion in breast cancer patients undergoing 
high dose chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation37.  We also 
investigated whether autologous MSC infusion at the time of PBSC transplantation facilitated hematopoietic 
engraftment, particularly megakaryopoiesis.  In this study, the bone marrow (BM) aspirate from 28 enrolled 
subjects was successfully cultured in excess of 1 x 106 cells/kg (mean expansion potential 19 x 106 cells/kg).  
Subjects were re-infused with 1-2.2 x 106 cells/kg autologous culture-expanded MSCs, either 24 or 1 hour after 
PBSC infusion.  Intravenous administration of MSCs was very well tolerated with no toxicity.  Neutrophil and 
platelet count recovery was rapid (median days to ANC>500/l=8 days and median days to 
platelets>20,000/l=8.5 days) with none of the patients experiencing engraftment delays.  In addition, we were 
able to isolate circulating clonogenic MSCs from the venous blood of subjects receiving intravenous infusion of 
MSCs either immediately at the end of infusion (3 out of 15 patients), 15 minutes after infusion (8 out of 15 
patients), and 60 minutes after infusion (2 out of 15 patients).  Clonogenic MSCs were not detected 6 and 18 
hours after infusion.  These data indicate that MSCs circulate for a short period of time following intravenous 
infusion and suggest that they distribute widely in the body.  Whether these cells home to specific locations or 
distribute in tissues in a non-specific manner is unknown.
1.3.4.3.2 OSIR 1Y98 Allogeneic Donor Mesenchymal Stem Cell Infusion at the Time of Allogeneic 
Peripheral Blood Stem Cell or Bone Marrow Transplant
Our group led a multi-center clinical trial with MHC-identical donor allogeneic MSCs to promote faster 
hematopoietic engraftment and to limit graft versus host disease (GVHD) after allogeneic BM or PBSC 
transplantation in patients with hematological malignancies38. Forty-three subjects received myeloablative 
chemo-radiation therapy, MHC-identical sibling marrow (N=17) or mobilized peripheral blood (N=26) stem 
cells, and escalating doses of culture-expanded MSCs from a hematopoietic stem cell donor (1-5 x 106 cells/kg).  
There were no instances of MSC infusion-related toxicities.  Median (range) time to neutrophil recovery 
>500/l was 14 (11-22) days and platelets >20,000/l (not transfused) was 21 (15-78) days for all subjects.  
Grade 0-I acute GVHD occurred in 29 subjects and grade II-III in 10 subjects; none had grade IV.  Of 36 
subjects at-risk, chronic GVHD did not develop in 17 participants, was of limited extent in 13 subjects, and 
extensive in 6 participants.  The expected incidence of acute and chronic GVHD in sibling-matched allogeneic 
stem cell transplantation varies.  In the two largest prospective studies, the incidence for grade II-IV and III-IV 

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acute GVHD ranged 44% to 64%39and 12% to 26%40. Extensive chronic GVHD rates in these two reports 
ranged from 30% to 46%. Our results compare favorably with these historic data.  Despite the fact that severe 
acute and chronic GVHD appeared to be reduced by the co-infusion of MSCs, we did not observe an excessive 
number of subjects developing tumor progression adding confidence to the use of MSCs in the context of non-
malignant diseases such as CF.
1.3.4.3.3 CWRU 1Y98 Late Allogeneic Donor Mesenchymal Stem Cell Infusion for Lysomsomal or 
Peroxisomal Disorders
Allogeneic BM transplantation can provide donor cells to correct inherited enzymatic deficiencies as 
well as skeletal disorders in non-malignant disorders41.  Many of these disorders are only partially corrected by 
an allogeneic transplantation.  We hypothesized that marrow derived stromal cells could have further beneficial 
effect in these patients by providing enzyme replacement to the tissues to which they distribute.  We previously 
determined that human MSCs express high levels of arylsulfatase A and L-Iduronidase.  Arylsulfatase A 
deficiency results in metachromatic leukodystrophy, which is manifested during the first decade of life with 
progressive dementia, convulsions and cranial nerve abnormalities.  L-Iduronidase deficiency results in Hurler 
disease that is manifested by hepatosplenomegaly, dysostosis multiplex, and neuropsychological decline.
To correct the enzyme deficiency and provide normal progenitor/stem cells to patients with 
metachromatic leukodystrophy and Hurler disease, we infused allogeneic MSCs into these patients37.  These 
patients previously underwent allogeneic BM transplantation from the same donor and were fully engrafted by 
donor hematopoietic cells.  Since these patients already had donor type immune systems, infusion of donor-
derived cells of mesenchymal lineage was expected to be safe and possibly provide a therapeutic benefit.  
Subjects were not given any myelosuppressive chemo- or radiotherapy.  Between March 1999 and July 2000, 
12 donors were enrolled and MSC cultures established in all cases.  Eleven subjects were enrolled and infused 
with donor MSCs.  One subject dropped out for personal reasons during the course of the investigation, after 
collection and cryopreservation of donor MSCs.  MSCs were culture-expanded in the CWRU Cell and Gene 
Therapy Facility.  Four subjects received 2 x 106 donor MSCs/kg, five subjects received 3.4 to 4.6 x 106 
MSCs/kg, and three subjects received 10 x 106 MSCs/kg.  Target donor MSCs were culture expanded in 8 
subjects.  One subject in the 4 x 106 MSCs/kg cohort and 2 subjects in 10 x 106 MSCs/kg cohort received fewer 
MSCs than planned.  This was mainly due to the excessive time and passage numbers that would have been 
required to achieve the target doses.  A decision was made to limit the time and the passage number in these 
subjects.  Relatively small amounts of starting BM aspirate and our culture conditions were adequate to grow 10 
x 106 cells/kg of human MSCs for small children (<40kg).
There were no acute or chronic toxicities related to donor MSC infusion with no significant toxicity with 
15-31 months of follow-up.  There was grade 1 fever in 3 subjects that was self-limited in all cases.  We have 
clinical follow-up as well as laboratory follow-up in all subjects.  Thus far, we have been able to re-culture 
donor MSCs from 2 recipients (0.2-2%) using the existing culture assay technique.  We have not detected any 
immune response against donor MSCs by ELISPOT assay using recipient lymphocytes and donor MSCs.  
Clinical outcome was evaluated by physical examination including neurological examination, psychosocial 
assessments, nerve conduction velocity, and bone mineral density measurements.  There was no dramatic 
change in subjects overall health and no readily detectable change in mental and physical development.  
Following allogeneic MSC infusion, bone mineral density was either maintained or slightly improved in all 
subjects.  Five of 6 metachromatic leukodystrophy patients had electrophysiological assessment, and in four 
there was a clear evidence of improvement in nerve conduction velocity.

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1.3.5
Factors Affecting the Characteristics of Isolated Mesenchymal Stem Cells
The factors that affect the characteristics of isolated MSCs have not been extensively studied.  MSC 
numbers appear to decrease with age42, and MSCs from elderly donors have decreased life span and 
proliferation rate43.  There appears to be no age effect on differentiation potential43. There was little variability 
between MSCs isolated from 50 healthy donors in proteomic profile or ability to inhibit proliferation in mixed 
lymphocyte reaction44. 
It is uncertain whether the functional properties of MSCs are altered in human diseases.  MSCs isolated 
from patients with advanced osteoarthritis had normal cell yield but reduced proliferation, chondrogenic and 
adipogenic capacity45. There are conflicting reports on whether MSC properties are altered in immune-mediated 
disease.  MSCs isolated from patients with severe aplastic anemia were deficient in their ability to inhibit T-cell 
proliferation and cytokine release, including T-cell proliferation in allogeneic mixed lymphocyte reactions, 
expression of the activation marker CD38 and IFN- production by phytohemagglutinin-stimulated cells, 
production of cyclic ADP-ribose, and T-cell-mediated inhibition of hematopoietic colony formation46.  In 1 
study, stromal progenitors isolated from subjects with systemic sclerosis were functionally impaired with 
reduced proliferation rate and capacity for adipogenic and osteogenic differentiation47. A similar decrease in 
proliferative potential was reported in MSCs isolated from 26 subjects with rheumatoid arthritis48. In contrast, 
in 2 other studies, MSCs isolated from patients with autoimmune diseases (systemic lupus erythematosus, 
rheumatoid arthritis, systemic sclerosis, Sjogrens syndrome, polymyalgia rheumatica, or diabetes) had similar 
surface phenotype, plaque-forming ability, differentiation capacity, ability to support hematopoiesis, and 
immunomodulatory properties as MSCs from controls, with no apparent effect of disease activity or 
immunosuppressant therapy49,50. 
BM stromal cells isolated from 15 MS patients had normal capacity to support hematopoiesis, with no 
apparent effect of recent IFN- treatment51.  MSCs isolated from 10 multiple sclerosis (MS) patients had similar 
proliferation, differentiation capacity, toll-like receptor expression, immunomodulatory actions, ability to inhibit 
dendritic cell differentiation and activation, but significantly greater LPS-stimulated IP10 production compared 
to 6 healthy controls52. Thus, it is conceivable that MSCs from MS patients may have reduced 
immunomodulatory and/or repair capacity as a manifestation of the underlying disease or its treatment.  
Therefore, the planned studies of the phenotype and function of MSCs from CF subjects as part of this trial will 
be of great interest.
It is important to note that there can be substantial variability between different MSC preparations either 
due to donor or specific culture conditions53.  Key factors include freshness of the starting material, starting cell 
number, culture medium, serum or serum substitute, the specific plasticware used, culture density, timing of 
passages, etc.  Experience in our facility and others, confirms that it is possible to cryopreserve cells and that 
frozen MSCs have preserved viability, proliferation, differentiation, and surface marker expression and 
functionality54-56.  We plan to cryopreserve our cells after primary culture only, and once thawed for culture 
they will be expanded and infused fresh.  In our studies, specific attention will be given to identifying a donor 
MSC preparation with the highest degree of efficacy and potency using our in vitro and in vivo pre-clinical 
diagnostic models.  Our assays evaluate the anti-inflammatory, antimicrobial and leukocyte recruitment 
potential of the MSCs in vitro followed by validation in our murine pre-clinical model of CF lung infection and 
inflammation.
In terms of MSC preparations, we will use our standardized protocols for culture and expansion of the 
identified donor cells, with the plan to utilize the same donor preparation for all infusions.  These specifics will 
minimize variability in the MSC donor preparation as well as minimize any development of alloantibodies to 
the allogeneic MSCs.   This clinical trial will utilize the standard protocols for collecting, expanding, 
cryopreserving, and infusing hMSCs from the Comprehensive Cancer Center (CCC) and the National Center 

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for Regenerative Medicine (NCRM) at Case Western Reserve University.  At the time of infusion, an aliquot of 
MSCs that will be used in the infusion will be assessed for pre-clinical efficacy to track any potential changes in 
clinical potency using our in vitro pre-clinical models.  During the infusions, attention to several factors will be 
important including minimization of prolonged storage in the syringe and rapid injection through a small-bore 
needle both of which would decrease cell viability57.
1.3.6
Potential Safety Concerns
In general, MSC infusion in humans, including allogeneic MSCs, has been very well tolerated.  
Autologous MSC infusion is not an option for this clinical trial due to the underlying genetic defect. Neither 
acute nor long-term clinically significant AEs attributable to allogeneic MSCs have been reported.  Up to 1 x 
107 cells/kg can be infused safely (our study will infuse up to a maximum of 5 x 106 cells/kg)37. There have 
been no reports of immunosuppression attributed to MSC infusion leading to opportunistic infection or 
autoimmunity reaction.  In one clinical trial a subject developed urticaria with the second infusion of allogeneic 
MSCs, thought to be due to development of antibodies to the fetal bovine serum (FBS) used to culture MSCs58.  
FBS will not be used in this protocol.  There have been no reports of de novo neoplasm in recipients, either 
potentially derived from MSCs or due to a permissive effect of MSCs.  MSCs are immune privileged and 
therefore infusion of allogeneic cells is possible.  There have been no pulmonary complications.  Nevertheless, 
several potential adverse effects will require close attention.
1.3.6.1
Infusion-Related Toxicity
During this study, we plan to use freshly expanded hMSCs.  By using freshly expanded hMSCs for the 
infusions, possible infusion-related toxicities will be reduced. However, there is a possibility that a subject may 
be unable to get fresh hMSCs on the day of the infusion.  In this instance, we may infuse expanded hMSCs that 
have been frozen with dimethylsulfoxide (DMSO).  Most studies have reported no infusion-related AEs.  A 
patient with encephalopathy, stroke, and myocardial infarction most likely related to DMSO used in freezing 
medium has been reported59.  Anti-FBS antibodies are common but usually not clinically significant60.  One 
study reported a single participant who developed an urticarial rash following a second allogeneic MSC 
infusion58.  That participant had a 150-fold increase in anti-FBS antibodies after the second infusion.  Because 
MSCs are relatively large cells (20-60 m)61 and cell clumping is possible, pulmonary embolism is a potential 
concern.  No study has reported pulmonary symptoms, change in oxygen-saturation, or change in chest 
radiograph.  Adherence to established procedures for thawing and infusing cells should minimize the potential 
for these AEs. 
1.3.6.2
Infection
MSC infusion per se could be a source of infection.  MSCs could be contaminated during harvest, 
manipulation, or infusion.  One case series reported a subject with GVHD who developed central line infection 
and cellulitis62, not uncommon in critically ill patients.  Aseptic technique during BM aspiration and infusion, 
strict adherence to culture protocols, and stringent microbiologic screening are intended to minimize the risk of 
administering a contaminated cell product. Furthermore, MSCs are potently antimicrobial as previously 
discussed.  Therefore, using our established good laboratory practices and extensive experience in infection 
control and conduct of clinical trials will minimize the potential risk of infection.
MSCs express CD13 (the cytomegalovirus (CMV) receptor) and to a lesser extent CD21 (the receptor 
for EBV)63.  MSCs can be infected in vitro with CMV and HSV-1 but not EBV.  Reassuringly, CMV, HSV-1, 
HSV-2, EBV, VZV RNAs were not detected by PCR in MSCs from seropositive donors.  Nevertheless, careful 
donor screening for herpes virus, cytomegalovirus and other infectious agents in potential future studies of 
allogeneic MSC infusion will remain important.

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Finally, because of the immunosuppressive actions of MSCs, recipients potentially are at increased risk 
for more severe or opportunistic infections.  MSCs inhibit lymphocyte proliferative responses to herpes viruses, 
candida, and S. aureus Protein A63.  MSC effects on virus-specific T-cell responses appear to be less than on 
other immune responses, e.g. to alloantigens64. Infections have occurred in a significant proportion participants 
receiving MSC infusion in some series.  However, all of the reported cases have involved already 
immunocompromised patients with cancer and/or GVHD following HSC infusion65-67. Therefore, it is difficult 
to discern whether MSC infusion played a role in the infections.  Furthermore, MSCs themselves are 
antimicrobial, producing peptides which aide in clearance and managing infections.
1.3.6.3
Cancer
The potential for malignant transformation would not be unexpected given some of the biologic 
similarities between stem cells and cancer cells.  MSCs in adults may become tumorigenic68,69 and have been 
implicated in several human or experimental tumors, including childhood leukemia70, gastric epithelial 
cancers71 and osteogenic sarcoma72  In the study by Tolar et al.72, the high frequency of osteogenic sarcoma in 
lung after MSC infusion in mice appeared to be related to the propensity of mouse cells to develop frequent 
karyotypic abnormalities even with short-term culture.  Karytotypic abnormalities were not seen in some studies 
of human MSCs73 but were reported in others, predominantly with prolonged culture74-76. An important factor 
appears to be continuing cultures following senescent crisis77,78. 
A number of studies demonstrate homing of MSCs to primary and metastatic cancers where they may 
form tumor stroma79. In addition, trophic or immunosuppressive effects of MSCs could create a permissive 
environment for cancer development.  For example, MSC-derived adipocytes reduced apoptosis of acute 
promyelocytic leukemia cells in culture80. MSCs promote experimental breast cancer metastasis in mice81. 
Human MSCs mixed with human breast cancer cells injected SC as xenograft in mice led to marked increase in 
metastatic potential.  MSCs prolonged B16 melanoma tumor cell survival when co-injected subcutaneously in 
mice82.  In a randomized trial in hematologic malignancy of HLA-identical sibling matched HSC +/- MSC, 
there was decreased GVHD in MSC recipients (11.1% vs. 53.3%) but increased leukemia relapse (6/10 (60.0%) 
vs. 3/15 (20.0%))66. 
Despite these theoretical concerns, there have been no reports of de novo tumor formation complicating 
MSC infusion in humans in the more than 500 MSC clinical trials documented in Clinicatrials.gov.  
Nevertheless, cells will be passaged the minimum number of times to obtain sufficient cell yield to lessen 
potential for cytogenetic abnormalities.  Also, in this trial participants with a history of invasive cancer 
requiring systemic therapy will be excluded.
1.3.6.4
Rejection
MSCs are immunoevasive and non-immunogenic, which allows them to be used in allogeneic and 
xenogeneic transplantation.  Humans have received well over 20,000 infusions of MSC, both autogeneic and 
allogeneic, and there have been no episodes of rejection.
1.3.6.5
Ectopic Tissue Formation
MSCs have the capability to differentiate into a number of mesodermal tissues and, possibly, tissues 
derived from other germ layers.  Ectopic calcification and/or ossification were observed with direct injection of 
MSCs into infarcted mouse heart74.  Ectopic tissue formation has not been reported in any human studies.  
Despite being specifically sought, ectopic tissue formation was not seen in 3+ years of follow-up in 7 subjects 
who underwent MSC/HSC co-infusion62.

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1.3.6.6
Graft vs. Host Disease
GVHD should not be an issue with removal of lymphocytes during culture expansion. In addition, 
allogeneic MSCs are now standard of care in pediatric patients requiring allogeneic bone marrow 
transplantations for the prevention of GVHD.
1.3.7
Experience in Isolation and Culture Expansion of Mesenchymal Stem Cells
MSCs have been isolated and cultured in large numbers in the Cellular Therapy Laboratory of the Case 
Western Reserve University Center for Stem Cell and Regenerative Medicine under several INDs, including 
IND 11176 and IND 13917.  MSCs are isolated from a BM aspirate (50-100 ml using a brisk pull) and culture-
expanded according to procedures outlined in existing SOPs.  Culture expanded MSCs are tested for 
morphology, surface antigen expression, potential microbiological contamination, and viability prior to release 
for infusion.  
Human MSCs have been generated from approximately 3000 individual donor marrows over the past 25 
years at Case Western Reserve University.  Typically, >250 x 106 MSCs can be generated from a 20-mL BM 
aspirate.  Human MSCs propagated in culture are ≥95% pure as judged by reactivity to MSC-specific 
monoclonal antibodies to CD105 and CD7383.  Culture conditions are specific for growth of MSCs.  Adherent 
CD14+ or CD45+ hematopoietic cells are eliminated from the culture after the first passage.  The techniques for 
propagating MSCs in tissue culture have been highly successful, and cultures remain free of contaminating 
bacteria, fungus, mycoplasma or endotoxin for at least 7 weeks (personal communication J. Reese).
1.3.8
Cystic Fibrosis Clinical Trial Experience at Rainbow Babies and Children’s Hospital
The Cystic Fibrosis Clinical Research Center located at Rainbow Babies and Children’s Hospitals/Case 
Western Reserve University has extensive experience in conducting clinical trials in CF.  We have a long 
standing tradition of research since the Clinical Care Center’s inception over 50 years ago.  Our Research 
Center was one of the original 7 Centers of the Cystic Fibrosis Foundation’s Therapeutics Development 
Network, which was established in 1998.  We have participated in nearly every clinical trial in CF since that 
time. This Center consistently has 30 or more active CF clinical research trials approved by the Institutional 
Review Board (IRB). Dr. Erica Roesch is the PI on this clinical trial.  Dr. Roesch has been site PI on 4 clinical 
trials and site Co-I on several other CF clinical trials since joining the CF clinical research team over two years 
ago. Dr. Roesch will be assisted in this study by Dr. Ross Myers and Dr. Michael Konstan, both of whom are 
experienced clinical investigators. Dr. Konstan has published well over 100 peer reviewed manuscripts on CF 
clinical trials and served as site PI, site Co-I and Lead PI on dozens of multicenter clinical trials in CF. He has 
been instrumental in bringing several approved therapies for CF to market. In addition, Dr. James Chmiel, the 
previous PI on this study, will serve as a collaborator from his new institution. This Center is well-known for its 
excellence in clinical research.   
2
STUDY RATIONALE
In CF, the current estimated median age of survival is 37 years84.  The leading cause of shortened 
survival is progressive lung disease85. Major accomplishments have been made in developing small molecule 
correctors and potentiators of CFTR, but a cure remains elusive.  One would predict that intervening at the gene 
level with gene replacement therapy or at the protein level with CFTR potentiators and/or correctors early in 
that pathophysiologic cascade would result in improvements in downstream consequences, particularly at the 
level of the exuberant inflammatory response.  However, recent clinical trials with drugs to improve CFTR 
function have not produced measurable improvement in airway inflammation despite improving lung function 

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and, at times, decreasing bacterial infection86.  As the pursuit for a cure continues, new and innovative 
therapeutic approaches are desperately needed to provide improved resolution of the on-going damaging 
infection and inflammation in the CF lung87. 
Bone marrow-derived hMSCs, which may ameliorate the consequences of CF, possess several 
advantageous properties 88.  First, hMSCs can be isolated from non-CF subjects by simple bone marrow 
aspiration and expanded in culture up to a billion fold within 8 weeks. This allows for potential wide-spread use 
of this therapy if hMSCs are found to be safe and effective.  Second, hMSCs can differentiate into gut and 
respiratory epithelial cells89,90, suggesting not just pulmonary, but systemic benefit. Third, hMSCs are 
immunoevasive because they lack major histocompatibility complex and co-stimulatory cell-surface antigens. 
Thus infusion of hMSCs from other humans is well tolerated91. Humans have received well over 20,000 
infusions of hMSCs, both autogeneic and allogeneic, and there have been no episodes of tissue rejection or 
adverse reactions. Fourth, hMSCs have both anti-inflammatory and antimicrobial properties 88.  Our preclinical 
data suggest that hMSCs decrease bacterial burden and inflammation in a murine model of CF lung infection, 
and we have been able to demonstrate in vitro that the hMSCs have the capacity to enhance the effectiveness of 
antibiotics often utilized to treat the infections associated with CF19.  Fifth, our studies also showed the unique 
capacity of the MSCs to cross species from humans into mice to demonstrate a beneficial effect without any 
major adverse effect.
The overall goal of this project is to determine the safety and tolerability of hMSCs and to explore 
efficacy endpoints for a subsequent clinical trial.   Baseline studies for inflammatory markers in blood and 
sputum will be determined.  This will be followed by a single infusion of hMSCs. These studies will be 
repeated at 7 and 28 days and compared to Baseline values (with-in subject comparison). If hMSC infusion is 
determined to be safe in this study, it could then be advanced to a Phase II double-blind, placebo-controlled 
clinical trial. If successful, hMSC therapy eventually could become part of a patient’s therapeutic maintenance 
regimen. Such alternatives are sorely needed, because the data show that anti-inflammatory therapy is likely to 
ameliorate disease and prolong life, yet it is not applied to most patients due to concerns about adverse effects. 
2.1
Risk / Benefit Assessment
While hMSCs are highly promising and supported by pre-clinical studies, they must be safe. The current 
data support their safety. While our proposal is the first for hMSCs in CF, there have been several other studies 
suggesting hMSCs are safe in COPD, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, acute 
respiratory distress syndrome, as well as many non-pulmonary diseases23 ,91. There are 500 completed or on-
going clinical trials using hMSCs, and a recent meta-analysis did not reveal any association between hMSC 
treatment and the development of acute infusion-related toxicity, organ system complications, infection 
(important for CF subjects), death, or malignancy 22,92.  
Our multidisciplinary team has extensive experience in isolating and expanding hMSCs.  We are 
fortunate to collaborate with world-renown investigators from the NCRM, a multi-institutional, state-sponsored 
organization composed of investigators and clinicians from University Hospitals Cleveland Medical Center and 
Case Western Reserve University. Our collaborators have a 30 year history of adult stem cell research including 
the first in man studies of hMSCs and experience with studies similar to ours in patients with other chronic 
inflammatory diseases93,94. We will be utilizing the NCRM Cellular Therapies Integrated Service to help with 
the preparation of cells and scale up from research to clinical operations.
Infusion with allogeneic hMSCs has been shown to be safe in follow-up periods lasting up to several 
years in patients with pulmonary disease and other inflammatory disorders including Crohn’s disease, graft-vs.-
host disease, multiple sclerosis, and type 1 diabetes20. Up to 1 x 107 cells/kg have been infused safely.  There 
have not been any issues with infusion-related toxicities or tumor development. Autopsy studies reveal limited 

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residual MSCs up to 18 months after administration21.  A meta-analysis of clinical trials of MSC infusions to 
evaluate safety identified 1012 participants with varying clinical conditions22.  The authors did not detect any 
association between hMSC infusion and acute infusion-related toxicities, organ system complications, infection, 
death or malignancy. However there was a significant association between MSCs and transient fever22.  
A significant concern in CF patients receiving potent anti-inflammatory drugs is the increased risk of 
pulmonary exacerbations.  Weiss and colleagues performed a placebo-controlled, randomized trial of 
mesenchymal stem cells in COPD where 31 subjects received four monthly stem cell infusions and there was no 
difference in hospitalizations for COPD exacerbations during the study (six in the MSC group and five in the 
placebo group)23.  A recent meta-analysis did not detect an association between MSC treatment and the 
development of infection22.  Preliminary data in CF animals suggest improvement in infection related outcomes, 
not worsening18,19.  In our studies of CF mice infected with P. aeruginosa, there was a decrease in the bacterial 
burden in the animals that received hMSC infusions (Figure 1).  No secondary spread or infectious 
complications were noted. 
Another potential concern is the possible increased risk of cancer.  Again, this has not been detected in 
clinical trials22,24. However, the potential for malignant transformation would not be unexpected given some of 
the biologic similarities between stem cells and cancer cells.  The risk of tumorigenesis is likely to be an 
extremely uncommon event with current culture conditions where cells are harvested for therapy well before the 
cultures reach senescence20.  Another potential risk could result if hMSCs engrafted for long periods of time 
leading to ectopic tissue formation and increased risk of malignant transformation.  Autopsy studies did not 
detect hMSCs in follow-up studies.  It appears that hMSCs work through a “hit and run” mechanism21.  Despite 
these theoretical concerns, there have been no reports of de novo tumor formation complicating MSC infusion 
in humans22,24.  Nevertheless, in our protocol, cells will be passaged the minimum number of times to obtain 
sufficient cell yield to lessen potential for cytogenetic abnormalities, and any potential CF subjects with a 
history of invasive cancer requiring systemic therapy will be excluded from the study.
3
STUDY OBJECTIVES
3.1
Primary Objective
To evaluate the infusion-related safety and tolerability of a single allogeneic hMSC infusion in adults 
with CF. 
3.2
Secondary Objectives
To explore preliminary evidence for the potential efficacy of hMSCs as a new therapeutic to treat CF 
pulmonary infection and inflammation as measured by
o
Change in sputum inflammatory markers
o
Change in serum inflammatory markers
To compare allogeneic hMSCs to autologous hMSCs in a preclinical model.  The potential efficacy of 
MSCs obtained from CF subjects who agree to undergo the optional bone marrow aspiration will be evaluated 
in validated animal models. 
3.3
Implications for Future Studies
This study is designed to address the safety and tolerability of a single hMSC infusion in subjects with 
CF.  While in the background section we have focused primarily on the impact of MSCs on the pulmonary 
inflammatory response, hMSCs have potential to impact multiple other aspects of CF lung pathophysiology.  
MSCs also likely possess antibacterial properties.  In our mouse models, hMSCs in combination with 

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gentamicin was more efficient in clearing bacteria than either therapy alone.  This suggests the potential to use 
MSCs to enhance antibiotic regimens for acute pulmonary exacerbations in CF.  In addition, because study 
subjects will be receiving hMSCs that do not possess a mutation in cftr, it is possible that hMSC infusion will 
provide a form of gene therapy.  In future Phase III studies, we will evaluate the effects of hMSC infusion on 
outcome measures related to infection, inflammation and CFTR correction.
4
STUDY DESIGN
4.1
Study Overview
Overview of Study Desig35Tn35T  A prospective, single-center, single-dose, dose-escalation, open-label interventional 
study to evaluate the safety and tolerability of allogeneic hMSCs in 15 clinically stable adult subjects with CF. 
Because the subject’s own cells will contain two CFTR mutations, allogeneic hMSC infusion is being employed 
in this study.  Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be entered into the study. The Tables in Appendix II review the 
schedule of study visits.  After a two to six week screening period, subjects will have the Baseline visit (Days 1-
2) where they will undergo a single infusion of up to 5 x 106 allogeneic hMSCs/kg. The CCC and NCRM at 
Case Western Reserve University have a long-standing approach to identifying, screening and using donors to 
provide hMSCs.  Donors are screened per FDA guidelines for cells and tissues (21 CFR 1271).  The FDA 
guidelines are similar to those used for blood donation by Red Cross.  The allogeneic hMSCs used in this study 
will come from one or two healthy donors who have been well-characterized by the CCC and whose sera test 
negative for CMV antibodies. Healthy donors will be followed by the PI or designee for any procedure-related 
AEs. Infusions will be performed in the Dahms Clinical Research Unit at University Hospitals Cleveland 
Medical Center. Study participants will be monitored for the development of infusion-related toxicities for 24 
hours.  Subjects will have subsequent study visits on Days 7, 14, 28, Months 3 and 6 and telephone calls on 
Days 4 (or 5), 21, 56 and Month 12.  Subject safety and tolerability of the single dose of hMSCs will be 
evaluated at the study visits by reviewing subject diaries, interval histories, and subject questionnaires, 
performing physical examinations and spirometry, and obtaining safety laboratories.  In addition to infusion 
related toxicities, special focus will also be placed upon detecting pulmonary exacerbations since an anti-
inflammatory therapy theoretically could suppress the immune system to the point where it leads to increased 
infectious complications.  Appendix I lists the criteria for a pulmonary exacerbation.   This study will also 
explore efficacy endpoints that previously have been shown to be key regulators in CF and/or hMSCs:  Serum 
inflammatory biomarkers  (calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL8, IL-17, and TNF-), and sputum 
inflammatory biomarkers (white cell counts with differentials, IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-
3, TNF-, and active proteases  including neutrophil elastase, R1
R-anti-trypsin, and MMP-9).  These studies 
will be repeated on Days 7 and 28 and compared to Baseline values (with-in subject comparison).  All subject 
samples will be archived for future studies to explore the impact on the microbiome and for future translational 
projects.  Finally, an optional diagnostic bone marrow exam will be performed between screening and Day 1 on 
CF subjects willing to undergo the procedure, banked, and used for future translational studies. 
The following treatment regimens will be used:

Experimental treatment hMSCs at the following doses: 1 x 106, 3 x 106 or 5 x 106 hMSCs/kg body 
weight
All subjects who begin an infusion of the investigational product will be considered evaluable for safety 
and efficacy analyses.  Incidence of AEs will be monitored during the trial. 

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Safety assessments will be based on the incidence of AEs including protocol defined pulmonary 
exacerbations and changes in lung function, sputum microbiology, safety labs, subject questionnaire, and 
physical examination. An Acute Illness Visit will be arranged for any subject who experiences any abrupt 
change in baseline clinical status, between Visit 2 and Visit 5 (the 28 days following infusion) that in the 
estimation of an investigator, research coordinator, other health care provider or the subject necessitates an in-
person office visit.
Total duration of subject participation in the study will be approximately 13 months.  Long-term post-
treatment follow-up will continue for 12 months after the infusion of the investigational product for each 
subject. Data on subject survival and on the occurrence of new health problems will be collected from all 
subjects who receive the investigational product infusion. The information will be gathered during a study visit, 
a routine clinic visit or via telephone. These data will be collected in the source documents (e.g., subject 
medical record) and transcribed into an electronic CRF. Any unsuccessful efforts to contact the subject (e.g., 
dates of unanswered phone calls, failure to show for a clinic visit, etc.) will be documented in the subject’s 
source documents.  
Total duration of conducting the study is expected to be approximately 24 months.
5
CRITERIA FOR EVALUATION
5.1
Primary Endpoint
The primary outcome will be the safety and tolerability of a single infusion of allogeneic hMSCs. Study 
participants will be monitored for potential dose limiting toxicities. The dose limiting toxicity (DLT) definition 
consists of the emergence of infusion-related allergic AEs as well as regimen related toxicities. For this study, a 
DLT will be considered for the occurrence in the first 24 hours after hMSC infusion of a grade ≥ 3 infusion-
related allergic toxicities, which include rash, flushing, urticaria, dyspnea, fever >40°C (>104.0°F) as scored 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. Finally, the CTCAE will be used to assess and grade AE severity, including laboratory 
abnormalities judged to be clinically significant.  In addition to infusion related toxicities, special focus will also 
be placed upon detecting pulmonary exacerbations since anti-inflammatory therapies theoretically could 
suppress the immune system to the point where it leads to increased infectious complications.  Appendix I lists 
the criteria for defining a pulmonary exacerbation treated with antibiotics.  All AEs encountered during the 
study period will be captured and graded.    
In addition to DLT, safety and tolerability of a single infusion of allogeneic mesenchymal stem cells will 
also be determined by 

Incidence and severity of AEs 

Number of pulmonary exacerbations (modified Fuch’s definition95)

Diary reports (Cystic Fibrosis Respiratory Symptom Diary)

Changes in subject reported symptoms as captured by the Respiratory and Systemic Symptoms 
Questionnaire from Baseline (Visit 2) Day 1 to Baseline (Visit 2) Day 2, Visits 3, 4, 5, 6, and 7 and at 
times when a pulmonary exacerbation is being considered. 

Changes in physical examination 

Changes in vital signs including oxygen saturation checked throughout the infusion

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
Changes in spirometry (FEVR1
R %, FEVR1
R (Liters), FEFR25-75
R) determined 30 minutes, 4 hours and 24 hours  
after completion of infusion and from Baseline (Visit 2) Day 1 to Baseline (Visit 2) Day 2, Visits 3, 4, 5, 
6 and 7.

Change in sputum quantitative microbiology (change in bacterial colony forming units between Baseline 
Day 1 and Day 7 and Day 28)

Changes in hematology, comprehensive chemistry, erythrocyte sedimentation rate (ESR), high-sensitivity 
C-reactive proteine (hs-CRP), and urinalysis results
5.2
Secondary Endpoints
Since this is a phase I study, the primary focus is on safety.  However, in a 15 subject dose-escalation 
study, we will also explore potential efficacy endpoints.  Secondary outcomes include:  changes in biomarkers 
of inflammation in blood  (calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL8, IL-17, and TNF-) between Baseline 
Day 1 and Day 7 and Day 28, and changes in biomarkers of inflammation in sputum (white cell counts with 
differentials, IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-3, TNF-, and active proteases  including 
neutrophil elastase, R1
R-anti-trypsin, and MMP-9) between Baseline Day 1 and Day 7 and Day 28.  
6
SUBJECT SELECTION
6.1
Study Population
Study Population: CF subjects will be recruited from the LeRoy W. Matthews Cystic Fibrosis Center 
located at Rainbow Babies and Children’s Hospital in Cleveland, OH.  Our Center provides care for over 200 
adult patients with CF.  Given the wide interest in hMSCs in CF, we do not anticipate any issues recruiting 15 
subjects for this study from our Center. However, should recruitment lag behind projected timelines, we could 
recruit potential study subjects from nearby CF Centers in Akron, OH, Ann Arbor, MI, Buffalo, NY, Columbus, 
OH, Pittsburgh, PA, and Toledo, OH.  Subjects will be studied for up to 13 months.  Screening will be between 
10 and 42 days.  Study treatment will be Day 1 with a 12-month follow-up.  We anticipate 15 months to recruit 
subjects (due to the 3+3 safety study design, the last subject in a given cohort must complete Visit 5 before the 
first subject in the next cohort can be enrolled). Subjects who fail screening or who withdraw prior to 
completing Visit 5 will be replaced.  Subjects with a diagnosis of CF who meet the inclusion and exclusion 
criteria will be eligible for participation in this study.  Subjects who fail screening may be re-screened one 
additional time. 
6.2
Inclusion Criteria
1. Male or female 18 years of age and above
2. Confirmed diagnosis of CF as evidenced by 1 or more clinical features consistent with the CF phenotype and 1 
or more of the following criteria:
a.
Sweat chloride equal to or greater than 60 mEq/L by quantitative pilocarpine iontophoresis test 
(QPIT) 
b. 2 well-characterized, disease causing mutations in the CFTR gene 
3. Clinically stable with no significant changes in health status within 2 weeks prior to screening 
4. FEVR1 
R≥ 40% predicted for age based on the global lung function initiative equations at the screening visit 

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5. Weight ≥ 40 kg at the screening visit
6. Able to perform repeatable, consistent efforts in pulmonary function testing
7. Written informed consent obtained from the subject
6.3
Exclusion Criteria
1. Use of an investigational agent within the 4-week period prior to Visit 1 (Day -42 to -10)
2. Chronic daily (>10 mg) or alternate daily (>20 mg on alternate days) use of systemic corticosteroids within 
the 4 weeks prior to Visit 1 (Day -42 to -10) or initiation of any dosage of systemic corticosteroids within 72 
hours prior to Visit 2 (Day 1) 
3. Use of hydroxychloroquine or immunosuppressants 
4. Initiation of a new antibiotic (oral, IV, and/or inhaled) that is not part of the subject’s maintenance regimen 
for treatment of acute respiratory symptoms within 2 weeks prior to screening through Visit 2 (Day 1)
5. Initiation of any new chronic therapy (e.g., Pulmozyme®, hypertonic saline, Kalydeco®,  Orkambi®, high-
dose ibuprofen azithromycin, TOBI®, Cayston®, nebulized colistiin, bronchodilators, inhaled corticosteroids, 
etc.) within 4 weeks prior to screening
6. Active treatment for non-tuberculous Mycobacteria 
7. History of a sputum culture positive for a Burkholderia cepacia complex organism in the previous 12 months 
8. Current tobacco smoker
9. Oxygen saturation < 92% on room air at Visit 1 (Day -42 to -10)
10. History of pulmonary hypertension
11. SGOT (ALT) or SGPT (AST) > 2.5 times the upper limit of normal at screening, documented biliary cirrhosis, 
or portal hypertension 
12. Total bilirubin concentration >1.2 mg/dL at screening
13. Creatinine > 1.8 mg/dL at screening
14. Pregnant, breastfeeding, or unwilling to practice birth control between Visit 2 (Day 1) and Telephone Call 3 (Day 
56) (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier 
method plus a spermicidal agent), unless surgically sterilized or postmenopausal
15. Screening hematology with white blood cell count < 4.5 x 109 cells/L, hematocrit < 30%, and platelets < 150 
x 109 platelets/L 
16. History of invasive cancer requiring systemic therapy 
17. History of organ transplantation
18. Currently listed for lung transplantation or having potential to be listed for lung transplantation in the 
succeeding 12 calendar months from screening
19. Subject unlikely to complete the study as determined by the Investigator

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7
CONCURRENT MEDICATIONS
All subjects should be maintained on the same medications from screening through Visit 5 (Day 28), as 
medically feasible, with no introduction of new chronic therapies. Medication history will be collected for all 
drugs for the 30 days prior to screening. If any changes in concomitant medications are required due to AEs (i.e. 
illness, laboratory abnormalities, surgical procedures, etc.), the reason(s) for the change(s) must be documented.  
Subjects who require treatment for a pulmonary exacerbation during the course of the trial will remain in the 
study. 
Subjects who have routinely taken more than 10 mg/day (or >20 mg on alternate days) of prednisone or 
other systemic corticosteroids 4 weeks prior to Visit 1 (Day -42 to -10) or who have taken these medications as 
needed within 72 hours prior to Visit 1 or 2 will be excluded from participation.  Subjects may be re-screened 
once. For those subjects taking alternate month TOBI® or Cayston® therapy, on/off cycles must be timed such 
that a subject is at the same phase of a cycle at Visits 2, 3, 4, and 5.
7.1
Allowed
Except as noted in the prohibited medications section below or in the exclusion criteria described above, 
all usual CF medications and treatments are allowed.  A stable therapeutic regimen (including physiotherapy) 
between screening and Visit 5 (Day 28) is the goal. Ongoing chronic treatment (> 4 weeks prior to screening) 
with Pulmozyme®, Cayston®, TOBI®, nebulized colistin, Kalydeco®, Orkambi®, high-dose ibuprofen, 
hypertonic saline, azithromycin, systemic or inhaled corticosteroids, short and long acting bronchodilators and 
airway clearance is allowed.  Unless otherwise medically indicated, subjects not using these therapies should 
not be started on them from screening through Visit 5 (Day 28) and subjects that have been using them 
chronically should be encouraged to continue them through Visit 5 (Day 28). Limited use of over-the-counter 
anti-inflammatory drugs (acetaminophen, aspirin, ibuprofen, or naproxen) from screening through Visit 5 (Day 
28) is acceptable.
7.2
Prohibited

Intravenous antibiotics from 14 days prior to the screening visit through Visit 2 (Day 1)

Newly prescribed oral or inhaled antibiotics prescribed for acute symptoms from 14 days prior to the 
screening visit through Visit 2 (Day 1)

Systemic corticosteroids prescribed for an acute issue or for chronic therapy if the dose exceeds a 
prednisone equivalent of 10 mg every day or 20 mg on alternate days (maximum allowable dose for 
chronic systemic corticosteroids is 20 mg of  prednisone or its equivalent over a two day period) 
from screening through Visit 5 (Day 28)

Hydroxychloroquine from screening through Visit 5 (Day 28)

Other immunosuppressants from screening through Visit 5 (Day 28)

The use of an investigational agent within 4 weeks prior to Visit 1 (Day -42 to -10)
8
STUDY TREATMENTS
8.1
Method of Assigning Subjects to Treatment Groups
In this Phase I open-label study, there is no placebo group.  All subjects will receive a single infusion of 
hMSCs.  15 eligible subjects will be recruited from the adult CF Center located at Rainbow Babies and 

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Children’s Hospital and will receive a single dose of one of the following doses of hMSCs: 1 x 106, 3 x 106 or 5 
x 106 hMSCs/kg body weight. A traditional 3+3 design will be utilized (Figure 4). If a maximum tolerated dose 
(MTD) is identified among the 3 doses, the next 3 subjects enrolled will receive the identified MTD. If there are 
no DLTs or one DLT, the next 3 subjects enrolled will receive same dose. If there are two or more DLTs, the 
next lower dose will be used as the MTD for the final 3 enrolled study subjects.
Figure 4. Study design for determining dose-limiting toxicity
 
8.2
Blinding
Because this is an open-label, safety and tolerability study in which all enrolled subjects will receive hMSCs, 
this study is unblinded.
8.3
Test and Control Formulation
The biological product (hMSCs) is manufactured in the Case Western Reserve University NCRM 
Cellular Therapy Laboratory under GMP-compliant regulations.  This laboratory is located on the campus of 
Case Western Reserve University/University Hospitals Cleveland Medical Center.
Address:
WRB 6-303
2103 Cornell Road
Cleveland, Ohio 44106
(216) 368-1007
The cells obtained from the donor(s) will be cryopreserved at primary culture.  There will be no 
passages involved.  Only plated and adherent cells will be harvested.  This occurs at approximately 14 days.  
The number of passages after thaw (prior to infusion) is dependent on the target dose (recipient receives a dose 
based upon weight).  For most participants, we will likely reach our target dose after 2 passages and no greater 
than 3 passages.  This translates into approximately 14 days. 

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The final hMSC formulation is a fresh cell suspension of 4 x 106 cells/ml with ≥70% viability in Plasma-
Lyte A + 2.5% HSA.  This product is distributed in a syringe for immediate infusion.
8.3.1
Packaging and Labeling
The biologic product is packaged and labeled for infusion according to FDA guidelines by Cell 
Processing Technologists employed by the CWRU NCRM Cellular Therapy Lab.  Blinding is not applicable to 
this study. The infusion product will be labeled as follows:
Investigational Drug (Study Name or #)
FOR INFUSION
Subject Unique Identifier:
Cellular Therapy Laboratory
WRB 6-303
2103 Cornell Road
Cleveland, Ohio 44106 (216) 368-1007
Date:  
Total Cells:
Volume:  X ml
 Expiration:  dd/mm/yyyy  Time hh:mm
CAUTION:  NEW DRUG-LIMITED BY FEDERAL LAW TO INVESTIGATIONAL USE
8.3.2
Handling/Dispensing
Human MSCs will be dispensed directly from manufacturing personnel to clinical personnel per 
conditions noted in the IND application and the clinical protocol.  Chain of custody will be tracked in writing 
and documents filed in both the subject study record and manufacturing record.
8.3.3
Dosage/Dosage Regimen
The first cohort of 3 subjects enrolled will receive a single infusion of 1 x 106 hMSCs/kg body weight, 
The second cohort of three subjects enrolled will receive a single infusion of 3 x 106 hMSCs/kg, and the third 
cohort of three subjects enrolled will receive a single infusion of 5 x 106 hMSCs/kg.  The first subject in the 
subsequent cohort will not be enrolled until the last subject in the preceding cohort has completed Visit 5 (Day 
28).  There will be a minimum of 1 week between the dosing of each study subject in the first three cohorts.  
The final six subjects will receive a single infusion of 5 x 106 hMSCs/kg if that dose was well tolerated.  If the 
highest dose was not well tolerated, then the final six subjects will receive the maximum tolerated dose (either 1 
x 106 or 3 x 106 hMSCs/kg body weight).
Table 1: hMSC dose cohorts
Cohort 1
1 x 106 hMSCs/kg
3 subjects

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Cohort 2
3 x 106 hMSCs/kg
3 subjects
Cohort 3
5 x 106 hMSCs/kg
3 subjects
Cohort 4
MTD
6 subjects
8.3.4
Administration Instructions 
The person infusing the cells should wear sterile gloves.  
Fresh hMSC will be administered as follows:
hMSCs are infused through a peripheral venous catheter by directly connecting the syringe of 
cells to the IV tubing via Y-connector.
1. Start infusing IV fluids (normal saline) at the maximal rate (250 ml/hr.).
2. Clean the port of the Y-connector as per hospital protocol.
3. Remove needle from syringe containing the hMSCs.
4. Attach the syringe with hMSCs directly to the in-line Y-connector.
5. Manually clamp the IV tubing leading back to the bag of saline behind the syringe by 
pinching the tubing between two fingers.
6. Administer a small aliquot (2-3 ml) of the cells from the syringe by slow IV push.
7. Release the IV tubing and allow the normal saline to flush the line for 1-2 minutes.
8. Repeat steps 5 through 7 until all the cells have been infused, completing the infusion 
over 10-15 minutes.
9. The first post cell infusion rinse of the syringe must now be performed.  
10. Manually clamp the IV tubing between the syringe and the study participant by bending 
the tubing and pinching it between two fingers to draw saline fluid into the syringe, 
complete filling the syringe.
11. Release the IV tubing leading between the syringe and the study participant.
12. Manually clamp the IV tubing between the bag of saline and the syringe by bending the 
tubing and pinching it between two fingers.
13. Administer an aliquot (3-5 ml) of fluid from the syringe by IV push.
14. Release the IV tubing and allow the normal saline to flush the line for 30 seconds to 1 
minute.
15. Repeat steps 12 through 14 until the syringe is empty.  Completing the saline rinse should 
take approximately 2 minutes.
16. Perform a second post cell infusion rinse of the syringe.
17. Repeat steps 10 through 15.
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19. Administer normal saline through the running IV at a rate of 250 ml/hr. for 4 hours while 
the study participant is being monitored after the infusion.
20. Document the infusion in a procedure note in the electronic medical record (EMR).
Infusion reactions are documented in the subject’s study chart and the principal investigator is notified 
in the event of severe reactions.
An infusion side-effect checklist is provided to the subject’s nurse (a modified version of the standard 
form used by University Hospitals Cleveland Medical Center Seidman Cancer Center).
Side effects are monitored for 24 hours after the completion of the infusion.
8.4
Supply of Investigational Product at the Site
The cell product will be expanded to the clinical dose in culture upon receipt of a physician 
investigator’s order.  Duration of culture expansion is approximately 15-20 days after which cells will be 
infused once release tests are complete.
8.4.1
Storage
Stock vials of primary culture hMSCs will be secured in liquid nitrogen vapor phase until indicated for 
expansion per physician investigator’s order.  Liquid nitrogen freezers are remote alarm monitored 24/7. The 
expanded hMSCs for infusion will be used fresh without further frozen storage.
8.5
Investigational Product Accountability
An accurate and current accounting of the amount of hMSCs administered to each subject will be 
maintained by research staff.  Research staff will document the total dosage of hMSCs administered to each 
subject.  If the infusion is stopped for any reason, including adverse reaction or technical difficulty, research 
staff will determine how much of the infusion the subject received and record the administered dose in the study 
records. 
8.6
Measures of Treatment Compliance
In this Phase I study, subjects will receive a single infusion of hMSCs that will be administered by 
research staff in the Dahms Clinical Research Unit of University Hospitals Cleveland Medical Center.  
Therefore we do not anticipate that there will be any issues with treatment compliance during this study. 
9
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the duration of 
the study is outlined in Appendix II.
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject.
9.1
Clinical Assessments
9.1.1
Concomitant Medications
All concomitant medications and concurrent therapies will be documented at all study visits including an 
Acute Illness/Early Termination Visit when applicable.  Dose, route, unit frequency of administration, and 
indication for administration and dates of medication will be captured for the 30 days prior to screening.

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9.1.2
Demographics 
Demographic information (date of birth, gender, race) will be recorded at Screening.
9.1.3
Medical History 
Relevant medical history, including history of current disease, cftr genotype analysis results, sweat 
chloride results, sputum microbiology, spirometry results, other pertinent respiratory history, and information 
regarding underlying diseases will be recorded at the screening visit (Visit 1).  An interval history will be 
obtained at all other visits. 
In the event of a pregnancy between Visit 2 (Day 1) and Telephone Call 3 (Day 56), medical information 
pertaining to the pregnancy will be collected through the birth of the child or the termination of the pregnancy.
9.1.4
Physical Examination
A complete physical examination will be performed by a physician (either the investigator or a sub-
investigator) at Visits 1, 2 and 5 and at an Acute Illness/Early Termination Visit.  Qualified staff (MD/DO, NP, 
RN, PA) may complete the abbreviated physical exam at all other visits.  The physical exam also includes 
height (at screening only) and weight.  The complete physical examination consists of general, HEENT, 
neck/thyroid, lymph nodes, cardiovascular system, chest/lung, abdomen, extremities, skin, musculoskeletal, 
nervous system, mental status, and other. An abbreviated exam will consist of HEENT, cardiovascular system, 
chest/lung, abdomen, extremities, skin, and other.  New abnormal physical exam findings must be documented 
and will be followed by a physician or other qualified staff at the next scheduled visit.
9.1.5
Vital Signs
Body temperature, blood pressure, pulse and respirations will be performed after resting for 5 minutes at 
all study visits.
9.1.6
Oximetry
Oximetry will be measured on room air with the subject at rest at all study visits.
9.1.7
Spirometry
Spirometry will be performed at all study visits and in accordance with the current American Thoracic 
Society recommendations for the performance and interpretation of tests. Spirometry will be obtained 
approximately 2 hours prior to the start of the hMSC infusion and 30 minutes, 4 hours and 24 hours after 
completion of the infusion.  Subjects will perform spirometry as is customary for that subject at clinical visits. If 
the subject typically does not take albuterol prior to spirometry, then he/she will not take albuterol prior to 
spirometry during the study.  If the subject typically takes albuterol prior to spirometry, they he/she will take 
albuterol prior to spirometry for this study.  However there is an exception.  In any subject in which it is 
anticipated that he/she might not be able to produce sputum spontaneously at any one of the study visits in 
which sputum will be obtained, then those subjects will undergo sputum induction at all visits regardless of his 
or her ability to spontaneously expectorate sputum at the current study visit. In these cases, those individuals 
will receive three inhalations of albuterol sulfate via metered dose inhaler prior to all spirometric tests obtained 
during the study. Approximately 15 minutes after administering albuterol sulfate, pulmonary function testing 
will be performed.  If a study subject is unable to produce sputum at the Baseline Visit (Day 1), then sputum 
will not be obtained at Visits 3 (Day 7) and 5 (Day 28).

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9.1.8
Acquisition of Sputum
Sputum (approximately 1.3-2.0 grams) will be obtained at Visit 2 (Day 1) prior to the infusion of stem cells and 
on Visits 3 (Day 7) and 5 (Day 28) via spontaneous expectoration.  Sputum samples will be split according to 
priority for analyses.  The first aliquot will be sent to the microbiology laboratory at University Hospitals 
Cleveland Medical Center where quantitative bacteriology will be performed, and the second aliquot will be 
processed and saved for research studies. Sputum will be processed according to the current standard operating 
procedure (SOP) developed by CF Foundation’s Therapeutics Development Network. Subjects unable to 
spontaneously expectorate sputum will undergo sputum induction according to the current SOP developed by 
CF Foundation’s Therapeutics Development Network.  If a sputum sample cannot be produced, or the quantity 
of the sample is not sufficient for all the tests to be performed, this is not considered a deviation.
9.1.9
Intravenous Infusion of hMSCs
Fresh MSCs are infused at Visit 2 (Day 1) from a syringe into a venous catheter followed by a saline 
wash.  After the infusion of cells is complete, 10-ml of a normal saline flush is given immediately and a running 
IV of normal saline is maintained at 250 ml/hr for 4 hours. Subjects are monitored for 24 hours for infusion-
related toxicity.  Temperature, blood pressure, heart rate, respiratory rate and oxygen-saturation are measured 
prior to infusion and at 10 (± 5), 20 (± 5), 30 (± 5), 60 (± 15), and 90 (± 15) minutes and 2 hours (± 15 minutes) 
and 4 (± 15 minutes) hours post-infusion and then every 4 (± 15 minutes) hours for the remainder of the 24-hour 
observation period.  Any toxicity is treated at the discretion of the managing physician, and toxicities are 
reported to the Principal Investigator, IRB, and FDA as appropriate.
MSC infusion has been very well tolerated.  Although theoretically of concern, there have been no 
reported cases of immunosuppression, autoimmunity, cancer, significant lung damage, severe infection, or 
clinically significant ectopic tissue formation attributable to MSC infusion.  MSC infusion could cause infection 
if the cells are contaminated.  Strict aseptic technique during bone marrow aspiration, culture, thawing, and 
infusion and stringent microbiologic screening minimize this risk.  Because of the immunosuppressive effects 
of MSCs, recipients potentially are at increased risk for infection.  
9.1.10 Bone Marrow Exam
Healthy volunteers who meet screening criteria and who consent to having their mesenchymal stem cells 
subsequently infused into study subjects with CF will undergo a bone marrow examination according to SOPs 
developed by the CCC well in advance of the infusion.  Either a unilateral or bilateral (depending on the yield 
of bone marrow aspirate) posterior iliac crest bone marrow aspiration will be performed using local anesthetics 
1% Xylocaine (approximately 10 ml intradermal and subcutaneous), preservative-free bupivacaine 0.25% 
(approximately 10-20 ml injected locally to the site), morphine sulfate (approximately 2-6 mg by IV). 
Lorazepam (1 mg oral or IV) may be used if needed. Approximately 60-80 ml of marrow is pulled into syringes 
containing preservative-free heparin (400 units/25cc marrow) using a few brisk pulls. Bone marrow samples 
will be processed, and MSCs will be prepared according to CCC SOPs as previously described. 
If a subject with CF consents to undergoing the optional bone marrow exam, screening procedures will 
be performed at Visit 1 and a single bone marrow aspiration of the posterior iliac crest will be performed at 
Visit 1A under local anesthetic 1% Xylocaine (approximately 10 ml intradermal and subcutaneous). For CF 
subjects, the optional bone marrow aspiration procedure (Visit 1A) must be completed at least 14 days before 
Day 1 (Visit 2). Preservative-free bupivacaine 0.25% (approximately 10-20 ml injected locally to the site), 
morphine sulfate (approximately 2-6 mg by IV), and lorazepam (1 mg oral or IV) may be used if needed.  
Approximately 5-20 ml of marrow is pulled into a syringe containing preservative-free heparin (400 units/25cc 

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marrow) using a brisk pull.  MSCs isolated from subjects with CF will be evaluated in pre-clinical models to 
determine how they differ from donor MSCs.  The CCC and NCRM at Case Western Reserve University have 
emerging cell therapy assay methods so that BM samples from subjects with CF are able to be archived and 
used at a later time to more fully characterize the CF defect.
The risks of a bone marrow aspiration include pain at the time of the aspirate, which is common but well 
controlled with adequate use of Xylocaine, bupivacaine and morphine. Other risks include bleeding, infection at 
the site of the aspirate, and occasional lightheadedness or fainting due to a vasovagal reaction after the 
procedure. Healthy volunteers and subjects with CF, who undergo the optional bone marrow examination, will 
be followed by the study PI or designee for AEs related to the procedure.
Inclusion Criteria for Healthy Volunteer Donors:
1)
Male/female age ≥ 18 years 
2)
Able to understand and sign ICF (a legally authorized representative will not be permitted)
Inclusion Criteria for CF Donors:
1)
CF subject enrolled in the main study and consented to this optional procedure
Exclusion Criteria for both Healthy Volunteer Donors and CF Donors:
1)
Fever or current illness on the day of the cell collection
2)
Evidence of communicable disease.
3)
Any significant change in health status within 2 weeks prior to cell collection that the PI/Sub-
Investigator deems relevant to exclude participation
4)
Subject-reported history of organ transplantation
5)
Subject-reported history of HIV, hepatitis B or C, or syphilis
6)
For HV donors only, subject-reported known history of being diagnosed with cystic fibrosis 
(CF) or being a CF carrier (one copy of CF gene mutation)
7)
Positive screening blood test result for any infectious disease.  
8)
For HV donors only, positive test result for CMV or a CF gene mutation.
9)
Pregnant, planning a pregnancy, or breast-feeding at screening.
9.1.11 Adverse Events
Information regarding occurrence of AEs will be captured throughout the study from the time of consent 
until Telephone Call 4 (Month 12 ±1). Duration (start and stop dates), severity/grade, outcome, treatment and 
relation to investigational product or study procedures will be recorded in the CRF.

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9.2
Clinical Laboratory Measurements
9.2.1
Hematology
Blood (5 ml) will be obtained at all study visits and sent to the clinical hematology laboratory at 
University Hospitals Cleveland Medical Center for a complete blood count (hemoglobin, hematocrit, red blood 
cell count, white blood cell count, white blood cell differential, and platelet count), ESR, and serum hs-CRP 
determinations for assessment of systemic evidence for infection and/or inflammation.
9.2.2
Blood Chemistry Profile
Blood (5 ml) will be obtained at all study visits and sent to the clinical chemistry laboratory at 
University Hospitals Cleveland Medical Center for determination of sodium, potassium, chloride, bicarbonate, 
random glucose, BUN, creatinine, aspartate aminotransferase (AST/SGOT), alanine aminotransferase 
(ALT/SGPT), alkaline phosphatase, total bilirubin, direct bilirubin, albumin and LDH.  Because vitamin D may 
influence hMSC function, a vitamin D concentration will be obtained at Visit 2 and analyzed post hoc. 
9.2.3
Pregnancy Test
A pregnancy test will be performed on female subjects who are of childbearing potential prior to their 
participation in the study. A serum pregnancy test will be done at screening (blood volume is included in the 
sample collected for chemistry profile) and urine pregnancy tests will be done at Visits 2, 5 and early 
termination.
9.2.4
Urinalysis
Urine will be obtained at all study visits and sent to the clinical laboratory at University Hospitals 
Cleveland Medical Center for determination of color, specific gravity, pH, protein, glucose, ketones, and blood.
9.3
Research Assessments
9.3.1
Serum Measurements of Inflammatory Mediators
40-mL of whole blood will be collected and placed in serum separator tubes at Visits 2 (Day 1), 3 (Day 
7), and 5 (Day 28).  Samples will be centrifuged.  The serum will be removed, aliquoted, and frozen at -80oC.  
Specimens will be batched and analyzed for calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL8, IL-17, and TNF- 
in the Bioanalyte Core of the CF Research Center at Case Western Reserve University.
9.3.2
Sputum Cell Count and Differential
Sputum (approximately 0.065 gm) will be collected at Visits 2 (Day 1), 3 (Day 7), and 5 (Day 28) for 
determination of white cell counts (by hand counting) and differential cell counts performed by the CF- 
Therapeutics Development Network (TDN) Center for Interpretive Cytology at Case Western Reserve 
University according to the current CF-TDN SOP.  
9.3.3
Sputum Cytokine Measurements
Sputum (approximately 0.75 gm) for determination of IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-
3, TNF-, neutrophil elastase, R1
R-anti-trypsin, and MMP-9 will be collected at Visits 2 (Day 1), 3 (Day 7), 
and 5 (Day 28).  Specimens will be collected in a sterile specimen cups. Sputum will be processed according to 
the current CF-TDN SOP.  Aliquots will be batched and analyzed in the Bioanalyte Core of the CF Research 
Center at Case Western Reserve University.

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9.3.4
Quantitative Bacteriology
Sputum (approximately 0.5 gm) will be collected at Visits 2 (Day 1), 3 (Day 7), and 5 (Day 28) for 
culture.  All sputum specimens will be collected in a sterile specimen cup, Quantitative culture for typical CF 
pathogens will be performed in the clinical microbiology laboratory at University Hospitals Cleveland Medical 
Center.  
9.3.5
Respiratory and Systemic Symptoms Questionnaire (RSSQ)
Investigators or their designee will interview each subject to complete an RSSQ (Boehringer Ingelheim), 
which is designed to capture signs and symptoms, at each study visit and for any other encounter for increased 
respiratory symptoms.  Such encounters may occur between study visits and include unscheduled visits and 
phone encounters. The RSSQ must be completed prior to any other study procedures.
9.3.6
Cystic Fibrosis Respiratory Symptom Diary (CFRSD)
Study participants will complete the CFRSD (University of Washington) five times, at Visits 2-5 and 
once at home between Visits 4 and 5. The CFRSD will also be completed if the subject has an acute illness visit 
between Visit 2 and Visit 5. The CFRSD is designed to capture a change in symptoms and to quantify their 
severity and magnitude for the previous 24 hours during periods of stability, medically treated pulmonary 
exacerbations, and recovery from pulmonary exacerbations. The CFRSD will be reviewed at Visits 2-5, during 
Phone Call #2, and at any applicable Acute Illness Visit/Early Termination Visit.  The CFRSD may be reviewed 
after the RSSQ is performed but must be reviewed prior to any other study procedures.
9.4
Screening Assessments for Bone Marrow Collection
9.4.1
Donor History Questionnaire (DHQ) for Healthy Volunteers Participating in the Bone Marrow 
Collection
The DHQ and its related materials (e.g., Medication Deferral List, Donor Educational Materials) will be 
used as a tool to screen donors for communicable disease risk factors. The DHQ and related documents 
will be obtained from the American Association of Blood Banks (AABB) website.
9.4.2
Measurements of Infectious Disease Markers for Healthy Volunteers Participating in the Bone 
Marrow Collection
Blood (28ml) will be obtained and sent to the Indiana Blood Center for determination of the following 
infectious disease markers:  hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), human 
immunodeficiency virus (HIV1,2), hepatitis B core antibody (HBcore), human T-cell lymphotropic virus types I 
and II (HTLVI/II), blood group and Rh antigen (ABORh), antibody screen (AbScr), Treponema pallidum; 
cytomegalovirus (CMV), HIV nucleic acid test (HIVNAT), hepatitis C nucleic acid test (HCVNAT), West Nile 
Virus nucleic acid test (WNVNAT), and Chagas. Any positive result will be reported to the subject (verbally 
and in writing) and to any local medical agencies as required by law, and the subject will be instructed to 
follow-up with a primary care physician or will be provided a referral to an appropriate physician. Bone marrow 
collection will occur within 7 days of communicable disease testing, per FDA guidelines stipulated in 
21CFR.1271.80(b).  

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9.4.3
Cystic Fibrosis Genetic Screening for Healthy Volunteers Participating in the Bone Marrow 
Collection
Blood (2-4ml) will be obtained and sent to the Center for Human Genetics Laboratory of University 
Hospitals Cleveland Medical Center to determine the carrier status of an individual for the most common 41 
mutations in the CFTR gene associated with cystic fibrosis.  Any positive results will be reported to the subject 
and genetic counseling will be provided.  
9.4.4
Measurements of Infectious Disease Markers for CF Subjects Participating in the Optional Bone 
Marrow Collection
Blood (10 ml) will be obtained and sent to the University Hospitals Cleveland Medical Center 
Laboratory for determination of the following infectious disease markers: hepatitis B and C, syphilis and HIV.  
Any positive result will be reported to the subject (verbally and in writing) and to any local medical agencies as 
required by law, and the subject will be instructed to follow-up with a primary care physician or will be 
provided a referral to an appropriate physician. 
9.4.5
Pregnancy Test
A serum pregnancy test will be performed on female subjects who are of childbearing potential during 
the screening visit (Visit 1) for both healthy volunteer donors and CF subject donors. For healthy volunteer 
donors, up to 2ml of blood will be obtained for this test. For CF subject donors, the serum pregnancy test is 
included as part of the screening visit procedures for the main study described earlier. A urine pregnancy test 
will be performed on female subjects of childbearing potential at Visit 2 for heathy volunteer donors and at 
Visit 1A for CF subject donors.
10 EVALUATIONS BY VISIT
In general, the order of the items listed below will be the chronological order in which they will be performed at 
each study visit.  However, this order may change once the logistics are finalized for each visit prior to the start 
of the clinical trial.
For CF Subjects:
10.1 Visit 1 (Screening Visit: Day -42 to -10)
1.
Review the study with the subject and obtain written informed consent and HIPAA authorization
2.
Review the “Consent for Specimen Banking” and the “Consent for Collection and Use of your CFF 
Registry ID Number” and ensure that the subject has checked one of the two options (Subjects who elect 
not to provide specimens for the bio-repository or to provide their CFF Registry ID number are still 
eligible for this study)
3.
Assign the subject a unique screening number
4.
Perform and record RSSQ prior to any other study procedures
5.
Record demographics and other baseline data
6.
Record medical and surgical history, including a history of CF, genotype, diagnosis date, and CF signs 
and symptoms
7.
Record concomitant medications
8.
Review inclusion/exclusion criteria

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9.
Measure and record height and weight without shoes
10.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
11.
Perform and record oximetry
12.
Perform a complete physical examination
13.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
14.
Collect urine for clinical laboratory test (urinalysis)
15.
Collect blood for serum pregnancy test
16.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum at any visit
17.
Perform and record spirometry
18.
Schedule subject for Visit 2
19.
Screening procedures for optional diagnostic bone marrow aspiration, if applicable:  
a.
Ensure that the subject has checked one of the two options regarding this optional procedure on the 
consent form. (Subjects who elect not to complete this procedure are still eligible for this study.)
b. Review eligibility for bone marrow aspiration
c.
Collect 10 ml blood for laboratory tests (infectious disease markers)
20.
Record any AEs that may have occurred during the study visit from the time of consent
10.2 Visit 1A (if applicable, Optional Bone Marrow Aspiration) (Day -35 to -14)
1.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes 
2.
Review and record interval history
3.
Review and record any changes to concomitant medications
4.
Perform urine pregnancy test if applicable
5.
Perform an abbreviated physical exam
6.
Review inclusion/exclusion criteria
7.
Perform bone marrow aspiration 
8.
Subject to rest for 30 minutes post-procedure
9.
Record any AEs that may have occurred during the study visit
10.3
Follow-up Phone Call (if applicable, 24 (± 12) hours after Optional Bone Marrow Aspiration)
1.
Review and record interval history
2.
Review and record any changes to concomitant medications
3.
Record any AEs that may have occurred since bone marrow aspiration

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10.4 Visit 2 (Baseline Visit: Day 1)
1.
Perform and record RSSQ prior to any other study procedures
2.
Administer and review CFRSD prior to any other study procedures and record any AEs that occurred 
since Visit 1
3.
Review and record interval history
4.
Review and record any changes to concomitant medications
5.
Review inclusion/exclusion criteria
6.
Measure and record weight without shoes
7.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
8.
Perform and record oximetry
9.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH) and vitamin D
10.
Collect blood for inflammatory mediators (calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL-8, IL-17, and 
TNF-)
11.
Collect urine for clinical laboratory test (urinalysis)
12.
Collect urine for pregnancy test prior to infusion
13.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum during the visit
14.
Perform and record spirometry approximately 2 hours before hMSC infusion
15.
Obtain sputum for clinical laboratory tests (quantitative culture and microbiology) and for research tests 
(cell count with differential, IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-3, TNF-, neutrophil 
elastase, R1
R-anti-trypsin, and MMP-9).  Subjects will be asked to provide sputum via spontaneous 
expectoration.  If a subject is unable to provide sputum spontaneously, then the subject may undergo 
sputum induction according to the current TDN SOP.  Any AEs related to the sputum procedure will be 
recorded.
16.
Temperature, blood pressure, heart rate, respiratory rate and oxygen-saturation are measured prior to the 
infusion.  Subjects should be seated for 5 minutes prior to obtaining vital signs.
17.
Perform a complete physical examination 
18.
Infusion of hMSCs
19.
Temperature, blood pressure, heart rate, respiratory rate and oxygen-saturation are measured prior to 
infusion and at 10 (± 5), 20 (± 5), 30 (± 5), 60 (± 15), and 90 (± 15) minutes and 2 hours (± 15 minutes) 
and 4 hours (± 15 minutes) post-infusion completion and then every 4 (± 15 minutes) hours for the remainder 
of the 24-hour observation period.  Subjects should be seated or lying down for 5 minutes prior to 
obtaining vital signs.
20.
Administer 3 puffs of albuterol 15 minutes (± 15 minutes) after the completion of the hMSC infusion if 
subject is likely to require induction to obtain sputum during the visit
21.
Perform and record spirometry 30 minutes and 4 hours (± 15 minutes) after the completion of the hMSC 
infusion

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22.
Monitor study participant for 24 hours (± 30 minutes) after completion of the infusion
23.
Record any AEs that may have occurred during the study visit
10.5
Visit 2 (Baseline Visit: Day 2)
1.
Perform and record RSSQ prior to any other study procedures
2.
Review and record interval history
3.
Review and record any changes to concomitant medications
4.
Measure and record weight without shoes
5.
Perform and record vital signs, including a blood pressure after the subject has been seated or lying 
down for 5 minutes
6.
Perform and record oximetry
7.
Perform a complete physical examination
8.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
9.
Collect urine for clinical laboratory test (urinalysis)
10.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum during the visit
11.
Perform and record spirometry 24 hours (± 1 hour) after the completion of the hMSC infusion
12.
Schedule subject for Telephone Call Visit 1 and for Visit 3.
13.
Record any AEs that may have occurred during the study visit
10.6 Telephone Call 1 (Day 4 or 5)
1.
Review and record interval history since Visit 2
2.
Perform and record RSSQ 
10.7 Visit 3 (Day 7 ± 2)
1.
Review and record RSSQ prior to any other study procedures
2.
Administer and review CFRSD prior to any other study procedures and record any AEs that occurred 
since Visit 2
3.
Review and record interval history
4.
Review and record any changes to concomitant medications
5.
Measure and record weight without shoes
6.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
7.
Perform and record oximetry
8.
Perform abbreviated physical examination

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9.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
10.
Collect blood for inflammatory mediators (calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL-8, IL-17, and 
TNF-)
11.
Collect urine for clinical laboratory test (urinalysis)
12.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum during the visit
13.
Perform and record spirometry
14.
Obtain sputum for clinical laboratory tests (quantitative culture and microbiology) and for research tests 
(cell count with differential, IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-3, TNF-, neutrophil 
elastase, R1
R-anti-trypsin, and MMP-9).  Subjects will be asked to provide sputum via spontaneous 
expectoration.  If a subject is unable to provide sputum spontaneously, then the subject may undergo 
sputum induction according to the current TDN SOP. Any AEs related to the sputum procedure will be 
recorded
15.
Schedule subject for Visit 4
16.
Record any AEs that may have occurred during the study visit 
10.8 Visit 4 (Day 14 ± 2)
1.
Perform and record RSSQ prior to any other study procedures
2.
Administer and review CFRSD prior to any other study procedures and record any AEs that occurred 
since Visit 3
3.
Distribute CFRSD that the subject must complete between Visit 4 and Visit 5
4.
Review and record interval history
5.
Review and record any changes to concomitant medications
6.
Measure and record weight without shoes
7.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 
minutes.
8.
Perform and record oximetry
9.
Perform abbreviated physical examination
10.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
11.
Collect urine for clinical laboratory test (urinalysis)
12.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum during the visit
13.
Perform and record spirometry
14.
Schedule Subject for Telephone Call 2 and for Visit 5
15.
Record any AEs that may have occurred during the study visit 

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10.9 Telephone Call 2 (Day 21 ± 2)
1.
Review and record interval history since Visit 4
2.
Perform and record RSSQ 
3.
Review CFRSD and record any AEs that occurred since Visit 4
10.10 Visit 5 (Day 28 ± 2)
1.
Review and record RSSQ prior to any other study procedures
2.
Administer and review CFRSD prior to any other study procedures and record any AEs that occurred 
since Telephone call 2
3.
Review and record interval history
4.
Review and record any changes to concomitant medications
5.
Measure and record weight without shoes
6.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
7.
Perform and record oximetry
8.
Perform complete physical examination
9.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
10.
Collect blood for inflammatory mediators (calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL-8, IL-17, and 
TNF-)
11.
Collect urine for clinical laboratory test (urinalysis)
12.
Collect urine for pregnancy test
13.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum during the visit
14.
Perform and record spirometry
15.
Obtain sputum for clinical laboratory tests (quantitative culture and microbiology) and for research tests 
(cell count with differential, IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-3, TNF-, neutrophil 
elastase, R1
R-anti-trypsin, and MMP-9).  Subjects will be asked to provide sputum via spontaneous 
expectoration.  If a subject is unable to provide sputum spontaneously, then the subject may undergo 
sputum induction according to the current TDN SOP.  Any AEs related to the sputum procedure will be 
recorded
16.
Schedule subject for Telephone Call 3 and for Visit 6
17.
Record any AEs that may have occurred during the study visit 
10.11 Telephone Call 3 (Day 56 ± 2)
1.
Review and record interval history since Visit 5
2.
Perform and record RSSQ 
3.
Record any AEs that occurred since Visit 5

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10.12 Visit 6 (Month 3 ± 14 days)
1.
Perform and record RSSQ prior to any other study procedures
2.
Review and record interval history
3.
Review and record any changes to concomitant medications
4.
Record any AEs that occurred since Telephone call 3
5.
Measure and record weight without shoes
6.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
7.
Perform and record oximetry
8.
Perform abbreviated physical examination
9.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
10.
Collect urine for clinical laboratory test (urinalysis)
11.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum during the visit
12.
Perform and record spirometry
13.
Schedule Subject for Visit 7
14.
Record any AEs that may have occurred during the study visit
10.13 Visit 7 (Month 6 ± 14 days)
1.
Perform and record RSSQ prior to any other study procedures
2.
Review and record interval history
3.
Review and record any changes to concomitant medications
4.
Record any AEs that occurred since Visit 6
5.
Measure and record weight without shoes
6.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
7.
Perform and record oximetry
8.
Perform abbreviated physical examination
9.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
10.
Collect urine for clinical laboratory test (urinalysis)
11.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject is likely to require induction to 
obtain sputum during the visit
12.
Perform and record spirometry
13.
Schedule Subject for Telephone Call 4
14.
Record any AEs that may have occurred during the study visit

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10.14 Telephone Call 4 (Month 12 ± 1)
1.
Review and record interval history since Visit 7
2.
Record any AEs that occurred since Visit 7
10.15 Acute Illness/Early Termination Visit
1.
Review and record RSSQ prior to any other study procedures
2.
If Acute Illness or Early Termination Visit occurs before Visit 5, administer and review CFRSD prior to 
any other study procedures and record any AEs that occurred since last Visit or Telephone call
3.
Review and record interval history
4.
Review and record any changes to concomitant medications
5.
Measure and record weight without shoes
6.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
7.
Perform and record oximetry
8.
Perform a complete physical examination
9.
Collect blood for clinical laboratory tests (comprehensive chemistry panel, ESR, hs-CRP, complete 
blood count with differential, direct bilirubin and LDH)
10.
Collect urine for clinical laboratory test (urinalysis) 
11.
Collect urine for pregnancy test
12.
Administer 3 puffs of albuterol 15 minutes prior to spirometry if subject performed a sputum induction 
during the study
13.
Perform and record spirometry
14.
Record any AEs that may have occurred during the study visit 
For Healthy Volunteer Subjects:
10.16 Visit 1 (Screening Visit: Day -30 to -7)
1.
Review the study with the subject and obtain written informed consent and HIPAA authorization
2.
Assign the subject a unique screening number
3.
Record demographics and other baseline data
4.
Record medical and surgical history
5.
Record concomitant medications
6.
Review inclusion/exclusion criteria
7.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes
8.
Complete Donor History Questionnaire (DHQ)

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9.
Collect 32 ml blood for laboratory tests (infectious disease markers, CMV, CF mutations).  Collect 2 ml 
blood for serum pregnancy test if applicable.
10.
Record any AEs that may have occurred during the study visit from the time of consent
10.17 Visit 2 (Bone Marrow Aspiration)
1.
Perform and record vital signs, including a blood pressure after the subject has been seated for 5 minutes 
2.
Review and record interval history
3.
Review and record any changes to concomitant medications
4.
Perform urine pregnancy test if applicable
5.
Perform an abbreviated physical exam
6.
Review inclusion/exclusion criteria
7.
Perform bone marrow aspiration 
8.
Subject to rest for 30 minutes post-procedure
9.
Record any AEs that may have occurred during the study visit
10.18  Follow-up Phone Call (24 (± 12) hours after Bone Marrow Aspiration)
1.
Review and record interval history
2.
Review and record any changes to concomitant medications
3.
Record any AEs that may have occurred since bone marrow aspiration
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
11.1 Adverse Events
An AE is any untoward medical occurrence in a clinical investigation of a patient administered a 
pharmaceutical product and that does not necessarily have a causal relationship with the treatment that occurs 
from the time of consent through Telephone Call 4 (Month 12 ±1).  An AE is therefore any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the 
administration of an investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the current Investigator’s 
Brochure or of greater severity or frequency than expected based on the information in the Investigator’s 
Brochure.
The Investigator or Research Coordinator will probe, via discussion with the subject, for the occurrence 
of AEs during each subject visit and record the information in the site’s source documents.  AEs will be 
recorded in the subject CRF.  AEs will be described by duration (start and stop dates and times), severity, 
outcome, treatment and relation to investigational product, or if unrelated, the cause.
AE Severity

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The NCI’s CTCAE Version 4.0, summarized in Table 2 below, should be used to assess and grade AE 
severity, including laboratory abnormalities judged to be clinically significant. It should be pointed out that the 
term “severe” is a measure of intensity and that a severe AE is not necessarily serious.
Table 2.  AE Severity Grading (based on NCI’s CTCAE Version 4.0)
Severity (Toxicity Grade)
Description
Grade 1
 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
Grade 2
 Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*.
Grade 3
 Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self care ADL**.
Grade 4
 Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
A Semi-colon indicates ‘or’ within the description of the grade.
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
AE Relationship to Investigational Product
The relationship of an AE to the study drug should be assessed using the following the guidelines in 
Table 3.
Table 3.  AE Relationship to Investigational Product
Relationship
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis.

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Relationship
to Drug
Comment
Probably
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions.
Possibly
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no relationship to the 
investigational product.
11.2 Serious Adverse Events (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes:

death

a life-threatening adverse experience

inpatient hospitalization or prolongation of existing hospitalization

a persistent or significant disability/incapacity

a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on appropriate medical 
judgment, they jeopardize the subject or require intervention to prevent one of the outcomes listed. 
11.2.1 Serious Adverse Experience Reporting
All SAEs will be documented (whether or not related to investigational product) on a SAE Report Form. 
The collection period for all SAEs will begin after informed consent is obtained and end at Telephone Call 4 
(Month 12 ±1).
All SAEs will be reviewed by the site investigator and sent to the TDNCC, within one business day of 
the site learning of the event.  The site will scan and email or fax the SAE report to:
Email address:  31Tcfsaesfacsys@seattlechildrens.org31T
Direct dial fax number: (206) 985-3278
Study staff will notify the TDNCC of additional information or follow-up to an initial SAE Report as 
soon as relevant information is available.  Follow-up information is reported on an SAE Report Form.
In accordance with the standard operating procedures and policies of the local IRB, the site investigator will 
report SAEs to the IRB.  SAEs will be reported to the FDA in accordance with 21 CFR 312.32.

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11.3 Medical Monitoring
TDNCC Medical Monitoring Group should be contacted directly at this number to report medical 
concerns or questions regarding safety:
Pager: (800) 341-0961 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS
12.1 Withdrawal of Subjects and Drop-outs 
A subject may be discontinued from the study at any time if the subject, the investigator feels that it is 
not in the subject’s best interest to continue.  The following is a list of possible reasons for study or treatment 
discontinuation: 

Subject withdrawal of consent

Subject is not compliant with study procedures

Adverse event

Lost to follow-up

Physician request for early termination of study
If a subject experiences an AE, the subject will be followed and treated by the Investigator or the 
subject’s physician until the abnormal parameter or symptom has resolved or stabilized.  Subjects will be 
encouraged to complete an Early Termination Visit.
All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, 
and without prejudice. If the subject withdraws from the study and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data should be collected. The 
Investigator may retain and continue to use any data collected before such withdrawal of consent. Any samples 
already being analyzed will be completed and any stored samples will be destroyed if still linkable.
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  The 
reason for the subject’s withdrawal from the study will be specified in the subject’s source documents.  Subjects 
who withdraw from the study will be replaced if they withdraw before Visit 5.  Refer to Section 10 for early 
termination procedures.  If a subject withdraws on the day of hMSC infusion, then the Early Termination Visit 
will be performed on Day 4-9.
13 PROTOCOL VIOLATIONS
A protocol violation occurs when the subject or investigator, fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  Protocol 
Violations for this study include, but are not limited to, the following: 

Failure to meet inclusion/exclusion criteria

Use of a prohibited concomitant medication
Failure of the investigators or study staff to comply with Good Clinical Practice (GCP) guidelines will 
also result in a protocol violation. The medical monitor will determine if a protocol violation will result in 
withdrawal of a subject. When a protocol violation occurs, it will be discussed with the investigator and a 
Protocol Violation Form detailing the violation will be generated. This form will be signed by the Investigator. 
A copy of the form will be filed in the site’s regulatory binder.  

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14 DATA SAFETY MONITORING 
The Cystic Fibrosis Foundation Data Safety Monitoring Board (DSMB) will establish a Data 
Monitoring Committee (DMC) to review data relating to safety and efficacy, to conduct and review interim 
analyses, and to ensure the continued scientific validity and merit of the study, according to the Cystic Fibrosis 
Foundation Data Safety Monitoring Board Operations Manual and a DMC Charter to be established for this 
protocol. There will be 3 interim review(s) conducted by the DMC for the purpose of monitoring study conduct 
and assessing subject safety.  Enrollment for subsequent cohorts will not begin until after the DMC reviews the 
data for the current cohort and approves proceeding to the next cohort.  Further details regarding the timing and 
content of the interim reviews is included in the statistical section below.
15 STATISTICAL METHODS AND CONSIDERATIONS (BASED UPON PRIMARY AND 
SECONDARY ENDPOINTS)
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be written 
describing all analyses that will be performed.  The SAP will contain any modifications to the analysis plan 
described below.  
15.1 Data Sets Analyzed
All eligible subjects who are enrolled into the study and receive at least one dose of the investigational 
product (the Safety Population) will be included in the safety analysis. The analyses will be conducted on all 
data available.  Subjects with missing data for a particular analysis will not be included as applicable.
15.2 Demographic and Baseline Characteristics
Demographic and baseline clinical characteristics including age, gender, race, CFTR genotype, height, 
weight, oxygen saturation, sputum microbiology (presence of P. aeruginosa, methicillin-sensitive S. aureus, 
methicillin-resistant S. aureus, and/other Gram-negative bacteria) and pulmonary function will be reported for 
each subject and summarized overall using descriptive statistics such as frequency, percentage, mean or 
median and range. For all analyses, Baseline will be defined as the measurement prior and closest to the 
administration of the infusion of hMSCs.
15.3 Analysis of Primary Endpoint
The primary endpoint of this study is to determine the maximum tolerate dose among 1 x 106 hMSCs/kg, 
3 x 106 hMSCs/kg, and 5 x 106 hMSCs/kg. Safety data will be analyzed at both the individual level and the dose 
cohort level.  Safety will be evaluated using reports of adverse events (AE) and measurements of vital signs, 
oxygen saturation, pulmonary function, laboratory parameters and adverse events associated with procedures 
(sputum induction for those subjects unable to spontaneously expectorate sputum and optional bone marrow 
aspiration). All measurements will be reported at each time point, changes from Baseline and from the previous 
time point will be summarized at each time point. Premature withdrawals and reasons of withdrawals will be 
listed. 
Clinically significant AEs and alterations in vital signs, oxygen saturation, and pulmonary function at 
baseline, 30 minutes, 4 hours and 24 hours after the infusion will be summarized by patient and by dose cohort 
using frequency/percentage and mean or median/range.  
Overall AEs and SAEs in each dose cohort will be coded by body system and MedDRA classification 
term using frequency and percentage. Frequency and percentage of all grades and grades ≥ 3 will be reported.  

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AEs among dose cohorts will be compared using Fisher’s exact test. All clinically significant vital sign and 
physical examination changes as well as laboratory test abnormalities will be presented in AE listings. 
Mean or percentage of clinically significant AEs, alterations in vital signs (including decreases in 
systolic blood pressure ≥ 20 mmHg or  diastolic blood pressure ≥ 10 mmHg), spirometry measurements (FEVR1
R 
%, FEVR1
R (Liters), FEFR25-75
R), sputum quantitative microbiology (bacterial colony forming units) and 
hematology, comprehensive chemistry, ESR, hs-CRP and urinalysis results measured at Baseline and at the 
follow-up visits will be graphically presented.  
15.4 Analysis of Secondary/Exploratory Endpoints
Although efficacy is not the primary aim of this dose escalation study, changes and patterns of change 
between MTD and lower doses on inflammatory biomarkers in blood and sputum measured at Baseline, day 7 
and day 28 will be explored using a mixed effects model, mean and standard deviation at each time point as 
well as each patient’s case profile will be graphically presented. 
15.5 Interim Analysis
No interim statistical analysis is planned.
15.6 Sample Size
This is a single center Phase I study.  Enrollment of 15 subjects will be feasible and allow us to ascertain 
if there are any clinically meaningful infusion-related adverse effects. 
16 DATA COLLECTION, RETENTION AND MONITORING
16.1 Data Collection Instruments
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific CRF when the information corresponding to that visit is available.  Subjects will not be 
identified by name in the study database but will be identified by subject number and initials. 
All clinical information requested in this protocol will be entered into the CRFs.  The study data will be 
entered into case report forms using Medidata Rave eCRFs which will be supported by the TDN Clinical Data 
Management and Programming Core at Seattle Children’s Hospital.  Medidata Rave is certified 21 CFR Part 11 
compliant.  Corrections to CRFs will have an audit trail.
The Investigator is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by the 
Investigator.  All study records will remain at the Investigator’s site at the completion of the study.
16.2 Data Management Procedures
All procedures for the handling and analysis of data will be conducted using good clinical practice 
(GCP) meeting FDA guidelines for the handling and analysis of data for clinical trials.  All data extracted from 
Medidata Rave will be downloaded to a 21 CFR Part 11 compliant cloud-based space where any manipulation 
of the data would occur.  
16.3 Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data validation checks 
will be implemented and applied to the database on a regular basis.

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16.4 Archival of Data
Appropriate archiving of the database will be completed according to Medidata Rave procedures.    
16.5 Availability and Retention of Investigational Records
The Investigator must make study data accessible to authorized personnel, IRB, and Regulatory Agency 
(e.g., FDA) inspectors upon request.  A file for each subject must be maintained that includes the signed 
Informed Consent, HIPAA Authorization and copies of all source documentation related to that subject.  The 
Investigator must ensure the reliability and availability of source documents from which the information on the 
CRF was derived.
All study documents (subject files, signed informed consent forms, CRFs, Study File Notebook, etc.) 
must be kept secured for a period of 2 years following marketing of the investigational product or for 2 years 
after centers have been notified that the IND has been discontinued.  
16.6 Monitoring
This is a single site investigator initiated study.  This study will be monitored by representatives from 
the office of the University Hospitals Cleveland Medical Center for Clinical Research and Technology per the 
monitoring plan as described in DMC charter.  By signing this protocol, the Investigator grants permission to 
the office of the University Hospitals Cleveland Medical Center for Clinical Research and Technology (or 
designee), and appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate 
study documentation. 
16.7 Subject Confidentiality
In order to maintain subject confidentiality, only a subject number and subject initials will identify all 
study subjects on CRFs.  Laboratory reports, spirometry reports, CRU flow sheets, and CRU physician order 
sheets will contain the subject’s name and medical registration number. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of Human Volunteers 
(21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will be 
identified by a coded number and initials only.  All non-electronic study records will be kept in a locked file 
cabinet/file room and code sheets linking a subject’s name to a subject identification number will be stored 
separately in another locked file cabinet.  Clinical information will not be released without written permission 
of the subject, except as necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data 
Protection Directive 95/46/EC).
17.1 Protocol Amendments
Any amendment to the protocol will be the responsibility of the Principal Investigator.
A protocol amendment intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the IRB is notified per IRB policy.

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17.2 Institutional Review Board
The protocol and consent form will be reviewed and approved by the IRB at University Hospitals 
Cleveland Medical Center prior to study initiation.  Serious adverse experiences regardless of causality will be 
reported to the IRB in accordance with the standard operating procedures and policies of the IRB, and the 
Investigator will keep the IRB informed as to the progress of the study.  The Investigator will obtain a list of 
IRB members or other assurance of compliance with regulations.
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning subject recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The IRB written 
unconditional approval of the study protocol and the informed consent form will be in the possession of the 
Investigator before the study is initiated.  This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without prior written 
IRB approval except when necessary to eliminate immediate hazards to the subjects or when the change(s) 
involves only logistical or administrative aspects of the study.  Such modifications will be submitted to the IRB 
and written verification that the modification was submitted and subsequently approved should be obtained.  
The IRB will be informed of revisions to other documents originally submitted for review; serious 
and/or unexpected adverse experiences occurring during the study in accordance with the standard operating 
procedures and policies of the IRB; new information that may affect adversely the safety of the subjects of the 
conduct of the study; an annual update and/or request for re-approval; and when the study has been completed.
17.3 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code 
of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, 
Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local 
regulations.
The Investigator will prepare the informed consent form and HIPAA authorization for submission to the 
IRB.  The consent form generated by the Investigator must be approved by the IRB.  The written consent 
document will embody the elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will retain an IRB-approved copy 
of the Informed Consent Form for the study file.
A properly executed, written, informed consent will be obtained from each subject prior to entering the 
subject into the trial.  Information should be given in both oral and written form and subjects must be given 
ample opportunity to inquire about details of the study.  If a subject is unable to sign the informed consent form 
(ICF) and the HIPAA authorization, a legal representative may sign for the subject.   A copy of the signed 
consent form will be given to the subject or legal representative of the subject and the original will be 
maintained with the subject’s records.
17.3.1 Consent for Collection and Use of CFF Registry ID Number and Sample Banking
Any remaining research samples will be stored for future studies in secured -80oC freezers in the 
laboratories of the Cystic Fibrosis Research Center at Case Western Reserve University/University Hospitals 
Cleveland Medical Center.   Samples will be labeled with the date, the subject’s unique identifying number, and 
visit number. 

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To facilitate possible future evaluation of long-term outcomes information from all patients who screen 
for this study, consent will also be sought to collect the subject’s CFF Registry ID number at the screening visit. 
The CFF registry collects data on all CF patients followed at CFF-accredited care centers at each clinical 
encounter, at each hospitalization or course of home IV antibiotics, and via a year-end survey. If specific 
consent is given to collect this number, the patient’s CF registry number will be recorded in the CRF.
17.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the study funding agency (Cystic 
Fibrosis Foundation Therapeutics) and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the Health Insurance 
Portability and Accountability Act of 1996. 
17.5 Investigator Responsibilities
1.
Conduct the study in accordance with the protocol and only make changes after obtaining appropriate 
approval, except when to protect the safety, rights or welfare of subjects.
2.
Personally conduct or supervise the study (or investigation).
3.
Ensure that the requirements relating to obtaining informed consent and IRB review and approval meet 
federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Report to the medical monitor any AEs that occur in the course of the study, in accordance with §21 CFR 
312.64.
5.
Ensure that all associates, colleagues and employees assisting in the conduct of the study are informed 
about their obligations in meeting the above commitments.
6.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those records 
available for inspection.
7.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for initial 
and continuing review and approval of the clinical study.
8.
Promptly report to the IRB all changes in the research activity and all unanticipated problems involving 
risks to subjects or others (to include amendments and IND safety reports).
9.
Seek IRB approval before any changes are made in the research study, except when necessary to eliminate 
hazards to the patients/subjects.
10. Comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements listed in § 21 CFR part 312.

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18 APPENDIX I: DEFINITION OF A PULMONARY EXACERBATION (MODIFIED FUCHS 
CRITERIA)95
An exacerbation of respiratory symptoms is defined as a subject undergoing a change in antibiotic 
therapy for any 4 of the following 12 signs or symptoms: 
1. Change in sputum
2. New or increased hemoptysis
3. Increased cough
4. Increased dyspnea
5. Malaise, fatigue, or lethargy
6. Temperature above 38 °C
7. Anorexia or weight loss
8. Sinus pain or tenderness 
9. Change in sinus discharge
10. Change in physical examination of the chest
11. Decrease in pulmonary function by 10 percent or more from a previously recorded value
12. Radiographic changes indicative of pulmonary infection

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19 APPENDIX II.  SCHEDULE OF STUDY VISITS
Visit 1
Screen
ing
Visit 2
Baseline
Phone 
Call 1
Visit 3
Visit 4
Phone 
Call 2
Visit 5
Phone
Call 3
Visit 6
and 
Visit 7
Acute 
Illnessp/ 
Early 
Term. 
Visitq
Phone
Call 4
Day
-42 to -
10
Day
1
Day
2
Day
4 or 5
Day
7 ± 2
Day
14 ± 2
Day
21 ± 2
Day
28 ± 2
Day
56 ± 2
Month 3 
± 14 days 
and 
Month 6 
± 14 days
Month 
12 ± 1
Informed consent
X
Medical & surgical history
X
Demographics and baseline 
characteristics
X
Interval history
Xc
X
X
X
X
X
X
X
X
X
X
Review previous and 
concomitant therapy
X
Xc
X
X
X
X
X
X
Review inclusion/exclusion 
criteria
X
Xc
Heighta, weight, vital signs, 
oximetry
X
Xc
X
X
X
X
X
X
Complete physical exam
X
Xc
X
X
X
Abbreviated physical exam
X
X
X
Blood draw-safety labsg
X
Xc
X
X
X
X
X
X
Blood draw-vitamin D
Xc
Blood draw inflammatory 
mediatorsh
Xc
X
X

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Visit 1
Screen
ing
Visit 2
Baseline
Phone 
Call 1
Visit 3
Visit 4
Phone 
Call 2
Visit 5
Phone
Call 3
Visit 6
and 
Visit 7
Acute 
Illnessp/ 
Early 
Term. 
Visitq
Phone
Call 4
Day
-42 to -
10
Day
1
Day
2
Day
4 or 5
Day
7 ± 2
Day
14 ± 2
Day
21 ± 2
Day
28 ± 2
Day
56 ± 2
Month 3 
± 14 days 
and 
Month 6 
± 14 days
Month 
12 ± 1
Serum pregnancy test 
(if applicable)
X
Urinalysis
X
Xc
X
X
X
X
X
X
Urine pregnancy test 
(if applicable)
Xc
X
X
Spirometry
X
Xc, d, e
Xo
X e
X
X e
X
X
Acquisition of sputumf
Xc
X
X
Sputum quantitative 
bacteriology
Xc
X
X
Sputum cell count
Xc
X
X
Sputum cytokine 
measurementsi
Xc
X
X
RSSQ
X
Xc
X
Xj
X
X
Xj
X
Xj
X
X
CFRSD
X
X
X
X
X
Xk
Diagnostic bone marrow 
exam (optional)b
X
Investigational product 
(hMSC) infusion
Xl, m, n
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X

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a Height will only be obtained one time in the study at the Screening Visit
b See Appendix IIa for Schedule of Events for Stem Cell Collection from CF Donors
c Other procedures and collections should be done prior to infusion of stem cells
d On the day of hMSC infusion, spirometry should be performed approximately 2 hours prior to infusion and 30 minutes (± 15 minutes) and 4 hours (±15 minutes) 
after completion of infusion
e At visits 2, 4, and 6, spirometry should be performed prior to the acquisition of sputum
f Sputum can be collected by spontaneous expectoration.  In those subjects unable to spontaneously expectorate, sputum may be induced by inhalation with 3% 
hypertonic saline using the current TDN SOP
g CBC with differential, comprehensive chemistry panel, hs-CRP, ESR, direct bilirubin and LDH
h Calprotectin, MPO, GM-CSF, IL-1β, IL-6, IL8, IL-17, and TNF-
I IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, MIP-3, TNF-, neutrophil elastase, R1
R-anti-trypsin, and MMP-9
j RSSQ should be administered if any increased respiratory symptoms
k Only if Acute Illness/Early Termination Visit is prior to Visit 5 
l MSCs will be derived from bone marrow samples obtained from healthy volunteers and processed and evaluated according to CCC SOP well in advanced of 
infusion.  CF study staff will inform CCC collaborators when hMSCs will be needed approximately 14 days prior to infusion.  CCC collaborators will prepare the 
proper dose to be infused based upon the weight of the subject with CF
m Infusion is given by slow IV push and takes less than 30 minutes depending upon the volume to be infused
n Subjects will be monitored in the CRU for 24 hours after the completion of the infusion. Temperature, blood pressure, heart rate, respiratory rate and oxygen-
saturation are measured prior to infusion and at 10 (± 5), 20 (± 5), 30 (± 5), 60 (± 15), and 90 (± 15) minutes and 2 hours (±15 minutes) and 4 (± 15 minutes) hours 
post-infusion and then every 4 (± 15 minutes) hours for the remainder of the 24-hour observation period.    
o On Day 2, spirometry should be performed at 24 (± 1) hours after completion of infusion
p An Acute Illness Visit will be arranged for any subject who experiences any abrupt change in baseline clinical status, between Visit 2 and Visit 5
q An Early Termination Visit will be completed for any subject terminating study participation between Visit 2 and Visit 7.

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APPENDIX IIa.  SCHEDULE OF STUDY VISITS FOR OPTIONAL STEM CELL COLLECTION 
FROM CF SUBJECT DONORS
Visit 1
Screening
Visit 1A
Follow-up Phone 
Call
Day 
-42 to -101
Day
-35 to -14
24 (± 12) hours 
after bone marrow 
aspiration
Informed consent
X
Interval history
X
X
Review previous and 
concomitant therapy
X
X
Review inclusion/exclusion 
criteria
X
X
Phlebotomy for infectious 
disease limited panel
X
Vital signs
X
Urine pregnancy test 
(if applicable)
X
Abbreviated physical exam
X
Bone marrow aspiration of 
the posterior iliac crest
X
Adverse events
X
X
X
1The Visit 1 Screening window in this table refers to the main study (for consistency with the table in Appendix 
II).  If a CF subject plans to participate in the optional stem cell collection procedure at Visit 1A, then the Visit 
1 Screening must be completed by Day -14 or earlier in order to complete Visit 1A and Visit 1 at the 
appropriate times.

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APPENDIX IIb.  SCHEDULE OF STUDY VISITS FOR STEM CELL COLLECTION FROM 
HEALTHY VOLUNTEER DONORS
Visit 1
Screening
Visit 2
Follow-up Phone 
Call
Day
-30 to -7
Day
1
24 (± 12) hours 
after bone 
marrow 
aspiration
Informed consent
X
Medical & surgical history
X
Demographics and baseline 
characteristics
X
Interval history
X
X
Review previous and 
concomitant therapy
X
X
X
Review inclusion/exclusion 
criteria
X
X
DHQ
X
Serum pregnancy test
X
Phlebotomy for infectious 
disease panel including CMV
X
Phlebotomy for CF mutation 
screening
X
Vital signs
X
X
Urine pregnancy test 
(if applicable)
X
Abbreviated physical exam
X
Bone marrow aspiration of 
the posterior iliac crest
X
Adverse events
X
X
X

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Revision History Log

Protocol CF-MSC-01
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Version 1.13
                     Version Date: 17Dec2019
73 of 73
Revision 
Number
Revision or Update
Date of Release 
(ddMMMyyyy)
Approver
1.12
Employment of Revision History Log for 
document control purposes.
Sponsor Investigator transfer from James 
Chmiel to Erica Roesch. 
Inclusion Criteria changed (#4) FEV ≥ 50% 
predicted to ≥ 40% predicted.
01NOV2018
Laura 
Dixon
1.13
Section 9.4.2 updated to indicate bone marrow 
collection will take place within 7 days of 
infectious disease testing. 
17DEC2019
Laura 
Dixon