Conditions: Degenerative Disc Disease
Keywords: Chronic Lumbar Back Pain Low back pain Back pain Degenerative Disc Disease Injection of Degenerated Lumbar Disc Intervertebral Disc Degeneration Bone Diseases Musculoskeletal Diseases Nervous System Diseases Neurologic Manifestations Pain Spinal Diseases Stem Cells Adult Stem Cells Allogeneic Mesenchymal Precursor cells (MPCs) Mesoblast Hyaluronic Acid Pharmaceutical Solutions Adjuvants, Immunologic Immunologic Factors Pharmacologic Actions Protective Agents rexlemestrocel-L Viscosupplements
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 404
Healthy volunteers: no

Brief summary:
This is a prospective, multicenter, randomized, double-blind, placebo-controlled Phase 3 study designed to evaluate the safety and efficacy of Mesoblast's rexlemestrocel-L alone or combined with hyaluronic acid (HA) in participants with chronic low back pain (\> 6 months) associated with moderate radiographic degenerative changes of a disc.

Detailed description:

Arms:
arm 1: Participants received rexlemestrocel-L 2.0 mL injection of approximately 6 million rexlemestrocel-L cells in freeze media mixed in a 1:1 by-volume ratio with saline on Day 0 (Visit 2). arm 2: Participants received rexlemestrocel-L 2.0 mL injection of approximately 6 million rexlemestrocel-L cells in freeze media mixed in a 1:1 by-volume ratio with hyaluronic acid (HA) solution on Day 0 (Visit 2). arm 3: Participants received saline solution as matching-placebo on Day 0 (Visit 2).

Interventions: intervention 1: Rexlemestrocel-L intervention 2: Rexlemestrocel-L + HA Mixture intervention 3: Placebo
Intervention descriptions: intervention 1: Rexlemestrocel-L injection intervention 2: Rexlemestrocel-L was combined in 1:1 by-volume ratio with HA solution and the resulting mixture was injected intervention 3: Saline control solution

Protocol document:
Prot_SAP_001.pdf: 
 
Official Title: 
A Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of a Single Injection of 
Rexlemestrocel-L Alone or Combined With Hyaluronic Acid (HA) in Subjects 
With Chronic Low Back Pain 
NCT Number: 
 
NCT02412735 
 
Document Date: 
 
Protocol Version 7.0: 17 December 2018 
 
 
 
 
 
 
 




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INVESTIGATOR’S SIGNATURE 
Study Title: A Prospective, Multicenter, Randomized, Double-blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of a Single Injection of rexlemestrocel-L Alone or 
Combined with Hyaluronic Acid (HA) in Subjects with Chronic Low Back Pain 
 
I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will 
only make changes in a protocol after notifying the sponsor, except when necessary to protect the 
safety, rights, or welfare of subjects.  
 
I agree to personally conduct or supervise the described investigation(s).  
 
I agree to inform any patients, or any persons used as controls, that the drugs are being used for 
investigational purposes. 
 
I agree to report to the sponsor adverse experiences that occur in the course of the 
investigation(s)  
 
I have read and understand the information in the investigator’s brochure, including the potential 
risks and side effects of the drug.  
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study(ies) are informed about their obligations in meeting the above commitments.  
 
I agree to maintain adequate and accurate records in accordance and to make those records 
available for inspection.  
 
I will ensure that an IRB/EC completed the initial and continuing review and approval of the 
clinical investigation. I also agree to promptly report to the IRB/EC all changes in the research 
activity and all unanticipated problems involving risks to human subjects or others. Additionally, 
I will not make any changes in the research without IRB/EC approval, except where necessary to 
eliminate apparent immediate hazards to human subjects.  
 
 
Agreement Signature: 
 
______________________ __________________________ 
_________________ 
Principal Investigator  
Principal Investigator  
 
Date 
(Please print)  
 
(Signature) 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
A Prospective, Multicenter, Randomized,  Double-blind,  Placebo-
Controlled Study to Evaluate the Efficacy and Safety of a Single Injection 
of rexlemestrocel-L alone or Combined with Hyaluronic Acid (HA) in 
Subjects with Chronic Low Back Pain 
Sponsor 
Mesoblast, Ltd. 
Study Phase 
Phase 3 
Investigators 
and Clinical 
Sites 
Up to 45 study centers from the United States, Australia, and potentially 
the European Union (EU) 
Indication 
Treatment of chronic low back pain (> 6 months duration) not adequately 
controlled by conservative measures and associated with moderate 
radiographic degenerative changes of a disc. 
Objectives 
Primary Efficacy Objective: 
• To determine Overall Treatment Success of rexlemestrocel-L alone 
or rexlemestrocel-L+HA at 12 AND 24 months based on a 
composite responder analysis of low back pain Visual Analog 
Scale (VAS) score, Oswestry Disability Index (ODI) score and no 
post-treatment interventions at the treated level. 
 
Secondary Efficacy Objectives: 
• To evaluate the effectiveness of rexlemestrocel-L alone or 
rexlemestrocel-L+HA in reducing chronic low back pain by 
performing a Pain Responder analysis at 12 AND 24 months post-
treatment 
• To evaluate the effectiveness of rexlemestrocel-L alone or 
rexlemestrocel-L+HA in improving function by performing a 
Functional Responder analysis at 12 AND 24 months post-
treatment 
• To evaluate the Treatment Success at 24 months of rexlemestrocel-
L alone or rexlemestrocel-L+HA based upon a composite 
responder analysis of low back pain Visual Analogue Scale (VAS) 
score, Oswestry Disability Index (ODI) score and no post-treatment 
interventions at the treated level. 
• To evaluate the effectiveness of rexlemestrocel-L alone or 
rexlemestrocel-L+HA in reducing chronic low back pain based on 
incidence of subjects with minimal to no low back pain and no 
post-treatment interventions at the treated level at 24 months post-
treatment (Minimal Pain Responder analysis) 
• To evaluate the effectiveness of rexlemestrocel-L alone or 
rexlemestrocel-L+HA in improving function based on incidence of 
subjects with minimal disability and no post-treatment 










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• Primary efficacy and safety evaluations will be performed through 
the 24 month follow-up visit  
• Study conduct and all safety will be supervised by an independent Data 
Safety Monitoring Board (DSMB) 
• Post-treatment interventions at the treated level and relationship of 
adverse events to treatment procedure or product will be adjudicated by 
a blinded and independent Treatment Events Committee (TEC). 
Analysis set 
Approximately 360 subjects, with the randomization ratio of 1:1:1, with a 
history of chronic (> 6 months) low back pain not adequately controlled by 
conservative measures for 6 months associated with moderate radiographic 
degenerative changes of a disc in the lumbar spine from L1 to S1. 
 
 
 
Efficacy 
Endpoints 
Primary Efficacy Endpoint:  
Overall Treatment Success at both 12 AND 24 months: Measured as 
subjects meeting each of the following criteria at both 12 AND 24 months 
post-treatment:  
• at least a 50% reduction from baseline in low back pain VAS score 
(average pain over 24 hours); AND 
• at least a 15 point decrease from baseline in ODI score; AND 
• no interventions at the treated level 
Secondary Efficacy Endpoints:  
1. Pain Responder at both 12 AND 24 months: Measured as 
subjects meeting at least a 50% decrease from baseline in low back 
pain VAS score (average pain over 24 hours) at both Study Visit 6 
(12 months post-treatment) and Study Visit 8 (24 months post-
treatment) with no adjudicated post-treatment intervention through 
Study Visit 8. 
2. Functional Responder at both 12 AND 24 months: Measured as 
subjects meeting at least a 15-point decrease from baseline in ODI 
at both Study Visit 6 (12 months post-treatment) and Study Visit 8 
(24 months post-treatment) with no adjudicated post-treatment 
intervention through Study Visit 8. 
3. Treatment Success at 24 months: Measured as subjects meeting 
each of the following criteria at Study Visit 8 (24 months post-
treatment): 
o at least a 50% reduction from baseline in low back pain 
VAS score (average pain over 24 hours); AND 
o at least a 15 point decrease from baseline ODI score; AND 
o no interventions at the treated level 
4. Minimal Pain Responder at 24 Months: Measured as subjects 
meeting low back pain VAS score (average pain over 24 hours) of 














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  Chronic low back pain associated with moderate 
radiographic degeneration at a lumbar disc is defined as the following 
(subject must meet all of the listed conditions): 
a. Chronic low back pain for at least 6 months 
b. Have failed 6 months of conservative back pain care. (Conservative 
treatment regimens may include any or all of the following: initial 
rest, medications [e.g., anti-inflammatory, analgesics, 
narcotics/opioids, muscle relaxants], massage, acupuncture, 
chiropractic manipulations, activity modification, home-directed 
lumbar exercise program, and non-invasive pain control treatments 
or procedures) 
c. Have at a minimum undergone supervised physical therapy, such as 
daily walking routines, therapeutic exercises, and back education 
programs specifically for the treatment of low back pain AND taken 
a pain medication for back pain (e.g. NSAID and/or opioid 
medication). 
d. Change from normal disc morphology of the index disc as defined 
by radiographic evaluation by the core imaging evaluation provider. 
Radiographs must show all of the following: 
i. A modified Pfirrmann score of 3, 4, 5 or 6 on MRI at the index 
disc as determined by radiographic core lab 
ii. Modic Grade II changes or less on MRI at the index disc as 
determined by radiographic core lab 
iii. With or without contained disc protrusion at the index disc on 
MRI as determined by radiographic core lab  
e. Low back pain of at least 40mm and not more than 90mm of 100mm 
on low back pain VAS (average pain over 24 hours)  
f. Leg pain ≤20mm in both legs on a 100mm VAS scale 
g. ODI score of at least 30 and no more than 90 on a 100 point scale. 
Exclusion 
Criteria 
 
Subjects will be excluded from participating in the study if they meet any 
of the following exclusion criteria: 
1. Female subjects who are pregnant or nursing, or women planning 
to become pregnant in the first 24 months post-treatment (if a 
subject becomes pregnant during the study, the subject will 
remain in the study and only the requirement for radiation (X-
Ray, MRI) should be removed)  
2. Extreme obesity, as defined by NIH Clinical Guidelines Body 
Mass Index (BMI > 40) 
3. Have undergone a surgical procedure (e.g. discectomy, 
intradiscal electrothermal therapy, intradiscal radiofrequency, 
artificial disc replacement, interbody fusion) on the disc at the 
index or adjacent level 
4. Osteoporosis, as defined by dual-energy X-ray absorptiometry 


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(DEXA) scan. A DEXA T-score of ≤ -2.5 will exclude the 
subject. Only the following at-risk subjects will be required to 
undergo a DEXA scan at screening: 
a. Female subjects with a Simple Calculated Osteoporosis 
Risk Estimation (SCORE) of ≥6 and male subjects with a 
Male Osteoporosis Risk Estimation Score (MORES) of ≥6 
b. Females ≥50 years of age or who are post-menopausal or 
post-hysterectomy with oophorectomy 
c. Subjects taking bisphosphonate medications for the 
treatment of osteoporosis 
d. Subjects with a history of chronic, high-dose steroid use 
(oral and/or inhaled). High-dose steroid use is defined as: 
i. Daily, chronic use of oral steroids of ≥5 mg/day 
ii. Daily, chronic use of inhaled corticosteroids (at least 
twice per day) 
iii. Use of short-term (less than 10 days) oral steroids at 
a daily dose >20mg prednisone (or equivalent ) 
within 1 month of study procedure 
5. Any lumbar intradiscal injection, including steroids, into the 
index or adjacent discs prior to treatment injection, with the 
exception of the following injections performed at least 2 weeks 
prior to study treatment:  
a. Contrast medium (discography or other diagnostic 
injection) 
b. NSAIDs 
c. Nerve-blocking anesthetics (e.g., lidocaine, bupivacaine) 
d. Antibiotics 
e. Saline 
6. Have undergone a procedure affecting the structure/biomechanics 
of the index disc level (e.g., posterolateral fusion) 
7. Epidural steroid injections within 8 weeks prior to treatment 
injection 
8. Have received chronic (more than 7 consecutive days) treatment 
with systemic corticosteroids at a dose equivalent to prednisone 
 ≥ 10 mg/day within 14 days prior to injection procedure 
9. Have a known history of hypersensitivity or anaphylactic reaction 
to murine or bovine products or dimethyl sulfoxide (DMSO) 
10. Have a known history of hypersensitivity or anaphylactic reaction 
to hyaluronic acid (HA) 
11. Active malignancy or tumor as source of symptoms or history of 
malignancy within the 5 years prior to enrolment on study, except 
history of basal cell carcinoma of the skin, squamous cell 
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if fully excised and with clear margins  
12. Currently participating in another investigational trial and/or 
plans to participate in any other allogeneic stem cell/progenitor 
cell therapy trial within 36 months after study treatment 
13. Have been a recipient of prior allogeneic stem cell/progenitor cell 
therapy for any indication or autologous stem cell/progenitor cell 
therapy or other biological intervention to repair the index 
intervertebral disc 
14. An average baseline morphine equivalent dose (MED) of 
>75mg/day as determined by e-diary entries during the screening 
period 
15. Taking systemic immunosuppressants 
16. Current infection or prior history of spinal infection at the index 
level (e.g., discitis, septic arthritis, epidural abscess) or an active 
systemic infection 
17. Pain catastrophizers, defined as having a score of 30 or more on 
the Pain Catastrophizing Scale 
18. A medical condition, serious intercurrent illness, or extenuating 
circumstance that would preclude participation in the study or 
potentially decrease survival or interfere with ambulation or 
rehabilitation.  Examples of conditions that should be excluded 
are as follows: 
• history of transient ischemic attack [TIA] 
• history of stroke 
• uncontrolled diabetes 
• autoimmune disease (only if it interferes with ambulation 
or  rehabilitation) 
• muscular dystrophy 
• rheumatoid arthritis 
• active liver disease 
• upper motor neuron disease 
• myelopathy 
• disorders of bone metabolism (osteomalacia or Paget’s 
disease) 
19. Cauda equina syndrome 
20. Subjects involved in spinal litigation, including workman’s 
compensation, unless litigation is complete  
21. Currently incarcerated (prisoners) 
22. Are transient or has a severe alcohol or substance abuse problem 
defined as answering yes to 6 or more symptoms on the DSM-5 
alcohol or substance/opioid questionnaires. 
23. Unable to complete all required e-diary entries, assessments and 
follow-up according to the protocol 


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24. A history of mental illness/incompetence. Mental 
illness/incompetence is defined as meeting the following criteria 
on the DSM-5 Self-Rated Level 1 Cross Cutting Symptom 
Measure – Adult questionnaire 
a. Domain 1, Depression - A response of 4 on either question 
b. Domain 6, Suicidal Ideation - A response of 4 on the 
question 
c. Domain 7, Psychosis - A response of 1 to 4 on either 
question 
d. Domain 9, Memory - A response of 4 on the question 
25. Have a serious intercurrent medical condition or any other 
conditions or social situations that would impair the ability to 
give informed consent or unacceptably reduce protocol 
compliance or safety of the study treatment 
26. Body habitus precluding adequate fluoroscopic visualization for 
the procedure or the procedure is physically impossible due to 
inability to inject the nucleus pulposus 
27. Presence of ferromagnetic implants that would disallow MRI of 
the index disc 
28. Presence of neurologic deficit on any component of the lumbar 
neurological exam at baseline (i.e., motor, sensory, or reflex 
portion of the exam) 
29. A positive screen for human immunodeficiency virus (HIV) by 
antibodies or nucleic acid test 
30. Clinically significant nerve pain (e.g., chronic radiculopathy or 
neuropathy) 
31. Clinically significant sacroiliac joint pain based on the 
Appropriate Use Criteria established by the Spine Intervention 
Society including a targeted, pre-specified physical examination, 
and, if deemed medically necessary, confirmed by anesthetic 
injection. If a previously performed anesthetic injection to 
confirm SI joint pain was performed up to 6 months prior to 
injection (with documentation indicating that the SI joint pain is 
not the source of the subject’s pain), this does not need to be 
repeated at screening  
32. Compressive pathology due to stenosis or disc protrusion on MRI 
with associated clinical symptoms defined as leg pain 
VAS>20mm out of 100mm or neurologic deficit on neurologic 
exam 
33. Disc extrusion with a maximum dimension greater or equal to 
twice the posterior height of the disc, or disc sequestration in the 
lumbar spine on MRI as determined by radiographic core lab 
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tear of the disc), this does not need to be repeated at screening. 
Number of 
Treatment 
Arms 
Subjects will be randomly assigned to 1 of 3 treatment arms, with the 1:1:1 
chance of receiving rexlemestrocel-L alone, rexlemestrocel-L + HA, or 
saline control. 
Investigational 
Treatment 
rexlemestrocel-L alone 
Subjects enrolled in the “rexlemestrocel-L alone” arm will receive 
1 injection of approximately 6 million rexlemestrocel-L cells in freeze 
media mixed in a 1:1 by-volume ratio with saline. A vial with 2mL of 
thawed rexlemestrocel-L cells and freeze media will be mixed with 2mL 
of saline. Two milliliters of the resulting mixture will be injected via 
pressure manometer syringe into the nucleus pulposus of the index level. 
rexlemestrocel-L + HA 
Subjects enrolled in the “rexlemestrocel-L + HA” arm will receive 1 
injection of approximately 6 million rexlemestrocel-L cells in freeze media 
mixed in a 1:1 by-volume ratio with 1% hyaluronic acid (HA) solution.  A 
vial with 2mL of thawed rexlemestrocel-L cells and freeze media will be 
mixed with 2mL of 1% HA solution. Two milliliters of the resulting 
mixture will be injected via pressure manometer syringe into the nucleus 
pulposus of the index level. 
Control 
Treatment 
Saline 
Subjects enrolled in the control arm will receive a saline injection.  Two 
milliliters of thawed saline from one vial will be mixed with 2mL of 
thawed saline from another vial of saline.  Two milliliters of the resulting 
saline mixture will be injected via pressure manometer syringe into the 
nucleus pulposus of the index level.  
Blinding 
Due to the appearance, configuration, and storage conditions of 
rexlemestrocel-L, saline, and HA, it is not possible to blind treatment.  A 
separate study-specific blinding plan is provided.  A blinding plan has been 
developed to ensure that the blind has been maintained throughout the 
study and bias is not introduced into the study.  Specific methods to 
maintain the blind are detailed in the blinding plan. 
 
In order to maintain the blind, each site will have an unblinded designee(s) 
(identified by the investigator) who receives all investigational and control 
product, performs accountability, properly stores it in a secure location, 
and prepares the injection.  Additionally, the health care professional who 
is performing the study treatment injection will be unblinded.  The 
unblinded health care professional who is performing the study treatment 
injection will perform all required procedures and evaluations associated 
with the treatment injection, including neurological exam prior to 
discharge, but will not be involved with any subject care or assessment 
beyond the subject’s discharge following the injection procedure. All other 
site personnel, specifically those administering subject assessments and 


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care, will be blinded to the treatment as will the subjects, radiographic 
evaluators, and members of the study team, with the following exceptions: 
unblinded CRAs (responsible for IP reconciliation) and unblinded 
statistician(s) (responsible for providing data for the interim analyses  and 
DSMB data).  Prior to the treatment administration visit, both blinded and 
unblinded personnel can perform screening activities. 
 
Importantly, all unblinded study site personnel will be specifically 
instructed to refrain from discussing any potentially unblinding 
information with either the subject or any blinded site, sponsor, or 
CRO personnel involved in the trial.   
 
Independent blinded radiologists will be evaluating radiographic images 
for key inclusion/exclusion criteria to maintain consistency and for post-
treatment radiographic endpoints. 
 
The DSMB will be unblinded in order to assess the safety of 
investigational product (IP). 
 
The TEC performing adjudication of post-treatment interventions at the 
treated disc and relationship of adverse events to the product or procedure 
will be blinded to treatment assignment. 
 
When the unblinded statistical analyses are conducted at the primary safety 
and efficacy evaluation (the 24-month safety and efficacy evaluation 
period), study subjects, as well as site personnel responsible for subject 
care and assessment, radiographic reviewers and TEC members, will 
continue to be blinded until completion of the study at 36 months post-
treatment. 
 
An unblinded statistician will conduct the specified interim analyses and 
only the information prescribed in the SAP will be provided so as to 
maintain the blind.   
Duration of 
Treatment 
This is a one-time treatment administration. 
Follow up 
Schedule 
All subjects will be followed for 36 months post-treatment. Subjects will 
be evaluated at baseline, treatment day (Day 0), as well as Study Visits 3, 
4, 5, 6, 7, 8, and 9 (corresponding to 1, 3, 6, 12, 18, 24, and 36 months 
post-treatment).  The primary analysis of safety and efficacy will be 
assessed at Visit 8 (24 months post-treatment).  A longer-term follow-up 
of safety and efficacy will be assessed at Visit 9 (36 months post-
treatment). 
Data & Safety 
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The per-protocol (PP) analysis set will contain all subjects in the ITT who 
received treatment to which they were randomized, had at least 1 post-
treatment efficacy measurement (VAS and ODI), and did not experience 
any major protocol deviations.  
 
Protocol deviations will be determined for all randomized subjects mainly 
from the clinical database and Clinical Trial Management System (CTMS) 
following clinical and/or medical review of subject data for relevant 
findings that might have an impact on the definition of the PP analysis set/ 
major protocol violations. Protocol deviations that occur during the study 
will be adjudicated by the sponsor (or designee) and categorized by 
severity. Protocol deviations will be classified as minor or major during a 
blinded review of the data prior to the lock of the database for analysis. If 
relevant deviations are identified, they will be designated as major protocol 
violations. 
 
Safety Analysis Set  
The safety analysis set will contain all subjects who were randomized and 
received treatment, and subjects will be classified according to the actual 
treatment received. Safety analysis set will be used for the safety analyses.  
 
If there is any doubt whether a subject was treated or not, they will be 
assumed treated (randomized treatment) for the purposes of analysis. 
 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized by 
treatment arm for the ITT and PP analysis sets, as well as presented in data 
listings. 
 
Continuous variables will be summarized using descriptive statistics 
(number of subjects, mean, standard deviation, median, minimum, and 
maximum).  In order to assess baseline comparability, treatment groups 
will be compared for all continuous variables using an ANOVA between 
individual treatment and control groups.  
 
Categorical variables will be summarized using counts and percentages for 
each category.  Treatment groups will be compared for all non-missing 
categorical variables using a Chi-Square test of association.  Missing 
categories will be presented if necessary, but excluded from any tests of 
association. 
 
Statistical Methods  
Primary efficacy analysis 


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The Primary Efficacy Endpoint for overall treatment success (responder vs 
non-responder) at 12 AND 24 months will be summarized for each 
treatment arm by numbers and percentages.  Each active treatment arm 
will be compared to the saline control group using a Bayesian test of 
superiority using non-informative Beta (0.5, 0.5) priors for each arm.  
 
 
Secondary and Other Efficacy Analyses 
The same Bayesian methodology used for the primary analysis will also be 
used for the secondary endpoints. The Bonferroni-adjusted posterior 
probability threshold of 0.9875 will apply to any subsequent secondary 
analyses performed.  
 
As part of the gatekeeper strategy, the evaluation will be carried out in a 
hierarchical fashion following the order given below. Specifically, if the 
primary endpoint objective is met, the secondary outcomes will be 
evaluated hierarchically within each arm using the posterior probability 
threshold of 0.9875 for each comparison, sequentially. Once a key 
secondary endpoint is not met at this threshold within an arm, all 
subsequent comparisons in that arm will be considered exploratory.  
1. Pain Responder at both 12 AND 24 months: Measured as 
subjects meeting at least a 50% decrease from baseline in low back 
pain VAS score (average pain over 24 hours) at both Study Visit 6 
(12 months post-treatment) and Study Visit 8 (24 months post-
treatment) with no adjudicated post-treatment intervention through 
Study Visit 8. 
2. Functional Responder at both 12 AND 24 months: Measured as 
subjects meeting at least a 15-point decrease from baseline in ODI 
at both Study Visit 6 (12 months post-treatment) and Study Visit 8 
(24 months post-treatment) with no adjudicated post-treatment 
intervention through Study Visit 8. 
3. Treatment Success at 24 months: Measured as subjects meeting 
each of the following criteria at Study Visit 8 (24 months post-
treatment): 
a. at least a 50% reduction from baseline in low back pain 
VAS score (average pain over 24 hours); AND 
b. at least a 15 point decrease from baseline ODI score; AND 
c. no interventions at the treated level 
4. Minimal Pain Responder at 24 Months: Measured as subjects 
meeting low back pain VAS score (average pain over 24 hours) of 
20mm or less at Study Visit 8 (24 months post-treatment) with no 
adjudicated post-treatment intervention through Study Visit 8. 
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prior to the date of Study Visit 8 (24 months), this subject will be 
considered a non-responder regardless if there is any missing data. For 
example, a subject that has a post-treatment intervention at the treated level 
at the time of Study Visit 4 (3 months) would be considered a non-
responder regardless of whether there are Visit 6 or Visit 8 data available 
for analysis, as they would have already failed one of the criteria to be 
considered a responder. 
 
If a subject has data available at both Study Visit 6 (12 months) and Study 
Visit 8 (24 months), with no post-treatment intervention at the treated level 
as of the date of Study Visit 8, that subject will be determined either a 
responder or non-responder based upon whether or not the subjects meets 
the pain and functional improvement criteria at both study visits.   
 
Any subject that is missing one or more components in an endpoint (e.g. 
VAS in the primary endpoint) at a visit will be considered a non-responder 
at that visit if any available component of the endpoint indicates that the 
subject is a non-responder (even if all components of the endpoint are not 
available). If none of the available components impose non-response, the 
outcome will be considered missing and will be handled according to the 
proposed methodology described below. 
 
Assumptions regarding responder analyses include the following: 
• If the subject does not meet the criteria of either pain or function at 
either Visit 6 or Visit 8, the subject will be considered a non-
responder.   
• If the subject meets the pain and function improvement criteria at 
both Visit 6 and Visit 8, and has no post-treatment intervention as 
of the date of Visit 8, the subject will be considered a responder. 
• Any subject that is a non-responder on one of the two primary 
study visits (Visit 6 or Visit 8) but has a missing outcome for the 
other study visit is deemed a non-responder and not considered to 
have a missing outcome for the primary analysis. 
• If a subject does not have a minimum of a visit at 3-months (Study 
Visit 4) they will be considered a non-responder.  
• Any subject that has a minimum of 3-months data (Study Visit 4) 
but is missing one or both of the two primary study visits, will have 
their outcome multiply imputed based on their available 
information. Separate models will be constructed for 
o Subjects that are missing one of the two primary  study 
visits (Visit 6 or Visit 8) but not both; 
o Subjects that are missing both of the primary study visits. 
 


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A detailed description of the statistical methodology for multiple 
imputation of missing data for responder analyses can be found in the 
SAP. 
 
For subjects who have a post-treatment interventional procedure at the 
treated level, the analyses of continuous and categorical efficacy variables 
will include only data collected before the post-treatment adjudicated 
intervention.   
 
MMRM will be used for the analysis of over time of quantitative variables 
and missing data will not be imputed.  
 
Examination of Subgroups 
Pre-specified subgroup analyses based on both the ITT and PP analysis 
sets for the primary and secondary efficacy variables will be performed for 
key demographic and baseline variables, as described in the SAP. 
 
 


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TABLE OF CONTENTS 
 
INVESTIGATOR’S SIGNATURE ..................................................................................2 
PROTOCOL SYNOPSIS ..................................................................................................3 
LIST OF TABLES ...........................................................................................................41 
LIST OF FIGURES .........................................................................................................41 
LIST OF APPENDICES .................................................................................................41 
GLOSSARY OF ABBREVIATIONS ............................................................................43 
1. 
BACKGROUND .......................................................................................................46 
1.1 
Degenerative Disc Disease and Low Back Pain .............................................46 
1.2 
Current Treatment Options for Low Back Pain ..............................................47 
 
48 
 
49 
 
50 
 
51 
 
52 
 
53 
1.6 
Study Rationale ...............................................................................................58 
1.6.1 
Rationale for the Study ....................................................................58 
1.6.2 
Rationale for Study Design ..............................................................59 
1.6.3 
Rationale for Dosing Regimen and Treatment Period .....................59 
1.7 
Risk/Benefit Summary ....................................................................................59 
1.7.1 
Reaction to Dimethyl Sulfoxide .......................................................60 
1.7.2 
Potential Cell Contamination ...........................................................60 
1.7.3 
Tumor Development ........................................................................61 
1.7.4 
Potential Inflammatory Responses ..................................................61 
1.7.5 
Effects on Treated and Adjacent Levels ..........................................61 
1.7.6 
Possible Effects of Cells on Fetus ....................................................62 


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1.7.7 
Radiation Exposure ..........................................................................62 
1.7.8 
Lumbar Disc Injection/Discography Risks and Complications .......63 
1.7.9 
Subsequent Surgical Interventions ...................................................65 
2. 
STUDY OBJECTIVES ............................................................................................65 
2.1 
Primary Efficacy Objective ............................................................................65 
2.2 
Secondary Efficacy Objectives .......................................................................66 
 
66 
 
68 
2.5 
Primary Safety Objective ................................................................................68 
 
69 
 
 
69 
 
69 
 
69 
 
.69 
3. 
STUDY DESIGN ......................................................................................................70 
3.1 
Overview of Study Design ..............................................................................70 
3.2 
Dosing Regimen .............................................................................................75 
3.3 
Study Sites ......................................................................................................76 
4. 
STUDY ANALYSIS SET .........................................................................................76 
4.1 
Overview .........................................................................................................76 
4.2 
Eligibility Criteria ...........................................................................................76 
4.2.1 
Inclusion Criteria .............................................................................76 
4.2.2 
Exclusion Criteria ............................................................................77 
4.3 
Information to be collected for Screen Failures and Randomized 
Not-treated Subjects ....................................................................................................81 
4.4 
Re-screening ...................................................................................................82 
4.5 
Subject Withdrawal ........................................................................................83 
4.6 
Withdrawal Procedure ....................................................................................83 


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4.6.1 
Lost to Follow-Up ............................................................................84 
4.7 
End of Study ...................................................................................................84 
5. 
INVESTIGATIONAL PRODUCT .........................................................................85 
5.1 
Investigational Product Labeling ....................................................................85 
5.2 
Description of Investigational Product ...........................................................85 
5.2.1 
Active Treatment .............................................................................85 
5.2.2 
Control Agent...................................................................................85 
5.3 
Investigational Product Storage ......................................................................86 
5.4 
Investigational Product Preparation and Administration ................................86 
5.4.1 
rexlemestrocel-L ..............................................................................86 
5.4.2 
All Investigational Product ..............................................................86 
5.4.3 
Investigational Product Handling and Accountability .....................87 
5.5 
Maintenance of the Treatment Blind ..............................................................87 
5.6 
Treatment Compliance ....................................................................................88 
6. 
STUDY PROCEDURE ............................................................................................89 
6.1 
Visit Schedule and Assessments .....................................................................89 
6.1.1 
Screening Period ..............................................................................94 
6.1.2 
Randomization .................................................................................95 
6.1.3 
Safety and Efficacy Evaluation Period (Day 0 to 24 Months 
Post-treatment) ................................................................................................95 
6.2 
Unscheduled Visits .........................................................................................96 
6.3 
Missing or Delayed Study Visits ....................................................................97 
6.4 
Screening Assessments ...................................................................................97 
6.4.1 
Subject Demographics/Other Baseline Characteristics ...................97 
6.4.2 
Pre-Treatment Pain Medication Usage Collection by E-Diary ........98 
6.4.3 
Prohibited Concomitant Medication and Procedures ......................98 
6.4.4 
Concomitant Treatments ..................................................................99 
6.4.5 
Determination of Baseline Bone Mineral Density ...........................99 


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6.4.6 
Determination of Baseline SI Joint Pain ........................................100 
6.4.7 
Pregnancy Tests .............................................................................101 
 
101 
6.4.9 
Worksheets for DSM-5 Criteria for Alcohol and Substance 
Abuse Disorder .............................................................................................102 
6.4.10 
Mental Illness/Incompetence .........................................................102 
6.4.11 
Pain Catastrophizer Scale ..............................................................103 
6.4.12 
Discography, if performed .............................................................103 
6.5 
Administration of Investigational Product ....................................................103 
6.6 
Safety Assessments .......................................................................................105 
6.6.1 
Prior and Concomitant Medication and Treatment ........................105 
6.6.2 
Post-treatment Interventions at the Treated Level .........................106 
6.6.3 
Neurological Examination .............................................................108 
6.6.4 
Disease-targeted, Abbreviated Physical Examination ...................110 
6.6.5 
Vital Signs ......................................................................................110 
6.6.6 
Height and Weight .........................................................................110 
6.6.7 
MRI Scans and X-rays ...................................................................111 
6.6.8 
Visual Analog Scale for Leg Pain Assessment ..............................112 
6.6.9 
Laboratory Evaluations ..................................................................112 
6.7 
Efficacy Assessments ...................................................................................113 
6.7.1 
Post-treatment Interventions Affecting the Treated Disc ..............113 
6.7.2 
Visual Analog Scale for Low Back Pain Evaluation .....................113 
6.7.3 
Oswestry Disability Index..............................................................114 
6.7.4 
Radiographic Evaluations ..............................................................115 
6.7.5 
iPCQ, SAT, EQ5D, and Patient-reported Utilization 
Questionnaires ..............................................................................................117 
6.7.6 
Post-Treatment Pain Medication Usage Collected by E-Diary .....117 
7. 
SAFETY GUIDANCE ............................................................................................121 
7.1 
Definitions ....................................................................................................121 


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7.1.1 
Adverse Event ................................................................................121 
7.1.2 
Serious Adverse Event (Reportable to the Sponsor within 
24 Hours) ......................................................................................................121 
7.1.3 
Severity ..........................................................................................122 
7.2 
Relationship of Adverse Event to Study Treatment or Study Procedure .....122 
7.3 
Adverse Events of Special Interest – Back Pain ...........................................123 
7.4 
Treatment and Follow-up of AEs and SAEs ................................................123 
7.5 
Laboratory Test Abnormalities .....................................................................124 
7.6 
Unblinding ....................................................................................................125 
8. 
REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ....125 
8.1 
Reporting of Serious Adverse Events [Immediately Reportable] ................125 
8.2 
Procedures for Reporting Pregnancies ..........................................................126 
8.3 
Expedited Reporting to Health Authorities, Investigators, IRBs, and ECs ..126 
9. 
STATISTICAL CONSIDERATIONS ..................................................................127 
9.1 
General Considerations .................................................................................127 
9.2 
Sample Size and Randomization ..................................................................128 
9.3 
Analysis Analysis sets ..................................................................................129 
9.3.1 
All Enrolled Subjects Analysis Set ................................................129 
9.3.2 
Intent-to-Treat (ITT) Analysis Set .................................................129 
9.3.3 
Full Analysis Set (FAS) .................................................................129 
9.3.4 
As Treated Analysis Set .................................................................129 
9.3.5 
Per Protocol (PP) Analysis Set ......................................................130 
9.3.6 
Safety Analysis Set ........................................................................130 
9.4 
Efficacy Endpoints ........................................................................................130 
9.4.1 
Primary Efficacy Endpoint ............................................................130 
9.4.2 
Secondary Efficacy Endpoints .......................................................131 
 
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9.6 
Statistical Methods ........................................................................................140 
9.6.1 
Demographic and Other Baseline Characteristics .........................140 
9.6.2 
Primary Efficacy Analysis .............................................................141 
9.6.3 
Secondary and Other Efficacy Analyses........................................141 
9.7 
Safety and Other Analyses ............................................................................144 
9.7.1 
Primary Safety Endpoint ................................................................144 
 
145 
 
146 
9.8 
Interim Analyses ...........................................................................................147 
9.9 
Handling of Missing Values, Early Termination, or 
Non-Interpretable Data .............................................................................................148 
9.10 
Subgroups .....................................................................................................149 
10.
DATA COLLECTION, MANAGEMENT AND QUALITY
ASSURANCE .................................................................................................................149 
10.1 
Investigator's Files/Retention of Documents ................................................150 
10.2 
Source Documents and Background Data ....................................................152 
10.3 
Electronic Case Report Forms ......................................................................152 
10.4 
Other Electronic Data ...................................................................................153 
10.5 
Coding of Medical Terms .............................................................................153 
10.6 
Audits and Inspections ..................................................................................153 
11.
MONITORING OF STUDY ......................................................................153 
12.
STUDY COMMITTEES ............................................................................154 
12.1 
Independent Data and Safety Monitoring Board (DSMB) ...........................154 
12.2 
Treatment Events Committee .......................................................................155 
12.2.1 
Post-treatment Interventions at the Treated Level .........................155 
13.
LAWS, REGULATIONS, AND ETHICS ................................................157 
13.1 
Local Regulations/Declaration of Helsinki ..................................................157 
13.2 
Informed Consent .........................................................................................157 
13.3 
Institutional Review Board/ Ethics Committees (IRB/EC) ..........................158 


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13.4 
Protocol Adherence ......................................................................................159 
14. 
CONDITIONS FOR MODIFYING THE PROTOCOL .........................159 
15. 
CONDITIONS FOR TERMINATING THE STUDY .............................159 
15.1 
Early Termination of Study ..........................................................................160 
15.2 
Early Termination of a Study Site ................................................................160 
15.3 
Study Stopping Rules Based on Safety Monitoring .....................................160 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND 
SUBJECT RECORDS ...................................................................................................161 
17. 
PUBLICATION POLICY ..........................................................................161 
18. 
REFERENCES ...........................................................................................162 
19. 
APPENDICES .............................................................................................167 
 
LIST OF TABLES 
.50 
Table 2:  Procedures Considered Treatment Interventions at the Treated Level ...............74 
Table 3:  Schedule of Assessments and Proceduresa .........................................................90 
Table 4:  Physical Examination for Evaluation of SI Joint Pain ......................................100 
Table 5:  Laboratory Parameters ......................................................................................112 
118 
120 
128 
134 
137 
 
LIST OF FIGURES 
55 
56 
Figure 3:  Diagram of Study Design ..................................................................................70 
 
LIST OF APPENDICES 
168 
Appendix 2:  Visual Analogue Scale (VAS): average low back pain, worst back pain, 
average leg pain .........................................................................................169 
Appendix 3:  Oswestry Disability Index (ODI) ...............................................................170 


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Appendix 4:  iMTA Productivity and Cost Questionnaire (iPCQ) ..................................171 
Appendix 5:  Subject Self-Assessment of Treatment (SAT) ...........................................172 
Appendix 6:  Euroqol-5D (EQ-5D) .................................................................................173 
Appendix 7:  Patient-reported Utilization Questionnaire ................................................174 
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GLOSSARY OF ABBREVIATIONS  
ACR 
Albumin-to-creatinine ratio 
ADA 
American Diabetes Association 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT [SGPT] 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
A/P 
Anterior/posterior 
AST [SGOT] 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BMI 
Body mass index 
BOCF 
Baseline observation carried forward 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
cABC 
Chondroitinase ABC 
CCS 
Composite clinical success 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CK 
Creatine kinase 
CLBP 
Chronic Low(er) Back Pain 
CMH 
Cochran Mantel Haenszel (test) 
CRF 
Case report form 
CRT 
Cardiac Resynchronization Therapy 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
CV 
DAS28 
Common Terminology Criteria for Adverse  Events 
Cardiovascular 
Disease Activity Score in 28 Joints 
DBP 
Diastolic blood pressure 
DCS 
Data collection specification 
DDD 
Degenerative disc disease 
DEXA 
Dual-energy X-ray absorptiometry (scan) 
DLCO 
Diffusing capacity for carbon monoxide 
DCSI 
Development Core Safety Information (document) 
DMC 
Data Monitoring Committee 
DMSO 
DSMB 
Dimethyl sulfoxide 
Data Safety Monitoring Board 
EAC 
Events Adjudication Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form(s) 


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GLOSSARY OF ABBREVIATIONS  
EDC 
Electronic data capture 
EEA 
EOT 
European Economic Area 
End of Treatment 
eGFR  
Estimated glomerular filtration rate 
eform 
Electronic form (page) 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
γ-GT 
Gamma-glutamyl transpeptidase 
GCP 
Good clinical practice 
GFR 
Glomerular filtration rate 
HA 
Hyaluronic acid 
HbA1c 
Glycosylated hemoglobin  
Hct 
Hematocrit 
HDL 
High density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
HLA 
Human leukocyte antigen 
HR 
Heart Rate 
hsCRP 
High sensitivity C-reactive protein 
IB 
ICD 
Investigator’s Brochure 
Implantable Cardioverter Defibrillator 
ICH 
IEC 
International Conference on Harmonization 
Independent Ethics Committee 
IL 
Interleukin 
IP 
Investigational product 
IND 
Investigational New Drug  
INN 
International Non-Proprietary Name 
iPCQ 
iMTA Productivity and Cost Questionnaire 
IRB 
Institutional Review Board 
ISF 
Investigator’s Study File  
ITT 
Intent to treat  
IVD 
Intervertebral disc 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LOCF 
Last Observation Carried Forward 
MED 
MPC 
Morphine equivalent dose 
Mesenchymal precursor cells 
MDRD 
Modification of Diet in Renal Disease 
mITT 
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GLOSSARY OF ABBREVIATIONS  
MedDRA 
Medical Dictionary for Regulatory Activities 
MORES 
Male Osteoporosis Risk Estimation Score 
MPC 
Mesenchymal precursor cell 
MRI 
Magnetic resonance imaging 
MSC  
Mesenchymal stem cells 
MTX 
Methotrexate 
NIH 
NSAID 
National Institutes of Health 
Non-Steroidal Anti-inflammatory Drugs 
NYHA 
New York Heart Association 
PFT 
Pulmonary Function Testing 
PHI 
Personal health information 
PP 
Per protocol analysis set 
PRA 
Panel reactive antibody 
PRP 
Platelet-rich plasma 
PT/INR 
Prothrombin time/International normalized ratio 
QSI 
QMA® Stability Index 
RANKL 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
RBC 
Red blood cell 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAT 
Self-assessment of Treatment (Questionnaire) 
SBP 
Systolic blood pressure 
SEM 
Standard Error of Mean 
SMBG 
Self-monitored blood glucose  
SMT 
SPC 
Study Management Team 
Summary of Product Characteristics 
SUSAR 
T2DM 
TG 
Suspected Unexpected Serious Adverse Reaction 
Type 2 Diabetes Mellitus 
Triglycerides 
TEC 
Treatment Events Committee 
TNF-α 
Tumor necrosis factor-α 
TPDR 
Translation per degree rotation 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 
 


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1. 
BACKGROUND  
1.1 
Degenerative Disc Disease and Low Back Pain 
The degenerative process in the disc, unlike many other tissues begins as early as the second 
decade of life. 1-6  Degeneration of the intervertebral disc(s), commonly referred to as 
Degenerative Disc Disease, is consistent with advancing age, and in many cases is also 
associated with pain (particularly in the lumbar spine)7 and biomechanical  
instability. 8-14  Currently, it is unknown what factors serve as an initiating event of painful 
degeneration, but genetic predisposition, smoking, infection, abnormal biomechanical loading, 
decreased nutrient transport across the vertebral endplates and ageing are implicated. 3,15,16 
 
Degenerative changes are believed to begin in the nucleus pulposus with cellular loss causing an 
imbalance in the anabolic to catabolic processes leading to net proteoglycan breakdown and the 
associated diminished water binding capacity. 10,15,17  This places abnormal compressive forces 
on the annulus fibrosus that cause damage resulting in cracks, tears and fissures. 9,12-14,18  
 
It has been hypothesized that an event secondary to a structural deficit, such as injury or leakage 
of nucleus pulposus material through annular fissures, is likely to result in recruitment of 
immune cells to the disc, which then triggers pain generation. 15  This is consistent with a theory 
that low back pain is associated with inflammation in the disc. 8,10,11, 15,16,19  As the annulus 
fibrosus begins to have more cracks and fissures, the inflammatory mediators come into contact 
with the nerves in the outer portion of the annulus potentially causing pain. 8,10,11, 15,16,19  This 
causes infiltration of immune cells, blood vessels and nerve fibers further into the disc in an 
attempt to repair the disc. However, this attempted reparative process further exposes the disc to 
increasing inflammatory mediators. 8,10,11, 15,16,19  The inflammatory mediators interact in a 
complex way to induce, enhance and propagate persistent pain. 19  Eventually, the degradative 
cascade causes the native cells to undergo phenotypic changes, senescence and apoptosis, which 
further reduces any anabolic capability of the disc.  8,10,11, 15,16  
 
The resultant low back pain from disc degeneration represents a substantial social and economic 
burden to the community as well as adding to one’s long-term physical disability and reduced 
quality of life. It is estimated that as much as 80% of the analysis set experiences at least one 
significant episode of low back pain during life and approximately 2.5% of the working analysis 
set will take some sick leave during the year as a result of low back pain.  The direct costs of low 
back pain in modern western countries has been estimated at billions of dollars, most of which is 
spent on consulting general practitioners, physical therapists and other conservative practitioners. 
20,21  Total indirect expenditure, including surgical management, may be ten times higher. 22 


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1.2 
Current Treatment Options for Low Back Pain 
For most patients with low back pain, symptoms resolve with over-the-counter (OTC) 
medication(s), rest and activity modification.  However for approximately 10% of patients, low 
back pain becomes chronic, which is defined as lasting 3 months or more in duration.  For these 
patients, current treatments include: 
• Conservative treatments: non-steroidal anti-inflammatory drugs (NSAIDs), aniline 
analgesics, physical therapy, and alternative therapies (including chiropractic treatments, 
acupuncture, serotonin-norepinephrine reuptake inhibitors, and anticonvulsants)  
• Opioids: short-acting combination opioid analgesics, long-acting opioids  
• Interventional therapy: epidural steroid injections (ESI), intrathecal pumps, surgically 
implanted spinal cord stimulation   
• Surgery: spinal fusion, artificial disc implantation. 
 
Conservative treatments are standard of care for acute and early chronic low back pain associated 
with degenerative changes of the disc.  Patients with moderate to severe chronic low back pain 
with degenerative changes of the disc, who fail to respond to conservative treatment, typically 
receive short-acting combination opioid analgesics, long-acting opioids, or interventional 
therapies.  Any of these therapies may be used in conjunction with conservative treatments.  
Opioids present a risk of tolerance and other safety concerns which limits their use in terms of 
dosage and duration, and prevents their use in certain analysis sets.  
 
In addition, it is important to note that the rationale that underlies the use of opioids in patients 
with chronic low back pain assumes that these agents are effective for improving pain severity 
and/or functional status.  However, recently this assumption has been challenged by numerous 
published reports which have questioned their therapeutic effectiveness.  23- 25 
 
For patients with long-term chronic low back pain and severe degenerative changes of the disc 
(black disc on MRI with 50% disc height loss), who have failed other therapies, surgery is the 
only choice.  While some patients with CLBP and severe disc degeneration receive pain relief 
and functional benefit from fusion or disc replacement, some do not.  Equally concerning in 
selecting fusion as an option is the potential for surgical complications, such as bleeding, 
infection, nerve damage, or non-unions (fusion failure) and altered spine biomechanics that could 
exacerbate degeneration at adjacent levels.  
There is an unmet need for a therapy that has the ability to reduce a patient’s low back pain, 
improve function and reverse, halt or slow the progression of degeneration of the disc.  Current 


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therapies are only palliative and the underlying cause of pain, the degenerating disc, continues to 
progress until the pain is no longer manageable or reduced function causes a sufferer to elect for 
surgical intervention.  As such, spine fusion and artificial disc replacement procedures continue 
to grow despite their invasiveness.  
 
 
  
 
 
 
 
   
 
 
 
 
 
 
   
 
  
 
   
 
   
 
    
 
 
    
 
 
 
 
 
 
 
 
 
   
 
  




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1.6 
Study Rationale 
1.6.1 
Rationale for the Study  
As previously discussed in Section 1.2, surgical intervention is currently the only means of 
arresting the progression of disc degeneration and associated low back pain. Results from the 
Phase 1b/2 study (MSB-DR001) have shown that a single injection of rexlemestrocel-L into the 
degenerated lumbar disc associated with CLBP is safe and tolerable for subjects.  Furthermore, 
clinically significant improvements in lower back pain and daily function are evident up to 
24 months post-injection with rexlemestrocel-L.  
 
Efficacy endpoints from the Phase 1b/2 study were exploratory; therefore, this subsequent 
Phase 3 study will serve to confirm these findings, particularly those from the Phase 1b/2 
“responder analyses.”  
 
 


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1.6.2 
Rationale for Study Design 
This Phase 3 study will consist of 3 treatment arms: 1) rexlemestrocel-L alone, 2) 
rexlemestrocel-L + HA, and 3) saline control.  Results from Study MSB-DR001 study 
demonstrated that saline control and HA control performed similarly in terms of safety and 
efficacy; therefore only the saline control will be used in this study.  Furthermore, the inclusion 
of the rexlemestrocel-L alone arm will determine a) whether or not HA has any synergistic effect 
when combined with rexlemestrocel-L and b) whether or not any benefit is demonstrated solely 
with the use of rexlemestrocel-L.  
 
1.6.3 
Rationale for Dosing Regimen and Treatment Period 
The dose of rexlemestrocel-L (approximately 6 million rexlemestrocel-L cells, also referred to as 
“6 million rexlemestrocel-L cells”) used in this study is based on that used in the Phase 1b/2a 
study, MSB-DR001.  Efficacy and safety results were generally similar between this “low dose” 
and the “high-dose” of 18 million rexlemestrocel-L cells, with the high-dose offering no 
consistent improvement in treatment effect.  For the proposed primary endpoint, the 6 million 
rexlemestrocel-L group had 12 subjects (44.4%) who met the primary endpoint while 11 subjects 
(37.9%) in the 18 million rexlemestrocel-L group met the primary endpoint.  There was no 
significant difference between the two MPC-treated groups, though the 6 million rexlemestrocel-
L group was significantly better when compared to saline (p=0.044), while the 18 million 
rexlemestrocel-L group did not reach statistical significance (p=0.090).  The safety profiles of 
the two rexlemestrocel-L groups were similar; however, the 18 million rexlemestrocel-L group 
had a greater proportion of subjects (27%) with reports of back pain within 7 days after injection 
compared to 0%, 5% and 3% in the saline, HA and 6 million rexlemestrocel-L groups, 
respectively.   
  
1.7 
Risk/Benefit Summary 
There are certain known risks associated with lumbar disc injection, expected risks with products 
that are used in the production of the rexlemestrocel-L, and potential risks related to allogeneic 
MPCs.  
 
These risks include the following: 
The administration of allogeneic MPCs may elicit immunogenic and/or inflammatory responses 
resulting from allogeneic exposure to the donor cells and/or manufacturing content.  In a 
previous Phase 2 clinical study in subjects with heart failure (Study HF-AB002), 11% of exposed 
subjects developed donor specific anti-HLA antibodies.  The incidence of anti-bovine or anti-


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murine antibodies is substantially less.  To date, no clinical signs or symptoms have been 
associated with the development of antibodies to HLA, bovine, or murine proteins.   
 
MPCs are a STRO 3–positive subanalysis set of mesenchymal stem cells (MSCs), and thus the 
safety experience with MSCs may be predictive of actions with MPCs.  Studies have 
demonstrated that human MSCs have a non-immunogenic phenotype and, by avoiding allo-
recognition, represent a potentially advantageous cell type for transplantation into an allogeneic 
host without the need for HLA matching or immunosuppression.  MPCs are highly similar to 
MSCs in that they not only lack HLA class II surface antigens and co-stimulatory molecules 
(CD86, CD80), but also exert in vitro immunomodulatory effects on T-lymphocyte activation 
and function. 
 
The risks of exposure to MPCs are not fully known but there is the theoretical risk that 
subsequent allogeneic transplant donor selection may be limited in the presence of persistent, 
cross-match reactive anti-HLA antibodies.  However, data from multiple exposures to other 
mesenchymal lineage cells suggest that this is not a clinically important issue. 
 
Additionally, for immunoselection of the allogeneic MPCs, the technology incorporates an 
antibody-based sorting process using murine-derived antihuman antibody.  In the cell expansion 
process, fetal calf serum is used.  Therefore there is the risk of a hypersensitivity reaction to 
these murine and/or bovine products.  The risk of sensitization from this formulation is unknown, 
but expected to be rare.  
 
1.7.1 
Reaction to Dimethyl Sulfoxide 
Dimethyl sulfoxide 7.5% is used as part of the rexlemestrocel-L cryopreservation process.  The 
therapeutic and toxic effects of DMSO include its own rapid penetration and enhanced 
penetration of other substances across biologic membranes, free radical scavenging, and effects 
on coagulation, anticholinesterase activity, and DMSO-induced histamine release by mast cells.  
The systemic toxicity of DMSO is considered to be low.  The DMSO exposure in this therapy is 
minimal and is locally applied. Subjects with hypersensitivity to DMSO will be excluded from 
study. 
 
1.7.2 
Potential Cell Contamination 
Rexlemestrocel-L is an allogeneic, immunoselected, ex-vivo expanded cell product which has the 
potential to become contaminated and subsequently cause infection in the study subject at the 
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Manufacturing Practice (GMP)-compliant production facility.  Prior to the release of 
rexlemestrocel-L from the GMP facility, rigorous screening tests for multiple infectious agents 
are performed in order to ensure that no contaminated product is released for use.  As with any 
blood or marrow-derived biological agent, infectious risks from unknown pathogens are 
possible. 
 
1.7.3 
Tumor Development 
MPCs such as rexlemestrocel-L are living cells that have undergone ex vivo expansion; therefore 
there is a theoretical risk that these cells could directly or indirectly cause the formation of 
unwanted tissue growth or a tumor.  Engraftment of MPCs has not been demonstrated in any 
preclinical or clinical setting to date.  The risk of tumor development is further minimized by 
testing each new cell bank used in clinical trials for tumor formation potential in animals.  To 
date, testing of these cells in animals has not revealed tumor formation or any unwanted tissue 
growth.  To minimize the theoretical risk of tumorigenesis and taking into consideration 
indication specific risk-benefit, subjects with a prior history of malignancy, with the exception of 
certain treated cancers such as skin cancer and carcinoma in situ, are excluded.  
 
1.7.4 
Potential Inflammatory Responses 
As with many cellular biologics, allogeneic MPCs may elicit immunogenic and/or inflammatory 
responses resulting from the allogeneic exposure to the donor cells and/or manufacturing 
content.  To date, no clinical signs or symptoms have been associated with the development of 
antibodies to bovine, murine, or HLA proteins.  The risks of exposure are not fully known but 
there is a remote potential risk that subsequent allogeneic transplant donor selection may be 
limited in the presence of persistent, cross-match reactive anti-HLA antibodies.  Subjects will be 
monitored for these responses by performing antibody-screening tests for HLA at designated 
follow-up visits. 
 
1.7.5 
Effects on Treated and Adjacent Levels 
It is unknown at this time what the long-term effects of injection of rexlemestrocel-L are.  There 
is the potential that over the longer-term, adverse effects on the disc or adjacent vertebral bodies, 
such as osteolysis or Schmorl’s nodes, could develop.  Through 24 months, no significant 
adverse effects on the treated disc or surrounding structures, such as the adjacent vertebral bodies 
or neurologic structures, were observed in the Phase 2 clinical study.  
 


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It is unknown what if any effects injection of rexlemestrocel-L, hyaluronic acid or any other 
substance may have on adjacent level(s).  Although, no significant changes in the adjacent levels 
after injection of rexlemestrocel-L with hyaluronic acid in the Phase 2 study were seen. 
 
Adverse effects on the disc or adjacent vertebral bodies of the treated or adjacent levels could 
cause additional or recurrent pain and reduced function that could require treatment through 
medication and/or interventional procedures such as additional injections or surgery to correct 
the degeneration of the index or adjacent level(s). 
 
1.7.6 
Possible Effects of Cells on Fetus 
Because of potential or unknown side effects of the study on the fetus, if the subject is a female 
of childbearing potential, the subject must have a negative pregnancy test prior to receiving study 
treatment.  In addition, females of childbearing potential will be included in study participation 
provided that they use adequate contraception (hormonal or barrier method or abstinence) from 
the time of screening and for a period of 24 months after study treatment. 
 
In the event that the study subject is confirmed to be pregnant during the study, the investigator 
must immediately notify the Clinical Research Associate and the Sponsor’s Medical Monitor 
about the pregnancy and record it on the Pregnancy CRF.  In addition, the investigator must 
report to the Sponsor follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome.  The study subject will continue to be monitored for the duration 
of the study. 
 
1.7.7 
Radiation Exposure 
X-rays will be performed at screening, 1, 3, 6, 12, 18, 24 and 36 months post-treatment.  There is 
also radiation exposure associated with the image amplifying during the preliminary diagnostic 
injection (for confirmation of full thickness annular tears) and at the time of treatment injection. 
 
The primary risk to the subjects enrolled in this study is radiation due to the X-ray scans required 
for this study.  The total estimated radiation dose for a subject that undergoes all study-required 
imaging is expected to be approximately 19.2 mSv.  Based on a large study of cancer risk 
associated with exposure to radiation, it was estimated that the excess relative risk for cancer is 
0.97 per Sv. 35 The excess relative risk of the radiation that each subject would receive from 
participation in this study is therefore 0.97/Sv * 19.2 mSv * 1 Sv/1000 mSv = 18.6 x 10-3.  To 
help place the radiation risk estimate for this study into perspective, a person will be exposed to 
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is exposed to approximately 3 mSv/year from background radiation. 37  Therefore, the effective 
radiation dose for subjects is approximately equivalent to 6.4 years of the natural environmental 
background radiation for the average US citizen. 
The FDA web site suggests that 10 mSv of radiation (a typical CT exam) would increase the 
possibility of fatal cancer by 1 chance in 200038 based on statistical calculations using data 
collected about Japanese atomic bomb survivors.  There are no direct data on the risks from 
clinical x-rays in adult patients. The actual risk is difficult to determine since 1/4 to 1/5th of all 
people will die from cancer39, with wide variations between communities and lifestyles.  
 
The American Association of Physicists in Medicine (AAPM) states that "[r]isks of medical 
imaging at effective doses below 50 mSv for single procedures or 100 mSv for multiple 
procedures over short time periods are too low to be detectable and may be nonexistent." 40 
 
1.7.8 
Lumbar Disc Injection/Discography Risks and Complications 
The complication rate of intravertebral disc injection is comparable to the complications 
associated with discography.  The complications associated with discography are low, and is 
accepted to be less than 1%.  
 
Although very unlikely, there is the potential that insertion of the spinal needle into the disc 
could damage adjacent visceral and/or neurologic structures as it is passed into the disc.  
Additionally, it is possible that the tip of the needle may not be placed into the nucleus pulposus 
of the disc.  This could result in the product not being able to perform its intended function or 
impacting surrounding structures.  This could lead to continued pain and functional deficit or 
even a worsening of symptoms.  The potential for inadvertent damaging of surrounding 
structures and/or misplacing the product is minimized by the use of fluoroscopy to provide real 
time imaging of the placement and path of the needle.  Furthermore, the use of trained and 
experienced physicians that routinely perform intra-discal procedures such a discography further 
reduces the likelihood of damaging adjacent structures and/or misplacing the product upon 
injection. 
 
In a retrospective analysis of 10 discography studies in which prophylactic antibiotics were not 
given, an infection rate of 0.25% in 4891 subjects and 0.094% in 12,770 discs was found, with 
the conclusion that the risk of post-discography discitis was minimal. 41  The most serious and 
frequently encountered complication is discitis.  One subject who received an injection of 
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The incidence of infection can be decreased with the use of double needles and styleted  
needles. 42,43  Many practitioners prophylactically administer broad-spectrum antibiotics as a 
precaution against possible discitis. 44-47  
Nerve damage may also occur but usually causes only transient symptoms.  Transthecal puncture 
may result in post-procedural headache.  Other possible complications are needle breakage, 
accidental intra-dural injection, intrathecal hemorrhage, meningitis, arachnoiditis, osteomyelitis, 
and epidural abscess.  
 
Some publications have shown that injections in the disc do not cause injury to the disc itself.48,49 
However, some recent literature has suggested that lumbar intradiscal injections, such as in 
discography, can result in disc degeneration.  Carragee et al.50 performed a 10-year matched 
cohort study comparing progression of common degenerative findings between lumbar discs 
injected 10 years earlier with those same disc levels in matched subjects not exposed to 
discography.  They found that over the 10-year follow-up period, discs that had been exposed to 
puncture and injection had greater progression of degenerative findings compared to control 
discs, greater progression of disc degeneration, increased rate of disc herniation, and greater loss 
of disc height and disc signal intensity.  
 
Other potential complications from intra-discal injection and/or discography include 
intravascular uptake, bleeding, epidural abscess, allergic contrast reaction, subarachnoid 
puncture, and meningitis.51  
 
Additionally, it is possible that rexlemestrocel-L and HA may leak from the intervertebral disc 
during or after the injection procedure.  Although, the risk is very low since each subject must 
undergo an injection of contrast media to demonstrate that there is no full thickness tear in the 
disc through which injected substances may leak outside of the disc.  If some or all of the 
rexlemestrocel-L leaks out of the intervertebral disc, it may reduce or prevent repair of the 
intervertebral disc and thereby potentially fail to relieve the subject’s back pain.  The effect of 
rexlemestrocel-L and/or hyaluronic on structures of the spine outside of the disc has not been 
studied.  There is a potential risk that the rexlemestrocel-Land/or hyaluronic acid could leak out 
and damage nearby neurologic structures that could cause a neurologic deficit requiring surgical 
intervention to correct.  There are no anticipated risks with saline leakage. 
 
Hyaluronic Acid:  
Hyaluronic acid is commonly used as viscosupplementation for knee osteoarthritis and is 
administered as an intra-articular injection in the knee.  There is a low incidence of mild to 
moderate adverse events local to the injection site. 52  These events usually resolve within 1 to 


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3 days, with minimal to no treatment.  The most common reactions are local knee joint pain and 
injection site pain. 53-58  Other common injection-related events include joint swelling/effusion, 
53-55, 57,58 joint stiffness, 53,55 local skin/injection site reaction (warmth, redness, rash, echymossis, 
itching, bruising). 53,54,56-58  Non-local events considered possibly related to intra-articular HA 
injection include headache, 54,56-58 gastrointestinal complaint/nausea/vomiting,  54,56,57 back pain,  
57,58 rash, dizziness, chills, hives, itching, muscle cramps, peripheral edema, malaise,  57 swelling of 
the face and/or extremities, redness of the face, rash, hives, and fever. 55,56  
 
Rare cases of allergic reactions, anaphylactic reactions, 54,56 and intra-articular infection 54 have 
been observed. 
 
In addition to the established use of HA as an intra-articular injection, HA alone was 
administered intra-discally as a control treatment in the Phase 2 study of chronic discogenic low 
back pain.  Of the 20 subjects treated with HA in a double-blind fashion, 3 AEs were reported 
that were considered possibly related to study treatment.  One subject experienced mild 
urticarial, which subsequently resolved, and another subject experienced 2 events of back pain, 
1 event of which was considered possibly related to investigational product and related to study 
procedure, the other of which was considered possibly related to investigational product and not 
related to study procedure.  
 
1.7.9 
Subsequent Surgical Interventions 
Failure of the treatment to alleviate the low back pain or to address potential complications 
which develop subsequent to initial implantation of the product can result in use of additional 
pain medication or surgical intervention.  Surgical intervention may include discectomy, fusion, 
disc replacement or other surgical intervention. 
 
2. 
STUDY OBJECTIVES 
2.1 
Primary Efficacy Objective 
To determine Overall Treatment Success of rexlemestrocel-L alone or rexlemestrocel-L+HA at 
12 AND 24 months based on a composite responder analysis of low back pain Visual Analog 
Scale (VAS) score, Oswestry Disability Index (ODI) score and no post-treatment interventions at 
the treated level. 
 








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3. 
STUDY DESIGN 
3.1 
Overview of Study Design 
Figure 3:  Diagram of Study Design 
 
This is a prospective, multicenter, randomized, double-blind, placebo-controlled Phase 3 study 
designed to evaluate the safety and efficacy of Mesoblast’s rexlemestrocel-L alone or combined 
with hyaluronic acid (HA) in subjects with chronic low back pain (> 6 months) not adequately 
controlled by conservative measures and associated with moderate radiographic degenerative 
changes of a disc.  
 
Up to 45 investigational centers in the US and Australia, and potentially the EU, will participate 
in this trial.  Approximately 360 subjects (approximately 120 subjects per treatment group) will 
be randomized and treated.  Centers will screen subjects with a diagnosis of chronic low back 
pain (>6 months) unresponsive to 6 months of conservative therapy (e.g., medication, 
chiropractic manipulation, activity modification, physical therapy) associated with moderate 
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Each eligible subject’s participation in Study MSB-DR003 will last approximately 39 months.  A 
screening period for Study MSB-DR003 (starting from the time of subject consent) of up to 
75 days will precede randomization. Screening evaluations will include those listed in Table 3. 
 
Eligible subjects in this study will undergo injection of a single degenerated lumbar 
intervertebral disc with 1 of 3 treatments: rexlemestrocel-L alone (approximately 6.0 million 
rexlemestrocel-L cells), rexlemestrocel-L (approximately 6.0 million rexlemestrocel-L cells) + 
HA, or saline.  The study treatment will be injected directly into the nucleus pulposus via a 
posterior-lateral approach under fluoroscopic guidance. 
 
After injection of study treatment, and as a general guideline, subjects will be discharged from 
the facility when they are comfortable.  Subjects will be given the following instructions for 
post-injection rehabilitation/treatment: 
• Day of Procedure – Bed rest 
• Day After procedure – Gentle ambulation with a gradual increase thereafter 
• Days 1 to 3 – Avoid repetitive bending, stooping and lifting greater than  
• 10-15 lbs. 
• Return to normal daily activity when pain has subsided to their baseline. 
 
In Study MSB-DR003, each subject will be evaluated clinically at 1, 3, 6, 12, 18, 24 and 
36 months after treatment.  The primary analysis of safety and efficacy will be conducted at 
24 months with a longer term assessment of safety and efficacy conducted at 36 months.  
Clinical assessments for Study MSB-DR003 will include those listed in Table 3.  X-rays will 
also be taken at 1, 3, 6, 12, 18, 24 and 36 months after treatment and will consist of AP and 
lateral radiographs as well as flexion and extension x-rays. MRI scans will be taken at 12, 18, 24 
and 36 months.   
 
Surgical and injection interventions should be avoided through at least the 24 month primary 
endpoint follow-up.  Surgical and injection interventions should only be undertaken if the 
subject’s pain, measured by VAS, and function, measured by ODI, is not improved compared to 
the baseline values since an intervention could confound the efficacy assessments and would 
classify a subject as a treatment failure. 
 
If a subject intends to undergo an intervention at the treated level, subjects should be encouraged 
to attend an unscheduled in-clinic visit for evaluation within 30 days prior to the new 
intervention (if a scheduled assessment does not already occur within that timeframe).  During 


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this visit, all assessments and activities regularly performed at Visits 3-9 will be performed, with 
the exception of imaging assessments, hematology, chemistry panel, Flow Class I and II % PRA 
with specificity testing and DSA.  If the subject’s originally planned assessment timepoint falls 
within 30 days prior to the post-treatment intervention, the unscheduled visit will not be 
necessary. 
 
It is strongly recommended that there be no changes (increase or decrease) from or additions to 
baseline pain medications (opioids, NSAIDs, aniline analgesics etc.).  This is designed to 
minimize possible confounding treatment effects due to alterations in pain medications.  
Furthermore, it is suggested that subjects do not schedule any medical procedures which would 
require an adjustment in pain medications during the 2 weeks prior to any study visit. Subjects 
not taking opioids at baseline should similarly refrain from starting opioid treatment.  However, 
should a significant increase in pain from baseline occur, as determined by a VAS score greater 
than baseline, the subject should be provided appropriate pain relief.  Should there be any 
deviation from the baseline dose, information regarding the deviation must be documented.  
 
All patient-reported outcomes (including VAS and ODI assessments), as well as baseline use of 
pain medication (i.e., 2-week e-diary record), will be established during screening.  All such 
assessments should be performed prior to the screening injection procedures:  diagnostic disc 
injection to confirm intact annulus or discography, medial branch block and SI joint injection, if 
deemed necessary.  However, in the case of a re-screen (see Section 4.4) or if the subject had 
previous diagnostic injection procedures performed prior to the screening period (but within the 
permitted timeframes to serve as the baseline evaluation; see Section 4.2.2), these patient-
reported outcomes and e-diary entries should be completed at least 14 days following the most 
recent injection procedure, provided original e-diaries are not available.  If an e-diary was 
collected during a previous screen, this may be used, provided it meets all criteria for 
acceptability. 
 
Based on the opioid information entered into the e-diary during baseline, subjects will be 
classified into one of the following groups for stratification at randomization: 
Opioid Non-User: subjects who did not take any opioids during the e-diary pain medication 
data collection period 
Opioid User: subjects who did take an opioid during the e-diary pain medication data 
collection period. 
 
 
 
 


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Pain medication (opioid, NSAID and/or aniline analgesic) usage will also be subsequently 
captured each day for a 2 week period during the 30 days prior to each clinic visit, other than the 
1 month visit that must be conducted within the 14 days prior to the 1 month visit using 
electronic diaries (e-diaries) completed by the subjects.  Based on the pain medication 
information entered into the e-diary during the 2 weeks prior to each post-treatment visit, it will 
be determined if subjects have significantly increased pain medication usage from baseline.  
 
Low back pain (average over past 24 hours and worst pain over 24 hours) and leg pain (average 
leg pain in left and right legs, individually over the past 24 hours) VAS and ODI evaluations will 
also be taken using e-diaries during the same 2 week period where pain medication usage is 
being collected.  The VAS scores will be collected every day for the 14 day period with at least 
evaluations for 7 days.  If more than 7 days of VAS scores are collected the last 7 days’ scores 
will be used to calculate the average pain over a week.  The ODI score must be taken at least 
once during the 14 day period.  If more than one ODI score is collected, the most recent ODI 
score will be used.  If a scheduled in-clinic visit is missed, the site should contact the subject to 
determine if any interventions that would classify the subject as a treatment failure have occurred 
since their last visit.  If any interventions are reported, the site should collect all the information 
required if the intervention had been reported at an in-clinic visit.  All intervention information 
collected remotely must be documented in a source document and/or worksheet.  
 
Review of concomitant treatments will also be performed at each clinic visit.  Subjects will be 
asked for all concomitant medications used since the last visit.  Additionally, at each clinic visit, 
subjects will be asked whether they have undergone or intend to undergo any spinal interventions 
such as surgery (e.g., discectomy, intervertebral fusion, or disc replacement) or any injection for 
alleviation of pain at the treated disc (e.g., epidural corticosteroid injection, or transforaminal 
injection).  In order to maintain standardized classification of post-treatment interventions 
affecting the treated disc, the TEC will be used. The TEC will perform ongoing independent 
blinded adjudication of post-treatment interventions.  Following are procedures that should be 
considered interventions and consequently treatment failures for responder analyses if they occur 
at the treated level: 
 
 




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Interim analyses 
Interim analyses may be performed during the course of the trial.  The timing and details of the 
interim analyses are outlined in the Statistical Analysis Plan (SAP).  
 
These will be conducted by external independent statistician(s) who will be unblinded to study 
data. All blinded personnel and subjects will remain blinded to the results of the analyses.  The 
integrity of the study database will be maintained as well, and no bias will be introduced to the 
evaluations in the study due to the conduct of these interim analyses.   
 
All subjects, independent reviewers and blinded personnel interacting with the subjects will 
remain blinded through completion of the study. 
 
3.2 
Dosing Regimen 
Each treatment solution will be prepared by an unblinded designee(s) who is otherwise not 
involved in study participation after the treatment injection.  The health care professional 
administering the injection will be unblinded to the treatment administered.  All other study staff, 
as well as each study subject, will be blinded to study therapy until the end of the study.   
Eligible subjects will be randomized to receive 1 of 3 treatments:  
• Rexlemestrocel-L alone:  One injection of approximately 6 million rexlemestrocel-L cells 
in freeze media mixed in a 1:1 by-volume ratio with saline.  A vial with 2mL of thawed 
rexlemestrocel-L cells and freeze media will be mixed with 2mL of saline.  Two 
milliliters of the resulting mixture will be injected via pressure manometer syringe into 
the nucleus pulposus of the index level. 
• Rexlemestrocel-L + HA:  One injection of approximately 6 million rexlemestrocel-L 
cells in freeze media mixed in a 1:1 by-volume ratio with 1% hyaluronic acid (HA) 
solution.  A vial with 2mL of thawed rexlemestrocel-L cells and freeze media will be 
mixed with 2mL of 1% HA solution.  Two milliliters of the resulting mixture will be 
injected via pressure manometer syringe into the nucleus pulposus of the index level; OR 
• Saline:  One injection of 2mL of thawed saline from one vial will be mixed with 2mL of 
thawed saline from another vial of saline.  Two milliliters of the resulting saline mixture 
will be injected via pressure manometer syringe into the nucleus pulposus of the index 
level.   
 
Treatment assignment will occur in sequential chronological order according to a central master 
list of random assignments.  Randomization will be stratified 
 
 


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3.3 
Study Sites 
In order to enroll approximately 360 subjects, up to 45 study centers in the US, Australia, and 
potentially the EU will participate.  
 
4. 
STUDY ANALYSIS SET 
4.1 
Overview  
This study will enroll approximately 360 subjects in the randomization ratio of 1:1:1.  Eligible 
subjects will be those with a history of chronic (> 6 months) low back pain not adequately 
controlled by conservative measures and associated with moderate radiographic degenerative 
changes of a disc in the lumbar spine from L1 to S1. 
 
4.2 
Eligibility Criteria 
4.2.1 
Inclusion Criteria 
Subjects who meet the following criteria will be included in the study: 
1. Male and female subjects 18 years of age and older 
2. If female of childbearing potential, subject is non-pregnant, non-nursing, and agrees to 
use highly effective methods of contraception for a minimum of 24 months post-
treatment (if a subject becomes pregnant during the study, the subject will remain in the 
study and only the requirement for radiation (x-ray or MRI) should be removed)  
3. Signed informed consent and country-appropriate privacy forms (e.g., HIPAA forms in 
the US) indicating subject is willing to undergo treatment and willing to be available for 
each examination scheduled over the study duration 
4. Have documented diagnosis of moderate radiographic degeneration of an intervertebral 
disc from L1 to S1, with a disc suspected of causing CLBP 
 
  Chronic low back pain associated 
with moderate radiographic degeneration at a lumbar disc is defined as the following 
(subject must meet all of the listed conditions): 
a. Chronic low back pain for at least 6 months 
b. Have failed 6 months of conservative back pain care.  (Conservative treatment 
regimens may include any or all of the following: initial rest, medications [e.g., 
anti-inflammatory, analgesics, narcotics/opioids, muscle relaxants], massage, 
acupuncture, chiropractic manipulations, activity modification, home-directed 
lumbar exercise program, and non-invasive pain control treatments or procedures) 
c. Have at a minimum undergone supervised physical therapy, such as daily walking 
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treatment of low back pain AND taken a pain medication for back pain (e.g. 
NSAID and/or opioid medication) 
d. Change from normal disc morphology of the index disc as defined by 
radiographic evaluation by the core imaging evaluation provider. Radiographs 
must show all of the following: 
i. A modified Pfirrmann score of 3, 4, 5 or 6 on MRI at the index disc as 
determined by radiographic core lab 
ii. Modic Grade II changes or less on MRI at the index disc as determined by 
radiographic core lab 
iii. With or without contained disc protrusion at the index disc on MRI as 
determined by radiographic core lab  
e. Low back pain of at least 40mm and not more than 90mm of 100mm on low back 
pain VAS (average pain over 24 hours)  
f. Leg pain ≤20mm in both legs on a 100mm VAS scale 
g. ODI score of at least 30 and no more than 90 on a 100 point scale. 
 
4.2.2 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Female subjects who are pregnant or nursing, or women planning to become pregnant in 
the first 24 months post-treatment (if a subject becomes pregnant during the study, the 
subject will remain in the study and only the requirement for radiation (x-ray or MRI) 
should be removed) 
2. Extreme obesity, as defined by NIH Clinical Guidelines Body Mass Index (BMI > 40) 
3. Have undergone a surgical procedure (e.g. discectomy, intradiscal electrothermal therapy, 
intradiscal radiofrequency, artificial disc replacement, interbody fusion) on the disc at the 
index or adjacent level 
4. Osteoporosis, as defined by dual-energy X-ray absorptiometry (DEXA) scan. A DEXA 
T-score of ≤ -2.5 will exclude the subject. Only the following at-risk subjects will be 
required to undergo a DEXA scan at screening: 
a. Female subjects with a Simple Calculated Osteoporosis Risk Estimation 
(SCORE) of ≥6 and male subjects with a Male Osteoporosis Risk Estimation 
Score (MORES) of ≥6 
b. Females ≥50 years of age or who are post-menopausal or post-hysterectomy with 
oophorectomy 
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d. Subjects with a history of chronic, high-dose steroid use (oral and/or inhaled). 
High-dose steroid use is defined as: 
i. Daily, chronic use of oral steroids of ≥5 mg/day 
ii. Daily, chronic use of inhaled corticosteroids (at least twice per day) 
iii. Use of short-term (less than 10 days) oral steroids at a daily dose >20mg 
prednisone (or equivalent ) within 1 month of study procedure 
5. Any lumbar intradiscal injection, including steroids, into the index or adjacent discs prior 
to treatment injection, with the exception of the following injections performed at least 2 
weeks prior to study treatment:  
a. Contrast medium (discography or other diagnostic injection) 
b. NSAIDs  
c. Nerve-blocking anesthetics (e.g., lidocaine, bupivacaine)  
d. Antibiotics 
e. Saline 
6. Have undergone a procedure affecting the structure/biomechanics of the index disc level 
(e.g. posterolateral fusion) 
7. Epidural steroid injections within 8 weeks prior to treatment injection 
8. Have received chronic (more than 7 consecutive days) treatment with systemic 
corticosteroids at a dose equivalent to prednisone ≥ 10 mg/day within 14 days prior to 
injection procedure   
9. Have a known history of hypersensitivity or anaphylactic reaction to murine or bovine 
products or dimethyl sulfoxide (DMSO) 
10. Have a known history of hypersensitivity or anaphylactic reaction to hyaluronic acid 
(HA) 
11. Active malignancy or tumor as source of symptoms or history of malignancy within the 5 
years prior to enrolment on study, except history of basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, or squamous cell carcinoma of the cervix if fully 
excised and with clear margins  
12. Currently participating in another investigational trial and/or plans to participate in any 
other allogeneic stem cell/progenitor cell therapy trial within 36 months after study 
treatment 
13. Have been a recipient of prior allogeneic stem cell/progenitor cell therapy for any 
indication or autologous stem cell/progenitor cell therapy or other biological intervention 
to repair the index intervertebral disc 
14. An average baseline morphine equivalent dose (MED) of >75mg/day as determined by e-
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15. Taking systemic immunosuppressants 
16. Current infection or prior history of spinal infection at the index level (e.g., discitis, septic 
arthritis, epidural abscess) or an active systemic infection 
17. Pain catastrophizers, defined as having a score of 30 or more on the Pain Catastrophizing 
Scale 
18. A medical condition, serious intercurrent illness, or extenuating circumstance that would 
preclude participation in the study or potentially decrease survival or interfere with 
ambulation or rehabilitation. Examples of conditions that should be excluded are as 
follows: 
• History of transient ischemic attack (TIA) 
• History of Stroke 
• Uncontrolled diabetes 
• Autoimmune disease (only if they interfere with ambulation or 
rehabilitation) 
• Muscular dystrophy 
• Rheumatoid arthritis 
• Active liver disease 
• Upper motor neuron disease 
• Myelopathy 
• Disorders of bone metabolism (osteomalacia or Paget’s disease) 
19. Cauda equina syndrome 
20. Subjects involved in spinal litigation, including workman’s compensation, unless 
litigation is complete 
21. Currently incarcerated (prisoners) 
22. Are transient or have a severe alcohol or substance abuse problem defined as answering 
yes to 6 or more symptoms on the DSM-5 alcohol or substance/opioid questionnaires 
23. Unable to complete all required e-diary entries, assessments and follow-up according to 
the protocol. 
24. A history of mental illness/incompetence.  Mental illness/incompetence is defined as 
meeting the following criteria on the DSM-5 Self-Rated Level 1 Cross Cutting Symptom 
Measure – Adult questionnaire 
• Domain 1, Depression – A response of 4 on either question 
• Domain 6, Suicidal Ideation – A response of 4 on the question 
• Domain 7, Psychosis – A response of 1 to 4 on either question 
• Domain 9, Memory – A response of 4 on the question 


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25. Have a serious intercurrent medical condition or any other conditions or social situations 
that would impair the ability to give informed consent or unacceptably reduce protocol 
compliance or safety of the study treatment. 
26. Body habitus precluding adequate fluoroscopic visualization for the procedure or the 
procedure is physically impossible due to inability to inject the nucleus pulposus 
27. Presence of ferromagnetic implants that would disallow MRI of the index disc 
28. Presence of neurologic deficit on any component of the lumbar neurological exam at 
baseline (i.e., motor, sensory, or reflex portion of the exam) 
29. A positive screen for human immunodeficiency virus (HIV) by antibodies or nucleic acid 
test 
30. Clinically significant nerve pain (e.g., chronic radiculopathy or neuropathy) 
31. Clinically significant sacroiliac joint pain based on the Appropriate Use Criteria 
established by the Spine Intervention Society including a targeted, pre-specified physical 
examination, and, if deemed medically necessary, confirmed by anesthetic injection. If a 
previously performed anesthetic injection to confirm SI joint pain was performed up to 6 
months prior to injection (with documentation indicating that the SI joint pain is not the 
source of the subject’s pain), this does not need to be repeated at screening.  
32. Compressive pathology due to stenosis or disc protrusion on MRI with associated clinical 
symptoms defined as leg pain VAS > 20mm out of 100mm or neurologic deficit on 
neurologic exam 
33. Disc extrusion with a maximum dimension greater or equal to twice the posterior height 
of the disc, or disc sequestration in the lumbar spine on MRI as determined by 
radiographic core lab 
34. This criterion left blank on purpose 
35. Modified Pfirrmann score of 7 or 8 at any lumbar level on MRI evaluation as determined 
by the core imaging provider  
36. Symptomatic involvement of more than one lumbar disc 
 
(i.e. more than one level with concordant 
pain upon provocative discography, if performed) 
37. Symptomatic central vertebral canal stenosis as defined by neurogenic claudication  
38. Spondylolisthesis or retrolisthesis Grade 2 and above (>25% of the AP dimension of the 
superior endplate of the inferior vertebrae) at the index or adjacent level(s) on 
radiographic evaluation as determined by radiographic core lab or Spondylolysis at the 
index or adjacent level(s). 
39. Lumbar spondylitis or other undifferentiated spondyloarthropathy affecting the index 
disc. 


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40. Spinal deformity defined as lumbar scoliosis with a Cobb angle of the lumbar spine 
greater than 15 degrees on radiographic evaluation as determined by radiographic core 
lab. 
41. An acute fracture of the spine at the index or adjacent levels that has not healed, or 
clinically compromised vertebral bodies at the index level due to current or past trauma 
(e.g. sustained pathological or multiple fractures of vertebrae.  
42. Facet pain at the index level or adjacent segments as determined by a diagnostic medial 
branch block (a facet block injection is not acceptable for making this determination) to 
rule out facet joint involvement. If a previously performed medial branch block was 
performed up to 6 months prior to injection (with documentation indicating that the facet 
joint is not the source of the subject’s pain), this does not need to be repeated at 
screening. 
43. Have not completed a minimum of 10 out of 14 daily e-diary entries of pain medication 
use (e.g. NSAID, aniline analgesics and opioid use) prior to screening injection 
procedures (i.e., diagnostic disc injection to confirm intact annulus, discography, medial 
branch block and SI joint injection, if deemed necessary).  If a historical screening 
injection procedure is used, the e-diary pain medication usage collection should be 
completed at least 14 days after the screening procedure. 
44. Full thickness annular tears in the index level as determined by free flowing contrast 
media through the annulus fibrosis. Injection of contrast media into the index level must 
take place at least 2 weeks prior to the treatment injection. If a previously performed 
discography with contrast was performed up to 6 months prior to injection (with 
documentation indicating no full tear of the disc), this does not need to be repeated at 
screening. 
 
4.3 
Information to be collected for Screen Failures and Randomized Not-treated 
Subjects 
Subjects who fail any inclusion/exclusion criteria up to the timepoint of randomization are 
considered screen failures.  Subjects who are randomized but do not receive treatment are 
considered randomized not-treated subjects.  
 
The following information must be recorded for all screen failures and randomized not-treated 
subjects: demography, medical history, concomitant treatment, inclusion/exclusion criteria met 
and not met, adverse events, if any, and reason for screen failure or withdrawal.  If diagnostic 
injection for confirmation of full thickness annual tears was performed, information regarding 
the procedure will also be collected. 


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4.4 
Re-screening 
Screen failures may be re-screened twice at the discretion of the investigator (however, subjects 
who have been previously randomized cannot be re-screened).  Subjects will be assigned a new 
study identification number upon re-screening.  All screening activities will need to be repeated 
with the possible exception of the following, if performed within the permitted timeframe: 
diagnostic medial branch block; diagnostic injection to confirm intact annulus or discography; 
possible anesthesia injection for detection of SI joint point, anterior/posterior (AP), lateral and 
flexion-extension X-rays; and screening MRI. For these screening activities to be waived (i.e., 
not repeated), they must have been performed within the following timeframes: 
 
Screening injection procedures: 
• Diagnostic medial branch block:  within 6 months prior to injection of study treatment 
(with documentation indicating no clinically significant facet pain in accordance with 
exclusion #42) 
• SI joint injection to determine SI joint pain (not required for all subjects):  within 
6 months prior to injection of study treatment (with documentation indicating no 
clinically significant SI joint pain in accordance with exclusion #31) 
• Diagnostic injection to confirm intact annulus or discography: at least 2 weeks but no 
longer than 6 months prior to injection of study treatment. 
 
Imaging: 
• MRI: within 6 months prior to injection of study treatment  
• DEXA: within 6 months prior to injection of study treatment 
• AP, lateral and flexion-extension x-rays: within 6 months prior to injection of study 
treatment and according to study-defined procedure. 
 
Note: MRIs and X-rays should be taken on the same machine using the same settings, and in 
accordance with the radiographic guidelines provided, from baseline to completion of the study 
to minimize potential differences in results caused by use of different machines.  Radiographic 
evaluations may vary for a given subject depending on the time of day the assessments are made. 
Therefore, for each subject, all radiographic evaluations of a specific type (e.g., X-ray) should be 
taken at the same time of day at each assessment if possible, preferably in the morning. 
 
If the diagnostic injection to confirm an intact annulus or discography is repeated in re-screening, 
a neurological exam must be performed prior to the injection procedure and again after the 
procedure.  If a recent diagnostic injection taken before the screening period serves as the 


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baseline evaluation for a subject, the pre-injection neurological exam may be waived, though a 
neurological exam will need to be performed prior to any additional invasive procedures or the 
treatment injection.  This post-diagnostic injection neurological exam will be used as the 
subject’s baseline neurologic status. 
 
For subjects who are re-screened, the following patient-reported outcomes must be repeated no 
sooner than 2 weeks after the most recent diagnostic injection procedure to confirm an intact 
annulus or discography: VAS assessments (leg and low back pain), ODI questionnaire, EQ-5D, 
iPCQ, and e-diary collection of pain medication usage for a minimum of 10 out of 14 days.   
 
4.5 
Subject Withdrawal 
Subjects will be free to withdraw from the study at any time, for any reason.  
 
A subject also may be withdrawn/removed by the investigator, if necessary, to protect the 
subject’s health.  The investigator has the right to withdraw subjects from the study in the event 
of intercurrent illness, adverse events, administrative, or other reasons.  Any reasons for 
withdrawal must be documented and explained to the subject. 
 
It is understood, however, by all concerned, that an excessive rate of withdrawals can render the 
study uninterpretable.  Therefore, unnecessary withdrawal of subjects should be avoided.  
 
If for any reason a treated subject is withdrawn from study participation, the reason for and date 
of withdrawal from the study must be recorded.  If the reason for withdrawal is an adverse event 
or a clinically significant abnormal laboratory test result, monitoring will continue until the event 
has resolved, stabilized, or until the follow-up period is complete.   
 
4.6 
Withdrawal Procedure 
When a subject withdraws from the study or if a subject is withdrawn by the investigator, all 
assessments normally required at the completion of the study will be obtained, where possible.  
All details available will be reported and recorded.  If the reason for removal of a subject from 
the study is an adverse event, intercurrent illness, surgical intervention or an abnormal laboratory 
value considered a clinically significant abnormality, i.e., requiring medical intervention or 
treatment, the specific event will also be recorded.  All AEs are intended to be followed through 
until resolved or stabilized or until the follow-up period is complete. 
 


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Case report forms are required for all subjects who are screened.  Subjects who sign an informed 
consent and undergo any procedures for the study, including those who are subsequently 
excluded or withdrawn from the study before randomization will be documented on the site’s 
screening log.  Whenever possible, all sections of the screening worksheets and relevant case 
report forms, up to the time of withdrawal, should be completed.  If applicable, efforts should be 
made to obtain complete information regarding safety.  
 
If during the course of the study a subject chooses to revoke his/her written authorization for the 
use and disclosure of personal health information (PHI; per HIPAA privacy ruling or other 
country and/or region specific law), the subject will then be withdrawn from the study as well 
(i.e., participation in the MSB-DR003 study is contingent upon an “active” written PHI use, 
collection, and disclosure authorization) and only safety data will be collected as required by 
applicable laws. PHI collected prior to the date that the subject revokes his/her written 
authorization may still be used.  If a subject decides to withdraw from the study, he/she should 
be asked if he/she can still be contacted for further information.  The outcome of that discussion 
should be documented in the medical records.  
 
If a subject decides to withdraw or is withdrawn from the study, the investigator will promptly 
notify the blinded CRA, or designee, and the reason for and date of withdrawal from study must 
be recorded. 
 
4.6.1 
Lost to Follow-Up 
A subject is considered to have been lost to follow-up if he/she is unable to be contacted by the 
investigator post-randomization.  The investigator should show “due diligence” by documenting 
in the source documents steps taken to contact the subject, e.g., dates of telephone calls or 
registered letters.  The end of participation for a subject lost to follow-up is the date of the last 
known contact (e.g., visit or telephone contact). 
 
4.7 
End of Study 
The end of study is defined as the date of the last follow-up visit or the date at which the last data 
point occurs for the last subject. 
 


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5. 
INVESTIGATIONAL PRODUCT  
5.1 
Investigational Product Labeling  
The product label will contain the elements for investigational products required by 21CFR, 
312.6 and other applicable regulatory agencies.  
 
5.2 
Description of Investigational Product 
5.2.1 
Active Treatment 
Rexlemestrocel-L cells are STRO-3 selected allogeneic MPCs, which are derived from adult 
bone marrow mononucleated cells that are immunoselected, culture-expanded, and subsequently 
cryopreserved.  
 
rexlemestrocel-L alone 
Subjects enrolled in the “rexlemestrocel-L alone” arm will receive 1 injection of approximately 
6 million rexlemestrocel-L cells in freeze media mixed in a 1:1 by-volume ratio with saline.  A 
vial with 2mL of thawed rexlemestrocel-L cells and freeze media will be mixed with 2mL of 
saline.  Two milliliters of the resulting mixture will be injected, under fluoroscopic imaging, via 
pressure manometer syringe into the nucleus pulposus of the index level.  
 
rexlemestrocel-L + HA 
Subjects enrolled in the “rexlemestrocel-L + HA” arm will receive 1 injection of approximately 
6 million rexlemestrocel-L cells in freeze media mixed in a 1:1 by-volume ratio with 1% 
hyaluronic acid (HA) solution.  A vial with 2mL of thawed rexlemestrocel-L cells and freeze 
media will be mixed with 2mL of 1% HA solution.  Two milliliters of the resulting mixture will 
be injected, under fluoroscopic imaging, via pressure manometer syringe into the nucleus 
pulposus of the index level. 
 
5.2.2 
Control Agent 
Subjects enrolled in the control arm will receive a saline injection.  Two milliliters of thawed 
saline from one vial will be mixed with 2mL of thawed saline from another vial of saline.  Two 
milliliters of the resulting saline mixture will be injected, under fluoroscopic imaging, via 
pressure manometer syringe into the nucleus pulposus of the index level.   
 


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5.3 
Investigational Product Storage  
Rexlemestrocel-L will be shipped just prior to treatment procedures in the vapor phase of liquid 
nitrogen at ≤ -140°C to -196°C until it is ready for use.  Additional details regarding the storage 
and preparation of rexlemestrocel-L are contained in the study materials provided to the site.  
 
Hyaluronic acid will also be shipped directly to the study sites.  Once received by the study sites, 
HA should be stored in accordance with the HA product labeling.  
 
Saline will also be shipped in a cryopreserved container, similar to rexlemestrocel-L.  In order to 
minimize the potential for unblinding, saline should be stored under similar conditions to that of 
rexlemestrocel-L.  
 
Any IP provided by the sponsor should be stored in a secure location with limited access to the 
unblinded designees assigned to the study.  Blinded designees should not have access to IP. 
 
5.4 
Investigational Product Preparation and Administration  
5.4.1 
rexlemestrocel-L 
The vial, in which the rexlemestrocel-L is supplied, will be removed from a shipping container 
and immersed with gentle shaking in a 37°C water bath.  With gentle agitation, the cells will be 
thawed after approximately 6-8 minutes of submersion and just before the last crystal of ice has 
fully melted.  Once the product is thawed, a timer should be started and run until the time the 
product is applied to the study subject.  
 
Warning:   
If the treatment is not injected within 75 minutes from the start of thaw, product cannot be 
administered. 
 
5.4.2 
All Investigational Product 
Refer to the Investigational Product (IP) Manual for details regarding product handling and 
preparation.  A detailed description of the process of injecting the investigational and control 
materials is also included in the IP Manual. 
 


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5.4.3 
Investigational Product Handling and Accountability 
All investigational product accountability records including records of randomization assignment 
will be maintained by the unblinded qualified designee, stored in a secure location and reviewed 
during monitoring visits by the unblinded CRA.  
 
If the rexlemestrocel-L alone, or rexlemestrocel-L + HA is prepared, but not used for whatever 
reason, the circumstances will be recorded in the accountability log/form(s) and destruction of 
investigational product container will occur per the site’s policy once accountability by the 
unblinded CRA has been performed.   
 
The final disposition of all investigational product, whether used or discarded, must be recorded.  
The final disposition of all unused, empty, and partially used vials will be handled in accordance 
with the institution’s policy and the supplied study materials.   
 
An unblinded CRA will be responsible for reconciliation of IP accountability throughout the 
study and at study completion. 
 
5.5 
Maintenance of the Treatment Blind 
Due to the appearance, configuration, and storage conditions of rexlemestrocel-L, saline, and 
HA, it is not possible to blind all personnel at the investigational study site. 
 
In order to maintain the blind, each site will have an unblinded designee(s) (identified by the 
investigator) who receives all investigational and control product, performs accountability, 
properly stores it in a secure location, and prepares the injection.  Additionally, the health care 
professional who is performing the study treatment injection will be unblinded.  The unblinded 
health care professional who is performing the study treatment injection will perform all required 
procedures and evaluations associated with the treatment injection, including neurological exam 
prior to discharge, but will not be involved with any subject care or assessment beyond the 
subject’s discharge following the injection procedure. All other site personnel, specifically those 
administering subject assessments and care, will be blinded to the treatment as will the subjects, 
radiographic evaluators, and members of the study team, with the following exceptions: 
unblinded CRAs (responsible for IP reconciliation) and unblinded statistician(s) (responsible for 
providing data for the interim analysis  and DSMB data).  Prior to the treatment administration 
visit, both blinded and unblinded personnel can perform screening activities. 
 


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Care should be taken to ensure that the subject does not know which investigational 
product he/she is receiving.  Additionally, care should be taken to ensure that blinded 
personnel at the site and CRO are not unblinded to treatment assignment.  All unblinded 
study site personnel will be specifically instructed to refrain from discussing any potentially 
unblinding information with either the subject or any blinded site, sponsor, or CRO 
personnel involved in the trial. Additional information is provided in the Blinding Plan. 
 
Independent blinded radiologists will be evaluating radiographic images for key 
inclusion/exclusion criteria to maintain consistency and for radiographic endpoints.  Two 
independent and blinded radiologists will review screening radiographic images to confirm 
subjects meet the radiographic inclusion/exclusion criteria with a third independent and blinded 
radiologist will adjudicate any differences between the two initial radiologist’s reviews.  Follow-
up evaluation of radiographic images will be performed by at least 2 blinded independent 
radiologists with a third radiologist to adjudicate any differences between two initial 
radiographic reviewers’ assessments. 
 
Any Interim analyses will be conducted by an unblinded independent statistician. 
 
The DSMB will also be unblinded in order to assess the safety of IP. 
 
The Treatment Events Committee (TEC), performing adjudication of post-treatment 
interventions and relationship of adverse events to product and/or procedure will be blinded.  
 
When the unblinded statistical analyses are conducted at the conclusion of the primary safety and 
efficacy evaluation period, study subjects, as well as site personnel responsible for subject care 
and assessment, will continue to be blinded until the completion of the long-term safety and 
efficacy follow-up period (i.e., when all subjects who remain active in the study have completed 
their 36-month treatment visit). 
 
5.6 
Treatment Compliance 
All subjects in this study will undergo an injection into a single lumbar disc with either 
rexlemestrocel-L in freeze media (“rexlemestrocel-L alone”), rexlemestrocel-L cells in freeze 
media mixed with HA (“rexlemestrocel-L + HA”), or saline.  
 


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Each qualified subject will be randomized to one of 2 active treatment arms (rexlemestrocel-L 
alone or with HA) or to the saline control arm.  All subjects will receive a single injection with 
the study product injected directly into the nucleus pulposus of the index level.  
 
Any randomized subjects who, upon re-examination just prior to the injection procedure, do not 
meet the inclusion criteria or withdraw consent prior to treatment, will be considered randomized 
not-treated and will not receive treatment.  
 
Throughout the study, the assigned unblinded CRA will monitor compliance with the treatment 
assignment, review and verify all investigational product accountability records and inventory at 
each participating investigational center. 
 
6. 
STUDY PROCEDURE 
6.1 
Visit Schedule and Assessments 
Table 3 shows all planned assessments, which are marked with an “X” for the visits at which 
they are performed.  Subjects should be seen for all visits on the designated days or within the 
given windows for those visits.  The study assessment schedule outlines all procedures to be 
performed on subjects at the scheduled visits.   
 
In order to minimize variability in evaluations, ideally, the same personnel should perform the 
same tests and assessments on all the subjects at a given trial site, if possible. 
 
Sites are required to access the interactive web response system (IWRS) at the beginning of the 
screening period to obtain a screening number.  Sites are also required to access IWRS at the 
conclusion of the screening period to register the subject status.  If the subject does not meet all 
inclusion and exclusion criteria, the subject will be considered a screen failure.  If the subject 
meets all inclusion and exclusion criteria, the subject must be randomized a minimum of 7 days 
prior to treatment (Day 0) to allow time for shipment of investigational product to the site.  In 
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b. 
For subjects who are re-screened, all screening assessments should be repeated with the exception of the following:  
• 
Diagnostic medial branch block: if performed within 6 months prior to injection of study treatment (with documentation indicating no clinically significant facet pain 
in accordance with exclusion #42) 
• 
SI joint injection to determine SI joint pain (not required for all subjects): within 6 months prior to injection of study treatment (with documentation indicating no 
clinically significant SI joint pain in accordance with exclusion criteria #31) 
• 
Diagnostic injection to confirm intact annulus: if performed at least 2 weeks but no longer than 6 months prior to injection of study treatment 
• 
MRI: if performed within 6 months prior to injection of study treatment  
• 
DEXA: if performed within 6 months prior to injection of study treatment 
• 
AP, lateral and flexion-extension x-rays: if performed within 6 months prior to injection of study treatment and according to study-defined procedure 
c. 
Low back pain VAS (average and worst pain over 24 hours), ODI, vital signs, height, weight, concomitant treatment, neurological exam and AE evaluation are required at all 
unscheduled visits. All other assessments may be performed at the discretion of the investigator. For any subjects who are planning a post-treatment intervention during the 
course of the study, every effort should be made to schedule an unplanned study visit within a 30-day time window prior to the intervention. During this pre-intervention visit, 
all assessments and activities regularly performed at Visits 3-9 will be performed, with the exception of imaging assessments, hematology, chemistry panel, and Flow Class I 
and II % PRA with specificity testing and DSA. If the subject’s originally planned assessment timepoint falls within 30 days prior to the post-treatment intervention, the 
unplanned study visit will not be necessary. 
d. 
Subjects will complete the informed consent process for Study MSB-DR003 at Screen/Baseline 
e. 
Disease targeted/abbreviated PE to include but not limited to examination of the musculoskeletal system. 
f. 
During screening, the neurological exam will be performed twice: one prior to the diagnostic injection to confirm an intact annulus and once after the diagnostic injection to 
assess if the injection procedure has resulted in any neurologic changes. The neurological exam prior to the diagnostic injection can be performed by the unblinded or blinded 
evaluator, but preferably the blinded evaluator. The post-diagnostic injection exam will be performed by the health care professional performing the injection procedure; this 
person may or may not be blinded. 
g. 
Neurological exam to be performed post treatment injection, prior to discharge to assess if the injection procedure has resulted in any neurologic changes.  This will be 
performed by the unblinded health care professional performing the injection procedure, to avoid the potential unblinding of the blinded evaluator. 
h. 
If findings are inconclusive, the investigator may perform a diagnostic injection of anesthetic to the SI joint (Section 6.4.6).  
i. 
To be performed prior to the procedure and then following the procedure prior to discharge. 
j. 
Screening Chemistry Panel includes: albumin, alkaline phosphatase, ALT, AST, BUN, creatinine, hsCRP, chloride, direct bilirubin, GGT, glucose, lactic dehydrogenase, 
sodium, potassium, phosphorous, total bilirubin, total calcium, carbon dioxide, total cholesterol, total protein and uric acid 
k. 
For women of child bearing potential. A serum pregnancy test will be analyzed by the central laboratory at screening. An additional urine pregnancy test will be performed 
prior to administration of study treatment to confirm a negative result. If the urine pregnancy test is positive, study treatment will not be administered that day, and the result 
will be confirmed by a serum pregnancy test. 
l. 
Specificity testing and DSA only for those Class I or II PRA results ≥5%. Specificity testing and DSA results will be blinded until the end of the study. 
m. MRIs and radiographs should be taken on the same machine using the same settings, and in accordance with the radiographic guidelines provided, from baseline to 
completion of the study to minimize potential differences in results caused by use of different machines. Radiographic evaluations may vary for a given subject depending on 
the time of day the assessments are made. Therefore, for each subject, all radiographic evaluations of a specific type (e.g., X-ray) should be taken at the same time of day at 
each assessment if possible, preferably in the morning. MRIs and radiographs will be evaluated by a core imaging provider for the criteria noted in the inclusion & exclusion 
criteria.  All other radiographic evaluations at screening will be assessed by the investigator. Evaluation of the change in macromolecular content and hydration of the treated 
disc will be performed on a subset of subjects where T1 rho and T2 mapping capability is available. 
n. 
Screening DEXA scans and AP, lateral and flexion-extension x-rays performed according to study-defined procedure may be performed up to 6 months prior to procedure. 
o. 
Any female subject with a SCORE of ≥6 or male subjects with a MORES of ≥ 6 will require a lumbar spine DEXA scan to be performed. Similarly, subjects who are 
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p. 
The DEXA scan will measure bone mineral density and determine whether or not the subject is considered to have severe osteoporosis. A T-score that is within ≤ -2.5 
standard deviations from the standard will exclude a potential subject from participating in this study. 
q. 
For subjects who are re-screened, this patient-reported outcome must be performed at least 2 weeks after the most recent diagnostic injection procedure (i.e., diagnostic disc 
injection to confirm intact annulus, medial branch block and SI joint injection, if deemed necessary). 
r. 
At screening, the VAS evaluation must be administered before any diagnostic injections or at least 2 weeks following any injections to relieve pain. 
s. 
If a previously performed medial branch block on and/or SI joint injection was performed up to 6 months prior to injection (with documentation indicating no facet pain 
and/or SI joint pain), this does not need to be repeated at screening  
t. 
There must be at least a 2-week “washout” period following the diagnostic disc injection and prior to the injection of study treatment (i.e., any injection of contrast 
media into the disc must be performed at least 2 weeks prior to the rexlemestrocel-L injection procedure). If an injection of contrast media was performed within 6 
months prior to the rexlemestrocel-L injection procedure and presence/absence of full thickness annular tears is documented, it will not have to be repeated.  
u. 
Must occur at least 7 days prior to treatment injection to allow for investigational product to be shipped to the site,  but not more than 30 days prior to treatment injection. 
v. 
A subject’s informed consent in this study will include permission for the release of any non-study-related medical records that will provide data for pharmacoeconomic 
analyses. However, this is optional and will not impact a subject’s participation in the study. 
w. Includes recording procedural information. Treatment injection must occur no later than 30 days after randomization. 
x. 
At a timepoint after informed consent, subjects should be instructed to complete the e-diary for 2 weeks. Subject e-diary should be completed each day for 2 weeks after 
signing informed consent but prior to diagnostic injection to confirm intact annulus unless a historical diagnostic injection or e-diary is used. 
y. 
Subjects should be contacted, either automatically by IWRS or by the site, approximately 2 weeks prior to each post-treatment visit as a reminder to complete daily pain 
medication patient e-diaries. 
z. 
Please see sections 6.7.2, 6.7.3, and 6.7.6 for collection details on VAS, ODI and pain medication. . 
aa. Subject will be asked about all medications being taken, including pain medications (e.g., NSAIDs, opioids), tricyclic anti-depressants, membrane stabilizers/anticonvulsants, 
sleeping pills, muscle relaxants, etc. and other treatments (chiropractic, acupuncture, physical therapy, spinal injections, etc.) used to treat their back pain. 
bb. A discography procedure may be performed to determine the index level.  
 a discography 
procedure may be required. 
 


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6.1.1 
Screening Period 
A subject will enter the screening period once a written informed consent has been signed by the 
subject.  In addition, all subjects must sign a HIPAA authorization or other local regulatory 
agency required form as applicable for use, collection, and disclosure of PHI. 
 
This initial screening period will not exceed 105 days (75 day screening period until 
randomization and a maximum of 30 days between randomization and study treatment).  During 
the screening period it will be determined that the subject meets all inclusion and exclusion 
criteria.  Baseline assessments will also be completed during this time.  All patient-reported 
outcomes (including VAS and ODI assessments), as well as baseline use of pain medication  
(i.e., 2-week e-diary record), will be established during screening.  All such assessments should 
be performed prior to the diagnostic disc injection to confirm intact annulus or discography, if 
deemed necessary.  However, if the subject had received a previous diagnostic injection 
procedure to confirm intact annulus or discography prior to the screening period (but within the 
permitted timeframes to serve as the baseline evaluation; see Section 4.2.2), these patient-
reported outcomes and e-diary entries must be started at least 14 days following the most recent 
injection procedure.  
 
A neurological exam will be performed prior to the diagnostic injection to confirm an intact 
annulus or discography and again after the procedure.  If a recent diagnostic injection or 
discography taken before the screening period serves as the baseline evaluation for a subject, the 
pre-injection neurological exam may be waived, though a neurological exam will need to be 
performed prior to any additional invasive procedures or the treatment injection.  This 
neurological exam will be used as the subject’s baseline neurologic status. 
 
If a subject is re-screened, most patient-reported outcomes must be completed again at least 
2 weeks after the most recent diagnostic injection procedure.  These patient-reported outcomes 
include VAS assessments (leg and low back pain), ODI questionnaire, EQ-5D, and iPCQ. 
However, if an e-diary was collected during a previous screen, this may be used, provided it 
meets all criteria for a valid e-diary collection (i.e. 10 out of 14 days pain medication usage 
collected). 
 
There must be at least a 2-week “washout” period following the diagnostic disc injection or 
discography prior to the injection of study treatment (see Section 6.4.8). 
 


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6.1.2 
Randomization 
Randomization must occur a minimum of 7 days prior to treatment (Day 0) to allow time for 
shipment of investigational product to the site.  In addition, treatment must be administered no 
later than 30 days following randomization.  Subjects will be enrolled in the study sequentially 
by dose via a central randomization system.  Randomization will be stratified by site and by 
whether the subject is taking an opioid medication or not. 
 
6.1.3 
Safety and Efficacy Evaluation Period (Day 0 to 24 Months Post-treatment) 
On Day 0/Treatment Administration day, each subject will receive an intradiscal injection of 
rexlemestrocel-L alone, rexlemestrocel-L +HA, or saline control in a 1:1:1 randomization ratio. 
This will commence the 24-month primary safety and efficacy period, which includes intensive 
safety and efficacy evaluations.  
 
Treatment injection and post-procedure care (anesthesia, prophylactic antibiotics, blood product 
[i.e., packed red blood cells and platelets], rehabilitation regimens, etc.) will be performed in 
accordance with standard of care, as appropriate in the judgment of the investigator, and 
documented. 
 
Subjects will be given the following directions for post-injection rehabilitation/treatment: 
• Day of Procedure – Bed Rest 
• Day After Procedure – Gentle Ambulation with gradual increase thereafter 
• Days 1 to 3 – Avoid repetitive bending, stooping and lifting greater than 10-15 lbs. 
• Return to normal daily activity when pain has subsided to their baseline. 
 
After the treatment injection visit, all safety and efficacy evaluations should be completed by 
blinded site staff. 
 
Subjects will attend study visits 3, 4, 5, 6, 7, and 8 (corresponding to 1, 3, 6, 12, 18 and 24 
months post-treatment) to complete the primary safety and efficacy period.  Subjects will return 
at Study Visit 9 for a 36 month long-term safety and efficacy evaluation before completing the 
study.  Subjects may also attend unscheduled visits for safety reasons as warranted.  
 
If, for any reason, additional medication must be prescribed, subjects should inform the study 
site personnel. 
 


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Subjects may call the investigator at any time during the study if they experience any problems. 
The investigator may decide to follow up with a telephone call and/or request an unscheduled 
visit. 
 
At least 2 blinded independent radiologists with a third radiologist to adjudicate any differences 
between two initial radiographic reviewers’ assessments will review the specified screening 
radiographic images to confirm subjects meet the radiographic inclusion/exclusion criteria.  
Follow-up evaluation of radiographic images and any screening assessments that are not 
inclusion/exclusion criteria will be performed by at least 2 blinded independent radiologists with 
a third radiologist to adjudicate any differences between two initial radiographic reviewers’ 
assessments as specified in Appendix 1.   
 
Study center personnel (with the exception of unblinded staff preparing and administering the 
investigational treatment) and subjects will remain blinded to the treatment allocation for the 
entire 36-month post-treatment period. Blinded radiographic evaluators will also remain blinded 
for the entire post-treatment study period.  
 
Treatment allocation for the primary analysis of safety and efficacy at 24 months post-treatment 
will occur only for the sponsor and any authorized representative.  These personnel include those 
members of the study team responsible for generating a summary and analysis of the data.  All 
site personnel, specifically those administering subject assessments and care, will be blinded to 
treatment allocation, with the following exceptions: unblinded CRAs (responsible for IP 
reconciliation) and unblinded statistician(s) (responsible for providing data for the interim 
analysis and DSMB data).  
 
During Study MSB-DR003, subjects may attend unscheduled visits for safety reasons if 
warranted.   
 
6.2 
Unscheduled Visits 
Unscheduled visits may be conducted at any time for safety reasons, if deemed medically 
necessary by the investigator.  During such visits vital signs, height, weight, VAS, ODI, 
concomitant treatments, neurological exam and AE evaluation will be required, while all other 
assessments may be performed at the investigator’s discretion. 
 


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For any subjects who are planning an intervention during the course of the study, every effort 
should be made to schedule an “unscheduled visit” within a 30-day time window prior to the 
intervention.  Surgical and injection interventions should be avoided through at least the 
24 month primary endpoint follow-up.  Surgical and injection interventions should only be 
undertaken if the subject’s pain, measured by VAS, and function, measured by ODI, are not 
improved compared to the baseline values since an intervention could confound the efficacy 
assessments and would classify a subject as a treatment failure.  During this visit, vital signs, 
height, weight, VAS, ODI, concomitant treatments, neurological exam and AE evaluation will be 
required, while all other assessments may be performed at the investigator’s discretion.  
However, if the subject’s originally scheduled visit falls within 30 days prior to the planned 
intervention, the unscheduled visit will not be necessary.  Such visits will allow for subject-
reported efficacy assessments (VAS and ODI) to be used in last observation carried forward 
(LOCF) analysis.  Details of this analysis are provided in Section 9.9. 
 
6.3 
Missing or Delayed Study Visits 
Subjects should be encouraged not to miss any visits.  Any visits that are missed or not 
completed within the specified timeframe (or window allowance) should be documented by the 
site and the CRA should be notified.  
 
If a scheduled in-clinic visit is missed, the site should contact the subject to determine if any 
interventions that would classify the subject as a treatment failure have occurred since their last 
visit.  If any interventions are reported, the site should collect all the information required if the 
intervention had been reported at an in-clinic visit.  All intervention information collected 
remotely must be documented in a source document and/or worksheet. 
 
6.4 
Screening Assessments 
6.4.1 
Subject Demographics/Other Baseline Characteristics 
Demographic and baseline characteristics will be recorded during the screening period.  This 
includes the following: demographics, including past and current smoking history, medical and 
surgical history including, but not limited to, surgical history of the spine (including all invasive 
spinal interventions) and history of packed red blood cells and platelets administration, 
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• Any lumbar intradiscal injection procedure (e.g., injection methylene blue, dextrose, 
PRP, or glucosamine and chondroitin sulphate) at the treated disc other than discography 
or epidural steroid injection prior to treatment injection are prohibited.  The injection of 
contrast medium must be done at least 2 weeks prior to study treatment procedure.   
• Use of surgical procedures or intradiscal injections should be avoided through at least the 
24 month primary endpoint so that an accurate assessment of the treatment’s 
effectiveness can be made.  Surgical and injection interventions should only be 
undertaken if the subject’s pain, measured by VAS, and function, measured by ODI, is 
not improved compared to the baseline values since an intervention could confound the 
efficacy assessments and would classify the subject as a treatment failure. 
• Epidural steroid injections within 8 weeks prior to study treatment.  Use of epidural 
steroids post-treatment are not prohibited, but should be discouraged so that an accurate 
assessment of the treatment’s effectiveness can be made. 
• Other investigational therapy or device within 6 months prior to the treatment injection 
and/or plans to participate in any other allogeneic stem cell/progenitor cell therapy trial 
for the 36-months following. 
 
6.4.4 
Concomitant Treatments 
Subjects may continue with all other baseline medication(s).  If for any reason, a subject requires 
additional medication(s) or a change in the dose of existing medication(s), the medication(s), 
route of administration, and the reason for which it was given should be recorded.  During the 
course of the study, a subject may decide to use over the counter medication(s).  As with 
prescription medications, all over the counter medication(s), including herbal medications must 
be recorded. 
 
Furthermore, subjects will be asked about medications and treatments to deal with their low back 
pain at each follow-up visit in addition to asking about potential AEs and other medications 
being taken. 
 
6.4.5 
Determination of Baseline Bone Mineral Density 
Prior to treatment, each female subject will be screened for risk of osteoporosis using the Simple 
Calculated Osteoporosis Risk Estimation (SCORE) and each male subject will be screened for 
risk of osteoporosis using the Male Osteoporosis Risk Estimation Score (MORES).  Any female 
subject with a SCORE of ≥6 or a male subject with a MORES score of ≥6 will require a lumbar 
spine DEXA scan to be performed or, alternatively, a historic T-score to be obtained, if the prior 




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6.4.7 
Pregnancy Tests 
A serum pregnancy test will be analyzed for all females of childbearing potential at screening. 
Women of childbearing potential are defined as premenopausal and not surgically sterilized or 
postmenopausal for fewer than 2 years.  A urine pregnancy test will be performed prior to 
administration of study treatment to confirm a negative result. If the urine pregnancy test is 
positive, study drug will not be administered that day, and the result will be confirmed by a 
serum pregnancy test.  
 
Serum pregnancy tests will be performed at the central clinical laboratory, whereas urine 
pregnancy tests will be performed by qualified clinical site personnel using kits. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 




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6.4.11 
Pain Catastrophizer Scale 
Subjects will complete the Pain Catastrophizer Scale to determine whether they are a pain 
catastrophizer.  Pain catastrophizers are less likely to receive benefit from any treatment for pain 
and should be excluded from the study.  Subjects that have a score of 30 or more on the pain 
catastrophizing scale are excluded from the study. 
 
6.4.12 
Discography, if performed 
Physicians may use a discography procedure to assist in determining what level should be treated 
  
Discography is not required to be performed on all subjects.  
 
 
 
 
 
 
NOTE:  The diagnostic injection to determine if the annulus is intact can be performed as part of 
the discography procedure as long as all of the information required to be collected during the 
diagnostic injection is collected during the discography procedure. 
 
6.5 
Administration of Investigational Product 
All subjects in this study will undergo an intervertebral lumbar injection into the target disc with 
1 of 3 possible treatments: 
• “rexlemestrocel-L alone”:  
2.0 mL of rexlemestrocel-L cells in freeze media (containing approximately 6 million 
rexlemestrocel-L cells) mixed in a 1:1 ratio with saline 
• “rexlemestrocel-L + HA”:  
2.0 mL of rexlemestrocel-L cells in freeze media solution (containing approximately 6 
million rexlemestrocel-L cells) mixed in a 1:1 ratio with 1% HA 
• saline control:  
2.0mL saline solution. 
 
Vital signs will be recorded prior to injection. 
 


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The treatment injection should be performed with a pressure manometer syringe provided by the 
sponsor. 
 
The injection procedure MUST be stopped if any of the following occur: 
• The investigator cannot accurately place the needle tip in the nucleus pulposus 
• The injection pressure is greater than 100 psi 
• The subject becomes hemodynamically unstable during the injection procedure. 
 
The following information regarding the treatment procedure must be documented in source 
documentation: 
• Procedure start and stop time, including start time of thaw 
• Treatment administration stop time 
• Treatment interruption information, if applicable 
• Opening pressure of the treated disc 
• Pressure when 2mL of treatment is injected 
• Maximum injection pressure achieved 
• Total volume of treatment injected 
• Anesthesia type(s). 
 
The following evaluations will be performed after procedure, but prior to discharge: 
• Record vital signs 
• Perform a disease targeted/abbreviated physical examination  
• Perform a neurological examination (motor, sensory, reflex) to assess if the injection 
procedure has resulted in any neurologic changes.  This will be performed by the 
unblinded health care professional performing the injection procedure, to avoid the 
potential unblinding of the blinded evaluator.  The neurologic exam should be performed 
after the treatment injection but prior to discharge. 
• Prescribe post-injection rehabilitation/treatment and record any prescriptions for post-
procedure pain 
• Record concomitant medications 
• Record adverse events. 
 
All injection and post-procedure care (anesthesia, prophylactic antibiotics, rehabilitation 
regimens, etc.) will be performed in accordance with standard of care.  
 


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Subjects will be given the following directions for post-injection rehabilitation/treatment: 
• Day of Procedure – Bed Rest 
• Day After Procedure – Gentle Ambulation with gradual increase thereafter 
• Days 1 to 3 – Avoid repetitive bending, stooping and lifting greater than 10-15 lbs. 
• Return to normal daily activity when pain has subsided to their baseline. 
 
Discharge instructions will include, as needed, prescriptions for pain management.  Subjects 
should be encouraged to remain on the medication they were taking prior to treatment for the 
first 24 months following treatment.  Following study treatment, each subject should adhere to 
the prescribed post-injection rehabilitation/treatment. Additional guidance can be found in the IP 
Manual. 
 
The injection procedure is deemed to be completed upon discharge of the subject.  After 
discharge of the subject, the unblinded health care professional should have no involvement in 
assessing the subject for the protocol or making treatment decisions for the subject. 
 
6.6 
Safety Assessments 
Measurement of all safety parameters should be performed as described in Table 3.  Adverse 
event reporting is discussed in detail in Section 7.  
 
Standardized instructions for determining all other safety parameters are provided in the 
following sections. 
 
6.6.1 
Prior and Concomitant Medication and Treatment  
Concomitant medications will be recorded at all study visits.  All pharmacologic (including, but 
not limited to opioids, NSAIDs, aniline analgesics, tricyclic antidepressants and membrane 
stabilizers/anticonvulsants) and non-pharmacologic treatment used by study subjects within 
6 months prior to screening should be recorded.  Any dose modification of concomitant 
medications should be checked at each visit and recorded.  Pain medication, specifically opioids 
and non-opioids (e.g. NSAIDS and aniline analgesics), usage will also be recorded by the subject 
into an e-diary to determine actual pain medication usage over a 2-week period during screening 
and prior to each in-clinic visit. 
 
 


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All subjects will be asked to enter pain medication (e.g. opioid, NSAID and aniline analgesics) 
usage information into an e-diary during screening.  For baseline assessment of pain medication 
use, subjects should complete pain medication e-diaries for 2 weeks prior to any screening 
injection procedures (i.e., diagnostic disc injection to confirm intact annulus or discography, 
medial branch block and SI joint injection, if deemed necessary). If a subject had received a 
previous diagnostic injection procedure to confirm intact annulus or discography prior to the 
screening period (but within the permitted timeframes to serve as the baseline evaluation; see 
Section 4.2.2), the 14-day e-diary must be started at least 14 days after that injection procedure.    
If more than 4 out of 14 daily entries are missing, the subjects should be asked to continue 
completing the e-diary until 10 out of 14 daily entries are obtained.  Following study treatment, 
subjects should complete the pain medication e-diary every day for a 2 week period during the 
30 days prior to each clinic visit, other than the 1 month visit that must be conducted within the 
14 days prior to the 1 month visit using electronic diaries (e-diaries) completed by the subjects. 
At each clinic visit at least 10 of 14 daily entries should be available.  The site is to review the 
pain medication reported and log the visit within the subject’s e-diary to close the reporting for 
that visit.  
 
6.6.2 
Post-treatment Interventions at the Treated Level 
Surgical and injection interventions should be avoided through at least the 24 month primary 
endpoint follow-up.  Surgical and injection interventions should only be undertaken if the 
subject’s pain, measured by VAS, and function, measured by ODI, is not improved compared to 
the baseline values since an intervention could confound the efficacy assessments and would 
classify a subject as a treatment failure. 
 
Records of secondary interventions during the post-treatment period are collected in this study 
for use in efficacy and safety analyses.  As a safety measure, subjects requiring post-treatment 
interventions may be monitored for newly occurring AEs, and other concomitant treatments 
received in the same period of time.  Post-treatment interventions will be adjudicated by a 
blinded and independent TEC.  Following are procedures that should be considered interventions 
and consequently treatment failures for responder analyses if they occur at the treated level: 
 
Surgical Interventions 
• Spine fusion, interbody or posterolateral 
• Artificial Disc Replacement 
• Interlaminar or Spinous Process Stabilization Device Implantation 


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• Discectomy 
• Surgical Disc Decompression, including minimally invasive decompression 
procedures such as mild® 
• Laminectomy 
• Laminotomy 
• Osteotomy 
• Foraminotomy 
• Facetectomy 
• Facet Joint Ablation/Denervation/Rhizotomy 
• Disc nucleoplasty 
• Spinal cord stimulation 
• Intradiscal Electrothermal Annuloplasty 
• Intradiscal Ablation Procedures 
• Intrathecal pump implantation. 
 
Spine Injections 
• Epidural steroid injections 
• Transforaminal injection of corticosteroid 
• Injection of any anesthetic, analgesic, steroid or other potential pain relieving 
substance into the disc 
• Facet Injection of corticosteroid. 
 
For any subjects who are planning a post-treatment intervention during the course of the study, 
every effort should be made to schedule an “unscheduled visit” within a 30-day time window 
prior to the intervention.  However, if the subject’s originally scheduled visit falls within 30 days 
prior to the planned intervention, the unscheduled visit will not be necessary.   
 
 


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6.6.3 
Neurological Examination 
Neurological examination will be performed at screening and at each scheduled study visit 
thereafter.  During screening, the neurological exam will be performed twice: once at any time 
during the screening period prior to the diagnostic injection to confirm an intact annulus or 
discography, and once after the diagnostic injection, prior to discharge, to assess if the injection 
procedure has resulted in any neurologic changes.  If a historical diagnostic injection to confirm 
an intact annulus is used, the neurologic exam prior to the injection can be waived.  In this case, 
the neurological exam will be performed during the screening period and will be used as the 
subject’s baseline neurological exam for inclusion/exclusion determination as well as comparing 
to follow-up visits for any changes from baseline.  The neurological exam prior to the diagnostic 
injection to confirm an intact annulus or discography, as well as the neurologic exam prior to the 
treatment injection, will be performed by either the unblinded or blinded evaluator, but 
preferably by the blinded evaluator who is to perform neurological exams from Visit 3 through 
the duration of the study.  The post-diagnostic injection exam will be performed by the health 
care professional performing the injection procedure; this person may or may not be blinded. 
 
Additionally, a neurological examination is to be performed after the treatment injection at 
Visit 2, prior to discharge, to assess if the injection procedure has resulted in any neurologic 
changes. This examination is to be performed by the unblinded health care professional 
performing the injection procedure to avoid the potential unblinding of the blinded evaluator. 
 
The neurologic exam should include an assessment of lumbar-associated motor function, reflexes 
and sensory functions at L1-S1 and will assist in determination of adverse events. 
 
The neurological evaluation must be conducted by the investigator or by a qualified medical 
practitioner delegated by the investigator.  The components of the exam are: 
 
Motor (Muscle Strength) 
Each of the following assessments will be performed on the left and right side: 
• Hip flexion 
• Knee flexion 
• Knee extension 
• Ankle dorsiflexion 
• Ankle plantar flexion 
• Great toe dorsiflexion. 


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Subjects will receive a grade for each assessment performed (e.g., a grade for the left-sided hip 
flexion and a grade for the right-sided hip flexion). The grading system is as follows: 
0 = no movement 
1 = trace of muscle contraction 
2 = active movement without gravity 
3 = active movement against gravity 
4 = active movement against resistance 
 
A subject who receives a grade of 4 for all assessments will be considered a success for the 
motor exam.  All other subjects will be considered failures for the motor exam.  A failed baseline 
motor exam at any location would exclude the subject. 
 
Sensory Exam of Dermatome Distribution:  
Using a pinwheel, the clinician will evaluate both left and right dermatomes at each of the 
following levels: 
• Hip Girdle and Groin Area (L1) 
• Mid-anterior Thigh (L2) 
• Medial Femoral Condyle (L3) 
• Medial Malleolus (L4)  
• Dorsum 3rd MTP Joint (L5) 
• Lateral Heel (S1). 
 
Subjects will be assessed as pass/fail for the sensory exam.  A subject who experiences sensation 
in response to the pinwheel stimulus at each of the dermatomes will be considered a success for 
the sensory exam; all other subjects will be considered failures for the sensory exam.  A failed 
baseline sensory exam at any dermatome would exclude the subject 
 
Patellar and Ankle Reflex Exam: 
• Patellar:  subject is seated on a table with legs hanging at the knee.  The clinician 
administers a patellar reflex response test 3 times on both the left and right side. 
• Ankle:  subject is seated similar to the patellar reflex exam.  The clinician dorsiflexes the 
ankle to put tension on the Achilles tendon, then administers an ankle reflex response test 
3 times on both the left and right sides. 
 


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If a subject experiences at least one reflex response for both the left and right side on both the 
patellar and ankle reflex response exams, that subject will be considered a success for the reflex 
exam.  All other subjects will be considered as failures for the reflex exam.  A failed baseline 
reflex exam for either patellar or ankle reflex would exclude the subject. 
 
Subjects will also be asked if they have experienced other neurological symptoms and will be 
observed for foot drop or other gait disturbances.  Affirmative responses or positive observations 
should be reported as adverse events. 
 
6.6.4 
Disease-targeted, Abbreviated Physical Examination 
A disease targeted/abbreviated physical examination including, but not limited to, examination 
of the musculoskeletal system will be performed at screening.  Abbreviated, symptom-driven 
physical examinations noting any adverse changes or new adverse findings since baseline as 
adverse events will be performed at each subsequent evaluation through the course of the study 
(Day 0 and 1, 3, 6, 12, 18, 24 and 36 months post-treatment).  Exams must be performed by 
qualified healthcare personnel. 
 
6.6.5 
Vital Signs 
Vital signs will be recorded at screening, at Day 0 pre- and post-treatment, and at 1, 3, 6, 12, 18, 
24 and 36 months post-treatment.  
 
Vital signs will include sitting (if possible) blood pressure, heart rate per minute and oral 
temperature.  
 
On the day of the treatment injection, these should be performed prior to the procedure and then 
following the procedure, prior to discharge.  Vital sign measurements will be taken at every visit. 
 
6.6.6 
Height and Weight 
Height, weight, and BMI measurements will be performed at screening, at Day 0 and 1, 3, 6, 12, 
18, 24 and 36 months post-treatment.  
 
 


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6.6.7 
MRI Scans and X-rays 
MRI scans will be performed at screening and at 12, 18, 24 and 36 months post treatment. 
Flexion/extension X-rays and AP, lateral X-rays will be performed at screening, 1, 3, 6, 12, 18, 
24 and 36 months.  MRIs and X-ray scans should be taken on the same machine using the same 
settings, and in accordance with the radiographic guidelines provided, from baseline to 
completion of the study to minimize potential differences in results caused by use of different 
machines.  Radiographic evaluations may vary for a given subject depending on the time of day 
the assessments are made.  Therefore, for each subject, all radiographic evaluations of a specific 
type (e.g., X-ray or MRI) should be taken at the same time of day at each assessment if possible, 
preferably in the morning. 
 
Radiographic images (MRI and X-rays) will be sent to the imaging core lab for blinded, 
independent radiographic evaluation.  Review of radiographic images will be conducted by two 
blinded independent radiologists with a third reviewer to adjudicate any differences between the 
reviewers.  Review of the radiographic images for the criteria specified in the inclusion/exclusion 
to be conducted by the radiographic core lab will be conducted by two reviewers with a third 
reviewer to adjudicate any differences.  The MRI and X-ray scans will be used for efficacy 
assessments. Investigators should also evaluate images for potential safety issues, such as disc 
herniation, worsening disc morphology, heterotopic ossification (osteophytes), annular 
tears/fissures and/or changes in bony structures.  The radiographic evaluations to be conducted 
are included in Appendix 1. 
 
Investigators will review the radiographic imaging provided on-site or locally, as well as any 
associated reports.  The investigator should document his or her review, including any clinically 
significant findings.  In addition, radiographic imaging reports for screening will be made 
available to the investigator from the core imaging provider.  Investigators should review such 
reports and maintain documentation of the review and any clinically significant findings. 
Radiographic imaging and reports should be kept as part of the subject’s medical record.  
 
As differences in readings between investigators and the core imaging provider are expected, 
reconciliation between imaging assessments will not be necessary.  Throughout the course of the 
study, radiographic efficacy endpoints will be based on results from the core imaging provider.  
The investigator reviews will be used to determine any potential safety issues (including AEs).  
 
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Any changes in clinical laboratory results deemed by the investigator to be clinically significant 
(see Section 7.5) or that qualifies as an adverse event should be documented.  
All analyses, with the exception of urine pregnancy, will be performed at the central clinical 
laboratories.  
 
Specificity testing and DSA results will be blinded until the end of the follow-up period. 
 
6.7 
Efficacy Assessments  
Measurement of all efficacy parameters should be performed as described in Table 3. 
Standardized instructions for determining these parameters are provided in the following 
sections. 
 
6.7.1 
Post-treatment Interventions Affecting the Treated Disc 
Post-treatment interventions over the 36-month post-treatment period are collected in this study 
for use in efficacy analyses as well as safety analyses.  As these post-treatment interventions are 
used for all responder analyses, such interventions should be reported in a consistent manner.  In 
order to maintain standardized classification of these interventions, a TEC will be used.  
(Section 12.2) provides greater detail regarding the TEC.  
 
6.7.2 
Visual Analog Scale for Low Back Pain Evaluation 
Measuring pain intensity with a VAS is a useful and widely recognized tool in describing spine 
subjects. 60  Pain intensity is recorded on a horizontal 100 mm VAS and measured as the distance 
in millimeters from the left origin of the horizontal VAS line and the point indicated by the 
subject as representing his/her level of pain. 
 
A horizontal 100 mm visual analog scale (VAS) anchored on the left with the words “No Pain” 
and on the right with the words “Worst Possible Pain”, will be used to measure low back, right 
and left leg pain intensity. Scores are obtained by measuring the distance in millimeters from the 
left origin of the line (0) to the point indicated with a slash placed by the subject to indicate the 
subject’s level of pain.  
 
During the course of this study low back pain (average pain over 24 hours and worst pain over 
24 hours) will be measured using a 100 mm VAS at the following visits: screening, 1, 3, 6, 12, 
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over the previous 24 hours (see Appendix 2).  At screening, the VAS evaluation must be 
administered at least 2 weeks following any injections to relieve pain. 
Prior to administering the VAS, subjects will be instructed on its completion.  
 
Subjects will be asked to complete the VAS directly on the corresponding worksheet completed 
during the in-clinic follow-up visits, which will serve as source documentation for this 
measurement.  The in-clinic VAS assessments are considered the primary data source for VAS 
evaluations.  However, the study source documents should reflect the date when each subject 
successfully completes the VAS or if there are any issues with VAS administration.  The results 
of the VAS will be then transferred to the eCRF by the site using a validated method. 
 
Under no circumstances should the worksheets containing the VAS be photocopied as 
photocopying may impact the length of the VAS line(s) and corresponding measurements. 
 
Low back (average over past 24 hours and worst pain over 24 hours) and leg pain (average leg 
pain in left and right legs, individually over the past 24 hours) VAS evaluations will also be 
taken using e-diaries during the same 14 day period where pain medication usage is being 
collected.  The VAS scores will be collected every day for the 14 day period with at least 
evaluations for 7 days.  If more than 7 days of VAS scores are collected the last 7 days’ scores 
will be used to calculate the average pain over a week.   
 
Note: Low back and/or leg pain may generally be considered an adverse event and used in the 
evaluation of treatment safety.  In this study, however, low back pain is also evaluated as an 
efficacy endpoint. Section 7.3 provides further details on how AEs of low back pain are defined. 
 
6.7.3 
Oswestry Disability Index 
The ODI was first developed in 1976 as a specific outcomes tool for patients suffering from back 
pain.  The validity, consistency and reproducibility of the ODI have been extensively tested and 
reviewed by Roland and Fairbank, 2000.60  The questionnaire scores 10 aspects of the patient’s 
home and work life and analgesic use. The disability index is then calculated as a percentage 
with a high percentage indicating a high level of disability.  The ODI has been generally adopted 
since the mid-1980s to monitor the progress of patients suffering from back pain. 
 
Improvements in functional mobility in this study will be based on the results of the ODI 
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administering the ODI, subjects should be instructed on its completion.  A qualified member of 
the clinic’s staff should review the completed ODI to ensure that all questions have been covered 
and answered appropriately and that subjects use standard procedures for making corrections 
(see Appendix 3).  
 
The questionnaire will be completed by the subject on the corresponding questionnaire forms at 
their in-clinic follow-up visit, which will serve as source documentation for this measurement.  
The in-clinic ODI assessment is considered the primary data source for ODI evaluations.  The 
source documents should reflect the date when each questionnaire was successfully completed 
and any issues with its administration.  The results of the questionnaire will be then transferred to 
the eCRF by the site. 
 
An ODI evaluation will also be taken using e-diaries during the same 14 day period where pain 
medication usage is being collected.  The ODI score must be taken at least once during the 
14 day period.  If more than one ODI score is collected, the most recent ODI score will be used.     
 
6.7.4 
Radiographic Evaluations 
Plain radiographs and MR images will be used to assess the treated disc (see Appendix 1).  All 
radiographic imaging will be sent to the imaging core lab for blinded, independent radiographic 
evaluation.  Radiographic images will be assessed by two blinded and independent radiologists 
with a third reviewer to adjudicate any differences between the two reviewers. 
 
Radiographic images will be made available to the investigator.  Investigators should review 
these images, and any clinically significant findings, as well as the review itself, should be 
documented in the source. 
 
During screening, the core imaging lab will assess the provided radiographic imaging (x-ray and 
MRI).  The specified screening review assessments will be conducted by two blinded and 
independent radiologists with a third blinded and independent radiographic reviewer to 
adjudicate any differences between the two initial reviewers.  The core lab will provide the 
investigator/site a report detailing the following:  
• Modified Pfirrmann score at all lumbar levels 
• Modic changes at all lumbar levels 
• Absence or presence of disc protrusion, extrusion and/or sequestration at each lumbar 
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• Absence or presence of spondylolisthesis/retrolisthesis of Grade 2 or more at each lumbar 
level 
• Absence or presence of lumbar scoliosis of greater than a Cobb angle of 15 degrees in the 
lumbar spine. 
 
The site will use the report provided by the core radiographic lab to determine whether the 
subject can be included in the study according to the inclusion/exclusion criteria (See 
Section 4.2)
 
 
 
 
MRI will be used specifically to assess change in the qualitative status of the intervertebral disc 
according to the Modified Pfirrmann scoring system.  Each treated disc, as well as adjacent discs, 
will be evaluated for improvement from screening.  The evaluation of modified Pfirrmann 
improvement will be made at screening and 12, 18, 24 and 36 months post-treatment.  These 
evaluations will be performed by the core imaging provider.  MRI will also be used for 
evaluation of the change in macromolecular content and hydration of the treated disc by using T1 
rho and T2 mapping at facilities with this capability from baseline to 12, 18, 24 and 36 months 
post-treatment on a subset of subjects. 
 
A/P and lateral X-rays of treated and adjacent levels will be collected at screening and 1, 3, 6, 12, 
18, 24 and 36 months post-treatment.  These images will be used to determine the height of the 
treated disc and any changes from baseline.  
 
Flexion/extension X-rays will also be taken at screening and 1, 3, 6, 12, 18, 24 and 36 months 
post-treatment and will be used to determine spinal stability.  The stability metric used in this 
study will be the QMA® Stability Index (abbreviated QSI, with units of standard deviations from 
mean).  QSI is based on the translation per degree of rotation (abbreviated TPDR with units of % 
endplate width/degree) normalized per lumbar level. QSI is further defined in Appendix 1.  
 
Radiographic evaluations may vary for a given subject depending on the time of day the 
assessments are made.  Therefore, for each subject, all radiographic evaluations of a specific type 
(e.g., X-ray or MRI) should be taken at the same time of day at each assessment if possible, 
preferably in the morning. 
 


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For this study, the definition of a composite clinical stability success (CSS), relative to disc 
stability, is defined as QSI < 0 (determined by flexion and extension spine radiographs and 
indicating an improvement in disc stability compared to baseline) and at least a 50% reduction 
from baseline in low back pain VAS score (average pain over 24 hours) with no intervention at 
the treated level compared to baseline. 
 
6.7.5 
iPCQ, SAT, EQ5D, and Patient-reported Utilization Questionnaires 
The iPCQ and EQ-5D questionnaires will be administered at each study visit: screening, 1, 3, 6, 
12, 18, 24 and 36 months after treatment.  The SAT will not be performed at screening, but at all 
post-treatment visits: 1, 3, 6, 12, 18, 24 and 36 months post-treatment.  The Patient-reported 
Utilization Questionnaire will be administered at screening and 12, 18, 24 and 36 months. 
 
iMTA Productivity and Cost Questionnaire (iPCQ) 
The iPCQ is a measure of indirect costs arising outside the scope of the healthcare system, also 
known as productivity costs, that derive from health problems.  The questionnaire consists of 
3 modules focusing lost productivity due to absenteeism, presenteeism, and unpaid work (see 
Appendix 4). 
 
Self-assessment of Treatment (SAT) Questionnaire 
The SAT questionnaire is comprised of 5 items that assess subject-reported improvement and 
satisfaction with treatment (see 
Appendix 5).  
 
EuroQoL EQ-5D 
The EQ-5D is a standardized measure of health outcomes (see Appendix 6).  
 
Patient-reported Utilization Questionnaire 
This questionnaire is used as a tool for assessing direct healthcare costs related to back pain 
associated with DDD.  The questionnaire requires subjects to provide a 12 month retrospective 
of relevant healthcare usage (see Appendix 7). 
 
6.7.6 
Post-Treatment Pain Medication Usage Collected by E-Diary 
For collection of post-treatment pain medication use, subjects should be contacted by either 
IWRS or by the site, approximately 2 weeks prior to each post-treatment visit as a reminder to 
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visit other than for the 1 month visit that must be collected during the 14 days prior to the 
scheduled visit.  At least 10 daily entries out of a possible 14 should be available at each study 
visit.  Otherwise, absence of more than 4 entries will be considered a protocol deviation.  Based 
on the opioid information entered into the e-diary during the 2 weeks prior to each post-treatment 
visit, it will be determined if subjects have shifted from baseline.  Category shifts in opioid usage 
will be defined as: 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
   
 
 
   
 


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should be provided appropriate pain relief and an adverse event documented.  Should there be 
any deviation from the baseline dose, information regarding the deviation must be documented. 
 
7. 
SAFETY GUIDANCE 
7.1 
Definitions  
7.1.1 
Adverse Event 
According to the International Conference of Harmonization [ICH] guideline for Good Clinical 
Practice, an AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment.   
An AE can therefore be any of the following: 
• Unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product. 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition)  
• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline  
• Any deterioration or abnormality in a laboratory value or other clinical test (e.g., ECG, 
X-ray) that is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug  
• Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., screening procedures such as biopsies 
etc.). 
 
Adverse events will be captured following signing of the informed consent form.  Pre-existing 
conditions (i.e., medical history) which worsen during a study are to be reported as AEs. 
 
7.1.2 
Serious Adverse Event (Reportable to the Sponsor within 24 Hours) 
An SAE is any adverse event that meets any of the following criteria:  
• Fatal (i.e., the adverse event actually causes or leads to death) 
• Life threatening (i.e., the adverse event, in the view of the investigator, places the subject 
at immediate risk of death).  This does not include any adverse event that had it occurred 
in a more severe form or was allowed to continue might have caused death  
• Requires or prolongs inpatient hospitalization  


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• Results in persistent or significant disability/incapacity (i.e., the adverse event results in 
substantial disruption of the subject’s ability to conduct normal life functions) 
• Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
investigational product 
• Significant medical event in the investigator's judgment (e.g., may jeopardize the subject 
or may require medical/surgical intervention to prevent one of the outcomes listed 
above). 
 
Any AE that is defined as serious and which occurs during the course of the study, regardless of 
the treatment arm must be reported within 24 hours of the investigator becoming aware of the 
event. 
 
7.1.3 
Severity 
A clinical determination will be made of the severity of an AE.  The terms “severe” and 
“serious” are not synonymous.  Severity is a description of the intensity of the manifestation of 
the AE and is distinct from seriousness, which implies a subject outcome.  Severity will be 
assessed according the following scale: 
 
Mild 
Discomfort noticed but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect daily activity 
Severe 
Inability to work or perform normal daily activity 
 
7.2 
Relationship of Adverse Event to Study Treatment or Study Procedure 
A determination will be made of the relationship between an AE and the treatment received.  A 
causal relationship is present if a determination is made that there is a reasonable possibility that 
the AE may have been caused by the study treatment and/or study procedure.  In general, a 
causal relationship will be assigned when evidence exists to support the causal relationship.  
When assessing a potential relationship between the study treatment and/or study procedure and 
an AE, the following parameters should be considered: 
• Temporal relationship between study treatment and/or protocol-specified procedures and 
the AE 
• The biological plausibility that the study treatment and/or procedure caused the event 
• Any underlying/concurrent illness in the subject 
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• How commonly the event occurs in the study analysis set independent of treatment. 
 
Examples of evidence to suggest a causal relationship between the study treatment and/or study 
procedure and the AE include the following:  
• A single occurrence of an event that is uncommon and known to be strongly associated 
with investigational product exposure or study procedure (e.g., angioedema, discitis, 
hepatic injury, Stevens-Johnson Syndrome). 
• One or more occurrences of an event that is not commonly associated with 
investigational product exposure or study procedure, but is otherwise uncommon in the 
analysis set exposed to the drug (e.g., tendon rupture). 
 
Low back pain within 14 days of the treatment procedure is expected. 
 
7.3 
Adverse Events of Special Interest – Back Pain 
Low back pain may generally be considered an adverse event and used in the evaluation of 
treatment safety.  In this study, however, low back pain is also evaluated as an efficacy endpoint.  
Pain data provided on the low back pain VAS will not routinely be considered an adverse event 
in this study.  If a subject reports an adverse event of low back pain, the following information 
will be collected from the subject:  
1. Whether or not the pain is of increased intensity from baseline  
2. Whether or not there is an increased frequency of pain, regardless of intensity, as 
compared to baseline  
3. Whether or not the pain is in a different location in the lower back as compared to 
baseline 
4. Whether the symptoms required an unscheduled visit 
5. The subject’s assessment of the cause of the event, if any specific cause is suspected. 
 
A back pain AE should be reported if the subject answers yes to questions 1-4 above.  If a back 
pain AE is reported, the subject’s assessment of the cause of the event should also be recorded if 
any specific cause is suspected. 
7.4 
Treatment and Follow-up of AEs and SAEs 
AEs and SAEs, especially those for which there is an established relationship to investigational 
product, should be followed up until they have returned to baseline status, stabilized, or the 
follow-up period is complete.   
 


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If after the follow-up period, return to baseline status or stabilization cannot be established an 
explanation should be recorded on the eCRF. 
 
7.5 
Laboratory Test Abnormalities 
Laboratory test results will appear on electronically produced laboratory reports directly from the 
central laboratory.  Local laboratory results should be recorded on the eCRF, if applicable.  
 
Any laboratory result fulfilling the criteria for an AE or SAE should be recorded on the eCRF 
and reported to the designated responsible parties in safety accordingly.  The preference is to 
report a diagnosis rather than the laboratory value as the adverse event.  However, if a diagnosis 
has not been confirmed, a clinically significant laboratory value should be reported including a 
modifier (e.g., worsening, increased, decreased) until a final diagnosis can be reported. 
 
Any treatment-emergent clinically significant abnormal laboratory result is defined as meeting 
one or more of the following conditions: 
• Accompanied by clinical symptoms 
• Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result from 
tests performed after informed consent form signature, which fall outside the laboratory 
reference range and are considered clinically significant by the investigator.  This does not apply 
to any abnormal laboratory result which falls outside the laboratory reference range but which 
does not meet the criteria for clinical significance (these will be analyzed and reported as 
laboratory abnormalities). 
 
 
 
In the event of clinically significant abnormal laboratory test values, the tests should be repeated 
and followed up until they have returned to the normal range and/or an adequate explanation of 
the abnormality is found.  If a clear explanation is established, it should be recorded on the 
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7.6 
Unblinding  
The study blind should not be broken except in a medical emergency and only where knowledge 
of the test material received would affect the treatment. In an emergency, the investigator can 
obtain treatment assignment of any subject at their study center by contacting the medical 
monitor.  If an emergency un-blinding becomes necessary, the investigator should notify the 
CRA or medical monitor, as soon as possible.  
 
In the event treatment assignment needs to be provided to any blinded member of the sponsor 
study team, it must be done in accordance with the pre-specified blinding plan to ensure that bias 
is not introduced. 
 
Importantly, all unblinded individuals will be specifically instructed to refrain from 
discussing any potentially unblinding information with either the subject or any blinded 
site, sponsor, or CRO personnel involved in the trial. 
 
8. 
REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.1 
Reporting of Serious Adverse Events [Immediately Reportable] 
All SAEs (as described in Section 7) that occur after the subject has signed informed consent 
(including the protocol-defined follow up period), regardless of judged relationship to 
investigational product, or after the study period, if considered serious and related to 
investigational product or to the subject’s participation in the study, must be reported to the 
sponsor or designee within 24 hours of the investigator’s knowledge of the event.  All subjects 
with an SAE must be followed up and the outcomes reported until the event has returned to 
baseline status or stabilized.  In the event of an SAE, the investigator must immediately notify 
sponsor or designee.  SAE reporting will originate in the electronic data capture (EDC) system 
and an email will be sent to the designated responsible parties in safety.   
 
 
The paper SAE form is in place as a back-up in the rare event that EDC is not accessible to the 
reporter of the SAE:  
• 
 
• Provide copy of all relevant source documents, including medical history, hospital 
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All SAEs that are considered unexpected, according to the Investigator’s Brochure (IB), and 
related to the investigational medicinal product will be reported by the sponsor or its designee as 
an expedited 15-day report to the regulatory authorities as applicable and to all participating 
investigators. 
 
Fatal or life-threatening suspected adverse reactions that are considered unexpected according to 
the IB and related to investigational product will be reported by the Sponsor or its designee to the 
regulatory authorities as applicable, and to all participating investigators as an expedited 7-day 
report. 
 
Each investigator must notify the IRB/EC responsible for reviewing the study at their site of all 
15-day or 7-day safety reports required by local regulations or IRB/EC requirements and shall 
provide the sponsor or its designee with written confirmation of said IRB/EC notification. 
 
This study will comply with all local regulatory requirements and adhere to the full requirements 
of ICH Guideline for Clinical Safety Data Management, Definitions and Standards for Expedited 
Reporting, Topic E2. 
 
8.2 
Procedures for Reporting Pregnancies  
All pregnancies that occur during the study are to be reported within 24 hours to the individual 
identified in the clinical study personnel contact information section of this protocol, and the 
investigator must provide sponsor or designee, by facsimile, a signed pregnancy tracking form.  
If a subject becomes pregnant during the study, the subject will remain in the study and only the 
requirement for radiation (x-ray or MRI) should be removed.  All subjects who become pregnant 
will be monitored to the completion or termination of the pregnancy, including perinatal and 
neonatal outcome.  Monitoring of the subject should continue until conclusion of the pregnancy.  
If the pregnancy is associated with an SAE (e.g., hemorrhage, spontaneous abortion), in addition 
to the Pregnancy Form, a separate SAE form must be provided as described in Section 8.1. 
 
If a subject becomes pregnant during the study, the subject will remain in the study and only the 
requirement for radiation (x-ray or MRI) should be removed. 
 
8.3 
Expedited Reporting to Health Authorities, Investigators, IRBs, and ECs 
The sponsor will promptly evaluate all SAEs and non-serious AEs of special interest against 
cumulative product experience to identify and expeditiously communicate possible new safety 


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findings to investigators, IRBs, ECs, and applicable health authorities based on applicable 
legislation. 
 
To determine reporting requirements for single adverse event cases, the sponsor will assess the 
expectedness of these events using the current Investigator’s Brochure. 
 
The sponsor will compare the severity of each event and the cumulative event frequency reported 
for the study with the severity and frequency reported in the applicable reference document. 
 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
 
9. 
STATISTICAL CONSIDERATIONS  
9.1 
General Considerations 
The statistical analysis plan (SAP) will be finalized and submitted to the appropriate health 
authorities before any interim analysis or unblinding occurs.  The primary unblinded statistical 
analyses will be conducted by the sponsor or authorized representative after all enrolled study 
subjects who remain active in the trial at the time of their 24 month study visit have completed 
this milestone event.  
 
 Interim analyses may be performed during the course of the trial.  These will be conducted by 
external independent statistician(s) who will be unblinded to study data.  All blinded personnel 
and subjects will remain blinded to the results of the analyses.  The integrity of the study 
database will be maintained as well, and no bias will be introduced to the evaluations in the study 
due to the conduct of these interim analyses.  
 
The details of interim analyses are outlined in the Statistical Analysis Plan (SAP).  All subjects, 
independent reviewers and blinded personnel interacting with subjects will remain blinded 
through the completion of the study. 
 
The primary efficacy objective of the study is to demonstrate that either rexlemestrocel-L alone 
or rexlemestrocel-L + HA has a higher rate of treatment success—defined as 50% reduction in 
low back pain VAS score, 15 point decrease in ODI score, and no interventions at the treated 
disc—compared to the saline control arm at 12 AND 24 months post-treatment.  The significance 
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9.3 
Analysis Analysis sets 
The classification of subjects into each of the following analysis analysis sets will be determined 
prior to database lock for the 24-month data analysis and prior to the 36 month longer-term 
follow-up analysis. 
 
9.3.1 
All Enrolled Subjects Analysis Set  
All subjects who signed the informed consent are included in the All Enrolled analysis set.  The 
All Enrolled Subjects analysis set will be used for summarizing subject disposition. 
 
9.3.2 
Intent-to-Treat (ITT) Analysis Set 
The ITT analysis set includes all subjects who are randomized, regardless of whether or not the 
subject is treated, or post-treatment measurements are performed. In these analyses, subjects will 
be assigned to treatment according to randomization (not actual treatment received). The ITT 
analysis set will be used for summarizing demographics, baseline characteristics, surgical 
procedures and treatment exposure. The ITT analysis set will be used as the primary analysis set 
for all primary and secondary efficacy analyses.  As sensitivity, the efficacy analyses will also be 
performed on the Full Analysis Set, the As Treated and the Per Protocol analysis sets, as defined 
herein. 
 
9.3.3 
Full Analysis Set (FAS)  
The FAS analysis set includes all subjects who are randomized and treated or randomized with 
an attempt to administer treatment (i.e. subjects taken to procedure room to receive treatment 
whether administered or not). In these analyses, subjects will be analyzed according to the 
treatment to which they were randomized (not actual treatment received). Subjects that were 
randomized but dropped out prior to attempting treatment will be omitted from the FAS analysis 
set. 
 
9.3.4 
As Treated Analysis Set  
The As Treated analysis set includes all subjects randomized, analyzed according to the 
treatment that was actually administered. 
 


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9.3.5 
Per Protocol (PP) Analysis Set   
The per-protocol (PP) analysis set will contain all subjects in the ITT who received treatment to 
which they were randomized, had at least 1 post-treatment efficacy measurement (VAS and 
ODI), and did not experience any major protocol deviations.  
 
Protocol deviations will be determined for all randomized subjects mainly from the clinical 
database and Clinical Trial Management System (CTMS) following clinical and/or medical 
review of subject data for relevant findings that might have an impact on the definition of the PP 
analysis set/ major protocol violations. Protocol deviations that occur during the study will be 
adjudicated by the sponsor (or designee) and categorized by severity. Protocol deviations will be 
classified as minor or major during a blinded review of the data prior to the lock of the database 
for analysis. If relevant deviations are identified, they will be designated as major protocol 
violations. 
 
9.3.6 
Safety Analysis Set  
The safety analysis set will contain all subjects who were randomized and received treatment, 
and subjects will be classified according to the actual treatment received. Safety analysis set will 
be used for the safety analyses.  
 
If there is any doubt whether a subject was treated or not, they will be assumed treated 
(randomized treatment) for the purposes of analysis. 
 
9.4 
Efficacy Endpoints 
The efficacy endpoints to be assessed include: 
 
9.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be a composite responder analysis for Overall Treatment 
Success at both Study Visit 6 (12 months post-treatment) AND Study Visit 8 (24 months post-
treatment), based on pain, function and post-treatment interventions: 
• at least a 50% reduction from baseline in low back pain VAS score (average pain over 24 
hours, in-clinic assessment); AND 
• at least a 15 point decrease from baseline in ODI score (in-clinic assessment; AND 
• no interventions at the treated level. 
 










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9.6 
Statistical Methods 
9.6.1 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment arm for the ITT and 
PP analysis sets, as well as presented in data listings. 
 
Continuous variables will be summarized using descriptive statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum). In order to assess baseline comparability, 
treatment groups will be compared for all continuous variables using an ANOVA between 
individual treatment and control groups.  
 
Categorical variables will be summarized using counts and percentages for each category. 
Treatment groups will be compared for all non-missing categorical variables using a Chi-Square 
test of association. Missing categories will be presented if necessary, but excluded from any tests 
of association. 
 
Demographic data will include: 
• Sex  
• Age 
• Race (White, Hispanic-White, Hispanic non-white, Black or African American, 
American Indian/Alaska Native, Asian, Native Hawaiian or Pacific Islander, Other) 
• Smoking status (Never Smoked, Current Smoker, and Previous Smoker). 
 
General baseline characteristics will include weight, height, and BMI, and baseline 
characteristics of the index level, as assessed by independent radiologist and will be listed and 
summarized based on the following assessments collected at the screening visit:   
• Medical history, including history of disc disease (DDD) at the index level (duration of 
low back/limb pain) 
• Spinal surgery history  
• Medication history  
• VAS, ODI, iPCQ, EQ-5D questionnaire 


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• Disc degeneration, Modified Pfirrmann score, herniation presence and score, average disc 
height 
• Opioid user or opioid non-user at baseline. 
 
General medical history will be listed and summarized, as well as medication history. Spinal 
surgery history and disease-specific history will be listed only.  
 
9.6.2 
Primary Efficacy Analysis 
The Primary Efficacy Endpoint for overall treatment success (responder vs non-responder) at 
12 AND 24 months will be summarized for each treatment by numbers and percentages.  Each 
active treatment arm will be compared to the saline control group using a Bayesian test of 
superiority using non-informative Beta (0.5, 0.5) priors for each arm.  An arm will be considered 
superior to the saline arm if there is sufficiently high posterior probability that the response rate 
of that arm is higher than the saline control arm. The posterior probability threshold is 
Bonferonni-adjusted to account for multiple comparisons. The value of the posterior probability 
threshold for success will be discussed in the study statistical analysis plan (SAP). 
 
The rationale for using a Bayesian approach for the primary analysis is that we are already using 
Bayesian methodology for multiple imputation of missing data (see Section 9.9).  Keeping the 
Bayesian methodology for the primary analysis ensures a consistent framework that naturally 
synthesizes the multiply imputed outcomes into the posterior distribution.  In this way, the 
uncertainty due to missing data is naturally incorporated into the inference, without the 
cumbersome necessity of combining p-values as in a frequentist framework.   
The methods for handling missing data are discussed in Section 9.9. 
 
9.6.3 
Secondary and Other Efficacy Analyses 
The same Bayesian methodology used for the primary analysis will also be used for the 
secondary endpoints. The Bonferroni-adjusted posterior probability threshold of 0.9875 will 
apply to any subsequent secondary analyses performed.  
 
As part of the gatekeeper strategy, the evaluation will be carried out in a hierarchical fashion 
following the order given below. Specifically, if the primary endpoint objective is met, the 
secondary outcomes will be evaluated hierarchically within each arm using the posterior 
probability threshold of 0.9875 for each comparison, sequentially. Once a key secondary 
endpoint is not met at this threshold within an arm, all subsequent comparisons in that arm will 
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9.7 
Safety and Other Analyses 
The Safety Analysis Set will be used for summary and analysis of the safety endpoints. 
 
9.7.1 
Primary Safety Endpoint 
Evaluation of overall safety, which includes the following: 
• Subject reported AEs and SAEs from baseline through 24 months post-treatment, 
including adverse events of special interest (i.e., AEs of worsening low back pain)  
• Laboratory tests (hematology, serum chemistry, inflammatory markers and antibody 
analysis). Abnormal results will be assessed relative to normative ranges and shift tables 
from baseline through 24 months post-treatment  
• Reported events from radiographic imaging from baseline through 24 months post-
treatment, including disc height at the treated level  
• Post-treatment interventions affecting the treated disc through Visit 8 (24 months post-
treatment) (comparison of the proportion of subjects in each group with an adjudicated 
post-treatment intervention at the treated level, and the proportion of subjects in each 
group with an adjudicated post-treatment intervention any lumbar level) 
• Vital signs (heart rate, blood pressure and temperature) and body measurements (height, 
weight and BMI) 
• Physical examinations (abbreviated). 
• Neurological examinations (motor, sensory, reflex). 
Descriptive statistics will be used for the summary of safety parameters – the number and 
percentage will be used for the incidences of AE/SAEs, deaths, early discontinuation due to AEs, 
and post-treatment interventions.  The AE/SAE severity and relationship with the study 
procedure and treatment will be summarized and presented. 
 
The mean, standard deviation/error, minimum, median, and maximum will be used for the 
laboratory parameters.  The shift table (cross-tabulation) for the changes from baseline 
(low/normal/high) for the laboratory parameters will also be also provided and the test for 
treatment difference.  
 
Safety parameters of special interest (i.e., AEs of worsening low back pain) will be summarized 
through 24 months post-treatment by treatment arm, severity, and the time from the study 
injection to the start of the AEs (0 to ≤7 days, >7 days to < 3 months, ≥3 months to 24 Months).  
 


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The incidence of this special interest AE (worsening low back pain) occurring within 3 to 
24 months after study treatment will be also summarized, by treatment arm, for the responders 
and non-responders of the Primary Efficacy Endpoint. 
 
The actual low back pain VAS score, the changes from the baseline and the responders with at 
least 50% reduction of low back pain VAS score at the time which the AEs of low back pain 
occurs will be summarized for each treatment, and the subject data listing will be presented for 
clinical review and assessment.  Shift tables of changes in opioid use from the baseline to the 
time of AE onset will be also presented. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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9.8 
Interim Analyses 
Interim analyses may be performed during the course of the trial.  These will be conducted by 
external independent statistician(s) who will be unblinded to study data. All blinded personnel 
and subjects will remain blinded to the results of the analyses. The integrity of the study database 
will be maintained as well, and no bias will be introduced to the evaluations in the study due to 
the conduct of these interim analyses.  
 
The details of interim analyses are outlined in the Statistical Analysis Plan (SAP).  All subjects, 
independent reviewers and blinded personnel interacting with subjects will remain blinded 
through the completion of the study. 
 


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9.9 
Handling of Missing Values, Early Termination, or Non-Interpretable Data 
For the responder analyses, including the primary efficacy endpoint, as well as pain and function 
responder analyses, subjects will be classified as having attained success (responder) or not 
attained success (non-responder).  
 
The Primary Efficacy Endpoint requires a subject to meet clinically significant improvements in 
both pain and function at both 12 and 24 months, as well as not undergo any post-treatment 
intervention at the treated level through 24 months, to be considered a success.  
 
If in-clinic assessments for Study Visits 6 and 8 (corresponding to 12 and 24 months) are 
unavailable, the data will be considered missing. If a scheduled in-clinic visit is missed, the site 
should contact the subject to determine if any interventions that would classify the subject as a 
treatment failure have occurred since their last visit.  If any interventions are reported, the site 
should collect all the information required if the intervention had been reported at an in-clinic 
visit.  All intervention information collected remotely must be documented in a source document 
and/or worksheet. 
 
If a subject receives a post-treatment intervention at the treated level on or prior to the date of 
Study Visit 8 (24 months), this subject will be considered a non-responder regardless if there is 
any missing data. For example, a subject that has a post-treatment intervention at the treated 
level at the time of Study Visit 4 (3 months) would be considered a non-responder regardless of 
whether there are Visit 6 or Visit 8 data available for analysis, as they would have already failed 
one of the criteria to be considered a responder. 
 
If a subject has data available at both Study Visit 6 (12 months) and Study Visit 8 (24 months), 
with no post-treatment intervention at the treated level as of the date of Study Visit 8, that subject 
will be determined either a responder or non-responder based upon whether or not the subjects 
meets the pain and functional improvement criteria at both study visits.   
 
Any subject that is missing one or more components in an endpoint (e.g. VAS in the primary 
endpoint) at a visit will be considered a non-responder at that visit if any available component of 
the endpoint indicates that the subject is a non-responder (even if all components of the endpoint 
are not available). If none of the available components impose non-response, the outcome will be 
considered missing and will be handled according to the proposed methodology described below. 
 
Assumptions regarding responder analyses include the following: 
• If the subject does not meet the criteria of either pain or function at either Visit 6 or Visit 
8, the subject will be considered a non-responder.   
• If the subject meets the pain and function improvement criteria at both Visit 6 and Visit 
8, and has no post-treatment intervention as of the date of Visit 8, the subject will be 
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• Any subject that is a non-responder on one of the two primary study visits (Visit 6 or 
Visit 8) but has a missing outcome for the other study visit is deemed a non-responder 
and not considered to have a missing outcome for the primary analysis. 
• If a subject does not have a minimum of a visit at 3-months (Study Visit 4) they will be 
considered a non-responder.  
• Any subject that has a minimum of 3-months data (Study Visit 4) but is missing one or 
both of the two primary study visits, will have their outcome multiply imputed based on 
their available information. Separate models will be constructed for 
o Subjects that are missing one of the two primary  study visits (Visit 6 or Visit 8) 
but not both; 
o Subjects that are missing both of the primary study visits. 
 
A detailed description of the statistical methodology for multiple imputation of missing data for 
responder analyses can be found in the SAP. 
 
For subjects who have a post-treatment interventional procedure at the treated level, the analyses 
of continuous and categorical efficacy variables will include only data collected before the post-
treatment adjudicated intervention.   
 
MMRM will be used for the analysis of over time of quantitative variables and missing data will 
not be imputed.   
 
The SAP provides additional details regarding methods for handling missing data.  
 
9.10 
Subgroups 
Pre-specified subgroup analyses based on both the ITT and PP analysis sets for the primary and 
secondary efficacy variables will be performed for key demographic and baseline variables, as 
described in the SAP.  
 
10. 
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE 
All aspects of the study will be monitored by Mesoblast or authorized representatives of 
Mesoblast according to Good Clinical Practices (GCP) and Standard Operating Procedures 
(SOPs) for compliance with applicable government regulations, (i.e., Informed Consent 
Regulations [US 21CFR, Part 50] and Institutional Review Board regulations [US 21CFR, Part 
56.103]).  Access to all records, both during the trial and after trial completion, should be made 
available to Mesoblast at any time for review and audit to ensure the integrity of the data. 
  


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The investigator must conduct the protocol in accordance with applicable GCP regulations and 
guidelines; applicable Informed Consent Regulations (US 21CFR, Part 50); and in compliance 
with the Declaration of Helsinki.  Every attempt must be made to follow the protocol and to 
obtain and record all data requested for each subject at the specified times.  If data is not 
recorded per protocol, the reasons must be clearly documented on the eCRF/records. 
 
Prior to the study, at a site initiation visit or Investigators’ Meeting, a Mesoblast representative 
will review the protocol and study procedures and processes to include IP receipt, storage, and 
accountability; investigator responsibilities and staff adequacy; event reporting timelines; 
monitoring and audit requirements; study documentation responsibilities; subject enrollment 
procedures; imaging and laboratory processes; and eCRF requirements to include system training 
with the Investigator and site staff.  Additional tasks and activities may be completed as needed 
for the study. 
 
During the study all protocol-specified data will be recorded in the source documents and data 
will be entered on the eCRFs from the source documents.  Checks will be performed by the CRA 
to ensure the quality, consistency, and completeness of the data.  Instances of missing or un-
interpretable data will be resolved with the investigator or study coordinator.  Site personnel will 
be responsible for providing resolutions to the data queries and for correcting the eCRFs, as 
appropriate. 
 
Any amendments and corrections necessary will be undertaken in both the source documents and 
eCRFs (as appropriate) and countersigned by the Investigator, or documented designee, stating 
the date of the amendment/correction.  Errors must remain legible and may not be deleted with 
correction aids.  The investigator must state his/her reason for the correction of any data.  
 
10.1 
Investigator's Files/Retention of Documents 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into two different separate categories, consisting of: 1) An Investigator's Study File 
(ISF) and 2) subject clinical source documents. 
 
The ISF will contain copies of all site specific essential documents to include the 
protocol/amendments and schedule of assessments, IRB/EC and governmental approval with 
correspondence, IRB/EC-approved informed consent, IP accountability, staff curriculum vitae, 


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and other appropriate documents/correspondence. Documents should be filed in reverse 
chronological order in their specified sections.  If a document is not filed in its designated 
section, a Note to File must be generated to document the location of the document.  CRAs will 
review the file on a regular basis to ensure that all documents are complete, current, and filed 
appropriately for the study.  Documents will be collected and received to ensure that the ISF files 
are consistent with the Central Investigator File for the study.  A final reconciliation of the ISF to 
the central investigational file will be performed at the end of the study.  In addition, at the end 
of the study the investigator will receive the subject eCRF data, including an audit trail 
containing a complete record of all changes to data, query resolution correspondence, and 
reasons for changes, in a readable format on CD that must be kept with the ISF. 
 
The investigator must keep written or electronic source documents for every subject participating 
in the study. Subject clinical source documents may include hospital/clinic records, physician's 
and nurse's notes, appointment book, original laboratory reports, ECG, special assessment 
reports, signed informed consent forms, and consultant letters.  There is an increase in the 
number of sites using electronic medical records (EMR).  Access to EMRs must be “Read Only” 
to ensure that the data integrity and/or quality of the monitoring is compromised in a way.  If 
“Read Only” access is not possible, then the site should provide a printout of the records that has 
the investigator’s signature on the front page and a note that documents that the printout is a 
verified copy as of that date.  Each page should have a date or version number, be bound by a 
secure staple, or have the investigator’s (or designee’s) initials and dates on each page. 
 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
 
If the investigator cannot guarantee compliance with this archiving requirement at the 
investigational site for any or all of the documents, special arrangements must be made between 
the investigator and the sponsor to store these documents in a sealed container(s) outside of the 
site in order to ensure that they can be returned sealed to the investigator in the event of a 
regulatory audit.  Where source documents are required for continued care of subjects, 
appropriate copies should be made for storing outside of the site. 
 
 


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10.2 
Source Documents and Background Data 
The investigator shall provide to the sponsor, upon request, any required background data from 
the study documentation or clinic records.  This is particularly important in cases where errors in 
data transcription are suspected.  In cases of special problems and/or governmental queries or 
requests for audit inspections, it is also necessary for the sponsor to have direct access to the 
complete source documents, provided that subject confidentiality is protected. 
 
10.3 
Electronic Case Report Forms  
Data for this study will be recorded using eCRFs. Sites will be responsible for data entry into the 
eCRF.  In the event of discrepant data, the sponsor or designee will request clarification from the 
sites. The sites will resolve discrepant data electronically in the eCRF.  A Mesoblast 
representative, or a designee, will perform final data review and external data reconciliations 
prior to all major milestones, including database close and lock. eCRFs and correction 
documentation will be maintained in the eCRF’s audit trail.  Records retention for the study data 
will be consistent with the SOPs of the sponsor or designee. 
 
An eCRF must be completed for each screened subject.  For each screen-failed subject, the 
reason for screen failure will be collected in the screening disposition eCRF.  The entire subject 
casebook of data must be reviewed and electronically signed by the investigator or by an 
authorized delegate from the study staff.  This also applies to records for those randomized-not-
treated and randomized subjects who fail to complete the study.  If a subject withdraws early 
from the study, the reason must be noted at the end of the study eCRF.  If a subject is withdrawn 
from the study because of a treatment-limiting AE, attempts should be made to clearly document 
the outcome. 
 
Sites will receive training for appropriate eCRF completion.  All eCRFs should be completed by 
designated, trained site staff. eCRFs should be reviewed and electronically signed and dated by 
the investigator or designee. 
At the end of the study, the investigator will receive subject data for his or her site in a readable 
format on a compact disc that must be kept with the study records.  Acknowledgement of receipt 
of the compact disc is required. 
 


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10.4 
Other Electronic Data 
Data from the central laboratory, core imaging provider, and electronic diary vendor will be sent 
directly to the sponsor or designee, using SOPs to handle and process the electronic transfer of 
these data. 
 
10.5 
Coding of Medical Terms 
Medical coding of verbatim medical terms will be performed for this study.  The verbatim terms 
for medical history, adverse events, reason for intervention/procedure will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA; English Version 17.0; Release date 
March 1, 2015 or more recent version).  Concomitant medications, including pain medications 
from the subject e-diaries will be coded using the World Health Organization Drug Dictionary 
Enhanced (WHODDE; version March 1, 2015 release date or more recent version).   
 
10.6 
Audits and Inspections 
Source documents for this trial must be made available by the investigator to appropriately 
qualified personnel from the sponsor’s (or designee's) Quality Assurance Unit or its designees, 
IRBs/ECs, or to health authority inspectors, upon appropriate notification.  Verification of the 
eCRF data must be by direct inspection of source documents. 
 
11. 
MONITORING OF STUDY 
The sponsor’s responsible CRA (or designee) will contact and visit the investigator regularly and 
will be permitted, upon request, to inspect the trial records, including eCRFs and other pertinent 
data, provided that subject confidentiality is maintained in accordance with local requirements. 
 
CRAs will visit the sites to review the accuracy of entries on the eCRFs, the adherence to the 
protocol and to GCP, the progress of enrollment, continued acceptability of site staff, facilities, 
third party vendors and equipment, address outstanding actions/issues, ensure protocol 
amendments and approval are acknowledged and filed appropriately, verify that laboratory test 
results are being assessed in a timely manner, and discuss findings with the investigator (or 
designee).  At regular intervals, CRAs will review the ISF to establish that all essential 
documents are present, current, and accurately filed.  The investigator (or designee) must agree 
to cooperate with the CRA to ensure that any problems detected in the course of these 
monitoring visits are resolved. CRAs will work according to the Source Documentation Plan. 
The CRAs will complete source document verification activities to verify that the correct version 


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of the informed consent form has been used to consent the subjects before any study activities 
began; verify that all subjects enrolled into the study are eligible for enrollment; ensure that all 
protocol deviations have been recorded and events are reported according to timelines and study 
specifications; and confirm that changes made in the data have been made by appropriate staff, 
that all resolved queries have been reviewed and approved by the investigator, and that the 
investigator has reviewed all clinical data.  
 
A separate unblinded CRA will ensure that the investigational product is being stored, prepared, 
administered, and accounted for according to specifications.  
 
A final close-out visit will be performed at the end of the study.  The CRA will complete any 
source data verification tasks, ensure that all events have been documented, reported, and 
followed-up appropriately.  The CRA will remind the investigator to report the end of the study 
to the IRB/EC.  This CRA will also perform a final reconciliation of IP and ensure the return or 
destruction of IP. complete the reconciliation of the ISF against the CIF and collect all 
documents required, confirm that all biological samples are labeled, stored, and/or shipped 
appropriately, review with the investigator regulatory and financial responsibilities, and any 
miscellaneous tasks as needed.  
 
Follow-up activities after each monitoring visit will include the dissemination of a follow-up 
letter to the investigator to document any issues and corrective actions.  Other activities will be 
the follow-up of any outstanding questions, outstanding data clarification forms, pending 
financial issues, and confirming the submission of any unreported events.  
 
12. 
STUDY COMMITTEES 
12.1 
Independent Data and Safety Monitoring Board (DSMB) 
The DSMB is an independent multidisciplinary group (independent of both the sponsor and 
CRO) who collectively has experience in the management of participating subjects as well as in 
the conduct and monitoring of randomized clinical trials.   
 
The DSMB will meet at regular intervals, and if needed, on an ad hoc basis.  The DSMB will 
review enrollment progress, baseline characteristics of the study analysis set, all treatment-
emergent safety reports, study findings including relevant clinical and non-clinical results, and 
status of therapeutic benefit.  DSMB reviews will be unblinded to treatment allocation.  The 
members of the DSMB will be notified of all SAEs.  


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The DSMB will recommend one of the following at each of their meetings: 
• Continue the trial 
• Modify the trial (amend the protocol) 
• Stop enrollment in the trial. 
 
Additional details regarding the specifics of the DSMB operations may be found in the 
DSMB Charter. 
 
12.2 
Treatment Events Committee 
A Treatment Events Committee (TEC) will be used during the course of the study in order to 
perform ongoing independent adjudication, identification and classification of post-treatment 
interventions at the treated disc and adjudication of the relatedness of adverse events to the 
product and/or procedure. 
 
Additional details regarding the specifics of the TEC operations may be found in the 
TEC Charter and SAP. 
 
12.2.1 
Post-treatment Interventions at the Treated Level 
As one of the criteria defining some of the primary endpoints, post-treatment interventions 
should be reported in a consistent manner. In order to maintain standardized classification of 
these interventions, the TEC will be used.  The TEC will evaluate all interventions after the 
treatment procedure to determine if an intervention has occurred at the treated level, indicating a 
failure of the treatment to provide symptomatic improvement (“treatment failure”). TEC 
Members will also have an opportunity to identify post-treatment interventions that may not have 
been reported previously. 
 
 


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Following is a list of procedures at the index level that will be considered an intervention and 
treatment failure for responder analyses: 
Surgical Interventions 
• Spine fusion, interbody or posterolateral 
• Artificial Disc Replacement 
• Interlaminar or Spinous Process Stabilization Device Implantation 
• Discectomy 
• Surgical Disc Decompression, including minimally invasive decompression 
procedures such as mild® 
• Laminectomy 
• Laminotomy 
• Osteotomy 
• Foraminotomy 
• Facetectomy 
• Facet Joint Ablation/Denervation/Rhizotomy 
• Disc nucleoplasty 
• Spinal cord stimulation 
• Intradiscal Electrothermal Annuloplasty 
• Intradiscal Ablation Procedures 
• Intrathecal pump implantation. 
 
Spine Injections 
• Epidural steroid injections 
• Transforaminal injection of corticosteroid 
• Injection of any anesthetic, analgesic steroid or other potential pain relieving 
substance into the disc 
• Facet Injection of corticosteroid. 
 
 


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13. 
LAWS, REGULATIONS, AND ETHICS 
13.1 
Local Regulations/Declaration of Helsinki 
This clinical study shall be conducted in full compliance with current material and relevant laws 
and regulations and investigator will use best efforts to ensure such compliance.  This clinical 
study will also be conducted in compliance with principles outlined in the “Guideline for Good 
Clinical Practices” ICH tripartite Guideline61 and with the ethical principles of the “Declaration 
of Helsinki”62 or with the laws and regulations of the country in which the research is conducted, 
including but not limited to the EU Clinical Trial Directive.63 
 
13.2 
Informed Consent  
It is the responsibility of the investigator, or a person designated by the investigator if local 
regulations permit, to obtain signed informed consent from each subject prior to the subject’s 
participation in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study.  For subjects who are not qualified to or are incapable of 
giving legal consent, written consent must be obtained from a legally acceptable representative. 
In cases where both the subject and his/her legal representative are unable to read, an impartial 
witness must be present during the entire informed consent discussion.  After the subject and 
representative have orally consented to participation in the trial, the witness’ signature on the 
form would attest that the information in the consent form was accurately explained and 
understood.  The investigator or designee must also ensure that the subject understands he/she is 
free to refuse to enter or withdraw from the study at any time and for any reason, that a copy of 
the consent would be provided to the subject, and that the process by which consent is obtained 
is described in the source documentation.  A subject’s informed consent in this study will include 
permission for the release of any non-study-related medical records that will provide data for 
pharmacoeconomic analyses.  However, this is optional and will not impact a subject’s 
participation in the study. 
 
The eCRFs for this study will contain a section for documenting subject informed consent, which 
must be completed appropriately.  If new safety information results in significant changes in the 
benefit/risk assessment, the consent form should be reviewed and updated.  All subjects, 
including those already being treated, should be informed of the new information, provided with 
a copy of the revised form, and give their consent to continue in the study in accordance with the 
IRB/EC requirements.  
 


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Subjects will authorize the use of their protected health information during the informed consent 
process in accordance with the applicable privacy requirements (HIPAA, local Regulatory 
Agency, etc.).  Subjects who deny permission to use and disclose protected health information 
will not be eligible to participate in the study.  The Investigator will ensure that study documents 
forwarded to Mesoblast, and any other documents, contain no mention of subject names or other 
sensitive information, in accordance with local privacy requirements. 
 
13.3 
Institutional Review Board/ Ethics Committees (IRB/EC) 
It is the understanding of the sponsor that this protocol and any modifications as well as 
appropriate consent procedures, any accompanying material provided to the subject, such as 
subject information sheets or descriptions of the study used to obtain informed consent and 
advertisements or compensation given to the subject, will be reviewed and approved by 
appropriate Competent Authority and IRBs/ECs. 
 
Before initiation of the trial at each investigational site, approval from the appropriate IRB/EC 
must be obtained.  Written approval must be obtained before the investigational product is 
released to the investigator.  
 
Any extensions or renewals of IRB/EC approval must be obtained during the course of the study.  
If required, approvals must also be obtained for any changes to the protocol, the informed 
consent form, the written information provided to subjects and/or other procedures. 
 
Any new information that may adversely affect the safety of the subjects or the conduct of the 
study will be reported promptly to the IRB/EC by the investigator and/or the sponsor, in 
accordance with applicable local requirements.  Written summaries of the study status will be 
submitted to the IRB/EC annually, or more frequently if required by the IRB/EC. On completion 
of the study, the IRB/EC will be notified that the study has ended. 
 
The Investigator must notify Mesoblast immediately if the responsible IRB/EC has been 
disqualified, IRB/EC approval has been suspended, or if proceedings leading to disqualification 
have begun. 
 
 


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13.4 
Protocol Adherence 
Investigators will ensure that due diligence is applied in order to avoid protocol deviations. 
Protocol waivers will not be granted; however, if the site needs to deviate from the protocol to 
remove a subject from an immediate safety hazard, permission is not required.  When protocol 
deviations do occur, they should be recorded and a CRA notified.  The clinical study report will 
provide a discussion of protocol deviations that occurred during the study.  
 
14. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Requests from investigators to modify the protocol for ongoing studies will be considered only 
by consultation between an appropriate representative of the sponsor and the investigator. 
Protocol modifications must be prepared by a representative of the sponsor and initially reviewed 
and approved by the sponsor. 
 
All protocol modifications must be submitted to the appropriate IRB/EC for information and 
approval in accordance with local requirements, and to regulatory agencies if required.  Approval 
must be obtained before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to trial subjects, or when the change(s) involves only logistical or 
administrative aspects of the trial (e.g., change in monitor[s], change of telephone number[s]). 
 
15. 
CONDITIONS FOR TERMINATING THE STUDY 
Mesoblast reserves the right to terminate the study at any or any study site at any time under the 
conditions specified in the Clinical Trial Agreement.  Termination will be preceded by written 
notices and submitted a reasonable time in advance of the intended termination.  The Investigator 
may also terminate the protocol at his or her site for reasonable cause, after providing written 
notice to Mesoblast a reasonable time in advance of the intended termination.  Advance notice is 
not required by either party if the protocol is stopped due to safety concerns.  If Mesoblast 
terminates the protocol for safety reasons, it will immediately notify the investigator by 
telephone and subsequently provide written instructions for termination.  If the investigator 
elects to terminate the study at his or her site, the investigator will be responsible for returning all 
investigational products and study-related documents to the sponsor in a timely manner.  Source 
documents supporting study-related data must be retained by the investigator as previously 
described. In the event the trial is terminated before the planned completion date, action will be 
taken to assure the protection of the subjects’ interests. 
 


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15.1 
Early Termination of Study 
Conditions that may warrant termination of the study include, but are not limited to, the 
following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study or if, in the sponsor’s judgment there are no further benefits to be achieved 
from the study. 
• A decision on the part of Mesoblast to suspend or discontinue testing, evaluation or 
development of a product. 
 
15.2 
Early Termination of a Study Site 
The study site may warrant suspension, closure and/or termination for the following reasons: 
• Failure of the investigator to enroll subjects into the study at an acceptable rate 
• Failure of the investigator to comply with pertinent regulatory authority regulations 
• Submission of knowingly false information from the study site to Mesoblast, its 
designee(s), study monitor, or a regulatory authority 
• Insufficient adherence to the protocol requirements 
• At the request of the investigator. 
 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
21 CFR 312.50 and 21 CFR 312.56, or applicable local regulations. 
 
15.3 
Study Stopping Rules Based on Safety Monitoring 
Safety will be continuously monitored.  All SAEs reported or observed during the trial, whether 
protocol defined or not and whether or not attributable to the IP, must be reported to Mesoblast 
within 24 hours of the knowledge of the occurrence.  
 
Mesoblast will notify all regulatory authorities and investigators in an expedited manner 
(according to 21 CFR 312.32, Directive 2001/83/EC or specified criteria stipulated in the 
institutions approval) by telephone or by facsimile transmission of any unexpected fatal or life-
threatening experience associated with the use of the IP as soon as possible but in no event later 
than 7 calendar days after their initial receipt of the information.  All other unexpected serious 
adverse reactions will be reported to all regulatory authorities and investigators within 15 days of 
receipt of the information.   
 


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16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The investigator must ensure that subject anonymity is maintained and that subject identity is 
protected from unauthorized parties.  On eCRFs or other documents submitted to the sponsor, 
subjects should be referenced by an identification code rather than by their names.  The 
investigator should keep a subject enrollment log showing codes, names and addresses.  The 
investigator should maintain documents that will not be submitted to the sponsor (e.g., subjects’ 
written consent forms) in strict confidence. 
 
17. 
PUBLICATION POLICY  
Mesoblast, Inc. shall retain ownership of all data.  All proposed publications based on this study must 
be subject to the sponsor’s approval requirements. 
 
 


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18. 
REFERENCES 
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3. Miller JA, Schmatz C, Schultz AB. Lumbar disc degeneration: correlation with age, sex, 
and spine level in 600 autopsy specimens. Spine 1988;13:173–8.  
4. Boos N, Dreier D, Hilfiker E, et al. Tissue characterization of symptomatic and 
asymptomatic disc herniations by quantitative magnetic resonance imaging. J Orthop Res 
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5. Antoniou J, Pike GB, Steffen T, et al. Quantitative magnetic resonance imaging in the 
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6. Boos N, Wallin A, Schmucker T, Aebi M, Boesch C. Quantitative MR imaging of lumbar 
intervertebral disc and vertebral bodies: methodology, reproducibility, and preliminary 
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7. DePalma MJ, Ketchum JM, Saullo T.  What is the source of chronic low back pain and 
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8. Walker MH and Anderson DG.  Molecular basis of intervertebral disc degeneration. The 
Spine Journal. 4 (2004) 158S-166S. 
9. Inoue N and Orias AAE.  Biomechanics of Intervertebral Disk Degeneration. Orthop Clin 
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10. Chan WCW, Sze KL, Samartzis, Leung VYL, Chan D.  Structure and biology of the 
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12. Karppinen J, Shen FH, Luk KDK, Andersson GBJ, Cheung KMC.  Management of 
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13. Stokes IA, Frymoyer JW.  Segmental motion and instability. Spine (Phila Pa 1976). 1987 
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15. Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and 
disc content. Nat Rev Rheumatol. 2014 Jan;10(1):44-56. 


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16. Anderson DG and Tannoury C.  Molecular pathogenic factors in symptomatic disc 
degeneration.  The Spine Journal. 5 (2005) 260S-266S. 
17. Buckwalter JA, Martin J. Intervertebral disk degeneration and back pain. In: Gordon SL, 
editor. Low back pain: A scientific and clinical overview. Rosemont, IL: American 
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18. Iatridis JC, Nicoll SB, Michalek AJ, Wlater BA, Gupta MS.  Role of biomechanics in 
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19. Omoigui S.  The biochemical origin of pain-Proposing a new law of pain: The origin of 
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pain. Medical Hypotheses (2007) 69, 70-82. 
20. Walker BF, Muller R, Grant WD.  Low back pain in Australian adults. The economic 
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21. Williams DA, Feuerstein M, Durbin D, Pezzullo J.  Health care and indemnity costs 
across the natural history of disability in occupational low back pain.  Spine 23:2329-
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22. Maetzel A, Li L.  The economic burden of low back pain: a review of studies published 
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23. Chen L, et al.  Lack of correlation between opioid dose adjustment and pain score change 
in a group of chronic pain patients.  J Pain. 2013; 14:384–392. 
24. Kissin I.  Long-term opioid treatment of chronic non-malignant pain:  unproven efficacy 
and neglected safety?  J Pain Res.  2013;6:513-529. 
25. Ashworth J, et al.  Opioid use among low back pain patients in primary care:  Is opioid 
prescription associated with disability at 6-month follow-up?  PAIN 2013;154:1038-
1044. 
26. Psaltis PJ, Paton S, See F, et al. Enrichment for STRO-1 expression enhances the 
cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell 
analysis sets. Journal of cellular physiology. May 2010;223(2):530-540. 
27. See F, Seki T, Psaltis PJ, et al. Therapeutic effects of human STRO-3-selected 
mesenchymal precursor cells and their soluble factors in experimental myocardial 
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28. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. 
Experimental hematology. Aug 2000;28(8):875-884. 


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29. Gronthos S, Fitter S, Diamond P, Simmons PJ, Itescu S, Zannettino AC. A novel 
monoclonal antibody (STRO-3) identifies an isoform of tissue nonspecific alkaline 
phosphatase expressed by multipotent bone marrow stromal stem cells. Stem cells and 
development. Dec 2007;16(6):953-963. 
30. Simmons PJ, Torok-Storb B. Identification of stromal cell precursors in human bone 
marrow by a novel monoclonal antibody, STRO-1. Blood. Jul 1 1991;78(1):55-62. 
31. Gronthos S, Graves SE, Ohta S, Simmons PJ. The STRO-1+ fraction of adult human 
bone marrow contains the osteogenic precursors. Blood. Dec 15 1994;84(12):4164-4173. 
32. Dennis JE, Carbillet JP, Caplan AI, Charbord P. The STRO-1+ marrow cell analysis set 
is multipotential. Cells, tissues, organs. 2002;170(2-3):73-82. 
33. Gronthos S, Zannettino AC, Hay SJ, et al. Molecular and cellular characterisation of 
highly purified stromal stem cells derived from human bone marrow. Journal of cell 
science. May 1 2003;116(Pt 9):1827-1835. 
34. Owen M, Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. 
Ciba Foundation symposium. 1988;136:42-60. 
35. Cardis E, Vrijheid M, Blettner M, et al. Risk of cancer after low doses of ionising 
radiation: retrospective cohort study in 15 countries. BMJ 331(7508):77. 2005. 
36. http://www.radiologyinfo.org/en/safety/index.cfm?pg=sfty_xray 
37. Huda W, Vance A. Patient radiation doses from adult and pediatric CT. Am J of 
Roentgenology 188(2):540-6. 2007. 
38. http://www.fda.gov/radiation-emittingproducts/radiationemittingproductsandprocedures/ 
medicalimaging/medicalx-rays/ucm115329.htm  
39. http://www.cancer.org/cancer/cancerbasics/lifetime-probability-of-developing-or-dying-
from-cancer 
40. AAPM Position Statement on Radiation Risks from Medical Imaging Procedures.  Policy 
Date 13-Dec-2011.  
http://www.aapm.org/org/policies/details.asp?id=318&type=PP&current=true.  Date 
accessed 16-Sep-14 
41. Willems PC, Jacobs W, Duinkerke ES, et al. Lumbar discography: should we use 
prophylactic antibiotics A study of 435 consecutive discograms and a systematic review 
of the literature. J Spinal Disord Tech 2004; 17(3):243-7. 
42. Guyer RD, Ohnmeiss DD. Lumbar discography. Position statement from the North 
American Spine Society Diagnostic and Therapeutic Committee. Spine 1995; 
20(18):2048-59. 
43. Fraser RD, Osti OL, Vernon-Roberts B. Discitis after discography. J Bone Joint Surg Br 
1987;69(1):26-35. 


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44. Osti OL, Fraser RD, Vernon-Roberts B. Discitis after discography. The role of 
prophylactic antibiotics. J Bone Joint Surg Br 1990; 72(2):271-4. 
45. Tehranzadeh J. Discography 2000. Radiol Clin North Am 1998; 36(3):463-95. 
46. Anderson MW. Lumbar discography: an update. Semin Roentgenol 2004; 39(1):52-67. 
47. Fenton DS, Czervionke LF. Discography. Fenton DS, Czervionke LF, Mayo Foundation 
for Medical Education and Research. Image-guided spine intervention. Philadelphia, PA: 
Saunders, 2003:227-55. 
48. Flanagan MN, Chung BU. Roentgenographic changes in 188 patients 10-20 years after 
discography and chemonucleolysis. Spine 1986; 11(5):444-8. 
49. Johnson RG. Does discography injure normal discs. An analysis of repeat discograms. 
Spine 1989; 14(4):424-6. 
50. Carragee E, Don A, Hurwitz E, et al. 2009 ISSLS Prize Winner: Does Discography 
Cause, Accelerated Progression of Degeneration Changes in the Lumbar Disc:  A Ten-
Year Matched Cohort Study, SPINE 2009; Volume 34, Number 21, pp 2338–2345. 
51. Manchikanti L, Benyamin R, Singh V, et al. An Update of the Systematic Appraisal of 
the Accuracy and Utility of Lumbar Discography in Chronic Low Back Pain. Pain 
Physician 2013; 16:SE55-SE95 • ISSN 2150-1149. 
52. Roque V, Agre M, Barroso J, Brito I. Managing knee ostheoarthritis: efficacy of 
hyaluronic acid injections. Acta Reumatol Port. 2013 Jul-Sep;38(3):154-61. 
53. Euflexxa [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc; 2011. 
54. Hyalgan [package insert]. Parsippany, NJ: Fidia Pharma USA Inc; 2013. 
55. Gel-One [package insert]. Warsaw, IN: Zimmer; 2011. 
56. Supartz [package insert]. Durham, NC: Bioventus LLC; 2012. 
57. Monovisc [information for prescribers]. Bedford, MA: DePuy Synthes Mitek Sports 
Medicine; 2014. 
58. Orthovisc [package insert]. Raynham, MA: DePuy Synthes Mitek Sports Medicine; 2014. 
59. Laslett M1, Williams M. The reliability of selected pain provocation tests for sacroiliac 
joint pathology. Spine (Phila Pa 1976). 1994 Jun 1;19(11):1243-9. 
60. Roland M(1), Fairbank J. The Roland-Morris Disability Questionnaire and the Oswestry 
Disability Questionnaire. Spine (Phila Pa 1976). 2000 Dec 15;25(24):3115-24.. 
61. International Conference on Harmonisation of technical requirements for registration of 
pharmaceuticals for human u. ICH harmonized tripartite guideline: Guideline for Good 
Clinical Practice. Journal of postgraduate medicine. Jan-Mar 2001;47(1):45-50. 
62. World Medical A. World Medical Association Declaration of Helsinki: ethical principles 
for medical research involving human patients. JAMA : the journal of the American 
Medical Association. Nov 27 2013;310(20):2191-2194. 


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63. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member 
states relating to the implementation of good clinical practice in the conduct of clinical 
trials on medicinal products for human use. 
 


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19. 
APPENDICES 
 
 
 


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Appendix 2:  Visual Analogue Scale (VAS): average low back pain, worst back pain, 
average leg pain 
 
 


Appendix 2:  Visual Analogue Scales (VAS) 
Version 2.0 
 
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Appendix 2: Visual Analogue Scales (VAS) 
 
Low Back Pain VAS – Average Pain Over 24 Hours 
 
What was your average low back pain over the last 24 hours? 
 
 
No pain 
 
 
 
 
 
 
 
 
The strongest 
 
 
 
 
 
 
 
 
 
possible pain 
 
 
 
 
 
 
 
 
 
 
          
 
Low Back Pain VAS – Worst Pain Over 24 Hours 
 
What was your worst low back pain over the last 24 hours? 
 
No pain 
 
 
 
 
 
 
 
 
The strongest 
 
 
 
 
 
 
 
 
 
possible pain 
 
 
 
 
 
 
 
 
 
 
          
 
 
Right Pain Vas – Average Pain Over 24 Hours 
 
What was your average right leg pain over the last 24 hours? 
 
 
No pain 
 
 
 
 
 
 
 
 
The strongest 
 
 
 
 
 
 
 
 
 
possible pain 
 
 
 
 
 
 
 
 
 
 
          
 
 
Left Leg Pain VAS – Average Pain Over 24 Hours 
 
What was your average left leg pain over the last 24 hours? 
 
 
No pain 
 
 
 
 
 
 
 
 
The strongest 
 
 
 
 
 
 
 
 
 
possible pain 
 
 
 
 
 
 
 
 
 
 
          
 
 
 
Do not photocopy for use. 


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Appendix 3:  Oswestry Disability Index (ODI) 
 
 


 
 
 
 
ODI © Jeremy Fairbank, 1980. All Rights Reserved. 
 
ODI - United States/English - Version of 29 Jul 11 - Mapi. 
ID6287 / ODI_AU2.1a_eng-US.doc 
 
Oswestry Disability Index Version 2.1a 
 
This questionnaire is designed to give us information as to how your back (or leg) trouble 
affects your ability to manage in everyday life. 
Please answer every section.  Mark one box only in each section that most closely 
describes you today.   
 
Section 1 - Pain intensity 
 
I have no pain at the moment.  
 
The pain is very mild at the moment. 
 
The pain is moderate at the moment. 
 
The pain is fairly severe at the moment. 
 
The pain is very severe at the moment. 
 
The pain is the worst imaginable at the moment. 
Section 2 - Personal care (washing, dressing, etc.) 
 
I can look after myself normally without causing additional pain. 
 
I can look after myself normally but it is very painful. 
 
It is painful to look after myself and I am slow and careful. 
 
I need some help but manage most of my personal care. 
 
I need help every day in most aspects of my personal care. 
 
I do not get dressed, I wash with difficulty and stay in bed. 
Section 3 - Lifting 
 
I can lift heavy weights without additional pain. 
 
I can lift heavy weights but it gives me additional pain. 
 
Pain prevents me from lifting heavy weights off the floor but I can manage if they are 
conveniently positioned, e.g. on a table. 
 
Pain prevents me from lifting heavy weights but I can manage light to medium weights if they 
are conveniently positioned.  
 
I can only lift very light weights. 
 
I cannot lift or carry anything at all. 
 


 
 
 
 
ODI © Jeremy Fairbank, 1980. All Rights Reserved. 
 
ODI - United States/English - Version of 29 Jul 11 - Mapi. 
ID6287 / ODI_AU2.1a_eng-US.doc 
 
Section 4 - Walking 
 
Pain does not prevent me from walking any distance. 
Pain prevents me from walking more than one mile. 
 
Pain prevents me from walking more than a quarter of a mile. 
 
Pain prevents me from walking more than 100 yards. 
I can only walk using a cane or crutches. 
 
I am in bed most of the time and have to crawl to the toilet. 
Section 5 - Sitting 
 
I can sit in any chair as long as I like. 
 
I can sit in my favorite chair as long as I like. 
 
Pain prevents me from sitting for more than 1 hour. 
 
Pain prevents me from sitting for more than half an hour. 
 
Pain prevents me from sitting for more than 10 minutes. 
 
Pain prevents me from sitting at all. 
Section 6 - Standing 
 
I can stand as long as I want without additional pain. 
 
I can stand as long as I want but it gives me additional pain. 
 
Pain prevents me from standing for more than 1 hour. 
 
Pain prevents me from standing for more than half an hour. 
 
Pain prevents me from standing for more than 10 minutes. 
 
Pain prevents me from standing at all. 
Section 7 - Sleeping 
 
My sleep is never interrupted by pain. 
 
My sleep is occasionally interrupted by pain. 
 
Because of pain I have less than 6 hours sleep. 
 
Because of pain I have less than 4 hours sleep. 
 
Because of pain I have less than 2 hours sleep. 
 
Pain prevents me from sleeping at all. 


 
 
 
 
ODI © Jeremy Fairbank, 1980. All Rights Reserved. 
 
ODI - United States/English - Version of 29 Jul 11 - Mapi. 
ID6287 / ODI_AU2.1a_eng-US.doc 
 
Section 8 - Sex life (if applicable) 
 
My sex life is normal and causes no additional pain. 
 
My sex life is normal but causes some additional pain. 
 
My sex life is nearly normal but is very painful. 
 
My sex life is severely restricted by pain. 
 
My sex life is nearly non existent because of pain. 
 
Pain prevents me from having any sex life at all. 
Section 9 - Social life 
 
My social life is normal and causes me no additional pain. 
 
My social life is normal but increases the degree of pain. 
 
Pain has no significant effect on my social life apart from limiting my more energetic interests, 
e.g. sport, etc. 
 
Pain has restricted my social life and I do not go out as often. 
 
Pain has restricted my social life to home. 
 
I have no social life because of pain. 
Section 10 - Traveling 
I can travel anywhere without pain. 
 
I can travel anywhere but it gives me additional pain. 
 
Pain is bad but I am able to manage trips over two hours. 
Pain restricts me to trips of less than one hour. 
 
Pain restricts me to short necessary trips of under 30 minutes. 
 
Pain prevents me from traveling except to receive treatment. 
 
Result  
Your ODI = 
%  
 
ODI% = Total score/5 x Number of questions answered x 100 


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Appendix 4:  iMTA Productivity and Cost Questionnaire (iPCQ) 
 
 


1 
Appendix 4: iMTA Productivity and Cost Questionnaire 
 
 
 
Please read this first! 
 
Who is this questionnaire for? 
This questionnaire is for you. There are different possibilities: 
 
You received this form from your (family) doctor or from (the) hospital. 
 
You received this form in the post with your name posted on the envelope. 
 
 
You cannot fill in the form on your own? 
If you are unable to fill in the form on your own, maybe someone can help you, for example a 
member of the family. 
 
What is the questionnaire about? 
The questionnaire is about your health and work during the last four weeks. We will start with 
general questions, for example about your gender and date of birth. 
 
 
How long does it take to fill in the form? 
It takes about 10 minutes to fill in the form. 
 
How should you fill in the form? 
 
Start with the first question and follow the numbering. 
 
Put 1 x in the question box, unless the question states that you may put more than 1 x. 
 
For some of the questions you may fill in a number or otherwise on the dotted line. 
 
There are no wrong answers. 
 
Do you want to change an answer? 
 
Cross out the old answer. 
 
Put an x in the new answer box. 
 
Put an arrow in front of the new answer. 
 
 
 old answer 
 
  new answer 
 
What happens to your answers? 
Your answers will be used for research. Only the researchers will see your answers. That 
means therefore no one else. 
 
The researchers do not write your name anywhere. And they will not tell anyone that you have 
participated in this research project. 
 
We greatly appreciate that you are willing to fill in this form for us! 


Appendix 4: iMTA Productivity and Cost Questionnaire 
 
 
 
General questions 
 
 
Question A1. What is the date while you are filling in this questionnaire? 
 
day 
month 
year 
 
 
 
 
 
Question A2. What is your date of birth? 
 
 
day 
month 
year 
 
 
 
Question A3. What is your gender? 
 
  Male 
  Female 
 
 
Question A4. What is the highest degree in education that you have 
achieved? Look for your highest degree in education and fill in an x in the box. 
 
  I never finished school or training programme 
  Primary school or elementary school 
  Junior vocational education 
  Lower general secondary school 
  Intermediate vocational education 
  Higher general secondary education 
  School for higher vocational education 
  University 
  I achieved another degree, namely…………… 
……………………………………………………………………. 
 
Question A5. What do you do? Place an x in the box for what you usually do. 
 
  I go to school, I am studying 
  I am employed 
  I am self employed 
  I am a housewife, househusband 
 
 
  I am unemployed 
  I am unable to work, for …. % 
  I am retired or on a pre-pension plan 
  I do something else, namely…………………………………… 
 


Appendix 4: iMTA Productivity and Cost Questionnaire 
 
 
 
Question A6. Do you have a paying job? 
 
 
  No 
  Yes 
 
The following questions refer to your work. That is work that you get paid for. 
 
You do not have a paying job? Skip to question 10. Please first read the explanation 
above the question. 
 
 
 
 
 
Question 1. What is your occupation? 
 
..…………………………………………………………………. 
 
Question 2. How many hours a week do you work? Count only the hours that you get 
paid. 
 
…….. hours 
 
Question 3. How many days a week do you work? 
 
 
………………………. days 
 
Question 4. Have you missed work in the last 4 weeks as a result of being sick? 
 
 
  No 
  Yes, I have missed ………… days. 
(Only count the missed work days in the last 4 weeks) 
 
 
Did you check "Yes"? Go to question 5. 
Otherwise skip to question 7. 
 
Question 5. Did you miss work earlier than the period of 4 weeks due to being 
sick? This is referring to one whole uninterrupted period of missed work as a result of being 
sick. 
 
  No 
  Yes 
 
 
Did you check "Yes"? Go to question 6. 
Otherwise skip to question 7. 


Appendix 4: iMTA Productivity and Cost Questionnaire 
 
 
 
 
Question 6. When did you call in sick? 
 
day 
month 
year 
 
 
 
Skip to question 10. Please first read the explanation above question 10. 
 
 
 
 
 
Question 7. During the last 4 weeks have there been days in which you worked 
but during this time were bothered by physical or psychological problems? 
 
  No 
  Yes 
 
 
Did you check "Yes"? Go to question 8 and 9. 
Otherwise skip to question 10. First read the explanation above question 10. 
 
Question 8. How many days at work were you bothered by physical or 
psychological problems? (Only count the days at work in the last 4 weeks) 
 
 
................... work days 
 
 
Question 9. On the days that you were bothered by these problems, was it 
perhaps difficult to get as much work finished as you normally do? On these days 
how much work could you do on average? Look at the figures below. A 10 means that you 
were able to do as much work as you normally do. A 0 means that you were unable to do 
any work on these days. Circle the figure that fits best. 
 
 
On these days 
I was able 
I was able o 
I could not 
to do half 
do just as do 
anything 
as much as I 
much as I 
normally do 
normally do 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Explanation 
Even for unpaid work, you can be bothered by physical or psychological problems. 
Sometimes as a result you (might) do less. For example you have trouble caring for your 
children or doing voluntary work. Or you are unable to run errands and pick up groceries, 
or to work in the garden. The following questions refer to this. 


Appendix 4: iMTA Productivity and Cost Questionnaire 
 
 
 
 
Question 10. Were there days in which you were forced to do less unpaid work 
because of physical or psychological problems? Only days in the last four weeks. 
 
 
  No 
  Yes 
 
 
 
Did you check "Yes"? Go to question 11 and 12. 
Otherwise skip to the end of the questionnaire. 
 
Question 11. How many days did this happen? Only count the days in the last 4 weeks. 
 
………………………. Days 
 
 
Question 12. Imagine that somebody, for example your partner, family member or 
friend helped you on these days, and he or she did all the unpaid work that you 
were unable to do for you. How many hours on average did that person spend 
doing this on these days? 
 
On average ………….. hours on these days 
 
 
That was the last question. 
 
 
 
 
Do you have any questions or comments? 
Perhaps you have some questions or comments? Please write these here below. 
 
 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 
……………………………………………………………………………………………. 


Clinical Study Protocol  
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Appendix 5:  Subject Self-Assessment of Treatment (SAT) 
 
 
 


 
 
 
 
Appendix 5: Self-Assessment of Treatment 
 
 
(1) How do you assess your pain relief after treatment in this study? 
 □ I feel my pain is much worse (−2) 
 □ I feel my pain is somewhat worse (−1) 
 □ I feel my pain is no better and no worse (0) 
 □ I feel my pain is somewhat better (1) 
 □ I feel my pain is much better (2) 
(2) How do you assess your activity level after treatment in this study? 
 □ I feel much less active (−2) 
 □ I feel somewhat less active (−1) 
 □ I feel no more and no less active (0) 
 □ I feel somewhat more active (1) 
 □ I feel much more active (2) 
(3) How has your quality of life changed after treatment in this study? 
 □ I feel my quality of life is much worse (−2) 
 □ I feel my quality of life is somewhat worse (−1) 
 □ I feel my quality of life is no better and no worse (0) 
 □ I feel my quality of life is somewhat better (1) 
 □ I feel my quality of life is much better (2) 
(4) Would you undergo this treatment again?* 
 □ No, definitely not (−2) 
 □ No, probably not (−1) 
 □ Unsure (0) 
 □ Yes, probably (1) 
 □ Yes, definitely (2) 
(5) How do you compare the treatment you received in this study to previous medication or 
therapies for your pain? 
 □ Very much prefer my previous treatments to this treatment (−2) 
 □ Somewhat prefer my previous treatments (−1) 
 □ No preference (0) 
 □ Somewhat prefer this treatment to my previous treatment (1) 
 □ Very much prefer this treatment to my previous treatments (2) 
 
 
n Study C116, SAT Item 4 was administered with 3 response options: “No, absolutely not” (−2), 
“Unsure” (0), and “Yes, definitely” (2). The item was administered in Study C117 with 5 response 
levels as shown above. 
 
 
 
 
http://www.hindawi.com/journals/prt/2012/621619/tab1/ 
1/1 


Clinical Study Protocol  
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CONFIDENTIAL 
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Appendix 6:  Euroqol-5D (EQ-5D) 
 
 




2 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 


3 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
The worst health 
you can imagine 
 
 
 
 
 
 We would like to know how good or bad your health is TODAY. 
 This scale is numbered from 0 to 100. 
 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 Mark an X on the scale to indicate how your health is TODAY. 
 Now, please write the number you marked on the scale in the box 
below. 
 
  
The best health 
you can imagine 
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95


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Appendix 7:  Patient-reported Utilization Questionnaire 
 
 


 
Appendix 7: Patient Reported Utilization Questionnaires 
Patient Reported Utilization Questionnaire - Baseline 
1. 
In the past 12 months, have you seen the following health care providers or sites to discuss your back pain?  
Primary care doctor 
○ Yes  
○ No 
a. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
b. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Pain specialist 
○ Yes  
○ No 
a. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
b. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Emergency department 
○ Yes  
○ No 
a. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
b. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
 
Hospital admission 
○ Yes  
○ No 
a. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
b. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Spine Surgeon (Orthopedic Surgeon or Neurosurgeon) 
○ Yes  
○ No 
a. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
b. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Acupuncturist 
○ Yes  
○ No 
a. 
If ‘Yes’, how many times? 
i. 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
b. 
If ‘Yes’, was treatment recommended? 
i. 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Physical therapist 
○ Yes ○ No 
a. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
b. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 






○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
B. 
Physical Therapy 
○  Yes 
○  No 
i. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
C. 
Massage Therapy 
○  Yes 
○  No 
i. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
 
D. 
Acupuncture 
○  Yes 
○  No 
i. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
 
6. 
In the past 12 months, have you seen a clinician for any mental health purposes? 
○  Yes 
○  No 
○  I don’t know 
 
7. 
If yes to question 7, estimate how often you received these services in the past 12 months? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
 
 
 


Patient Reported Utilization Questionnaire – Follow-up 
1. 
In the past 12 months, have you seen the following health care providers or sites to discuss your back pain?  
Primary care doctor 
○ Yes  
○ No 
c. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
d. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
ii. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Pain specialist 
○ Yes  
○ No 
c. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
d. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
i. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Emergency department 
○ Yes  
○ No 
c. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
d. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
ii. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
 
Hospital admission 
○ Yes  
○ No 
c. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
d. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
ii. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Spine Surgeon (Orthopedic Surgeon or Neurosurgeon) 
○ Yes  
○ No 
c. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
d. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
ii. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Acupuncturist 
○ Yes  
○ No 
c. 
If ‘Yes’, how many times? 
i. 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
d. 
If ‘Yes’, was treatment recommended? 
i. 
○ Yes 
○ No 
○ I don’t know   
ii. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Physical therapist 
○ Yes ○ No 
c. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
d. 
If ‘Yes’, was treatment recommended? 
○ Yes 
○ No 
○ I don’t know   
ii. 
If ‘Yes’, describe treatment recommendations. 
___________________________________________________________________________________________________ 
Massage therapist 
○ Yes ○ No 
c. 
If ‘Yes’, how many times? 




ii. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
F. 
X-Rays 
○  Yes 
○  No 
ii. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
4. 
In the past 12 months, have you had any of the following treatments/services for your back pain?  
E. 
Chiropractic Manipulation 
○  Yes 
○  No 
ii. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
F. 
Physical Therapy 
○  Yes 
○  No 
ii. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
G. 
Massage Therapy 
○  Yes 
○  No 
ii. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
 
H. 
Acupuncture 
○  Yes 
○  No 
ii. 
If ‘Yes’, how many times? 
○  0-1 
○  2-3 
○ 4-5 
○  6 or more 
 
5. 
In the past 12 months, have you seen a clinician for any mental health purposes? 
○  Yes 
○  No 
○  I don’t know 
 
6. 
If yes to question 5, estimate how often you received these services in the past 12 months? 
○  0-1 
○  2-3 
○ 4-5 
○  6-7 
○  8-9 
○ 10 or more   
 
 
 


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