Clinical trial NCT01978912
Conditions: Lumbar Disc Herniation
Sponsor: Teijin America, Inc.
Start date: 2013-02-01; Completion date: 2018-10-16
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety and exploratory efficacy of KTP-001 in subjects with lumbar disc herniation.

Detailed description:
This study was a first-in-human, open-label, non-controlled single ascending dose study of KTP-001 in male and female subjects between the ages of 30 and 70 years with a single herniated lumbar disc. After obtaining informed consent, subjects were evaluated during a screening period of no more than 3 weeks (21 days). This study was conducted in 10 centers in the US.

Subjects that met all screening requirements and inclusion criteria and none of the exclusion criteria were enrolled into the study. Overall, 24 subjects were enrolled and treated: 6 subjects in each cohort. Cohort 1 received a 5 μg/disc dose of KTP-001 by intradiscal injection. Following administration of study drug, subjects were confined to the study center for 24 hours to collect data for safety and efficacy measures and collect blood samples for safety, PK evaluation, exploratory PD and anti-KTP-001 antibody and then returned for further assessments at various intervals from weeks 1 through to month 24.

After all subjects in Cohort 1 had received study drug, safety measures were evaluated by a Data and Safety Monitoring Board (DSMB) to determine whether to escalate KTP-001 administration to the next dose level. If appropriate, Cohort 2 subjects received 15 μg/disc of KTP-001, Cohort 3 subjects received 50 μg/disc of KTP-001, and Cohort 4 subjects received 150 μg/disc of KTP-001 by intradiscal injection. All safety, PK, and exploratory efficacy assessments were performed for the subjects in the subsequent cohorts as were performed for Cohort 1.

Arms: arm 1: one time 5 μg/disc dose of KTP-001 by intradiscal injection arm 2: one time 15 μg/disc dose of KTP-001 by intradiscal injection arm 3: one time 50 μg/disc dose of KTP-001 by intradiscal injection arm 4: one time 150 μg/disc dose of KTP-001 by intradiscal injection
Interventions: intervention 1: KTP-001
Intervention descriptions: intervention 1: KTP-001 is one time dose intradiscally.

Protocol documents:
Prot_000.pdf: 
NCT01978912


 
Protocol Number: KTP-001-CL-101 
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Document History 
 
Document 
Version Date 
Amendment 4 
20 October 2015 
Amendment 3 
11 April 2014 
Amendment 2 
16 August 2013 
Amendment 1 
06 November 2012 
Original protocol 
10 August 2012 


 
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TABLE OF CONTENTS 
1 
SYNOPSIS ............................................................................................... 8 
1.1 
Schedule of Assessments and Procedures ........................................... 16 
2 
GENERAL INFORMATION .............................................................. 19 
2.1 
Study Administrative Structure .......................................................... 19 
2.2 
List of Abbreviations ............................................................................ 20 
3 
INTRODUCTION AND BACKGROUND ........................................ 22 
3.1 
Introduction ........................................................................................... 22 
3.2 
Description of Investigational Product ............................................... 23 
3.3 
Nonclinical Studies ................................................................................ 23 
3.3.1 
Primary Pharmacology............................................................................ 23 
3.3.2 
Safety Pharmacology .............................................................................. 23 
3.3.3 
Pharmacokinetics .................................................................................... 24 
3.3.4 
Anti-KTP Antibody Production .............................................................. 25 
3.3.5 
Toxicology Studies ................................................................................. 25 
3.4 
Clinical Studies ...................................................................................... 27 
4 
STUDY OBJECTIVES AND ENDPOINTS ....................................... 28 
4.1 
Objectives............................................................................................... 28 
4.1.1 
Primary Objective ................................................................................... 28 
4.1.2 
Secondary Objectives.............................................................................. 28 
4.1.3 
Exploratory Objectives ........................................................................... 28 
5 
STUDY DESIGN ................................................................................... 29 
5.1 
Design Summary ................................................................................... 29 
5.1.1 
Treatments Administered ........................................................................ 30 
5.1.2 
Dose Escalation ....................................................................................... 30 
5.1.3 
Halting Rules .......................................................................................... 31 
5.1.4 
Duration of Study .................................................................................... 32 
5.2 
Discussion of Study Design ................................................................... 32 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................... 33 
6.1 
Inclusion Criteria .................................................................................. 33 
6.2 
Exclusion Criteria ................................................................................. 34 
6.3 
Women of Nonchildbearing Potential and Acceptable Forms of 
Contraception ........................................................................................ 36 
6.4 
Prior and Concomitant Therapy ......................................................... 37 
6.5 
Restrictions on Concomitant Therapies or Procedures During the 
Study....................................................................................................... 37 
6.5.1 
Pain Management During First 13 Weeks Post-dose ............................. 37 
6.5.2 
Pain Medications ..................................................................................... 37 


 
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6.5.3 
Antiplatelet therapy ................................................................................. 39 
6.5.4 
Disallowed Treatments ........................................................................... 39 
6.5.5 
Tobacco and Alcohol Use ....................................................................... 39 
6.6 
Subject Withdrawal and Discontinuation .......................................... 39 
6.7 
Early Termination of Study ................................................................. 40 
7 
STUDY DRUG ...................................................................................... 41 
7.1 
Description of Investigational Product ............................................... 41 
7.2 
Treatments ............................................................................................. 41 
7.2.1 
Local Anesthetic and Chemonucleolysis Procedures ............................. 41 
7.3 
Dose Rationale ....................................................................................... 41 
7.4 
Method of Assigning Subjects to Treatment Groups ........................ 42 
7.5 
Measurements of Treatment Compliance .......................................... 42 
7.6 
Investigational Product Storage and Accountability ......................... 42 
7.6.1 
Storage Conditions .................................................................................. 42 
7.6.2 
Drug Accountability................................................................................ 42 
7.7 
Packaging and Labeling ....................................................................... 42 
7.8 
Preparation of Investigational Product .............................................. 43 
8 
EFFICACY ASSESSMENTS .............................................................. 44 
8.1 
Lower Back or Leg Pain ....................................................................... 44 
8.2 
Use of Rescue Medication or Surgical Intervention .......................... 44 
8.3 
Spinal Flexion and Tension .................................................................. 44 
8.4 
Functional Ability ................................................................................. 44 
8.5 
Quality of Life ....................................................................................... 45 
8.6 
Global Impression of Change or Improvement ................................. 45 
8.7 
Appropriateness of Efficacy Measures ............................................... 45 
8.8 
Magnetic Resonance Imaging Assessment.......................................... 45 
9 
SAFETY ASSESSMENTS ................................................................... 46 
9.1 
Vital Signs .............................................................................................. 46 
9.2 
Clinical Laboratory Tests..................................................................... 46 
9.3 
Electrocardiograms............................................................................... 46 
9.4 
Physical Examination ........................................................................... 46 
9.5 
Anti-KTP-001 Antibodies ..................................................................... 47 
9.6 
Magnetic Resonance and X-ray Imaging Acquisition and 
Evaluation .............................................................................................. 47 
9.6.1 
Lumbar (or lumbosacral) Spine X-ray Examination Requirements ....... 47 
9.6.2 
Safety Evaluation of MRI and X-ray ...................................................... 48 
9.7 
Neurologic Examination ....................................................................... 48 
9.8 
Halting Rules ......................................................................................... 48 
9.9 
Adverse Events ...................................................................................... 48 
9.9.1 
Assessing Severity .................................................................................. 49 
9.9.2 
Assessing Causality ................................................................................ 49 


 
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9.9.3 
Adverse Events of Special Interest ......................................................... 50 
9.9.4 
Following Adverse Events ...................................................................... 50 
9.9.5 
Discontinuation due to Adverse Events .................................................. 50 
9.9.6 
Pregnancy ................................................................................................ 50 
9.9.7 
Serious Adverse Events .......................................................................... 51 
9.9.8 
Reporting Serious Adverse Events ......................................................... 52 
9.10 
Appropriateness of Safety Assessments .............................................. 52 
10 
PHARMACOKINETIC ASSESSMENTS.......................................... 53 
10.1 
Drug Concentration Measurements .................................................... 53 
10.2 
Pharmacokinetic Parameters ............................................................... 53 
10.3 
Pharmacodynamic Parameters (Exploratory) ................................... 53 
11 
METHODOLOGY/STUDY VISITS ................................................... 54 
11.1 
Screening Procedures (Day -21 to Day 1) ........................................... 54 
11.2 
Visit 1 (Day 1) ........................................................................................ 55 
11.2.1 
Pre-dose................................................................................................... 55 
11.2.2 
At 2 hours post-dose (±15 minutes) ........................................................ 55 
11.2.3 
At 4 hours post-dose (±15 minutes) ........................................................ 56 
11.2.4 
At 6 hours post-dose (±15 minutes) ........................................................ 56 
11.2.5 
At 24 hours post-dose (±1 hour) ............................................................. 56 
11.3 
Visit 2 (1 Week ±2 days) ....................................................................... 57 
11.4 
Visit 3 (2 Weeks ±2 days) ...................................................................... 57 
11.5 
Visit 4 (4 Weeks ±2 days) ...................................................................... 58 
11.6 
Visit 5 (6 Weeks ±5 days) ...................................................................... 58 
11.7 
Visit 6 (13 Weeks ±5 days) .................................................................... 59 
11.8 
Visit 7 (6 Months/26 Weeks ±1 week) ................................................. 59 
11.9 
Visit 8 (9 Months/39 Weeks ± 1 week) ................................................ 60 
11.10 
Visits 9 (12 Months/52 Weeks ±2 weeks) ............................................ 60 
11.11 
Visit 10 (18 months/78 Weeks ±4 weeks) ............................................ 60 
11.12 
End of Study Visit (24 Months/104 Weeks ±4 weeks) ....................... 61 
11.13 
Early Termination Before Week 13 .................................................... 61 
11.14 
Early Termination Between Week 13 and Month 24/Week 104 ...... 61 
11.15 
Withdrawal Procedures........................................................................ 61 
11.16 
Total Blood Volume Required for Study ............................................ 62 
11.17 
Protocol Deviations ............................................................................... 62 
12 
STATISTICAL CONSIDERATIONS ................................................ 64 
12.1 
General Considerations ........................................................................ 64 
12.2 
Sample Size Calculation ....................................................................... 64 
12.3 
Analysis Populations ............................................................................. 64 
12.4 
Demographic and Baseline Characteristics ........................................ 64 
12.5 
Safety Analysis ...................................................................................... 64 
12.5.1 
Vital Signs ............................................................................................... 64 


 
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12.5.2 
Clinical Laboratory Tests ........................................................................ 65 
12.5.3 
Concomitant Medications ....................................................................... 65 
12.5.4 
Electrocardiograms ................................................................................. 65 
12.5.5 
Physical Examinations ............................................................................ 65 
12.5.6 
Neurologic Examinations........................................................................ 65 
12.5.7 
Adverse Events ....................................................................................... 65 
12.5.8 
Imaging Data ........................................................................................... 66 
12.5.9 
Additional Safety Analyses..................................................................... 66 
12.6 
Procedures for Handling Missing Data............................................... 66 
12.7 
Efficacy Analysis ................................................................................... 66 
12.8 
Pharmacokinetic Analysis .................................................................... 66 
12.9 
Exploratory Pharmacodynamic Analysis ........................................... 66 
12.10 
Interim Analysis .................................................................................... 67 
13 
ACCESS TO SOURCE DATA/DOCUMENTS ................................. 68 
14 
QUALITY CONTROL AND QUALITY ASSURANCE .................. 69 
14.1 
Conduct of Study................................................................................... 69 
14.2 
Protocol Amendments .......................................................................... 69 
14.3 
Monitoring of Study .............................................................................. 69 
15 
ETHICS ................................................................................................. 71 
15.1 
Institutional Review Board/Independent Ethics Committee 
Approval ................................................................................................ 71 
15.1.1 
Ethics Review Prior to Study .................................................................. 71 
15.1.2 
Ethics Review of Other Documents ........................................................ 71 
15.2 
Written Informed Consent ................................................................... 71 
16 
DATA HANDLING AND RECORD KEEPING ............................... 72 
16.1 
Data Reporting and Case Report Forms ............................................ 72 
16.1.1 
Data Collection and Case Report Forms ................................................. 72 
16.1.2 
Laboratory Data ...................................................................................... 72 
16.1.3 
Serum concentration of KTP-001 and anti-KTP-001 antibody .............. 72 
16.1.4 
Imaging Data ........................................................................................... 72 
16.1.5 
Retention of Source Documents ............................................................. 73 
16.2 
Retention of Essential Documents ....................................................... 73 
17 
ADMINISTRATIVE INFORMATION .............................................. 74 
17.1 
Financing and Insurance ...................................................................... 74 
17.2 
Publication Policy.................................................................................. 74 
18 
REFERENCES ...................................................................................... 75 
19 
SIGNATURES....................................................................................... 77 
19.1 
Investigator’s Signature ....................................................................... 77 


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19.2 
 Clinical Research Signatures .................................................... 78 
19.3 
Teijin America, Inc. Signatures ........................................................... 79 
APPENDIX A: PAIN MEDICATIONS ................................................................... 80 
APPENDIX B: 
INTRADISCAL INJECTION PROCEDURE ............................. 82 
APPENDIX C: 
LOWER BACK OR LEG PAIN ASSESSMENT ........................ 84 
APPENDIX D: 
STRAIGHT-LEG-RAISING AND FEMORAL STRETCH 
TESTS .............................................................................................. 85 
APPENDIX E: 
OSWESTRY DISABILITY INDEX, VERSION 2.1A ................ 86 
APPENDIX F: 
SHORT FORM-12 QUESTIONNAIRE, VERSION 2.0 ............. 88 
APPENDIX G: PATIENT GLOBAL IMPRESSION OF CHANGE SCALE ..... 89 
APPENDIX H: SCREENING AND CLINICAL LABORATORY 
ASSESSMENTS .............................................................................. 90 
APPENDIX I: 
NEUROLOGIC EXAMINATION ................................................ 91 


 
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1 
SYNOPSIS 
Protocol Title: 
Open-label, non-controlled, single-ascending dose study to evaluate safety, 
tolerability, pharmacokinetics, and exploratory efficacy of KTP-001 in 
subjects with lumbar disc herniation 
Sponsor: 
Teijin America, Inc. 
Study Phase: 
Phase 1/2 
Indication: 
Herniated lumbar disc 
Objectives: 
The primary objective of this study is: 
• 
To evaluate the safety and tolerability of a single intradiscal injection 
of KTP-001 in subjects with a single herniated lumbar disc. 
The secondary objectives of this study are: 
• 
To determine the pharmacokinetics (PK) of KTP-001 in the serum of 
circulating blood after intradiscal injection of the study drug. 
• 
To determine the presence of anti-KTP-001 antibody in the serum of 
circulating blood after intradiscal injection of the study drug. 
The exploratory objectives of this study are: 
• 
To explore the pharmacodynamics (PD) of keratan sulfate in the serum 
of circulating blood after intradiscal injection of the study drug.  
• 
To assess changes in pain, neurologic examination, disability, magnetic 
resonance imaging (MRI) and X-ray assessments, Quality of Life 
(QOL), and patient global impression of change (PGI-C) scores in 
subjects receiving study drug. 
Number of Sites: 
This study will be conducted at approximately 8 sites in the United States. 
Study Design: 
This study is designed as an open-label, non-controlled single ascending 
dose study. Twenty-four subjects with a diagnosis of a single herniated 
lumbar disc will be divided into 4 cohorts of 6 subjects. Dose escalation 
will begin with a 5 μg intra-disc administration. After all subjects in the 
first cohort have reached the Week 13 assessment, relevant safety data will 
be reviewed. If adequate safety and tolerability has been demonstrated, 
KTP-001 dose escalation will continue in subsequent escalating doses of 
15, 50, and 150 μg/disc with safety reviews conducted prior to each dose 
escalation.  
Planned Sample Size: 
Approximately 48 subjects will be screened to ensure that 24 subjects are 
enrolled into this study. Subjects who discontinue from the study after 
enrollment but prior to receiving study drug will be replaced to ensure that 
at least 6 subjects are treated in each of the 4 cohorts. 


 
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Subject Selection Criteria: 
Subject eligibility must be reviewed and documented by an appropriately 
qualified member of the investigator’s study team before subjects are 
included in the study. Subjects must meet all of the following inclusion 
criteria to be eligible for enrollment into the study : 
Inclusion Criteria: 
1. Has had a single unilateral contained or noncontained (extruded) 
lumbar disc herniation at the L3-L4 or L4-L5 or L5-S1 level diagnosed 
by clinical symptoms and/or physical findings and confirmed by MRI. 
Symptom duration should be at least 6 weeks prior to screening. 
2. Has radicular symptoms with a documented positive straight-leg 
raising or femoral stretch test consistent with the level of the disc 
herniation. 
3. Has had at least 6 weeks of conservative therapy prior to screening. 
4. Has a daily average leg pain score of ≥ 4 (using an 11-point numerical 
scale) on at least 3 out of the 5 days immediately prior to treatment 
AND on all 5 days immediately prior to treatment the daily average leg 
pain score is ≥ 2. 
5. Has completed the subject diary for at least 4 out of the 5 days 
immediately prior to treatment. 
6. Has an Oswestry Disability Index (ODI) of ≥ 30% at screening. 
7. Is a male or female subject between 30 and 70 years of age, inclusive. 
8. Has a body mass index of 18 to 35 kg/m2. 
9. Is medically healthy, other than lumbar disc herniation, with clinically 
insignificant screening results (including laboratory profiles, medical 
histories, electrocardiograms [ECGs], and physical examination) as 
deemed by the investigator. 
10. Uses or agrees to use effective contraception methods or is a female of 
nonchildbearing potential (See Section 6.3).     
11. Voluntarily provides written consent to participate in the study.  
 
Exclusion Criteria: 
Any subject that meets any of the following exclusion criteria will not be 
enrolled in this study or will be discontinued at the discretion of the 
investigator if he/she develops any of the following exclusion criteria 
during the study: 
1. Has a sequestered lumbar disc herniation or intrathecal herniation 
confirmed by MRI. 
2. Has 2 or more symptomatic lumbar disc herniations as assessed by 
clinical symptoms and/or physical findings and confirmed by MRI. 
3. Has had previous intradiscal therapeutic intervention at the level of the 
current symptomatic disc herniation or has had any lumbar surgery in 
the past. Previous therapeutic intradiscal injections (e.g., steroids) at 
the level of the current symptomatic disc herniation are not permitted 
within 6 weeks of screening. 
4. Has undergone chemonucleolysis at any level of disc herniation or has 
had previous exposure to study drug. 
5. Has had previous epidural injections, a selective nerve root block, or a 
facet block within 2 weeks before screening. 
6. Has had any changes in the frequency of physical therapy or the 
introduction of new modalities of physical therapy, acupuncture, 
transcutaneous electrical nerve stimulation (TENS) or any other 
nonpharmacologic treatment modalities within 2 weeks prior to 
screening. 


 
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7. Has had any changes in dosing of pain medications or introduction of 
new pain medications/muscle relaxants within 1 week prior to 
screening. 
8. Has had any changes in antidepressant treatment or “pain modulating” 
therapy, including gabapentin and pregabalin within 4 weeks before 
screening. 
9. Has the presence of lumbar spine disease and/or deformity other than a 
lumbar disc herniation, including spondylolisthesis Grade 2 or above, 
clinically significant scoliosis, spinal stenosis including significant 
lateral recess stenosis not related to the lumbar disc herniation, 
vertebral compression fracture, ankylosing spondylitis, inflammatory 
bone or disc disease, primary or metastatic malignancy, or any other 
clinically significant spine disease. 
10. Has symptoms of cauda equina syndrome or progressive neurologic 
deficit, especially motor weakness. 
11. Has a concomitant neurologic disorder, such as polyneuropathy, 
myopathy or motor neuron disease, lumbosacral plexopathy, 
radiculitis, multiple sclerosis, myelopathy, spinal cord compression, 
prior poliomyelitis or stroke, or any other condition resulting in 
sensory-motor deficit in the lower extremities. 
12. Has other concomitant painful condition such as fibromyalgia, 
rheumatoid arthritis, severe osteoarthritis of the hip and/or knee joints 
or other painful condition that may interfere with pain assessments in 
the study. 
13. Has a history of and/or clinical evidence of peripheral vascular disease. 
14. Has the presence of an apophyseal ring in the vertebral disc as 
confirmed by X-ray 
15. Is pregnant, breastfeeding, or has a positive serum pregnancy test at 
screening or a positive urine pregnancy test prior to receiving the study 
drug. 
16. Has a history or presence of significant cardiovascular, pulmonary, 
hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, 
dermatologic, neurologic, or psychiatric disease.  
17. Has a history or presence of cancer within 5 years of screening, with 
the exception of localized basal cell skin cancer 
18. Has a history of heavy alcohol consumption (defined as more than 
2 standard alcohol beverages per day for males or more than 1 standard 
alcohol beverage per day for a woman, or more than 5 standard alcohol 
beverages on 1 occasion more than 5 times in the last 30 days for either 
gender) or drug abuse within the past 2 years or has a positive urine 
drug screen prior to enrollment (except for prescription medications). 
19. Is a current, active smoker or is unable to abstain from tobacco use for 
2 weeks prior to study injection. 
20. Has a history of multiple drug allergies (2 or more classes of drugs), 
food allergies or other life-threatening allergies deemed significant by 
the principal investigator. 
21. Has used or is using systemic steroids within 2 weeks prior to 
screening (not including inhalation, ophthalmic, and topical steroids). 
22. Is taking anticoagulants including (but not limited to) warfarin, 
heparin/low molecular weight heparins, thrombin inhibitors, factor Xa 
inhibitors; or has any condition/treatment associated with 
coagulopathy/bleeding tendency. 
23. Is receiving workers’ compensation or other disability benefits or has a 


 
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pending disability claim or litigation related to a back condition/disc 
herniation. 
24. Has participated in any clinical study within 30 days prior to screening. 
25. Has a positive screen for hepatitis B surface antigen (HBsAg), 
anti-hepatitis C virus (HCV), or anti-human immunodeficiency virus 
(HIV), or has any active, clinically significant infection. 
26. Has an elevation of aspartate aminotransferase (AST) and/or alanine 
aminotransaminase (ALT) ≥ 2 X upper limit of normal (ULN), or a 
total bilirubin > ULN, or a creatinine ≥ 1.5 X ULN, or any other 
clinically significant laboratory abnormalities that, in the investigator’s 
judgment, would preclude the subject from participation in the study. 
27. Has any clinically significant ECG abnormalities at screening. 
28. Has any contraindication to undergo an MRI or has declared inability 
to tolerate an MRI. 
29. Has any condition that would, in the investigator’s opinion, limit the 
subject’s ability to complete the study. 
Duration of Study: 
After a single intradiscal injection of study drug, subjects will be confined 
to the study facility for the first 24 hours and will be asked to participate in 
this study for at least 24 months (2 years). 
Study Drug: 
KTP-001 1.0 mg/vial will be provided as a lyophilized powder in 2.0 mL 
glass vials. Each vial contains 1.0 mg of KTP-001 drug substance, which 
will be reconstituted with 0.5 mL of sterile water for injection and then 
diluted with a buffer solution to administer the required injection dose per 
1.0 mL. 
Dose and Route of 
Administration: 
A single intradiscal injection of doses 5, 15, 50, and 150 µg/disc of 
KTP-001 will be administered intradiscally under fluoroscopic or computer 
tomography (CT) visualization and guidance after a local anesthetic is 
administered. The final injection volume per subject will be 1.0 mL. Use of 
an imaging dye is not permitted for the intradiscal injection. 
Response Criteria: 
Safety 
Measures of safety and tolerability will include vital signs, 12-lead ECGs, 
determination of adverse events (AEs), clinical laboratory (hematology, 
serum chemistry, coagulation, urinalysis), MRI, X-ray (morphological 
assessment), and physical and neurologic examinations.  
 
Blood samples for measures of serum anti-KTP-001 antibody will be drawn 
pre-dose (just prior to administration of study drug) and at the 1-, 2-, 4-, 6-, 
and 13-week visits post-dose or early termination visit. 
 
Data and Safety Monitoring Board (DSMB): 
Escalation to a higher dose in a cohort will be permitted only if adequate 
safety and tolerability have been demonstrated at the previous lower dose. 
An independent Data and Safety Monitoring Board (DSMB) will determine 
whether to proceed to the next dose level as planned by evaluating safety 
measures, including AEs and clinical laboratory values. This evaluation 
will be conducted at the 13-week follow-up visit for all subjects in each 
dose cohort.  
 


 
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Halting Rules: 
If any of the following AEs occur in any subject, further recruitment will be 
held until the event is assessed by the DSMB and a recommendation is 
made regarding continuation of the study and/or escalation to the next dose 
cohort:  
• 
Neurologic deficit consistent with cauda equina syndrome or 
myelopathy 
• 
Exacerbation of radicular symptoms associated with onset of a new 
motor deficit in one or both legs following administration of study 
drug 
• 
Modic changes consistent with significant endplate edema or sclerosis 
compared to baseline, as determined by an expert spine radiologist 
• 
Loss of height of the disc of > 30% relative to the baseline and defined 
as the average of anterior and posterior disc height evaluated by X-ray 
• 
Evidence by X-ray of lumbar segmental instability at the treated 
segment defined as either: 
o 
Anterior translation of the posterior edge of the superior 
vertebral body relative to the posterior edge of the inferior 
vertebral body increase from baseline greater than 3 mm 
is considered strong evidence of instability  
o 
Sagittal rotation change from extension to flexion of >5° 
(as measured by the Dupuis method) is weak evidence of 
instability, and without observed translation as defined 
above, will require further evaluation before it would be 
considered a halting event 
 
NOTE: if the subject’s condition does not permit the 
acquisition of flexion and extension films, instability will 
be evaluated solely on the basis of translation on the 
lateral view, as described above 
• 
Destructive cartilage endplate changes as confirmed by MRI. 
 
Efficacy (exploratory) 
The following measures of efficacy after administration of study drug will 
be explored in this study: 
• 
Lower back pain and leg pain (measured by 11-point numerical pain 
scale) at baseline, on Day 1 pre-dose, at 2, 4, 6, and 24 hours 
post-dose, at all post-dose visits (Weeks 1, 2, 4, 6 and 13, Months 6, 9, 
12, 18, 24 or early termination visit). 
• 
Use and amount of any pain medications (including extra 
acetaminophen) added to the subject's baseline pain regimen within 
the first 13 weeks post-dose. 
• 
Spinal flexion and tension (measured by straight-leg raising or 
femoral stretch test) at 6 and 13 weeks after injection of study drug or 
early termination visit. 
• 
Improvement in functional ability measured by ODI at 6 and 13 weeks 
after injection of study drug or early termination visit. 
• 
Improvements in QOL as measured by the Short Form (SF)-12 Health 
Survey at 6 and 13 weeks after injection of study drug or early 
termination visit. 
• 
Improvements in symptom severity as measured by the PGI-C scale at 
6 and 13 weeks after injection of study drug or early termination visit.  
 


 
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Pharmacokinetics 
Blood samples for measures of serum concentrations of KTP-001 will be 
drawn pre-dose (just prior to administration of study drug), at 2, 4, 6, and 
24 hours post-dose, and at the 1-, 2-, 4-, 6-, and 13-week follow-up visits or 
early termination visit. 
 
Pharmacodynamics (exploratory) 
Blood samples for measures of serum concentrations of keratan sulfate will 
be drawn pre-dose (just prior to administration of study drug), at 6 and 
24 hours post-dose, and at the 1-, 2-, 4-, 6-, and 13-week follow-up visits or 
early termination visit.  
Statistical Analysis: 
All statistical analyses will be conducted using SAS software, version 9.1.2 
or higher (SAS® Institute, Cary, NC). Additional analyses of study 
endpoints will be detailed in the statistical analysis plan. 
 
Analysis populations 
The following 5 analysis populations will be defined in this study. 
 
Intent-to-Treat Population: 
The Intent-to-Treat population will be defined as any subject who is 
enrolled into the study and whether or not he/she receives study drug. 
 
Full Analysis Set: 
The Full Analysis Set population will be defined as any subject who is 
enrolled into the study, receives study drug and has at least 1 efficacy 
evaluation after receiving study drug. 
 
 
Per Protocol Set: 
The Per Protocol Set will be defined as any subject who is enrolled into the 
study, receives study drug as planned, has at least 1 efficacy evaluation 
after receiving study drug, completes the Week 13 visit, and has no 
significant protocol violations. 
 
Safety Population: 
The Safety population will be defined as any subject who is enrolled into 
the study and receives study drug.  
 
PK Evaluable Population: 
The PK population will be defined as any subject enrolled into the study, 
receives study drug, and has at least 1 evaluable PK sample. 




 
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raising or femoral stretch test) on the affected side at 6 and 13 weeks 
• 
Change from baseline in ODI at 6 and 13 weeks 
• 
Change from baseline in SF-12 at 6 and 13 weeks 
• 
Change from baseline in the PGI-C at 6 and 13 weeks. 
 
Exploratory PD analysis: 
The following exploratory PD endpoint will be analyzed and presented 
using descriptive statistics (n, mean, median, minimum, maximum, SD, 
percentage of analysis population, and CI): 
• 
Change from baseline in serum concentrations of keratan sulfate at 
every time point. 
 
 


 
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1.1 
Schedule of Assessments and Procedures 
Study Procedures 
Screening 
Pre-dose 
Post-dose 
Confinement a 
Clinic Visits 
Day -21 
to Day 1 
Day 1 
1 wk 
2 
wk 
4 wk 
6 wk 
13 wk 
(EOS)
b 
6 mth 
9 
mth 
12 
mth 
 
18 
mth 
24 
mth 
0 hr 
 
2 hr 
4 hr 
6 hr 
24 hr 
 
(EOS)c 
±15 min 
±1 hr 
±2 days 
±5 days 
±1 wk 
±2 wk 
±4 wk 
Screening 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
Concomitant/Prior Medications 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X-ray 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
Weight (kg) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic Examination 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG d 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Clinical Laboratory Tests e  
X 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Urine Pregnancy Test f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, anti-HCV, anti-HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
◄----------------------------------------------------------------------------------------------------------------------------------------------► 
Investigational Product Administration 
Investigational Product 
Administration g 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Study Procedures 
Screening 
Pre-dose 
Post-dose 
Confinement a 
Clinic Visits 
Day -21 
to Day 1 
Day 1 
1 wk 
2 
wk 
4 wk 
6 wk 
13 wk 
(EOS)
b 
6 mth 
9 
mth 
12 
mth 
 
18 
mth 
24 
mth 
0 hr 
 
2 hr 
4 hr 
6 hr 
24 hr 
 
(EOS)c 
±15 min 
±1 hr 
±2 days 
±5 days 
±1 wk 
±2 wk 
±4 wk 
PK and PD Sampling 
Blood Sampling for anti-KTP-
001 Antibody  
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Blood Sampling for KTP-001  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Blood Sampling for keratan 
sulfate  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Efficacy Assessments (exploratory) 
Dispense Study Diary 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Collect and Review Study 
Diary 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Current Lower Back Pain and 
Leg Pain  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X h 
X h 
X h 
 
 
Spinal Flexion/Tension  
X 
X 
 
 
 
X 
X 
X  
X  
X  
X  
X  
X  
X  
 
 
ODI 
X 
X 
 
 
 
X 
X 
X  
X  
X  
X  
X  
X  
X  
 
 
SF-12 
X 
X 
 
 
 
X 
X 
X  
X  
X  
X  
X  
X  
X  
 
 
PGI-C 
X 
X 
 
 
 
X 
X 
X  
X  
X  
X  
X  
X  
X  
 
 
Abbreviations: PGI-C=Patient Global Impression of Improvement; ODI=Oswestry Disability Index; SF-12=Short Form 12 (QOL assessment); PK=pharmacokinetics; 
PD=pharmacodynamics; MRI= magnetic resonance imaging; ECG= electrocardiogram; HBsAg=hepatitis B surface antigen, HCV=hepatitis C, HIV=human 
immunodeficiency virus; hr = hour(s); mth = month(s); wk = week(s) 
a. 
24 hours hospitalization after the intradiscal injection is performed. Discharge is based on data up to 24 hours. 
b. 
The same procedures as described in Section 11.13 will be used for early termination prior to Week 13. 
c. 
The same procedures as described in Section 11.12 will be used for early termination between Week 13 and Month 24. 
d. 
Follow-up ECG(s) will be obtained if any significant abnormalities are detected after dose administration to document resolution and as clinically indicated. 
e. 
Hematology, coagulation, serum chemistry, and urinalysis. 
f. 
Urine pregnancy tests will also be completed whenever one menstrual cycle is missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study to confirm the subject has not become pregnant during the study. Pregnancy tests may also be repeated as per request of the 
ethical board or if required by local regulations. 
 
 


 
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Study Procedures 
Screening 
Pre-dose 
Post-dose 
Confinement a 
Clinic Visits 
Day -21 
to Day 1 
Day 1 
1 wk 
2 
wk 
4 wk 
6 wk 
13 wk 
(EOS)
b 
6 mth 
9 
mth 
12 
mth 
 
18 
mth 
24 
mth 
0 hr 
 
2 hr 
4 hr 
6 hr 
24 hr 
 
(EOS)c 
±15 min 
±1 hr 
±2 days 
±5 days 
±1 wk 
±2 wk 
±4 wk 
g. 
Investigational product will be given intradiscal by injection under fluoroscopic or CT visualization and guidance and confirmed by MRI. 
h. 
Performed at the time of the clinical visit only. 




 
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2.2 
List of Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransaminase 
AP 
Anterior-posterior 
AST 
Aspartate aminotransferase 
AUCt 
Area under the serum concentration-time curve from time zero to time t 
BLQ 
Below the limit of quantification 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
CRF 
Case report form 
CT 
Computerized tomography 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ELISA  
Enzyme-linked immunosorbent assay  
FDA 
US Food and Drug Administration 
FIH 
First in human 
GCP 
Good Clinical Practice 
H.E. 
Hematoxylin and Eosin 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
HR 
Halting rules  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IU 
International unit 
LOAEL 
Lowest observed adverse effect level 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
µg 
Microgram 
MMP 
Matrix metalloproteinase 


 
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MRI 
Magnetic Resonance Imaging 
N, n 
Number of subjects/subjects in a sample from a population or analysis 
group 
NSAID 
Nonsteroidal anti-inflammatory drug 
NOAEL 
No observed adverse effect level 
ODI 
Oswestry Disability Index  
PD 
Pharmacodynamics 
PGI-C 
Patient global impression of change  
PK 
Pharmacokinetics 
QOL 
Quality of life 
QRS 
Principal deflection in ECG 
QT 
ECG interval 
QTc 
QT interval corrected heart rate 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SD 
Standard deviation 
SF-12 
Short form-12 (QOL scale) 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SOC 
Standard of care 
TEAE 
Treatment-emergent AE 
TENS 
Transcutaneous electrical nerve stimulation 
tmax 
Time at which the maximum concentration was observed 
ULN 
Upper limit of normal 
WBC 
White blood cell count 
 
 


 
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3 
INTRODUCTION AND BACKGROUND 
3.1 
Introduction 
Teijin is developing recombinant human Matrix metalloproteinase 7 (MMP-7, code name:   
KTP-001) for chemonucleolysis therapy for the relief of herniated disc, characterized by a 
protrusion or prolapse of the nucleus pulpous through the annulus fibrosus, which in turn presses 
against a nerve, and causes lower back pain and/or leg pain.  
The prevalence of lumbar disc herniation is approximately 1% of the population [1]. Patients with 
severe neurological deficits such as cauda equina syndrome will have surgery immediately. Of 
the remaining patients who opt for conservative therapy, approximately 10 to 54% will not be 
satisfied with the treatment [2-6]. Currently, when conservative therapy does not provide sufficient 
relief, the physician has 3 options:  to continue with conservative therapy; administer epidural 
steroid injections/selective nerve root blocks or intradiscal therapies; or perform surgery.  
Surgery eliminates nerve impingement directly and often achieves immediate relief. However, 
this technique is invasive and has risk related to the operation such as muscle, ligament, bone and 
nerve root damage. Intradiscal therapies such as percutaneous nucleotomy, percutaneous laser 
disc decompression or intradiscal electrothermal annuloplasty are less invasive compared with 
surgery, but the patient has to be carefully selected because the hernia type to which this 
technique is applicable is strictly defined. Therefore, it is desirable to develop a novel treatment 
that is efficacious, safe and applicable to broad types of hernia. 
Chemonucleolysis is a procedure that dissolves the matrix in the herniated disc by the intradiscal 
injection of an enzyme. The technique is very simple and less invasive than current surgery and 
is expected to contribute to shortened hospital stays. No drug for chemonucleolysis is currently 
available in the US. A novel and promising agent that can be used for chemonucleolysis is 
desired. 
Proteoglycans are the main solid components of the nucleus pulposus. MMP-7 enzymatically 
cleaves aggrecan, the major proteoglycan of the disc [7-8]. MMP-7 is significantly expressed in 
surgical samples of human herniated discs and degrades in vitro and in vivo proteoglycans. 
MMP-7 is an endogenous protease that results in the natural resorption of a herniated disc [9-10]. 
From a theoretical standpoint, recombinant human MMP-7 should be ideal for the purpose of 
chemonucleolysis because of its lack of antigenicity in humans and its substrate selectivity 
toward proteoglycans. 
Based on the scientific background above, Teijin and Kaketsuken intend to develop recombinant 
human MMP-7 as a novel therapeutic agent for lumbar disc herniation. Kaketsuken has 
established the manufacturing process for pharmaceutical grade recombinant human MMP-7 
(KTP-001) 
 Teijin has completed extensive 


 
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nonclinical studies to support this first-in human (FIH) study in subjects with lumbar disc 
herniation. 
3.2 
Description of Investigational Product 
KTP-001 is a recombinant human MMP-7 
 
KTP-001 is supplied as a lyophilized powder, which is reconstituted using 0.5 mL of sterile 
water before injection.   
3.3 
Nonclinical Studies 
Complete information for this compound may be found in the Investigator’s Brochure (IB). 
Summaries of nonclinical drug development studies are presented below to support the rationale 
for the proposed study design and doses selected for clinical evaluation. 
3.3.1 
Primary Pharmacology 
Because KTP-001 digests proteoglycan (including aggrecan), the proteoglycan content of the 
nucleus pulposus was selected as a marker in the nonclinical development program to evaluate 
the effects of KTP-001 on nonherniated lumbar discs in animals.
 
 
 
The proteoglycan content of the nucleus pulposus was determined by the intensity of alcian blue 
staining; the breakdown of aggrecan in the nucleus pulposus by KTP-001 was assessed by 
measures of the serum concentrations of keratan sulfate, and a decrease of disc height was 
assessed using disc height index. 
 
 
 
 
  
 
 
 
3.3.2 
Safety Pharmacology 
Safety pharmacology studies conducted 
 




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3.3.4 
Anti-KTP Antibody Production 
Anti-KTP-001 antibody production 
was determined 
. 
 Consequently, the risk of KTP-001 
immunogenicity is considered to be low at the administered doses.  
3.3.5 
Toxicology Studies 
3.3.5.1 
Single Dose Toxicity 
In single dose toxicology studies conducted 
3.3.5.2 
Repeated Dose Toxicity 
In repeated dose toxicology studies conducted 
l 
3.3.5.3 
Developmental and Reproductive Toxicity 
Single intravenous doses of KTP-001 at doses of up to 
 were given 


 
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3.3.5.4 
Intradiscal Single Dose Local Tolerance 
Intradiscal single dose local tolerance studies
 were 
performed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.3.5.5 
Epidural Single Dose Local Tolerance 
The epidural single dose studies 
 were performed  
 
 
 
 
 
3.3.5.6 
Intrathecal Single Dose Local Tolerance 
The intrathecal single dose study 
 was performed 
 
 
 
 
 
 
 
3.3.5.7 
Subcutaneous and Intramuscular Single Dose Local Toxicity 
 
 
 
 
3.4 
Clinical Studies 
The safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of KTP-001 will be 
evaluated in an open-label, non-controlled, single ascending dose study in subjects with lumbar 
disc herniation. This study will be the FIH study. 


 
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4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
4.1.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of a single intradiscal 
injection of KTP-001 in subjects with a single herniated lumbar disc. 
4.1.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To determine the PK of KTP-001 in the serum of circulating blood after intradiscal 
injection of study drug. 
• To determine the presence of anti-KTP-001 antibody in the serum of circulating blood 
after intradiscal injection of study drug. 
4.1.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To determine the pharmacodynamics (PD) of keratan sulfate in the serum of circulating 
blood after intradiscal injection of study drug. 
• To assess changes in pain, neurologic examination, magnetic resonance imaging (MRI) 
and X-ray assessments, disability, quality of life (QOL), and patient global impression of 
change (PGI-C) scores in subjects receiving study drug. 


 
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5 
STUDY DESIGN 
5.1 
Design Summary 
Study KTP-001-CL-101 is an open-label, non-controlled single ascending dose study of 
KTP-001 in male and female subjects between the ages of 30 and 70 with a single herniated 
lumbar disc. After obtaining informed consent, subjects will be evaluated during a screening 
period of no more than 3 weeks (21 days). The following procedures will be performed at the 
screening visit: collection of subject baseline demographics, medical history (including the 
symptoms associated with herniated lumbar disc), prior medications, height, weight, a full 
physical and neurologic examination (including straight-leg raising and femoral stretch test), and 
collection of vital signs, 12-lead ECG, and clinical laboratory tests (hematology, serum 
chemistry, coagulation, urinalysis, and urine drug screen). A serum pregnancy test will be 
conducted for female subjects of childbearing potential. The following baseline exploratory 
efficacy measures will be assessed: lower back and leg pain using a numerical scale (using a 
subject diary for 5 consecutive days prior to treatment), spinal flexion/tension using straight-leg 
raising and femoral stretch test, MRI assessment, lumbar spine X-ray assessment, the severity of 
disability using the Oswestry Disability Index (ODI), QOL using the Short Form-12 (SF-12) 
questionnaire, and symptom severity as measured by the PGI-C scale. A pain assessment diary 
will be administered and collected between screening and treatment on Day 1. 
Subjects that meet all screening requirements and inclusion criteria and none of the exclusion 
criteria will be enrolled into 1 of 4 study cohorts and receive KTP-001. Following administration 
of study drug, subjects will be confined to the study unit for 24 hours to collect data for safety 
and efficacy measures and collect blood samples for the following purposes: safety, PK 
evaluation, and exploratory PD (keratan sulfate), including anti-KTP-001 antibody. 
Subjects enrolled in Cohort 1 will have pre-dose assessments of concomitant medications, 
weight, physical and neurologic examinations, and vital signs. Female subjects will have a urine 
pregnancy test, and all subjects in the cohort will have blood samples taken for PK and PD 
analyses. Efficacy assessments will be repeated. Subjects in this cohort will receive a 5 µg/disc 
dose of KTP-001 by intradiscal injection. Subjects will be observed for 24 hours after injection 
to facilitate post-procedural monitoring and collection of additional PK samples. Subjects will 
return to the clinic for visits at Weeks 1, 2, 4, 6, and 13, and at Months 6, 9, 12 (1 year), 
Month 18 (1.5 years), and Month 24 (2 years) for safety, and exploratory efficacy assessments 
(including X-ray and MRI at Week 13 and Months 6, 12, 18, and 24). Subjects will be provided a 
study diary to record their level of leg and lower back pain on a daily basis up to Week 13. 
Thirteen weeks after all subjects in Cohort 1 have received study drug, safety measures will be 
evaluated by a Data and Safety Monitoring Board (DSMB) to determine whether to escalate 


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KTP-001 administration to the next dose level. This evaluation will be conducted after the 
13-week follow-up visit for all subjects in each dose cohort.
If escalation is appropriate as determined by the DSMB (see Section 5.1.2), then the Cohort 2 
subjects will receive KTP-001 15 µg/disc, Cohort 3 subjects will receive 50 µg/disc of KTP-001, 
and Cohort 4 subjects will receive 150 µg/disc of KTP-001 by intradiscal injection (Figure 5.1). 
All safety, PK, and exploratory efficacy assessments will be performed for the subjects in the 
subsequent cohorts as were performed for Cohort 1.  
Figure 5.1 
KTP-001-CL-101 Study Design 
5.1.1 
Treatments Administered 
The proposed clinical dose concentrations for this FIH study are 5 μg/disc (Cohort 1), 15 μg/disc 
(Cohort 2), 50 μg/disc (Cohort 3), and 150 μg/disc (Cohort 4). Single doses of the proposed 
clinical dose concentrations will be administered intradiscally at the level of lumbar disc 
herniation by injection under fluoroscopic or computerized tomography (CT) visualization and 
guidance to 24 male and female human subjects between the ages of 30 and 70 with a single 
herniated lumbar disc as confirmed by MRI.  
5.1.2 
Dose Escalation 
Escalation to a higher dose in a cohort will be permitted only if adequate safety and tolerability 
have been demonstrated at the previous lower dose level after review by the DSMB. The 
responsibilities of the DSMB are to monitor the safety and welfare of the study subjects by 
reviewing the data from the study at regular intervals and determining whether it is safe to 
continue the study according to the protocol. The DSMB will have the authority to recommend 


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stopping the study early or modifying the study design for safety concerns. Details regarding 
DSMB membership, dose escalation criteria, schedule and format of meetings, format for 
presentation of data, access to interim data, and other information relevant to the operations of 
the committee will be described in a separate DSMB charter. The DSMB will conduct a safety 
review at the 13-week follow-up visit for all subjects in each dose cohort.  
5.1.3 
Halting Rules 
The AEs or imaging abnormalities described below will be defined in this study as a halting rule 
(HR). If a HR occurs in any subject during the dose escalation phase of the study, further 
recruitment and dosing of the current study cohort will be held until the event is assessed by the 
DSMB. The DSMB will make a recommendation regarding continuation of the study and/or 
escalation to the next dose cohort when one of the following events occurs:  
•
Neurologic deficit consistent with cauda equina syndrome or myelopathy
•
Exacerbation of radicular symptoms associated with onset of a new motor deficit in one
or both legs following administration of study drug
•
Modic changes consistent with significant endplate edema or sclerosis compared to
baseline, as determined by an expert spine radiologist
•
Loss of height of the disc of > 30% relative to the baseline and defined as the average of
anterior and posterior disc height evaluated by X-ray
•
Evidence by X-ray of lumbar segmental instability at the treated segment defined as
either:
o
Anterior translation of the posterior edge of the superior vertebral body relative to
the posterior edge of the inferior vertebral body increase from baseline greater
than 3mm is considered strong evidence of instability
o
Sagittal rotation change from extension to flexion of >5° (as measured by the
Dupuis method)[11] is weak evidence of instability, and without observed
translation as defined above, will require further evaluation before it would be
considered a halting event
NOTE: if the subject’s condition does not permit the acquisition of flexion and
extension films, instability will be evaluated solely on the basis of translation on
the lateral view, as described above
•
Destructive cartilage endplate changes as confirmed by MRI.


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Once the last 13-week follow up period after the last dose cohort has occurred, any future 
instances of these events will be reported as AESI, but will not be treated as a HR. Further details 
on the role of the DSMB to evaluate study conduct will be provided in a separate DSMB charter. 
5.1.4 
Duration of Study 
Subjects will be enrolled in this study for up to 24 months. After 24 hours of confinement, the 
subject will return to the clinic for visits at Weeks 1, 2, 4, 6, and 13, and at Months 6, 9, 12, 18, 
and 24 for safety and exploratory efficacy assessments. 
5.2 
Discussion of Study Design 
Because intradiscal injection is too invasive to be performed on healthy volunteers, this study 
will be conducted with patients with documented herniated lumbar discs. Due to the chronic pain 
caused by herniated lumbar discs, concomitant medications to control pain are necessary for this 
subject population.  
Calculations for the starting dose in this FIH study is based on nonclinical studies and described 
in Section 7.3. Based on these findings, the DSMB will review all relevant safety data after the 
Week 13 visit to guide subsequent dosage escalation, as appropriate. Further details on dose 
escalation criteria will be provided in a separate DSMB charter. 


 
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6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subject eligibility should be reviewed and documented by an appropriately qualified member of 
the investigator’s study team before subjects are included in the study. Subjects must fully meet 
the following inclusion criteria and none of the exclusion criteria in order to enroll in the study. 
In keeping with regulatory requirements, 
 does not grant protocol waivers to 
inclusion/exclusion criteria and does not contract to review or approve any protocol waivers. 
Any waiver granted by the Sponsor will be treated as a protocol deviation (Section 11.17).    
6.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. 
Has had a single unilateral contained or noncontained (extruded) lumbar disc herniation 
at the L3-L4 or L4-L5 or L5-S1 level diagnosed by clinical symptoms and/or physical 
findings and confirmed by MRI. Symptom duration should be at least 6 weeks prior to 
screening. 
2. 
Has radicular symptoms with a documented positive straight-leg raising or femoral 
stretch test consistent with the level of the disc herniation. 
3. 
Has had at least 6 weeks of conservative therapy prior to screening. 
4. 
Has a daily average leg pain score of ≥ 4 (using an 11-point numerical scale) on at least 
3 out of the 5 days immediately prior to treatment AND on all 5 days immediately prior 
to treatment the daily average leg pain score is ≥ 2.  
5. 
Has completed the subject diary for at least 4 out of the 5 days immediately prior to 
treatment. 
6. 
Has an ODI of ≥ 30% at screening. 
7. 
Is a male or female subject between 30 and 70 years of age, inclusive. 
8. 
Has a body mass index of 18 to 35 kg/m2. 
9. 
Is medically healthy, other than lumbar disc herniation, with clinically insignificant 
screening results (including laboratory profiles, medical histories, electrocardiograms 
[ECGs], and physical examination) as deemed by the investigator. 
10. 
Uses or agrees to use effective contraception methods or is a female of nonchildbearing 
potential (See Section 6.3).     


 
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11. 
Voluntarily provides written consent to participate in the study. 
6.2 
Exclusion Criteria 
A subject will not be eligible for study participation if he/she meets any of the exclusion criteria, 
or will be discontinued at the discretion of the investigator if he/she develops any of the 
following exclusion criteria during the study: 
1. 
Has a sequestered lumbar disc herniation or intrathecal herniation confirmed by MRI. 
2. 
Has 2 or more symptomatic lumbar disc herniations as assessed by clinical symptoms 
and/or physical findings and confirmed by MRI. 
3. 
Has had previous intradiscal therapeutic intervention at the level of the current 
symptomatic disc herniation or has had any lumbar surgery in the past. Previous 
therapeutic intradiscal injections (e.g., steroids) at the level of the current symptomatic 
disc herniation are not permitted within 6 weeks of screening. 
4. 
Has undergone chemonucleolysis at any level of disc herniation or has had previous 
exposure to study drug. 
5. 
Has had previous epidural injections, a selective nerve root block, or a facet block within 
2 weeks before screening. 
6. 
Has had any changes in the frequency of physical therapy or the introduction of new 
modalities of physical therapy, acupuncture, transcutaneous electrical nerve stimulation 
(TENS) or any other nonpharmacologic treatment modalities within 2 weeks prior to 
screening. 
7. 
Has had any changes in dosing of pain medications or introduction of new pain 
medications/muscle relaxants within 1 week prior to screening. 
8. 
Has had any changes in antidepressant treatment or “pain modulating” therapy, including 
gabapentin and pregabalin within 4 weeks before screening. 


 
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9. 
Has the presence of lumbar spine disease and/or deformity other than a lumbar disc 
herniation, including spondylolisthesis Grade 2 or above, clinically significant scoliosis, 
spinal stenosis including significant lateral recess stenosis not related to the lumbar disc 
herniation, vertebral compression fracture, ankylosing spondylitis, inflammatory bone or 
disc disease, primary or metastatic malignancy, or any other clinically significant spine 
disease. 
10. 
Has symptoms of cauda equina syndrome or progressive neurologic deficit, especially 
motor weakness. 
11. 
Has a concomitant neurologic disorder, such as polyneuropathy, myopathy or motor 
neuron disease, lumbosacral plexopathy, radiculitis, multiple sclerosis, myelopathy, 
spinal cord compression, prior poliomyelitis or stroke, or any other condition resulting in 
sensory-motor deficit in the lower extremities. 
12. 
Has other concomitant painful condition such as fibromyalgia, rheumatoid arthritis, 
severe osteoarthritis of the hip and/or knee joints or other painful condition that may 
interfere with pain assessments in the study. 
13. 
Has a history of and/or clinical evidence of peripheral vascular disease. 
14. 
Has the presence of an apophyseal ring in the vertebral disc as confirmed by X-ray. 
15. 
Is pregnant, breastfeeding, or has a positive serum pregnancy test at screening or a 
positive urine pregnancy test prior to receiving the study drug. 
16. 
Has a history or presence of significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or 
psychiatric disease.  
17. 
Has a history or presence of cancer within 5 years of screening, with the exception of 
localized basal cell skin cancer.  
18. 
Has a history of heavy alcohol consumption (defined as more than 2 standard alcohol 
beverages per day for males or more than 1 standard alcohol beverage per day for a 
woman, or more than 5 standard alcohol beverages on one occasion more than 5 times in 
the last 30 days for either gender) or drug abuse within the past 2 years or has a positive 
urine drug screen prior to enrollment (except for prescription medications). 


 
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19. 
Is a current, active smoker or is unable to abstain from tobacco use for 2 weeks prior to 
study injection. 
20. 
Has a history of multiple drug allergies (2 or more classes of drugs), food allergies or 
other life-threatening allergies deemed significant by the principal investigator. 
21. 
Has used or is using systemic steroids within 2 weeks prior to screening (not including 
inhalation, ophthalmic, and topical steroids). 
22. 
Is taking anticoagulants including (but not limited to) warfarin, heparin/low molecular 
weight heparins, thrombin inhibitors, factor Xa inhibitors; or has any condition/treatment 
associated with coagulopathy/bleeding tendency. 
23. 
Is receiving workers’ compensation or other disability benefits or has a pending disability 
claim or litigation related to a back condition/disc herniation. 
24. 
Has participated in any clinical study within 30 days prior to screening. 
25. 
Has a positive screen for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV), or anti-human immunodeficiency virus (HIV), or has any active, clinically 
significant infection. 
26. 
Has an elevation of aspartate aminotransferase (AST) and/or alanine aminotransaminase 
(ALT) ≥ 2 X upper limit of normal (ULN), or a total bilirubin > ULN, or a creatinine 
≥ 1.5 X ULN, or any other clinically significant laboratory abnormalities that, in the 
investigator’s judgment, would preclude the subject from participation in the study. 
27. 
Has any clinically significant ECG abnormalities at screening. 
28. 
Has any contraindication to undergo an MRI or has declared inability to tolerate an MRI. 
29. 
Has any condition that would, in the investigator’s opinion, limit the subject’s ability to 
complete the study. 
6.3 
Women of Nonchildbearing Potential and Acceptable Forms of Contraception 
Women of nonchildbearing potential are defined as any female who is postmenopausal or 
posthysterectomy (medical documentation of hysterectomy must be available to the investigator). 
Postmenopause is defined as meeting 1 of the following conditions: 
• Amenorrhea ≥ 12 consecutive months without another cause and ≥ 50 years of age  


 
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• Women younger than 50 years of age who have not menstruated for ≥ 12 consecutive 
months (or with irregular menstrual periods) AND have a documented serum follicle 
stimulating hormone level > 35 mIU/mL  
Women who are of childbearing potential must be using 1 or more of the following contraceptive 
methods during the study:  
• Oral or other hormonal contraceptives:  vaginal products, skin patches, or implanted or 
injectable products 
• Mechanical product such as an intrauterine device 
• Double-barrier method:  diaphragm or condoms with spermicides 
• Practicing abstinence or who has a sterile (e.g., vasectomy) partner 
6.4 
Prior and Concomitant Therapy 
All medications (prescription and over-the-counter, vitamin and mineral supplements, and herbs) 
and all therapies for disc herniation (including but not limited to physical therapy, acupuncture, 
epidural injections/selective nerve root block) taken or received by the participant within 
1 month of screening and throughout study participation will be documented on the concomitant 
medication case report form (CRF) and will include: start and stop dates, dose and route of 
administration, and indication. Medications taken for a surgical procedure should also be 
included. 
6.5 
Restrictions on Concomitant Therapies or Procedures During the Study 
6.5.1 
Pain Management During First 13 Weeks Post-dose 
Subjects will be allowed to continue their pre-study pain regimen. However, introduction of a 
new analgesic or dose escalation of an already used analgesic will be disallowed with the 
exception of temporary use to treat a documented adverse event (AE) if required and at 
discretion of the investigator, and only for the duration of the event. Beyond treatment for an AE, 
acetaminophen will be the only allowed as rescue medication in the study and use will be 
captured as a secondary outcome measure. The maximum total daily dose of acetaminophen 
(rescue plus any other combination analgesic containing acetaminophen) must not exceed 
4 grams. 
6.5.2 
Pain Medications  
A summary of allowed pain medication by study phase is provided in Appendix A. The 
following restrictions on pain medications are to be followed during the first 13 weeks post-dose 
and do not apply beyond the Week 13 visit.   


 
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1. Initiation of treatment or change in the dose regimen is disallowed for antidepressants, 
anticonvulsants, or any prescription or over the counter pain modulating drugs from 
screening to 13 weeks post-dose. If subjects are on a stable dose of any of the above 
medications for at least 4 weeks prior to screening, the same dose regimen should be 
continued through 13 weeks post-dose. 
2. Initiation of treatment or dose escalation of muscle relaxants or sedatives/hypnotics is 
disallowed. A stable dose regimen if initiated at least 1 week prior to screening may be 
continued unchanged through 13 weeks post-dose. However, temporary use of a new 
muscle relaxant or sedative/hypnotic or dose increase of already used muscle relaxant or 
sedative/hypnotic will be allowed for treatment of a documented AE, for the duration of 
the event only. If clinically indicated, dose reduction or discontinuation of treatment is 
also permitted. 
3. Epidural steroid injections/selective nerve root block/facet block are allowed if medically 
necessary within the first 13 weeks post-dose and beyond. However, the indication for 
the procedure (e.g., intractable lower back pain/worsening of lower back pain) must be 
documented as an AE (or SAE if it meets the SAE criteria defined in Section 9.9.7). 
Subjects who require a surgical intervention for treatment of disc herniation will be 
discontinued from the study. 
4. Opioid and nonopioid analgesics (including topical analgesics) used for pain management 
on a stable dose at least 1 week prior to screening may be continued at the same or lower 
dose during the first 13 weeks post-dose. No dose escalation and no new opioid or 
nonopioid analgesics will be allowed except for acetaminophen. However, as described 
in Section 6.5.1, temporary use of a new analgesic or dose increase of an already 
administered analgesic will be allowed to treat a documented AE, for the duration of the 
event only. Daily doses of all analgesics including rescue doses of acetaminophen will be 
recorded by the subjects in the provided diaries. 
5. Systemic steroids are disallowed during the first 13 weeks post-dose, except for 
temporary use to treat a documented AE, for the duration of event only. Topical, 
ophthalmic and inhalation steroids are allowed. 
6. Subjects treated with a nonsteroidal anti-inflammatory drug (NSAID) should have their 
treatment discontinued at least 10 days prior to the study procedure. The NSAIDs may be 
restarted 24 hours post-dose. Use of an alternative analgesic during that period of time 
will be allowed at the discretion of investigator.  
7. Therapeutic intradiscal interventions including intradiscal injections, other than the study 
injection are not permitted in the study. 


 
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6.5.3 
Antiplatelet therapy 
It is recommended that antiplatelet therapy be withheld prior to the study procedure for the 
duration of time consistent with the type of antiplatelet drug and local standard of care (on 
average 7 to 10 days). It may be restarted 24 hours after the procedure. A low dose aspirin (e.g., 
81 mg) for cardiovascular protection may be continued at the discretion of the investigator. 
6.5.4 
Disallowed Treatments 
Initiation of acupuncture, TENS, physical therapy modalities, biofeedback or psychotherapy are 
disallowed. Continuation of the same therapy modalities/frequency as received prior to screening 
is allowed (if prior therapy has been stable for at least 2 weeks prior to screening). Reduced 
frequency of treatments and discontinuation of prior therapy is allowed. The above restrictions 
do not apply beyond the Week 13 visit. 
6.5.5 
Tobacco and Alcohol Use  
Subjects are prohibited from using any tobacco products from 2 weeks prior to the study 
injection through 2 weeks post-dose. Consumption of alcohol should be limited to that defined in 
the exclusion criteria. 
6.6 
Subject Withdrawal and Discontinuation 
Subjects are free to discontinue the study at any time, for any reason, and without prejudice to 
further treatment. The investigator may remove a subject if, in the investigator’s judgment, 
continued participation would pose unacceptable risk to the subject or to the integrity of the 
study data.  
Subjects must discontinue from the study for any of the following reasons: 
• The subject experiences an intercurrent illness that in the opinion of the investigator 
indicates continued participation in the study is not in the subject’s best interest 
• The subject is unable or unwilling to comply with the protocol 
• The subject withdraws informed consent 
• The subject is lost to follow-up 
• The subject requires lumbar spine surgery 
• A female subject tests positive for pregnancy 
All procedures for early termination must be completed (Section 11.13). Subjects who are 
withdrawn prior to administration of study drug will be replaced to ensure a total of 6 evaluable 
subjects in each study cohort.  


 
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6.7 
Early Termination of Study 
The study may be terminated at any time by the Sponsor if serious side effects occur, if the 
investigator does not adhere to the protocol, or if, in the Sponsor’s judgment, there are no further 
benefits to be achieved from the study. In addition, the study may be terminated at any time at 
the Sponsor’s discretion. In the event that the clinical development of the study drug is 
discontinued, Teijin America, Inc. shall inform all investigators/institutions and regulatory 
authorities. 


 
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7 
STUDY DRUG 
7.1 
Description of Investigational Product 
The active ingredient of KTP-001 is recombinant human MMP-7 
 
 KTP-001 is a lyophilized powder for reconstitution provided in a sterile glass 
vial. Each vial contains 1.0 mg of KTP-001 drug substance in a 2 mL USP Type 1 glass vial to 
be reconstituted with 0.5 mL of sterile water for injection. Further details regarding the study 
drug are provided in the IB, and details on drug preparation for intradiscal injection will be 
provided in the Pharmacy Manual. 
7.2 
Treatments  
The study procedure should be performed under sterile conditions in an ambulatory surgical 
center, or special-procedure ambulatory radiology suite, or an operating room. The staff of 
treatment facility must be appropriately trained and prepared to respond to medical emergencies 
including the remote possibility of systemic allergic reaction. 
A single intradiscal injection of 5, 15, 50, or 150 µg/disc of KTP-001 will be administered 
intradiscally using a two-needle technique under fluoroscopic or CT visualization and guidance. 
The procedure will be performed under local anesthesia as per investigator’s standard of care. 
Light sedation will be allowed as per local standard of care. However, the subject must remain 
awake and able to cooperate during the procedure. The injection volume per subject will be 
1.0 mL. Use of an imaging dye is not permitted for the intradiscal injection. A prophylactic 
antibiotic may be used as per local standard of care. 
The intradiscal injection procedure is detailed in Appendix B. 
7.2.1 
Local Anesthetic and Chemonucleolysis Procedures 
Details on local anesthetic and chemonucleolysis procedures will be provided in the Study 
Manual. 
7.3 
Dose Rationale 
The disc volume where KTP-001 will be injected is a closed space as demonstrated in numerous 
animal studies, and therefore, the volume of the nucleus pulposus in animals and humans was 
used to calculate dose levels. 
 
 
 
 
 
 


 
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7.4 
Method of Assigning Subjects to Treatment Groups 
Approximately 48 subjects will be screened to ensure that 24 subjects are enrolled into this study. 
After the first cohort of 6 subjects, the remaining subjects will be enrolled into the 3 subsequent 
cohorts and receive the KTP-001 dose as assigned for that cohort. Subjects who discontinue from 
the study after enrollment but prior to receiving study drug will be replaced to ensure that at least 
6 subjects are treated in each of the 4 cohorts. 
7.5 
Measurements of Treatment Compliance 
Subjects will receive a single dose of study drug by intradiscal injection. The injection will be 
performed under fluoroscopic or CT guidance and documented by X-ray or CT scan, as well as 
in the CRF by the investigator. No other measures of treatment compliance will be used.  
7.6 
Investigational Product Storage and Accountability 
7.6.1 
Storage Conditions 
The investigator will ensure that all drug supplies are kept in a secure, temperature controlled, 
locked area with access limited to those authorized by the investigator. 
A minimum/maximum daily temperature log must be maintained. 
All study drugs will be stored at 2 to 8 °C (35 to 46 °F). Any temperature excursion outside the 
storage temperature must be notified to 
 immediately. 
7.6.2 
Drug Accountability 
The investigator must ensure that all drug supplies are kept in a secure locked area with access 
limited to those authorized by the investigator. The investigator must maintain accurate records 
of the receipt of all study drug shipped by Sponsor or their designee, including but not limited to 
the date received, lot number, expiration date, amount received, and the disposition date and 
place of all study materials. Current dispensing records will also be maintained including the 
date and amount of study drug dispensed and the subject receiving the drug. All unused study 
drug not required by regulations to be held by the clinical facility must be returned to Sponsor or 
their representative immediately after the study is completed. Unused needles, syringe, etc. 
should be disposed of per the pharmacy manual or site procedure. 
7.7 
Packaging and Labeling 
KTP-001 is a white powder provided in a sterile 2 mL USP Type 1 glass vial. After 
reconstitution in 0.5 mL of sterile water for injection, it appears as a clear and colorless solution. 
KTP-001 product labels will comply with FDA regulations for investigational products. 


 
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7.8 
Preparation of Investigational Product 
KTP-001 will be provided to the study sites as lyophilized powder in 2 mL glass vials. Each vial 
contains 1.0 mg of KTP-001 drug substance, which is to be reconstituted with 0.5 mL of sterile 
water for injection. Each vial is to be reconstituted with 0.5 mL of sterile water for injection. 
Further details regarding preparation of the study drug will be provided in the Pharmacy Manual. 
 


 
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8 
EFFICACY ASSESSMENTS 
The following efficacy measures are all exploratory in nature and all analyses will be presented 
using descriptive statistics. For all measures, the baseline value is defined as the last assessment 
result collected prior to the first dose of study medication. Unless otherwise noted, the endpoint 
for all efficacy measures will be changes from baseline at 6 and 13 weeks post-dose. 
8.1 
Lower Back or Leg Pain 
Lower back and leg pain will be assessed using an 11-point numerical rating scale in response to 
the questions provided in Appendix C at screening, for 5 consecutive days prior to Day 1, 
pre-dose, at 2, 4, 6, and 24 hours post-dose, and then daily until the Week 13 visit. A numerical 
rating scale is considered to be a valid and reliable means of measuring pain in subjects with 
chronic pain conditions [14].  
8.2 
Use of Rescue Medication or Surgical Intervention 
The number of subjects and amount of rescue medication will be recorded and summarized when 
any of the following occurs:  extra pain medication is administered that is in addition to the 
baseline pain regimen defined at screening prior to treatment, an epidural injection or a selective 
nerve root block within 13 weeks after receiving study drug, or surgical intervention for lumber 
disc herniation.  
8.3 
Spinal Flexion and Tension  
Spinal flexion and tension will be measured using the straight-leg raising or femoral stretch test 
at baseline, on Day 1 pre-dose, at 24 hours post-dose, and at all post-dose visits. Details on 
administering the straight-leg or femoral stretch test are provided in Appendix D.  
8.4 
Functional Ability 
The degree to which lower back or leg pain interferes with the subject’s ability to manage 
everyday tasks will be measured using the ODI (version 2.1A) and is provided in Appendix E.  
The ODI is a patient self-scored questionnaire in use since 1980. The ODI is a validated tool to 
measure how functional level is restricted by disability, and can also be used to determine 
improvement in functional levels as a result of treatment. The improvement or lack of 
improvement in functional level is determined as a change from baseline in the score. 
The ODI measures 10 areas of daily function:  pain intensity, personal care, lifting, walking, 
sitting, standing, sleeping, sex life, social life, and travelling. The items are scored from 0 to 5, 
with 0 being the best functional level and 5 being the worst functional level. A percentage is then 
derived from these responses (patient score/total possible score x 100 = %) and recorded as that 
day’s ODI. Scores are then grouped into levels of disability: 


 
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0% - 20% = minimal disability 
20% - 40% = moderate disability 
40% - 60% = severe disability 
60% - 80% = crippled 
80% - 100% = bed bound 
The ODI will be administered at baseline, on Day 1 pre-dose, at 24 hours post-dose, and at all 
post-dose visits.  
8.5 
Quality of Life 
Quality of life will be evaluated using the SF-12 form (version 2.0). The SF-12 asks 12 questions 
to measure functional health and well-being from the subject’s point of view across 8 health 
domains. Subjects provide a response to each question using a 5-point Likert scale and the 
resulting score provides a measurement of the subject’s health compared with the general 
population or compared with prior scores. The SF-12 is provided in Appendix F. 
The SF-12 will be administered at baseline, on Day 1 pre-dose, at 24 hours post-dose, and at all 
post-dose visits. The endpoint for QOL will be changes from baseline at 6 and 13 weeks 
post-dose. 
8.6 
Global Impression of Change or Improvement 
Global impression of improvement as measured by the PGI-C (Appendix G) is a single question 
survey that will be administered at baseline, on Day 1 pre-dose, at 24 hours post-dose, and at all 
post-dose visits. The endpoint for global impression of change or improvement will be changes 
from baseline at 6 and 13 weeks post-dose.  
8.7 
Appropriateness of Efficacy Measures 
The efficacy measures for this study are exploratory in nature and were chosen based on prior 
experience with the patient population. 
8.8 
Magnetic Resonance Imaging Assessment 
Magnetic resonance evaluation on the modification/shrinkage of the treated herniated disc size, 
the improvement of the stenosis of spinal canal, and the reduction of associated lateral neural 
foramen compression will be performed at Week 13, and at Months 6, 12, 18, and 24 (or early 
termination). The correlation between imaging findings and symptoms (e.g., pain score or ODI 
score) will be conducted after database lock as part of the report analysis. The herniated disc size 
will be assessed quantitatively while the compression of lateral neural formation and spinal canal 
stenosis will be evaluated qualitatively by an independent radiological reviewer. 


 
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9 
SAFETY ASSESSMENTS 
Unless otherwise noted, the endpoint for all safety assessments is changes from baseline. 
9.1 
Vital Signs 
Vital signs (heart rate, systolic and diastolic blood pressures, respiratory rate, and body 
temperature) will be measured at screening, pre-dose and post-dose at specified times on Day 1, 
at each follow-up visit during the study, and at the end of study visit or upon discontinuation 
from the study as specified in the Schedule of Assessments (Section 11).  
9.2 
Clinical Laboratory Tests 
Samples will be obtained for the clinical laboratory tests at defined in Appendix H outlined in the 
Schedule of Assessments (Section 11) at screening, at specified times during the study. 
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests. The baseline laboratory test results for clinical assessment for a particular test 
will be defined as the last measurement prior to the initial dose of study drug. 
For any laboratory test value outside the reference range that the investigator considers clinically 
significant, the investigator will: 
• Repeat the test to verify the out-of-range value. 
• Follow the out-of-range value to a satisfactory clinical resolution. 
• Record as an AE any laboratory test value that (1) is confirmed and the investigator 
considers clinically significant; or (2) that requires a subject to be discontinued from the 
study; or (3) that requires a subject to receive treatment. 
9.3 
Electrocardiograms 
A standard 12-lead ECG will be obtained at screening, and at 24 hours and 13 weeks post-dose.  
Additional ECGs may be obtained if clinically indicated. Follow-up ECGs will be obtained if 
any significant abnormalities are detected after dose administration to document resolution and 
as clinically indicated. Any additional relevant data obtained by the investigator during the 
course of this study will be supplied to the Sponsor. 
9.4 
Physical Examination 
A complete physical examination, including height and weight, will be performed at screening. 
Physical examinations and weight assessments will be performed during the visits specified in 
Schedule of Assessments (Section 11). Any findings or absence of findings relative to each 
subject’s physical examination will be carefully documented in the subject’s CRF. 


 
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9.5 
Anti-KTP-001 Antibodies 
Blood samples for measures of serum anti-KTP-001 antibody will be drawn pre-dose (just prior 
to administration of study drug) and at the 1-, 2-, 4- , 6-, and 13-week visits post-dose or early 
termination visit. The DSMB must be notified if antibodies are detected and the DSMB will 
advise on how to proceed. The investigators and relevant Institutional Review Board (IRB) will 
be notified about the DSMB decision. 
9.6 
Magnetic Resonance and X-ray Imaging Acquisition and Evaluation 
Imaging examination, including lumbar spine MRI and X-ray, will be acquired as outlined in the 
Schedule of Assessments (Section 11) at screening, Week 13 (±5 days), Month 6 (±1 week), 
Month 12 (±2 weeks), Month 18 (±4 weeks), and Month 24 (±4 weeks), or upon subject 
discontinuation. For subjects with contraindication for MR during the study, the alternative 
imaging modality is a lumbar spine CT. 
The MRI lumbar spine protocol includes sagittal fast (or turbo) spin echo T2-weighted, sagittal 
spin echo T1-weighted, sagittal STIR (Short Tau Inversion Recovery) images, axial fast spin 
echo T2-weighted with and without fat suppression, and axial spin echo T1-weighted images [15]. 
Axial diffusion-weighted images, axial and/or coronal Short Tau Inversion Recovery images are 
optional and upon the discretion of on-site radiologists. Unenhanced lumbar MR imaging is 
generally adequate for the imaging examination, unless contrast enhancement is specifically 
requested by the investigator or radiologist (e.g., for suspected infection). If gadolinium is 
administered, both sagittal and axial contrast-enhanced T1-weighted images with fat saturation 
will be required. If a hematoma is suspected at a post-procedure examination, an axial 
T2*-weighted image should be added.  
Both sagittal and axial images should include the area of clinical interest. Axial images should be 
obtained through the relevant lumbar disc and adjacent spine treated by chemonucleolytic 
procedure (e.g., L3-4, or L4-5 or L5-S1). Axial slice orientation should be set up in parallel with 
the treated disc and be consistent through each time point. Additional axial images may be 
placed at the level/location in which occurrence of adverse effect is suspected. Slice thickness of 
equal or less than 5.0 mm is required for sagittal images with a gap less than 1.0 mm, while slice 
thickness of equal or less than 3.0 mm for axial images without gap.  
9.6.1 
Lumbar (or lumbosacral) Spine X-ray Examination Requirements 
An anterior-posterior (AP) position and lateral neutral position views of the lumbar spine are 
required.  The flexion-extension views are optional when the patients have radicular symptom 
with the restriction of flexion.  


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9.6.2 
Safety Evaluation of MRI and X-ray 
Evaluation of both X-rays and MRI images will be performed by an independent radiological 
reviewer who shall be a spine imaging specialist. The X-ray safety evaluation will include 
assessment of disc height and segmental instability as defined in the halting rules in Section 5.1.3. 
The MR safety evaluation will focus on assessment of Modic changes at Week 13 according to 
the halting rules (HRs) described in Section 5.1.3. The reviewer will also assess for evidence of 
hematoma/hemorrhage, infection, discitis, and any other complications that may contribute to 
AE reporting. Qualitative information will also be collected by the independent radiological 
reviewer on the size of the herniated disc, the degree of spinal canal stenosis, and compression of 
the nerve root in the lateral neural foramen. 
Additional evaluations will be performed at Months 6, 12, 18, and 24. Lumbar spinal MR 
examination may be ordered upon discretion of the investigator if there is an emergency 
indication to conduct an examination.  
9.7 
Neurologic Examination 
A neurological examination will be performed on at screening, on Day 1 at pre-dose, 2 hours 
post-dose, 24 hours post-dose, and at all consecutive visits. The neurological examination will 
include sensory and motor examination of both lower extremities, Babinski’s sign (Appendix I), 
deep tendon reflexes, and the straight-leg raising test and femoral stretch test (Appendix D). The 
results of the neurological examination will be summarized by the investigator as unchanged, 
improved, or worsened, and documented in the CRF. Changes from baseline on this evaluation 
will be considered the neurologic safety endpoint. 
9.8 
Halting Rules 
The number of subjects with AEs defined as HRs will be described and evaluated. 
9.9 
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product during the course of a clinical investigation. An AE can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of a 
study drug, whether or not thought to be related to the study drug. Adverse events of special 
interest (AESI) are defined in Section 9.9.3. 
Subjects will be monitored throughout the study for AEs, from the ICF signing until the last 
study visit unless the AE is considered related to the study drug/procedure, in which case the AE 
will be followed until resolution. Action taken will be categorized as none, study drug not given 
(for events occurring prior to study drug dosing), required concomitant medication, required 
procedure, or other. Event outcome at resolution or time of last follow-up will be recorded as 
event resolved, resolved with sequelae, ongoing, or death. Adverse events that are identified at 


 
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the last assessment visit (or the early termination visit) as specified in the protocol must be 
recorded on the AE CRF with the status of the AE noted, and the AE must be followed until 
resolution. All events that are ongoing at this time will be recorded as ongoing on the CRF. The 
procedures specified in Section 9.9.8 are to be followed for reporting SAEs. 
9.9.1 
Assessing Severity 
The severity of an AE will be graded according to the following definitions: 
• Mild:  The subject experiences awareness of symptoms but these are easily tolerated or 
managed without specific treatment 
• Moderate:  The subject experiences discomfort enough to cause interference with usual 
activity, and/or the condition requires specific treatment 
• Severe:  The subject is incapacitated with inability to work or do usual activity, and/or the 
event requires significant treatment measures. 
Note:  it is important to distinguish between a severe AE and an SAE. Severity is a measure of 
intensity, whereas seriousness is classified by the criteria based on regulatory definitions as 
described in Section 9.9.7. An AE of severe intensity need not necessarily be classified as serious 
(e.g., a severe incapacitating migraine headache). 
9.9.2 
Assessing Causality 
The relationship of the event to the study drug should be determined by the investigator 
according to the following criteria: 
• Not related:  The event is most likely produced by other factors such as the subject’s clinical 
condition, intercurrent illness, or concomitant drugs, and does not follow a known response 
pattern to the study drug, or the temporal relationship of the event to administration of study 
drug makes a causal relationship unlikely 
• Possibly related:  The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, but could have 
been produced by other factors such as the subject's clinical condition, intercurrent illness, or 
concomitant drugs  
• Probably related:  The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, and cannot be 
reasonably explained by other factors such as the subject's clinical condition, intercurrent 
illness, or concomitant drugs.  


 
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9.9.3 
Adverse Events of Special Interest 
The following AEs will be considered an AESI that must be reported to 
 within 24 hours of 
the investigative site becoming aware of the event.       
1. MRI or X-ray findings of Modic changes, reduction of disc height, or evidence of lumbar 
instability as defined in Section 5.1.3, or any other acute MRI or X-ray changes from 
baseline images deemed significant by the central reader/spine imaging specialist. 
2. Exacerbation of back or leg pain meeting at least 1 of the following criteria: 
a) increase in average daily leg or back pain score by ≥ 3 to 6 or above on the numerical 
rating scale for at least 5 days out of a week 
b) increase in average daily pain level associated with a new onset of focal neurological 
symptoms such as numbness and/or tingling or weakness lasting for > 5 days.  
3. New onset of neurological symptoms associated with objective changes on neurological 
examination (weakness, sensory deficit, changes in deep tendon reflexes) whether or not 
associated with increase in pain level. 
4. Any deterioration of subject’s condition that in the investigator’s judgment requires: 
a) emergency MRI 
b) epidural steroid injection/selective nerve root block, facet block, or surgical 
intervention. 
Any AESI meeting seriousness criteria for SAE reporting must be reported as an SAE as defined 
in Section 9.9.8. 
9.9.4 
Following Adverse Events 
All (both serious and nonserious) AEs must be followed until they are resolved or stabilized, or 
until all attempts to determine resolution of the event are exhausted. The investigator should use 
his/her discretion in ordering additional tests as necessary to monitor the resolution of such 
events.  
9.9.5 
Discontinuation due to Adverse Events 
Any subject who experiences an AE may be withdrawn at any time from the study at the 
discretion of the investigator. Subjects withdrawn from the study due to an AE, whether serious 
or nonserious, must be followed by the investigator until the clinical outcome of the AE is 
determined. The AE(s) should be noted on the appropriate CRFs and the subject’s progress 
should be followed until the AE is resolved. The medical monitor must be notified.  
9.9.6 
Pregnancy 
Subjects must be instructed to inform the study investigator immediately if they or their female 
partner become pregnant during the study.  


 
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The investigator must report any pregnancy to the medical monitor within 1 business day of 
becoming aware of it and to the 
 SAE hotline per procedure. The pregnant female subject 
must be discontinued from the study. An uncomplicated pregnancy will not be considered an AE 
or SAE, but it will be documented on an AE CRF page. All pregnancies will be followed through 
birth.  
Pregnancies are captured if they occur in female subjects from the time of first signed consent for 
study participation until last visit. Female subjects with a positive pregnancy test at screening or 
pre-dose time point will be considered a screen failure.  
Any congenital abnormalities in the offspring of a subject who received study drug will be 
reported as an SAE. Any complications of pregnancy or elective termination due to a medical 
reason will be reported as an AE and follow as such. A spontaneous abortion is considered an 
SAE. The outcome of any pregnancy and the presence or absence of any congenital abnormality 
will be recorded in the source documentation and reported to the medical monitor and Sponsor.  
9.9.7 
Serious Adverse Events 
The investigator is responsible for determining whether an AE meets the definition of an SAE. 
An SAE is any AE occurring from ICF signing through final study visit, at any dose, that results 
in any of the following outcomes:  
• Death 
• A life-threatening event, defined as an event in which the subject was at risk of death at the 
time of the event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect in a child or fetus of a subject exposed to the study drug 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
any of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Note:  SAEs require immediate reporting to the medical monitor. See Section 9.9.8 for details. 






 
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11 
METHODOLOGY/STUDY VISITS 
11.1 
Screening Procedures (Day -21 to Day 1) 
The investigator will inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject prior to performing any 
study-related procedures and prior to the administration of study drug or check-in to the clinical 
site. 
Screening evaluations will consist of the following: 
• Assessment of eligibility 
• Collect subject demographic information 
• Review medical and surgical history 
• Review concomitant and prior medications 
• MRI and X-ray 
• Physical examination including measurement of height and weight without shoes 
• Neurologic examination 
• Vital signs (including blood pressure [BP], pulse, respiratory rate, and temperature) 
• 12-lead ECG 
• Urine drug screen 
• Clinical laboratory tests including hematology, coagulation, serum chemistry, and urinalysis 
• Serum pregnancy test for women of childbearing potential (result must be negative to 
continue to be eligible) 
• Serology (HBsAg, anti-HCV, and anti-HIV) 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Dispense Study Diary 
• ODI, SF-12, PGI-C 
Subjects will be instructed not to take any medications without the approval of the investigator. 
The results of the screening evaluation must meet the inclusion/exclusion criteria for the subject 
to continue in the study. 


 
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11.2 
Visit 1 (Day 1) 
11.2.1 
Pre-dose 
• Admit to study unit. The subject will be hospitalized for 24 hours after intradiscal injection of 
the study drug and will be discharged once all procedures are completed and the investigator 
determines the subject is safe to be discharged. 
• Review concomitant and prior medications  
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Urine pregnancy test for women of childbearing potential (result must be negative to 
continue to be eligible) 
• Collect and review Study Diary 
• Dispense Study Diary 
• Review AEs 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Administer study drug  
• Draw blood samples for measurement of anti-KTP-001 antibody 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
11.2.2 
At 2 hours post-dose (±15 minutes) 
• Physical examination  
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Draw blood samples for measurement of KTP-001 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Review AEs  


 
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11.2.3 
At 4 hours post-dose (±15 minutes) 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Draw blood samples for measurement of KTP-001 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Review AEs 
11.2.4 
At 6 hours post-dose (±15 minutes) 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Review AEs 
11.2.5 
At 24 hours post-dose (±1 hour) 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• 12-lead ECG 
• Clinical laboratory tests including hematology, coagulation, serum chemistry, and urinalysis 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Collect and review Study Diary 
• Dispense Study Diary 
• Review AEs 


 
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11.3 
Visit 2 (1 Week ±2 days) 
• Review concomitant and prior medications 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Clinical laboratory tests including hematology, coagulation, serum chemistry, and urinalysis 
• Draw blood samples for measurement of anti-KTP-001 antibody 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Collect and review Study Diary 
• Dispense Study Diary 
• Review AEs 
11.4 
Visit 3 (2 Weeks ±2 days) 
• Review concomitant and prior medications 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Clinical laboratory tests including hematology, coagulation, serum chemistry, and urinalysis 
• Draw blood samples for measurement of anti-KTP-001 antibody 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Collect and review Study Diary 


 
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• Dispense Study Diary 
• Review AEs 
11.5 
Visit 4 (4 Weeks ±2 days) 
• Review concomitant and prior medications 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Draw blood samples for measurement of anti-KTP-001 antibody 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Collect and review Study Diary 
• Dispense Study Diary 
• Review AEs 
11.6 
Visit 5 (6 Weeks ±5 days) 
• Review concomitant and prior medications 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Draw blood samples for measurement of anti-KTP-001 antibody 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Collect and review Study Diary 


 
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• Dispense Study Diary 
• Assess adverse events 
11.7 
Visit 6 (13 Weeks ±5 days) 
• Review concomitant and prior medications 
• MRI and X-ray 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• 12-lead ECG 
• Serum pregnancy test for women of childbearing potential (result must be negative to 
continue to be eligible) 
• Clinical laboratory tests including hematology, coagulation, serum chemistry, and urinalysis 
• Draw blood samples for measurement of anti-KTP-001 antibody 
• Draw blood samples for measurement of KTP-001 
• Draw blood samples for measurement of serum keratan sulfate 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C  
• Collect and review Study Diary 
• Review AEs 
11.8 
Visit 7 (6 Months/26 Weeks ±1 week) 
• Review concomitant and prior medications 
• MRI and X-ray 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 


 
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• Assess ODI, SF-12, and PGI-C 
• Review AEs 
11.9 
Visit 8 (9 Months/39 Weeks ± 1 week) 
• Review concomitant and prior medications 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Review AEs 
11.10 
Visits 9 (12 Months/52 Weeks ±2 weeks) 
• Review concomitant and prior medications 
• MRI and X-ray 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Assess current lower back and leg pain using the 11-point numerical rating scale 
• Assess Spinal Flexion/Tension (Straight-leg Raising/Femoral Stretch Test) 
• Assess ODI, SF-12, and PGI-C 
• Review AEs 
11.11 
Visit 10 (18 months/78 Weeks ±4 weeks) 
• Review concomitant and prior medications 
• MRI and X-ray 
• Physical examination including measurement of weight without shoes 
• Neurologic examination 
• Vital signs (including BP, pulse, respiratory rate, and temperature) 
• Review AEs 


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11.12 
End of Study Visit (24 Months/104 Weeks ±4 weeks) 
•
Review concomitant and prior medications
•
MRI and X-ray
•
Physical examination including measurement of weight without shoes
•
Neurologic examination
•
Vital signs (including BP, pulse, respiratory rate, and temperature)
•
Review AEs
11.13 
Early Termination Before Week 13
Same procedures as those outlined for Visit 6 (Week 13) in Section 11.7. 
11.14 
Early Termination Between Week 13 and Month 24/Week 104 
Same procedures as those outlined for the End of Study visit in Section 11.12. 
11.15 
Withdrawal Procedures 
In the event of a subject’s withdrawal, the investigator will promptly notify the medical monitor 
and will make every effort to complete the end-of-study assessments. All withdrawn subjects 
will be followed until resolution of any AEs or until the unresolved AEs are judged by the 
investigator to have stabilized. 


 
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11.16 
Total Blood Volume Required for Study 
Test 
Number of 
Samples 
Volume 
(mL) 
Total (mL) 
Hematology  
5 
3 
15 
Hepatitis/HIV 
1 
4 
4 
Coagulation panel 
5 
2.7 
13.5 
Serum chemistry 1  
5 
4 
20 
PK of KTP-001  
10 
1.0 
10 
Anti-KTP-001 antibodies 
6 
2.0 
12 
Serum keratan sulfate 
8 
1.0 
8 
Total volume for study 
82.5 
1. The 4 mL at screening and Week 13 will include testing for serum 
βHCG for female subjects.  
A total of 15 mL will be collected from each subject for hematology assessments, 20 mL for 
serum chemistry assessments, 10 mL for PK analysis of KTP-001, 10 mL for analysis of 
anti-KTP-001 antibodies, and 8 mL for analysis of serum keratan sulfate levels. The total blood 
volume to be collected per subject for the entire study will be 82.5 mL. 
11.17 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to:  
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications, food, drink, herbal remedies, or supplements that are specifically 
prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc either tests not done, incorrect tests done, 
or not done within the time frame specified in the protocol 


 
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• Procedural deviations such as incorrect storage of study drug, failure to update the ICF when 
new risks become known, failure to obtain IRB approvals for the protocol and ICF revisions 
At the outset of the study, a process for defining and handling protocol deviations will be 
established. This will include determining which violations will be designated “key,” requiring 
immediate notification to the medical monitor and Sponsor. The investigator is responsible for 
seeing that any known protocol deviations are recorded and handled as agreed.  


 
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12 
STATISTICAL CONSIDERATIONS 
12.1 
General Considerations 
All statistical analyses will be conducted using SAS software, version 9.1.3 or higher (SAS® 
Institute, Cary, NC). Additional analyses of study endpoints will be detailed in the statistical 
analysis plan. 
12.2 
Sample Size Calculation 
The sample size of 24 subjects in 4 cohorts is considered appropriate for a study of this type and 
was determined by practical considerations. No formal sample size calculation was made as no 
formal hypothesis testing will be performed.  
12.3 
Analysis Populations 
The populations used for analysis will include the following: 
Intent-to-Treat Population:  The Intent-to-Treat population will be defined as any subject who 
is enrolled into the study, whether or not he/she receives study drug. 
Full Analysis Set:  The Full Analysis Set population will be defined as any subject who is 
enrolled into the study, receives study drug, and has at least 1 efficacy evaluation after receiving 
study drug. 
Per Protocol Set:  The Per Protocol Set will be defined as any subject who is enrolled into the 
study, receives study drug as planned, has at least 1 efficacy evaluation after receiving study 
drug, completes the Week 13 visit, and has no significant protocol violations. 
Safety Population:  The Safety Population will be defined as any subject who is enrolled into 
the study and receives study drug.  
PK Evaluable Population:  The PK Evaluable Population will be defined as any subject who is 
enrolled into the study, receives study drug, and has at least 1 evaluable PK serum sample. 
12.4 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized, including age, gender, race, 
ethnicity, weight, height, primary diagnosis and other parameters as appropriate. 
12.5 
Safety Analysis 
12.5.1 
Vital Signs 
Descriptive statistics (mean, standard deviation [SD], minimum, maximum, and n), including 
change from baseline (pre-dose value of the relevant treatment period) for actual values of vital 
sign parameters will be presented for all scheduled time points by dose level. Additionally, the 


 
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number of subjects with "substantial" increases or decreases in BP (>20 mmHg) and heart rate 
(>15 bpm) will be tabulated. 
12.5.2 
Clinical Laboratory Tests 
Descriptive statistics, including change from baseline, for the actual values of laboratory 
parameters will be presented for all scheduled time points by dose level. For subject data listings, 
abnormal values outside normal ranges will be flagged.  
If data permits, urinalysis (pH and specific gravity) will be summarized (mean, SD, median, 
minimum, maximum, and n) at each time point. 
Shift tables for laboratory parameters will be generated based on changes in National Cancer 
Institute Common Terminology Criteria for Adverse Events grade from baseline to worst 
postbaseline value. Graphical displays of key safety parameters, such as scatter plots of baseline 
versus worst postbaseline values, may be generated to better understand the study drug safety 
profile. 
12.5.3 
Concomitant Medications 
All concomitant medications collected from screening through the study period will be classified 
to preferred terms according to the World Health Organization drug dictionary and presented as 
subject data listings. 
12.5.4 
Electrocardiograms 
Descriptive statistics (mean, SD, minimum, maximum, and n) from the 12-lead ECG assessment 
will be summarized at each time point when the ECG evaluation is performed. 
12.5.5 
Physical Examinations 
The physical examination will include descriptive statistical summaries of all abnormalities 
recorded. 
12.5.6 
Neurologic Examinations 
Neurological examination results will be summarized by visit and listed by subject. 
12.5.7 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
The frequency of AEs will be tabulated by preferred term and system organ class. The maximum 
intensity and frequency of AEs will be summarized by treatment. 
A treatment-emergent AE (TEAE) is defined as an AE that was not present prior to treatment 
with study drug, but appeared following treatment or was present at treatment initiation but 
worsened in severity during treatment. An AE that was present at treatment initiation but 


 
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resolved and then reappeared while the subject was on treatment will be considered a TEAE 
(regardless of the intensity of the AE when the treatment was initiated). 
All TEAEs will be tabulated according to MedDRA by system organ class, high level terms and 
preferred terms and will include the following categories: 
• TEAEs 
• Drug-related TEAEs 
• Severe or higher TEAEs 
• Severe or higher drug-related TEAEs 
• SAEs 
Deaths and SAEs will be displayed in a subject data listing. 
12.5.8 
Imaging Data 
MRI and X-ray data will be displayed in subject data listings. 
12.5.9 
Additional Safety Analyses 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of the study drug. 
12.6 
Procedures for Handling Missing Data 
All available safety and efficacy data will be included in data listings and tabulations. No 
imputation of values for missing data will be performed. Data that are potentially spurious or 
erroneous will be examined according to standard data management operating procedures. 
12.7 
Efficacy Analysis 
All efficacy analyses are exploratory in nature and will be presented using descriptive statistics 
only (n, mean, median, minimum, maximum, SD, percentage of analysis population, and 
confidence intervals). Post-dose change from baseline in lower back or leg pain will be tabulated 
by dose level in a table summary. 
12.8 
Pharmacokinetic Analysis 
Serum concentrations will be presented descriptively by time. All derived PK parameters will be 
presented with individual values and descriptive statistics. Serum anti-KTP-001 antibody 
detection will be presented descriptively by time.  
12.9 
Exploratory Pharmacodynamic Analysis 
Pharmacodynamic analyses are exploratory in nature and will be presented using descriptive 
statistics (n, mean, median, minimum, maximum, SD, percentage of analysis population, and 


 
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confidence intervals). Post-dose change from baseline in serum concentrations of keratan sulfate 
will be tabulated by dose level in a table summary. 
12.10 
Interim Analysis 
An interim analysis at Month 12 will be conducted, the details of which will be described in a 
separate statistical analysis plan. 


 
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13 
ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator will provide direct access to source data and documents for individuals 
conducting study-related monitoring, audits, IRB/Independent Ethics Committee (IEC) review, 
and regulatory review. The investigator must inform the study subject that his/her study-related 
records may be reviewed by the above individuals without violating the subject’s privacy of 
personal health information in compliance with Health Insurance Portability and Accountability 
Act of 1996 regulations.  
Attention is drawn to the regulations promulgated by the FDA under the Freedom of Information 
Act providing, in part, that information furnished to clinical investigators and IRBs will be kept 
confidential by the FDA only if maintained in confidence by the clinical investigator and IRB. 
By signing this protocol, the investigator affirms to the Sponsor that the investigator will 
maintain, in confidence, information furnished to him or her by the Sponsor and will divulge 
such information to the IRB under an appropriate understanding of confidentiality with such 
board.  


 
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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
Sponsor/
 will implement and maintain quality control and quality assurance procedures 
with written standard operating procedures to ensure the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, Good Clinical Practice 
(GCP), and applicable regulatory requirements.  
14.1 
Conduct of Study 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki 
and all revisions thereof (Tokyo 2004), and in accordance with the FDA Code of Federal 
Regulations (CFR §312.50 and §312.56) and the International Conference on Harmonisation 
(ICH) E6 Guidelines on GCP (CPMP/ICH/135/95). Specifically, this study is based on 
adequately performed laboratory and animal experimentation; the study will be conducted under 
a protocol reviewed by an IRB or IEC; the study will be conducted by scientifically and 
medically qualified persons; the benefits of the study are in proportion to the risks; the rights and 
welfare of the subjects will be respected; the physicians conducting the study do not find the 
hazards to outweigh the potential benefits; and each subject will give his or her written, informed 
consent before any protocol-driven tests or evaluations are performed. 
The investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB/IEC, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve only logistical or administrative 
aspects of the study and are approved by the medical monitor and/or Teijin America, Inc. Any 
deviation may result in the subject having to be withdrawn from the study, and may render that 
subject nonevaluable.  
14.2 
Protocol Amendments 
Only the Sponsor may modify the protocol. Amendments to the protocol will be made only after 
consultation and agreement between the Sponsor, the medical monitor and the investigator. All 
amendments that have an impact on subject risk or the study objectives, or require revision of the 
ICF, must receive approval from the IRB/IEC prior to their implementation. 
14.3 
Monitoring of Study 
The investigator will permit the site monitor to review study data as frequently as is deemed 
necessary to ensure data are being recorded in an adequate manner and protocol adherence is 
satisfactory.  
The investigator will provide access to medical records for the monitor to verify CRF entries. 
The investigator is expected to cooperate with the Sponsor/designee in ensuring the study 
adheres to GCP requirements.  


 
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The investigator may not recruit subjects into the study until Sponsor or its designee has 
conducted a visit at the site to conduct a detailed review of the protocol and CRF. With 
agreement of the Sponsor, attendance at an investigator meeting may fulfill this requirement. 


 
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15 
ETHICS 
15.1 
Institutional Review Board/Independent Ethics Committee Approval 
15.1.1 
Ethics Review Prior to Study 
The investigator will ensure that the protocol and consent form are reviewed and approved by the 
appropriate IRB/IEC prior to the start of any study procedures. The IRB/IEC will be 
appropriately constituted and will perform its functions in accordance with FDA regulations, 
ICH GCP guidelines, and local requirements as applicable. 
15.1.2 
Ethics Review of Other Documents 
In addition, the IRB will approve all protocol amendments (except for Sponsor-approved 
logistical or administrative changes), written informed consent documents and document updates, 
subject recruitment procedures, written information to be provided to the subjects, available 
safety information, information about payment and compensation available to subjects, the 
investigator’s curriculum vitae and/or other evidence of qualifications, and any other documents 
requested by the IRB/IEC and regulatory authority as applicable. 
15.2 
Written Informed Consent 
The nature and purpose of the study will be fully explained to each subject (or the subject’s 
legally responsible guardian). The subjects must be given ample time and opportunity to inquire 
about details of the trial, to have questions answered to their satisfaction, and to decide whether 
to participate. Written informed consent must be obtained from each subject (or guardian) prior 
to any study procedures being performed.  
 


 
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16 
DATA HANDLING AND RECORD KEEPING 
16.1 
Data Reporting and Case Report Forms 
16.1.1 
Data Collection and Case Report Forms 
All relevant observations and data related to the study, as per the study protocol, will be recorded 
on electronic case report forms (eCRF). Adequate and accurate case records shall be maintained, 
including the evaluation of inclusion and exclusion criteria, medical history, physical 
examination, clinical assessments, a record of clinical safety laboratory sample collection, PK 
and PD sample collection if available, drug administration, AEs and final evaluation. 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting and releasing) will be generated and maintained 
by
 Data Management with approval from Teijin. 
The eCRFs must be completed for each subject who signs the ICF and undergoes screening 
procedures. The eCRF data entry shall be completed within 7 calendar days of clinical visit 
completion. eCRF completion guidelines will be provided to the sites to ensure accurate entry of 
data into the database. The investigator must sign and date the eCRF. The signature shall indicate 
that the investigator has reviewed the data and data queries recorded on eCRFs, and agrees with 
the content. 
16.1.2 
Laboratory Data 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to trial start. If a central laboratory has been selected to 
conduct any or all tests, it is essential all samples be analyzed at that laboratory. The investigator 
must maintain source documents such as laboratory reports and complete history and physical 
examination reports. 
16.1.3 
Serum concentration of KTP-001 and anti-KTP-001 antibody  
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to trial start. If a central laboratory has been selected to 
conduct any or all tests, it is essential all samples be analyzed at that laboratory. The investigator 
must maintain source documents such as laboratory reports and complete history and physical 
examination reports. 
16.1.4 
Imaging Data 
On-site safety and efficacy assessments will be performed by the investigator or on-site 
radiologist. One copy of the MRI and X-ray images will be stored on site. In addition, all scans 
archived in Digital Imaging and Communications in Medicine (a.k.a., DICOM) format will be 


 
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required to be sent to an independent medical imaging laboratory (
 
) for the purpose of independent review. 
16.1.5 
Retention of Source Documents 
The investigator must maintain source documents such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete history and physical examination reports. 
16.2 
Retention of Essential Documents 
The study essential documents must be maintained as specified in the ICH guidelines for GCP 
and the applicable regulatory requirements. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with Sponsor. It is the responsibility of Sponsor to inform the investigator/institution 
as to when these documents no longer need to be retained. 


 
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17 
ADMINISTRATIVE INFORMATION 
17.1 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement between Sponsor and the 
investigator. 
17.2 
Publication Policy 
Teijin America, Inc. will retain ownership of all data. All proposed publications based on this 
study will be subject to Sponsor’s approval requirements. 


 
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18 
REFERENCES 
[01] 
McCulloch JA. Focus issue on lumbar disc herniation: Macro- and microdiscectomy. 
Spine. 1996;21(24 Suppl):45S-56S. 
[02] 
Saal JA, Saal JS. Nonoperative treatment of herniated lumbar intervertebral disc with 
radiculopathy. An outcome study. Spine. 1989; 14: 431-7. 
[03] 
Buttermann GR. Treatment of lumbar disc herniation: epidural steroid injection 
compared with discectomy. A prospective, randomized study. J Bone Joint Surg Am. 
2004; 86(4): 670-9. 
[04] 
Peul WC, van Houwelingen HC, van den Hout WB, Brand R, Eekhof JA, Tans JT, et al. 
Surgery versus prolonged conservative treatment for sciatica. N. Engl. J. Med. 2007; 
356(22): 2245-56. 
[05] 
Weinstein JN, Tosteson TD, Lurie JD, Tosteson AN, Hanscom B, Skinner JS, et al. 
Surgical vs nonoperative treatment for lumbar disk herniation: the Spine Patient 
Outcomes Research Trial (SPORT): a randomized trial. JAMA. 2006; 296(20): 2441-50. 
[06] 
Weinstein JN, Lurie JD, Tosteson TD, Skinner JS, Hanscom B, Tosteson AN, et al. 
Surgical vs nonoperative treatment for lumbar disk herniation: the Spine Patient 
Outcomes Research Trial (SPORT) observational cohort. JAMA. 2006; 296(20): 2451-9. 
[07] 
Mercuri FA, Doeges KJ, Arner EC, Pratta MA, Last K, Fosang AJ. Recombinant human 
aggrecan G1-G2 exhibits native binding properties and substrate specificity for matrix 
metalloproteinases and aggrecanase. J Biol Chem. 1999; .274(45): 32387-95. 
[08] 
Fosang AJ, Neame PJ, Last K, Hardingham TE, Murphy G, Hamilton JA. The 
interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and 
cathepsin B. J Biol Chem. 1992; 267(27): 19470-4. 
[09] 
Haro H, Shinomiya K, Murakami S, Spengler DM. Up-regulated expression of matrilysin 
and neutrophil collagenase in human herniated discs. J Spinal Disord. 1999; 12(3): 245-9. 
[10] 
Haro H, Komori H, Kato T, Hara Y, Tagawa M, Shinomiya K, et al. Experimental studies 
on the effects of recombinant human matrix metalloproteinases on herniated disc tissues-
how to facilitate the natural resorption process of herniated discs. J Orthop Res. 2005; 
23(2): 412-9. 
[11] 
Pierre R Dupuis, Ken Yong-Hing, J David Cassidy, William H Kirkaldy Willis. 
Radiological diagnosis of degenerative lumbar spinal instability. Spine 1985; 10((3): 
262-76. 


 
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[12] 
Raj PP. Intervertebral disc: anatomy-physiology-pathophysiology-treatment. Pain Pract. 
2008; 8 (1): 18-44. 
[13] 
Holm S, Maroudas A, Urban JPG, Selstam G, Nachemson A, Nutrition of the 
intervertebral disc: solute transport and metabolism, Connect Tissue Res. 1981; 8(2): 
101-19. 
[14] 
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core 
outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 
2005; 113(1-2): 9-19. 
[15] 
ACR-ASNR practice guideline for the performance of magnetic resonance imaging 
(MRI) of the adult spine. Practice Guideline. MRI of the adult spine. Revised 2006. 
(http://www.acr.org/guidelines). 


 
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19 
SIGNATURES 
19.1 
Investigator’s Signature 
I agree to conduct the study outlined above according to the terms and conditions of the protocol, 
GCP guidelines, and with applicable regulatory requirements. All information pertaining to the 
study will be treated in a confidential manner. 
 
Investigator’s Signature  
___________________________________ 
Date 
 
 
 
____________________ 




 
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19.3 
Teijin America, Inc. Signatures 
This clinical study protocol has been reviewed and approved by Teijin America, Inc. 
 
 
 
 
 
 
 
 
 
 
 
Date 
President, Teijin America, Inc. 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX A:  
PAIN MEDICATIONS 


 
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APPENDIX C: 
LOWER BACK OR LEG PAIN ASSESSMENT 












 
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APPENDIX H: 
SCREENING AND CLINICAL LABORATORY ASSESSMENTS 


 
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APPENDIX I: 
NEUROLOGIC EXAMINATION  


 
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SAP_001.pdf: 
Teijin America, Inc. 
Protocol No.: KTP-001-CL-101 
Statistical Analysis Plan Final V1.0 
03May2018 
CONFIDENTIAL 
Page 1 of 29 
Teijin America, Inc. 
Clinical Study Protocol KTP-001-CL-101 
Phase 1/2 
Open-Label, Non-controlled, Single Ascending Dose Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, and Exploratory Efficacy of KTP-001 in 
Subjects with Lumbar Disc Herniation 
STATISTICAL ANALYSIS PLAN 
Version: Final 1.0 
Date: 03May2018 
NCT01978912


Teijin America, Inc. 
Protocol No.: KTP-001-CL-101 
Statistical Analysis Plan Final V1.0 
03May2018 
CONFIDENTIAL 
Page 2 of 29 
 APPROVAL SIGNATURES 
Study Title: 
Open-Label, Non-controlled, Single Ascending Dose Study to Evaluate 
Safety, Tolerability, Pharmacokinetics, and Exploratory Efficacy of 
KTP-001 in Subjects with Lumbar Disc Herniation 
Protocol Date: 
Version 4.1 Amendment 4 – 20 October 2015 
Prepared at 
 by: 
Senior Statistician I 
Biostatistics and Programming 
Date 
Reviewed at 
 by: 
Principal Statistician 
Biostatistics and Programming 
Date 


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Protocol No.: KTP-001-CL-101 
Statistical Analysis Plan Final V1.0 
03May2018 
CONFIDENTIAL 
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TEIJIN AMERICA APPROVAL SIGNATURES 
Study Title: 
Open-Label, Non-controlled, Single Ascending Dose Study to Evaluate 
Safety, Tolerability, Pharmacokinetics, and Exploratory Efficacy of 
KTP-001 in Subjects with Lumbar Disc Herniation 
Protocol Date: 
Version 4.1 Amendment 4 – 20 October 2015 
Reviewed at Teijin America, Inc. by: 
 President 
Date 




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Protocol No.: KTP-001-CL-101 
Statistical Analysis Plan Final V1.0 
03May2018 
CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 6 
1.0 
INTRODUCTION ................................................................................................................. 8 
2.0 
STUDY OBJECTIVES ......................................................................................................... 8 
3.0 
STUDY DESIGN .................................................................................................................. 9 
3.1 
Study Design and Population ....................................................................................... 9 
3.2 
Study Treatments and Assessments ........................................................................... 10 
3.3 
Randomization and Blinding ..................................................................................... 11 
3.4 
Sample Size Justification ........................................................................................... 11 
4.0 
STATISTICAL CONSIDERATIONS ................................................................................ 12 
5.0 
ANALYSIS POPULATION ............................................................................................... 13 
6.0 
METHODS OF ANALYSES AND PRESENTATIONS ................................................... 14 
6.1 
Subject Disposition .................................................................................................... 14 
6.2 
Protocol Deviations ................................................................................................... 14 
6.3 
Demographic and Baseline Characteristics ............................................................... 14 
6.4 
Medical History ......................................................................................................... 15 
6.5 
Prior and Concomitant Medication ............................................................................ 15 
6.6 
Study Drug Treatment Compliance ........................................................................... 15 
6.7 
Data Endpoints and Analyses .................................................................................... 15 
6.7.1 
Analysis of Primary Endpoint - Safety ........................................................ 16 
6.7.2 
Analysis of Exploratory Efficacy Endpoints ............................................... 19 
6.8 
Other Safety Endpoints .............................................................................................. 22 
7.0 
HANDLING OF MISSING VALUES AND OUTLIERS .................................................. 23 
8.0 
INTERIM ANALYSIS ....................................................................................................... 24 
9.0 
CHANGES FROM ANALYSIS METHODS PLANNED IN THE PROTOCOL ............. 24 
10.0  REFERENCES .................................................................................................................... 24 
11.0  APPENDIX ......................................................................................................................... 25 






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Statistical Analysis Plan Final V1.0 
03May2018 
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1.0 
INTRODUCTION 
 
The purpose of this document is to provide further details about the statistical analysis 
methods specified in the study protocol KTP-001-CL-101: a Phase 1/2, open-label, non- 
controlled, single ascending dose study to evaluate safety, tolerability, pharmacokinetics, and 
exploratory efficacy of KTP-001 in subjects with lumbar disc herniation. This statistical analysis 
plan (SAP) has been based on International Conference on Harmonisation (ICH) E3 and E9 
guidelines and in reference to protocol version 4.1 amendment 4 dated 20October2015. The 
statistical analysis plan covers statistical analysis, tabulations and listings of safety and efficacy 
data. 
Any major deviations from the methods specified in this document and the protocol will be 
discussed and documented. 
2.0 
STUDY OBJECTIVES 
Primary objective 
The primary objective of this study is to evaluate the safety and tolerability of a single 
intradiscal injection of KTP-001 in subjects with a single herniated lumbar disc. 
Secondary objectives 
The secondary objectives of this study are: 
• To determine the PK of KTP-001 in the serum of circulating blood after intradiscal 
injection of study drug. 
• To determine the presence of anti-KTP-001 antibody in the serum of circulating blood 
after intradiscal injection of study drug. 
Exploratory objectives 
The exploratory objectives of this study are: 
• To determine the pharmacodynamics (PD) of keratan sulfate in the serum of circulating 
blood after intradiscal injection of study drug. 
• To assess changes in pain, neurologic examination, magnetic resonance imaging (MRI) 
and X-ray assessments, disability, quality of life (QOL), and patient global impression of 
change (PGI-C) scores in subjects receiving study drug. 


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3.0 
STUDY DESIGN 
3.1 
Study Design and Population 
Study KTP-001-CL-101 is an open-label, non-controlled single ascending dose study of 
KTP-001 in male and female subjects between the ages of 30 and 70 with a single herniated 
lumbar disc. After obtaining informed consent, subjects will be evaluated during a screening 
period of no more than 3 weeks (21 days). The screening procedures will be performed at the 
screening visit as per the appendix 1. Subjects that meet all screening requirements  and  
inclusion criteria and none of the exclusion criteria will be enrolled into 1 of 4 study cohorts and 
receive KTP-001. Following administration of study drug, subjects will be confined to the study 
unit for 24 hours to collect data for safety and efficacy measures and collect blood samples for 
the following purposes: safety, PK evaluation, and exploratory PD (keratan sulfate), including 
anti-KTP-001 antibody. 
Subjects enrolled in Cohort 1 will have pre-dose assessments of concomitant medications, 
weight, physical and neurologic examinations, and vital signs. Female subjects will have a urine 
pregnancy test, and all subjects in the cohort will have blood samples taken for PK and PD 
analyses. Efficacy assessments will be repeated. Subjects in this cohort will receive a 5 
µg/disc dose of KTP-001 by intradiscal injection. Subjects will be observed for 24 hours after 
injection to facilitate post-procedural monitoring and collection of additional PK samples. 
Subjects will return to the clinic for visits at Weeks 1, 2, 4, 6, and 13, and at Months 6, 9, 12 (1 
year), Month 18 (1.5 years), and Month 24 (2 years) for safety, and exploratory efficacy 
assessments (including X-ray and MRI at Week 13 and Months 6, 12, 18, and 24). Subjects will 
be provided a study diary to record their level of leg and lower back pain on a daily basis up to 
Week 13. 
Thirteen weeks after all subjects in Cohort 1 have received study drug, safety measures 
will be evaluated by a Data and Safety Monitoring Board (DSMB) to determine whether to 
escalate KTP-001 administration to the next dose level. This evaluation will be conducted after 
the 13-week follow-up visit for all subjects in Cohorts 1, 2, and 3. The DSMB will conduct a 
safety review at the 13-week follow-up visit for all subjects in each dose cohort. 
If escalation is appropriate as determined by the DSMB, then the Cohort 2 subjects will 
receive KTP-001 15 µg /disc, Cohort 3 subjects will receive 50 µg /disc of KTP-001, and Cohort 
4 subjects will receive 150 µg /disc of KTP-001 by intradiscal injection (Figure 1). All safety, 
PK, and exploratory efficacy assessments will be performed for the subjects in the subsequent 
cohorts as were performed for Cohort 1. 


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Statistical Analysis Plan Final V1.0 
03May2018 
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Figure 1:  KTP-001-CL-101 Study Design 
Approximately 48 subjects will be screened to ensure that 24 subjects are enrolled into 
this study. This study will be conducted at approximately 8 sites in the United States. Subjects 
who discontinue from the study after enrollment but prior to receiving study drug will be 
replaced to       6 subjects are treated in each of the 4 cohorts. 
After a single intradiscal injection of study drug, subjects will be confined to the study 
facility for the first 24 hours and will be asked to participate in this study for at least 24 months  
(2 years). 
3.2 
Study Treatments and Assessments 
KTP-001 is the investigational medicinal product. Neither placebo nor any comparator is 
used. The proposed clinical dose concentrations for this first in human (FIH) study are 5 μg/disc 
(Cohort 1), 15 μg/disc (Cohort 2), 50 μg/disc (Cohort 3), and 150 μg/disc (Cohort 4). KTP-001 
1.0 mg/vial will be provided as a lyophilized powder in 2.0 mL glass vials. The injection volume 
per subject will be 1.0 mL. Each vial contains 1.0 mg of KTP-001 drug substance, which will be 
reconstituted with 0.5 mL of sterile water for injection and then diluted with a buffer solution to 
administer the required injection dose per 1.0 mL. Single doses of the proposed clinical dose 
concentrations will be administered intradiscally at the level of lumbar disc herniation by 
injection under fluoroscopic or computerized tomography (CT) visualization and guidance to 24 
male and female human subjects between the ages of 30 and 70 with a single herniated lumbar 
disc as confirmed by MRI. 
Throughout the study, patients will be assessed for the study objectives as outlined in the 
schedule of assessments (appendix 1). 


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Statistical Analysis Plan Final V1.0 
03May2018 
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3.3 
Randomization and Blinding 
The study is an open-label, non-controlled, clinical trial. There is no randomization of 
patients or blinding. 
3.4 
Sample Size Justification 
No formal sample size calculation was made as no formal hypothesis testing will be 
performed. The sample size of 24 subjects in 4 cohorts is considered appropriate for a study of 
this type and was determined by practical considerations. Approximately 48 subjects will be 
screened to ensure that 24 subjects are enrolled into this study. 


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Statistical Analysis Plan Final V1.0 
03May2018 
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4.0 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be performed using SAS software, version 9.3 or higher. The  
safety population will be used as the analysis population for the primary endpoints and all safety 
end points. Full analysis set and per protocol set will be used as the analysis population for 
secondary and exploratory efficacy endpoints. 
Continuous data will be summarized using n, mean, median, standard deviation (SD), 
minimum value, maximum value, 95% confidence interval (CI) and, if appropriate, number of 
missing values. Unless noted otherwise, summaries will be produced by visit (where applicable) 
and cohort. Summaries by visit will be based on nominal reporting. If more than one value is 
reported at a scheduled  visit, the value collected closest to the intended visit date will be used.   
In the case of a tie, the latest version will be summarized. 
Categorical data will be summarized using n, percentages. Percentages will be calculated 
based on the number of non-missing values.  The number of missing values will be presented as  
a separate category with no percentage, if 1 or more patients are missing data for the summary. 
Otherwise, all categories will be presented (even if no patients are counted in the category). 
Counts of zero in any category will be presented with percentage as (0%). 
Precision of summary statistics: 
o
Integer – Sample size (n, N) and number of missing responses (if displayed).
o
One additional decimal place than reported/collected on the case report form (CRF) – mean,
median, confidence interval.
o
Two additional decimal places than reported/collected on the CRF – standard deviation.
o
Same number of decimal places as reported/collected on the CRF – minimum, maximum.
o
Percentages – one decimal place.
All data will be presented on listings in order of dosing cohort, patient, assessment
date/time and assessment (in order collected on eCRF, unless specified otherwise). For display 
purposes, cohort labels will be ordered from smallest to largest. Dates will be presented in the 
format DDMMMYYYY. Times will be displayed in 24-hour clock format. Numbering of tables, 
figures and listings will follow ICH E3 guidelines. 
Unscheduled measurements will be excluded from the descriptive statistical analysis. 
However, unscheduled measurements that were performed immediately after the scheduled 
measurement, in case of a previous measurement error (e.g. equipment failure), will not be 
excluded from the analysis. In these cases, the original erroneous measurement will be excluded 
from the analysis and the unscheduled visit substituted. All the unscheduled measurements will 
be included in the listing. 
Unless otherwise stated, the baseline value is defined as the as the last assessment result 
collected prior to the first dose of study medication. 


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5.0 
ANALYSIS POPULATION 
The populations used for analysis will include intent-to-treat population, full analysis set, 
per protocol set and safety population. The primary objective endpoints analysis and safety 
endpoints will be performed based on safety population. Full analysis set and per protocol set  
will be used as the analysis population for secondary and exploratory efficacy endpoints. 
Baseline characteristics analysis will be performed on intent-to-treat population. 
Intent-to-Treat Population 
The Intent-to-Treat population is defined as any subject who is enrolled into the study, 
whether or not he/she received study drug. 
Full Analysis Set 
The full analysis set is defined as any subject who is enrolled into the study, received 
study drug, and has at least 1 efficacy evaluation after receiving study drug. 
Per Protocol Set 
The per protocol set is defined as any subject who is enrolled into the study, received 
study drug as planned, has at least 1 efficacy evaluation after receiving study drug, completes the 
week 13 visit, and has no significant protocol violations. Significant protocol violation list will 
be documented in a separate file. 
Safety Population 
The safety population is defined as any subject who is enrolled into the study and 
received study drug. 


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03May2018 
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6.0 
METHODS OF ANALYSES AND PRESENTATIONS 
The following sub-sections would be considered for logical presentation of study data. 
6.1 
Subject Disposition 
The number of subjects screened, screen failure, enrolled, study completion status will be 
summarized. Subjects who discontinued from the study will be summarized and listed by their 
primary reason for discontinuation. Inclusion/exclusion criteria evaluation will also be listed. 
Analysis populations will be summarized. Subject disposition will be summarized by dosing 
cohort. 
6.2 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or 
noncompliance with, the approved protocol procedures or requirements. Deviations may result 
from the action or inaction of the subject, investigator, or site staff. Examples of deviations 
include, but are not limited to: 
•
Failure to adhere to study exclusion and inclusion criteria.
•
Failure to comply with dispensing or dosing requirements.
•
Use of medications, food, drink, herbal remedies, or supplements that are specifically
prohibited in the protocol.
•
Missed or out-of-window visits.
•
Drug dosing not administered within the time frame specified in the protocol.
•
Failure to adhere to test requirements, including vital signs, laboratory tests, physical
examinations, PK blood draws, medical history, etc. either tests not done, incorrect tests
done, or not done within the time frame specified in the protocol.
•
Procedural deviations such as incorrect storage of study drug, failure to update the
Internal Consent Form (ICF) when new risks become known, failure to obtain Internal
Review Board (IRB) approvals for the protocol and ICF revisions.
Protocol deviations will be identified by the project team prior to database lock. A
summary of major protocol deviations will be provided by cohort. All protocol deviations will be 
listed. Intent-to-treat population will be used as an analysis population for this analysis. 
6.3 
Demographic and Baseline Characteristics 
Demographic data and subjects’ baseline characteristics at screening will be summarized 
and listed using descriptive summary statistics for intent-to-treat population. The demographic 
information of age, gender, ethnicity and race will be summarized by cohort. Apart from that, 
additional information’s of height, weight, primary diagnosis and other parameters such as 
anatomical location of the intervertebral disc (e.g. L5-S1), Location of herniation (e.g. anterior), 
etc. as appropriate will also be summarized. All demographic and baseline characteristics will be 
listed in full. 


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03May2018 
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6.4 
Medical History 
An analysis of the medical history (including the symptoms associated with herniated 
lumbar disc) will be performed at screening. A summary table of medical history conditions by 
body system and preferred term will be presented by cohort. The table will be sorted in 
alphabetical order by body system and in decreasing frequency of preferred terms based on total 
number of reports within each body system. The frequency and percentage of subjects who 
present at least 1 occurrence of the medical history or concurrent condition will be presented. 
Medical history will be coded using the most recent version available of the Medical Dictionary 
for Regulatory Activities (MedDRA). All medical history will be listed.  The medical history  
will be analyzed using intent-to-treat population. 
6.5 
Prior and Concomitant Medication 
All medications (prescription and over-the-counter, vitamin and mineral supplements,  
and herbs) and all therapies for disc herniation (including but not limited to physical therapy, 
acupuncture, epidural injections/selective nerve root block) taken or received by the participant 
within 1 month of screening and throughout study participation will be included on the 
concomitant medication. Medications taken for a surgical procedure should also be included. 
Prior medication is defined as any medication starting and ending before the first study 
dose. 
Prior and Concomitant medications will be classified using the latest version of World 
Health Organization Drug Dictionary (WHO drug) and will be summarized by the number and 
percentage of subjects by anatomical therapeutic chemical classification (ATC) level 2 and 
preferred term. The table will be sorted in alphabetical order by ATC level 2 and in decreasing 
frequency of preferred terms based on total number of reports within each ATC level. All 
prior/concomitant medication will be listed. 
Concomitant procedures/therapy, rescue medication details also will be summarized by 
cohort and listed same as mentioned above. Intent-to-treat population will be used as an analysis 
population. 
6.6 
Study Drug Treatment Compliance 
Subjects received a single dose of study drug by intradiscal injection. The injection will 
be performed under fluoroscopic or computerized tomography (CT) guidance and documented  
by X-ray or CT scan, as well as in the CRF by the investigator. No other measures of treatment 
compliance will be used. Study drug administration details will be listed for safety population, 
full analysis set and per protocol population separately. 
6.7 
Data Endpoints and Analyses 
The primary objective endpoints analysis and safety endpoints will be performed based  
on safety population. Full analysis set and per protocol set will be used as the analysis population 
for secondary and exploratory efficacy endpoints. All the results will be summarized by cohort. 
Descriptive summary statistics mentioned in the section 4.0 will be used for the analysis. 
Comprehensive listings of all data will be presented. 


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03May2018 
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6.7.1 
Analysis of Primary Endpoint - Safety 
Primary endpoint of this study is safety and tolerability. The following are the primary 
safety endpoints: 
•
Adverse events (AE)
•
Serious adverse events (SAE)
•
Deaths or discontinuations due to AEs (including subjects who have lumbar surgery) that
occur after administration of study drug.
•
Change and shifts from baseline in vital signs of
o
Heart rate
o
Systolic/Diastolic blood pressure
o
Respiratory rate
o
Body temperature
•
Tabulation of number of subjects with "substantial" increases or decreases in BP (>20
mmHg) and heart rate (>15 bpm)
•
12-lead Electrocardiograms (ECGs)
o
Heart rate
o
Rhythm
o
PR
o
RR
o
PQ
o
QT intervals
o
QTc [Bazett’s and Fridericia’s]
o
QRS
•
Clinical laboratory tests
o
Hematology
o
Serum chemistry
o
Coagulation
o
Urinalysis
•
Data from MRI and X-ray (including morphological assessment)
•
Data from neurologic assessments
o
Positive straight-leg raising or femoral stretch test


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o
Alteration of deep tendon reflexes (knee and ankle)
o
Sensory, or motor deficits in the lower extremities.
•
Abnormalities in physical examinations
•
Number of subjects who experienced any AEs defined as a halting rule
•
Serum anti-KTP-001 antibody analysis by electrochemiluminescence
6.7.1.1 Adverse events
Adverse events (AEs) will be collected from the time of first dose until the last study visit
or premature discontinuation of the study drug KTP-001. All (both serious and non-serious) AEs 
must be followed until they are resolved or stabilized, or until all attempts to determine  
resolution of the event are exhausted. 
All AEs will be coded using the latest version of MedDRA. The frequency of AEs will be 
tabulated by system organ class and preferred term. The maximum intensity and frequency of 
AEs will be summarized by treatment. 
A treatment-emergent AE (TEAE) is defined as an AE that was not present prior to 
treatment with study drug, but appeared following treatment or was present at treatment initiation 
but worsened in severity during treatment. An AE that was present at treatment initiation but 
resolved and then reappeared while the subject was on treatment will be considered a TEAE 
(regardless of the intensity of the AE when the treatment was initiated). 
All TEAEs will be tabulated according to MedDRA by system organ class and preferred 
terms. Adverse events table will be summarized for 
•
Overall summary of adverse events, it includes number of treatment-emergent adverse
events, subjects with any TEAE, subjects with any TE- serious adverse events (SAE),
subjects with TEAEs leading to discontinuation, subjects with any related TEAE,
subjects with any severe TEAE
•
Summary of adverse events by system organ class and preferred terms
•
Summary of SAEs by system organ class and preferred terms
•
Deaths or discontinuations due to AEs (including subjects who have lumbar surgery) that
occur after administration of study drug by system organ class and preferred terms.
•
Summary of TEAEs by system organ class and preferred terms
•
Summary of drug-related TEAEs by system organ class and preferred terms
•
Summary of severe TEAEs by system organ class and preferred terms
•
Summary of drug-related TEAEs by system organ class and preferred terms
•
Adverse events of special interest (AESI) by system organ class and preferred terms
The following AEs will be considered an AESI 


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1. MRI or X-ray findings of Modic changes, reduction of disc height, or evidence of lumbar 
instability as defined in Appendix 4, or any other acute MRI or X-ray changes from 
baseline images deemed significant by the central reader/spine imaging specialist.
2. Exacerbation of back or leg pain meeting at least 1 of the following criteria:
a) increase in average daily leg or back pain score by ≥ 3 to 6 or above on the numerical 
rating scale for at least 5 days out of a week
b) increase in average daily pain level associated with a new onset of focal neurological 
symptoms such as numbness and/or tingling or weakness lasting for > 5 days.
3. New onset of neurological symptoms associated with objective changes on neurological 
examination (weakness, sensory deficit, changes in deep tendon reflexes) whether or not 
associated with increase in pain level.
4. Any deterioration of subject’s condition that in the investigator’s judgment requires:
a) emergency MRI
b) epidural steroid injection/selective nerve root block, facet block, or surgical 
intervention. 
All AEs, SAEs and deaths will be listed. 
6.7.1.2 Vital signs 
Descriptive statistics (mean, standard deviation [SD], minimum, maximum, and n) 
including change from baseline (pre-dose value of the relevant treatment period) for actual  
values of vital sign parameters will be presented for all scheduled time points by cohort. 
Additionally, the number of subjects with "substantial" increases or decreases in BP (>20 
mmHg) and heart rate (>15 bpm) will be tabulated as shift table. It includes heart rate, systolic 
and diastolic blood pressures, respiratory rate, and body temperature. Vital signs details will be 
listed. 
6.7.1.3 12-Lead electrocardiograms 
Descriptive statistics (mean, standard deviation [SD], minimum, maximum, and n), 
including change from baseline (pre-dose value of the relevant treatment period) for 12-Lead 
Electrocardiograms parameters of heart rate, rhythm, PR, RR, PQ, and QT intervals, QTc 
[Bazett’s and Fridericia’s], and QRS will be presented for all scheduled time points by cohort. 
ECG results will be listed. 
6.7.1.4 Clinical laboratory tests 
Descriptive statistics (mean, standard deviation [SD], minimum, maximum, and n), 
including change from baseline (pre-dose value of the relevant treatment period) for laboratory 
parameters of hematology, serum chemistry, coagulation, and urinalysis will be presented for all 
scheduled time points by cohort. Laboratory test results will be listed and abnormal values 
outside normal ranges will be flagged. 


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If data permits, urinalysis (pH and specific gravity) will be summarized (mean, SD, 
median, minimum, maximum, and n) at each time point. Shift tables for laboratory parameters 
will be generated based on changes in National Cancer Institute Common Terminology Criteria 
for AE grade from baseline to worst post-baseline value. 
6.7.1.5 MRI and X-ray data 
The results of independently evaluated imaging assessments will be provided 
. 
Absolute and change from baseline in MRI and X-ray (including morphological assessment) 
results will be analyzed for all scheduled time points and cohort using descriptive statistics. MRI 
and X-ray data will be displayed in subject data listings. 
6.7.1.6 Neurologic assessments 
Neurological examination results and change from baseline will be summarized for all 
scheduled time points by cohort. Information includes: deep tendon reflexes (patellar [or knee], 
Achilles [or ankle] as normal, decreased, absent, increased or clonus and Babinski’s Sign as 
present, plantar flexion or no response); muscle strength (hip flexion, knee flexion, knee 
extension, ankle dorsiflexion/long toe extension, ankle plantar flexion as normal, decreased to 
resistance, against gravity only/no resistance, or no movement); sensory exam to pin-prick 
(anterior knee, medial malleolus, dorsum of the foot, anterior toes 1-3 and anterior toes 4-5 and 
lateral malleolus as normal, decreased/abnormal or absent) and overall clinical impression since 
baseline (as improved, remain unchanged or worsened). Positive straight-leg raising or femoral 
stretch test will also be summarized. A data listing of neurological evaluations will be provided. 
6.7.1.7 Physical examinations 
The number of patients reporting abnormalities for physical examination will be  
tabulated for all scheduled time points using counts and percentages for each body system. 
Physical examination results will be displayed in the subject data listings. 
6.7.1.8 Halting rules 
The number of subjects with AEs defined as halting rules (HRs) will be described and 
evaluated. Halting rule is explained in the appendix 4. 
6.7.2 
Analysis of Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints analyses will be performed on the full analysis set and per 
protocol set and all analyses will be presented using descriptive statistics as mentioned in 
the section 4. For all measures other than the daily pain, the baseline value is defined as the 
last assessment result collected prior to the first dose of study medication. For daily pain 
assessments, the baseline value is defined as the average of the results of 5 consecutive days 
prior to the first dose of study medication. 
The following are the primary exploratory efficacy endpoints: 
•
Change from baseline in lower back pain or leg pain (numerical pain scale for each sub
categories as mentioned below) at 6 and 13 weeks


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o
Leg average daily pain
o
Leg worst daily pain
o
Low back average daily pain
o
Low back worst daily pain
o
Current leg pain
o
Current low back pain
•
Number of subjects requiring:
o
Additional pain medication (and amounts) added to the subject's baseline pain
regimen within the first 13 weeks post-dose
o
An epidural injection, a selective nerve root block, or a facet block after
receiving study drug,
o
Surgical intervention for lumbar disc herniation
•
Change from baseline in spinal flexion and tension signs (straight-leg raising or femoral
stretch test) on the affected side at 6 and 13 weeks
•
Change from baseline in ODI at 6 and 13 weeks
•
Change from baseline in SF-12 at 6 and 13 weeks
•
Change from baseline in the PGI-C at 6 and 13 weeks
Pharmacodynamic Parameters 
•
Serum concentrations of keratan sulfate at every time point.
Lower back or leg pain 
Lower back and leg pain assessed using an 11-point numerical rating scale. Visit value 
and change from baseline average daily, worst daily and current lower back pain or leg pain 
(numerical pain scale) at 6 and 13 weeks will be summarized by cohort. Visit value and change 
from baseline for other visits also summarized in a separate table. Listing will be provided for 
lower back and leg pain data [1]. Line graphs of baseline and post-baseline values for each pain 
categories will be graphically displayed for each subject by cohort. 
Use of rescue medication or surgical intervention 
The number of subjects used rescue medications and list of rescue medication will be 
summarized by cohort and it will be listed. Summarization includes additional pain medication 
(and amounts) added to the subject's baseline pain regimen within the first 13 weeks post-dose, 
an epidural injection, a selective nerve root block, or a facet block after receiving study drug and 
surgical intervention for lumbar disc herniation. 


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Spinal flexion and tension 
Spinal flexion and tension measured using the straight-leg raising or femoral stretch test 
at baseline, on day 1 pre-dose, at 24 hours post-dose and at all post-dose visits. Visit value and 
change from baseline (i.e. percentage change from baseline) in spinal flexion and tension signs 
(straight-leg raising or femoral stretch test) on the affected side at 6 and 13 weeks will be 
summarized by cohort. Rest of the time point details will be summarized same as mentioned 
above as a separate table. Listing will be provided for the spinal flexion and tension data. 
Functional ability 
The Oswestry disability index (ODI) is a patient self-scored questionnaire and a validated 
tool to measure how functional level is restricted by disability, and can also be used to determine 
improvement in functional levels as a result of treatment. The ODI will be administered at 
baseline, on day 1 pre-dose, at 24 hours post-dose, and at all post-dose visits. The improvement 
or lack of improvement in functional level is determined as a change from baseline in the score. 
Visit value and change from baseline in ODI at 6 and 13 weeks will be summarized by cohort. 
Rest of the time point details will be also summarized. Listing will be provided. 
Score is calculated as patient score/total possible score x 100 = %. Scores will be grouped 
into levels of disabilities of 0% - 20% = minimal disability, 20% - 40% = moderate disability, 
40% - 60% = severe disability, 60% - 80% = crippled, 80% - 100% = bed bound and it will also 
summarize. 
Quality of life 
Quality of life evaluated using the SF-12 form (version 2.0). 8 domains scores will be 
summarized for change from baseline in the SF-12 at 6 and 13 weeks descriptive by cohort. 
Quality of life results will be displayed in the subject data listings. The SF-12 will be 
administered at baseline, on day 1 pre-dose, at 24 hours post- dose, and at all post-dose visits. 
Rest of the time point details will also be summarized. 
Global impression of change or improvement 
Global impression of improvement as measured by the patient global impression of 
change (PGI-C) is a single question survey that will be administered at baseline, on day 1 pre- 
dose, at 24 hours post-dose and at all post-dose visits. Visit value and change from baseline in 
PGI-C score at 6 and 13 weeks will be summarized by cohort. Visit value and change from 
baseline for other visits also summarized in a separate table same as mentioned above. Listing 
will be provided for PGI-C score. 
Magnetic Resonance Imaging Assessment 
Magnetic resonance evaluation on the modification/shrinkage of the treated herniated disc 
size, the improvement of the stenosis of spinal canal, and the reduction of associated lateral 
neural foramen compression will be performed at Week 13, and at Months 6, 12, 18, and 24 (or 
early termination). Visit value in treated herniated disc size, the improvement of the stenosis of 
spinal  canal, and the reduction of associated lateral  neural  foramen compression  for each  visit 


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will be summarized by cohort and will be presented using descriptive statistics as mentioned in 
the section 4. 
The correlation between imaging findings and symptoms (e.g., average daily, worst daily 
and current lower back pain or leg pain values and ODI score) will be conducted after database 
lock as part of the report analysis for each visit by cohorts. Spearman rank correlation coefficient 
and p-value will be presented. Additionally listing will also be provided. 
Pharmacodynamic Parameters 
Serum concentrations of keratan sulfate and change from the baseline at every time point 
will be summarized and corresponding listings will also be provided. 
6.8 
Other Safety Endpoints 
Other safety endpoint includes serum pregnancy test and KTP-001 Antibody and serum 
concentration of KTP-001 will be summarized and listed. Other tests of urine pregnancy test, 
HBsAg, anti-HCV, anti-HIV, KTP-001 Antibody and serum concentration will be listed as 
subject data listings. Line graphs of baseline and post-baseline values will be graphically 
displayed for each subject by cohort. 


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7.0     HANDLING OF MISSING VALUES AND OUTLIERS 
All available safety and efficacy data will be included in data listings and tabulations. No 
imputation of values for missing data will be performed. 
When laboratory test results are above or below the limit of quantification (i.e proceeded 
by a “<” or “>” sign, for example “<xx”), the numerical value, xx, will be used for calculation in 
summary tables. 
Missing or partially date missing for AEs/TEAE: 
if due to partial dates or times it is not possible to definitively conclude that an AE is not 
treatment emergent, then a conservative approach will be taken whereby it will be classified as a 
TEAE e.g. if the first dose of study drug is “13May” and the AE starts in “May”, then that AE 
will be classified as a TEAE, unless the AE stop date precludes this (i.e. the AE stop date is 
definitively prior to the first dose of study drug). 
Missing or partially missing medication date and Prior or Concomitant Medication (CM) 
determination: 
If due to partial dates it is not possible to categorize a medication as prior or concomitant, then a 
conservative approach will be taken whereby it will be classified as such e.g. if the first dose of 
study drug is “13May” and another medication is started in “May”, then that medication will be 
classified as both previous and concomitant, unless the medication stop date precludes one of 
these classifications. 
Missing safety data will not be replaced, except for AE and CM dates as described above. 
Adverse events with missing severity will be summarized as severe. Adverse events  with 
missing causal relationship will be summarized as related. 


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8.0 
INTERIM ANALYSIS 
 
No Interim analysis will be performed. 
 
9.0 
CHANGES FROM ANALYSIS METHODS PLANNED IN THE PROTOCOL 
 
The planned protocol analysis of PK parameters and summary on counting the rescue 
medications were removed. 
 
10.0 REFERENCES 
 
1. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core 
outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain.2005; 
113(1-2):9-19. 
2. Pierre R Dupuis, Ken Yong-Hing, J David Cassidy, William H Kirkaldy Willis.  
Radiological diagnosis of degenerative lumbar spinal instability. Spine 1985; 10((3): 262- 
76. 


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11.0  APPENDIX 
Appendix 1: Schedule of assessment and procedures 
 
 


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Appendix 2: Screening and Clinical Laboratory Assessments 


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Appendix 3: Definition 
Adverse event (AE) 
An AE is defined as any untoward medical occurrence in a subject administered  a 
pharmaceutical product during the course of a clinical investigation. An AE can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of a 
study drug, whether or not thought to be related to the study drug. 
Adverse Events of Special Interest 
The following AEs will be considered an AESI: 
1. MRI or X-ray findings of Modic changes, reduction of disc height, or evidence of lumbar 
instability, or any other acute MRI or X-ray changes from baseline images deemed significant by 
the central reader/spine imaging specialist. 
2. Exacerbation of back or leg pain meeting at least 1 of the following criteria: 
a) Increase in average daily leg or back pain score by ≥3 to 6 or above on the numerical  
rating scale for at least 5 days out of a week 
b) Increase in average daily pain level associated with a new onset of focal neurological 
symptoms such as numbness and/or tingling or weakness lasting for > 5 days. 
3. New onset of neurological symptoms associated with objective changes on neurological 
examination (weakness, sensory deficit, changes in deep tendon reflexes) whether or not 
associated with increase in pain level. 
4. Any deterioration of subject’s condition that in the investigator’s judgment requires: 
a) Emergency MRI 
b) Epidural steroid injection/selective nerve root block, facet block, or surgical intervention. 
Serious Adverse event (SAE) 
The investigator is responsible for determining whether an AE meets the definition of an SAE. 
An SAE is any AE occurring from ICF signing through final study visit, at any dose, that results 
in any of the following outcomes: 
• Death 
• A life-threatening event, defined as an event in which the subject was at risk of death at 
the time of the event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect in a child or fetus of a subject exposed to the study 
drug 


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• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent any of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Assessing Severity 
The severity of an AE will be graded according to the following definitions: 
• Mild: The subject experiences awareness of symptoms but these are easily tolerated or 
managed without specific treatment 
• Moderate: The subject experiences discomfort enough to cause interference with usual 
activity, and/or the condition requires specific treatment 
• Severe: The subject is incapacitated with inability to work or do usual activity, and/or the 
event requires significant treatment measures. 
Assessing Causality 
The relationship of the event to the study drug should be determined by the investigator 
according to the following criteria: 
• Not related: The event is most likely produced by other factors such as the subject’s 
clinical condition, intercurrent illness, or concomitant drugs, and does not follow  a 
known response pattern to the study drug, or the temporal relationship of the event to 
administration of study drug makes a causal relationship unlikely. 
• Possibly related: The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, but could have 
been produced by other factors such as the subject's clinical condition,  intercurrent 
illness, or concomitant drugs. 
• Probably related: The event follows a reasonable temporal sequence from the time of  
drug administration, and/or follows a known response pattern to the study drug, and 
cannot be reasonably explained by other factors such as the subject's clinical condition, 
intercurrent illness, or concomitant drugs. 


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Appendix 4: Halting Rules 
The AEs or imaging abnormalities described below will be defined in this study as a halting rule 
(HR). If a HR occurs in any subject during the dose escalation phase of the study, further 
recruitment and dosing of the current study cohort will be held until the event is assessed by the 
Data and Safety Monitoring Board (DSMB). The DSMB will make a recommendation regarding 
continuation of the study and/or escalation to the next dose cohort when one of the following 
events occurs: 
• Neurologic deficit consistent with cauda equina syndrome or myelopathy 
• Exacerbation of radicular symptoms associated with onset of a new motor deficit in one or 
both legs following administration of study drug 
• Modic changes consistent with significant endplate edema or sclerosis compared to baseline, 
as determined by an expert spine radiologist 
• Loss of height of the disc of > 30% relative to the baseline and defined as the average of 
anterior and posterior disc height evaluated by X-ray 
• Evidence by X-ray of lumbar segmental instability at the treated segment defined as either: 
o Anterior translation of the posterior edge of the superior vertebral body relative to the 
posterior edge of the inferior vertebral body increase from baseline greater than 3mm is 
considered strong evidence of instability. 
o Sagittal rotation change from extension to flexion of >5° (as measured by the Dupuis 
method) [2] is weak evidence of instability, and without observed translation as defined 
above, will require further evaluation before it would be considered a halting event. 
NOTE: if the subject’s condition does not permit the acquisition of flexion and extension 
films, instability will be evaluated solely on the basis of translation on the lateral view, as 
described above. 
• Destructive cartilage endplate changes as confirmed by MRI. 
Once the last 13-week follow up period after the last dose cohort has occurred, any future 
instances of these events will be reported as AESI, but will not be treated as a HR.