Clinical trial NCT01919164
Conditions: Osteoarthritis, Knee
Keywords: Osteoarthritis of knee Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18) Sprifermin Placebo
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2013-07-29; Completion date: 2019-05-07
Enrollment: 549 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2 trial of Sprifermin administered intra-articularly in participants with primary osteoarthritis of the knee and Kellgren-Lawrence Grade 2 or 3. The trial was intended to investigate the efficacy and safety of different intra articular dosages of Sprifermin in these individuals.

Detailed description:
Participants were equally randomized to either one of 4 treatment arms or a placebo arm. The trial consists of a Screening period lasting up to 42 days, a two-year double-blind placebo-controlled (DBPC) treatment phase, which begins at randomization (Week 0) and ends at Year 2, and a 3-year extended follow-up phase.

Arms: arm 1: Participants received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. arm 2: Participants received Sprifermin 30 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. arm 3: Participants received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. arm 4: Participants received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. arm 5: Participants received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
Interventions: intervention 1: Sprifermin intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received Sprifermin as intra-articular injection. intervention 2: Participants received Placebo matched to sprifermin as intra-articular injection.

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol
Clinical Trial Protocol Number
EMR700692_006
Title
A multicenter, randomized, double-blind, 
placebo-controlled, parallel-group trial to 
investigate the efficacy and safety of different 
intra-articular (i.a.) dosages of sprifermin in subjects 
with primary osteoarthritis of the knee 
(FORWARD)
Trial Phase
II
IND Number
EudraCT Number
2011-003059-20
Coordinating Investigator
 
 
Sponsor
Merck KGaA
Frankfurter Strasse 250, 64293 Darmstadt, Germany
(for the USA)
EMD Serono, Inc.
One Technology Place, Rockland, MA 02370 USA
Medical Responsible:
EMD Serono, Inc.
One Technology Place, Rockland, MA 02370, USA
Clinical Trial Protocol Version
05 Mar 2013/Version 4.0 (including Amendments 1
and 2)
Replaces Clinical Trial Protocol 
Version
13 Oct 2011/Version 3.0
Current Clinical Trial Protocol 
Amendment
Amendment No. 2 (Global), 05 Mar 2013
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated 
companies. It is intended for restricted use only and may not – in full or part – be passed on, 
reproduced, published or used without express permission of Merck KGaA, Darmstadt, 
Germany, or its affiliate. Copyright © 2013 by Merck KGaA, Darmstadt, Germany, or its 
affiliate. All rights reserved.
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Previous Protocol Amendments
! Amendment No. 1 (Non-substantial), 13 Oct 2011 (Global)
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Further Sponsor Responsible Persons
Medical Responsible:
EMD Serono, Inc.
One Technology Place, Rockland, MA 02370
Tel: 
; Fax: 
Biostatistician:
Merck Serono S.A. – Geneva
9 chemin des Mines, 1202 Geneva Switzerland
Tel.: 
; Fax: 
e-mail: 
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Principal Investigator Signature
Trial Title
A multicenter, randomized, double-blind, placebo-
controlled, parallel-group trial to investigate the 
efficacy and safety of different intra-articular (i.a.) 
dosages of sprifermin
in subjects with primary 
osteoarthritis 
of 
the 
knee 
(FORWARD) 
(EMR700692_006)
EudraCT Number
2011-003059-20
Clinical Trial Protocol Version/Date
05 Mar 2013/ Version 4.0 (including Amendments 1
and 2)
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that:
! I understand and will conduct the trial according to the clinical trial protocol, any approved 
protocol amendments, International Conference on Harmonization Good Clinical Practice 
(ICH Topic E6 GCP) and all applicable Health Authority requirements and national laws.
! I will not deviate from the clinical trial protocol without prior written permission from the 
Sponsor and prior review and written approval from the Institutional Review Board or 
Independent Ethics Committee, except where necessary to prevent immediate danger to the 
subject.
! I understand that some Health Authorities require the Sponsors of clinical trials to obtain and 
supply, when required, details about the Investigators’ ownership interests in the Sponsor or 
Investigational Medicinal Product and information regarding any financial ties with the 
Sponsor. The Sponsor will use any such information that is collected solely for the purpose of 
complying with the regulatory requirements. I therefore agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties (including those of my 
spouse and dependent children), and to provide updates as necessary.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function
Institution
Address
Telephone number
Fax number
E-mail address
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Table of Contents
Signature Page
..............................................................................................................3
Table of Contents
..............................................................................................................7
Table of Tables
............................................................................................................11
Table of Figures
............................................................................................................11
List of Abbreviations .........................................................................................................12
1
Synopsis..............................................................................................17
2
Sponsor, Investigators and Trial Administrative Structure ................26
3
Background Information.....................................................................27
4
Trial Objectives ..................................................................................30
5
Investigational Plan ............................................................................31
5.1
Overall Trial Design and Plan ............................................................31
5.2
Discussion of Trial Design .................................................................37
5.2.1
Inclusion of Special Populations ........................................................42
5.3
Selection of Trial Population..............................................................42
5.3.1
Inclusion Criteria ................................................................................42
5.3.2
Exclusion Criteria...............................................................................43
5.4
Criteria for Randomization.................................................................44
5.5
Criteria for Subject Withdrawal..........................................................45
5.5.1
Withdrawal from the Trial..................................................................45
5.5.2
Withdrawal from the Investigational Medicinal Product ...................45
5.6
Premature Discontinuation of the Trial ..............................................46
5.7
Definition of End of Trial...................................................................46
6
Investigational Medicinal Products and Other Drugs Used in the 
Trial.....................................................................................................46
6.1
Description of Investigational Medicinal Products ............................46
6.1.1
Sprifermin...........................................................................................47
6.1.2
Placebo................................................................................................47
6.2
Dosage and Administration ................................................................47
6.3
Assignment to Treatment Groups.......................................................48
6.4
Other Drugs to be used in the Trial ....................................................48
6.5
Concomitant Medications and Therapies ...........................................49
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6.5.1
Permitted Medicines...........................................................................49
6.5.2
Non-permitted Medicines ...................................................................50
6.5.3
Other Trial Considerations .................................................................51
6.5.4
Special Precautions.............................................................................51
6.6
Packaging and Labeling......................................................................51
6.7
Preparation, Handling and Storage.....................................................51
6.8
Investigational Medicinal Product Accountability.............................52
6.9
Assessment of Investigational Medicinal Product Compliance .........52
6.10
Method of Blinding.............................................................................53
6.11
Emergency Unblinding.......................................................................53
6.12
Treatment of Overdose .......................................................................53
6.13
Medical Care of Subjects after End of Trial.......................................54
7
Trial Procedures and Assessments......................................................54
7.1
Schedule of Assessments....................................................................54
7.1.1
General Instructions............................................................................54
7.1.2
Screening Period (Visits 1a and 1b) ...................................................57
7.1.3
Double-Blind Placebo-Controlled Treatment Phase (Visits 2 to 
22).......................................................................................................59
7.1.4
Extended Follow-Up Phase ................................................................65
7.1.5
Follow-Up in Case of Early Termination...........................................66
7.2
Demographic and Other Baseline Characteristics ..............................67
7.3
Assessment of Efficacy.......................................................................67
7.3.1
Magnetic Resonance Imaging.............................................................68
7.3.2
WOMAC Questionnaire.....................................................................69
7.3.3
Patient’s Global Assessment...............................................................70
7.3.4
X-Ray Imaging ...................................................................................70
7.3.5
20-Meter Walk Test............................................................................71
7.4
Assessment of Safety..........................................................................71
7.4.1
Adverse Events ...................................................................................71
7.4.2
Pregnancy and In Utero Drug Exposure.............................................76
7.4.3
Laboratory Assessments .....................................................................77
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............78
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7.5
Pharmacokinetics................................................................................78
7.5.1
Body Fluids.........................................................................................79
7.5.2
Pharmacokinetic Calculations ............................................................79
7.6
Biomarkers and Pharmacogenetics.....................................................79
7.6.1
Biomarkers to be Analyzed ................................................................79
7.6.2
Body Fluids for Biomarker Assessment.............................................80
7.6.3
Pharmacogenetics ...............................................................................80
7.7
Other Assessments..............................................................................81
7.7.1
Knee Injury and Osteoarthritis Outcome Score - Quality of Life 
and Symptom Index Subscales ...........................................................81
7.7.2
Medical Outcomes Study Short Form-36 General Health Survey .....81
7.7.3
Measure of Intermittent and Constant Osteoarthritis Pain 
Questionnaire......................................................................................82
7.7.4
Patient Global Impression of Change.................................................82
7.7.5
11-Point Numerical Rating Scale Pain Score .....................................83
7.7.6
Pain in Other Joints.............................................................................83
8
Statistics..............................................................................................83
8.1
Sample Size ........................................................................................83
8.2
Randomization....................................................................................86
8.3
Endpoints............................................................................................86
8.3.1
Primary Endpoint................................................................................86
8.3.2
Secondary Endpoints ..........................................................................86
8.3.3
Safety Endpoints.................................................................................87
8.3.4
Exploratory Endpoints........................................................................87
8.4
Analysis Sets.......................................................................................88
8.5
Description of Statistical Analyses.....................................................89
8.5.1
General Considerations.......................................................................89
8.5.2
Analysis of Primary Endpoint ............................................................90
8.5.3
Analysis of Secondary Endpoints.......................................................91
8.5.4
Safety Analyses ..................................................................................92
8.5.5
Analysis of Further Endpoints............................................................92
8.6
Interim Analysis..................................................................................93
9
Ethical and Regulatory Aspects..........................................................93
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9.1
Responsibilities of the Investigator ....................................................93
9.2
Subject Information and Informed Consent .......................................94
9.3
Subject Identification and Privacy......................................................95
9.4
Emergency Medical Support and Subject Card..................................95
9.5
Clinical Trial Insurance and Compensation to Subjects.....................96
9.6
Independent Ethics Committee or Institutional Review Board..........96
9.7
Health Authorities...............................................................................97
10
Trial Management...............................................................................97
10.1
Case Report Form Handling...............................................................97
10.2
Source Data and Subject Files............................................................97
10.3
Investigator Site File and Archiving...................................................98
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................98
10.5
Changes to the Clinical Trial Protocol................................................99
10.6
Clinical Trial Report and Publication Policy......................................99
10.6.1
Clinical Trial Reports .........................................................................99
10.6.2
Publication..........................................................................................99
11
References.........................................................................................100
12
Appendices .......................................................................................104
Appendix A:
American College of Rheumatology Criteria for the Classification 
and Reporting of Osteoarthritis of the Knee.....................................104
Appendix B:
Safety Laboratory Parameters...........................................................105
Appendix C:
Subject Questionnaires: WOMAC, MOS SF-36, and ICOAP .........106
Appendix D:
Knee Injury and Osteoarthritis Outcome Score Quality of Life 
(KOOS QOL) and Symptom Index Subscales .................................107
Appendix E:
Schedule of Trial Procedures............................................................109
Appendix F:
Pain in Other Joints...........................................................................113
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Table of Tables
Table 1
Drug Administration Diagram............................................................47
Table 2
Trial Visits during DBPC Treatment Phase........................................60
Table 3
Power Calculations for Pairwise Differences (Sprifermin versus 
Placebo) on Normalized WOMAC Scores with 76 Evaluable 
Subjects per Treatment Group............................................................86
Table 4
Summary of Criteria for Classification of Idiopathic Osteoarthritis 
of the Knee........................................................................................104
Table 5
Schedule of Trial Procedures for Visits 1 to 11................................109
Table 6
Schedule of Trial Procedures for Visits 12 to 22 and Extended 
Follow-up Visits ...............................................................................111
Table of Figures
Figure 1
Trial Schema: Screening and DBPC Treatment Phases .....................32
Figure 2
Trial Schema: Extended Follow-up Phase..........................................33
Figure 3
Expected Mean Changes in Cartilage Thickness (mm) in Total 
Knee at 2 Years (SD = 0.10)...............................................................85
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List of Abbreviations
AE
Adverse event
AIR
Acute inflammatory reaction
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
BLOKS
Boston-Leeds Osteoarthritis Knee Score
BUN
Blood urea nitrogen
CFR
(United States) Code of Federal Regulations
CI
Confidence interval
CK
Creatine kinase
COMP
Cartilage oligomeric matrix protein
coxib
COX-2 selective inhibitor
CRF
Case Report Form
CS846
Chondroitin sulfate epitope 846
CTX-II
C-telopeptide cross-linking of type II collagen
DBPC
Double-blind placebo-controlled
DMPK
Drug Metabolism and Pharmacokinetics
ECG
Electrocardiogram
EEA
European Economic Area
EF
Extended follow-up
EMA
European Medicines Agency
ESR
Erythrocyte sedimentation rate
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EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European clinical trials database)
FDA
Food and Drug Administration
FGF
Fibroblast growth factor
FGF-18
Fibroblast growth factor-18
FGFR
Fibroblast growth factor receptor
FIM
First-in-man
FORWARD
FGF-18 Osteoarthritis Randomized trial With Administration of 
Repeated Doses
GBS
Global Biostatistics (department)
GCDU
Global Clinical Development Unit
GCP
Good Clinical Practice
GDS
Global Drug Safety (department)
GMP
Good Manufacturing Practice
HIV
Human immunodeficiency virus
hsCRP
High-sensitivity C-reactive protein
i.a.
Intra-articular(ly)
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICOAP
Measure of Intermittent and Constant Osteoarthritis Pain
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IL
Interleukin
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IL-1ra
Interleukin-1 receptor antagonist
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intention-to-Treat
IVRS
Interactive Voice Response System
JSW
Joint space width
KOOS
Knee Injury and Osteoarthritis Outcome Score
KOOS QOL
Knee Injury and Osteoarthritis Outcome Score quality of life subscale
LFTC
Lateral femorotibial compartment
LLOQ
Lower limit of quantitation
mcg
Microgram(s)
MedDRA
Medical Dictionary for Regulatory Activities
MFTC
Medial femorotibial compartment
mITT
Modified Intention-to-Treat
MOP
Manual of Operations
MOS SF-36
Medical Outcomes Study Short Form-36 General Health Survey
MRI
Magnetic resonance imaging
NCD
Non-Clinical Development (department)
N.B.
Nota bene (please note)
NRS
Numerical Rating Scale
NSAID
Non-steroidal anti-inflammatory drug
OA
Osteoarthritis
OAI
Osteoarthritis Initiative
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OARSI
Osteoarthritis Research Society International
OMERACT-OARSI
Outcome Measures in Rheumatology – Osteoarthritis Research Society 
International (responder criteria)
PD
Pharmacodynamic(s)
PGA
Patient’s Global Assessment
PGIC
Patient Global Impression of Change
PGt
Pharmacogenetics
PIINP
II form of the propeptides from the N-terminus processed type II 
collagen
PIICP
Propeptides from the C-terminus processed type II collagen
PK
Pharmacokinetic(s)
POC
Proof of concept
PP
Per Protocol
PRO
Patient Reported Outcome
QOL
Quality of life
QTc
Corrected electrocardiogram QT interval
RF
Rheumatoid factor
rhFGF-18
Recombinant human fibroblast growth factor 18
SAE
Serious Adverse Event
SF
Synovial fluid
SUSAR
Suspected unexpected serious adverse reaction
TNF
Tumor necrosis factor
ULN
Upper limit of normal (range)
VAS
Visual analogue scale
W
Week
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WBC
White blood cell
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index
WORMS
Whole Organ Magnetic Resonance Imaging Score
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1
Synopsis
Trial title
A multicenter, randomized, double-blind, placebo-
controlled, parallel-group trial to investigate the efficacy 
and safety of different intra-articular (i.a.) dosages of 
sprifermin in subjects with primary osteoarthritis of the 
knee (FORWARD)
Trial number
EMR700692_006
EudraCT number
2011-003059-20
Sponsor
Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, 
Germany
(for the United States of America)
EMD Serono, Inc.
One Technology Place, Rockland, MA 02370 USA
Phase
II
Trial under IND
yes
no
FDA “covered trial”
yes
no
Trial centers/countries
Approximately 10 to 15 trial sites located in Europe, the 
United States, and possibly other geographical regions
Planned trial period
(first enrollment-last subject 
out)
Aug 2013 (first subject’s first visit) to Aug 2019 (last 
visit of follow-up phase)
Trial objectives
Primary:
To evaluate structural changes in cartilage thickness in 
the total femorotibial joint of the target knee in terms of 
imaging by magnetic resonance imaging (MRI)
Secondary:
! To evaluate different dose regimens of sprifermin
! To evaluate changes in symptoms of osteoarthritis 
(OA)
! To evaluate changes in structure in terms of imaging 
by X-ray
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! To evaluate other changes in cartilage morphology in 
terms of imaging by MRI (sub-regions)
! To evaluate changes in physical functioning
! To evaluate the safety of sprifermin
! To evaluate the pharmacokinetics (PK) of sprifermin
in serum and in synovial fluid following i.a. injection
Exploratory:
! To evaluate responder criteria in symptoms
! To explore treatment effect on OA pain and other 
patient-reported outcomes (PROs)
! To evaluate changes in quality of life (QOL)
! To explore treatment effect on the knee joint and bone 
structures by MRI
! To evaluate long-term treatment effects
! To explore the relationship between the change over 
time in synovial, serum, and urine biomarkers (e.g.,
cartilage 
and 
bone 
tissue 
turnover
markers, 
inflammation markers) and the response to the drug
! To evaluate potential associations of biomarkers (e.g.,
genetic variations or protein biomarkers measured at 
baseline) with drug response, and/or disease severity 
or disease progression
! To explore the relationship between dosing (dose and 
regimen), cartilage structure, and clinical scores as a 
function of time, by means of modeling
Trial design and plan
The trial consists of a screening period, a double-blind 
placebo-controlled (DBPC) treatment phase, and an 
extended follow-up phase.
Subject eligibility for the trial will be determined during 
the screening period based on clinical and radiographic 
criteria, in addition to responses to pain questionnaires 
after withdrawal of analgesic medications.
In the 2-year DBPC treatment phase, subjects will be 
randomized in equal allocation to one of 5 treatment 
groups (see below).
All subjects will receive 4 cycles of treatment with the 
Investigational Medicinal Product (IMP; sprifermin or 
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matching placebo) at intervals of 6 months. Each cycle 
will consist of 3 once-weekly i.a. injections over a period 
of 3 consecutive weeks.
Efficacy assessments will include MRI and X-ray of the 
target knee, the WOMAC, the 20-meter walk test, and a 
Patient’s Global Assessment of disease impact (PGA). 
The Patient Global Impression of Change (PGIC), the 
Knee Injury and Osteoarthritis Outcome Score (KOOS) 
QOL subscale (KOOS QOL), the KOOS Symptom 
Index, the Medical Outcomes Study Short Form-36 
General Health Survey (MOS SF-36), assessment of pain 
(on a numerical rating scale [NRS]) in the target and 
contralateral knee, identification of pain in other joints, 
and 
the 
Measure 
of 
Intermittent 
and 
Constant 
Osteoarthritis Pain (ICOAP) questionnaire will be 
assessed as exploratory outcomes.
Adverse events (AEs), concomitant medications, and 
procedures will be monitored throughout the trial.
See below for details of safety and other assessments.
The 3-year extended follow-up phase will include 
periodic assessment of the WOMAC, NRS pain score in 
the target and contralateral knee, PGA, PGIC, KOOS 
QOL and Symptom Index, MOS SF-36, 20-meter walk 
test, identification of pain in other joints, and ICOAP as 
well as safety assessments. MRI and X-ray will be 
performed at yearly intervals.
It is planned to perform the statistical analysis in two 
steps, as described in Section 8.5.1: results from the 
DBPC treatment phase will be analyzed and reported at 
the end of this phase, and long-term follow-up data will 
be analyzed and reported separately. MRI readers, 
Investigators, and subjects will remain blinded during the 
extended follow-up phase.
Planned number of subjects
545 subjects will be randomized.
Approximately 10 to 15 trial sites in Europe, the United 
States, and possibly other geographical regions will 
participate in the trial.
Schedule of visits and 
assessments
The screening period will comprise a period of 4 to 42
days during which a subject’s eligibility will be 
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determined, beginning at signature of the ICF. During the 
screening visits, eligibility will be assessed and the target 
knee will be defined. At the baseline visit, eligibility will 
be confirmed, randomization will occur, and the first IMP 
injection will be given (Week 0/Visit 2). The last of the 
four cycles of 3 injections of IMP will be given on Week 
78/Visit 17, and the last dose of IMP is scheduled to be 
administered at Week 80/Visit 19.
Trial visits during the two-year DBPC treatment phase 
will take place at Weeks 0 (randomization and first IMP 
injection), 1, 2, 3, 12, 26, 27, 28, 29, 38, 52, 53, 54, 55, 
64, 78, 79, 80, 81, 90, and 104.
Major efficacy assessments will take place on the first 
day of each treatment cycle and then at the end of the 
DBPC treatment phase (Week 104/Visit 22).
Minor efficacy assessments will take place 9 weeks after 
each treatment cycle.
AEs and concomitant medications will be reviewed and 
vital signs will be measured at all trial visits.
Trial assessments during the 3-year extended follow-up 
phase will take place at 6-month intervals from Week 
104/Visit 22 through Week 260/Visit 28.
Diagnosis and main inclusion 
and exclusion criteria
The trial will enroll adult subjects of either sex with 
primary 
femorotibial 
osteoarthritis 
according 
to 
American College of Rheumatology (ACR) clinical and 
radiographic criteria who have Kellgren-Lawrence grades 
of 2 or 3 and a minimum joint space width (JSW) of ≥ 2.5 
mm in the medial compartment.
Subjects must have pain in the target knee on most days
and/or require symptomatic treatment of knee pain with 
paracetamol (acetaminophen), systemic non-steroidal 
anti-inflammatory drugs (NSAIDs) including COX-2 
selective inhibitor (coxibs), or tramadol on most days of 
the previous month, and must have both:
! A history of pain due to OA in the target knee for at 
least 6 months, and
! Pain score for the target knee of 4 to 9 points in 
response to Question 1 of the WOMAC pain index 
(“how much pain have you had [in the target knee, 
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over the past 48 hours] when walking on a flat 
surface?”) at screening and baseline, after washout of 
at least 5-half-lives of analgesic medication(s): 
acetaminophen, topical or oral systemic NSAIDS, 
coxibs, opioids, and/or tramadol. 
Women of childbearing potential must use a form of 
contraception with a failure rate of less than 1% per year 
throughout the trial.
Main exclusion criteria are malalignment of > 5 degrees 
in the femorotibial axis of the target knee,  clinical signs 
of inflammation (i.e., redness) in the target knee, i.a. 
administration of corticosteroids or hyaluronic acid into 
either knee within 6 months before screening, any plan 
for knee surgery (affecting either the target or the 
contralateral 
knee) 
within 
the 
next 
two 
years, 
concomitant conditions or treatments deemed to be 
incompatible with trial participation, contraindications to 
MRI scanning (including inability to fit in the scanner or 
knee coil), pregnancy or breastfeeding, participation in 
another clinical trial within the past 30 days, and legal 
incapacity or limited legal capacity.
Full lists of inclusion and exclusion criteria are presented 
in Sections 5.3.1 and 5.3.2, respectively.
Written informed consent must be obtained prior to any 
trial-related activity.
Investigational Medicinal 
Product: dose/mode of 
administration/ dosing schedule
Sprifermin (rhFGF-18) 30 mcg or 100 mcg, administered 
intra-articularly.
Subjects will receive 4 cycles of treatment (each 
consisting of 3 once-weekly i.a. injections over 3 
consecutive weeks) at intervals of 6 months.
Subjects will be randomized in equal allocation to one of 
5 treatment groups:
! 4 cycles of sprifermin (100 mcg per injection)
! 2 cycles of sprifermin (100 mcg per injection) 
alternating with 2 cycles of placebo
! 4 cycles of sprifermin (30 mcg per injection)
! 2 cycles of sprifermin
(30 mcg per injection) 
alternating with 2 cycles of placebo
! 4 cycles of placebo (see below)
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Reference therapy: dose/mode of 
administration/dosing schedule
Placebo to match sprifermin, administered i.a. (see 
treatment regimen described above for sprifermin)
Planned treatment duration per 
subject
2 years
Primary endpoint
Change from baseline in cartilage thickness in the total 
femorotibial joint as evaluated by MRI at 2 years
Secondary endpoints
! Changes from baseline in the WOMAC total score and 
in the WOMAC pain, function, and stiffness index 
scores over 2 years
! Change from baseline in the 20-meter walk test over 2 
years
! Change from baseline in the PGA over 2 years
! Change from baseline in minimal joint space width in 
the medial and lateral compartments as evaluated by 
X-ray over 2 years
! Change from baseline in cartilage thickness in the 
medial and lateral compartments as well as in the total 
femorotibial joint over 2 years
! Change from baseline in cartilage volume in the 
medial and lateral compartments as well as in the total 
femorotibial joint over 2 years
! Synovial fluid levels of sprifermin/FGF-18 
! Serum levels of sprifermin/FGF-18 
Safety endpoints
! Nature, incidence and severity of local and systemic 
AEs
! Incidence of acute inflammatory reactions (AIRs), 
defined as increase of pain by 30 mm on a 100 mm 
visual analogue scale (VAS) and a self-reported 
synovial fluid effusion (i.e., joint swelling) within 3 
days following i.a. injection (see Section 7.4.1.1)
! Changes in laboratory safety parameters, vital signs, 
12-lead electrocardiogram (ECG) parameters, weight,
and physical examinations
! Incidence of surgical interventions in the target knee 
(including any surgical revision, cartilage removal, or 
any other type of surgical intervention).
! Occurrence of binding and neutralizing antibodies to 
sprifermin/FGF-18
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Exploratory endpoints
! Outcome Measures in Rheumatology – Osteoarthritis 
Research Society International (OMERACT-OARSI) 
responder rate (1) at 2 years
! PGIC over 2 years
! Changes from baseline in the scores of the KOOS 
QOL and the MOS SF-36 questionnaire over 2 years
! Change from baseline in KOOS Symptom Index over 
2 years
! Change from baseline in NRS pain score in the target 
and contralateral knee over 2 years using an 11-point 
NRS
! Change from baseline in presence of pain in other 
joints over 2 years
! Change from baseline in ICOAP scores over 2 years
! Change 
over 
time 
in 
structural 
as 
well 
as 
compositional parameters of the knee joint (e.g., 
synovium, menisci, bone, and other structures) as 
evaluated by MRI
! Change from baseline in serum, urine, and synovial 
markers associated with administration of the 
compound
! Baseline protein markers and/or genetic markers  
associated with response to treatment or disease 
progression (response assessed by
MRI and/or 
questionnaire)
! Changes in MRI outcomes, WOMAC scores, 20-meter 
walk test, PGA, PGIC, JSW, OMERACT-OARSI 
responder rate, KOOS QOL, KOOS Symptom Index, 
MOS SF-36, NRS pain score in the target and 
contralateral knee, presence of pain in other joints, 
ICOAP, safety laboratory values, and vital signs over 
the extended follow-up period and nature, incidence 
and severity of local and systemic AEs during the 
extended follow-up period (to be summarized 
descriptively)
! Relationship between dosing (dose and regimen), 
cartilage structure, and clinical scores as a function of 
time
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Pharmacokinetics
Levels of sprifermin/FGF-18 will be measured in serum 
and synovial fluid for pharmacokinetic (PK) assessment 
Other assessments
Subject diary information about maximum levels of 
target knee pain and presence or absence of target knee 
swelling will be used to identify potential acute 
inflammatory reactions to the IMP.
Exploratory pharmacogenetic (PGt) analyses will be 
performed for subjects who provide separate informed 
consent.
Statistical methods (includes 
sample size calculation)
Sample Size Calculation
The number of 545 randomized subjects has been 
calculated to provide 90% power to detect a dose 
relationship as well as an overall treatment effect in the 
change from baseline in cartilage thickness in the total 
femorotibial joint at 2 years, assuming a discontinuation 
rate of 30% at that time. The study is also adequately 
powered to detect significant difference in at least one 
active treatment group and the placebo group for a 
secondary WOMAC endpoint such as the pain, function 
or total WOMAC score.
Statistical Methodology
The treatment effect on the primary endpoint will be 
assessed 
through 
dose-ranging 
using 
a 
repeated 
measurement analysis of variance (ANOVA, using 
PROC MIXED in SAS) on absolute change from 
baseline, including the baseline value, the treatment 
group, the time, and the country as factors and treatment 
by time as interaction.
The primary efficacy analysis will consist of testing the 
linear dose relationship and the overall treatment effect at 
2 years. The significance level will be set at 5% two-
sided for both tests.
Pairwise comparisons (sprifermin versus placebo, and 
between sprifermin dose and regimen groups) will be 
performed within the context of this modeling 
framework. For each pairwise comparison, the difference 
between 
treatments 
and 
the 
corresponding 
95% 
confidence interval (CI) and p-value will be presented.
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The same ANOVA model used for the primary endpoint 
will be used to assess the treatment effect on continuous 
secondary endpoints such as MRI endpoints, WOMAC 
endpoints (total, pain, function, and stiffness scores), and 
X-ray endpoints at each time point and over time.
Logistic regression will be used to assess the treatment 
effect on the binary efficacy endpoints such as the 
OMERACT-OARSI responder rate. Point estimates for 
each pairwise comparison and corresponding 95% CIs 
and p-values will be provided.
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2
Sponsor, Investigators and Trial Administrative Structure
Sponsor
For countries other than the United States of America, the Sponsor of this trial is Merck KGaA, 
Frankfurter Strasse 250, 64293 Darmstadt, Germany.
For the United States of America, the Sponsor of this trial is EMD Serono Inc. (One Technology 
Place, Rockland, MA 02370, USA).
Sponsor Responsibilities
The sponsor will be responsible for overseeing all aspects of the study.
External Service Providers
External service providers will be responsible for trial management, including central 
randomization and central laboratory analyses. Magnetic resonance imaging (MRI) and X-ray 
imaging data will also be acquired and read centrally. Details regarding the vendors involved and
the responsibilities of each will be described in the MOP.
Investigators and Trial Sites
Overall, approximately 10 to 15 trial sites located in Europe, the United States, and possibly 
other geographical regions will contribute to this trial.
It is estimated that 2 of the enrolling sites will be located in the United States.
Coordinating Investigator
The Coordinating Investigator for this trial is
 
 
(contact information is provided on the title page of this 
clinical trial protocol).
The Coordinating Investigator will serve as a representative of the trial Investigators in decisions 
and discussions regarding this trial (see International Conference on Harmonization Topic E6, 
Good Clinical Practice (ICH GCP), 1.19), providing expert medical input and advice relating to 
trial design and execution and being responsible for the review and sign-off of the clinical trial 
report on behalf of all Investigators.
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be constituted and will perform 
periodic reviews to evaluate the safety of the subjects participating in the trial on an ongoing 
basis. Detailed description of the safety monitoring will be specified in a dedicated IDMC 
charter.
Trial Administrative Structure
Details of the trial’s administrative structure are presented in the trial Manual of Operations 
(MOP).
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3
Background Information
Osteoarthritis (OA) is an ever-increasing health problem in both industrialized nations and
developing countries (2). The risk factors contributing to this epidemic are increasing body 
weight, lack of exercise, and the aging of a significant proportion of the population (3),(4),(5). 
The increasing number of individuals being affected by degenerative joint disease also translates 
into a significant financial burden on the health care system (6).
Despite the variety of treatment modalities available, no existing pharmacological treatments can 
influence OA disease progression or outcome. Consequently, there is considerable interest in the 
development of disease-modifying OA drugs.
Sprifermin is a truncated recombinant form of human fibroblast growth factor-18 (FGF-18). 
Endogenous human FGF-18 is a protein expressed by chondrocytes of articular cartilage which
has been identified as a trophic factor for mature chondrocytes. In cell culture experiments, FGF-
18 was shown to induce proliferation of articular chondrocytes and to stimulate synthesis of 
extracellular matrix (7). Furthermore, in an animal experiment, FGF-18 induced dose-dependent 
increases of cartilage thickness of the tibial plateau in rats after they had been subjected to 
meniscal injury. Both reductions in the cartilage degeneration scores and generation of new 
cartilage were seen in the treated animals (8).
Human FGF-18 is a 20-kilodalton secreted protein expressed by cells including chondrocytes 
and osteoblasts (9),(10). FGF-18 increases chondrocyte proliferation/differentiation and cartilage 
deposition and induces osteoblast differentiation, leading to bone remodeling effects (e.g., 
closure of growth plates) (7),(8),(10),(11),(12). FGF-18 is required for normal development, as 
homozygous knockout mice die shortly after birth (13),(14). Their phenotype includes skeletal 
defects.
Cell surface receptors for FGF-18 have been identified. Upon ligand binding mediated by 
heparin/heparin sulfate-containing proteoglycans, high-affinity fibroblast growth factor receptors 
(FGFR) 3c, 4, and 2c transduce intracellular signaling via tyrosine-kinase activity (15). FGFR3c, 
FGFR4, and FGFR2c are naturally expressed on chondrocytes of articular cartilage, as 
demonstrated by in situ hybridization (14),(15). FGF-18 has been shown to signal through 
FGFR3 to promote mesenchymal cell differentiation (chondrogenesis) and production of the 
cartilage matrix, leading to repair and reconstruction of a variety of cartilaginous tissues (7).
Sprifermin (recombinant human FGF-18; rhFGF-18; formerly known as AS902330) produced by 
Merck Serono is a truncated, non-glycosylated form of FGF-18, containing 170 amino acids. 
Sprifermin
increases chondrocyte proliferation/differentiation and cartilage deposition, 
potentially leading to repair and reconstruction of a variety of cartilaginous tissues.
Unlike other members of the fibroblast growth factor (FGF) family, FGF-18 is not a general 
growth mediator but exhibits its effects specifically on chondrocytes (proliferation) and 
osteoblasts (differentiation). Nonetheless, significant systemic exposure to sprifermin may result 
in unacceptable side effects such as general cartilage and bone growth. Therefore, in order to 
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minimize systemic exposure and to limit the trophic effect of sprifermin to intra-articular 
cartilage, intra-articular (i.a.) injection will be used.
Nonclinical Data
Nonclinical studies performed with sprifermin are described in the sprifermin Investigator’s 
Brochure (IB).
Clinical Data
Clinical trials performed to date with sprifermin are described in the sprifermin IB. To date, two 
Phase I trials of sprifermin in subjects with OA of the knee have been completed.
The randomized, double-blind, placebo-controlled multicenter first-in-man (FIM) trial 27575 
included 73 subjects with OA in the femorotibial compartments of the knee who were candidates 
for total knee replacement. Subjects were randomized to receive i.a. injections of sprifermin at 
dosages of 3 mcg, 10 mcg, 30 mcg, 100 mcg, and 300 mcg or placebo in either single-dose or 
multiple-dose regimens. Multiple-dose regimens consisted of one treatment cycle of three 
injections given once weekly over a period of three weeks. Twenty-three subjects who received 
single-dose regimens and 26 subjects who received multiple-dose regimens underwent total knee 
replacement within a period of three months after completion of treatment. When the cartilage 
tissue specimens of the resected knees were examined by pathologists, specimens from subjects 
who had been exposed to dosages of 10 to 300 mcg sprifermin showed a trend to lower Mankin 
scores and higher Young modulus, both indicating an improvement of cartilage morphology, 
compared to subjects who received placebo. These effects were more pronounced in the 
multiple-dose groups. Furthermore, sprifermin had a favorable safety profile and was well 
tolerated in this trial.
The randomized, double-blind, placebo-controlled, multicenter proof-of-concept (POC) trial 
28980 included 192 subjects with primary knee OA and Kellgren-Lawrence grade 2 or 3 who 
were not candidates for knee replacement. Subjects were randomized into groups receiving either 
placebo or three dosages of sprifermin (10 mcg, 30 mcg or 100 mcg) in either single-dose or 
multiple-dose regimens. Multiple-dose regimens involved two treatment cycles given 3 months 
apart.
A dose-dependent anabolic effect was seen on total cartilage volume and thickness as measured 
by MRI. The effect on structure was more pronounced in the lateral as compared to the medial 
compartment; statistical significance was not reached for the primary endpoint of change from 
baseline in cartilage thickness in the central medial femorotibial compartment. A significant 
dose-dependent effect was also seen for JSW, particularly in the lateral compartment, with the 
highest dose actually reversing joint space narrowing.
No local tolerability or systemic safety concerns were identified. One SAE was considered 
potentially treatment-related: bacterial arthritis in a subject who had received placebo. Subjects 
who received active treatment appeared to have slightly more acute inflammatory reactions 
(AIRs; defined as increase of pain by 30 mm on a 100-mm visual analogue scale (VAS) 
associated with a self-reported synovial fluid effusion within 3 days following i.a. injection) in 
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the treated knee; however, no dose-response relationship was evident. For additional updated 
clinical safety data on sprifermin, refer to the Investigator’s Brochure.
In terms of modification of symptoms, WOMAC total score improved over the 12-month period 
in all groups, including placebo. The improvement of symptoms was most pronounced in the 
placebo group, while sprifermin-treated subjects experienced less symptom relief. This 
unexpected result was also seen for the WOMAC pain and function index scores and requires 
further investigation.
Rationale for the Present Trial
Sprifermin is a completely novel compound in the field of degenerative joint disease and it may 
be the first disease-modifying drug to become available to patients with OA.
Based on the results described above, this phase II trial is proposed to assess the dose-response-
relationship of sprifermin in subjects with knee OA of Kellgren-Lawrence grades 2 and 3. The 
trial design is presented in Section 5.1; rationales for choices of trial design, subject population, 
dose regimen, and trial assessments are presented in Section 5.2, and the reasoning behind the 
choice of planned sample size is presented in Section 8.1.
This clinical trial will be conducted in compliance with the clinical trial protocol, Good Clinical 
Practice (ICH Topic E6, GCP) and the applicable regulatory requirements.
If the trial is positive, it will provide data on an optimized dose and dosing schedule of 
sprifermin, i.e., a dose and dosing schedule of the drug that will exert a disease-modifying action 
(i.e., both modification of structure and improvement of symptoms).
Currently very little is known about how modification of structure is linked to change in 
symptoms (i.e., perception of pain and function by the subject). This trial will also help to 
understand how change in cartilage structure correlates with change in symptoms.
To date, a total of 265 subjects have been included in the FIM and the POC trials using i.a. 
administration. All systemic levels of sprifermin/FGF-18 measured to date have been below the 
lower limit of quantitation (LLOQ), and no local or systemic safety issues have emerged. No 
systemic antibodies to sprifermin/FGF-18 have been detected, except in 3 subjects who already 
tested positive for binding antibodies at baseline. There may be a slightly higher incidence of 
AIRs in the target knee with dosages of 300 mcg sprifermin; however, the 300 mcg dosage will 
not be used in this trial. Considering all clinical and non-clinical experience, sprifermin can be 
regarded as having a favorable safety profile.
The risk-benefit relationship has been carefully considered in the planning of the trial. Based on 
the pre-clinical and clinical data available to date, the conduct of the trial is considered justifiable 
using the doses and dosage regimen of the Investigational Medicinal Product (IMP) as specified 
in this clinical trial protocol.
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4
Trial Objectives
The trial’s objectives are as follows.
Primary
! To evaluate structural changes in cartilage thickness in the total femorotibial joint of the target 
knee in terms of imaging by MRI
Secondary
! To evaluate different dose regimens of sprifermin
! To evaluate changes in symptoms of OA
! To evaluate changes in structure in terms of imaging by X-ray
! To evaluate other changes in cartilage morphology in terms of imaging by MRI (sub-regions)
! To evaluate changes in physical functioning
! To evaluate the safety of sprifermin
! To evaluate the PK of sprifermin in serum and in synovial fluid following i.a. injection
Exploratory
! To evaluate responder criteria in symptoms
! To explore treatment effect on OA pain and other patient-reported outcomes (PROs)
! To evaluate changes in quality of life (QOL)
! To explore the treatment effect on the knee joint and bone structures by MRI
! To evaluate long-term treatment effects
! To explore the relationship between the change over time in synovial, serum and urine 
biomarkers (e.g., cartilage and bone tissue turnover markers, inflammation markers) and the 
response to the drug
! To evaluate potential associations of biomarkers (e.g., genetic variations or protein 
biomarkers measured at baseline) with drug response and/or disease severity or disease 
progression
! To explore the relationship between dosing (dose and regimen), cartilage structure, and 
clinical scores as a function of time, by means of modeling
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5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase II trial 
of sprifermin administered i.a. in subjects with primary OA of the knee and Kellgren-Lawrence 
grade 2 or 3.
The trial will randomize approximately 545 subjects (109 per treatment group); sample size 
calculations are described in Section 8.1.
The trial consists of a screening period lasting up to 42 days, a 2-year (104-week) double-blind 
placebo-controlled (DBPC) treatment phase, which will start at randomization (Week 0/Visit 2), 
and a 3-year extended follow-up phase (see Figure 1 and Figure 2).
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Figure 1
Trial Schema: Screening and DBPC Treatment Phases
W104
W0
Cycle
1
W52
Cycle
3
Cycle
2
W26
W12
W38
W64
W90
Cycle
4
W78
4 cycles sprifermin (100 mcg/injection)
2 cycles sprifermin (100 mcg/injection) alternating with 2 cycles Placebo
4 cycles sprifermin (30 mcg/injection)
2 cycles sprifermin (30 mcg/injection) alternating with 2 cycles Placebo
4 Cycles Placebo
Screening 
Period
(up to 6 weeks)
Extended
Follow-up
Phase
If eligible,
randomize
(equal allocation)
Double-Blind Placebo-Controlled Treatment Phase
(2 years)
Major efficacy assessment: MRI, X-ray, WOMAC, PGA, KOOS QOL, KOOS
Symptom Index, PGIC, NRS pain score, MOS SF-36, pain in other joints, ICOAP, 
20-meter walk test.
Minor efficacy assessment:  WOMAC, PGA, KOOS QOL, KOOS Symptom Index, 
PGIC, NRS pain score, ICOAP, 20-meter walk test.
Primary endpoint  assessment.
Safety will be assessed at all visits.
Abbreviations: W: Week; MRI: magnetic resonance imaging; WOMAC: Western Ontario and McMaster Universities 
Osteoarthritis Index; PGA: Patient’s Global Assessment; KOOS QOL: Knee Injury and Osteoarthritis Outcome Score 
quality of life subscale; KOOS Symptom Index: Knee Injury and Osteoarthritis Outcome Score symptom index 
subscale; PGIC: Patient’s Global Impression of Change; NRS pain score: numerical rating scale pain score; MOS
SF-36: Medical Outcomes Study Short Form-36 General Health Survey; ICOAP: Measure of Intermittent and 
Constant Osteoarthritis Pain.
Each treatment cycle consists of one i.a. injection per week for 3 consecutive weeks.
DBPC treatment phase visits will occur at Weeks 0 (randomization and first IMP injection), 1, 2, 3, 12, 26, 27, 28, 29, 
38, 52, 53, 54, 55, 64, 78, 79, 80, 81, 90, and 104.
Pain medications must be withheld for at least 5 half-lives before a visit involving completion of the WOMAC.
Adverse events, concomitant medications, and concomitant procedures (including concomitant surgical procedures 
on the target knee) will be monitored throughout the trial. Time points for safety, laboratory, PK, and biomarker 
assessments are shown in Appendix E.
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Figure 2
Trial Schema: Extended Follow-up Phase
EF2
(W156;
Year 1)
EF4
(W208;
Year 2)
EF6
(W260;
Year 3)
EF1
(W130)
EF3
(W182)
EF5
(W234)
W104
2-Year 
DBPC
Treatment
Phase
All Subjects Who Complete DBPC Treatment Phase Visits
Extended Follow-up Phase (3 years)
MRI, X-ray, WOMAC, PGA, KOOS QOL, KOOS Symptom Index, PGIC, NRS pain score, 
pain in other joints, MOS SF-36, ICOAP, 20-meter walk test
WOMAC, PGA, KOOS QOL, KOOS Symptom Index, PGIC, NRS pain score, pain in other
joints, MOS SF-36, ICOAP, 20-meter walk test.
Safety will be assessed at all visits.
Abbreviations: W: Week; EF: Extended Follow-up; WOMAC: Western Ontario and McMaster Universities 
Osteoarthritis Index; PGA: Patient’s Global Assessment; KOOS QOL: Knee Injury and Osteoarthritis Outcome Score 
quality of life subscale; KOOS Symptom Index: Knee Injury and Osteoarthritis Outcome Score symptom index 
subscale; PGIC: Patient’s Global Impression of Change; NRS pain score: numerical rating scale pain score; MOS 
SF-36: Medical Outcomes Study Short Form-36 General Health Survey; ICOAP: Measure of Intermittent and 
Constant Osteoarthritis Pain; MRI: magnetic resonance imaging.
Pain medications must be withheld for at least 5 half-lives before a visit involving completion of the WOMAC.
Adverse events, concomitant medications, and concomitant procedures (including concomitant surgical procedures 
on the target knee) will be monitored throughout the trial. Safety assessments during the extended follow-up phase 
are shown in Appendix E.
Screening Period
The screening period will comprise a period of 4 to 42 days during which a subject’s eligibility 
for the trial will be determined, beginning at signature of the informed consent form (ICF)
(Visit 1a).  Subjects who have taken analgesia within 5 half-lives of the visit will be scheduled to 
return for complete screening procedures (Visit 1b) after a washout of all analgesic medications.  
Subjects not taking analgesic medication at the time of ICF signature may complete Visit 1a and 
1b procedures at one visit. Screening will include completion of Question 1 of the WOMAC pain 
index and pain on an 11-point pain numerical rating scale (NRS) in both the target and 
contralateral knee. Subjects who have a WOMAC Question 1 score in the target knee of 4 to 9
after a predefined analgesic washout period equivalent to at least 5 half-lives of the analgesic 
medication(s) will continue with other screening procedures. During the screening period, 
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demographic and medical history data will be collected and subjects will undergo physical 
examination including height and weight and safety laboratory assessment (hematology, 
biochemistry, and urinalysis). X-rays will be taken of both knees, and the target knee will be 
identified.
If subjects fulfill all inclusion and no exclusion criteria (see Sections 5.3.1, 5.3.2, and 5.4), they 
will be randomized into the trial.
DBPC Treatment Phase
In the DBPC treatment phase, all subjects will receive 4 cycles of treatment with the IMP 
(sprifermin or matching placebo) at intervals of 6 months. Each cycle will consist of 3 once-
weekly i.a. injections over a period of 3 consecutive weeks.
The DBPC treatment phase will begin at the baseline visit (Week 0/Visit 2), when eligibility will 
be confirmed, subjects will be randomized, and the first IMP injection will be administered.
Subjects will be randomized in equal allocation to one of the following treatment groups, as 
shown in Figure 1 (randomization is described in Section 6.3).
! 4 cycles of sprifermin (100 mcg per injection)
! 2 cycles of sprifermin (100 mcg per injection) alternating with 2 cycles of placebo
! 4 cycles of sprifermin (30 mcg per injection)
! 2 cycles of sprifermin (30 mcg per injection) alternating with 2 cycles of placebo
! 4 cycles of placebo
The last of the four cycles of 3 injections of IMP will be given on Week 78/Visit 17, and the last 
dose of IMP is scheduled to be administered at Week 80/Visit 19. IMP administration for each 
treatment group is summarized in Table 1, Section 6.2.
Major efficacy assessments will take place at intervals of 6 months, on the first day of each 
treatment cycle and at the end of the DBPC treatment phase (Week 104/Visit 22).
Minor efficacy assessments will also take place at intervals of 6 months, occurring 9 weeks after 
the end of each treatment cycle.
Details of DBPC treatment phase visits are presented in Section 7.1.3.
Efficacy assessments will include MRI and X-ray of the target knee, the WOMAC, the 20-meter 
walk test, and the Patient’s Global Assessment of disease impact (PGA). The Knee Injury and 
Osteoarthritis Outcome Score QOL subscale (KOOS QOL) and the Medical Outcomes Study 
Short Form-36 General Health Survey (MOS SF-36) will be assessed for exploratory analysis of 
treatment effect on health-related QOL. The NRS will be used to explore treatment effect on 
worst pain in the past 24 hours in the target knee. The Measure of Intermittent and Constant 
Osteoarthritis Pain (ICOAP) and the KOOS Symptom Index questionnaires will be used to 
explore treatment effect on OA-related symptomatology in the target knee. The NRS pain scale 
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for the contralateral knee and a scale model of the human body (homunculus) identifying 
potentially painful joints will be used to assess pain in non-target joints and the progression of 
OA. The Patient Global Impression of Change (PGIC) will be used to measure the subject’s 
assessment of the clinical importance of their improvement or worsening over the course of the 
trial.
At specified visits, blood samples will be collected for measurement of serum sprifermin/FGF-18 
levels and biomarkers, and urine will be collected for measurement of biomarkers (see Section 
7.6). These biomarker specimens will be collected after an 8-hour fast. At visits where IMP is 
injected, samples of synovial fluid will be collected for PK and biomarker assessment as part of 
the i.a. injection procedure, using the same needle that will be used for IMP injection.
Exploratory PGt analyses will be performed for subjects who provide separate informed consent.
AEs and concomitant medications and procedures will be monitored throughout the trial, and 
vital signs will be measured at each trial visit. Safety assessments will also include 12-lead 
electrocardiograms (ECGs), physical examination, weight measurements, safety laboratory 
analyses (hematology, biochemistry, and urinalysis), and testing for antibodies to 
sprifermin/FGF-18. Height will be measured at screening and at the end of the DBPC and
extended follow-up phases. Data regarding any surgical procedures on the target knee will also 
be collected.
Subjects will use trial diaries to record information about AEs, concomitant medications, and 
local tolerability between trial visits. Diary information about maximum levels of target knee 
pain and presence or absence of target knee swelling will be used to identify potential acute 
inflammatory reactions (AIRs) to the IMP (see below).
Extended Follow-Up Phase
Subjects who complete the DBPC treatment phase visits will be followed for a further 3 years, 
during which trial assessments will take place at 6-month intervals.
Safety assessments will be performed and the WOMAC, NRS pain in the target and contralateral 
knee, KOOS QOL, KOOS Symptom Index, MOS SF-36, PGA, PGIC, identification of pain in 
other joints, ICOAP, and 20-meter walk test will be assessed at each visit during the follow-up 
phase. MRI and X-ray will be performed at yearly intervals.
Trial Endpoints
The primary endpoint of this trial is change from baseline in cartilage thickness in the total 
femorotibial joint as evaluated by MRI at 2 years.
Secondary endpoints are:
! Changes from baseline in the WOMAC total score and in the WOMAC pain, function, and 
stiffness index scores over 2 years
! Change from baseline in the 20-meter walk test over 2 years
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! Change from baseline in the PGA over 2 years
! Change from baseline in minimal joint space width (JSW) in the medial and lateral 
compartments as evaluated by X-ray over 2 years
! Change from baseline in cartilage thickness in the medial and lateral compartments as well as 
in the total femorotibial joint over 2 years
! Change from baseline in cartilage volume in the medial and lateral compartments as well as in 
the total femorotibial joint over 2 years
! Synovial fluid levels of sprifermin/FGF-18 
! Serum levels of sprifermin/FGF-18 
Safety endpoints are:
! Nature, incidence and severity of local and systemic AEs
! Incidence of acute inflammatory reactions (AIRs), defined as increase of pain by 30 mm on a 
100 mm VAS and a self-reported synovial fluid effusion (i.e., joint swelling) within 3 days 
following i.a. injection (see Section 7.4.1.1)
! Changes in laboratory safety parameters, vital signs, 12-lead ECG parameters, weight, and 
physical examinations
! Incidence of surgical interventions in the target knee (including any surgical revision, 
cartilage removal, or any other type of surgical intervention)
! Occurrence of binding and neutralizing antibodies to sprifermin/FGF-18
Exploratory endpoints are:
! Outcome Measures in Rheumatology – Osteoarthritis Research Society International 
(OMERACT-OARSI) responder rate (1) at 2 years
! PGIC over 2 years
! Changes from baseline in the scores of the KOOS QOL and the MOS SF-36 questionnaire 
over 2 years
! Change from baseline in KOOS Symptom Index over 2 years
! Change from baseline in NRS pain score in the target and contralateral knee over 2 years 
using an 11-point NRS
! Change from baseline in presence of pain in other joints over 2 years
! Change from baseline in ICOAP scores over 2 years
! Change over time in structural as well as compositional parameters of the knee joint (e.g., 
e.g., synovium, menisci, bone, and other structures) as evaluated by MRI
! Change from baseline in serum, urine, and synovial markers associated with administration of 
the compound
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! Baseline protein markers and/or genetic markers associated with response to treatment or 
disease progression (response assessed by MRI and/or questionnaire)
! Changes in MRI outcomes, WOMAC scores, 20-meter walk test, PGA, PGIC, JSW, 
OMERACT-OARSI responder rate, KOOS QOL, KOOS Symptom Index, MOS SF-36, NRS
pain score in the target and contralateral knee, presence of pain in other joints, ICOAP, safety 
laboratory values, and vital signs over the extended follow-up period and nature, incidence 
and severity of local and systemic AEs during the extended follow-up period (to be 
summarized descriptively)
! Relationship between dosing (dose and regimen), cartilage structure, and clinical scores as a 
function of time
Details of trial endpoints and their analysis are presented in Section 8.
Interim Analysis and Data Monitoring
No interim analysis is planned.
An IDMC will be constituted and will perform periodic reviews to evaluate the safety of the 
subjects participating in the trial on an ongoing basis. Detailed description of the safety 
monitoring will be specified in a dedicated IDMC charter.
Planned Duration of the Trial
It is estimated that the subject recruitment period for this trial will be up to one year.
It is anticipated that the first subject’s first visit will take place in Aug 2013 and that the last 
subject’s last visit (extended follow-up phase) will take place in August 2019.
It is planned to perform the statistical analysis in two steps, as described in Section 8.5.1: results 
from the DBPC treatment phase will be analyzed and reported at the end of this phase, and long-
term follow-up data will be analyzed and reported separately. MRI readers, Investigators, and 
subjects will remain blinded during the extended follow-up phase.
5.2
Discussion of Trial Design
Overall Trial Design
The trial will consist of a screening period, a 2-year DBPC treatment phase, and a 3-year 
extended follow-up phase.
A screening period of up to 42 days is considered appropriate for assessment of subject 
eligibility. The screening period will include an assessment of pain levels at screening and 
baseline prior to randomization. The subject must have a pain score in the target knee of 4 to 9 in 
response to Question 1 of the WOMAC after a predefined washout period that will be equivalent 
to at least 5 half-lives of analgesic medication(s) to be eligible for the study (see Section 5.4).
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The duration of the DBPC treatment phase of the trial will be set at 2 years in order to permit 
assessment of potential symptomatic and structural benefit. Results of the POC trial suggested 
that a period longer than 1 year would be necessary to observe treatment benefit on symptoms 
relative to placebo resulting from the demonstrated anabolic effect on structure.
The extended follow-up phase is intended to permit evaluation of the durability of the effects of 
sprifermin.
Sprifermin may be the first drug used in OA to have a disease-modifying action. In the absence 
of an active comparator, placebo will be used as a control.
A considerable placebo effect on symptoms in OA trials (with an effect size of 0.5 and a duration 
of 1 year) has been described in the literature (16), and was observed in the POC trial. In this 
trial, use of pain medication will be controlled to permit greater consistency of pain and function 
evaluations and eliminate the confounding effects of concomitant analgesia: subjects will need to 
refrain from taking analgesics, anti-inflammatory medications, or corticosteroids for ≥ 5 half-
lives before a visit involving completion of the WOMAC. This requirement and the withdrawal 
of analgesic medication for 5 half-lives prior to pain assessments is a common practice in clinical 
trials in OA (17).
Subject Population
This trial will include symptomatic subjects who have sufficient residual cartilage to respond to 
sprifermin, and will include better control for external factors such as malalignment than the 
POC trial. The aim is to select a knee OA population where an improvement in structure may 
ultimately translate into improvements in symptoms and quality of life.
In the POC trial (Study 28980), an anabolic effect of sprifermin was demonstrated in subjects 
with Kellgren-Lawrence grades (KLG) of 2 or 3, confirming the appropriateness of Kellgren-
Lawrence grades as a selection criterion.
However, in the POC trial, no minimal JSW was specified. The average JSW in the POC trial 
was approximately 3.5 mm and the minimum JSW was 0.2 mm. The requirement of JSW of at 
least 2.5 mm in the medial compartment in this trial will lead to the inclusion of patients with 
sufficient remaining interbone distance (i.e., a higher average JSW) that will thus permit 
demonstration of either progression (worsening) or improvement during the trial.
Malalignment will be limited to 5 degrees in order to limit confounding factors regarding 
biomechanical loading.
Women of childbearing potential will be allowed to participate in the trial, provided they adhere 
to the use of a highly effective method of contraception.
Dose and Dose Regimen
The aim of this trial is to optimize the dose and the dosing interval for sprifermin and to find a 
balance between effects on symptoms and structure.
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OA is a chronic disease, and therefore treatment will most likely need to be repeated at regular 
intervals.
The use of repeated cycles of 3 once-weekly injections over 3 consecutive weeks is based on 
preclinical data generated in the dog meniscectomy model (see the sprifermin IB), which 
suggested that anabolic effects on cartilage tissue were more pronounced when a given dose of 
sprifermin was administered as three i.a. injections than when it was administered as a single 
injection.
In this trial, 2 dosage strengths of sprifermin (30 and 100 mcg) and 2 regimens (4 treatment 
cycles given at 6-month intervals and 2 treatment cycles given at a 12-month interval) will be 
used in this trial. Each regimen of sprifermin will be compared with placebo.
The 10 mcg dosage of sprifermin used in the POC trial will not be used in this trial: despite 
observation of some biological effect, there was limited effect on MRI or clinical outcomes with 
this dose. Furthermore, results from the POC trial suggested that an interval of 3 months between 
cycles may have been too short.
Trial Assessments
Evaluation of Structure by MRI and Choice of MRI as Primary Endpoint
Conventional radiography can visualize dense structures such as cortical and trabecular bone; 
however, other components of the human knee such as cartilage, menisci, ligaments, synovium, 
synovial fluid, and pathological alterations of bony structures such as cysts and edema can only 
be visualized with MRI (18). In recent years, MRI has been shown to have high inter-observer 
agreement among trained radiologists and to have a high internal validity in the assessment of 
OA through its ability to define soft-tissue structures with high precision. Thus, a comparison of 
MRI scans with conventional X-rays revealed that joint space narrowing was more due to loss of 
meniscal structure than loss of hyaline cartilage structure (19).
Change from baseline in cartilage thickness in the total femorotibial joint at 2 years as evaluated 
by MRI has been chosen as primary endpoint for this trial because this parameter is thought to be 
most appropriate for demonstrating reversal of the degeneration of cartilage tissue.
Change in total cartilage volume may be less sensitive than change in thickness, as it may not 
reflect growth of cartilage in regions of the knee that have importance in mechanical loading.
Because sprifermin has been shown to exert a structure-modifying effect, it appears imperative to 
use MRI data (specifically change in thickness) to either confirm or disprove this effect on 
cartilage structure.
Evaluation of Symptoms
The WOMAC is a validated instrument used to assess symptom modification in clinical OA 
trials. This clinical score was developed in 1981 and is regarded as a valid instrument by both
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clinical researchers and regulatory authorities (20). The WOMAC questionnaire is further 
described in Section 7.3.2.
Considering that sprifermin has been shown to exert an anabolic effect on cartilage matrix, i.e., 
that it has a structure-modifying effect, it is expected that if it also has a symptom-modifying 
effect, this will become more evident in terms of the functional aspect of the WOMAC compared 
to those addressing pain and stiffness.
The 20-meter walk test will be used to provide an objective evaluation of the subject’s physical 
functioning, to complement the results of the (subject-assessed) WOMAC function index score. 
This test consists of measuring the time needed for the subject to walk 20 meters at a normal 
pace.
In addition to the WOMAC, multiple questionnaires will be used to explore the treatment effect 
on the symptoms associated with OA. The Symptom Index subscale of the KOOS, a knee-
specific questionnaire described in Section 7.7.1, will be used to assess symptoms associated 
with tibiofemoral cartilage loss. Pain, a major component of OA, will additionally be assessed 
using an 11-point NRS, evaluating the worst knee pain in the past 24 hours (Section 7.7.5). In 
addition, the ICOAP questionnaire will be used to explore the effect of treatment on intermittent 
and continuous OA pain (Section 7.7.3). Both of these assessments will complement the 
WOMAC pain index score.
Pain in other joints may be a confounding variable in the assessment of self-reported activities of 
daily living (WOMAC ADL), performance on the 20-meter walk test, and overall health-related 
quality of life (MOS SF-36). Pain in other joints may also serve as indicator of overall OA 
progression. Pain in the non-target knee will be assessed using the same 11-point NRS used in 
the target knee. In addition, pain in joints other than the knees will be identified using a scale 
model of the human body (homunculus; Section 7.7.6).
The PGA and PGIC will be used to capture the subject’s global impression of their target knee 
pain and measure global improvement with treatment relative to baseline symptoms. As 
described in Sections 7.7.3 and 7.7.4, these are responsive and readily interpretable measures of 
participant's assessments of the clinical importance of their improvement or worsening over the 
course of the clinical trial.
Evaluation of JSW by X-ray
Change in joint space narrowing will be visualized with the “fixed flexion” knee radiograph 
protocol ((21); see Section 7.3.4).
Among rheumatologists, determination of joint space narrowing by X-ray is considered to be a 
semi-quantitative method for assessment of progression of knee OA. This outcome is recognized 
as valid by regulatory authorities in Europe and the USA (20),(22).
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Evaluation of Safety
AE monitoring, safety laboratory measurements, measurement of vital signs, weight, physical 
examinations, ECGs, incidence of surgery, and, in case of a non-systemic drug, assessment of 
local tolerability are standard measures to evaluate the safety profile of an investigational 
product. Safety endpoints to be assessed in this trial are consistent with those used in previous 
studies with sprifermin.
One of the trial’s safety endpoints is the incidence of acute inflammatory reactions (AIRs), 
defined as increase of pain by 30 mm on a 100 mm VAS and a self-reported synovial fluid 
effusion (i.e., joint swelling) within 3 days following i.a. injection. A similar definition based on 
a 30-mm increase in pain on VAS and observation of local swelling was used successfully in a 
trial in rheumatoid arthritis involving i.a. injections of interleukin-1 receptor antagonist (IL-1ra; 
anakinra (23)).
The extension phase of the trial will allow exploration of the drug’s long-term safety.
Biomarker Assessment
Assessment of biomarkers of bone and joint tissue turnover is expected to identify candidate 
markers potentially predictive of response to treatment, prognostic for disease progression, or 
associated with response to the compound (see Section 7.6.1.).
Pharmacokinetic Assessment
The levels of sprifermin/FGF-18 in serum will be assessed 2 hours after the last dose of each 
cycle and will give an indication of whether sprifermin reaches the systemic circulation. Based 
on previous trials, systemic levels of sprifermin/FGF-18 are expected to be below the LLOQ.
Levels of sprifermin/FGF-18 in synovial fluid will be measured in order to give a first estimate 
of the residence time of sprifermin in the synovial fluid.
Evaluation of Health-related Quality of Life
The KOOS (see Section 7.7.1) is a knee-specific questionnaire designed to evaluate both short-
term and long-term consequences of knee injury, including OA; it is intended for use in knee 
injury potentially leading to post-traumatic OA or in primary OA. The KOOS QOL subscale is 
more specific to QOL in subjects with knee OA than the more general MOS SF-36 (see below), 
and may better predict future need for knee replacement.
The MOS SF-36 (see Section 7.7.2) is a generic patient-reported health-related QOL instrument 
that is widely used in different diseases and conditions (including OA). MOS SF-36 results from
this trial will be used to determine whether the MOS SF-36 is sensitive enough to measure 
changes in QOL in the trial population.
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5.2.1
Inclusion of Special Populations
The trial population will consist of adults aged between 40 and 85 years. The inclusion of elderly 
subjects is considered justified because this is the group most frequently affected by OA.
5.3
Selection of Trial Population
The trial will randomize approximately 545 subjects, in about 10 to 15 centers located in Europe, 
the United States of America, and possibly other geographical regions.
5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. Written informed consent given prior to any trial-related activity: subjects must understand 
and sign the appropriate approved Informed Consent Form(s) – one for the trial (mandatory) 
and one for the pharmacogenetic evaluation (optional)
2. Investigator judgment that the subject is able to comply with trial procedures and 
assessments
3. Primary femorotibial OA according to American College of Rheumatology (ACR) clinical 
and radiographic criteria (see Appendix A)
4. Radiological grade of 2 or 3 according to Kellgren-Lawrence and a minimum joint space 
width (JSW) of ≥2.5 mm in the medial compartment in the target knee, obtained during 
screening.  
Note: X-rays conducted up to 6 months prior to screening are acceptable, provided they were 
performed according to the specifications in the MOP and the quality is acceptable to allow 
confirmation of the entry criteria when read centrally.
5. Age from 40 to 85 years; of either sex
6. A history of pain due to OA in the target knee for at least 6 months
7. Pain in the target knee and/or the need for regular symptomatic treatment of knee pain with 
paracetamol (acetaminophen), systemic non-steroidal anti-inflammatory drugs (NSAIDs) 
including COX-2 selective inhibitors (coxibs), or tramadol on most days in the  previous 
month (i.e., more than half of the days in the previous month)
8. Pain score for the target knee of 4 to 9 points in response to Question 1 of the WOMAC pain 
index (“how much pain have you had [in the target knee, over the past 48 hours] when 
walking on a flat surface?”) after washout of at least 5-half-lives of analgesic medication(s): 
acetaminophen, topical or oral NSAIDS, coxibs, opioids, and/or tramadol. The pain score 
must qualify at screening (Visit 1a for subjects not receiving analgesic medication at the time 
of screening and Visit 1b for subjects requiring a washout of analgesic medications) and 
baseline (Visit 2). 
9. Women of childbearing potential (defined as any female subjects after puberty, unless 
postmenopausal for at least two years or surgically sterile) must use methods of 
contraception with a failure rate less than 1% per year when used consistently and correctly, 
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such as implants, injectables, combined oral contraceptives, some intrauterine devices 
(IUDs), sexual abstinence, vasectomized partners, or a double barrier method (use of both a 
condom and a diaphragm or cervical/vault cap) with spermicide. Contraceptive use must be 
continued throughout the throughout the trial (i.e., until the final extended follow-up visit).
5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. Malalignment of > 5 degrees in the femorotibial axis of the target knee as assessed by the X-
ray with a long-axis view that will be performed during screening
2. Intra-articular administration of corticosteroids or hyaluronic acid into either knee within 6 
months, or arthroscopy to the target knee within the past year before the start of screening
3. Planned knee surgery (affecting either the target or the contralateral knee) within the next 
two years
4. Clinical signs of inflammation (i.e., redness) in the target knee
5. Concomitant treatment with any parenteral or oral corticosteroids at study entry
6. Concomitant treatment with parenteral, oral, or topical opioids at study entry, with the 
exception of oral tramadol
7. Concomitant treatment with a parenteral or
oral anticoagulant including
heparin,
coumadin/warfarin or their derivatives, or any other anticoagulant.
8. History of sarcoma or other malignancy within the past five years, except adequately treated 
basal cell or squamous cell carcinoma of the skin, or resected cervical atypia or carcinoma in 
situ.
9. Secondary OA such as joint dysplasia, aseptic osteonecrosis, acromegaly, Paget disease,
Ehlers-Danlos
syndrome, 
Stickler 
syndrome, 
joint 
infection
(septic 
arthritis), 
hemochromatosis, gout, chondrocalcinosis (pseudogout), or calcium pyrophosphate 
deposition disease.
(Exception: subjects who have undergone meniscal resection may be enrolled.)
10. Plan to relocate from the region
11. Previous participation as a subject in another trial of sprifermin
12. Any contraindication to MRI according to MRI guidelines, including the inability to undergo 
a knee MRI exam because of inability to fit in the scanner or knee coil
13. Significant co-morbidity that would interfere with trial participation
14. Any known active infection, including suspicion of intra-articular infection or infection that 
might compromise the immune system such as human immunodeficiency virus (HIV) or 
hepatitis B or C
15. Abnormal laboratory results including:
! Hemoglobin < 11.5 g/dL (female) or < 13.2 g/dL (male)
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! White blood cell (WBC) count < 3500 cells/mm3 and >20000 cells/mm3
! Platelet count or coagulation tests (prothrombin time, partial thromboplastin time, 
International Normalized Ratio) outside the central laboratory’s normal range
! Creatinine clearance rate < 30 mL/min estimated using the Cockroft-Gault formula 
! Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline 
phosphatase (ALP) > 2.5 times ULN, or total bilirubin > 1.5 x ULN. In cases of 
documented Gilbert syndrome, subjects with elevated bilirubin levels will be permitted to 
enroll in the study if other liver function tests are within the specified limits.
! Any other abnormal laboratory results that the Investigator believes should preclude the 
subject’s participation in the trial
16. Pregnancy or breastfeeding
17. Participation in another clinical trial within the 30 days (or 5 half-lives of the investigated 
compound, whichever is longer) before screening
18. Known hypersensitivity to the trial treatment (including placebo) or diluent
19. Legal incapacity or limited legal capacity
5.4
Criteria for Randomization
Subject’s pain level will be assessed during the screening, and eligibility will be confirmed at 
baseline.
! As an essential part of the eligibility determination process, subjects will be asked to complete 
Question 1 of the WOMAC pain index (“How much pain have you had [in the target knee, 
over the past 48 hours] when walking on a flat surface?”; see Appendix C).
The WOMAC questions that determine eligibility must be obtained after the patient has 
provided informed consent and, if taking pain medications, has withheld them, as described 
below.
! Subjects who are taking pain medications and who are potentially eligible for the trial will be 
asked to withhold all pain medications including paracetamol (acetaminophen), NSAIDs 
including coxibs, opioids, and tramadol for at least 5 half-lives of the given medication before 
the screening (Visit 1b) and baseline (Visit 2) WOMAC assessments.
Aspirin (acetylsalicylic acid) used for cardiovascular protection does not need to be withheld, 
nor do antidepressants used for management of OA pain and depression.
Subjects must have a score of 4 to 9 points for Question 1 of the WOMAC pain index at the 
time of screening (after washout of analgesic medications).
! To be eligible for randomization subjects must again respond with a score of 4 to 9 in 
response to Question 1 on the WOMAC at the time of the baseline visit - after washout of 
pain medications for a period of at least 5 half-lives.
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Subjects who satisfy all eligibility criteria and who are willing to continue in the trial will be 
randomized as described in Section 6.3. Randomization and administration of the first IMP 
injection will take place on the same day as the baseline MRI scan (see Section 7.1.3.1).
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from the Trial
Subjects are free to discontinue the trial at any time without giving their reasons.
The Investigator may withdraw a subject at any time if this is considered to be in the subject’s 
best interest.
A subject must be withdrawn in the event of any of the following:
! Withdrawal of the subject’s consent
! Subject’s participation in another trial
If a subject fails to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
In case of premature withdrawal from the trial, the procedures scheduled for Week 104/Visit 22 
should be performed at the time of withdrawal whenever possible, with focus on the most 
relevant assessments. In any case, the appropriate Case Report Form section must be completed.
Subjects who withdraw from the trial will not be replaced.
5.5.2
Withdrawal from the Investigational Medicinal Product
Treatment with the IMP must be discontinued in the event of any of the following:
! Occurrence of an exclusion criterion which is clinically relevant and affects the subject’s 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor
! Occurrence of AEs, if discontinuation of trial drug is desired or considered necessary by the 
Investigator and/or the subject
! Occurrence of pregnancy (see Section 7.4.2 for reporting of pregnancies and follow-up of 
subjects who become pregnant during the trial)
! Use of a non-permitted concomitant medication, as defined in Section 6.5.2, where the 
predefined consequence is withdrawal from the IMP
! Substantial non-compliance or protocol violation
Subjects who discontinue IMP treatment prematurely will be followed up as described in Section 
7.1.5.
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5.6
Premature Discontinuation of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
! Recommendation by the trial’s IDMC.
! New information leading to unfavorable risk-benefit judgment of the IMP, e.g., due to:
! Evidence of lack of efficacy of the IMP,
! Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions, or
! Other unfavorable safety findings.
! Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons.
! Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely.
! Discontinuation of development of the Sponsor’s IMP.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) will be informed about the discontinuation of the trial in accordance with applicable 
regulations.
The whole trial may be terminated or suspended at the request of Health Authorities.
5.7
Definition of End of Trial
For administrative and safety reporting purposes, the end of the trial will be defined as the date 
of the final clinical database lock at the end of the extended follow-up phase. This provides for a 
single and conservative definition across all trial sites.
6
Investigational Medicinal Products and Other Drugs Used in 
the Trial
The term “Investigational Medicinal Product” (IMP) refers to both the investigational drug 
undergoing trial (sprifermin) and the placebo.
6.1
Description of Investigational Medicinal Products
Clinical trial materials are manufactured in accordance with Good Manufacturing Practice 
(GMP). All clinical trial materials will be supplied with Certificates of Analysis and/or Release 
Statements. Trial drugs will be identified by trial code, kit number, and Sponsor name.
IMP packaging and labeling are described in Section 6.6; IMP preparation, handling, and storage 
are described in Section 6.7 and in the MOP.
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6.1.1
Sprifermin
Sprifermin is a truncated, non-glycosylated form of FGF-18, containing 170 amino acids.
Two strengths of sprifermin will be supplied in this trial: 30 mcg and 100 mcg.
Sprifermin will be supplied as a white, sterile, freeze-dried powder in 3-mL glass vials, sealed 
with rubber stoppers, flip-off caps and aluminum rings. Each vial will contain either 31.5 mcg or 
105 mcg of sprifermin active substance; these quantities will include a 5% overage, permitting 
extraction of respectively 30 mcg or 100 mcg of sprifermin active substance following 
reconstitution with 0.9% w/v Sodium Chloride Injection (referred to herein as “saline solution”). 
Excipients of the formulation are sodium phosphate buffer (pH 7.2), sodium hydroxide, O-
phosphoric acid, sucrose, and poloxamer 188.
For all treatment groups, the volume to be administered is 2 mL.
6.1.2
Placebo
Placebo will be supplied as a white, sterile, freeze-dried powder visually identical to the active 
product, and will be supplied in packaging identical to that for sprifermin. The excipients will be 
identical to those in the active product.
6.2
Dosage and Administration
In the DBPC treatment phase, all subjects will receive 4 cycles of treatment with the IMP 
(sprifermin or matching placebo) at intervals of 6 months. Each cycle will consist of 3 once-
weekly i.a. injections over a period of 3 consecutive weeks.
IMP administration for each treatment group is summarized in Table 1.
Table 1
Drug Administration Diagram
Cycle 1
W0, W1, W2
Cycle 2
W26, W27, W28
Cycle 3
W52, W53, W54
Cycle 4
W78, W79, W80
Dose per cycle
Total dose
Group 1
100 mcg
100 mcg
100 mcg
100 mcg
300 mcg
1200 mcg
Group 2
100 mcg
Placebo
100 mcg
Placebo
300 mcg/placebo
600 mcg
Group 3
30 mcg
30 mcg
30 mcg
30 mcg
90 mcg
360 mcg
Group 4
30 mcg
Placebo
30 mcg
Placebo
90 mcg/placebo
180 mcg
Group 5
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Each cycle consists of 3 once-weekly i.a. injections of the specified dose over 3 consecutive weeks.
The central randomization service’s interactive voice response system (IVRS) will be used to 
randomize subjects and to assign a blinded treatment kit at each treatment visit, as described in 
Section 6.3.
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Each treatment kit will include materials for a single injection.
All kits will include 1 glass vial of IMP (sprifermin or placebo) and 1 glass ampule of sterile 
saline solution for injection (2 mL per ampule) to be used for reconstitution (see Section 6.6).
Instructions for reconstitution are provided in the MOP. Once reconstituted, the IMP may remain 
in the syringe for up to 2 hours prior to administration.
The Investigator or a suitably qualified designee will administer the IMP. The exact time of IMP 
administration will be documented in the CRF.
I.a. administration of the IMP will be guided through the use of ultrasound to ensure delivery 
into the joint space. Detailed instructions for injection are provided in the MOP.
Before injecting the IMP solution, an aspiration of the synovial fluid for local PK and biomarker 
analysis will be performed as part of the i.a. injection procedure, using the same needle that will 
be used for IMP injection. If possible, up to 2.5 mL should be collected (instructions for sample 
handling are provided in the MOP).
The volume of IMP solution to be injected will be 2 mL. The needle for injection will be flushed 
with 0.5 mL saline to make sure the entire dose has been injected (thus, the total volume injected 
will be 2.5 mL).
At visits where samples are collected for PK analyses, subjects will be requested to stay in the 
study site for approximately 2 hours post-injection for collection of the post-dose samples.
6.3
Assignment to Treatment Groups
Eligible subjects will be randomized to one of the 5 treatment groups with an allocation ratio of 
1:1:1:1:1. Statistical aspects of randomization are described in Section 8.2.
The central randomization service’s IVRS will be used to randomize subjects to treatment. 
Immediately prior to dosing, the Investigator or delegate will follow randomization procedures 
as explained in the MOP. The allocated randomization number will only be used for dosing.
The IVRS will also be used to assign a blinded treatment kit at each subsequent treatment visit 
(see Section 7.1.3.2 and Appendix E).
6.4
Other Drugs to be used in the Trial
No other drugs will be provided in the context of this trial.
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6.5
Concomitant Medications and Therapies
6.5.1
Permitted Medicines
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary for the subjects’ welfare and will not interfere with the trial medication may be given 
at the Investigator’s discretion.
The Investigator will record all concomitant medications taken by the subject during the trial, 
from the date of signature of informed consent, in the appropriate section of the CRF.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant medication must be recorded in the corresponding section of the CRF, noting the 
name, dose, frequency of administration, duration, and indication of each medication.
During the screening period, all analgesic medication must be withheld for 5 half-lives before the 
screening (Visit 1b) and baseline WOMAC assessments. Aspirin (acetylsalicylic acid) used for 
cardiovascular protection does not need to be withheld, nor do antidepressants used for 
management of OA pain or depression.
Paracetamol (acetaminophen), NSAIDs including coxibs, and tramadol may be resumed 
following randomization and continued as needed during the trial, except during the brief 
analgesic withdrawal periods prior each study visit at which WOMAC data are obtained.
During the trial, paracetamol (acetaminophen) is recommended as rescue medication for the 
treatment of breakthrough pain. The dosage of acetaminophen or paracetamol that the subjects 
will be allowed to take per day will be defined according to the standard of care in the countries 
where the trial will be carried out; however, the maximum dose should not exceed 1 gram per 
dose 
and 
4 
grams/day. 
Low-dose 
narcotics 
or 
combination 
products 
such 
as 
paracetamol/acetaminophen and oxycodone (Percocet) may be used only as needed for more 
severe painful episodes. Duration of opioid use is limited to 14 days per episode. If the subject 
requires regular narcotic analgesia to control his/her arthritis pain, s/he should not be considered 
for the trial.
After the initial screening visit (Visit 1a), subjects will be requested to discontinue the intake of 
all pain medications, including NSAIDs, coxibs, narcotics, and paracetamol (acetaminophen) for 
at least 5 half-lives before a visit involving completion of the WOMAC, as described in Section
7.1.1. This is to ensure the most accurate assessment of pain and function, and is standard 
practice in OA trials. Aspirin (acetylsalicylic acid) used for cardiovascular protection does not 
need to be withheld, nor do antidepressants used for management of OA pain or depression.
Oral supplements such as glucosamine, diacerin, chondroitin sulfate may be used during the trial 
if they have been taken at a stable dose over at least 4 weeks prior to the first injection and are 
maintained at the same stable dose throughout the trial.
Women of childbearing potential must use a method of contraception with a failure rate less than 
1% per year (as defined in the trial inclusion criteria; see Section 5.3.1) throughout the trial (i.e., 
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until the final extended follow-up visit). In case of premature withdrawal from the trial, there is 
no specific requirement for contraceptive use after the last trial visit.
Local anesthetic (e.g., lidocaine) is permitted prior to the injection of IMP at the investigator’s 
discretion according to the local standard of care. Anesthetic should not be administered intra-
articularly at any time.
6.5.2
Non-permitted Medicines
Subjects who have received i.a. corticosteroids or i.a. hyaluronic acid within the 6 months before 
the beginning of screening will not be eligible for this trial, nor will subjects who are receiving 
concomitant treatment with oral corticosteroids or with a parenteral or oral anticoagulant, 
including heparin, coumadin/warfarin or their derivatives, or any other anticoagulant.
Subjects who have taken part in another clinical trial within the 30 days (or 5 half-lives of the 
investigated compound, whichever is longer) before the beginning of screening or in any 
previous trial of sprifermin will not be eligible.
Use of the following medications is not permitted at any time during the trial (i.e., from signature 
of the Informed Consent Form (ICF) until the final trial visit (end of extended follow-up phase or 
early termination):
! Intra-articular injection of corticosteroids or hyaluronic acid into either knee
! Long-term treatment (>14 days) with oral corticosteroids >5 mg/day 
Note: However, the use of oral corticosteroids, ≤5 mg/day oral prednisone (or equivalent) for 
an indication other than OA pain during the trial will be allowed. In addition, short term use 
of any tapering course of oral corticosteroids for ≤ 14 days will be allowed. If oral 
corticosteroids >5 mg/day are used during the trial, efficacy assessments (e.g., WOMAC) 
should not be scheduled until it has been at least 5-half lives since completing the medication
! Any parenteral or oral anticoagulant, including heparin, coumadin/warfarin, or their 
derivatives, or any other anticoagulant medications
! Any investigational agent
If the administration of a non-permitted concomitant medication becomes necessary during the 
trial, e.g., because of AEs, treatment with the IMP will be discontinued and the subject will be 
followed up as described in Section 7.1.5.
Subjects who receive any investigational treatment or participate in any other trial will be 
withdrawn from this trial.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant medications must be recorded in the corresponding section of the CRF, noting the 
name, dose, frequency of administration, duration, and indication of each medication.
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6.5.3
Other Trial Considerations
Other Permitted Therapies
Patient education and physical or occupational therapy (e.g., assisting device for walking, diet 
for weight loss, muscle-strengthening exercises) are allowed.
Other Non-Permitted Therapies
Interventional or diagnostic arthroscopy affecting the target knee is not permitted.
Use of electrotherapy (e.g., transcutaneous electrical stimulation) or acupuncture for OA 
affecting the target knee is not permitted.
If any of these procedures are used during the trial, treatment with the IMP will be discontinued 
and the subject will be followed up as described in Section 7.1.5.
6.5.4
Special Precautions
No special precautions are necessary beyond those applicable to i.a. administration in general.
6.6
Packaging and Labeling
IMP (sprifermin and placebo) will be provided in glass vials as described in Section 6.1.1.
Packaging and labeling will be identical for placebo and active medication to ensure the blinded 
nature of the trial, and will be in accordance with applicable local regulatory requirements and 
applicable GMP guidelines and with the storage requirements of the IMP.
Vials of IMP will come in kits as described in Section 6.2. All kits will contain 1 vial of IMP 
(sprifermin or placebo) and 1 ampule of sterile saline solution for reconstitution:
! Kits for 30 mcg treatments will contain 1 glass vial of sprifermin (30 mcg strength) and 1 
glass ampule of sterile saline solution for injection (2 mL per ampule)
! Kits for 100 mcg treatments will contain 1 glass vial of sprifermin (100 mcg strength) and 1 
glass ampule of sterile saline solution for injection (2 mL per ampule)
! Kits for placebo treatments will contain 1 glass vial of placebo and 1 glass ampule of sterile 
saline solution for injection (2 mL per ampule)
6.7
Preparation, Handling and Storage
Preparation and administration of the IMP are described in Section 6.2 and in the MOP.
Once reconstituted, the IMP may remain in the syringe for up to 2 hours prior to administration.
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The IMP must be stored at ambient temperature (< 25°C; do not freeze) in a locked dispensary, 
with a temperature log maintained daily. It will be transferred to the clinical unit when needed 
for administration to the subjects.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring accountability for IMP, including reconciliation of 
drugs and maintenance of drug records.
! Upon receipt of IMP, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the 
distribution center and returning it to the distribution center. A copy will be retained for the 
Investigator File.
! The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
forms provided by the Monitor and an accurate accounting will be available for verification 
by the Monitor at each monitoring visit.
! IMP accountability records will include:
! Confirmation of IMP delivery to the trial site.
! The inventory at the site of IMP provided by the distribution center and prepared at the 
site.
! Administration of each dose to each subject.
! The return to the distribution center or alternative disposition of unused IMP.
! Dates, quantities, batch numbers, expiry dates and (for IMP prepared at the site) 
formulation, as well as the subjects’ trial numbers.
! The Investigator should maintain records that adequately document:
! That the subjects were administered the doses specified by the clinical trial 
protocol/amendment(s), and
! That all IMP provided by the distribution center was fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. IMP that 
has been dispensed to a subject must not be re-dispensed to a different subject.
The Monitor will periodically collect the IMP accountability forms and will check all returns 
(both unused and used containers) before arranging for their return to the distribution center or 
authorizing their destruction by the trial site.
6.9
Assessment of Investigational Medicinal Product Compliance
The Investigator or a suitably qualified designee will administer the IMP. IMP administration 
must be recorded in the CRF.
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6.10
Method of Blinding
The Sponsor will supply active sprifermin and placebo in glass vials which will be visually 
identical. Packaging and labeling will be identical for placebo and active medication (see Section 
6.6).
At each trial visit at which IMP is administered, the central randomization service’s IVRS will be 
used to obtain a blinded treatment kit number corresponding to the subject’s randomized 
treatment (see Section 6.3). The subject will then be treated with the medication from that 
numbered kit.
All kits will include 1 glass vial of IMP (sprifermin or placebo) and 1 glass ampule of sterile 
saline solution for injection (2 mL per ampule) to be used for reconstitution (see Section 6.6). 
Reconstitution of IMP and preparation of injections will be identical for all treatments 
(sprifermin 100 mcg, sprifermin 30 mcg, and placebo).
6.11
Emergency Unblinding
The trial blind may be broken for an individual subject only in the case of an emergency when 
knowledge of the IMP is essential for the clinical management of the subject. The Investigator 
must make every effort to contact the Sponsor prior to breaking the trial blind.
If it is not possible to contact the Sponsor, the Investigator will be able to access the subject’s 
treatment assignment 24 hours a day through the IVRS system, using specific procedures defined 
in the MOP.
Contact information for breaking the blind in an emergency will also be provided on the subject 
emergency card handed out to each subject (see Section 9.4).
If the blind is broken, the Investigator must inform the Sponsor immediately without revealing to 
the Sponsor personnel the result of the code break. The Investigator must record in the subject’s 
CRF the date of unblinding and the reason for unblinding. Code breaks performed at a place 
other than the trial site will also be documented carefully.
If emergency unblinding is required, discontinuation of the affected subject from the trial is not 
mandatory unless there are other circumstances that require subject discontinuation.
6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in the clinical 
trial protocol (i.e., 100 mcg). Any overdose must be recorded in the trial medication section of 
the CRF.
For monitoring purposes, any case of overdose – whether or not associated with an AE (serious 
or non-serious) – must be reported to the Sponsor’s Global Drug Safety (GDS) department in an 
expedited manner using the appropriate reporting form (see Section 7.4.1.4).
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The effects of an overdose of sprifermin are unknown, and there is no known specific treatment 
in case of overdose. In the event of overdose, subjects should be closely monitored and managed 
according to the Investigator’s clinical judgment.
6.13
Medical Care of Subjects after End of Trial
Subjects who have completed the trial or have withdrawn early should be managed in accordance 
with the Investigator’s clinical judgment, as appropriate for each subject’s individual medical 
needs.
7
Trial Procedures and Assessments
Outlines of trial procedures and assessments are presented in Section 7.1. Procedures and 
assessments are described in more detail in Sections 7.2 (baseline characteristics), 7.3 (efficacy), 
7.4 (safety), 7.5 (PK), 7.6 (biomarkers), and 7.7 (assessment of health-related QOL and OA 
pain).
7.1
Schedule of Assessments
The trial will consist of a screening period, a DBPC treatment phase (which will begin with 
randomization and initiation of therapy at Week 0/Visit 2), and an extended follow-up phase (see 
Section 5.1, Figure 1, and Figure 2).
General instructions and procedures to be performed throughout the trial are described in Section
7.1.1, and outlines of the visits included in each of the trial phases are presented in Sections 7.1.2
(screening period), 7.1.3 (DBPC treatment phase), and 7.1.4 (extended follow-up phase).
The procedures to be performed at each trial visit are presented in the Schedule of Trial 
Procedures in Appendix E.
7.1.1
General Instructions
Informed Consent
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent according to the procedure described in Section 9.2.
Subjects who agree to take part in the optional PGt analysis will also need to sign a specific PGt 
ICF.
Assignment of a Subject Identifier
Once a subject has provided written informed consent for trial participation, a subject 
identification number will be assigned through the IVRS. Subjects will be referred to by their 
subject identification number throughout the trial.
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Subjects Who Fail Screening
The Investigator is required to maintain a subject screening log to identify the subjects who were 
screened.
In the CRFs, the minimum information to be recorded for subjects who fail screening is:
! Informed consent
! Demographics
! AEs
! Date and reason for screening failure
! Investigator signature
Adverse Events and Concomitant Medications
Information about AEs and about concomitant medications and procedures will be collected 
throughout the trial, beginning at the time of signature of the ICF (see Sections 7.4.1 and 6.5).
Allowable Time Frame for Trial Visits and Assessments
Study visits, beginning with Visit 3, should be planned for the study day specified in the 
protocol. Visits should always be scheduled from the date of the first injection (Week 0/Visit 2) 
while maintaining the minimum and maximum restrictions between injections and between 
injection cycles. If a visit cannot be completed within the study days specified in this section the 
sponsor should be contacted.
Allowable intervals between weekly IMP injections:
The interval between each injection within a treatment cycle should be 7 days. If it is not 
possible to complete the visit in exactly 7 days, or if an emergency occurs, the interval to the 
next injection should be no shorter than 6 days and no longer than 9 days (i.e., -1/+2 days). This 
interval allowance applies to Visits 3, 4, 8, 9, 13, 14, 18, and 19.
Allowable intervals between six month treatment cycles:
The interval between the last injection of a treatment cycle and the first injection of the 
subsequent treatment cycle is 24 weeks. If a visit cannot be done as planned, or if an emergency 
occurs, it can be rescheduled ±3 weeks from the planned day (i.e., between 21 and 27 weeks). 
Specifically:
! Visit 7 must be conducted within 21 to 27 weeks of the actual date of Visit 4, 
! Visit 12 must be conducted within 21 to 27 weeks of the actual date of Visit 9, and
! Visit 17 must be conducted within 21 to 27 weeks of the actual date of Visit 14
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Allowable intervals for other visits:
During the DBPC treatment phase, visits may take place within ±4 days of the planned day. This 
interval allowance applies to Visits 5, 6, 10, 11, 15, 16, 20, and 21. 
Extended follow-up visits may take place within ±21 days of the planned day. This interval 
allowance applies from Visit 22 (EF1) through Visit 28 (EF6).
Allowable intervals for X-rays and MRIs:
At time points where IMP administration is scheduled, X-rays and MRIs may be performed up to 
3 days before the IMP administration. 
During the DBPC phase, at time points where there is no IMP administration scheduled, X-rays 
and MRIs may be performed within ±4 days of the planned day.
During the extended follow up phase, at time points when there is no IMP administration 
scheduled, X-rays and MRIs may be performed within ± 7 days of the planned day.
Pain Medication Washout
Subjects will be requested to discontinue the intake of all pain medications for 5 half-lives before 
a visit involving completion of the WOMAC. At least 3 days before each such visit, subjects will 
be contacted by phone to remind them of this requirement.
Aspirin (acetylsalicylic acid) used for cardiovascular protection does not need to be withheld, nor 
do antidepressants used for management of OA pain or depression.
Subject Questionnaires
At visits involving completion of subject questionnaires (WOMAC, PGA, KOOS QOL, KOOS 
Symptom Index, PGIC, NRS pain score in the target and contralateral knee, MOS SF-36, pain in 
other joints, and ICOAP), these questionnaires must be completed before any other trial 
procedures are performed. The WOMAC should be completed first.
Subject Diaries
Subjects will receive diaries at each visit for recording of the following information:
! Any adverse reaction occurring between trial visits and any concomitant medications used, 
with particular attention to the use of NSAIDs, coxibs, and any other pain medications
! Maximum pain level (using a 100-mm VAS) and presence or absence of joint swelling, to be 
recorded once daily on the day before each IMP injection and on each of the 3 days following 
an IMP injection.
! Diaries given at the visit before the beginning of a treatment cycle (e.g., screening or 
Week 12/Visit 6) will collect pain and swelling information for the day before the next 
visit. Telephone contacts concerning the need to withhold pain medications before the next 
visit will include a reminder to complete this diary information.
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! Diaries given at visits where the first and second doses of a cycle are administered will 
collect pain and swelling information for the 3 days after the injection and for the day 
before the next visit.
! Diaries given at visits where the last dose of a cycle is administered will collect pain and 
swelling information for the 3 days after the injection.
! Diaries given at all other visits will collect adverse reactions and concomitant medications 
only.
Different diaries will be dispensed, depending on the data to be completed prior to the next visit.  
Completed diaries will be collected and reviewed at each visit, and information will be 
transcribed to the CRFs (following medical review in case of AE or concomitant medication 
information).
Pharmacogenetic Analysis
All subjects who are enrolled in the trial will be eligible to participate in an optional PGt analysis 
(except in countries where collection of PGt samples is not allowed; the analysis is described in 
Section 7.6.3). Participation is optional, and the subjects who choose to participate will need to 
sign a specific PGt ICF (see Section 9.2).
For consenting subjects, a single blood sample will be collected for PGt analysis. This sample 
can be obtained at any trial visit, preferably at baseline.
7.1.2
Screening Period (Visits 1a and 1b)
The screening period will comprise a period of 4 to 42 days before the baseline visit, beginning 
at signature of the ICF, during which a subject’s eligibility for the trial will be determined.
Eligibility will be confirmed at the baseline visit (Week 0/Visit 2) as described in Section 5.4.
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent according to the procedure described in Section 9.2.
Visit 1a
The following procedures will be performed during the subject’s first screening visit.
! Informed consent for trial
! Informed consent for optional PGt analysis
! WOMAC (Question 1 of the WOMAC pain index only; see Section 5.4 and Appendix C): this 
assessment should be done after informed consent is obtained and before any other procedures 
or examinations are performed. The question should be answered for both knees, since the 
target knee has not yet been identified.
! PGA (see Section 7.3.3)
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! NRS pain score for both knees
! Collection of demographic characteristics (see Section 7.2)
! Medical/medication history (see Section 7.2)
Subjects will be asked to withhold all pain medications, including narcotics and paracetamol 
(acetaminophen) for 5 half-lives and a visit will be scheduled to continue screening. Aspirin 
(acetylsalicylic acid) used for cardiovascular protection does not need to be withheld, nor do 
antidepressants used for management of OA pain or depression.
Subjects not taking analgesic medication at the time of informed consent signature can have Visit 
1a and 1b procedures completed at the same visit.
Visit 1b
The following procedures are to be performed in all subjects. Subjects taking analgesic 
medications at the time of Visit 1a must undergo washout of all analgesic medications and 
schedule a follow-up visit as described above. Subjects not taking analgesic medications can 
proceed with the following procedures at the time of the initial study visit.
! WOMAC (Question 1 of the WOMAC pain index only; see Section 5.4 and Appendix C): this 
assessment should be done before any other procedures or examinations are performed and 
completed for both knees, since the target knee has not yet been identified.
! NRS pain score for the target and contralateral knee
NOTE: if Visit 1a and 1b are being combined do not repeat the WOMAC Question 1 or the 
NRS pain score.
! Review of AEs and concomitant medications (see Sections 7.4.1 and 6.5)
! Vital signs measurement (see Section 7.4.4)
! Physical examination, including height and weight
! 12-lead ECG (see Section 7.4.4)
! Sample collection for hematology, biochemistry, and urinalysis (see Section 7.4.3 and 
Appendix B): coagulation tests will also be performed during the screening period (to be done 
locally).
! Serum pregnancy test for women of childbearing potential
NOTE: In women of childbearing potential, a negative serum pregnancy test must be obtained 
before knee X-rays.
! 20-meter walk test (see Section 7.3.5)
! X-rays of both the target knee and the contralateral knee, plus a long-axis view of the target 
knee (see Section 7.3.4)
! Identification of the target knee
! Review of inclusion and exclusion criteria (see Sections 5.3.1 and 5.3.2)
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These procedures can be spread out over the screening period if this is necessary for logistical 
reasons. However, subject questionnaires (WOMAC Question 1, PGA, and NRS pain) must be 
done on the same day at the beginning of screening. Subjects must have a pain score for the 
target knee of 4 to 9 points in response to Question 1 of the WOMAC pain index after drug 
washout at the time of Visit 1b to be eligible for continued screening.
Subjects will again be asked to withhold all pain medications, including narcotics and 
paracetamol (acetaminophen) for 5 half-lives before the baseline WOMAC assessment (Visit 2). 
At the beginning of the screening period, subjects will be given trial diaries for recording of any
AEs occurring or concomitant medications used during screening and for recording of maximum 
pain and presence or absence of joint swelling in the target knee on the day before the first IMP 
administration (Week 0/Visit 2; see Section 7.1.1).
7.1.3
Double-Blind Placebo-Controlled Treatment Phase (Visits 2 
to 22)
The duration of the DBPC treatment phase will be 2 years (104 weeks). Trial visits during this 
phase are outlined in Table 2, and details of the procedures to be performed are presented in 
Appendix E.
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Table 2
Trial Visits during DBPC Treatment Phase
Visit Number
Week*
Treatment
Visit Name or Type
2
0
X
Baseline – Major Efficacy
3
1
X
4
2
X
5
3
6
12
Minor Efficacy
7
26
X
Major Efficacy
8
27
X
9
28
X
10
29
11
38
Minor Efficacy
12
52
X
Major Efficacy
13
53
X
14
54
X
15
55
16
64
Minor Efficacy
17
78
X
Major Efficacy
18
79
X
19
80
X
20
81
21
90
Minor Efficacy
22
104
Major Efficacy
* Relative to randomization and initiation of therapy at Week 0. Assessments performed at “major” and “minor” 
efficacy visits are described in Sections 7.1.3.3 and 7.1.3.4 respectively.
Subject eligibility for the trial will be confirmed at the baseline visit (Week 0/Visit 2; see Section 
7.1.3.1) based on scores for Question 1 of the WOMAC pain index at screening and baseline (see 
Section 5.4). Eligible subjects will then be randomized and the first i.a. injection of IMP will be 
administered.
I.a. injections of the IMP will be administered at the baseline visit (Week 0/Visit 2) and at the 
visits identified in Section 7.1.3.2.
Major efficacy assessments will take place at intervals of 6 months, at the beginning of each 
treatment cycle and at the end of the DBPC treatment phase (Week 104/Visit 22; see Section 
7.1.3.3).
Minor efficacy assessments will also take place at intervals of 6 months, occurring 9 weeks after 
the end of each treatment cycle (see Section 7.1.3.4).
Subjects will be requested to discontinue the intake of all pain medications for 5 half-lives before 
a visit involving completion of the WOMAC (see Sections 5.4 and 7.1.2). At least 3 days before 
each such visit, subjects will be contacted by phone to remind them of this requirement. When 
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the upcoming visit includes injection of IMP, this phone contact will include a reminder to 
complete trial diary information about target knee pain and swelling for the day before the visit.
Vital signs measurement (see Section 7.4.4) and review of AEs and concomitant medications 
(see Sections 7.4.1 and 6.5) will be performed at all DBPC treatment phase visits.
For women of childbearing potential, urine pregnancy tests will be performed before dosing on 
each treatment day (see Section 7.1.3.3).
Blood samples will be collected for testing for antibodies to sprifermin/FGF-18 at the baseline 
visit and at major efficacy visits (see Section 7.1.3.3), and also one week after the last dose of 
each treatment cycle (at Weeks 3, 29, 55, and 81/Visits 5, 10, 15, and 20).
Blood samples will be collected for PK analysis at the baseline visit (Week 0/Visit 2), at the end 
of each treatment cycle (Weeks 2, 28, 54, and 80/Visits 4, 9, 14, and 19), and at the end of the 
DBPC treatment phase (Week 104/Visit 22). PK samples will be taken pre-injection at baseline 
and 2 hours post-injection at subsequent visits where IMP is administered.
Fasting blood and urine samples for biomarker analysis will be collected at the baseline visit
(Week 0/Visit 2) and at other visits (see Appendix E). For time points where IMP injections are 
administered, samples will be collected pre-dose. For urine, second morning void samples should 
be obtained.
12-lead ECGs will be performed at Week 52 (Visit 12; pre-dose) and Week 104 (Visit 22).
At each visit, subjects will be given trial diaries for recording of any AEs occurring or 
concomitant medications used between visits and for recording of maximum pain and presence 
or absence of joint swelling in the target knee for the day before and the 3 days after each IMP 
injection (see Section 7.1.1). Diaries will be collected and reviewed at the following visit.
7.1.3.1
Baseline Visit (Week 0; Visit 2)
The baseline visit must take place within 42 days after the beginning of screening, following the 
pain medication washout necessary for confirmation of trial eligibility (see Section 5.4).
The following procedures will be performed at the baseline visit before administration of IMP. 
Subject questionnaires (WOMAC, PGA, KOOS QOL, KOOS Symptom Index, NRS pain score 
in the target and contralateral knee, pain in other joints, MOS SF-36, and ICOAP) should be 
completed before any other procedures are performed; the WOMAC should be completed first.
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! WOMAC (see Appendix C)
! PGA (see Section 7.3.3)
! KOOS QOL (see Appendix D)
! KOOS Symptom Index (see Appendix D)
! NRS pain (see Section 7.7.5)
! Pain in other joints (see Appendix F)
! MOS SF-36 (see Appendix C)
! ICOAP (see Appendix C)
! Review of AEs and concomitant medications (see Sections 7.4.1 and 6.5)
! Review of subject diaries (see Section 7.1.1)
! Vital signs measurement (see Section 7.4.4)
! Sample collection for hematology, biochemistry, and urinalysis (see Section 7.4.3 and 
Appendix B)
! Blood collection for testing for antibodies to sprifermin/FGF-18 (see Section 7.4.3)
! Blood collection for PK analysis (see Section 7.5.1)
! Blood collection (fasting) for biomarker analysis (see Section 7.6.2)
! Blood collection for optional PGt analyses (for subjects who have signed the PGt informed 
consent). If a blood sample cannot be obtained at the baseline visit, this sample can be taken 
at any subsequent visit (see Section 7.6.3).
! Urine collection (second morning void) for biomarker analysis (see Section 7.6.2)
! Urine pregnancy test for women of childbearing potential
! 20-meter walk test (see Section 7.3.5)
! Target knee MRI (see Section 7.3.1)
! Review of inclusion and exclusion criteria (see Sections 5.3.1, 5.3.2, and 5.4)
! Randomization
Provided that the subject fulfills all inclusion and no exclusion criteria, s/he will be randomized 
to treatment using the IVRS as described in Section 6.3. Medication from the assigned treatment 
kit will be prepared as described in Section 6.2 and administered i.a. according to instructions in 
the MOP.
! Using aseptic technique, i.a. administration of IMP will be guided by ultrasound to ensure 
delivery of the IMP into the joint space.
! Before injecting the IMP solution, an aspiration of the synovial fluid for PK and biomarker 
analysis will be performed as part of the i.a. injection procedure, using the same needle that 
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will be used for IMP injection. If possible, up to 2.5 mL of synovial fluid should be collected 
(instructions for sample handling are provided in the MOP).
If it is not possible to schedule an MRI scan for the same day as the other baseline assessments 
(including confirmation of eligibility by baseline WOMAC) for logistical reasons, the baseline 
MRI may be performed up to 3 days after confirmation of eligibility. Randomization and IMP 
administration will then take place on the day of the baseline MRI (following the scan), and 
subsequent visits will be planned relative to the day of randomization and IMP administration.
If confirmation of eligibility and baseline MRI scanning are performed on different days, all 
assessments of symptoms (WOMAC, PGA, KOOS QOL, KOOS Symptom Index, NRS pain 
score in the target and contralateral knee, MOS SF-36, pain in other joints, and ICOAP) must be 
performed on the day of eligibility confirmation and all safety assessments and laboratory 
sampling must be performed on the day of MRI scanning (at appropriate times relative to IMP 
administration). Details of the division of procedures between these days are provided in 
Appendix E.
7.1.3.2
IMP Administration
Subsequent IMP injections will be given at the following time points:
! Cycle 1:
Weeks 1 and 2 (Visits 3 and 4)
! Cycle 2:
Weeks 26, 27, and 28 (Visits 7, 8, and 9)
! Cycle 3:
Weeks 52, 53, and 54 (Visits 12, 13, and 14)
! Cycle 4:
Weeks 78, 79, and 80 (Visits 17, 18, and 19).
At visits where IMP is administered, all procedures should be performed before dosing unless 
otherwise specified.  Urine pregnancy testing will be conducted in women of childbearing 
potential prior to each injection.
Immediately prior to dosing at each of these visits, the Investigator or delegate will obtain a 
blinded treatment kit number from the IVRS as described in Section 6.3. Medication from the 
assigned treatment kit will be prepared as described in Section 6.2 and administered i.a. 
according to instructions in the MOP.
! Using aseptic technique, i.a. administration will be guided by ultrasound to ensure delivery of 
the IMP into the joint space.
! Before injecting the IMP solution, an aspiration of the synovial fluid for PK and biomarker 
analysis will be performed as part of the i.a. injection procedure, using the same needle that 
will be used for injection. If possible, up to 2.5 mL should be collected (instructions for 
sample handling are provided in the MOP).
At visits where samples are collected for PK analyses (see Appendix E), subjects will be 
requested to stay in the study site for approximately 2 hours post-injection for collection of the 
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post-dose samples. At visits where biomarkers are collected, samples will be collected in the 
fasting state.
7.1.3.3
Major Efficacy Visits (Weeks 26, 52, 78, and 104; Visits 7, 12, 
17, and 22)
Major efficacy visits will take place at intervals of 6 months (on the first day of each treatment 
cycle) and then at the end of the DBPC treatment phase (Week 104/Visit 22).
The following procedures will be performed at major efficacy visits. At visits where IMP is 
administered, all procedures should be performed before dosing unless otherwise specified. 
Subject questionnaires (WOMAC, PGA, KOOS QOL, KOOS Symptom Index, PGIC, NRS pain 
score in the target and contralateral knee, MOS SF-36, pain in other joints, and ICOAP) should 
be completed before any other procedures are performed; the WOMAC should be completed 
first.
! WOMAC (see Appendix C)
! PGA (see Section 7.3.3)
! KOOS QOL (see Appendix D)
! KOOS Symptom Index (see Appendix D)
! PGIC (see Section 7.7.4)
! NRS pain (see Section 7.7.5)
! Pain in other joints (see Appendix F)
! MOS SF-36 (see Appendix C)
! ICOAP (see Appendix C)
! Review of AEs, concomitant medications, and concomitant procedures on the target knee (see 
Sections 7.4.1 and 6.5)
! Review of subject diaries (see Section 7.1.1)
! Vital signs measurement (see Section 7.4.4),
! Physical examination including weight measurement (and height at Visit 22 only)
! Sample collection for hematology, biochemistry, and urinalysis (see Section 7.4.3 and 
Appendix B)
! Blood collection for testing for antibodies to sprifermin/FGF-18 (see Section 7.4.3)
! Urine pregnancy test for women of childbearing potential
! 20-meter walk test (see Section 7.3.5)
! Target knee MRI (see Section 7.3.1)
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! Knee X-ray (Weeks 52 and 104/Visits 12 and 22 only; see Section 7.3.4). An X-ray of the 
contralateral knee will be taken at Week 104/Visit 22.
IMP dosing and synovial fluid collection will take place at the following major efficacy visits: 
Weeks 26, 52, and 78/Visits 7, 12, and 17 (see Section 7.1.3.2).
7.1.3.4
Minor Efficacy Visits (Weeks 12, 38, 64, and 90; Visits 6, 11, 
16, and 21)
Minor efficacy visits will take place at intervals of 6 months (12 weeks after the beginning of 
each treatment cycle).
The following procedures will be performed at these visits. Subject questionnaires (WOMAC, 
PGA, KOOS QOL, KOOS Symptom Index, PGIC, NRS pain score in the target and contralateral 
knee, and ICOAP) should be completed before any other procedures are performed.
! WOMAC (see Appendix C)
! PGA (see Section 7.3.3)
! KOOS QOL (see Appendix D)
! KOOS Symptom Index (see Appendix D)
! PGIC (see Section 7.7.4)
! NRS pain (see Section 7.7.5)
! ICOAP (see Appendix C)
! Review of AEs, concomitant medications, and concomitant procedures on the target knee (see 
Sections 7.4.1 and 6.5)
! Review of subject diaries (see Section 7.1.1)
! Vital signs measurement (see Section 7.4.4)
! Physical examination
! 20-meter walk test (see Section 7.3.5)
7.1.4
Extended Follow-Up Phase
Visits during the 3-year extended follow-up phase will take place at 6-month intervals (see 
Appendix E). Subjects will be requested to discontinue the intake of all pain medications for 5 
half-lives before each extended follow-up visit. At least 3 days before each visit, site staff will 
contact subjects by phone to remind them of this requirement.
The following procedures will be performed at all extended follow-up visits. Subject 
questionnaires (WOMAC, PGA, KOOS QOL, KOOS Symptom Index, PGIC, NRS pain score in 
the target and contralateral knee, pain in other joints, and ICOAP) should be completed before 
any other procedures are performed; the WOMAC should be completed first.
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! WOMAC (see Appendix C)
! PGA (see Section 7.3.3)
! KOOS QOL (see Appendix D)
! KOOS Symptom Index
! PGIC (see Section 7.7.4)
! NRS pain (see Section 7.7.5)
! Pain in other joints (see Appendix F)
! MOS SF-36 (see Appendix C)
! ICOAP (see Appendix C)
! Review of AEs, concomitant medications, and concomitant procedures on the target knee (see 
Sections 7.4.1 and 6.5)
! Review of subject diaries (see Section 7.1.1)
! Vital signs measurement (see Section 7.4.4)
! Physical examination including weight measurement 
! Sample collection for hematology, biochemistry, and urinalysis (see Section 7.4.3 and 
Appendix B)
! 20-meter walk test (see Section 7.3.5)
The following additional procedures will be performed at Extended Follow-up Visits 2, 4, and 6 
(Weeks 156, 208, and 260/Visits 24, 26, and 28; i.e., at yearly intervals):
! Urine pregnancy test for women of childbearing potential (before performing X-ray and MRI)
! Target knee MRI (see Section 7.3.1)
! Knee X-ray (see Section 7.3.4). An X-ray of the contralateral knee will be taken at the final 
extended follow-up visit.
! Height will be measured at the final extended follow-up visit.
At each visit (with the exception of the final extended follow-up visit), subjects will be given 
trial diaries for recording of any AEs occurring or concomitant medications used between visits 
(see Section 7.1.1). Diaries will be collected and reviewed at the following visit.
7.1.5
Follow-Up in Case of Early Termination
Early Treatment Discontinuation
Subjects who discontinue treatment prematurely will undergo the assessments planned for Week 
104/Visit 22 at the time of discontinuation (see Appendix E). If they are willing to continue in 
the trial, they will undergo all subsequent assessments planned for the remainder of their trial 
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participation (Visit 23 through Visit 28; with no further administration of IMP). Subjects who 
discontinue participation during the extended follow-up phase should have Week 260/Visit 28 
procedures completed whenever possible.
Early Trial Withdrawal
Subjects who withdraw from the trial should undergo the assessments planned for Week 
104/Visit 22 at the time of withdrawal whenever possible (see Appendix E).
7.2
Demographic and Other Baseline Characteristics
The demographic variables to be documented will be the subject identifier (to be assigned by the 
IVRS), age, sex, race, weight and height. Weight will also be measured every six months and 
height will be measured at the end of the DBPC and extended follow-up phases.
A complete medical history should be taken, covering all organ systems, diagnoses so far 
established, medications prescribed (including any vitamins and nutritional supplements taken), 
and surgical interventions performed. The medical history should also cover aspects such as 
allergies, consumption of alcohol, and smoking habits. Particular attention should be given to 
conditions potentially affecting trial eligibility.
Concerning concomitant treatments, particular attention should be given to the subject’s use of 
NSAIDs, coxibs, and analgesics in general. These medications must be painstakingly recorded at 
baseline, as this information is needed for determination of eligibility for the trial. It will also be 
important to carefully record concomitant medication use throughout the trial. 
A complete physical exam should also be performed, as detailed in the MOP.
Concerning the diagnosis of knee OA, it should be established for how long the disease has 
persisted and how it has been treated.
The target knee that will be treated with the IMP will be selected during the screening period. In 
case of bilateral OA, the more symptomatic knee should be chosen as the target knee.
7.3
Assessment of Efficacy
Assessment of efficacy in this trial will focus on MRI evaluation of treatment effect on knee 
cartilage. Effects of treatment on OA symptoms and functional limitations will be explored using 
the WOMAC questionnaire, the PGA, and the 20-meter walk test. The recognized endpoint of 
JSW measured by X-ray will also be used. These assessments are described in the sections 
below.
Exploratory analysis of treatment effect on health-related QOL will be performed using the 
KOOS QOL and the MOS SF-36 questionnaire. The NRS will be used to explore treatment 
effect on worst pain in the past 24 hours in the target knee.  The ICOAP and the KOOS 
Symptom Index questionnaires will be used to explore the effect of treatment on OA-related 
symptomatology in the target knee. The NRS pain scale for the contralateral knee and a scale 
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model of the human body identifying potentially painful joints will be used to assess pain in non-
target joints and the progression of OA. The PGIC will be used to measure the subject’s 
assessment of the clinical importance of their improvement or worsening over the course of the 
trial. See Section 7.7 for description of these assessments.
The OMERACT-OARSI responder rate ((1); see Section 8.3.4) at 2 years will also be 
determined as an exploratory analysis, based on assessment of pain and function using the 
WOMAC and the PGA described in Section 7.3.3.
The rationale for the selection of efficacy measures and the timing of assessments is presented in 
Section 5.2.
7.3.1
Magnetic Resonance Imaging
MRI Scanning
MRI scanning will be performed using a high-resolution, 3-dimensional MRI machine with a 
commercially available dedicated knee coil. A 1.5 Tesla machine should be used.
It is recommended that machines from the same manufacturer be used to scan a given subject 
throughout the trial.
The scanning procedure is detailed in the MOP.
MRI Analysis
The trial’s MRI endpoints will be addressed through quantitative MRI assessment of cartilage 
thickness and volume and semi-quantitative MRI assessment of cartilage structure.
MRI scans will be read centrally.
Quantitative MRI Assessment
OA is characterized by a progressive loss of cartilage that can be quantified by MRI. MRI is 
believed to detect structural changes faster than X-ray, although only JSW as measured by X-ray 
is accepted as a primary structural endpoint in confirmatory OA trials. For the purpose of 
quantification, the joint is divided into different compartments that may be more or less affected 
by OA. Quantitative MRI analysis in this trial will focus on the total knee and on the lateral and 
medial femorotibial compartments (LFTC and MFTC, respectively).
Quantitative MRI analysis for this trial will be performed under the direction of 
 
.
Semi-quantitative MRI Assessment
Semi-quantitative assessment of the target knee will be performed using the Whole Organ 
Magnetic Resonance Imaging Score (WORMS (18)) and the Boston-Leeds Osteoarthritis Knee 
Score (BLOKS (24),(25)).
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The WORMS permits whole-organ assessment of the knee in OA based on conventional MRI 
images, and inter-observer agreement is high among trained readers. In its complete form, 
WORMS incorporates assessment of 14 features: articular cartilage integrity (signal and 
morphology), subarticular bone marrow abnormality (bone marrow edema), subarticular cysts, 
subarticular bone attrition, marginal osteophytes, medial and lateral meniscal integrity, anterior 
and posterior cruciate ligament integrity, medial and lateral collateral ligament integrity, 
synovitis/effusion, intra-articular loose bodies, and periarticular cysts/bursitis.
The BLOKS scoring method assesses 9 intra-articular regions and contains 8 items, including 
features of bone marrow lesions, cartilage, osteophytes, synovitis, effusions and ligaments. 
Possible scores for each feature range from 0 to 3. Maximal bone marrow lesion size using the 
BLOKS has been shown to have a positive linear relation with VAS pain, while this has not been 
demonstrated for the WORMS.
Semi-quantitative MRI analysis for this trial will be performed and centrally analyzed as 
described in the Manual of Procedures (MOP). 
7.3.2
WOMAC Questionnaire
The self-administered 24-question WOMAC Version 3.1 ((26); see Appendix C) will be used to 
assess pain, disability, and joint stiffness in the knee.
Subjects will answer all of the 24 questions themselves, using an 11-box numerical rating scale 
(with categories of 0 to 10), with reference to the past 48 hours. Different forms of the 
questionnaire exist for the right and the left knees: in order to reduce confounding of WOMAC 
responses by symptoms in the contralateral knee, subjects will use the WOMAC questionnaire 
specific to the target knee.
For administration of the questionnaire, instructions for the WOMAC 3.1 Index should be 
followed.
The WOMAC is widely used in clinical trials in hip and knee OA, and has been extensively 
validated. Appropriate validated translations will be used in each participating country.
The questionnaire addresses the degree of pain experienced with different activities or positions 
(5 questions), the degree and timing of joint stiffness (2 questions), and the degree of difficulty 
experienced in performing daily activities (17 questions). The maximum possible total score, 
indicating the worst possible OA symptoms, is 240 points. For convenience and ease of 
interpretation, all scores will be normalized on scales of 0 to 100 points.
The minimum clinically important difference in WOMAC scores is considered to be about 10% 
of the maximum possible score (27).
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7.3.3
Patient’s Global Assessment
In the Patient’s Global Assessment (PGA) used in this trial, subjects will be asked to answer the 
following question using an 11-box numerical rating scale:
“Considering all the ways your osteoarthritis of the knee has affected you during the last 48 
hours, circle the number that best describes the impact of your knee osteoarthritis on your daily 
life.”
0
1
2
3
4
5
6
7
8
9
10
None
Extreme
7.3.4
X-Ray Imaging
X-Ray Image Acquisition
Fixed flexion radiography will be used for the measurement of JSW. For the posterior-anterior 
projection of the target knee, the distance between focus and film will be equivalent to 183 cm 
(72 inches), and subjects must be positioned with their knees flexed at an angle of 20-30 degrees 
and their feet rotated internally at an angle of 10 degrees. Foot maps and a standardized 
radiological protocol will be used.
During the screening period, at the end of the DBPC treatment phase, and at the end of the 
extended follow-up phase, X-rays of both the target knee and the contralateral knee will be 
performed. At other time points, X-rays will be performed for the target knee only. A long-axis 
view of the target knee will also be obtained during screening to permit evaluation of 
malalignment.
Details are provided in the MOP.
X-Ray Image Analysis
X-rays will be read centrally.
X-ray images will be used to measure JSW in the medial and lateral femorotibial compartments 
and to determine the subject’s baseline Kellgren-Lawrence grade.
Measurement of Joint Space Width
Change in JSW as measured by X-ray is a recognized endpoint accepted by the European 
Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) for use in 
efficacy trials in OA.
JSW will be measured using standardized technique that is described in the MOP.
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Kellgren-Lawrence Scoring
The Kellgren-Lawrence (K-L) scale (28),(29) assigns severity grades for knee OA based on 
radiological assessment of the femorotibial joint (it is important to note that only the femorotibial 
joint is considered). A number from 0 to 4 is assigned, as follows:
! Grade 0: No feature of osteoarthritis
! Grade 1: Doubtful narrowing of joint space and possible osteophytic lipping
! Grade 2: Definite osteophytes and possible narrowing of joint space
! Grade 3: Moderate multiple osteophytes, definite narrowing of joint space and some sclerosis 
and possible deformity of bone ends
! Grade 4: Large osteophytes, marked narrowing of joint space, severe sclerosis and definite 
deformity of bone ends
Kellgren-Lawrence scoring will be performed by the trial’s imaging provider.
7.3.5
20-Meter Walk Test
The 20-meter walk test is an objective test of physical function which consists of measuring the 
time needed for the subject to walk 20 meters at a normal pace (30),(31). A stopwatch will be 
used for time measurement.
7.4
Assessment of Safety
The safety profile of sprifermin will be assessed through the recording, reporting and analyzing 
of baseline medical conditions, AEs, physical examination findings including vital signs, weight, 
laboratory tests, and incidence of surgical interventions in the target knee (including any surgical 
revision, cartilage removal, operation, or any other type of surgical intervention).
Comprehensive assessment of any apparent toxicity experienced by the subject will be 
performed throughout the course of the trial, from the time of the subject’s signature of informed 
consent. Trial site personnel will report any AE, whether observed by the Investigator or reported 
by the subject (see Section 7.4.1.4, “Methods of Recording and Assessing Adverse Events”).
The reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
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(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product.
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
In case of a fatality, the cause of death is considered as the AE, and the death is considered as its 
OUTCOME.
The Investigator is required to grade the severity of each AE.
Investigators must assess the severity of AEs according to the Qualitative Toxicity Scale, as 
follows:
Mild:
The subject is aware of the event or symptom, but the event or symptom is easily
tolerated.
Moderate:
The subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity.
Severe:
Significant impairment of functioning: the subject is unable to carry out usual 
activities.
Investigators must also systematically assess the causal relationship of AEs to the IMP using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to the 
IMP include, but may not be limited to, temporal relationship between the AE and the IMP, 
known side effects of the IMP, medical history, concomitant medication, course of the 
underlying disease, and trial procedures.
Not related: Not suspected to be reasonably related to the IMP. AE could not medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. A reasonable alternative explanation must be available.
Related:
Suspected to be reasonably related to the IMP. AE could medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol.
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG 
trace) should not be reported as AEs unless they are associated with clinical signs and symptoms, 
lead to treatment discontinuation or are considered otherwise medically important by the 
Investigator. If an abnormality fulfills these criteria, the identified medical condition (e.g., 
anemia, increased ALT) must be reported as the AE rather than the abnormal value itself.
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Serious Adverse Event
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
! Results in death.
! Is life-threatening.
NOTE: The term “life-threatening” in this definition refers to an event in which the subject is 
at risk of death at the time of the event; it does not refer to an event that hypothetically might 
cause death if it were more severe.
! Requires inpatient hospitalization or prolongation of existing hospitalization.
! Results in persistent or significant disability/incapacity.
! Is a congenital anomaly/birth defect.
! Is otherwise considered as medically important.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such 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.
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is 
also considered a serious adverse reaction and all such cases should be reported in an expedited 
manner as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g., an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered as SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Medical conditions present at the initial trial visit that do not worsen in severity or frequency 
during the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs.
Progression of underlying disease is not an AE and therefore not an SAE per se, rather an 
efficacy endpoint, unless deemed to be causally related to IMP administration.
Pre-defined AEs of Special Interest for Safety Monitoring
One of the trial’s safety endpoints is the incidence of AIRs, defined as increase of pain by 30 mm 
on a 100-mm VAS and a self-reported synovial fluid effusion (i.e., joint swelling) within 3 days 
following i.a. injection.
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It is recognized that events meeting this definition will not be necessarily drug-related or 
inflammatory in nature; however, it is believed that the definition will permit capture of most 
clinically relevant local reactions. A similar definition based on a 30-mm increase in pain and 
local swelling was used in a trial in rheumatoid arthritis involving i.a. injections of interleukin-1 
receptor antagonist (IL-1ra; anakinra (23)).
At each visit, subjects will be given trial diaries for recording of any AEs occurring or 
concomitant medications used between visits. These diaries will also be used to record maximum 
pain (using a 100-mm VAS) and presence or absence of joint swelling in the target knee for the 
day before and the 3 days after each IMP injection (see Section 7.1.1).
Completed diaries will be collected and reviewed at each visit, and information will be 
transcribed to the CRFs following medical review. AIRs will be identified by the Sponsor based 
on the information about pain and swelling that is transcribed from the diaries to the CRFs.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his/her condition. During the 
reporting period of the trial, any unfavorable changes in the subject’s condition will be recorded 
as AEs, whether reported by the subject or observed by the Investigator.
Subjects will be asked to record information about any adverse reactions experienced between 
trial visits on their trial diaries (see Section 7.1.1). Diaries will be reviewed at each trial visit; 
information thus collected will be reviewed and assessed medically before it is transcribed to the 
CRF.
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
CRF. Among these AEs, all serious AEs must be additionally documented and reported using an 
Adverse Event Safety Report Form (Clinical Trial) as described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates (and times, if relevant)), its severity, its relationship with the trial treatment, any 
other potential causal factors, any treatment given or other action taken (including dose 
modification or discontinuation of the IMP), and its outcome. In addition, serious cases should 
be identified and the appropriate seriousness criteria documented.
Because of the i.a. route of administration used and the expectation that the great majority of the 
injected drug will remain within the knee joint, Investigators must classify each reported AE as 
“local (i.e., concerning only the knee that is treated)” or “systemic” in the subject’s CRF to 
permit separate evaluation of AEs classified as local and AEs classified as systemic.
Specific guidance can be found in the CRF Completion and Monitoring Conventions provided 
by the Sponsor.
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7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is included into the trial 
(date of first signature of informed consent) and continues until the end of the trial’s post-
treatment extended follow-up phase, or until the subject’s final trial visit in case of early 
withdrawal.
7.4.1.4
Procedure for Reporting Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (i.e., within a maximum 24 HOURS after becoming aware of the event) inform the 
Sponsor’s GDS department by fax or by e-mail.
Reporting procedures and timelines are the same for any new information on a previously 
reported SAE (i.e., follow-up).
For names, addresses, telephone and fax numbers for SAE reporting, see information included in 
the Adverse Event Safety Report Form (Clinical Trials).
All written reports should be transmitted using the Adverse Event Safety Report Form (Clinical 
Trials), which must be completed by the Investigator following specific completion instructions.
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
medications). In all cases, the information provided in the Adverse Event Safety Report Form 
(Clinical Trials) must be consistent with the data on the event that are recorded in the 
corresponding sections of the CRF.
The Investigator/Reporter must respond to any request for follow-up information (e.g., additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor may have on the AE within the same timelines as described for initial reports. This is 
necessary to permit a prompt assessment of the event by the Sponsor and (as applicable) to allow 
the Company to meet strict regulatory timelines associated with expedited safety reporting 
obligations.
Requests for follow-up will usually be made by the responsible Monitor, although in exceptional 
circumstances the GDS department may contact the Investigator directly to obtain clarification or 
to discuss a particularly critical event.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (and in particular deaths) involving his/her subjects to the IEC/IRB that 
approved the trial.
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In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of “findings 
that could adversely affect the safety of subjects, impact the conduct of the trial or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” or SUSARs). The Investigator should place copies of Safety reports in 
the Investigator Site File. National regulations with regard to Safety report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety reports directly to the concerned lead IEC/IRB and will maintain records of these 
notifications. When direct reporting by the Sponsor is not clearly defined by national or site-
specific regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety reports provided by the Sponsor and of filing copies of all related 
correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidances.
7.4.1.6
Monitoring of Subjects with Adverse Events
Any AE that occurs during the course of a clinical trial and is considered to be possibly related to 
the IMP must be monitored and followed up by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable attempts 
to obtain this information must be made and documented. It is also the responsibility of the 
Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. The Sponsor will actively follow up and collect information on any 
AE that occurs during the course of a clinical trial; however, while this activity will continue for 
any serious AEs until stabilization or until the outcome is known, it will be discontinued at the 
time of database lock for non-serious AEs.
7.4.2
Pregnancy and In Utero Drug Exposure
Only pregnancies considered by the Investigator as related to trial treatment (e.g., resulting from 
a drug interaction with a contraceptive medication) are considered as AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 7.4.1.3 must 
be recorded by convention in the AE page/section of the CRF. The Investigator must notify the 
Sponsor in an expedited manner of any pregnancy using the Pregnancy Report Form, which must 
be transmitted according to the same process as described for SAE reporting in Section 7.4.1.4.
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor of these outcomes using the Pregnancy Report Form, 
and in case of abnormal outcome, the Adverse Event Safety Report Form (Clinical Trials) when 
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the subject sustains an event, and the Parent-Child/Fetus Adverse Event Report Form when the 
child/fetus sustains an event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days from delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor must be notified without delay 
and the subject must be followed as mentioned above.
7.4.3
Laboratory Assessments
Standard laboratory assessments in this trial will consist of hematology, clinical biochemistry, 
and urinalysis panels: complete lists of parameters are presented in Appendix B.
As an exogenous protein, sprifermin has the potential to trigger antibody formation, which could 
conceivably have safety, PK, or efficacy implications. Thus, subjects will be tested for binding 
and neutralizing antibodies to sprifermin/FGF-18. Only samples that are found to be positive for 
binding antibodies will be tested for neutralizing antibodies.
Blood, urine, and synovial fluid samples for laboratory assessment will be collected at the time 
points indicated in Appendix E.
! Subjects are not required to fast before routine laboratory sample collection in this protocol, 
however, an 8-hour fast is required before blood or urine sample collection for biomarkers.
! For time points where IMP injections are administered, blood and urine samples will be 
collected pre-dose.
! For measurement of biomarkers in urine, second morning void samples should be obtained.
! Synovial fluid samples will be collected immediately before injection of the IMP as described 
in the MOP.
PK assessments are described in Section 7.5, and biomarker and PGt assessments are described 
in Section 7.6.
All laboratory assessments will be performed centrally. Instructions for sample collection, 
handling, and shipment are provided in the MOP.
Pregnancy Tests
For women of childbearing potential, pregnancy tests will be performed at the time points shown 
in Appendix E (during screening, before each injection of IMP, and at each visit involving X-ray 
and MRI). A serum test will be performed during screening, and urine tests will be performed at 
subsequent time points.
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Management of Subjects with Laboratory Abnormalities
Laboratory abnormalities that Investigators consider to be clinically significant should be 
reported as AEs (see Section 7.4.1).
The best interest of the participating subject will always come before that of the trial. 
Abnormalities of any safety laboratory analysis considered to represent a significant danger to 
the subject will lead to immediate discontinuation of the drug, and the Medical Responsible must 
be informed immediately.
In the event of significant abnormalities considered not to represent a danger, continuation of the 
drug may be allowed after discussion with the Medical Responsible. These subjects will be 
followed up with appropriate medical management until there is a return to normal or baseline 
values, or until a clinical diagnosis of a trial-emergent illness is confirmed.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
Physical examinations and measurement of height, weight, and vital signs (sitting systolic and 
diastolic blood pressure, heart rate, and body temperature) will be performed at the time points 
specified in Appendix E.
Standard 12-lead ECGs (reporting ventricular rate, PR, QRS, QT, and QTc intervals) will be 
obtained at the time points specified in Appendix E. ECGs will be read centrally; procedures for 
transfer of data to the central reader are provided in the MOP. Original 12-lead ECG tracings 
will be retained in each individual subject’s medical file. In case of abnormal results, a second 
original will be provided to the Sponsor. ECGs can be repeated at the discretion of the 
Investigator or co-Investigator.
One of the trial’s safety endpoints is the incidence of AIRs, defined as increase of pain by 30 mm 
on a 100-mm VAS and a self-reported synovial fluid effusion (i.e., joint swelling) within 3 days 
following i.a. injection (see Section 7.4.1.1). Subjects will use trial diaries to record maximum 
levels of target knee pain experienced, using a 100-mm VAS, and presence or absence of joint 
swelling in the target knee. Completed diaries will be collected and reviewed at each visit, and 
information will be transcribed to the CRFs following medical review. AIRs will be identified by 
the Sponsor based on the information about pain and swelling transcribed from the diaries to the 
CRFs.
7.5
Pharmacokinetics
PK assessment will be performed for sprifermin/FGF-18 in serum and synovial fluid.
Sprifermin differs from the endogenous FGF-18 molecule in that it is truncated (i.e., it has 170 
instead of 180 amino acids), it has a methionine extension, and it is not glycosylated. 
Merck Serono internal Standard Operating Procedure HP01 describes the process for handling 
bioanalytical, PK, and pharmacodynamic (PD) data from double-blind clinical trials. To maintain 
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the blind for PK data during this trial, the randomization list will only be provided to the PK 
bioanalytical scientist or clinical trial team members after clinical database lock.
7.5.1
Body Fluids
Blood and synovial fluid samples for measurement of serum/synovial fluid sprifermin/FGF-18 
levels will be collected at the time points indicated in the schedule of assessments in Appendix 
E.
Detailed description of sample preparation, labels, and shipments will be given in the MOP. 
Details of the assays such as the validation procedure and definition of lower limit of 
quantification (LLOQ) will be described by the Sponsor/external laboratory in a separate 
analytical protocol. Some samples might be stored and used for additional analysis or for 
validation of new assays.
! Blood samples for the measurement of sprifermin/FGF-18 serum levels will be collected at 
pre-dose at Week 0 and thereafter at 2 hours after the last dose of each cycle.
! Synovial fluid for the measurement of sprifermin/FGF-18 levels will be aspirated under 
ultrasound guidance (32) prior to i.a. injection of sprifermin, as part of the i.a. injection 
procedure and using the same needle that will be used for IMP injection, as described in the 
MOP.
7.5.2
Pharmacokinetic Calculations
The PK analysis will be performed under the responsibility of the Sponsor according to the 
Sponsor’s appropriate standard operating procedures. Sprifermin/FGF-18 serum and synovial 
fluid concentrations will be summarized at the time points shown in Appendix E. Details of the 
analysis and data displays will be provided in the Statistical Analysis Plan (SAP). Analytes to be 
tested in this study will include serum and synovial fluid sprifermin/FGF-18.
7.6
Biomarkers and Pharmacogenetics 
Circulating biomarkers will be assessed for all subjects in serum, urine, and (if sample volumes 
permit) synovial fluid. Exploratory PGt analyses will be performed only for subjects who 
provide separate informed consent.
7.6.1
Biomarkers to be Analyzed
Serological and urine biochemical markers of bone and joint tissue turnover will be evaluated. 
Potential biomarkers may include, but are not limited to: aggrecan chondroitin sulfate epitope 
846 (CS846), II form of the propeptides from the N- terminus processed type II collagen 
(PIINP), propeptides from the C-terminus processed type II collagen (PIICP), and C-telopeptide 
cross-linking of type II collagen (CTX-II).
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Measurement of biomarkers in synovial fluid is also foreseen. However, if the quantity of 
synovial fluid collected is not sufficient to permit both PK and biomarker measurement, priority 
will be given to PK.
Samples will be stored for up to 5 years after trial completion under the Sponsor’s responsibility. 
During this time, it is possible that the samples will be re-analyzed by the Sponsor or its 
designee. This may include analyses for newly identified markers and/or a repeat of the original 
analysis with newer improved technologies. After this period of 5 years, either the samples will 
be destroyed or fully anonymized or new IEC/IRB approval will be requested to keep them for 
an additional period.
7.6.2
Body Fluids for Biomarker Assessment
Blood and urine samples for systemic biomarker assessment will be collected at the time points 
specified in Appendix E. For time points where IMP injections are administered, samples will be 
collected pre-dose. For urine collection, second morning void samples should be obtained.
Synovial fluid samples will be collected at the time points specified in Appendix E. These 
samples will be taken just before injection of the IMP as described in the MOP, as part of the i.a. 
injection procedure and using the same needle that will be used for IMP injection. If sample 
volume permits, biomarkers will be analyzed in the samples collected at Week 0/Visit 2, 
Week 28/Visit 9, Week 54/Visit 14 and Week 80/Visit 19; otherwise, priority will be given to 
PK.
Instructions for the preparation and handling of blood samples for assessment of circulating 
proteins can be found in the MOP.
7.6.3
Pharmacogenetics
Exploratory analyses are planned to identify potential associations of genetic variations with 
safety events, drug response, and/or treatment efficacy.
All subjects who are enrolled in the trial will be eligible to participate in the optional PGt 
analysis (except in countries where collection of PGt samples is not allowed). Participation is 
optional, and the subjects who choose to participate will need to sign a specific PGt ICF (see 
Section 9.2).
The results of the genetic analysis are for research purposes only. The results of the genetic tests 
will not be made available to the subject, members of his/her family, his/her personal physician, 
or other third parties, except as specified in Section 9.3.
Once a subject has given appropriate consent, a single blood sample for PGt analysis will be 
collected; this sample can be taken at any trial visit (including pre-dose at the baseline visit).
Instructions for the preparation and handling of blood samples for PGt analysis can be found in 
the MOP.
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Samples will be stored for up to 5 years after trial completion under the Sponsor’s responsibility. 
During this time, it is possible that the samples will be re-analyzed by the Sponsor or its 
designee. This may include analyses for newly identified markers and/or a repeat of the original 
analysis with newer improved technologies. After this period of 5 years, either samples will be 
destroyed or fully anonymized or new IEC/IRB approval to keep the samples for an additional 
period will be requested.
7.7
Other Assessments
7.7.1
Knee Injury and Osteoarthritis Outcome Score - Quality of 
Life and Symptom Index Subscales
The KOOS (33) is a knee-specific questionnaire designed to evaluate both short-term and long-
term consequences of knee injury, including OA; it is intended for use in knee injury potentially 
leading to post-traumatic OA or in primary OA. It consists of 42 items grouped into 5 subscales: 
pain, other symptoms (including swelling, restricted range of motion, and mechanical 
symptoms), function in daily living (ADL), function in sport and recreation (i.e., impact on more 
demanding physical activities), and impact on quality of life (including awareness of the knee 
condition and changes in lifestyle). The subscales are scored separately; each yields a score 
between 0 and 100, with 0 representing extreme knee problems and 100 representing absence of 
problems. The 42 items of the complete KOOS include the 24 items of the WOMAC 
Osteoarthritis Index (26), the most frequently used patient-assessed measure of treatment effect 
in OA. In this study, there will be no duplication of questions from the WOMAC and the KOOS.
The KOOS has been validated for use in patients undergoing total knee replacement for OA. 
Content validity in this patient group was assessed before surgery by asking patients to rate the 
importance of improvement in each of the KOOS subscales. Notably, larger effect sizes were 
seen with the KOOS compared to the WOMAC following TKR for severe knee OA (33),(34). A 
change of 10 points in KOOS score has been proposed as representing clinically meaningful 
difference based on experience with the WOMAC; however, the minimal perceptible clinical 
improvement (MPCI; defined as the change in score associated with the smallest change in 
health status detectable by the patient) has not been formally assessed for the KOOS (33).
In this trial, the KOOS quality of life subscale will be evaluated at the same time points as the 
WOMAC, as a complement to the more general MOS SF-36 (see below). The KOOS Symptom 
Index will also be completed at the same time points for correlation with the other indicators of 
tibiofemoral cartilage loss (e.g., MRI, X-ray).
7.7.2
Medical Outcomes Study Short Form-36 General Health 
Survey
The MOS SF-36 (version 2.0) is a multi-purpose questionnaire that measures general health 
status and QOL, is not knee specific, and is the single PRO measure included to assess the 
overall status of the patient. It consists of 36 items that evaluate 8 dimensions of health: physical 
function, bodily pain, general mental health, vitality (energy and fatigue), social function, 
physical role (role limitations due to physical health), emotional role (role limitations due to 
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personal or emotional problems), and general health perceptions. Scores for the 8 
dimensions/subscales range from 0 to 100, with higher scores representing better QOL. The 
MOS SF-36 is a generic measure as opposed to one targeting a specific age group, disease, or 
treatment. Accordingly, it has proven useful in surveys of general and specific populations, 
comparing the relative burden of different diseases, and examining the health benefits associated 
with a wide range of treatments. It should be noted that there is no defined MOS SF-36 score that 
represents a healthy, unimpaired condition. A subject with no disease symptoms would not 
necessarily have subscale scores of 100 or corresponding physical, mental, and summary scores 
of 400 or 800.
According to the User’s Manual for the MOS SF-36 v. 2.0 Health Survey and Kosinski et 
al. (35), “minimal important differences” in MOS SF-36 scores consist of changes of 2 to 4 
points, depending on the subscale concerned.
7.7.3
Measure of Intermittent and Constant Osteoarthritis Pain 
Questionnaire
The ICOAP (36),(37),(38) is an 11-item questionnaire for assessment of pain in subjects with 
OA that considers both constant and intermittent experiences of pain. Questions address the 
frequency and severity of pain and its impact on the subject’s QOL (including sleep and 
emotional distress).
The ICOAP is designed to be responsive to change in pain over time and with treatment. 
Subjects are asked to respond to the questionnaire considering their symptoms over the past
week, taking into consideration any pain medication that they may be using (i.e., to report their 
experience of pain while taking the medication).
The ICOAP yields a total pain score that can range from 0 to 44 points, a constant pain subscore 
that can range from 0 to 20 points, and an intermittent pain subscore that can range from 0 to 24 
points; higher scores indicate more severe, frequent, or distressing pain.
7.7.4
Patient Global Impression of Change
Global impression scales (39) are recommended for use in chronic pain clinical trials as a core 
outcome measure of global improvement with treatment relative to baseline symptoms (40). It 
provides a responsive and readily interpretable measure of participant's assessments of the 
clinical importance of their improvement or worsening over the course of the clinical trial. 
The PGIC used in this trial is based on the IMMPACT recommendations (40) and will assess the 
subject’s global improvement since starting study treatment using a 7-point scale:
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“Since getting the first injection of study treatment in your knee how would you describe 
the change in overall symptoms for this knee:”
1 = very much improved
2 = much improved
3 = minimally improved
4 = no change
5 = minimally worse
6 = much worse
7 = very much worse
7.7.5
11-Point Numerical Rating Scale Pain Score
The subject will indicate the worst pain in past 24 hours in the target and contralateral knee using 
an 11-point NRS. The NRS for pain is a patient-reported unidimensional pain scale 
recommended for assessing pain intensity (41) which is frequently used instrument in pain trials, 
and also in subjects with osteoarthritis.
The NRS is scaled from 0 (no pain) to 10 (worst possible pain). It has good validity, reliability, 
and sensitivity, being similar in sensitivity to a 100-mm VAS when comparing postoperative 
pain intensity (42).
In this protocol, the NRS will be used as a supplementary pain scale to the WOMAC. The NRS 
has a 24-hour recall period, which may be preferable for detecting recent changes in health status 
compared to PRO questionnaires with longer recall periods (43). Also, the NRS involves a single
overall question whereas the WOMAC uses a group questions to characterize different aspects of 
knee pain. 
7.7.6
Pain in Other Joints 
Data on the presence of pain in ‘other’ joints (that is, joints other than the knee) will be obtained 
because, like pain in the contralateral knee, pain in other joints could potentially become a 
confounding variable when assessing self-reported activities of daily living (WOMAC ADL), 
physical functioning during the 20-meter walk test, and overall health-related quality of life 
(MOS SF-36). Pain in other joints may also serve as indicator of overall OA progression. As has 
been recommended for use in OA studies (44), a scale model of the human body (homunculus) 
will be used (see Appendix F). During subject interview, the homunculus, with circles in six
bilateral joints (shoulder, elbow, wrist, hand/finger, ankle, foot) and neck, for a total of 13 joints, 
will be shown to subjects to indicate painful joints.
8
Statistics
8.1
Sample Size
The sample size was determined from expected changes in the primary endpoint: the change 
from baseline in cartilage thickness in the total femorotibial joint as evaluated by MRI at 2 years.
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This trial is set up to detect a potential dose relationship, based on the total dose of sprifermin
received over the 2 years, in limiting the reduction of or increasing the cartilage thickness in the 
total femorotibial joint, assuming:
! A mean change from baseline at 2 years of
! -0.03 mm in the placebo group (i.e., 0 mcg over 2 years)
! -0.01 mm in the sprifermin 30 mcg once a year group (i.e., 180 mcg over 2 years)
! +0.01 mm in the sprifermin 30 mcg twice a year group (i.e., 360 mcg over 2 years)
! +0.01 mm in the sprifermin 100 mcg once a year group (i.e., 600 mcg over 2 years)
! +0.03 mm in the sprifermin 100 mcg twice a year group (i.e., 1200 mcg over 2 years)
! A common SD (standard deviation) of 0.10 mm
! A type-one error, α, of the primary efficacy analysis set at 5% two-sided
! Normal distribution.
The above assumptions were based on available MRI data from the OAI (http://oai.epi-
ucsf.org/datarelease/) and from the POC trial (28980; see Figure 3).
A minor deviation from linearity has been introduced in these hypotheses based on the 
expectation of similar changes for the sprifermin 30 mcg twice a year and sprifermin 100 mcg 
once a year groups. Indeed, according to the current knowledge of the biological mechanism of 
action of sprifermin, the treatment effect of the highest dose (100 mcg) given once a year could 
be similar to that of a lower dose (30 mcg) given twice a year. Moreover, the variability of the 
measure is large, and therefore a deviation from perfect linearity may be expected.
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Figure 3
Expected Mean Changes in Cartilage Thickness (mm) in Total Knee at 
2 Years (SD = 0.10)
-0.04
-0.03
-0.02
-0.01
0.00
0.01
0.02
0.03
0.04
 Placebo  30 mcg  
x 2
 30 mcg  
x 4
 100 mcg
x 2
 100 mcg
x 4
Placebo
10 mcg
30 mcg
100 mcg
Ph II OA expected (2 years)
POC OA (1 year)
OA: osteoarthritis; POC: proof of concept; SD: standard deviation
Calculations showed that:
! 55 evaluable subjects in each group (total 275 subjects) will ensure a power of 90% for 
detecting a linear dose relationship using a linear trend test,
! 76 evaluable subjects in each group (total 380 subjects) will ensure a power of 90% for 
detecting an overall treatment effect (meaning that at least one group differs from the other 
groups) as well.
Based on recent literature and other trial experience (45, 46), the subject discontinuation rate is 
estimated to be close to 30% at two years. Assuming a 30% drop-out rate, a total of 545 subjects 
should be randomized (109 subjects per group) in order to detect an overall treatment effect.
In order to be able to demonstrate that structure improvement translates into symptomatic 
benefit, it is important that the study be adequately powered to detect significant differences in 
normalized WOMAC scores. With 76 evaluable subjects per treatment group, the power to show 
a statistically significant difference between at least one active treatment group and the placebo 
group for the secondary WOMAC endpoints ranges from 69% to 87% for the total score, from 
80% to 99% for the pain score and from 53% to 83% for the function score, depending on the 
expected mean difference from placebo (see Table 3).
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Table 3
Power Calculations for Pairwise Differences (Sprifermin
versus 
Placebo) on Normalized WOMAC Scores with 76 Evaluable Subjects 
per Treatment Group
Expected mean difference from 
Placebo
Common SD
Power
Total Score - Normalized
(range 0-100 points)
8 points
20
69%
9 points
79%
10 points
87%
Pain Score - Normalized
(range 0-100 points)
10 points
22
80%
15 points
99%
Function Score - Normalized
(range 0-100 points)
7 points
21
53%
9 points
75%
10 points
83%
SD: standard deviation; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index
For reference, a difference of 10 points from placebo in the normalized WOMAC scores is 
considered as clinically meaningful (highlighted in bold type in the table).
8.2
Randomization
Randomization will be coordinated centrally, using an IVRS system which will allocate subjects 
to the treatment groups (see Section 6.3 for further details concerning the technical and logistical 
aspects of treatment allocation).
Eligible subjects will be randomized to one of the 5 treatment groups with an allocation ratio of 
1:1:1:1:1, using a computer-generated randomization list in random permuted blocks.
Randomization will be stratified by country to ensure balance of treatment groups with respect to 
intrinsic and extrinsic factors that may affect OA outcomes. Moreover, it may not be practical to 
stratify randomization by site as numbers of subjects in each site are expected to be small.
8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint of this trial is the change from baseline in cartilage thickness in the total 
femorotibial joint as evaluated by MRI at 2 years.
8.3.2
Secondary Endpoints
Secondary efficacy endpoints are:
! Changes from baseline in the WOMAC total score and in the WOMAC pain, function, and 
stiffness index scores over 2 years
! Change from baseline in the 20-meter walk test over 2 years
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! Change from baseline in the PGA over 2 years
! Change from baseline in minimal JSW in the medial and lateral compartments as evaluated by 
X-ray over 2 years
! Change from baseline in cartilage thickness in the medial and lateral compartments as well as 
in the total femorotibial joint over 2 years
! Change from baseline in cartilage volume in the medial and lateral compartments as well as in 
the total femorotibial joint over 2 years
! Synovial fluid levels of sprifermin/FGF-18 
! Serum levels of sprifermin/FGF-18 
8.3.3
Safety Endpoints
Safety endpoints are:
! Nature, incidence and severity of local and systemic AEs
! Incidence of acute inflammatory reactions (AIRs), defined as increase of pain by 30 mm on a 
100 mm VAS associated with a self-reported synovial fluid effusion (i.e., joint swelling) 
within 3 days following i.a. injection
! Changes in laboratory safety parameters, vital signs, 12-lead ECG parameters, weight, and 
physical examinations
! Incidence of surgical interventions in the target knee (including any surgical revision, 
cartilage removal, or any other type of surgical intervention)
! Occurrence of binding and neutralizing antibodies to sprifermin/FGF-18
8.3.4
Exploratory Endpoints
Exploratory endpoints are:
! Outcome Measures in Rheumatology – Osteoarthritis Research Society International 
(OMERACT-OARSI) responder rate (1) at 2 years
! PGIC over 2 years
! Changes from baseline in the scores of the KOOS QOL and the MOS SF-36 questionnaire 
over 2 years
! Change from baseline in KOOS Symptom Index over 2 years
! Change from baseline in pain score in the target and contralateral knee over 2 years using an 
11-point NRS
! Change from baseline in presence of pain in other joints over 2 years
! Change from baseline in ICOAP scores over 2 years
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! Change over time in structural as well as compositional parameters of the knee joint (e.g., 
synovium, menisci, bone, and other structures) as evaluated by MRI
! Change from baseline in serum, urine, and synovial markers associated with administration of 
the compound
! Baseline protein markers and/or genetic markers  associated with response to treatment or 
disease progression (response assessed by MRI and/or questionnaire)
! Changes in MRI outcomes, WOMAC scores, 20-meter walk test, PGA, PGIC, JSW, 
OMERACT-OARSI responder rate, KOOS QOL, KOOS Symptom Index, MOS SF-36, NRS
pain score in the target and contralateral knee, presence of pain in other joints, ICOAP, safety 
laboratory values, and vital signs over the extended follow-up period and nature, incidence 
and severity of local and systemic AEs during the extended follow-up period (to be 
summarized descriptively)
! Relationship between dosing (dose and regimen), cartilage structure, and clinical scores as a 
function of time
The Outcome Measures in Rheumatology – Osteoarthritis Research Society International 
(OMERACT-OARSI) responder rate (1) will be determined as an exploratory analysis. The 
OMERACT-OARSI responder criteria involve changes that are deemed to be clinically relevant 
in three domains: pain, function, and Patient’s Global Assessment. For each of these domains, 
ranges are defined for absolute and percent changes from baseline that correspond to “high 
improvement” and “moderate improvement”. OMERACT-OARSI response is defined as either 
i) high improvement in pain or function or ii) moderate improvement in at least 2 of the 3 
domains (pain, function, and Patient’s Global Assessment).
In this trial, OMERACT-OARSI response will be determined using WOMAC pain and function
index scores and the PGA described in Section 7.3.3.
8.4
Analysis Sets
Intention-to-Treat Analysis Set (Full Analysis Set)
The Intention-to-Treat (ITT) Analysis Set will include all subjects randomly allocated to a
treatment, based on the intention to treat “as randomized” principle (i.e., the planned treatment 
regimen rather than the actual treatment given in case of any difference).
Modified Intention-to-Treat Analysis Set
The Modified ITT (mITT) Analysis Set will include all subjects from the ITT Analysis Set who 
have a baseline and at least one post-treatment MRI assessment available.
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Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will include all subjects from the mITT Analysis Set who 
have been treated according to the clinical trial protocol and fulfill the following criteria:
! Compliance with all entry criteria
! Absence of major clinical trial protocol violations with respect to factors likely to affect the 
efficacy of treatment, where the nature of such clinical trial protocol violations will be defined 
before breaking the blind
! Adequate compliance with trial medication (this will be defined in the SAP)
Safety Analysis Set
The Safety Analysis Set will include all subjects who receive at least one dose of trial treatment. 
Subjects will be analyzed according to the actual treatment they receive.
Pharmacokinetic Analysis Set
The PK Analysis Set will include all subjects from the Safety Analysis Set with at least one 
available serum or synovial fluid measurement.
Subgroup Analyses
Subgroup analyses (especially for the analysis of the primary endpoint) will be considered for 
categories including Kellgren-Lawrence grade (Grade 2, Grade 3), sex (Male, Female), age 
(< 65 years old, ≥ 65 years old), body mass index (BMI; < 30 kg/m2, ≥ 30 kg/m2), and country.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
An outline of the analysis currently planned is presented in the following sections. The full 
documentation will be provided in the Statistical Analysis Plan (SAP), which will be finalized 
before database lock and unblinding.
It is planned to perform the statistical analysis in two steps. Approximately three months after the 
last subject’s last visit of the DBPC treatment phase, the database will be locked, the treatment 
code will be unblinded, complete analyses will be performed, and a detailed Clinical Trial Report 
will be written based on the data collected up to the end of the DBPC treatment phase. Long-
term follow-up data will be analyzed and reported separately from the DBPC treatment phase 
results. MRI readers, Investigators, and subjects will remain blinded during the extended follow-
up phase.
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Summary Statistics
The summary statistics presented for quantitative variables will be the number of observations 
(n), the number of missing values (missing), mean, standard deviation (SD), median, first and 
third quartiles (Q1, Q3), and minimum (min) and maximum (max) values.
The summary statistics presented for categorical data will be the number of observations (n), the 
number of missing values (missing), and the count and percentage of subjects in each category.
Adjustment for Multiplicity
The main objective of this Phase II trial is to select a dose regimen for further development in 
Phase III; therefore, no adjustment for multiplicity will be made. Caution should be used in 
interpreting significant p-values (p < 0.05). Interpretation of the results will involve global 
consideration of all efficacy results obtained in combination with an appropriate judgment of 
clinical significance.
Missing Data
As a general rule, all data collected and available will be used in the analysis. No imputation of 
missing data will be applied independently of the statistical method used to analyze the data.
Handling of missing data from questionnaires will depend on whether only single items are 
missing or a complete questionnaire is missing. If only single items are missing, the rules defined 
by the authors of the questionnaires (if any) will be followed. If a complete questionnaire is 
missing, different methods of imputation will be used and results will be compared in a 
sensitivity analysis.
8.5.2
Analysis of Primary Endpoint
The primary endpoint is the change from baseline in cartilage thickness in the total femorotibial 
joint as evaluated by MRI at 2 years.
The cartilage thickness in the total femorotibial joint as evaluated by MRI will be tabulated per 
time point (visit) and treatment group, along with the absolute change from baseline and the 
percent change from baseline.
The treatment effect on the primary endpoint will be assessed through dose-ranging using a 
repeated measurement analysis of variance (ANOVA, using PROC MIXED in SAS) on absolute 
change from baseline, including the baseline value, the treatment group, the time, and the 
country as factors and including treatment by time as interaction.
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The primary efficacy analysis will consist of testing the linear dose relationship and the overall 
treatment effect at 2 years. The significance level will be set at 5% two-sided for both tests.
For the linear dose relationship testing, the null and alternative hypotheses will be:
H0: -2 Mean (Placebo) - 1 Mean (180 mcg) + 0 Mean (360 mcg) + 1 Mean (600 mcg) + 2 Mean (1200 mcg) = 0
H1: -2 Mean (Placebo) - 1 Mean (180 mcg) + 0 Mean (360 mcg) + 1 Mean (600 mcg) + 2 Mean (1200 mcg) ∀0
where the doses shown are the total doses of sprifermin to be administered over the DBPC 
treatment phase (see Table 1).
If the null hypothesis is rejected, the alternative hypothesis will be accepted and it will be 
concluded that there is a dose relationship versus placebo over time.
For the overall treatment effect testing, the null and alternative hypotheses will be:
H0: Mean (Placebo) = Mean (180 mcg) = Mean (360 mcg) = Mean (600 mcg) = Mean (1200 mcg)
H1: Mean (i) ∀Mean (j) for some i ∀j and i, j = Placebo or 180 mcg or 360 mcg or 600 mcg or 
1200 mcg.
where the doses shown are the total doses of sprifermin to be administered over the DBPC 
treatment phase (see Table 1).
If the null hypothesis is rejected, the alternative hypothesis will be accepted and it will be 
concluded that there is at least one group that differs from the other groups.
Pairwise comparisons (sprifermin versus placebo, and between sprifermin dose and regimen 
groups) will be performed within the context of this modeling framework. For each pairwise 
comparison, the difference between treatments and the corresponding 95% confidence interval 
(CI) and p-value will be presented.
The primary efficacy analysis will be performed on the mITT Analysis Set.
In order to assess the robustness of the primary results, sensitivity analyses will be performed 
with modification of subject population (PP Analysis Set), statistical methods (influence of the 
distribution, influence of the time effect, and so on), and influence of covariates.
8.5.3
Analysis of Secondary Endpoints
Descriptive statistics for secondary efficacy endpoints will be presented by time point (visit) and 
treatment group.
The same ANOVA model used for the primary endpoint will be used to assess the treatment 
effect on continuous secondary endpoints such as MRI endpoints, WOMAC endpoints (total, 
pain, function, and stiffness scores), and X-ray endpoints at each time point and over time.
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Logistic regression will be used to assess the treatment effect on the binary efficacy endpoints 
such as the OMERACT-OARSI responder rate. Point estimates for each pairwise comparison 
and corresponding 95% CIs and p-values will be provided.
8.5.4
Safety Analyses
Safety data will be summarized descriptively overall and by treatment group, using the Safety 
Analysis Set.
AEs will be coded using the latest available version of the Medical Dictionary for Regulatory 
Activities (MedDRA).
All local and systemic AEs will be reported overall, by severity, and by relationship to trial drug, 
and summaries will be prepared of events leading to discontinuation and events leading to death.
The incidence of protocol-defined AIRs and the incidence of surgical procedures occurring to the 
target knee during the trial will be tabulated separately.
Laboratory safety parameters and vital signs will be descriptively summarized as appropriate.
8.5.5
Analysis of Further Endpoints
The following domains will be described overall and by treatment group using summary 
statistics:
! Disposition of subjects and discontinuations
! Protocol deviations
! Demographics, medical history, and other baseline characteristics
! Past and concomitant medications and procedures, with particular attention to pain 
medications
! Treatment compliance and exposure, as assessed by the number of injections received
PK sample bioanalysis will be performed by Merck Serono NCD-DMPK; and PK data analyses, 
as well as investigation of the relationship between dosing (dose and regimen), cartilage 
structure, and clinical scores as a function of time will be performed by Merck Serono 
Exploratory Medicine.
Exploratory biomarker sample and data analyses will be performed under the responsibility of 
Merck Serono NCD – Biomarker Technologies. The sample analytes will be further specified in 
the Manual of Procedures (MOP), and data analysis will be described in an Exploratory 
Biomarkers Statistical Analysis Plan (SAP). Results will be reported separately in an Exploratory 
Biomarkers Report. 
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Analysis of Data from the Extended Follow-up Phase
Data reported during the extended follow-up phase will be presented mainly using descriptive 
statistics.
Exploratory Pharmacometric Modeling
A modeling analysis will be performed in order to evaluate the disease-modifying effect of 
sprifermin, i.e., improvement of cartilage structure and clinical symptoms (WOMAC).
In particular, the relationship between cartilage structure changes and improvement of clinical 
symptoms will be investigated, in order to support the selection of the optimal dose/dosing 
regimen for future trials.
In order to derive a better understanding of sprifermin
effects, other potential 
influencing/confounding factors such as the placebo effect will be included in the model.
The development of the models implies a covariate analysis to explore the influence of various 
potential predictors of variability, e.g., demographics/anthropometrics, biomarkers (including 
PGt markers), and concomitant medications.
Finally, simulations will be performed to address various scenarios, to support decision making 
and planning of future studies.
Additional models focusing on other secondary/exploratory endpoints could be developed if 
deemed appropriate.
The details of modeling and simulation analyses will be described in a Modeling and Simulation 
Data Analysis Plan.
8.6
Interim Analysis
No interim analysis is planned.
An IDMC will be constituted and will perform periodic reviews to evaluate the safety of the 
subjects participating in the trial on an ongoing basis. Detailed description of the safety 
monitoring will be specified in a dedicated IDMC charter.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at his/her site. S/he will ensure that the 
trial is performed in accordance with the clinical trial protocol and with the ethical principles that 
have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on 
Good Clinical Practice (ICH Topic E6, 1996) and applicable regulatory requirements. In 
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particular, the Investigator must ensure that only subjects who have given their informed consent 
are included into the trial.
In 1998, the US Food and Drug Administration (FDA) introduced a regulation (21 CFR, Part 54) 
entitled “Financial Disclosure by Clinical Investigators”. For trials conducted in any country that 
could result in a product submission to the FDA for marketing approval and could contribute 
significantly to the demonstration of efficacy and safety of the IMP (named “covered trials” by 
the FDA), the Investigator and all sub-Investigators are obliged to disclose any financial interest 
which they, their spouses or their dependent children may have in the Sponsor or the Sponsor’s 
product under study. This information is required during the trial and for 12 months following 
completion of the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the trial is his/her written informed 
consent. The subject’s written informed consent to participate in the trial must be given before 
any trial-related activities are carried out.
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if 
permitted by local regulations). A subject information sheet in the local language and prepared in 
accordance with the Note for Guidance on Good Clinical Practice (ICH Topic E6, 1996) will be 
provided by the Sponsor for the purpose of obtaining informed consent. In addition to providing 
this written information to a potential subject, the Investigator or his/her designate will inform 
the subject verbally of all pertinent aspects of the trial. The language used in doing so must be 
chosen so that the information can be fully and readily understood by laypersons.
Depending on national regulations, a person other than the Investigator may inform the subject 
and sign the ICF, as above.
Where the information is provided by the Investigator, the ICF must be signed and personally 
dated by the subject and the Investigator.
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information and 
ICF should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be provided to each subject in the trial 
for signing and dating. The Investigator will explain the changes to the previous version.
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Pharmacogenetics Informed Consent
All subjects who are enrolled in the trial will be eligible to participate in the optional PGt 
analysis (except in countries where collection of PGt samples is not allowed). Participation is 
optional, and the subjects who choose to participate will need to sign a specific PGt ICF.
9.3
Subject Identification and Privacy
A unique subject number will be assigned to each subject at inclusion, immediately after 
informed consent has been obtained. This number will serve as the subject’s identifier in the trial 
as well as in the clinical trial database.
The subject’s data collected in the trial will be stored under this number. Only the Investigator 
will be able to link the subject’s trial data to the subject via an identification list kept at the site. 
The subject’s original medical data that are reviewed at the site during source data verification 
by the Monitor, audits and Health Authority inspections will be kept strictly confidential.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations.
Confidentiality of Pharmacogenetic Data
The results of the genetic analysis are for research purposes only. The results of the genetic tests 
will not be made available to the subject, members of his/her family, his/her personal physician, 
or other third parties, except as specified below.
Unless otherwise required by law or by regulatory authorities for the purpose of verifying 
information obtained from this trial, only the Sponsor’s authorized personnel and agents will 
have access to the confidential genetic data. The results of the PGt part of the trial may be 
submitted to the regulatory authorities and governmental agencies in countries where the IMP 
may be considered for approval; however, the subject will be identified by trial number and 
subject number only. The subject will not in any case be identifiable in reports or publications 
resulting from this trial.
9.4
Emergency Medical Support and Subject Card
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor. The Emergency Medical 
Support card is based on the need to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial, and subsequently to give health care providers 
access to the information about this participation that may be needed to determine the course of 
the subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical trial; and this may include the possibility of emergency unblinding if needed, in case of 
blinded trials.
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Clinical trial Investigators, who are already aware of the clinical trial protocol and treatment, 
have other means of accessing the necessary medical information for the management of 
emergencies occurring in their subjects.
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, s/he will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard processes 
established for the Investigators.
In cases where the Investigator is not available, Merck Serono/EMD Serono provides the 
appropriate means to contact a Sponsor physician. This includes the provision of a 24-hour 
contact number at a call center, whereby the health care providers will be given access to the 
appropriate Sponsor physician to assist with the medical emergency and to provide support for 
the potential unblinding of the subject concerned.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage shall be provided for each country participating to the trial. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent
Ethics Committee or Institutional Review 
Board
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents (the ICF, IB, subject questionnaires, and subject diaries) 
to the responsible IEC/IRB for its favorable opinion/approval.
The written favorable opinion/approval of the IEC/IRB will be filed in the Investigator Site File, 
and a copy will be filed in the Trial Master File at an external service provider (Trial Master File 
documents will be transferred to the Sponsor at the completion of the trial).
The trial must not start at a site before the Sponsor has obtained written confirmation of 
favorable opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the 
meeting minutes should be obtained.
Amendments to the clinical trial will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes (see Section 10.5). Relevant safety information 
will be submitted to the IEC/IRB during the course of the trial in accordance with national 
regulations and requirements.
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9.7
Health Authorities
The clinical trial protocol and any applicable documentation (e.g., Investigational Medicinal 
Product Dossier, Subject Information and ICF) will be submitted or notified to the Health 
Authorities in accordance with the regulations of the countries involved in the trial.
10
Trial Management
10.1
Case Report Form Handling
The main purpose of the CRF is to obtain those data required by the clinical trial protocol in a 
complete, accurate, legible and timely fashion. The data in the CRF should be consistent with the 
relevant source documents.
The data collected in the course of this trial must be documented in the CRFs and/or the Adverse 
Event Safety Report Form (Clinical Trials). It is the Investigator’s responsibility to ensure the 
accuracy of the data entered in the CRFs.
Details regarding CRF handling and instructions concerning CRF completion are provided in the 
MOP.
10.2
Source Data and Subject Files
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible. In 
particular, the following data should be available in this file:
! Subject’s full name,
! Date of birth,
! Sex,
! Height,
! Weight,
! Medical history and concomitant diseases,
! Prior and concomitant therapies, including nonpharmacological therapies for OA and the use 
of assistive devices for ambulation (e.g., cane) (including changes during the trial),
! Trial identification (EMR700692_006),
! Date of subject’s inclusion into the trial (i.e., date of giving informed consent),
! Subject number in the trial,
! Dates of the subject’s visits to the site,
! Any medical examinations and clinical findings predefined in the clinical trial protocol,
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! Subject diaries,
! All AEs observed in the subject,
! Date of subject’s end of trial, and
! Date of and reason for early withdrawal of the subject from the trial or from IMP, if 
applicable.
It must be possible to identify each subject by using this subject file.
Additionally, any other documents containing source data must be filed. This includes X-rays, 
MRI scan images, ECG recordings, and laboratory value listings. Such documents must bear at 
least the subject number and the date when the procedure was performed. Information should be 
printed by the instrument used to perform the assessment or measurement, if possible. 
Information that cannot be printed by an automated instrument will be entered manually. 
Medical evaluation of such records should be documented as necessary and the documentation 
signed and dated by the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site.
10.3
Investigator Site File and Archiving
The Investigator will be provided with an Investigator Site File upon initiation of the trial. This 
file will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial. It must be available for review by the Monitor, and must be ready 
for Sponsor audit as well as for inspection by Health Authorities during and after the trial, and 
must be safely archived for at least 15 years (or per local requirements or as otherwise notified 
by the Sponsor) after the end of the trial. The documents to be thus archived include the Subject 
Identification List and the signed subject ICFs. If archiving of the Investigator Site File is no 
longer possible at the site, the Investigator must notify the Sponsor.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per 
ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH Note for Guidance on Good Clinical 
Practice (ICH Topic E6, 1996). The site Monitor will perform visits to the trial site at regular 
intervals.
Representatives of the Sponsor’s Quality Assurance unit or a designated organization, as well as 
Health Authorities, must be permitted to inspect all trial-related documents and other materials at 
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the site, including the Investigator Site File, the completed CRFs, the IMP(s), and the subjects’ 
original medical records/files.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the trial to ensure the validity and 
integrity of the trial data.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the Health Authorities 
and to the relevant IEC/IRB for approval or favorable opinion. In such cases, the amendment 
will be implemented only after approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health 
Authorities only where requested by pertinent regulations.
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the subject’s informed consent prior to implementation (see Section 9.2).
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Reports
Clinical Trial Reports according to ICH Topic E3 will be written by the Sponsor in consultation 
with the Coordinating Investigator.
It is planned to perform the statistical analysis in two steps, as described in Section 8.5.1. A 
detailed Clinical Trial Report will be written based on the data collected up to the end of the 
DBPC treatment phase, and long-term follow-up data will be analyzed and reported separately 
from the DBPC treatment phase results.
10.6.2
Publication
The first publication will be a publication of the results of the analysis of the primary endpoint 
that will include data from all trial sites.
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require pre-submission review by the Sponsor.
The Sponsor will not suppress or veto publications, but maintains the right to delay publication 
in order to protect intellectual property rights.
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11
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Liu Z, Xu J, Colvin S, et al. Coordination of chondrogenesis and osteogenesis by 
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flexion positioning with fluoroscopic semi-flexed positioning for quantifying 
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Committee for Medicinal Products for Human use. Guideline on Clinical Investigation 
of Medicinal Products Used in the Treatment of Osteoarthritis. European Medicines 
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Chevalier X, Giraudeau B, Conrozier T, Marliere J, Kiefer P, Goupille P. Safety study 
of intraarticular injection of interleukin 1 receptor antagonist in patients with painful 
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Felson DT, Lynch J, Guermazi A, Roemer FW, Niu J, et al. Comparison of BLOKS 
and WORMS scoring systems part II. Longitudinal assessment of knee MRIs for 
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Osteoarthritis Initiative. Osteoarthritis Cartilage 2010;18(11):1402-7.
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Lynch JA, Roemer FW, Nevitt MC, Felson DT, Niu J, et al. Comparison of BLOKS 
and WORMS scoring systems part I. Cross sectional comparison of methods to assess 
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from the osteoarthritis initiative. Osteoarthritis Cartilage 2010;18(11):1393-401.
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26.
Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of 
WOMAC: a health status instrument for measuring clinically important patient relevant 
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knee. J Rheumatol 1988;15(12):1833-40.
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Tubach F, Ravaud P, Baron G, et al. Evaluation of clinically relevant changes in 
patient reported outcomes in knee and hip osteoarthritis: the minimal clinically 
important improvement. Ann Rheum Dis 2005;64:29-33.
28.
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Simonsick EM, Gardner AW, Poehlman ET.Assessment of physical function and 
exercise tolerance in older adults: reproducibility and comparability of five measures. 
Aging (Milano) 2000 Aug;12(4):274-80.
31.
Marks R. Reliability and validity of self-paced walking time measures for knee 
osteoarthritis. Arthritis Care Res 1994;7(1):50-3.
32.
Berkoff DJ, Miller LE, Block JE. Clinical utility of ultrasound guidance for intra-
articular knee injections: a review. Clin Interv Aging 2012;7:89-95. 
33.
Roos EM, Lohmander LS. The Knee Injury and Osteoarthritis Outcome Score 
(KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64.
34.
Roos EM, Toksvig-Larsen S. Knee Injury and Osteoarthritis Outcome Score (KOOS) -
validation and comparison to the WOMAC in total knee replacement. Health Qual Life 
Outcomes 2003;1:17.
35.
Kosinski M, Zhao SZ, Dedhiya S, Osterhaus JT, Ware JE, Jr. Determining minimally 
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36.
Hawker G. Measure of Intermittent and Constant Osteoarthritis Pain: ICOAP. User's 
Guide. 2010.
37.
Maillefert JF, Kloppenburg M, Fernandes L, Punz L, Gunther KP, et al. Multi-
language translation and cross-cultural adaption of the OARSI/OMERACT measure of 
intermittent and constant osteoarthritis pain (ICOAP). Osteoarthritis Cartilage 
2009;17:1293-6.
38.
Davis AM, Lohmander LS, Wong R, Venkataramanan V, Hawker GA. Evaluating the 
responsiveness of the ICOAP following hip or knee replacement. Osteoarthritis 
Cartilage 2010;18:1043-5.
39.
Salaffi F, Stancati A, Silvestri CA, Ciapetti A, Grassi W. Minimal clinically important 
changes in chronic musculoskeletal pain intensity measured on a numerical rating 
scale. Eur J Pain 2004;8(4):283-91.
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40.
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, et al. Core 
outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 
2005;113(1-2):9-19.
41.
Veenhof C, Bijlsma JW, van den Ende CH, van Dijk GM, Pisters MF, Dekker J. 
Psychometric evaluation of osteoarthritis questionnaires: a systematic review of the 
literature. Arthritis Rheum 2006;55(3):480-92.
42.
Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, et al. 
Assessment of pain. Br J Anaesth 2008;101(1):17-24.
43.
Ware JE, Jr., Kosinski M, Dewey JE. How to score version 2 of the SF-36 health 
survey. 3 ed. 2000.
44.
Abramson SB, Berenbaum F, Hochberg MC, Moskowitz RW. Introduction to OARSI 
FDA initiative OAC special edition. Osteoarthritis Cartilage 2011;19(5):475-7. 
45.
Hellio le Graverand MP, Clemmer RS, Redifer P, Brunell RM, Hayes CW, Brandt KD, 
Abramson SB, Manning PT, Miller CG, Vignon Eet al. A 2-year randomised, double-
blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, 
cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann 
Rheum Dis 2013;72(2):187-95.
46.
Wang Y, Hall S, Hanna F, Wluka AE, Grant G, Marks P, et al. Effects of Hylan G-F 20 
supplementation on cartilage preservation detected by magnetic resonance imaging in 
osteoarthritis of the knee: a two-year single-blind clinical trial. BMC Musculoskelet 
Disord 2011;12:195.
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12
Appendices
Appendix A:
American College of Rheumatology Criteria for the 
Classification and Reporting of Osteoarthritis of the Knee
For this trial, please use the following reference:
Altman R, Asch E, Bloch D, Bole G, Borenstein K, Brandt W, et al. Development of criteria for 
the classification and reporting of osteoarthritis: Classification of osteoarthritis of the knee. 
Arthritis & Rheumatism 1986;29(8): 1039-49.
Table 4
Summary of Criteria for Classification of Idiopathic Osteoarthritis of 
the Knee
Clinical and Laboratory
Clinical and Radiographic
Clinical†
Knee pain
+ at least 5 of 9:
!
Age > 50 years
!
Stiffness < 30 minutes
!
Crepitus
!
Bony tenderness
!
Bony enlargement
!
No palpable warmth
!
ESR < 40 mm/hour
!
RF < 1:40
!
SF OA
Knee pain
+ at least 1 of 3:
!
Age > 50 years
!
Stiffness < 30 minutes
!
Crepitus
!
Osteophytes
Knee pain
+ at least 3 of 6:
!
Age > 50 years
!
Stiffness < 30 minutes
!
Crepitus
!
Bony Tenderness
!
Bony enlargement
!
No palpable warmth
92% sensitive
91% sensitive
95% sensitive
75% specific
86% specific
69% specific
ESR = erythrocyte sedimentation rate (Westergren); RF = rheumatoid factor; SF OA = synovial fluid signs of OA
(clear, viscous, or white blood cell count < 2,000/mm3).
† Alternative for the clinical category would be 4 of 6, which is 84% sensitive and 89% specific.
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Appendix B:
Safety Laboratory Parameters
The following laboratory parameters will be measured.
Hematology
!
White blood cell (WBC) count
!
Lymphocytes (absolute count, %)
!
Monocytes (absolute count, %)
!
Neutrophils (absolute count, %)
!
Eosinophils (absolute count, %)
!
Basophils (absolute count, %)
!
Red blood cells
!
Hematocrit
!
Hemoglobin
!
Platelets
Coagulation (screening assessment only; 
to be done locally)
!
Partial thromboplastin time (PTT)
!
International Normalized Ratio (INR)
Clinical biochemistry
!
Aspartate aminotransferase (AST)
!
Alanine aminotransferase (ALT)
!
Alkaline phosphatase (ALP)
!
Total protein
!
Total bilirubin
!
Creatine kinase (CK)
!
Creatinine
!
Calcium
!
Phosphorus
!
Sodium
!
Potassium
!
Magnesium
!
Blood urea nitrogen (BUN)
!
Glucose (not fasting)
!
Chloride
!
Albumin
!
High-sensitivity C-reactive protein (hsCRP)
!
Erythrocyte sedimentation rate (ESR)
!
Interleukin-6 (IL-6)
Urinalysis
!
Dipstick parameters:
!
pH
!
Specific gravity
!
Protein
!
Glucose
!
Ketones
!
Bilirubin
!
Blood
!
Urobilinogen
!
Leukocytes
Pregnancy tests (to be done locally)
!
Serum during screening; urine at other time points.
Immunogenicity
!
Presence of antibodies to sprifermin/FGF-18
Instructions for sample collection, handling, and shipping are provided in the MOP.
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Appendix C:
Subject Questionnaires: WOMAC, MOS SF-36, and ICOAP
Subjects will complete all of the following questionnaires themselves.
Western 
Ontario 
and 
McMaster
Universities 
Osteoarthritis 
Index 
(WOMAC) 
Questionnaire
Appropriate translations of the entire WOMAC# version 3.1 questionnaire (11-box numerical 
scale version) by 
 and the corresponding User’s Guide 3.1 will be used.
For administration of the questionnaire, instructions for the WOMAC 3.1 Index should be 
followed.
The WOMAC# version 3.1 questionnaire and User’s Guide will be provided separately.
Medical Outcomes Study Short Form-36 General Health Survey (MOS SF-36)
Appropriate translations of the MOS SF-36 version 2.0 and the corresponding User’s Manual 
will be used.
The MOS SF-36 questionnaire version 2.0 and User’s Manual will be provided separately.
Measure of Intermittent and Constant Osteoarthritis Pain Questionnaire (ICOAP)
Version 3 of the ICOAP questionnaire and the corresponding User’s Guide will be used in this 
trial.
The ICOAP will only be used in countries for which an appropriate validated translation of the 
questionnaire is available.
For administration of the questionnaire, instructions in the User’s Guide for the ICOAP, version 
3, should be followed. In this trial, the questionnaire will be completed by the subject.
The questionnaire and the corresponding User’s Guide will be provided separately.
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Appendix D:
Knee Injury and Osteoarthritis Outcome Score Quality of 
Life (KOOS QOL) and Symptom Index Subscales
The KOOS QOL consists of the following 4 questions, to be evaluated by the subject using the 
indicated 5-point scales.
Q1. How often are you aware of your knee problem?
Never
Monthly
Weekly
Daily
Constantly
Q2. Have you modified your life style to avoid potentially damaging activities to your knee?
Not at all
Mildly
Moderately
Severely
Totally
Q3. How much are you troubled with lack of confidence in your knee?
Not at all
Mildly
Moderately
Severely
Extremely
Q4. In general, how much difficulty do you have with your knee?
None
Mild
Moderate
Severe
Extreme
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The KOOS Symptom Index consists of the following 5 questions, to be evaluated by the subject 
using the indicated 5-point scales with the following instructions:
These questions should be answered thinking of your knee symptoms during the last week:
Q1. Do you have swelling in your knee?
Never
Rarely
Sometimes
Often
Always
Q2. Do you feel grinding, hear clicking or any other type of noise when your knee moves?
Never
Rarely
Sometimes
Often
Always
Q3. Does your knee catch or hang up when moving?
Never
Rarely
Sometimes
Often
Always
Q4. Can you straighten your knee fully?
Always
Often
Sometimes
Rarely
Never
Q5. Can you bend your knee fully?
Always
Often
Sometimes
Rarely
Never
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Appendix E:
Schedule of Trial Procedures
Table 5
Schedule of Trial Procedures for Visits 1 to 11
Visit
Screening(1)
Baseline 
V3
V4
V5
V6
V7
V8
V9
V10
V11
V1a
V1b
V2
Week(2)
-42 to -4 
days
0(3)
1
2
3
12
26
27
28
29
38
Informed consents (4)
X
Demographics
X
Medical/medication history
X
Inclusion/Exclusion criteria
X
X
X
Withdraw analgesia prior to visit(5)
X
X
X
X
X
Identification of target knee
X
Randomization
X
WOMAC (question 1 only)
X
X
WOMAC (full questionnaire)
X
X
X
X
Patient’s Global Assessment
X
X
X
X
X
KOOS QOL and Symptom Index
X
X
X
X
PGIC
X
X
X
Pain NRS both knees
X
X
X
X
X
X
Pain in other joints
X
X
MOS SF-36
X
X
ICOAP
X
X
X
X
AEs
Continuous
Concomitant medications 
Continuous
Surgical procedures (target knee)
Continuous
Review of subject diaries
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (6)
X
X
X
X
X
X
X
X
X
X
X
Physical examination(7)
X
X
X
ECG
X
Clinical laboratory specimens (8)
X
X
X
Antibodies to sprifermin/FGF-18
X
X
X
X
PK serum collection (9)
X
X
X
Biomarker serum collection(10)
X
X
Biomarker urine collection
X
X
PGt sample collection (11)
One sample needed. Can be obtained at any trial visit, preferably at baseline.
Pregnancy test (12)
X
X
X
X
X
X
X
20-meter walk test
X
X
X
X
X
Knee X-ray(s) (13)(14)
X
Target knee MRI (3)(14)
X
X
Synovial fluid collection(15)
X
X
X
X
X
X
i.a. injection of IMP
X
X
X
X
X
X
Table footnotes appear on following page.
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Abbreviations: AEs: adverse events; ECG: electrocardiogram; i.a: intra-articular; ICOAP: Measure of Intermittent and 
Constant Osteoarthritis Pain; KOOS: Knee Injury and Osteoarthritis Outcome Score; MRI: magnetic resonance 
imaging; NRS: numerical rating scale; PGIC: Patient Global Impression of Change; PK: pharmacokinetic; QOL: 
quality of life; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index
Subjects will be requested to discontinue the intake of any pain medications for at least 5 half-lives before a visit 
involving completion of the WOMAC.
At visits where IMP is administered, all procedures should be performed before dosing unless otherwise specified. 
Subject questionnaires (WOMAC, PGA, KOOS QOL, KOOS Symptom Index, PGIC, NRS in both knees, pain in other 
joints, MOS SF-36, and ICOAP) should be completed before any other procedures are performed; the WOMAC 
should be completed first.
At each visit, subjects will be given trial diaries which will be collected and reviewed at the following visit (see Section 
7.1.1).
1. After informed consent for the trial is obtained, screening procedures can be spread out over this period if 
necessary for logistical reasons. However, subject questionnaires (WOMAC question 1, PGA, and NRS pain) must 
be completed on the same day at the beginning of screening. Subjects not taking analgesic medication at the time of 
informed consent signature can have Visit 1a and 1b procedures completed at the same visit. If Visit 1a and 1b are 
being combined do not repeat the WOMAC Question 1 or the NRS pain score. See Section 7.1.2 for details.
2. Study visits, beginning with Visit 3, should be planned for the study day specified in the protocol. If it is not possible 
to complete the visit on the planned day, or if an emergency occurs, the protocol does allow for some exceptions as 
long as the minimum and maximum between injection and between treatment cycle restrictions are maintained. See 
Section 7.1.1 for details.  
3. If it is not possible to schedule an MRI scan for the same day as the other baseline assessments for logistical 
reasons, the baseline MRI may be performed up to 3 days after confirmation of eligibility by baseline WOMAC. 
Randomization and IMP administration will then take place on the day of the baseline MRI (following the scan), and 
subsequent visits will be planned relative to the day of IMP administration. If baseline procedures are done on 
different days, those shown in the first column must be performed on the day of the WOMAC, and those shown in the 
second column must be performed on the day of the MRI (the scan must be performed before IMP injection). If an 
MRI scan can be scheduled on the same day as the confirmation of eligibility, all procedures listed for the baseline 
visit (in either column) must be performed on the same day.
4. Study informed consent and separate PGt consent.
5. All pain medications must be withheld for at least 5 half-lives before any visit with a WOMAC assessment 
beginning with Visit 1b.
6. Sitting systolic and diastolic blood pressure, heart rate, and body temperature.
7. Including height and weight at screening and weight at Week 26/Visit 7.
8. Hematology, biochemistry, urinalysis. See Appendix B for complete list. Coagulation tests will be performed locally 
at the screening assessment only.
9. Blood samples for PK will be taken pre-dose at Week 0/Visit 2, and thereafter 2 hours after the last dose of each 
cycle.
10. Fasting samples for biomarker analysis.
11. PGt samples will be collected for consenting subjects only. 
12. Pregnancy testing: serum during screening; urine at subsequent time points (prior to IMP injection) and prior to 
each X-ray and MRI.
13. X-rays of both the target and the contralateral knee will be taken during screening, at Week 104/Visit 22/Early 
Termination, and at the last EFU visits; X-rays of only the target knee will be taken at other time points. During 
screening, a long-axis view of the target knee will be taken in addition to the anterior/posterior view.
14. At time points where IMP administration is scheduled, X-rays and MRIs may be performed up to 3 days before 
the planned day of IMP administration. At time points where there is no IMP administration scheduled, X-rays and 
MRIs may be performed within ±4 days (DBPC treatment phase) or ± 7 days (extended follow-up phase) of the 
planned day.
15. At visits where IMP is injected, synovial fluid will be collected as part of the i.a. injection procedure, using the 
same needle that will be used for IMP injection. PK will be analyzed in synovial fluid at all indicated sampling time 
points. If the volume of synovial fluid collected permits, biomarkers will also be analyzed at Week 0/Visit 2 and at 
Week 26/Visit 7.
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Table 6
Schedule of Trial Procedures for Visits 12 to 22 and Extended Follow-up Visits
Visit
V12
V13
V14
V15
V16
V17
V18
V19
V20
V21
V22/ 
ET
V23
(EF1)
V24
(EF2)
V25
(EF3)
V26
(EF4)
V27
(EF5)
V28
(EF6)
Week(1)
52
53
54
55
64
78
79
80
81
90
104
130
156
182
208
234
260
Withdraw of analgesia prior to visit
X
X
X
X
X
X
X
X
X
X
X
WOMAC 
X
X
X
X
X
X
X
X
X
X
X
PGA
X
X
X
X
X
X
X
X
X
X
X
KOOS QOL and Symptom Index
X
X
X
X
X
X
X
X
X
X
X
PGIC
X
X
X
X
X
X
X
X
X
X
X
NRS in both knees
X
X
X
X
X
X
X
X
X
X
X
Pain in other joints
X
X
X
X
X
X
X
X
X
MOS SF-36
X
X
X
X
X
X
X
X
X
ICOAP
X
X
X
X
X
X
X
X
X
X
X
AEs
Continuous
Concomitant medications
Continuous
Surgical procedures (target knee)
Continuous
Review of subject diaries
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination(3)
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
Clinical laboratory specimens(4)
X
X
X
X
X
X
X
X
X
Antibodies to sprifermin/FGF-18
X
X
X
X
X
PK serum collection (5)
X
X
X
Biomarker serum collection(6)
X
X
X
Biomarker urine collection
X
X
X
PGt sample collection (7)
One sample is needed. It can be taken at any trial visit.
Pregnancy test (urine) (8)
X
X
X
X
X
X
20-meter walk test
X
X
X
X
X
X
X
X
X
X
X
Knee X-ray (9)(10)
X
X
X
X
X
Target Knee MRI (10)
X
X
X
X
X
X
Synovial fluid collection (11)
X
X
X
X
X
X
i.a. injection of IMP
X
X
X
X
X
X
Table footnotes appear on following page.
CCI
CCI


Sprifermin
Phase II Trial of Sprifermin in Knee OA
EMR700692_006
Document No. 
Object No. 
112/113
Abbreviations: AEs: adverse events; ECG: electrocardiogram; i.a: intra-articular; ICOAP: Measure of Intermittent and Constant Osteoarthritis Pain; KOOS: Knee 
Injury and Osteoarthritis Outcome Score; MRI: magnetic resonance imaging; NRS: numerical rating scale; PGIC: Patient Global Impression of Change; PK: 
pharmacokinetic; QOL: quality of life; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index
ET: Early Termination (procedures shown for this visit should be performed at the time of early treatment discontinuation or trial withdrawal.) EF: Extended follow-
up.
Subjects will be requested to discontinue the intake of any pain medications for at least 5 half-lives before a visit involving completion of the WOMAC.
At visits where IMP is administered, all procedures should be performed before dosing unless otherwise specified. Subject questionnaires (WOMAC, PGA, KOOS 
QOL, KOOS Symptom Index, PGIC, NRS in both knees, pain in other joints, MOS SF-36, and ICOAP) should be completed before any other procedures are 
performed; the WOMAC should be completed first.
At each visit, subjects will be given trial diaries which will be collected and reviewed at the following visit (see Section 7.1.1).
1. Study visits, beginning with Visit 3, should be planned for the study day specified in the protocol. If it is not possible to complete the visit on the planned day, or if 
an emergency occurs, the protocol does allow for some exceptions as long as the minimum and maximum between injection and between treatment cycle 
restrictions are maintained. See Section 7.1.1 for details.
2. Sitting systolic and diastolic blood pressure, heart rate, and body temperature.
3. Including weight every six months (Weeks 78 and 104; Visits 17 and 22 in the treatment phase and all visits is the extended follow-up phase) and height at the 
end of the DBPC phase (Week 104/Visit 22/Early Termination) and last extended follow-up visit.
4. Hematology, biochemistry, urinalysis. See Appendix B for complete list. Coagulation tests will be performed locally at the screening assessment only.
5. Blood samples for PK will be taken 2 hours after the last dose of each cycle.
6. Fasting samples for biomarker analysis.
7. PGt samples will be collected for consenting subjects only.
8. Urine pregnancy test at scheduled time points (prior to IMP injection) and prior to each X-ray and MRI.
9. X-rays of both the target and the contralateral knee will be taken during screening, at Week 104/Visit 22, and at the last EF visits; X-rays of only the target knee 
will be taken at other time points. During screening, a long-axis view of the target knee will be taken in addition to the anterior/posterior view.
10. At time points where IMP administration is scheduled, X-rays and MRIs may be performed up to 3 days before the planned day of IMP administration. At time 
points where there is no IMP administration scheduled, X-rays and MRIs may be performed within ±4 days (DBPC treatment phase) or ± 7 days (extended follow-
up phase) of the planned day.
11. At visits where IMP is injected, synovial fluid will be collected as part of the i.a. injection procedure, using the same needle that will be used for IMP injection.
PK will be analyzed in synovial fluid at all indicated sampling time points. If the volume of synovial fluid collected permits, biomarkers will also be analyzed at Week 
52/Visit 12.
CCI
CCI


Sprifermin
Phase II Trial of Sprifermin in Knee OA
EMR700692_006
Document No. 
Object No. 
113/113
Appendix F:
Pain in Other Joints
CCI
CCI

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Study week window 
Questionnaires/20
M/Labs (for 2-5 
years part) 
/NRS/SF36/Pain in 
other joints target 
day 
 (min, max)~ 
qMRI and 
SF36/Pain in 
other joints and 
Labs (for the 
year-2 part) 
target day  
(min, max)~ 
X-ray, 
sqMRI, ECG 
target day 
(min, max) 
AVISIT
N for 
ADQS 
AVISIT
N for 
MRI 
AVISIT
N for 
XRAY 
Baseline * 
1 (-42, 1) 
1 (-42, 1) 
1 (-42, 1) 
1 
1 
1 
Month 3/Week 12~ 
85 (2, 133) 
183 
 (2, 224) 
365  
(2, 406) & 
2 
3 
5 
Month 6/Week 26 * 
183 (134, 224) 
3 
Month 9/Week 38~ 
267 (225, 315) 
365 
 (225, 406) 
4 
5 
Month 12/Week 52 * 
365 (316, 406) 
5 
Month 15/Week 64~ 
449 (407, 497) 
547 
 (407, 588) 
729  
(407, 819) 
6 
7 
9 
Month 18/Week 78 * 
547 (498, 588) 
7 
Month 21/Week 90~ 
631 (589, 679) 
729  
(589, 819) 
8 
9 
Month 24/Week 104 
729 (680, 819) 
9 
Month 30/Week 130 
911 (820, 1001) 
1093 
 (820, 1183) 
1093  
(820, 1183) 
10 
11 
11 
Month 36/Week 156 
1093 (1002, 1183) 
11 
Month 42/Week 182 
1275 (1184, 1365) 
1457 
 (1184, 1547) 
1457  
(1184, 1547) 
12 
13 
13 
Month 48/Week 208 
1457 (1366, 1547) 
13 
Month 54/Week 234 
1639 (1548, 1729) 
1821 
 (1548, 1849) 
1821  
(1548, 1849) 
14 
15 
15 
Month 60/Week 260 
1821 (1730, 1849) 
15 
LOCF1 (up to Month 
24) 
Last post-baseline measurement in DBPC  (2, 819) 
20 (for 2 years) 
LOCF2 (Up to Month 
60) 
Last post-baseline measurement in Follow-up period 
(2, 1849) 
50 (for 5 years) 
*treatment cycle; Day 1 is first treatment day. If multiple assessments are available within each study 
week window, the one closest to target day will be used. At Baseline, week 26, 52 and 78 [injections 
visits] pre injection assessments will be considered for the corresponding study week window). & for 
X-ray and this timepoint with injections - only compare to first injection in cycle # 3. don't compare to 
first injection in cycle #2 to determine if used in analysis or not. ~For SF36, lab, height, weight (and 
BMI), and pain in other joint, in the 2-years period, assessments are scheduled as qMRI, so qMRI 
windowing will be used. For the 2-5 years the scheduling is like ADQS, therefore, ADQS windowing will 
be used for these assessments.  
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Study week window 
To be used 
relative to 
injection visit 
independent of 
ADY  
AVISITN for 
injection -
related 
 ADVS 
Cycle 1/Week 0/pre-injection assessment/Baseline  
Yes 
1 
Cycle 1/Week 1/pre-injection assessment 
Yes 
2 
Cycle 1/Week 2/pre-injection assessment 
Yes 
3 
Cycle 1/Week 3 
Yes 
4 
  
  
  
Cycle 2/Week 0/pre-injection assessment 
Yes 
5 
Cycle 2/Week 1/pre-injection assessment 
Yes 
6 
Cycle 2/Week 2/pre-injection assessment 
Yes 
7 
Cycle 2/Week 3 
Yes 
8 
  
  
  
Cycle 3/Week 0/pre-injection assessment 
Yes 
9 
Cycle 3/Week 1/pre-injection assessment 
Yes 
10 
Cycle 3/Week 2/pre-injection assessment 
Yes 
11 
Cycle 3/Week 3 
Yes 
12 
  
  
  
Cycle 4/Week 0/pre-injection assessment 
Yes 
13 
Cycle 4/Week 1/pre-injection assessment 
Yes 
14 
Cycle 4/Week 2/pre-injection assessment 
Yes 
15 
Cycle 4/Week 3 
Yes 
16 
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Study week window 
ADVS target day (min, max) 
AVISITN for relative visit  ADVS 
Baseline 
1 (-42, 1) 
1 
Month 3/Week 12 
85 (2, 133) 
2 
Month 6/Week 26 
183 (134, 224) 
3 
Month 9/Week 38 
267 (225, 315) 
4 
Month 12/Week 52  
365 (316, 406) 
5 
Month 15/Week 64 
449 (407, 497) 
6 
Month 18/Week 78 
547 (498, 588) 
7 
Month 21/Week 90 
631 (589, 679) 
8 
Month 24/Week 104 
729 (638, 819) 
9 
Month 30/Week 130 
911 (820, 1001) 
10 
Month 36/Week 156 
1093 (1002, 1183) 
11 
Month 42/Week 182 
1275 (1184, 1365) 
12 
Month 48/Week 208 
1457 (1366, 1547) 
13 
Month 54/Week 234 
1639 (1548, 1729) 
14 
Month 60/Week 260 
1821 (1730, 1849) 
15 
LOCF1 (up to Month 24) 
Last post-baseline measurement  
in DBPC  (2, 819) 
20 
LOCF2 (Up to Month 60) 
Last post-baseline measurement  
in Follow-up period (2, 1849) 
50 
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