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	PPD
Sponsor	Merck KGaA Frankfurter Strasse 250, 64293 Darmstadt, Germany (for the USA) EMD Serono, Inc. One Technology Place, Rockland, MA 02370 USA Medical Responsible: PPD 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

Previous Protocol Amendments

• Amendment No. 1 (Non-substantial), 13 Oct 2011 (Global)

Signature Page

Protocol Lead responsible for designing the clinical trial:

Coordinating Investigator:

Further Sponsor Responsible Persons

Principal Investigator Signature

• 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.

Table of Tables

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

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

List of Abbreviations

1 Synopsis

Trial title	A multicenter, randomized, double-blind, placebocontrolled, 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

2

Sponsor

Sponsor Responsibilities

External Service Providers

Investigators and Trial Sites

Coordinating Investigator

Independent Data Monitoring Committee

Trial Administrative Structure

3 Background Information

Nonclinical Data

Clinical Data

Rationale for the Present Trial

4 Trial Objectives

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

5 Investigational Plan

5.1 Overall Trial Design and Plan

Figure 1

Figure 2 Trial Schema: Extended Follow-up Phase

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,

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.

DBPC Treatment Phase

• 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

Extended Follow-Up Phase

Trial 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 (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

• 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

• 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
• 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

Interim Analysis and Data Monitoring

Planned Duration of the Trial

5.2 Discussion of Trial Design

Overall Trial Design

Subject Population

Dose and Dose Regimen

Trial Assessments

Evaluation of Structure by MRI and Choice of MRI as Primary Endpoint

Evaluation of Symptoms

Evaluation of JSW by X-ray

Evaluation of Safety

Biomarker Assessment

Pharmacokinetic Assessment

Evaluation of Health-related Quality of Life

5.2.1 Inclusion of Special Populations

5.3 Selection of Trial Population

5.3.1 Inclusion Criteria

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 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 per year when used consistently and correctly,
   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

1. Malalignment of degrees in the femorotibial axis of the target knee as assessed by the Xray 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 < (female) or < (male)
• White blood cell (WBC) count cells and cells
• Platelet count or coagulation tests (prothrombin time, partial thromboplastin time, International Normalized Ratio) outside the central laboratory's normal range
• Creatinine clearance rate min estimated using the Cockroft-Gault formula
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) times ULN, or total bilirubin 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

• 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.

• 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.

5.5

Criteria for Subject Withdrawal

5.5.1 Withdrawal from the Trial

• Withdrawal of the subject's consent
• Subject's participation in another trial

5.5.2 Withdrawal from the Investigational Medicinal Product

• 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

5.6 Premature Discontinuation of the Trial

• 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.

5.7 Definition of End of Trial

6 Investigational Medicinal Products and Other Drugs Used in the Trial

6.1 Description of Investigational Medicinal Products

6.1.1 Sprifermin

6.1.2 Placebo

6.2 Dosage and Administration

6.3 Assignment to Treatment Groups

6.4
Other Drugs to be used in the Trial

6.5 Concomitant Medications and Therapies

6.5.1 Permitted Medicines

6.5.2 Non-permitted Medicines

• Intra-articular injection of corticosteroids or hyaluronic acid into either knee
• Long-term treatment (>14 days) with oral corticosteroids day

• Any parenteral or oral anticoagulant, including heparin, coumadin/warfarin, or their derivatives, or any other anticoagulant medications
• Any investigational agent

6.5.3 Other Trial Considerations

Other Permitted Therapies

Other Non-Permitted Therapies

6.5.4 Special Precautions

6.6 Packaging and Labeling

• 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

6.8

Investigational Medicinal Product Accountability

• 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.

6.9

Assessment of Investigational Medicinal Product Compliance

6.10 Method of Blinding

6.11 Emergency Unblinding

6.12 Treatment of Overdose

6.13 Medical Care of Subjects after End of Trial

7 Trial Procedures and Assessments

7.1 Schedule of Assessments

7.1.1 General Instructions

Informed Consent

Assignment of a Subject Identifier

Subjects Who Fail Screening

• Informed consent
• Demographics
• AEs
• Date and reason for screening failure
• Investigator signature

Adverse Events and Concomitant Medications

Allowable Time Frame for Trial Visits and Assessments

Allowable intervals between weekly IMP injections:

Allowable intervals between six month treatment cycles:

• 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

Allowable intervals for other visits:

Allowable intervals for X-rays and MRIs:

Pain Medication Washout

Subject Questionnaires

Subject Diaries

• 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 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.
• 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.

Pharmacogenetic Analysis

7.1.2 Screening Period (Visits 1a and 1b)

Visit 1a

• 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)
• NRS pain score for both knees
• Collection of demographic characteristics (see Section 7.2)
• Medical/medication history (see Section 7.2)

Visit 1b

• 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

• 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

• 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)

7.1.3 Double-Blind Placebo-Controlled Treatment Phase (Visits 2 to 22)

• 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.

7.1.3.1 Baseline Visit (Week 0; Visit 2)

• 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

• 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
  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).

7.1.3.2 IMP Administration

• 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).

• 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).

7.1.3.3 Major Efficacy Visits (Weeks 26, 52, 78, and 104; Visits 7, 12, 17, and 22)

• 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)
• 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.

• 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

• 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)

• 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.

7.1.5 Follow-Up in Case of Early Termination

Early Treatment Discontinuation

Early Trial Withdrawal

7.2 Demographic and Other Baseline Characteristics

7.3 Assessment of Efficacy

7.3.1 Magnetic Resonance Imaging

MRI Scanning

MRI Analysis

Quantitative MRI Assessment

Semi-quantitative MRI Assessment

7.3.2 WOMAC Questionnaire

7.3.3 Patient's Global Assessment

7.3.4 X-Ray Imaging

X-Ray Image Acquisition

X-Ray Image Analysis

Measurement of Joint Space Width

Kellgren-Lawrence Scoring

• 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

7.3.5 20-Meter Walk Test

7.4 Assessment of Safety

7.4.1 Adverse Events

7.4.1.1 Adverse Event Definitions

Adverse Event

Abnormal Laboratory Findings and Other Abnormal Investigational Findings

Serious Adverse Event

• Results in death.
• Is life-threatening.

• 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.

Events that Do Not Meet the Definition of an SAE

Pre-defined AEs of Special Interest for Safety Monitoring

7.4.1.2 Methods of Recording and Assessing Adverse Events

7.4.1.3 Definition of the Adverse Event Reporting Period

7.4.1.4 Procedure for Reporting Serious Adverse Events

7.4.1.5 Safety Reporting to Health Authorities, Independent Ethics Committees/ Institutional Review Boards and Investigators

7.4.1.6 Monitoring of Subjects with Adverse Events

7.4.2 Pregnancy and In Utero Drug Exposure

7.4.3 Laboratory Assessments

• 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.

Pregnancy Tests

Management of Subjects with Laboratory Abnormalities

7.4.4 Vital Signs, Physical Examinations, and Other Assessments

7.5 Pharmacokinetics

7.5.1 Body Fluids

• 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

7.6 Biomarkers and Pharmacogenetics

7.6.1 Biomarkers to be Analyzed

7.6.2 Body Fluids for Biomarker Assessment

7.6.3 Pharmacogenetics

7.7 Other Assessments

7.7.1 Knee Injury and Osteoarthritis Outcome Score - Quality of Life and Symptom Index Subscales

7.7.2 Medical Outcomes Study Short Form-36 General Health Survey

7.7.3 Measure of Intermittent and Constant Osteoarthritis Pain Questionnaire

7.7.4 Patient Global Impression of Change

7.7.5 11-Point Numerical Rating Scale Pain Score

7.7.6 Pain in Other Joints

8 Statistics

8.1 Sample Size

• 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, , of the primary efficacy analysis set at two-sided
• Normal distribution.

2 Years

• 55 evaluable subjects in each group (total 275 subjects) will ensure a power of 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 for detecting an overall treatment effect (meaning that at least one group differs from the other groups) as well.

8.2 Randomization

8.3 Endpoints

8.3.1 Primary Endpoint

8.3.2 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 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

• 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

• 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
• 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

8.4 Analysis Sets

Intention-to-Treat Analysis Set (Full Analysis Set)

Modified Intention-to-Treat Analysis Set

Per-Protocol Analysis Set

• 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

Pharmacokinetic Analysis Set

Subgroup Analyses

8.5 Description of Statistical Analyses

8.5.1 General Considerations

Summary Statistics

Adjustment for Multiplicity

Missing Data

8.5.2 Analysis of Primary Endpoint

8.5.3 Analysis of Secondary Endpoints

8.5.4 Safety Analyses

8.5.5 Analysis of Further Endpoints

• 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

Analysis of Data from the Extended Follow-up Phase

Exploratory Pharmacometric Modeling

8.6 Interim Analysis

9

Ethical and Regulatory Aspects

9.1

Responsibilities of the Investigator

9.2 Subject Information and Informed Consent

Pharmacogenetics Informed Consent

9.3 Subject Identification and Privacy

Confidentiality of Pharmacogenetic Data

9.4 Emergency Medical Support and Subject Card

9.5 Clinical Trial Insurance and Compensation to Subjects

9.6 Independent Ethics Committee or Institutional Review Board

9.7 Health Authorities

10

Trial Management

10.1 Case Report Form Handling

10.2 Source Data and Subject Files

• 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,
• 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.

10.3 Investigator Site File and Archiving

10.4 Monitoring, Quality Assurance and Inspection by Health Authorities

10.5 Changes to the Clinical Trial Protocol

10.6 Clinical Trial Report and Publication Policy

10.6.1 Clinical Trial Reports

10.6.2 Publication

1. Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, et al. OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage 2004;12:389-99.
2. Hoorman J, Bolen J, Helmick C, Langmaid G. Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United States, 2003-2005. MMWR 2006;55(40):1089-92.
3. Felson DT, Anderson JJ, Naimark A, Swift M, Castelli W, Meenan RF. Obesity and symptomatic knee osteoarthritis. Results from the Framingham Study. Arthritis Rheum 1987;30(Suppl 4):S130.
4. Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med 1988;109(1):18-24.
5. Murphy L, Schwartz TA, Helmick CG, Renner JB, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum 2008;59(9):1207-13.
6. Dunlop DD, Manheim LM, Yelin EH, Song J, Chang RW. The cost of arthritis. Arthritis Rheum 2003;49(1):101-13.
7. Ellsworth JL, Berry J, Bukowski T, Claus J, Feldhaus A, Holderman S, et al. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthr Cartil 2002;2002(10):-308.
8. Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 2005;13(7):623-31.
9. Ohbayashi N, Hoshikawa M, Kimura S, Yamasaki M, Fujui S, Itoh N. Structure and expression of the mRNA encoding a novel fibroblast growth factor, FGF-18. J Biol Chem 1998;273(29):18161-4.
10. Kapadia RM, Guntur AR, Reinhold MI, Naski MC. Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18 . Dev Biol 2005;285:496-507.
11. Davidson D, Blane A, Filion D, Wang H, Plut P, Pfeffer G, et al. Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem 2005;280(21):20509-15.
12. Valverde-Franco G, Binette JS, Li W, Wang H, Chai S, Laflamme F, et al. Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. Hum Mol Genet 2006;15(11):-1783.

References

Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, et al.
OMERACT-OARSI initiative: Osteoarthritis Research Society International set of
responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage
2004;12:389-99.
Hoorman J, Bolen J, Helmick C, Langmaid G. Prevalence of doctor-diagnosed arthritis
and arthritis-attributable activity limitation-United States, 2003-2005. MMWR and arthritis-attributable activity limitation-United States, 2003-2005. MMWR
2006;55(40):1089-92. elson DT, Anderson JJ, Naimark A, Swift M, Castelli W, Meenan RF. Obesity and ymptomatic knee osteoarthritis. Results from the Framingham Study. Arthritis Rheum 987;30(Suppl 4):S130.

osteoarthritis. The Framingham Study. Ann Intern Med 1988;109(1):18-24.
M11 Ellsworth JL, Berry J, Bukowski T, Claus J, Feldhaus A, Holderman S, et al. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthr Cartil 2002;2002(10):-308.
. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat
model of injury-induced osteoarthritis. Osteoarthritis Cartilage 2005;13(7):623-31.

12

Appendices

Appendix A: American College of Rheumatology Criteria for the Classification and Reporting of Osteoarthritis of the Knee

Appendix B: Safety Laboratory Parameters

Appendix C: Subject Questionnaires: WOMAC, MOS SF-36, and ICOAP

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Questionnaire

Medical Outcomes Study Short Form-36 General Health Survey (MOS SF-36)

Measure of Intermittent and Constant Osteoarthritis Pain Questionnaire (ICOAP)

Appendix D: Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS QOL) and Symptom Index Subscales

Appendix E: Schedule of Trial Procedures

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 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 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 days (DBPC treatment phase) or 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 Visit 2 and at Week 26/Visit 7.

Sprifermin
EMR700692_006

Phase II Trial of Sprifermin in Knee OA

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 days (DBPC treatment phase) or days (extended followup 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.

Appendix F: Pain in Other Joints