Long-Term Management of "Younger, Active" Patients With Pain From Early Knee Osteoarthritis With Synvisc-One (Hylan G-F 20)
Phase: NA
Conditions: Osteoarthritis
Sponsor: Anthony Luke

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University of California, San 
Francisco UCSF-SYNVISC-ONE 001 
NCT01625013

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GENZYME SYNVISC-ONE 
Clinical Research Protocol 
LONG-TERM MANAGEMENT OF “YOUNGER, ACTIVE” PATIENTS WITH 
PAIN FROM EARLY KNEE OSTEOARTHRITIS WITH SYNVISC-ONE (HYLAN 
G-F 20)
Protocol Number: 
UCSF-SYNVISC-1 Version 001 
Version Date: 
05-17-12
Investigational Product: 
Synvisc-One 
IDE Number: 
Pending 
Development Phase: 
Phase III 
Sponsor: 
Anthony Luke, MD, MPH 
1500 Owens St, San Francisco, CA, 94158 
Funding Organization: 
Genzyme 
Principal Investigator: 
Name: Anthony Luke, MD, MPH 
Telephone: 415-885-3807 
Fax: 415-885-3838 
 
E-mail:lukea@orthosurg.ucsf.edu
Medical Monitor: 
Name: Anthony Luke, MD, MPH 
Telephone: 415-885-3807 
Fax: 415-885-3838 
 
E-mail:lukea@orthosurg.ucsf.edu
Coordinating Center: 
Single Site 

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TABLE OF CONTENTS 
 
1 
BACKGROUND .............................................................................................................4 
      1.1     Overview of Non-Clinical Studies ............................................................................15 
1.2 
Overview of Clinical Studies ...................................................................................15 
2 
STUDY RATIONALE ....................................................................................................16 
2.1 
Risk / Benefit Assessment .......................................................................................16 
3 
STUDY OBJECTIVES ...................................................................................................17 
3.1 
Primary Objective....................................................................................................17 
3.2 
Secondary Objectives ..............................................................................................17 
4 
STUDY DESIGN ............................................................................................................17 
4.1 
Study Overview .......................................................................................................17 
      4.2     Indications……………………………………………………………………..16 
5 
CRITERIA FOR EVALUATION ..................................................................................18 
5.1 
Primary Efficacy Endpoint ......................................................................................18 
5.2 
Secondary Efficacy Endpoints .................................................................................19 
5.3 
Safety Evaluations ...................................................................................................19 
6 
SUBJECT SELECTION .................................................................................................19 
6.1 
Study Population .....................................................................................................19 
6.2 
Inclusion Criteria .....................................................................................................19 
6.3 
Exclusion Criteria .................................................................................................... 
7 
CONCURRENT MEDICATIONS .................................................................................21 
7.1 
Allowed ..................................................................................................................21 
8 
STUDY TREATMENTS ................................................................................................21 
8.1 
Method of Assigning Subjects to Treatment Groups ................................................21 
8.2 
Blinding ..................................................................................................................21 
8.3 
Test and Control Formulation ..................................................................................21 
8.4 
Supply of Study Medication at the Site ....................................................................25 
8.5 
Study Medication Accountability .............................................................................26 
8.6 
Measures of Treatment Compliance .........................................................................27 
9 
STUDY PROCEDURES AND GUIDELINES ...............................................................27 
9.1 
Clinical Assessments ...............................................................................................27 
9.2 
Clinical Laboratory Measurements (include sections as appropriate) ........................28 
10 EVALUATIONS BY VISIT ...........................................................................................28 
10.1 Visit 1  
10.2 Visit 2 
10.3 Visit 3 
10.4 Visit 4  
10.5 Visit 5 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION .......................31 
11.1 Adverse Events........................................................................................................31 

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11.2 Serious Adverse Experiences (SAE) ........................................................................32 
11.3 Protocol Defined Important Medical Findings Requiring Real Time Reporting ........ 
11.4 Medical Monitoring .................................................................................................33 
11.5 Safety Management Plan .........................................................................................4 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ..................................33 
12.1 Withdrawal of Subjects............................................................................................33 
12.3 Replacement of Subjects ..........................................................................................34 
13 PROTOCOL VIOLATIONS ..........................................................................................34 
14 STATISTICAL METHODS AND CONSIDERATIONS ..............................................35 
14.1 Data Sets Analyzed..................................................................................................35 
14.2 Demographic and Baseline Characteristics ...............................................................35 
14.3 Analysis of Primary Endpoint ..................................................................................35 
14.4 Analysis of Secondary Endpoints .............................................................................37 
14.5 Interim Analysis ......................................................................................................37 
14.6 Sample Size and Randomization ..............................................................................38 
15 DATA COLLECTION, RETENTION AND MONITORING ......................................38 
15.1 Data Collection Instruments.....................................................................................38 
15.2 Data Management Procedures ..................................................................................38 
15.3 Data Quality Control and Reporting .........................................................................39 
15.4 Archival of Data ......................................................................................................39 
15.5 Availability and Retention of Investigational Records ..............................................39 
15.6 Monitoring ..............................................................................................................39 
15.7 Subject Confidentiality ............................................................................................39 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ..................39 
16.1 Protocol Amendments .............................................................................................40 
16.2 Institutional Review Boards and Independent Ethics Committees.............................40 
16.3 Informed Consent Form ...........................................................................................40 
16.4 Publications .............................................................................................................41 
16.5 Investigator Responsibilities ....................................................................................41 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
NSAID 
 
OA 
Serious adverse experience 
Non-steroidal anti-inflammatory drugs: also known as 
“NSAIDs”; medication used to treat pain or swelling. 
Osteoarthritis  
 

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PROTOCOL SYNOPSIS 
TITLE 
 
Long-term Management of “Younger, Active” Patients with Pain 
from Early Knee Osteoarthritis with Synvisc-One (hylan G-F 20) 
 
SPONSOR 
 
Dr. Anthony Luke, University of California San Francisco 
 
FUNDING 
ORGANIZATION 
 
Genzyme 
 
NUMBER OF SITES 
 
1 
 
RATIONALE 
 
The objectives of the study are to assess the effectiveness, duration of 
symptom relief, improvements on activity level and safety of one or 
more hylan G-F 20 injections for symptomatic early knee 
osteoarthritis (OA) treatment in younger, active patients over a three-
year period.   
•From a pain management perspective, reduction of knee pain knee 
pain will target a Patient Acceptable Symptom State (PASS) 
•Repeated hylan G-F 20 treatment will be allowed as necessary to 
maintain patients in PASS throughout the duration of the study period. 
 
STUDY DESIGN 
 
Typically viscosupplementation is considered an intervention for knee 
osteoarthritis in older patients who are less active.   Many young 
active patients can also develop knee osteoarthritis after trauma or 
surgery or for congenital reasons.  Treatment of these patients 
commonly are steroid injections which have more biologically 
detrimental effects for cartilage compared to viscosupplementation.  
This study aims to study use of viscosupplementation for young 
individuals who are active.  Synvisc One injections, which are a single 
injection, will be used to determine effectiveness of reducing pain and 
maintaining an active healthy lifestyle for younger patients aged 30-
50 years old. 
  
This study, for research purposes only, will be an open label 
longitudinal cohort study with natural history over 3 years.  Subjects 

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enrolled in the cohort will have baseline functional testing performed 
including a motion gait analysis, 12 minute walk test, and 3-day 
accelerometer data.  Subjects will receive a single 6 mL intra-articular 
injection of hylan G-F 20 in the target knee at baseline.  All ongoing 
treatments will be monitored at 6-month intervals over the 3-year 
duration of the study.  Patients can receive any other conservative 
treatments (e.g., oral medications, physical or other therapy, 
acupuncture, etc., except other injection treatments) and current 
treatments will be documented during each patient encounter.  An 
initial injection of hylan G-F 20 will be injected in the symptomatic 
knee using a standard supine lateral  approach using a 20-gauge 
needle.  A face-to-face follow up visit will be carried out 6 months 
after first injection with additional face to face meetings every 6 
months thereafter unless the subject requires an additional injection of 
hylan G-F 20.  Hylan G-F 20 treatments can be administered up to 
three times each year during the study duration.  After each injection, 
follow up measures will be carried out using secure e-mail or phone 
contact at 6 weeks, 12 weeks, 18 weeks after each in-office evaluation 
or injection.  Follow up will consist of WOMAC, Lysholm score, and 
Tegner score.   Patients may return for retreatment of hylan G-F 20 if 
symptoms recur after at least 4 months following their previous 
injection and they meet the inclusion criteria for pain levels on the 
following WOMAC questions A1 (How much pain have you had 
walking on a flat surface?), C8 (How much difficulty have you had 
going down the stairs?), C9 (How much difficulty have you had when 
going up the stairs?), C10 (How much difficulty have you had when 
getting up from a sitting position?) and/or C23 (How much difficulty 
have you had while doing heavy household chores?). Inclusion criteria 
for pain level is defined by selecting moderate, severe, or extreme on 
all questions A1, C8, C9, C10 and/or C23. Those subjects who select 
mild or no pain levels on any of A1, C8, C9, C10 and/or C23, will not 
meet the criteria for WOMAC pain level and retreatment.  Patients 
requiring three injections of hylan G-F 20 in 4 months or less will be 
allowed to exit the cohort after their six-month follow up following 
the third injection.  Otherwise, patients will be followed until they 
reach the 3-year follow up, or drop out for other injection treatments 
or surgical treatment.  Therefore, patients would potentially be able to 
receive up to 9 injections during the 3-year study. 
 
PRIMARY 
OBJECTIVES 
 
Specific Aim 1:  To identify whether injection of 6 mL hylan G-F 20 
decreases pain over 26 weeks in young (ages 30 to 50 years) active 
patients with symptomatic primary osteoarthritis of the knee not 
treated previously with hylan G-F 20.  
 

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SECONDARY 
OBJECTIVES 
 
Specific Aim 2:  Though symptoms can be improved for periods up to 
6 months, pain symptoms can recur.  The effect of repeated treatments 
of hylan G-F 20 will be studied. 
 
Specific Aim 3:  To identify the effects of treatment with hylan G-F 
20 on activity levels (using objective activity measures utilizing 
accelerometer and Physical Activity Enjoyment Scale (PACES) and 
quality of life scores (WOMAC, SF-12) comparing baseline to 
treatment at 3 months. 
 
Specific Aim 4:  To understand the natural history of conservative 
treatment on this cohort of patients over a 3 year period. 
 
NUMBER OF 
SUBJECTS 
 
150 
 
SUBJECT 
SELECTION 
CRITERIA 
 
Inclusion Criteria:  
Male or female patients aged 30-50 years 
History of symptomatic unilateral primary or secondary knee OA for 
more than 6 months 
Signed written informed consent 
 
Radiographic evidence of  Kellgren-Lawrence Grade I or II OA of the 
target knee 
Body Mass Index (BMI) < 30 kg/m2 
Activity criteria (Tegner score > 3) 
Continued target knee OA pain despite conservative treatment ≥ 3 
months (e.g., weight reduction, physical therapy, analgesics) 
Willing to withhold intake of NSAIDs (including COX-2 inhibitors) 
and analgesics, for a washout period of minimum 3 days up to 21 days 
prior to baseline visit (depending on medication) 
Willing to discontinue prohibited treatments and medications 
throughout study period 
Baseline inclusion criteria 
•              Completed OA medication washout period 
•              Target knee pain 4-8 (0-10 NRS) during most painful knee 
movement (Worst Knee Pain) 
•              If female, must have had a negative urine pregnancy test and 

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used a medically acceptable form of contraception for at least 1 month 
prior to baseline and agree to continued use of contraception for the 
duration of the study.  Otherwise, females must be surgically sterile, 
or postmenopausal (as documented in medical history) for at least 1 
year. The fetal safety profile for G-F 20 is unknown.  Pregnancy will 
affect the individual's regular activity levels.  Females who become 
pregnant during the study will be excluded from the study.  Subjects 
who become pregnant will be followed up by telephone every 3 
months to check for any adverse effects.  They willl also be 
recommended to follow routine obstetric visits.  Males should be able 
to father children as it has no expected effects on activty levels. 
 
Exclusion Criteria: Known allergy to hylan G-F 20 or any of its 
components, or to avian proteins, eggs, feathers, down, or poultry 
Clinically apparent tense effusion or other acute inflammation of the 
target knee at baseline 
History of target knee viscosupplementation treatment 
History of major surgery for OA in target knee including arthroplasty 
or tibial osteotomy 
Arthroscopic surgery or intraarticular steroid injection in target knee 
within six months of baseline visit 
Significant (as judged by the Investigator) alignment deformity of 
target knee 
Ipsilateral symptomatic OA of hip or ankle; contralateral symptomatic 
OA of hip, knee, or ankle 
 
History of: 
Septic OA of any joint 
Inflammatory arthropathy such as RA, gout, pseudogout, lupus, 
crystaline in-flammatory arthopathy 
Active infection of lower extremity 
Known significant acute and/or concurrent medical disease including, 
but not limited to current malignancy, history of transplant surgery, 
congestive heart failure, significant unstable cardiovascular disease, 
renal hepatic pulmonary, endocrine, metabolic, or GI condition 
Any known contraindication to acetaminophen 
Venous or lymphatic stasis in either leg 
Peripheral vascular disease 
Patient has been prescribed chronic opioid analgesics at time of 
baseline visit 
Concurrent multi-system or multi-limb trauma 
Patient plans to become pregnant during study period 

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Patient plans to move significantly out of area, have surgery, or 
initiate or cease other OA treatments 
Knee pain improves during washout period 
Workman’s Comp patient 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Synvisc G-F 20 will be injected in the symptomatic knee using a 
standard supine lateral approach using a 20-gauge needle.  Patients 
will be treated at baseline and followed out to three years.  Patients 
may return for retreatment as early as 4 months post their prior 
injection if they meet the retreatment criteria pain levels for Worst 
Knee Pain.  If the subjects need another injection, the follow-up cycle 
will restart at Visit 1 and the subject will be seen every 6 months and 
followed-up for 3 years. 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
N/A 

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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Patients may return for retreatment as early as 4 months post their 
prior injection if they meet the retreatment criteria pain levels for 
Worst Knee Pain.  If the subjects need another injection, the follow-up 
cycle will restart at Visit 1 and the subject will be seen every 6 months 
and followed-up for 3 years. 
Approximate Time Requirements: 
 
Baseline Screening: Informed Consent, Physical exam, patient 
questionnaire, injection, X-ray, walk test (Approx. 2 hours) 
and accelerometer test (3 days) 
 
6 months after injection: Physical exam, patient questionnaire, 
walk test (Approx. 1 hr) and accelerometer test (3 days) 
 
12 months after injection: Physical exam, patient 
questionnaire, walk test (Approx. 1 hr) and accelerometer test 
(3 days) 
 
18 months after injection: Physical exam, patient 
questionnaire, walk test (Approx. 1 hr) and accelerometer test 
(3 days) 
 
24 months after injection: Physical exam, patient 
questionnaire, walk test (Approx. 1 hr) and accelerometer test 
(3 days) 
 
30 months after injection: Physical exam, patient 
questionnaire, walk test (Approx. 1 hr) and accelerometer test 
(3 days) 
 
36 months after injection: Physical exam, patient 
questionnaire, walk test (Approx. 1 hr) and accelerometer test 
(3 days) 
 
15 min email or phone contact at 6, 12, and 18 weeks post 
each injection and clinic visit (total 4.5 hrs) 
Total time for the study will be approximately 8 clinical hours over 3 
years, 21 days for the accelerometer test and 4.5 hrs of email/phone 
contact. 
 
CONCOMMITANT 
MEDICATIONS 
Allowed: Patients can receive any other conservative treatments 
(e.g., oral medications, physical or other therapy, acupuncture, etc., 
except other injection treatments) and current treatments will be 
documented during each patient encounter.   
Prohibited: Since Synvisc is an elastoviscous fluid device injected 
directly into the knee joint, it does not interfere with any medicine 
that your physician recommends, including pain relievers and anti-
inflammatory drugs. 
 
EFFICACY 
EVALUATIONS 
Efficacy will be measured and evaluated using data from the 
following assessments: KOOS, Lysholm, SF-12, WOMAC, and 
Accelerometer ™.  

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PRIMARY ENDPOINT 
 
The primary endpoint for the study will be analyzed using a responder 
analysis. The proportion of responders following injection within the 
6 months following the baseline injection will be calculated based on 
Worst Knee Pain scores ≤ 3 on a 0-10 pain scale, which is a threshold 
consistent with other similar studies (Tubach 2005, Bellamy 2010).  
The primary endpoint is defined as non-inferiority of the proportion of 
responders in our study relative to an external criterion for the 
responder proportion (Bellamy 2010).  
 
SECONDARY 
ENDPOINTS 
 
Survival analysis statistics will be performed to assess duration of 
benefit from the hylan G-F 20 injections over time.  A specific 
timeframe of interest will be the initial 6 months of treatment 
following the second and any subsequent hylan G-F 20 injection.  
Changes from baseline to three months post-treatment in activity 
levels (using objective activity measures utilizing accelerometer and 
Physical Activity Enjoyment Scale) and quality of life scores 
(WOMAC, SF-12) will be determined. We will examine the time 
courses of longitudinal measures of pain score, activity level, and 
quality of life over the entire three-year span of the study. 
 
SAFETY 
EVALUATIONS 
 
The repeat treatment phase evaluated the safety profile of a second 
injection of Synvisc-One. One hundred and sixty patients were treated 
during this phase of the study, of which 77 patients received a second 
injection of Synvisc-One. These patients were followed for 4 weeks 
and out of 77 patients, only 4 (5.2%) experienced device-related AEs 
in the injected knee. All such events were mild to moderate and were 
treated symptomatically. Patients who developed injected knee AEs 
during the initial phase of the study, and who subsequently received 
repeat treatment, did not experience injected knee AEs upon repeat 
exposure to Synvisc-One. 
 
PLANNED INTERIM 
ANALYSES  
 
There is no interim analysis planned. Serious adverse events will be 
monitored by the committee on an ongoing basis throughout the 
study. 
 

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STATISTICS 
Primary Analysis 
Endpoint 
 
The primary endpoint for the study will be analyzed using a responder 
analysis.  The proportion of responders following injection within the 
6 months following the baseline injection will be calculated based on 
Worst Knee Pain scores ≤ 3 on a 0-10 pain scale, which is a threshold 
consistent with other similar studies (Tubach 2005, Bellamy 2010).    
The primary endpoint is defined as non-inferiority of the proportion of 
responders in our study relative to an external criterion for the 
responder proportion (Bellamy 2010).  Bellamy demonstrated in his 
paper from 2007 (table 3) that a BLISS response at any time during 
the study was achieved in 70% receiving appropriate care and Hylan 
G-F 20 and only in 38% of patients receiving appropriate care 
(P<0.0001).   We propose a non-inferiority delta of 20% relative to 
this external criterion, and thus the primary endpoint will be tested by 
a test of our sample proportion (p) with null hypothesis H0: p<0.50 
vs. alternative hypothesis H1: p>0.50. This test will be performed 
using the Wilson-Agresti method for testing a single binomial 
proportion at a one-sided significance level of 0.025 (i.e. non-
inferiority will be satisfied if the 95% Wilson-Agresti (REF BROWN 
ET AL 2001) interval for the proportion of responders excludes the 
null rate of 0.50). 
 
STATISICS 
Secondary Endpoints 
 
For subsequent injections, duration of response over time and median 
duration of response will be estimated using survival analysis 
techniques.   Inference for activity levels and quality of life will focus 
on changes from baseline to 3 months.   We will examine the time 
course for the longitudinal data on pain score, activity level, and 
quality of life measures across the three years of the study using 
mixed effects models.  
 
Rationale for Number 
of Subjects 
 
Power Calculation 
 Bellamy demonstrated in his paper from 2007 (table 3) that a BLISS 
response at any time during the study was achieved in 70% receiving 
appropriate care and Hylan G-F 20 and only in 38% of patients 
receiving appropriate care (P<0.0001).   A power calculation using a 
one-sample comparison of proportion with hypothesized value sample 
size was performed to determine non-inferiority to the 70% results 
quoted by Bellamy. Power calculations were measured using 
STATA’s SAMPSI calculator.  If we postulate a 20% non-inferiority 
limit (i.e. that at least 50% of patients receiving G-F 20 will achieve a 
BLISS response), the sample size required to have 90% power and  

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∝=0.025 to show non-inferiority at 50% would be 70.  For a 10% 
non-inferiority limit with 90% power and ∝=0.025, the required 
sample size is 274, and for 15% non-inferiority limit with 90% power 
and ∝=0.025, it is 124 patients.  These numbers do not allow for 
dropouts, therefore, we intend to recruit 150 subjects to account for 
dropout. 
Conservatively assuming a 20% rate of drop-out, the resulting sample 
size of n=120 has better than 90% power (one sided test with 
∝=0.025) to show non-inferiority assuming the true responder rate is 
65% (i.e. not quite as high as the 70% external reference).   
 
DATA 
MANAGEMENT 
PLAN 
 
Data management and analysis for the study will be performed by the 
Biostatistics Consulting Unit (BCU) of UCSF’s Clinical and 
Translational Science Institute (CTSI).  Data will be stored on a 
HIPAA-compliant server.  The server room has state-of-the-art 
environmental controls and security features and is protected by a 
firewall and anti-virus software.   
 
 

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1 BACKGROUND 
Treatment of younger patients between 30-50 years of age with knee osteoarthritis is a 
challenging treatment problem for physicians.  The younger, active population has 
different expectations for management of osteoarthritis with a strong desire to maintain 
their physical activities and quality of life.  Ideally, treatments for osteoarthritis in these 
patients that can allow them to maintain their activity levels and provide clear future 
health benefits of regular exercise are preferred.  There is a lack of effective treatment for 
individuals including surgical options with mild osteoarthritis outside of physical therapy 
exercises, oral analgesic medications, and steroid injections which have possible negative 
side effects and short durations of symptom improvement.  Hylan G-F 20 in a single 
injection form can provide analgesic benefit up to 6 months and can be used as a treatment 
in younger patients not improving with traditional treatments.1  
1.1 Overview of Non-Clinical Studies 
Preclinical investigations have demonstrated that Hylan G-F 20 can favorably affect 
chondrocyte metabolism and recent clinical studies [Ann Rheum Dis. 2004 May; 
63(5):478-82; Osteoarthritis Cartilage. 2005 Mar;13(3):216-24] provide support for a 
disease-modifying effect of Hylan G-F 20 therapy.   An evaluation of the non-clinical tests 
by FDA was based in large part on the previous device approval (for three injections). 
There were no unresolved safety issues.  
1.2 Overview of Clinical Studies 
Studies in populations with osteoarthritis of the knee demonstrate that after 3 or more 
years of follow-up, individuals have worsening of limitations in activities.2  In one study 
48.7% of limitations (n= 405) participants with knee symptoms were classified as 
experiencing a poor two-year outcome using a dichotomous outcome measure of 
activity.3  Prognostic factors for worsening of limitations in activities include increased 
pain, reduced ROM, and decreased muscle strength at 1-year follow-up; higher morbidity 
count; and to a lesser extent poor cognitive functioning.   Continuing exercise is 
important, as there are numerous health benefits for reducing chronic diseases such as 
hypertension, diabetes and obesity.  While osteoarthritis is also a chronic disease, it is 
focal in nature whereas lack of exercise can result in increased incidence of systemic 
chronic diseases that have more detrimental health effects and health care costs.5  A single 
injection preparation of hylan G-F 20 (6 mL) has shown improvement over placebo in a 
double blind randomized control trial.1  Hylan G-F 20 has demonstrated improvements 
with repeated treatment of knee osteoarthritis using a series of three 2 mL preparations4; 
however, the effectiveness of repeated injections of the 6 mL is not yet known.   
Maintaining activity levels and pain tolerance are important in the younger age group as 
this translates to continuing good mobility and ability to work.  
A randomized, double-blind, saline-controlled, multicenter trial of 253 patients (mean age 
63 years) with moderate to severe OA knee pain. Most had radiographically confirmed 
Kellgren-Lawrence grade II or III OA at baseline. Patients initially received arthrocentesis 
and then either one 6-mL injection of Synvisc-One or one 6-mL injection of placebo 
(saline). Follow-up visits occurred at weeks 1, 4, 8, 12, 18, and 26. The primary end point 

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was the difference between the groups in the change from baseline in patient-assessed 
pain as measured by the WOMAC A score (average of 5 questions) over 26 weeks. A 
responder was defined as a patient with a ≥1 category improvement in WOMAC question 
A1 and no knee-related adverse events. The safety of repeat treatment (week 26) with 
Synvisc-One was assessed in all patients over a 4-week period. Acetaminophen rescue 
was permitted up to 48 hours before study visits. 
Two medical studies involving a total of 132 patients were done in Germany. The patients 
in these studies were at least 40 years old and had knee pain due to OA. The patients were 
placed in one of two groups. One group was given an injection of SYNVISC into one or 
both knees once a week for three weeks. The second group was given an injection of salt 
water once a week for three weeks. As part of the study, knee joint pain was measured for 
26 weeks. Also, patients and doctors were asked to judge the success of the treatment for 
26 weeks. Patients with OA knee pain, who did not get pain relief with other medicines, 
got pain relief with SYNVISC. The patients given SYNVISC had more pain relief than 
the patients given salt water. Some patients started to feel pain relief after the first week of 
SYNVISC treatment. The most pain relief and the greatest amount of treatment success 
was seen 8 to 12 weeks after SYNVISC treatment started. A medical study done in the 
United States involved 90 patients. The patients were at least 40 years old and had knee 
pain due to OA. Patients were placed into one of two groups. One group was given 
SYNVISC once a week for three weeks. The second group had a needle inserted into the 
knee to have any fluid removed (this procedure is called arthrocentesis [pronounced AR-
thro-sen-TEE-sis]) once a week for three weeks. Patients improved after SYNVISC 
treatment, but not more than patients who had arthrocentesis. This study was different 
from the German studies because the last time the two groups were compared was only 
two weeks after the last SYNVISC injection. The study was also different in other ways, 
including length of time that patients had to stop taking medicines before they could start 
treatment. The length of time patients had to stop taking medicines was two weeks in the 
German studies and, four weeks in the U.S. study. 
2 STUDY RATIONALE 
There is a lack of effective treatment for individuals including surgical options with mild 
osteoarthritis outside of physical therapy exercises, oral analgesic medications, and steroid 
injections which have possible negative side effects and short durations of symptom 
improvement.  Hylan G-F 20 in a single injection form can provide analgesic benefit and 
can be used as a treatment in younger patients not improving with traditional treatments. 
This study is for research purposes only.  
RISK / BENEFIT ASSESSMENT 
Young patients with osteoarthritis are typically not surgical candidates.  Randomized 
control trials for arthroscopy in arthritis patients do not show long term benefits.  Patients 
want conservative treatment with low side effect profiles which can improve their quality 
of life. Hylan G-F 20 in a single injection form can provide analgesic benefit for patients 
with knee osteoarthritis.  The treatment may reduce the need for oral medications and 
facilitate rehabilitation exercises.  Patients may have better exercise tolerance with less 
pain. As shown in medical studies of patients with osteoarthritis (OA) of the 

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knee, where approximately half received a single injection of SYNVISC and the other half 
either had fluid removed from the knee and/or received injections of the same volume of 
salt water (a “Saline Control” injection), the major benefits of SYNVISC are pain relief 
and improvement in other symptoms related to OA of the knee. 
 STUDY OBJECTIVES 
2.1 
Primary Objective 
There are two primary objectives to this study:  
Specific Aim 1:  To identify whether injection of 6 mL hylan G-F 20 decreases pain over 
26 weeks in young (ages 30 to 50 years) active patients with symptomatic primary 
osteoarthritis of the knee not treated previously with hylan G-F 20.  
Specific Aim 2:  Though symptoms can be improved for periods up to 6 months, pain 
symptoms can recur.  The effect of repeated treatments of hylan G-F 20 will be studied. 
2.2 Secondary Objectives 
There are two secondary objectives to this study:  
Specific Aim 3:  To identify the effects of treatment with hylan G-F 20 on activity levels 
(using objective activity measures utilizing accelerometer and Physical Activity 
Enjoyment Scale (PACES)) and quality of life scores (WOMAC, SF-12) comparing 
baseline to treatment at 3 months. 
Specific Aim 4: is to understand the natural history of conservative treatment on this 
cohort of patients over a 3 year period.  
3 STUDY DESIGN 
3.1 Study Overview 
This study aims to study use of viscosupplementation as a treatment of pain for young 
individuals who are active. Typically viscosupplementation is considered an intervention 
for knee osteoarthritis often for older patients who are less active.   Many young active 
patients can also develop knee osteoarthritis after trauma or surgery or for congenital 
reasons.  Treatment of these patients commonly are steroid injections which have more 
biologically detrimental effects for cartilage compared to viscosupplementation Synvisc 
One injections which are a single injection will be used to determine effectiveness of 
reducing pain and maintaining an active healthy lifestyle for younger patients aged 30-50 
years old. 
 
This study will be an open label longitudinal cohort study with natural history over 3 
years. Screening data will be reviewed to determine subject eligibility.  Subjects who meet 
all inclusion criteria and none of the exclusion criteria will be entered into the study. 
Subjects enrolled in the cohort will have baseline functional testing performed including a 
motion gait analysis, 12 minute walk test, and 3-day accelerometer data.  Subjects will 
receive a single 6 mL intra-articular injection of hylan G-F 20 in the target knee at 
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duration of the study.  Patients can receive any other conservative treatments (e.g., oral 
medications, physical or other therapy, acupuncture, etc., except other injection 
treatments) and current treatments will be documented during each patient encounter.  An 
initial injection of hylan G-F 20 will be injected in the symptomatic knee using a standard 
supine lateral approach using a 20 gauge needle.  A face to face follow up visit will be 
carried out 6 months after first injection with additional face to face meetings every 6 
months thereafter unless the subject requires an additional injection of hylan G-F 20.  
Hylan G-F 20 treatments can be administered up to three times each year during the study 
duration.  After each injection, follow up measures will be carried out using secure e-mail 
or phone contact at 6 weeks, 12 weeks, 18 weeks after each in-office evaluation or 
injection.  Follow up will consist of WOMAC, Lysholm score, and Tegner score.   .   
Patients may return for retreatment of hylan G-F 20 if symptoms recur after at least 4 
months following their previous injection and they meet the inclusion criteria for pain 
levels on the following WOMAC questions A1 (How much pain have you had walking on 
a flat surface?), C8 (How much difficulty have you had going down the stairs?), C9 (How 
much difficulty have you had when going up the stairs?), C10 (How much difficulty have 
you had when getting up from a sitting position?) and/or C23 (How much difficulty have 
you had while doing heavy household chores?). Inclusion criteria for pain level is defined 
by selecting moderate, severe, or extreme on all questions A1, C8, C9, C10 and/or C23. 
Those subjects who select mild or no pain levels on any of A1, C8, C9, C10 and/or C23, 
will not meet the criteria for WOMAC pain level and retreatment.  Patients requiring three 
injections of hylan G-F 20 in 4 months or less will be allowed to exit the cohort after their 
six-month follow up following the third injection.  Otherwise, patients will be followed 
until they reach the 3 year follow up, or drop out for other injection treatments or surgical 
treatment.  Therefore, patients would potentially be able to receive up to 9 injections 
during the 3 year study. 
Total time for the study will be approximately 8 clinical hours over 3 years, 21 days for 
the accelerometer test and 4.5 hrs of email/phone contact.  
3.2 This experimental Synvisc-One indication is for the treatment of pain in osteoarthritis 
(OA) of the knee in patients who have failed to respond adequately to conservative non-
pharmacologic therapy and simple analgesics (e.g., acetaminophen).   
 
4 CRITERIA FOR EVALUATION 
4.1 Primary Efficacy Endpoint 
Co‐Primary endpoints 
o 
Proportion of subjects reporting being in PASS during at least one Study Contact 
Point during entire 36 month study period 
o 
Proportion of Study Contact Points that each subject reports being in PASS during 
entire 36 month study period 
Secondary endpoints 
o Change in scores over 36 months for: 

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o Worst Knee Pain 
o Five KOOS domains 
o SF‐12 
o 12‐minute walk test 
o 3‐day accelerometer test 
 
The primary endpoint for the study will be analyzed using a responder analysis.  The 
proportion of responders following injection within the 6 months following the baseline 
injection will be calculated based on Worst Knee Pain scores.  A specific timeframe of 
interest will be the initial 6 months of treatment following the second and any subsequent 
hylan G-F 20 injection. 
4.2 Secondary Efficacy Endpoints 
o Change in scores over 36 months for: 
o Worst Knee Pain 
o Five KOOS domains 
o SF‐12 
o 12‐minute walk test 
o 3‐day accelerometer test 
4.3 Safety Evaluations 
Adverse reactions will be checked on all phone interviews and clinic visits. Adverse 
reactions will be captured and tabulated  
The most commonly reported related local adverse events were transient, mild-to-
moderate arthralgia, arthritis, arthropathy, injection site pain and joint effusion. No serious 
adverse events were reported in clinical trials in knees injected with Synvisc-One. Serious 
local adverse events have been reported only rarely in post-marketing use.  Repeat 
treatment did not affect the safety profile. In the pivotal clinical trial, there was one related 
systemic event of syncope. The most common systemic side effects irrespective of 
relationship to Synvisc-One were headache, back pain, nasopharyngitis and influenza. 
Systemic adverse event profiles were similar between patients in the Synvisc-One and 
Saline Control groups.   
5 SUBJECT SELECTION 
5.1 Study Population 
Subjects with a history of symptomatic unilateral primary or secondary knee OA for more 
than 6 months, who meet the inclusion and exclusion criteria, will be eligible for 
participation in this study.   
5.2 Inclusion Criteria 
Inclusion Criteria:  
1. Male or female patients aged 30-50 years 
2. History of symptomatic unilateral primary or secondary knee OA for more than 6 
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3. Signed written informed consent 
4. Radiographic evidence of  Kellgren-Lawrence Grade I or II OA of the target knee 
5. Body Mass Index (BMI) < 30 kg/m2 
6. Activity criteria (Tegner score > 3) 
7. Continued target knee OA pain despite conservative treatment ≥ 3 months (e.g., 
weight reduction, physical therapy, analgesics) 
8. Willing to withhold intake of NSAIDs (including COX-2 inhibitors) and analgesics, 
for a washout period of minimum 3 days up to 21 days prior to baseline visit 
(depending on medication) 
9. Willing to discontinue prohibited treatments and medications throughout study period 
Baseline inclusion criteria 
10. Completed OA medication washout period 
11. Target knee pain 4-8 (0-10 NRS) during most painful knee movement (Worst Knee 
Pain) 
12.  If female, must have had a negative urine pregnancy test and used a medically 
acceptable form of contraception for at least 1 month prior to baseline and agree to 
continued use of contraception for the duration of the study.  Otherwise, females must 
be surgically sterile, or postmenopausal (as documented in medical history) for at 
least 1 year. The fetal safety profile for G-F 20 is unknown.  Pregnancy will affect the 
individual's regular activity levels.  Females who become pregnant during the study 
will be excluded from the study.  Subjects who become pregnant will be followed up 
by telephone every 3 months to check for any adverse effects.  They will also be 
recommended to follow routine obstetric visits.  Males should be able to father 
children as it has no expected effects on activity levels. 
 
5.3 
Exclusion Criteria:  
1. Known allergy to hylan G-F 20 or any of its components, or to avian proteins, eggs, 
feathers, down, or poultry 
2. Clinically apparent tense effusion or other acute inflammation of the target knee at 
baseline 
3. History of target knee viscosupplementation treatment 
4. History of major surgery for OA in target knee including arthroplasty or tibial 
osteotomy 
5. Arthroscopic surgery or intra-articular steroid injection in target knee within six 
months of baseline visit 
6. Significant (as judged by the Investigator) alignment deformity of target knee 
7. Ipsilateral symptomatic OA of hip or ankle; contralateral symptomatic OA of hip, 
knee, or ankle 
8. History of: 
9. Septic OA of any joint 
10. Inflammatory arthropathy such as RA, gout, pseudogout, lupus, crystaline in-
flammatory arthopathy 
11. Active infection of lower extremity 
12. Known significant acute and/or concurrent medical disease including, but not limited 
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significant unstable cardiovascular disease, renal hepatic pulmonary, endocrine, 
metabolic, or GI condition 
13. Any known contraindication to acetaminophen 
14. Venous or lymphatic stasis in either leg 
15. Peripheral vascular disease 
16. Patient has been prescribed chronic opioid analgesics at time of baseline visit 
17. Concurrent multi-system or multi-limb trauma 
18. Patient plans to become pregnant during study period 
19. Patient plans to move significantly out of area, have surgery, or initiate or cease other 
OA treatments 
20. Knee pain improves during washout period 
21. Workman’s Comp patient 
22. Written informed consent (and assent when applicable) obtained from subject or 
subject’s legal representative and ability for subject to comply with the requirements 
of the study. 
23. Pregnant, breastfeeding, or unwilling to practice birth control during participation in 
the study. 
24. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
6 CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. Patients can 
receive any other conservative treatments (e.g., oral medications, physical or other 
therapy, acupuncture, etc., except other injection treatments) and current treatments will 
be documented during each patient encounter.   
6.1 Allowed Medications and Treatments 
Patients can receive any other conservative treatments (e.g., oral medications, physical or 
other therapy, acupuncture, etc., except other injection treatments) and current treatments 
will be documented during each patient encounter.   
7 
STUDY TREATMENTS 
7.1 Method of Assigning Subjects to Treatment Groups 
All subjects in this study will receive the treatment.  
7.2 Blinding 
Since there is no randomization in this study, blinding will not be necessary,   
7.3 Formulation of Test and Control Products 
There will be no control products in this study. 

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7.3.1 Formulation of Test Product 
The test product, Synvisc-One, has a unique composition. Synvisc-One, like SYNVISC® 
, is a mixture of two hylan polymers derived from American and Canadian chicken comb 
hyaluronan. Hylans are produced by chemically cross-linking hyaluronan in two steps 
(shown in figure).  Synvisc-One is hylan G-F 20, meaning it is 80% hylan A fluid plus 
20% hylan B gel. This composition yields a molecular weight and viscoelastic properties 
that closely match healthy synovial fluid. 
Synvisc-One™ (hylan G-F 20) is an elastoviscous high molecular weight fluid containing 
hylan A and hylan B polymers produced from chicken combs. Hylans are derivatives of 
hyaluronan (sodium  hyaluronate). Hylan G-F 20 is unique in that the hyaluronan is 
chemically cross-linked. Hyaluronan is a long-chain polymer containing repeating 
disaccharide units of Na-glucuronate- N-acetylglucosamine 
Hylan polymers (hylan A + hylan B) 16 mg 
Sodium chloride 17 mg 
Disodium hydrogen phosphate 0.32 mg 
Sodium dihydrogen phosphate monohydrate 0.08 mg 
Water for injection q.s. to 2.0 mL 
 
SYNVISC® (hylan G-F 20) and Synvisc-One® (hylan G-F 20) are indicated for the 
treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond 
adequately to conservative non pharmacologic therapy and simple analgesics, e.g., 
acetaminophen.  
7.3.2 Formulation of Control Product 
There will be no control or placebo product in this study.  
7.3.3 Packaging and Labeling   
The package insert is attached. Synvisc-one is supplied in single use boxes that will 
contain the statement, “CAUTION-Investigational device Limited by Federal law to 
investigational use.”  The boxes will be labeled and shipped with this investigational 
packing to the UCSF Investigational Pharmacy.    
7.4 Supply of Study Drug at the Site 
Genzyme will ship Synvisc-One to the UCSF Investigational Pharmacy.  The initial study 
drug shipment will be shipped after site activation. For this trial, devices shall be received 
in M39A, the IDS office. Products are unpacked from shippers by IDS staff, verified 
against invoice then placed in room temperature storage in M69C, pending transfer to the 
investigator. If the shipper requires verification of device receipt (fax email, etc.), this will 
be done at the time of receipt.  Subsequent study drug shipments will be made after site 
request for resupply. The Synvisc-One devices will be couriered to the Orthopaedic 
Institute on the Mission Bay UCSF campus by the UCSF investigational pharmacy 
according to subject enrollment by a pharmacy staff member. 
 

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Shipping address where all study products will be shipped: 
UCSF Inpatient Pharmacy 
Attn: Investigational Drugs  
505 Parnassus Ave, Room M39C 
San Francisco, CA 94143 
 
Pharmacist of Record (PoR): 
Scott Fields, PharmD 
Investigational Drug Pharmacist  
UCSF Inpatient Pharmacy- Attn: Investigational Drugs  
505 Parnassus Ave, Room M39C -San Francisco, CA  94143 
415 353 1798  (phone) -415 353 8543 (fax) 
415 443-9424 (pager)-scott.fields@ucsfmedctr.org 
 
Pharmacist who will assume these responsibilities when the PoR is not available: 
Yelena Koplowicz, PharmD  
Investigational Drug Pharmacist 
 
UCSF Inpatient Pharmacy- Attn: Investigational Drugs  
505 Parnassus Ave, Room M39C -San Francisco, CA 94143 
415 353 1798 (phone) -415 353 8543 (fax) 
Yelena.Belkin@ucsfmedctr.org 
 
Other pharmacy staff, under the direct supervision of the Pharmacist of Record, who may 
assist with the day-to-day activities: 
Christopher Quan, Pharmacy Technician, California licensure 
Jane Tam, PharmD, Pharmacist, California licensure 
 
Pharmacy Supervisor: 
Courtney Yuen, PharmD, BCOP - Oncology Pharmacy Supervisor 
 
Medical Monitor: 
Orthopaedic Institute 

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Dr. Anthony Luke 
Investigator and Medical Monitor 
1500 Owens  
San Francisco, CA 94158 
 
7.4.1 Dosage/Dosage Regimen 
Subjects will receive a single 6 mL intra-articular injection of hylan G-F 20 in the target 
knee at baseline.  Patients can receive any other conservative treatments (e.g., oral 
medications, physical or other therapy, acupuncture, etc., except other injection 
treatments) and current treatments will be documented during each patient encounter.  An 
initial injection of hylan G-F 20 will be injected in the symptomatic knee using a standard 
supine lateral approach using a 20 gauge needle.  A face to face follow up visit will be 
carried out 6 months after first injection with additional face to face meetings every 6 
months thereafter unless the subject requires an additional injection of hylan G-F 20.  
Hylan G-F 20 treatments can be administered up to three times each year during the study 
duration.  After each injection, follow up measures will be carried out using secure e-mail 
or phone contact at 6 weeks, 12 weeks, 18 weeks after each in-office evaluation or 
injection.  Follow up will consist of WOMAC, Lysholm score, and Tegner score.   .   
Patients may return for retreatment of hylan G-F 20 if symptoms recur after at least 4 
months following their previous injection and they meet the inclusion criteria for pain 
levels on the following WOMAC questions A1 (How much pain have you had walking on 
a flat surface?), C8 (How much difficulty have you had going down the stairs?), C9 (How 
much difficulty have you had when going up the stairs?), C10 (How much difficulty have 
you had when getting up from a sitting position?) and/or C23 (How much difficulty have 
you had while doing heavy household chores?). Inclusion criteria for pain level is defined 
by selecting moderate, severe, or extreme on all questions A1, C8, C9, C10 and/or C23. 
Those subjects who select mild or no pain levels on any of A1, C8, C9, C10 and/or C23, 
will not meet the criteria for WOMAC pain level and retreatment.    Patients requiring 
three injections of hylan G-F 20 in 4 months or less will be allowed to exit the cohort after 
their six-month follow up following the third injection.  Otherwise, patients will be 
followed until they reach the 3 year follow up, or drop out for other injection treatments or 
surgical treatment.  Therefore, patients would potentially be able to receive up to 9 
injections during the 3 year study. 
7.4.2 Dispensing 
The Synvisc-One devices will be couriered to the Orthopaedic Institute by the UCSF 
investigational pharmacy according to subject enrollment by a pharmacy staff member. 
Upon device transfer from the pharmacy, the investigator shall maintain the devices at 
controlled room temperature in a designated area in a locked cabinet until they are 
released for patient administration upon the order of the investigator. The study 
investigators will administer the injections.  
 

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7.4.3 Administration Instructions  
The syringe containing SYNVISC (hylan g-f 20) is intended for single use. The contents 
of the syringe must be used immediately after the syringe has been removed from its 
packaging. Precaution: Do not concomitantly use disinfectants containing quaternary 
ammonium salts for skin preparation because hyaluronan can precipitate in their presence. 
SYNVISC (hylan g-f 20) (2ml) is administered by intra-articular injection once a week 
(one week apart) for a total of three injections. Strict aseptic administration technique 
must be followed. Using an 18- to 22-gauge needle, remove synovial fluid or effusion 
before each SYNVISC (hylan g-f 20) (2ml) injection. Do not use the same syringe for 
removing synovial fluid and for injecting SYNVISC (hylan g-f 20) however the same 18- 
to 22-gauge needle should be used. Twist the tip cap before pulling it off, as this will 
minimize product leakage. To ensure a tight seal and prevent leakage during 
administration, secure the needle tightly while firmly holding the luer hub. Inject the full 2 
mL in one knee only 
7.5 Supply of Study Drug at the Site 
SYNVISC (hylan g-f 20) is supplied in a 2.25 mL glass syringe containing one 2 mL (16 
mg) dose of hylan G-F 20. The contents of the syringe are sterile and non-pyrogenic. The 
injections will be sent in the standard approved market packaging, with one syringe per 
box. Replacements will be provided by the manufacturer per site request.   
7.5.1 Storage 
Investigational Pharmacy  
Study devices will be stored in protocol-specific bins on wire rack shelving units in a 
locked room (M69C) adjacent to the Investigational Drug Service office.  Room 
temperature products are stored in protocol-specific bins on wire rack shelving units in a 
locked room (M69C) adjacent to the Investigational Drug Service office. Temperature is 
maintained between 20-25 degrees C. with occasional excursions within the range of 15-
30 degrees C. as per the USP definition for Controlled Room Temperature.  Two 
maximum/minimum thermometers (values recorded in whole degree C units) are used to 
track room temperature, one at the entrance and another at the other end of the storage 
racks; values are recorded on a daily basis. In addition, a Dickson temperature logger 
(values recorded every 5 minutes) is used to track temperatures on a continual basis.   
The room is also subject to continual monitoring by Awarepoint, a wireless temperature 
monitoring system that sends text-page alerts to key personnel (pharmacist in charge in 
the main pharmacy and Investigational Drug Pharmacist) in the event of potential 
temperature excursions in storage areas. Awarepoint temperature sensors will send a page 
to the pharmacist in charge in the Inpatient Pharmacy and the PoR in the event of near 
excursions for all devices monitored by the Awarepoint system: room temperature, 
refrigerator and -20C freezer. In the event that the alarm is not addressed within 30 
minutes, an alert is sent out to the Pharmacy manager on call.  Max/min values are 
recorded daily on a month-specific paper record that is maintained in the room until the 
end of the month. After this, the records are stored in the IDS files. A copy of the logger 
readout is downloaded weekly and stored in the same IDS temperature files. The PoR will 
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max/min thermometer at the door also measures relative humidity max/min. These values 
are recorded on the same record as the max/min temperatures.  Reports from the system 
can be downloaded at any time for documentation of appropriate storage.  Temperature 
monitoring devices are certified annually-biannually.  
The PoR will secure the supplies while in possession of the pharmacy.   Staff pharmacists 
have access to investigational agents; a copy of the key to the investigational drug storage 
room is on the narcotic key ring held by the Central Unit Dose pharmacist or narcotic 
technician on duty. Additional keys are in the possession of the IDS pharmacist and the 
Director of Pharmacy and 2 others are maintained in the IDS office, accessible to the 
Investigational Drug technician and IDS Pharmacists. Staff pharmacists have access to 
investigational agents; a copy of the key to the investigational drug storage room is on the 
narcotic key ring held by the Central Unit Dose pharmacist on duty. Additional keys are in 
the possession of the IDS pharmacist, the Director of Pharmacy and 2 others are 
maintained in the IDS office, accessible to the Investigational Drug technician and IDS 
Pharmacists. Limited key distribution as described. 
 
Orthopaedic Institute 
Upon transfer from the pharmacy, the investigator shall maintain the devices at controlled 
room temperature in a designated area in a locked cabinet at 1500 Owens Street until the 
investigator administrates them. Temperatures in the Orthopaedic Institute are also 
monitored using the AwarePoint system. AwarePoint enables the Investigational 
Pharmacy to monitor the Orthopaedic Institute’s temperature remotely.   Temperature is 
maintained between 20-25 degrees C. with occasional excursions within the range of 15-
30 degrees C. as per the USP definition for Controlled Room Temperature.  Study devices 
will be stored in the clinic until the protocol is closed or until their expiration date has 
been reached. In those events, those devices shall be returned to the pharmacy for final 
disposition. The investigator shall be responsible for maintaining the security of the 
material at the Orthopaedic Institute to prevent unauthorized use. Cabinet key access will 
be limited to investigators and study key personal. 
 
7.6 Study Drug Accountability 
The UCSF investigational pharmacy on the Parnassus campus will be responsible for 
study drug storage, handling, dispensing, record retention, and return of unused Synvisc-
One. Scott Fields, investigational pharmacist, will be responsible for maintaining accurate 
records about devices received; facilitating the couriering of the devices to the 
investigative site; and returning devices to manufacturer as needed.  An accurate and 
current accounting of the dispensing and return of study drug for each subject will be 
maintained on an ongoing basis by a member of the pharmacy staff. In supplement to 
paper based records, this pharmacy uses WebIDS/Vestigo, an internet based drug 
accountability system. The system will track inventory and expiration dates, generate 
prescription labels and recharge for services rendered.  
At the Orthopaedic Institute, the devices will be locked in a secure cabinet and regularly 
monitored by Dr. Luke. Dr. Luke and study staff are responsible for maintaining adequate 

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records of the disposition of the drug including clinical the date, subject number, number 
of doses and amount dispensed. The number of study drug dispensed and returned by the 
subject will be recorded on the Investigational Drug Accountability Record. The study 
monitor will verify these documents throughout the course of the study. 
 
7.7 Measures of Treatment Compliance 
A member of the research team will contact the subjects every 6 weeks, either by email or 
phone, to assess for pain, other treatment history and any adverse events. 
 
8 STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject. If appropriate, assent must also be obtained prior to conducting any 
study-related activities. 
8.1 Clinical Assessments 
8.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at each visit.  
Dose, route, unit frequency of administration, and indication for administration and dates 
of medication will be captured. 
8.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at screening visit. 
8.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at screening visit. 
8.1.4 Physical Examination 
A complete physical examination will be performed by either the investigator or a sub-
investigator who is a physician at the screening visit and visit numbers 2-7.   Qualified 
staff (MD, NP, RN, and PA) may complete the abbreviated physical exam at all other 
visits.  New abnormal physical exam findings must be documented and will be followed 
by a physician or other qualified staff at the next scheduled visit. 
8.1.5 Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes will be performed as needed and during physical examinations.  

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8.1.6 Standardized X-rays 
45° flexion standing weight-bearing, lateral and merchant views x-rays should be 
completed at or before screening visit 
8.1.7 Functional Testing 
12-minute walk test, gait analysis, and 3-day accelerometer test will be completed during 
the screening visit.  The walk test involves simple physical movements such as walking 
and the accelerometer is worn by the patient prior to the visit to measure activity levels.  
The 12-minute walk test and 3-day accelerometer test will be administered again during 
their 6 month, 18 month, 24 month, 30 month, and 36 month visits.   
8.1.8 Administration of Injection 
Using an 18- to 22-gauge needle, the doctor will remove synovial fluid or effusion before 
each SYNVISC (hylan g-f 20) (2ml) injection. Using an 18- to 22-gauge needle, the 
doctor will inject the full 2 mL in one knee only.   
8.1.10 Concomitant Medication Review 
Patient will be asked about any medications they are taking.  Current treatments and 
medications will be documented during each patient encounter.   
8.1.11 Email or phone contact  
A member of the research team will contact the subjects every 6 weeks, either by email or 
phone, to assess for pain, other treatment history and any adverse events.   
8.1.12 Questionnaires and Assessments 
Patients will either complete on their own or be asked questions from the WOMAC, 
Lysholm-Tegner, Worst Knee Pain, KOOS, and SF-12 assessments by their doctor or 
another study staff member who will record the appropriate scores during the screening 
visit.  Patients will be assessed again with the Worst Knee Pain, KOOS, SF-12 and 
WOMAC assessments during their 6month, 18 month, 24 month, 30month, and 36month 
visits. 
8.1.13 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF). 
8.2 Clinical Laboratory Measurements  
8.2.1 Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age 
prior to their participation in the study. 
9 
EVALUATIONS BY VISIT  
Baseline Screening (1-3 weeks before Synvisc-One treatment) 

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Complete history 
 
Physical examination 
1. History of symptomatic unilateral primary or secondary knee OA for more than 6 
months 
2. Lysholm-Tegner 
3. SF-12 
4. WOMAC 
Visit 1 
 
Synvisc-One injection 
Visit 2 (6 months post injection) 
 
Physical examination 
 
Functional testing: 
1.12-minute Walk test 
2.3-day accelerometer test 
 
Evaluation instruments (study questionnaire): 
1. Worst Knee Pain 
2. KOOS 
3. SF-12 
4. WOMAC 
Visit 3 (12 months post injection) 
 
Physical examination 
 
Functional testing: 
1. 12-minute Walk test 
2. 3-day accelerometer test 
 
Evaluation instruments (study questionnaire): 
1. Worst Knee Pain 
2. KOOS 
3. SF-12 
4. WOMAC 
Visit 4 (18 months post injection) 
 
Physical examination 
 
Functional testing: 
1. 12-minute Walk test 
2. 3-day accelerometer test 
 
Evaluation instruments (study questionnaire): 
1. Worst Knee Pain 
2. KOOS 
3. SF-12 
4. WOMAC 
Visit 5 (24 months post injection) 
 
Physical examination 
 
Functional testing: 
1. 12-minute Walk test 
2. 3-day accelerometer test 
 
Evaluation instruments (study questionnaire): 
1. Worst Knee Pain 

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2. KOOS 
3. SF-12 
4. WOMAC 
Visit 6 (30 months post injection) 
 
Physical examination 
 
Functional testing: 
1. 12-minute Walk test 
2. 3-day accelerometer test 
 
Evaluation instruments (study questionnaire): 
1. Worst Knee Pain 
2. KOOS 
3. SF-12 
4. WOMAC 
Visit 7 (36 months post injection) 
 
Physical examination 
 
Functional testing: 
1. 12-minute Walk test 
2. 3-day accelerometer test 
 
Evaluation instruments (study questionnaire): 
1. Worst Knee Pain 
2. KOOS 
3. SF-12 
4. WOMAC 
Email or phone contact at 6, 12 and 18 weeks post each injection and clinic visit to check 
for any changes in medical condition. 
 
Worst Knee Pain (0-10 NRS) 
 
Other treatment history 
 
Adverse events 
Office Visit 
What you do 
1-3 weeks before starting study treatment 
Physical exam 
X-ray 
Study questionnaire 
12 minute walk test 
3-day accelerometer test 
Visit 1 - Baseline 
        Synvisc-One injection in the 
affected knee 

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10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Visit 2 – 6 months after 
injection Visit 3 – 1 
year after injection 
Visit 4 – 1.5 years after 
injection Visit 5 – 2 
years after injection 
Visit 6 – 2.5 years after 
Physical exam 
Study questionnaire 
12 minute walk test 
3-day accelerometer test 
Email or phone contact at 6, 12 and 18 weeks 
after each injection and office visit 
Check up on your medical 
condition 

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Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may 
be aware of the sign or symptom but tolerates it reasonably 
well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal 
medical intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience 
as it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more 
severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to Synvisc-One should be assessed using the following the 
guidelines in Table 2. 
Table 2. AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known 
or expected response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is not explained by 
any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to the 
suspected drug; that is confirmed by stopping or reducing the dosage of the 
drug; and that is unlikely to be explained by the known characteristics of 
the subject’s clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to that 
suspected drug; but that could readily have been produced by a number of 
other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to 
the study drug. 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
 
death 

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a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
10.1.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed.  
Institution and Investigator understand and agree that Investigator and Institution are 
obligated under applicable law and regulations to report any serious and related adverse 
event, if any, that occurs during treatment with the Product to the Institution’s IRB and to 
the governing regulatory authority in accordance with applicable filing timelines promptly 
after any such event occurs.  Prior to or at the time of filing any such report with the 
governing regulatory authority, Investigator, within 24 hours of first knowledge of such 
serious and related adverse event, will also transmit an information copy of the report to 
Genzyme via fax, attention: Genzyme PV, 617-761-8506 or by e-mail to 
pharmacovigilancesafety@genzyme.com. In accordance with the standard operating 
procedures and policies of the local Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), the site investigator will report SAEs to the IRB/IEC.   
10.2 Medical Monitoring 
Dr. Luke should be contacted directly at these numbers to report medical concerns or 
questions regarding safety. 
Phone: 415-885-3807 
Cell: 415-238-7721 
Pager: 415-719-8691 
 
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
11.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:  
 
Subject withdrawal of consent (or assent) 
 
Subject is not compliant with study procedures 
 
Adverse event that in the opinion of the investigator would be in the best interest of 
the subject to discontinue study treatment 

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Protocol violation requiring discontinuation of study treatment 
 
Lost to follow-up 
 
Sponsor request for early termination of study 
 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  
11.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.   
11.3 Replacement of Subjects 
Subjects who withdraw from the study treatment in the first 6 months of the study will be 
replaced.  Replacement injected will be requested from Genzyme based on need.  
12 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, manufacturer, or investigator fails to adhere 
to significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
 
Failure to meet inclusion/exclusion criteria 
 
Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. Dr. Luke will determine if a protocol violation will result in withdrawal 
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When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
13 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
Data Sets Analyzed 
The primary endpoint is based on a responder analysis.  Response is defined as 
maintaining a Worst Knee Pain score ≤ 3 on a 0-10 pain scale throughout the 6 months 
following the baseline injection.  Trial success will be based on a non-inferiority test (with 
20% non-inferiority threshold) of this response rate in comparison to an external criterion 
of 70% (Bellamy 2010).  Secondary endpoints include determining the duration of 
response after subsequent injection, determining the effects of treatment on activity levels 
and quality of life, and describing the three-year time course of each of the study 
endpoints.  The sample size will be n=150 subjects followed for up to 3 years after 
baseline injection. The power to conclude non-inferiority for a true response rate of 65% 
is better than 92%. 
Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by: race, gender, 
age, height and weight. 
Analysis of Primary Endpoint 
The primary endpoint for the study will be analyzed using a responder analysis.  The 
proportion of responders following injection within the 6 months following the baseline 
injection will be calculated based on Worst Knee Pain scores ≤ 3 on a 0-10 pain scale, 
which is a threshold consistent with other similar studies (Tubach 2005, Bellamy 2010).  
The primary endpoint is defined as non-inferiority (with 20% non-inferiority threshold) of 
the proportion of responders in our study relative to an external criterion of 70% for the 
responder proportion (Bellamy 2010). 
 
Primary Statistical Analysis: Define the true probability of a subject being a responder 
as  and the non-inferiority threshold 
 = 0.20.  We require the test of  
 
 
H0:
 < 0.70 - 
vs. the alternative  
 
 
H1:
 > 0.70 - 

Pr ot oc ol U C S F - S Y N VI S C- 1 
C o nfi de nti al 
 
V er si o n # 0 0 1  
V er si o n D at e: 5 .1 7 .1 2  
P a g e 3 6  of 4 5  
 
 
N o n-i nferi orit y will be acc e pt e d if t he n ull h y p ot hesis ca n be reject e d wit h a 2. 5 % o ne-
si d e d t y pe I err or.  T o t est t his h y p ot hesis, we will use t he Wils o n- A gresti met h o d f or a 
si n gle bi n o mial pr o p orti o n.  N o n i nferi orit y will be acce pt e d if t he 9 5 % Wils o n- A gresti 
( R E F B R O W N E T A L 2 0 0 1) i nt er val f or t he pr o p orti o n of res p o n ders e x cl u d es t he n ull 
rat e of 0. 5 0. 
 
Missi n g D at a: F or t he a nal ysis of t he perce nt a ges of p ositi ve res p o n ders, patie nts w h o 
dis c o nti n ue t he st u d y pri or t o t he We e k  2 6 assess me nt d ue t o eit her t ar get k nee -relat e d 
A Es or d ue t o lac k of effica c y will be classifie d as n o n -res p o n ders i n t he effica c y 
a nal ysis.   Patie nts w h o disc o nti n ue t he st u d y f or ot her reas o ns will ha ve t he res p o n der 
st at us i m p ut e d usi n g t he last o bser vati o n carrie d f or war d ( L O C F) met h o d.  
 
O per ati n g C h ar acte ristics 
T he f oll o wi n g t a ble s h o ws t he p o wer t o acce pt n o n-i nferi orit y f or t w o ass u m pti o ns o n 
sa m ple size ( n = 1 5 0 a n d a s maller sa m ple size refle cti n g p ot e ntial dr o p o ut of n = 1 2 0): 
 
Tr ue Res p o n der Rat e 
( 
Sa m ple Siz e  
n = 1 5 0  
Sa m ple Siz e  
n = 1 2 0  
0. 6 0  
7 2 %  
6 1 %  
0. 6 5  
9 7 %  
9 2 %  
0. 7 0  
> 9 9 %  
> 9 9 %  
0. 7 5  
> 9 9 %  
> 9 9 %  
 
 
T a ble 1.  P o wer t o c o ncl u de n o n-i nferi orit y f or variet y of tr ue res p o n der rat es a n d t w o 
val ues f or sa m ple size. 
 
T h us, e ve n aft er c o nser vati vel y acc o u nti n g f or s u bject dr o p o ut, we will be well- p o were d 
t o c o ncl u de n o n-i nferi orit y if t he tr ue res p o n der rate is at least 6 5 %. 
 
Sec o n d ar y O utc o mes: 
 
- D ur ati o n of res p o nse t o s u bse q ue nt i njecti o ns:  T h o u g h s y m pt o ms ca n be i m pr o ve d 
f or peri o ds u p t o 6 m o nt hs, pai n s y m pt o ms ca n rec ur i n w hic h case patie nts will recei ve a 
s u bse q ue nt i njecti o n.  T he d urati o n of t hese re peat e d tr eat me nts of h yla n G- F 2 0 will be 
st u die d. 
 
- Effect of tre at me nt o n acti vit y le vels a n d q u alit y of life: T he effects of treat me nt wit h 
h yla n G- F 2 0 o n acti vit y le vels ( usi n g o bjecti ve acti vit y meas ures utilizi n g acceler o met er 

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and Physical Activity Enjoyment Scale) and quality of life scores (WOMAC, SF-12) 
comparing baseline to treatment at 3 months. 
 
- Three year follow up:  Patients will be followed for up to three years.  We will 
examine the time courses of pain score, activity level, and quality of life over the entire 
three year span. 
Analysis of Secondary Endpoints 
Secondary Analyses: Secondary endpoints will be analyzed using confidence intervals as 
no specific hypothesis tests are being conducted. 
 
The following secondary analyses will be conducted: 
 
- Duration of response: Using Kaplan-Meier survival analysis techniques, we will 
estimate the probability of duration of response over time curve (survival curve) and its 
confidence limits and also the median duration time and confidence interval.  Duration of 
response analyses will be conducted for the initial injection and also in the subset of 
patients that receive a follow-up injection. 
 
- Activity levels and quality of life:  We will estimate the average change and 
corresponding confidence limits from baseline to 3 months in each of the activity level 
measures (accelerometer test , walk test, Physical Activity Enjoyment Scale) and the 
quality of life measures (WOMAC, SF-12).  The confidence intervals will be constructed 
using one sample t-distributions; in the event of strongly skewed measures, we will either 
use bootstrapping or transformation to construct more accurate intervals.  The average 
change and the endpoints of the confidence intervals can be referenced to external 
clinically important improvements for comparison. 
 
- Long term outcome:  We will examine the time course for the pain score, activity 
level, and quality of life measures across the three years of the study.  Estimates and 
confidence intervals will be derived using mixed effects linear models.  Specifically, for 
each longitudinal outcome measure, we will model it as a function of the (categorical) 
time point.  Intrasubject correlation will be accommodated by either a compound 
symmetry, autoregressive, or general covariance structure depending on best fit according 
to BIC.  In the event of very non-normally distributed outcomes, we will employ 
normalizing transformations prior to the analysis.  These analyses will be conducted using 
the Mixed procedure in SAS. 
 
13.5 Interim Analysis 
There is no interim analysis planned. Serious adverse events will be monitored by the 
committee on an ongoing basis throughout the study. 

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13.6  Sample Size and Randomization 
Bellamy demonstrated in his paper from 2007 (table 3) that a BLISS response at any time 
during the study was achieved in 70% receiving appropriate care and Hylan G-F 20 and 
only in 38% of patients receiving appropriate care (P<0.0001).   A power calculation 
using a one-sample comparison of proportion with hypothesized value sample size was 
performed to determine non-inferiority to the 70% results quoted by Bellamy. Power 
calculations were measured using STATA’s SAMPSI calculator.  If we postulate a 20% 
non-inferiority limit (i.e. that at least 50% of patients receiving G-F 20 will achieve a 
BLISS response), the sample size required to have 90% power and ∝=0.025 to show non-
inferiority at 50% would be 70.  For a 10% non-inferiority limit with 90% power and 
∝=0.025, the required sample size is 274, and for 15% non-inferiority limit with 90% 
power and ∝=0.025, it is 124 patients.  These numbers do not allow for dropouts, 
therefore, we intend to recruit 150 subjects to account for dropout. 
14 DATA COLLECTION, RETENTION AND MONITORING 
Data Collection Instruments 
Study personnel will enter data into REDCap (Research Electronic Data Capture). 
REDCap is a secure, web-based application designed to support data capture for research 
studies. Subjects will not be identified by name in the study database, but will be 
identified by a subject number and initials. 
14.2 Data Management Procedures 
Once data has been successfully entered into the database, the Biostatistics Consulting 
Unit (BCU) of UCSF’s Clinical and Translational Science Institute (CTSI) will perform 
data management and analysis for the study.  Most CTSI personnel have office space 
within the area occupied by the Department of Epidemiology and Biostatistics at China 
Basin Landing near UCSF’s Mission Bay campus, along with desktop computers and 
access to departmental “cloud” computing resources.  These include secure data storage 
and access on a HIPAA-compliant server, along with SAS and Stata statistical software.  
The server room has state-of-the-art environmental controls and security features that 
include secure, limited access and alarm systems; floor-mount, locking server racks with 
built-in AC and mounted power strips; dedicated AC unit with temperature monitoring; 
dedicated circuit breaker and power distribution units; uninterruptible power supply 
equipment; and fire detection and suppression. Servers are protected by a firewall and 
anti-virus software. Files and databases are backed up daily. Back-up tapes are sent to an 
off-site record storage facility every two weeks, with a 2-month tape rotation. 
Access to network resources is granted based on documented authorization from a 
supervisor and permissions are based on user responsibilities. Each user is given a 
network account consisting of a unique username and a user-designated password that 
must meet network security criteria. Before network access is given, users are required to 
train on university electronic security policies.  All procedures for the handling and 
analysis of data will be conducted using good computing practices meeting FDA 
guidelines for the handling and analysis of data for clinical trials. 
 

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Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. The 
study database will be updated in accordance with the resolved queries.  All changes to 
the study database will be documented. 
14.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents will be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.   
14.6 Monitoring 
Monitoring will be conducted by representatives of the Sponsor according to the U.S. 
CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).   
Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number and subject initials will 
identify all study subjects on study documentation.   
15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 

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applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
Protocol Amendments 
Any amendment to the protocol will be submitted by Dr. Luke prior to implementation.  
Protocol amendments cannot be implemented without prior written IRB approval except 
as necessary to eliminate immediate safety hazards to patients.  A protocol amendment 
intended to eliminate an apparent immediate hazard to patients may be implemented 
immediately, provided the IRBs are notified within five working days. 
15.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form has been approved by the will be reviewed and approved 
by the IRB of the center prior to study initiation.  Serious adverse experiences regardless 
of causality will be reported to the IRB in accordance with the standard operating 
procedures and policies of the IRB, and the Investigator will keep the IRB informed as to 
the progress of the study.  The Investigator will obtain assurance of IRB compliance with 
regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB.  The IRB’s written unconditional approval of the study 
protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB’s unconditional approval statement will be 
transmitted by the Investigator to Genzyme prior to the shipment of study supplies to the 
site.  This approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB and written verification that the 
modification was submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
15.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
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the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonization and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 
Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
15.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports). 

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9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 
References 
Brown, L. D., T. T. Cai, and A. DasGupta. 2001.  Interval estimation for a binomial 
proportion.  Statistical Science 16: 101-133. 

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APPENDIX 1. SCHEDULE OF STUDY VISITS 
 
SCREENING 
 
VISIT 1 
 
VISIT 2 
6 months 
VISIT 3 
12 months 
VISIT 4 
18 months 
VISIT 5 
24 months 
VISIT 6 
30 months 
VISIT 7 
36 months 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Complete Physical Exam 
x 
 
X 
X 
x 
X 
x 
x 
Abbreviated Physical Exam 
 
x 
 
 
 
 
 
 
Height/weight 
x 
X 
X 
X 
X 
X 
X 
X 
X-rays (flexion, weight bearing, lateral, and 
merchant views) 
x 
 
 
 
 
 
 
 
Vital Signs  
x 
x 
x 
x 
x 
x 
x 
x 
Motion Gait Analysis 
X 
 
 
 
 
 
 
 
12 Minute Walk Test 
X 
 
X 
X 
X 
X 
X 
X 
3-day Accelerometer Test 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
 
 
 
 
 
 
 
Worst Knee Pain 
X 
 
X 
X 
X 
X 
X 
X 
KOOS 
X 
 
X 
X 
X 
X 
X 
X 
Lysholm-Tegner 
X 
 
 
 
 
 
 
 
WOMAC 
X 
 
X 
X 
X 
X 
X 
X 
SF-12 
X 
 
X 
X 
X 
X 
X 
X 
Dispensing or Administration of Study Drug 
 
X 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Experiences 
 
 
X 
X 
X 
X 
X 
X 
a  
2 days 
 
 
 
 

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APPENDIX II 
 
Case Report Forms (Assessments) from the electronic data gathering system, Redcap, are attached. 

Protocol UCSF-SYNVISC-1 
 
 
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