Optimization of Synvisc-One for Knee OA

Inclusion Criteria: * Male or female subjects meeting the American College of Rheumatology (ACR) criteria for primary knee OA who are age 21 or greater with radiographic and symptomatic evidence of tibio-femoral OA for more than 6 months (unilateral, single joint, Kellgren-Lawrence Grading Scale Score of 2 or 3, medial or lateral +/- patellofemoral). * Subjects with persistent target knee OA pain despite treatment ≥ 3 months with acetaminophen 4 grams or less or other OA pain treatments. * Subjects willing to discontinue all prohibited treatments and medications (e.g. opioids, narcotic analgesics, Tramadol) throughout the study period. * Subjects currently on prescription strength NSAIDs (Non steroidal antiinflammatory drugs) must maintain a stable regimen (no dose increase and no new analgesics) during the entire study period. * Female subjects of child bearing potential must have a negative serum or urine pregnancy test prior to Synvisc-One® or sham injection. * Female subjects of child bearing potential must agree to use a medically acceptable form of contraception for at least 1 month prior to Synvisc-One® or sham injection and must agree to continue the use of an acceptable form 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. * Subjects willing and able to commit to a standard 10 week course of physical therapy. * Subjects willing and able to sign written informed consent. Exclusion Criteria: * Kellgren-Lawrence Grading Scale score of Grade 1 or Grade 4 given the low efficacy of viscosupplements in this population and the KOOS is not validated in this patient population. * Known allergy to hylan G-F 20 or any of its components, or to avian proteins, eggs, feathers, down, or poultry. * History of viscosupplementation in the target knee joint within 3 months of the baseline visit. * Isolated patellofemoral OA or isolated anterior knee pain (patellofemoral OA coexisting with tibiofemoral knee OA may be included). * Symptomatic bilateral knee OA (unless the contralateral knee involvement is limited to radiographic OA and not symptomatic). * Ipsilateral symptomatic OA of hip or ankle; contralateral symptomatic OA of hip, knee, or ankle, or clinical evidence of hip disease. * Clinically apparent knee joint infection, tense effusion or other acute inflammation of the target knee at baseline. * History of septic OA of any joint; and / or Inflammatory arthropathy such as RA (Rheumatoid Arthritis), gout, pseudogout, lupus, crystalline inflammatory arthropathy, chondrocalcinosis etc. * Active infection of a lower extremity (e.g. cellulitis). * Prosthetic implant in either knee. * Subjects with any clinical indication for arthroscopic surgery. * Subjects with a planned or scheduled surgery during the course of the study (scheduled or awaiting for arthroscopy or a knee replacement procedure for OA of the knee). * Subjects with plans to initiate or cease other OA treatments including, but not limited to non- pharmacologic, pharmacologic, surgical, chiropractic, or acupuncture during the course of the study. * Subjects with plans to initiate, cease or continue any other intra-articular knee joint injection during the course of the study. * History of systemic and/or intra-articular steroid injection in target knee within one month prior to the baseline visit. * History of open knee surgery in affected knee or history of arthroscopic surgery in affected knee in past year. * History of complete menisectomy. * Suspected meniscus injury, including a positive McMuray's test or significant joint line tenderness. * Cruciate / collateral knee ligament instability, ligament laxity, or meniscal instability of target knee. * Obvious cartilage defects producing mechanical symptoms (i.e. locking). * Patellar tendonitis. * Significant alignment deformity such as varus / valgus of target knee in the judgment of the investigator. * Venous or lymphatic stasis in either leg. * Past or current history of peripheral vascular disease pertaining to the involved limb. * Concurrent multisystem or multilimb trauma. * Known significant acute and / or concurrent medical comorbidities including, but not limited to current malignancy, history of transplant surgery, congestive heart failure, significant unstable cardiovascular disease, renal, hepatic, pulmonary, endocrine, metabolic, gastrointestinal, or neurological condition that in the judgment of the investigator would significantly impact life expectancy and / or the conduct of the trial. * Known psychiatric disorder. * Body mass index (BMI) \> 40. * Female subjects interested in conceiving a child during the study period. * Currently pregnant or new mothers who are breastfeeding. * Subjects currently prescribed chronic opioid analgesics at time of baseline visit that cannot be discontinued. * Use of prohibited pain medications. * Any known contraindication to acetaminophen. * Subjects currently enrolled in any other experimental clinical trial or history of trial enrollment within three months of baseline. * Subjects who plan to move or relocate out of area inhibiting their ability to complete the entire physical therapy regimen as defined by the protocol and prescribed by the investigator. * Knee pain is associated with a Worker's Compensation Claim.