Evaluate the safety and exploratory efficacy of single intra-articular injections of PEP reconstituted with 0.9% Normal Saline at a low dose (one vial PEP) and high dose (two vials PEP), with and without EUFLEXXA, for the treatment of Knee Osteoarthritis

Study Plan (with Dose Escalation): Arm 1 and Arm 2 will run in parallel such that initially 3 subjects will be enrolled in Arm 1a (PEP Low Dose) and 3 subjects will be enrolled in Arm 2a (PEP-EUFLEXXA Low Dose). After all 6 subjects complete the 30 day follow up and there was not more than 1 AE grade 3 or higher per Arm, a further 9 subjects will be enrolled in Arm 1b (PEP High Dose) and a further 9 subjects will be enrolled in Arm 2b (PEP-EUFLEXXA High Dose).

Inclusion Criteria:

• Age: Adults aged 18-90 years of age

Type of Participant and Disease Characteristics:

• Diagnosis of unilateral or bilateral symptomatic KOA of at least 6 months duration (meets American College of Rheumatology/Arthritis [ACR] criteria)

• Daily knee pain in the more symptomatic knee of ≥ 30 and ≤ 80 on a 100-point VAS for greater than 6 months

• Kellgren Lawrence Grade 2 to 3 osteoarthritis in the more symptomatic knee based on standard knee radiographs

• Failed conservative management including at least 2 of the following:

• Lack of improvement with attempted weight loss in the past year if body mass index (BMI) > 30 kg/m2;

• Lack of response to a 4-week trial in the past year of oral acetaminophen or NSAIDs taken as needed;

• Lack of response to a 4-week trial in the past year of topical NSAIDs or capsaicin applied as needed;

• Lack of improvement after injection therapy with cortisone, PRP or hyaluronic acid;

• Lack of improvement after a 4-week course of physical therapy in the past year; or

• Lack of improvement after a 4-week trial of quadriceps strengthening home exercise program in the past year.

• Requesting injection therapy for pain management

• Contraceptive use by participants and their partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

  o A serum pregnancy test (human chorionic gonadotropin [hCG]) should be done for all women of childbearing potential (WOCBP) at Screening, and a urine pregnancy test should be done on Day 1, prior to injection, with results reviewed before injection to confirm the participant's eligibility. Participants who have positive pregnancy test result will not be permitted to continue in the study (see Section 5.2, Exclusion criteria 18 and 19).

• Signed informed consent as described in Appendix 1 (Section 10.1) which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

• Ability to comply with protocol.

Exclusion Criteria:

• Steroid or viscosupplement injection in the planned treatment knee(s) within the past 3 months.
• PRP injection in the planned treatment knee(s) within the past 6 months.
• History of documented allergy to intra-articular EUFLEXXA.
• History of cancer including melanoma (with the exception of localized skin cancer) in the past 2 years.
• HIV positive participants.
• BMI > 40 kg/m2.
• Arthroscopic debridement in the planned treatment knee(s) in the last 6 months.
• Cartilage restoration procedure in the planned treatment knee(s) in the last 5 years.
• History of gout or pseudogout.
• History of or evidence of active rheumatologic disease, severe peripheral neuropathy, clinically evident cardiac or respiratory disease that interferes with functional status.
• Poorly controlled diabetes defined as a glycated hemoglobin (HbA1c) concentration of ≥ 8.0%.
• Currently taking any cancer treatment regimen (including aromatase inhibitors).
• Calcium pyrophosphate deposition disease (CPPD) evident on X-ray.
• Systemic (oral, intravenous, or intramuscular) steroids in the last 3 months.
• Concurrent participation in another investigational drug or device study or participation in the last 30 days prior to enrollment.
• Evidence of recent alcohol or drug abuse, or history of medication misuse or addiction.
• Female participants who are pregnant, breast feeding, or trying to become pregnant.
• Women unwilling to use approved contraception method for 3 months after receiving dose of investigational drug.
• Unwilling or unable to comply with Telehealth visits (eg, ability to access internet, on camera capabilities, etc).