A Phase 3 Study to Evaluate the Efficacy and Safety of Resiniferatoxin for Pain Due to Osteoarthritis of the Knee

Key Inclusion Criteria: * Male or female 35 to 85 years of age (inclusive). * Diagnosis of moderate to severe pain in the index knee due to OA. * Pain in the non-index knee is less than pain in the index knee. * Body mass index ≤40 kg/m². * Experienced treatment failure with at least 2 prior categories of therapies. * Able to understand and complete study-related forms and communicate with the Investigator and/or site staff. Key Exclusion Criteria: * Evidence or history of a serious coagulopathy or hemostasis problem, such as inherited bleeding disorders or thrombocytopenia. * History of or current condition of poorly controlled hypertension, QTc prolongation, history of risk factors for Torsades de Pointes, or family history of long QT syndrome; or is using concomitant medications that prolong the QT interval. * Received index knee injections with corticosteroids within 30 days, or hyaluronic acid within 3 months, or platelet-rich plasma within 6 months prior to the injection day. * Pre-existing osteonecrosis, subchondral insufficiency fracture, severe bone on bone OA, or knee pain attributable to disease other than OA. * Instability or misalignment in the index knee. * Concurrent use of opioids or indications other than knee pain. * History within the past 2 years of substance abuse, including alcohol. * Allergy or hypersensitivity to chili peppers, capsaicin, resiniferatoxin, acetaminophen, tramadol, or radiographic contrast agents. * Female participants who are pregnant, planning on becoming pregnant, or currently breastfeeding. * Any medical condition or comorbidities that, in the Investigator's opinion, could adversely impact study participation or safety, conduct of the study, or interfere with pain assessments. * Sensory peripheral neuropathy that is of moderate severity or higher. * Arterial or venous thrombi (including stroke), myocardial infarction, hospital admission for unstable angina, cardiac angioplasty, or stenting within the past 12 months. * Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome-related illness, acute or history of chronic hepatitis B or hepatitis C. Participants with these viral infections who are receiving or have received antiviral treatment and have a viral load that is undetectable are eligible. * Concurrent medical or arthritic conditions that could interfere with the evaluation of the index knee joint including chondromalacia patellae, metabolic diseases, gout/pseudogout, hemochromatosis, acromegaly, fibromyalgia, rheumatoid arthritis, or other inflammatory arthropathies affecting the knee joint. * Undergone arthroscopic surgery of the index knee within 6 months of the injection day, or open surgery to the index knee within 24 months of the injection day. * Undergone replacement surgery of the index knee. * Presence of surgical hardware or other foreign bodies in the index knee.