This OT Award funds clinical trials within The Early Phase Pain Investigation Clinical Network (EPPIC-Net). EPPIC-NET is part of the NIH Helping to End Addiction Long-term (HEAL) Initiative. More than 100 people die each day of opioid-related overdoses. Many of these can be traced to addiction related to the treatment of acute and chronic pain. There is an urgent need to develop non-addictive pain treatments to limit opioid exposures that can lead to addiction, as well as to treat pain conditions that are currently without effective treatments. The EPPIC- Net OT provides a robust infrastructure for the rapid design and execution of high-quality early phase clinical trials to test promising novel therapeutics and devices for the treatment of pain and for carrying out in-depth phenotyping and biomarker studies in patients with specific pain conditions. Such studies bring intense focus to patients with well-defined pain conditions and high unmet therapeutic needs. Studies funded under this award are described below. EPPIC-Net Clinical Trial EN20-01 Project Title: A 24-week Week Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects with Moderate to Severe Knee Osteoarthritis Pain. This trial will test the novel oral drug CNTX-6970 in patients with moderate to severe knee osteoarthritis pain. 150 participants will be enrolled at 20 EPPIC-Net sites across the U.S. Preclinical studies of CNTX-6970, a C-C chemokine type 2 (CCR2) receptor antagonist, demonstrated potent analgesia in multiple pain models. Phase 1 clinical studies showed robust and dose-proportional target engagement and no emergent safety issues. The rationale for exploring CNTX-6970 for the management of pain in knee osteoarthritis stems from the emerging understanding of the pathophysiology of the affected joint as well as CNTX-6970 effects on neural signaling. Participants will be randomized to receive CNTX-6970, placebo, or an approved pain medication and will be followed for 24 weeks. EPPIC-Net Master Protocol to Assess Treatments for Painful Diabetic Peripheral Neuropathy People with diabetes are at risk for painful diabetic peripheral neuropathy. Diabetic neuropathic pain may be experienced as burning, aching, hypersensitivity to touch, or simply as pain. The currently FDA-approved medications for painful diabetic peripheral neuropathy (PDPN) provide inadequate pain relief for many. The EPPIC-Net Master Protocol for Diabetic Peripheral Neuropathy (Master Platform Protocol (MPP)) provides a platform for EPPIC-Net Phase II clinical trials testing therapeutic assets for the treatment of PDPN. The MPP provides the common over-arching structure with a modular design of required and optional elements to be included for study of each asset. All clinical trials under the MPP include HEAL Common Data Elements and required PDPN assessments as well as asset-specific procedures and measurements described in an Intervention Specific Appendix (ISA) to the MPP. The follow...