EPPIC-Net Pain Research - Application for Clinical Trial and Related Activities (OT2)

该OT奖资助早期疼痛研究临床网络（EPPIC-Net）内的临床试验。EPPIC-NET是NIH帮助结束成瘾长期计划（HEAL）的一部分。每天有100多人死于阿片类药物过量。其中许多可以追溯到与治疗急性和慢性疼痛有关的成瘾。迫切需要开发非成瘾性疼痛治疗方法，以限制可能导致成瘾的阿片类药物暴露，以及治疗目前没有有效治疗方法的疼痛状况。EPPIC-Net OT为快速设计和执行高质量的早期临床试验提供了强大的基础设施，以测试有前途的新型疼痛治疗方法和设备，并对患有特定疼痛疾病的患者进行深入的表型分析和生物标志物研究。这些研究将重点放在具有明确定义的疼痛状况和高度未满足的治疗需求的患者身上。该奖项资助的研究如下。 EPPIC-Net临床试验EN 20 - 01 项目名称：一项在中度至重度膝关节骨关节炎疼痛受试者中评价CNTX-6970安全性和疗效的24周研究。 这项试验将测试新型口服药物CNTX-6970在中度至重度膝关节骨关节炎疼痛患者中的作用。150名参与者将在美国的20个EPPIC-Net研究中心入组。CNTX-6970（一种C-C趋化因子2型（CCR2）受体拮抗剂）的临床前研究在多种疼痛模型中表现出强效镇痛作用。I期临床研究显示了稳健的和与剂量成比例的靶点结合，并且没有出现安全性问题。探索CNTX-6970治疗膝关节骨关节炎疼痛的基本原理源于对受累关节病理生理学以及CNTX-6970对神经信号传导的影响的新认识。受试者将随机接受CNTX-6970、安慰剂或批准的止痛药，并随访24周。 EPPIC-Net评估疼痛性糖尿病周围神经病变治疗的主协议 糖尿病患者有患上疼痛性糖尿病周围神经病变的风险。糖尿病性神经性疼痛可能表现为烧灼感、疼痛、对触摸过敏或简单的疼痛。目前FDA批准的治疗疼痛性糖尿病周围神经病变（PDPN）的药物对许多人的疼痛缓解不足。EPPIC-Net糖尿病周围神经病变主方案（主平台方案（MPP））为EPPIC-Net II期临床试验提供了一个平台，测试PDPN治疗的治疗资产。MPP提供了通用的over-rocket结构，其模块化设计包含了研究每项资产所需的和可选的元素。MPP下的所有临床试验包括HEAL通用数据元素和所需的PDPN评估以及MPP干预特定附录（ISA）中描述的资产特定程序和测量。 将根据EPPIC-NET主方案进行以下EPPIC-Net临床试验，以评估疼痛性糖尿病周围神经病变的治疗： EPPIC-Net临床试验EN 21 - 01 项目名称：一项在患有疼痛性糖尿病周围神经病变的成人和老年受试者中评估NRD 135 S.E1 80 mg每日一次相较于安慰剂的安全性和疗效的多中心、随机化、双盲、安慰剂对照研究（SERENDIPITY-1） 该奖项是根据EPPIC网络主协议疼痛糖尿病周围神经病变的临床试验。将NRD 135S.E1确定为潜在的疼痛治疗药物是现代转化医学中一个真正的"床边到长凳"故事。NRD135S.E1是一种小分子，是西伯利亚一个村庄传统上用来泡茶治疗疼痛的天然物质的实验室优化版本。在临床研究中，受试者对NRD 135S.E1的耐受性良好，并显示出临床相关的疼痛缓解。EPPIC-Net中的研究将进一步开发这种治疗资产，作为疼痛性糖尿病周围神经病变（PDPN）的可能治疗方法。在为期12周的平行设计试验中，260例PDPN成人受试者将被随机分配至NRD 135S.E1组或安慰剂组。 EPPIC-Net临床试验EN 21 - 02 项目名称：一项随机、双盲、安慰剂对照、平行、20周、2b期研究，在2型糖尿病伴疼痛性糖尿病周围神经病变患者中比较哌仑西平（WST-057）或安慰剂 该奖项是根据EPPIC网络主协议疼痛糖尿病周围神经病变的临床试验，以测试一种潜在的新的局部治疗疼痛糖尿病周围神经病变。治疗资产，WST-057（外用哌仑西平4%），是一种分子，在20世纪80年代开发，并在整个欧洲和亚洲以口服形式销售，以治疗胃溃疡。初步研究表明，皮肤中的神经纤维密度增加，这表明它可以促进神经再生，并可能有助于减轻疼痛的糖尿病周围神经病变的疼痛。本EPPIC-Net研究将在12个临床试验机构入组260例受试者。受试者将被随机分配到WST-057或匹配的安慰剂霜应用于足部和小腿20周。

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 following EPPIC-Net Clinical Trials will be conducted under the EPPIC-NET Master Protocol to assess treatments for painful diabetic peripheral neuropathy: EPPIC-Net Clinical Trial EN21-01 Project Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of 80mg daily of NRD135S.E1 Versus Placebo in Adult and Elderly Participants with Painful Diabetic Peripheral Neuropathy (SERENDIPITY-1) This award is for a clinical trial under the EPPIC-Net Master Protocol for Painful Diabetic Peripheral Neuropathy. The identification of NRD135S.E1 as a potential pain treatment is a true “bedside-to-bench" story in modern-day translational medicine. NRD135S.E1 is a small molecule, a lab-optimized version of a natural substance traditionally used in a village in Siberia to brew tea to treat pain. In clinical studies, NRD135S.E1 was well tolerated by participants and showed clinically relevant pain relief. Study in EPPIC-Net will further development of this therapeutic asset as a possible treatment for painful diabetic peripheral neuropathy (PDPN). 260 adult participants with PDPN will be randomized to NRD135S.E1 or placebo in the 12-week, parallel design trial. EPPIC-Net Clinical Trial EN21-02 Project Title: A Randomized, Double-blind, Placebo-controlled, Parallel, 20-week, Phase 2b Study of Topical Pirenzepine (WST-057) or Placebo in Type 2 Diabetes Mellitus Patients with Painful Diabetic Peripheral Neuropathy This award is for a clinical trial under EPPIC-Net Master Protocol for Painful Diabetic Peripheral Neuropathy to test a potential new topical treatment for painful diabetic peripheral neuropathy. The therapeutic asset, WST-057 (topical pirenzepine 4%), is a molecule that was developed in the 1980s and marketed throughout Europe and Asia in an oral form to treat gastric ulcers. Preliminary studies showed an increase in nerve fiber density in the skin, suggesting it can enhance nerve regrowth and may help alleviate pain in painful diabetic peripheral neuropathy as well. This EPPIC-Net study will enroll 260 participants at 12 clinical sites. Participants will be randomized to apply WST-057 or a matching placebo cream to the feet and calves for 20-weeks.