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

该OT奖资助早期疼痛调查临床网络(EPPIC-NET)内的临床试验。EPPIC-NET是NIH帮助结束成瘾长期(Hear)倡议的一部分。每天有100多人死于与阿片类药物相关的过量。其中许多可以追溯到与治疗急性和慢性疼痛有关的上瘾。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，以测试治疗疼痛的有前景的新疗法和设备，并在有特定疼痛状况的患者中进行深入的表型和生物标记物研究。这类研究将重点放在疼痛状况明确和高度未得到满足的治疗需求的患者身上。本奖项资助的研究情况如下。 EPPIC-Net临床试验EN20-01 项目标题：一项为期24周的研究，旨在评估CNTX-6970在中度至重度膝骨性关节炎疼痛患者中的安全性和有效性。 这项试验将测试新型口服药物CNTX-6970在中到重度膝骨性关节炎疼痛患者中的作用。150名参与者将在美国20个EPPIC-Net网站登记。对C-C趋化因子2型(CCR2)受体拮抗剂CNTX-6970的临床前研究表明，它在多种疼痛模型中具有有效的止痛作用。1期临床研究显示，靶向结合稳健且剂量成比例，没有紧急的安全问题。探索CNTX-6970用于治疗膝骨性关节炎疼痛的理论基础源于对受影响关节的病理生理学以及CNTX-6970对神经信号的影响的新认识。参与者将被随机接受CNTX-6970、安慰剂或经批准的止痛药，并将接受24周的跟踪。 EPPIC-Net主方案评估痛性糖尿病周围神经病变的治疗 糖尿病患者有患疼痛性糖尿病周围神经病变的风险。糖尿病神经病理性疼痛可表现为灼热、疼痛、触摸过敏，或仅表现为疼痛。目前FDA批准的治疗痛性糖尿病周围神经病变(PDPN)的药物对许多人来说并不能充分缓解疼痛。EPPIC-Net糖尿病周围神经病变主方案(主平台方案(MPP))为EPPIC-Net第二阶段临床试验提供了一个平台，用于测试治疗PDPN的治疗资产。MPP提供了通用的拱形结构，采用模块化设计，包括研究每项资产所需的和可选的要素。MPP下的所有临床试验都包括医疗公共数据元素和所需的PDPN评估，以及MPP干预特定附录(ISA)中描述的特定于资产的程序和测量。 以下EPPIC-Net临床试验将在EPPIC-Net主协议下进行，以评估疼痛的糖尿病周围神经病变的治疗： EPPIC-Net临床试验EN21-01 项目标题：一项多中心、随机、双盲、安慰剂对照研究，评估每日80毫克NRD135S.E1与安慰剂对患有痛性糖尿病周围神经病变的成人和老年参与者的安全性和有效性。 该奖项是根据EPPIC-Net治疗痛性糖尿病周围神经病变的主协议进行的一项临床试验。在现代转化医学中，NRD135S.E1被确认为一种潜在的疼痛治疗药物，这是一个真正的“床边到工作台”的故事。NRD135S.E1是一种小分子，是一种天然物质的实验室优化版本，传统上在西伯利亚的一个村庄用来泡茶治疗疼痛。在临床研究中，NRD135S.E1被参与者耐受性良好，并显示出临床相关的止痛效果。EPPIC-Net的研究将进一步开发这种治疗资产，作为一种可能的治疗糖尿病周围神经病变(PDPN)的可能方法。260名患有PDPN的成年参与者将在为期12周的平行试验中随机接受NRD135S.E1或安慰剂治疗。 EPPIC-Net临床试验EN21-02 项目标题：外用哌仑西平(WST-057)或安慰剂治疗伴有痛性糖尿病周围神经病变的2型糖尿病患者的随机、双盲、安慰剂对照、平行、为期20周的2b期研究 这一奖项是根据EPPIC-Net针对痛性糖尿病周围神经病变的主协议进行的一项临床试验，以测试治疗痛性糖尿病周围神经病变的潜在新局部治疗方法。治疗资产WST-057(外用4%吡仑西平)是一种于20世纪80年代开发的分子，以口服形式在整个欧洲和亚洲销售，用于治疗胃溃疡。初步研究显示，皮肤中的神经纤维密度增加，这表明它可以促进神经再生，也可能有助于缓解糖尿病周围神经病变的疼痛。这项EPPIC-Net研究将在12个临床站点招募260名参与者。参与者将被随机分配，在脚和小腿上涂抹WST-057或匹配的安慰剂乳膏，为期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.