Repurposing Sulfasalazine in a Two-Arm Phase Two Double-Blind Randomized Clinical Trial for the Adjunct Management of Breast Cancer-Induced Bone Pain

在一项双臂二期双盲随机临床试验中重新利用柳氮磺吡啶辅助治疗乳腺癌引起的骨痛

• 批准号: 10097670
• 负责人: Mohab M Ibrahim
• 金额: $ 21.53万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097670
• 关键词: Adjunct Clinical Trials; Adjuvant; Adoption; Aftercare; Analgesics; Animal Model; Anti-Inflammatory Agents; Area; Arizona; Bone Pain; Breast Cancer Treatment; Cancer Control; Cancer Model; Cancer Pain Management; Cancer Patient; Cell Survival; Characteristics; Chronic; Clinic; Clinical; Clinical Trials; Conduct Clinical Trials; Cysteine; Data; Disseminated Malignant Neoplasm; Dose; Double-Blind Method; Drowsiness; Emotional; Family; Fiber; General Population; Glutamates; Gold; Health; Healthcare Systems; Hospitalization; Human; Inflammation Mediators; Inflammatory; Institutional Review Boards; Interleukin-6; Laboratories; Length of Stay; Malignant - descriptor; Malignant Neoplasms; Measures; Metastatic Neoplasm to the Bone; Neoplasm Metastasis; Opioid; Opioid Analgesics; Osteoclasts; Outcome Measure; Oxidative Stress; Pain; Pain Nature; Pain Research; Pain intensity; Pain management; Pain quality; Paper; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physical Dependence; Physicians; Plasma; Play; Predisposing Factor; Prevalence; Psychological Dependence; Quality of life; Randomized; Randomized Clinical Trials; Reporting; Rest; Risk; Role; Safety; Savings; Secondary to; Serum; Serum Markers; Stress; Suicide; Sulfasalazine; Surveys; TNF gene; Testing; Time; Tumor Burden; Tumor Markers; United States; United States National Institutes of Health; Universities; addiction; arm; base; bone loss; brain circuitry; cancer cell; cancer imaging; cancer survival; cancer therapy; cell injury; chemokine; chronic pain; cost; cytokine; experience; experimental study; extracellular; imaging study; improved; innovation; malignant breast neoplasm; non-opioid analgesic; opioid use; pain patient; pain perception; pain receptor; pain reduction; painful neuropathy; primary outcome; routine imaging; secondary outcome; side effect; suicide rate; tumor

Abstract Cancer-induced bone pain (CIBP) is a significant health problem in the USA and the rest of the world. With the improvement of treatment options to manage cancer, a greater number of cancer patients are now living longer yet, experiencing chronic pain. Metastasis to the bones inflicts severe and debilitating pain. The golden standard pharmaceutical agent to manage pain is opioids. Cancer patients need to take increasing doses of opioids to control their pain. Sadly, opioids come with significant side effects. Many attempts have been made to create better regiments for pain control while reducing opioids yet, most patients are simply not achieving better control of CIBP. Eliminating opioids entirely is not a reasonable approach. A better approach for controlling CIBP and lower opioids would be to add a non-opioid agent that has different mechanism(s) of action. This may better control pain while lowering opioids needed resulting in the reduction of side effects. Sulfasalazine is such possibility. It is an anti-inflammatory drug with an established safety profile. It has been in use for over fifty years for the treatment of some inflammatory conditions. In addition, sulfasalazine has the capacity to decrease the survival of cancer cells and also to lower the amount of inflammatory mediators. Sulfasalazine inhibits the influx of cysteine and the efflux of glutamate from cancer cells. Cysteine is needed for cell survival against oxidative stress, while extracellular glutamate activates pain receptors. Therefore, sulfasalazine will act as an anti- inflammatory agent, an agent to accelerate cancer cells damage, and decrease the release of glutamate that activates pain fibers. This one agent with three mechanisms of actions may lower the amount of opioids needed for patients with CIBP. Lowering of opioid dosing will decrease unwanted side effects. The purpose of this clinical trial is to co-administer sulfasalazine with opioids to patients with CIBP and characterize their opioid use and the improvement of their pain. Our central hypothesis is that adding sulfasalazine to the opioid pain medication regiment will reduce the amount of opioids used resulting in a reduction in opioid-induced side effects while reducing pain and improving the overall quality of life. We also predict that sulfasalazine may reduce the inflammatory mediators as well as tumor markers in the serum. This study will be conducted in a double- blind randomized fashion with two independent, but related, specific aims (SA) and one exploratory aim (EA). We will assess whether sulfasalazine will improve both of our primary and secondary outcomes. Our primary outcome is reduction in opioids. The secondary outcome is reduction in pain and improvement of the quality of life (SA1). Secondly, we will assess the levels of serum glutamate and IL-6, TNF-alpha and tumor markers before and after treatment with sulfasalazine (SA2). We expect sulfasalazine to decrease inflammatory mediators. Thirdly, we will assess the levels of serum tumor markers before and after treatment with sulfasalazine and correlate with tumor imaging studies (EA1). We expect sulfasalazine to decrease plasma tumor markers. The data obtained may provide physicians with additional options to manage CIBP patients.

抽象的 癌症引起的骨痛 (CIBP) 是美国和世界其他地区的一个重大健康问题。随着 改善癌症治疗方案，更多癌症患者的寿命更长 然而，正在经历慢性疼痛。骨转移会造成严重且令人衰弱的疼痛。黄金标准 控制疼痛的药剂是阿片类药物。癌症患者需要增加阿片类药物的剂量 控制他们的疼痛。遗憾的是，阿片类药物具有显着的副作用。已经进行了许多尝试来创建 尽管有更好的疼痛控制方案，同时减少阿片类药物，但大多数患者根本无法实现更好的控制 的 CIBP。完全消除阿片类药物并不是一个合理的方法。控制 CIBP 的更好方法 较低的阿片类药物是添加具有不同作用机制的非阿片类药物。这可能会更好 控制疼痛，同时降低阿片类药物的用量，从而减少副作用。柳氮磺吡啶是这样的 可能性。它是一种具有既定安全性的抗炎药。它已经使用了五十多年 用于治疗某些炎症性疾病。此外，柳氮磺吡啶能够降低 癌细胞的存活并降低炎症介质的量。柳氮磺吡啶抑制流入 半胱氨酸和谷氨酸从癌细胞中流出。细胞抵抗氧化的生存需要半胱氨酸 压力，而细胞外谷氨酸激活疼痛感受器。因此，柳氮磺吡啶将作为一种抗 炎症剂，一种加速癌细胞损伤并减少谷氨酸释放的物质 激活疼痛纤维。这种具有三种作用机制的药物可以降低阿片类药物的需求量 对于 CIBP 患者。降低阿片类药物剂量将减少不必要的副作用。本次临床试验的目的 试验的目的是向 CIBP 患者联合给予柳氮磺吡啶和阿片类药物，并描述他们的阿片类药物使用情况以及 改善他们的疼痛。我们的中心假设是在阿片类止痛药中添加柳氮磺胺吡啶 该团将减少阿片类药物的使用量，从而减少阿片类药物引起的副作用 同时减少疼痛并提高整体生活质量。我们还预测柳氮磺吡啶可能会减少 血清中的炎症介质和肿瘤标志物。这项研究将在双 盲法随机方式具有两个独立但相关的特定目标（SA）和一个探索性目标（EA）。 我们将评估柳氮磺吡啶是否会改善我们的主要和次要结局。我们的主要 结果是减少阿片类药物的使用。次要结果是减轻疼痛并提高治疗质量 寿命（SA1）。其次，在治疗前我们会评估血清谷氨酸和IL-6、TNF-α和肿瘤标志物的水平。 以及用柳氮磺吡啶（SA2）治疗后。我们预计柳氮磺吡啶能够减少炎症介质。 第三，我们将评估柳氮磺吡啶治疗前后血清肿瘤标志物的水平。 与肿瘤影像学研究 (EA1) 相关。我们预计柳氮磺吡啶能够降低血浆肿瘤标志物。这 获得的数据可以为医生提供更多选择来管理 CIBP 患者。