Boehmerle Wolfgang, Hagenacker Tim, Leo Markus, Schmitt Linda-Isabell, Lehmann Helmar C, Klein Ines, Stegherr Regina, Konietschke Frank, Endres Matthias, Huehnchen Petra
Klinik und Hochschulambulanz für Neurologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Anna-Louisa-Karsch Straße 2, 10178, Berlin, Germany.
BMC Res Notes. 2025 Apr 8;18(1):145. doi: 10.1186/s13104-025-07206-2.
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and serious side effect of many cytotoxic drugs, including paclitaxel. Despite the identification of treatment options in animal models, clinical trials for the treatment or prevention of CIPN have been negative. Major challenges for successful clinical translation of preclinical data include a lack of reproducibility and randomization, small sample sizes and insufficient statistical tests. We therefore conducted a confirmatory, preclinical multicenter randomized controlled replication trial to test the safety and efficacy of three drugs for preventing paclitaxel-induced polyneuropathy: (1) nilotinib, (2) lithium carbonate and (3) interleukin-6-neutralizing antibodies. We preregistered the data analysis plan as well as the two-step study protocol: the optimal doses of the three compounds were assessed first and then tested in a mouse breast cancer xenograft model to compare safety and efficacy.
Unfortunately, toxicity of intraperitoneally administered nilotinib in combination with paclitaxel was observed, and higher-than-expected tumor growth resulted in a lack of power when the trial was analyzed. Thus, although lithium carbonate and IL-6-neutralizing antibodies tended toward neuroprotection, the differences between these groups were not statistically significant. However, the PINPRICS study ultimately still provides important lessons with regard to the planning and conduction of multicenter preclinical trials.
化疗引起的周围神经病变（CIPN）是包括紫杉醇在内的许多细胞毒性药物常见且严重的副作用。尽管在动物模型中已确定了治疗方案，但治疗或预防CIPN的临床试验均为阴性。临床前数据成功进行临床转化面临的主要挑战包括缺乏可重复性和随机化、样本量小以及统计检验不足。因此，我们开展了一项验证性的临床前多中心随机对照重复试验，以测试三种预防紫杉醇引起的多发性神经病变的药物的安全性和有效性：（1）尼洛替尼，（2）碳酸锂，（3）白细胞介素-6中和抗体。我们预先登记了数据分析计划以及两步研究方案：首先评估这三种化合物的最佳剂量，然后在小鼠乳腺癌异种移植模型中进行测试，以比较安全性和有效性。
遗憾的是，观察到腹腔注射尼洛替尼与紫杉醇联合用药存在毒性，且在分析试验时，高于预期的肿瘤生长导致检验效能不足。因此，尽管碳酸锂和白细胞介素-6中和抗体有神经保护的趋势，但这些组之间的差异无统计学意义。然而，PINPRICS研究最终仍为多中心临床前试验的规划和实施提供了重要经验教训。
