Department of Oral Medicine, Liverpool University Dental Hospital, Pembroke Place, Liverpool, L3 5PS, UK.
Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, Crown Street, Liverpool, L69 3BX, UK.
Trials. 2021 Jul 5;22(1):428. doi: 10.1186/s13063-021-05373-8.
Sodium valproate (VPA) has been associated with a reduced risk of head and neck cancer development. The potential protective mechanism of action is believed to be via inhibition of histone deacetylase and subsequent epigenetic reprogramming. SAVER is a phase IIb open-label, randomised control trial of VPA as a chemopreventive agent in patients with high-risk oral epithelial dysplasia (OED). The aim of the trial is to gather preliminary evidence of the clinical and biological effects of VPA upon OED and assess the feasibility and acceptability of such a trial, with a view to inform a future definitive phase III study.
One hundred and ten patients with high-risk OED will be recruited from up to 10 secondary care sites in the UK and randomised into either VPA or observation only for 4 months. Women of childbearing potential will be excluded due to the teratogenic properties of VPA. Tissue and blood samples will be collected prior to randomisation and on the last day of the intervention/observation-only period (end of 4 months). Clinical measurement and additional safety bloods will be taken at multiple time points during the trial. The primary outcome will be a composite, surrogate endpoint of change in lesion size, change in grade of dysplasia and change in LOH profile at 8 key microsatellite regions. Feasibility outcomes will include recruitment targets, compliance with the study protocol and adverse effects. A qualitative sub-study will explore patient experience and perception of the trial.
The current management options for patients with high-risk OED are limited and mostly include surgical resection and clinical surveillance. However, there remains little evidence whether surgery can effectively lead to a notable reduction in the risk of oral cancer development. Similarly, surveillance is associated with concerns regarding delayed diagnosis of OED progressing to malignancy. The SAVER trial provides an opportunity to investigate the effects of a repurposed, inexpensive and well-tolerated medication as a potential chemopreventive strategy for patients with high-risk OED. The clinical and biological findings of SAVER will inform the appropriateness, design and feasibility of a definitive phase III trial.
The trial is registered with the European Clinical Trials Database ( Eudra-CT 2018-000197-30 ). ( http://www.isrctn.com/ISRCTN12448611 ). The trial was prospectively registered on 24/04/2018.
丙戊酸钠（VPA）已被证明与降低头颈部癌症发展的风险有关。其潜在的作用机制被认为是通过抑制组蛋白去乙酰化酶和随后的表观遗传重编程。SAVER 是一项评估 VPA 作为高危口腔上皮异型增生（OED）化学预防药物的 IIb 期开放性标签、随机对照试验。该试验的目的是初步评估 VPA 对 OED 的临床和生物学影响，并评估这种试验的可行性和可接受性，以便为未来的 III 期研究提供信息。
将从英国多达 10 家二级保健机构招募 110 例高危 OED 患者，并将其随机分为 VPA 组或仅观察组，进行 4 个月的治疗。由于 VPA 的致畸特性，有生育能力的女性将被排除在外。在随机分组前和干预/仅观察期最后一天（4 个月结束时）采集组织和血液样本。在试验期间的多个时间点进行临床测量和额外的安全性血液检测。主要终点是 8 个关键微卫星区域的病变大小变化、异型增生程度变化和 LOH 谱变化的复合替代终点。可行性结局包括招募目标、对研究方案的依从性和不良反应。一项定性子研究将探讨患者对试验的体验和看法。
目前高危 OED 患者的治疗选择有限，主要包括手术切除和临床监测。然而，目前几乎没有证据表明手术能否有效降低口腔癌发展的风险。同样，监测也存在对 OED 进展为恶性肿瘤的延迟诊断的担忧。SAVER 试验提供了一个机会，以研究一种重新利用的、廉价的、耐受性良好的药物作为高危 OED 患者潜在的化学预防策略的效果。SAVER 的临床和生物学发现将为 III 期试验的适当性、设计和可行性提供信息。
该试验在欧洲临床试验数据库（Eudra-CT 2018-000197-30）注册。（http://www.isrctn.com/ISRCTN12448611）。该试验于 2018 年 4 月 24 日前瞻性注册。
