Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 600 North Wolfe St, Phipps 255, Baltimore, MD 21287, United States of America.
Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 600 North Wolfe St, Phipps 255, Baltimore, MD 21287, United States of America; Greater Baltimore Medical Center, 6701 N. Charles St, Physicians Pavilion West Suite 306, Towson, MD 21204, United States of America.
Gynecol Oncol. 2020 Apr;157(1):188-194. doi: 10.1016/j.ygyno.2019.12.035. Epub 2020 Jan 28.
Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3.
Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline.
A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression.
Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.
大多数治疗宫颈上皮内瘤变 2/3（CIN2/3）的方法是切除或消融，需要患者多次到医疗机构就诊。青蒿琥酯是一种经世界卫生组织批准用于治疗急性疟疾的化合物，对 HPV 转化的鳞状细胞也具有细胞毒性作用。我们进行了首次人体 I 期剂量递增研究，以评估自我管理的青蒿琥酯阴道栓剂在活检证实的 CIN2/3 中的安全性和疗效。
安全性分析基于至少接受一剂治疗的患者，并根据报告的不良事件的严重程度、频率和持续时间进行评估。耐受性评估为能够完成指定剂量方案的受试者的百分比。基于至少接受一剂且终点数据可用的患者的改良意向治疗分析评估疗效和病毒清除率。疗效定义为组织学回归至 CIN1 或更低。病毒清除定义为基线时未检测到 HPV 基因型（s）。
共有 28 名患者在第 0、2 和 4 周分别接受了 1、2 或 3 个为期 5 天的治疗周期，然后在第 15 周计划进行标准护理切除。报告的不良事件为轻度且自限性。在改良意向治疗分析中，28 名患者中有 19 名（67.9%）观察到组织学缓解。在组织学缓解的 19 名患者中，有 9 名（47.4%）患者的基线病变 HPV 基因型清除。
自我管理的阴道青蒿琥酯栓剂在治疗 CIN2/3 时安全且耐受性良好，剂量在临床有效范围内。这些发现支持进行 II 期临床研究。
