Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan.
Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan.
Lancet Infect Dis. 2024 Nov;24(11):1254-1265. doi: 10.1016/S1473-3099(24)00404-3. Epub 2024 Aug 1.
Eumycetoma is an implantation mycosis characterised by a large subcutaneous mass in the extremities commonly caused by the fungus Madurella mycetomatis. Despite the long duration of treatment, commonly a minimum of 12 months, treatment failure is frequent and can lead to amputation. We aimed to compare the efficacy of two doses of fosravuconazole, a synthetic antifungal designed for use in onychomycosis and repurposed for mycetoma, with standard-of-care itraconazole, both in combination with surgery.
This phase 2, randomised, double-blind, active-controlled, superiority trial was conducted in a single centre in Sudan. Patients with eumycetoma caused by M mycetomatis, who were aged 15 years or older, with a set lesion diameter (>2 cm and ≤16 cm) requiring surgery were included. There was a limit of 20 female patients in the initial enrolment, owing to preclinical toxicity concerns. Exclusion criteria included previous surgical or medical treatment for eumycetoma; presence of loco-regional lymphatic extension; osteomyelitis, or other bone involvement; pregnancy or lactation; severe concomitant diseases; a BMI under 16 kg/m; contraindication to use of the study drugs; pre-existing liver disease; lymphatic extension; osteomyelitis; transaminase levels more than two times the laboratory's upper limit of normal, or elevated levels of alkaline phosphatase or bilirubin; or any history of hypersensitivity to any azole antifungal drug. Patients were randomly allocated in a 1:1:1 ratio to 300 mg fosravuconazole weekly for 12 months (group 1); 200 mg fosravuconazole weekly for 12 months (group 2); or 400 mg itraconazole daily for 12 months (group 3) using a random number list with non-disclosed fixed blocks of size 12, with equal allocation to each of the three arms within a block. To ensure masking between groups, placebo pills were used to disguise the difference in dosing schedules. All groups took pills twice daily with meals. In all groups, surgery was performed at 6 months. The primary outcome was complete cure at end of treatment at the month 12 visit, as evidenced by absence of mycetoma mass, sinuses, and discharge; normal ultrasonography or MRI examination of the eumycetoma site; and, if a mass was present, negative fungal culture from the former mycetoma site. The primary outcome was assessed in the modified intention-to-treat (mITT) population (all patients who received one or more treatment dose with one or more primary efficacy assessment). Safety was assessed in all patients who received one or more doses of the study drug. This study is registered with ClinicalTrials.gov (NCT03086226) and is complete.
Between May 9, 2017, and June 10, 2021, 104 patients were randomly allocated (34 in group 1 and 2, respectively, and 36 in group 3). 86 (83%) of 104 patients were male and 18 (17%) patients were female. After an unplanned second interim analysis, the study was terminated early for futility. Complete cure at 12 months in the mITT population was 17 (50%) of 34 (95% CI 32-68) for group 1, 22 (65%) of 34 (47-80) for group 2, and 27 (75%) of 36 (58-88) in group 3. Neither dose of fosravuconazole was superior to itraconazole (p=0·35 for 200 mg fosravuconazole vs p=0·030 for 300 mg fosravuconazole). 83 patients had a total of 205 treatment-emergent adverse events, and two patients had serious adverse events that led to discontinuation, neither related to treatment.
Treatment with either dose of fosravuconazole was not superior to itraconazole, and the two doses had a numerically lower efficacy. However, fosravuconazole presented no new safety signals, and its lower pill burden and reduced risk of drug-drug interactions compared with the relatively expensive and inaccessible itraconazole suggests further research into effective treatments with a shorter duration and higher cure rate, without the need for surgery are warranted.
Drugs for Neglected Diseases initiative.
芽生菌病是一种植入性真菌感染，其特征为四肢有大的皮下肿块，通常由真菌马杜拉分枝霉引起。尽管治疗时间长，通常至少 12 个月，但治疗失败很常见，可能导致截肢。我们旨在比较两种剂量的福沙鲁康唑（一种专为治疗甲真菌病而设计的合成抗真菌药，现已重新用于治疗真菌病）与标准治疗药物伊曲康唑（联合手术）的疗效，均用于治疗马杜拉分枝霉引起的芽生菌病。
这是一项在苏丹的单中心进行的 2 期、随机、双盲、活性对照、优效性试验。纳入了年龄在 15 岁及以上、有需要手术的马杜拉分枝霉引起的芽生菌病且设定病变直径（>2 cm 且≤16 cm）的患者。由于临床前毒性问题，最初的入组限制了 20 名女性患者。排除标准包括：先前接受过芽生菌病的手术或药物治疗；存在局部区域淋巴扩散；骨髓炎或其他骨骼受累；怀孕或哺乳；严重并存疾病；体重指数（BMI）<16 kg/m；使用研究药物的禁忌证；先前存在肝病史；淋巴扩散；骨髓炎；转氨酶水平是实验室正常值上限的两倍以上，或碱性磷酸酶或胆红素水平升高；或对任何唑类抗真菌药物过敏。患者按 1:1:1 的比例随机分配至每周 300 mg 福沙鲁康唑组（1 组）、每周 200 mg 福沙鲁康唑组（2 组）或每日 400 mg 伊曲康唑组（3 组），采用无披露固定大小为 12 的随机数列表，每组各有 12 个，每组内按 3 等分分配。为确保组间掩蔽，使用安慰剂药丸来掩盖剂量方案的差异。所有组均在进餐时每日服用两次药物。在所有组中，在 6 个月时进行手术。主要终点是在第 12 个月的治疗结束时（即无芽生菌病肿块、窦道和分泌物；芽生菌病部位的超声或 MRI 检查正常；如果有肿块，原芽生菌病部位的真菌培养为阴性）完全治愈，主要疗效终点在改良意向治疗（mITT）人群（所有接受过一种或多种治疗剂量并进行过一次或多次主要疗效评估的患者）中评估。所有接受过一种或多种研究药物剂量的患者均进行安全性评估。该研究在 ClinicalTrials.gov（NCT03086226）注册，已完成。
2017 年 5 月 9 日至 2021 年 6 月 10 日期间，共有 104 名患者随机分配（每组 34 名，其中 1 组和 2 组分别为 34 名，3 组为 36 名）。104 名患者中 86 名（83%）为男性，18 名（17%）为女性。在计划外的第二次中期分析后，该研究因无效而提前终止。mITT 人群在 12 个月时的完全治愈率为 34 名（17%，95%CI 32-68），2 组为 34 名（65%，47-80），3 组为 36 名（75%，58-88）。两种剂量的福沙鲁康唑均不比伊曲康唑有效（200 mg 福沙鲁康唑与 p=0.35，300 mg 福沙鲁康唑与 p=0.030）。83 名患者共发生 205 次治疗中出现的不良事件，2 名患者发生了导致停药的严重不良事件，均与治疗无关。
使用任何一种剂量的福沙鲁康唑治疗均不比伊曲康唑有效，两种剂量的疗效均略低。然而，福沙鲁康唑未显示出新的安全性信号，与相对昂贵且难以获得的伊曲康唑相比，其较低的药丸负担和减少药物相互作用的风险表明，需要进一步研究更有效的治疗方法，治疗时间更短，治愈率更高，而无需手术。
被忽视的疾病药物研发倡议。
