Wannigama Dhammika Leshan, Hurst Cameron, Phattharapornjaroen Phatthranit, Hongsing Parichart, Sirichumroonwit Natchalaikorn, Chanpiwat Kanokpoj, Rad S M Ali Hosseini, Storer Robin James, Ounjai Puey, Kanthawee Phitsanuruk, Ngamwongsatit Natharin, Kupwiwat Rosalyn, Kupwiwat Chaisit, Brimson James Michael, Devanga Ragupathi Naveen Kumar, Charuluxananan Somrat, Leelahavanichkul Asada, Kanjanabuch Talerngsak, Higgins Paul G, Badavath Vishnu Nayak, Amarasiri Mohan, Verhasselt Valerie, Kicic Anthony, Chatsuwan Tanittha, Pirzada Kashif, Jalali Farid, Reiersen Angela M, Abe Shuichi, Ishikawa Hitoshi
Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan.
Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
EClinicalMedicine. 2024 Mar 14;70:102517. doi: 10.1016/j.eclinm.2024.102517. eCollection 2024 Apr.
Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries.
We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381).
Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms.
Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients.
Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.
具有宿主导向抗病毒和免疫调节特性的 repurposed 药物在 COVID-19 治疗中显示出前景，但很少有试验研究这些药物的联合使用。本试验的目的是评估联合使用价格低廉、广泛可得的 repurposed 药物治疗 COVID-19 的有效性，这可能对资源匮乏国家尤为重要。
我们于 2021 年 10 月 1 日至 2022 年 6 月 21 日在泰国进行了一项开放标签、随机、门诊、对照试验，以评估确诊为轻度 SARS-CoV-2 感染的成年人在症状出现后 48 小时内使用氟伏沙明、溴己新、赛庚啶和氯硝柳胺联合治疗，与标准治疗相比，是否能预防 28 天临床恶化。参与者被随机分配接受单独使用氟伏沙明、氟伏沙明 + 溴己新、氟伏沙明 + 赛庚啶、氯硝柳胺 + 溴己新或标准治疗。测量的主要结局是使用 6 点序贯量表在 9、14 或 28 天内的临床恶化情况。本试验已在 ClinicalTrials.gov 注册（NCT05087381）。
在招募的 1900 名参与者中，共有 995 名完成了试验。在接受氟伏沙明加溴己新（0%）、氟伏沙明加赛庚啶（0%）或氯硝柳胺加溴己新（0%）治疗的参与者中，9 天、14 天或 28 天时均无临床恶化情况。氟伏沙明组有 9 名参与者（5.6%）在 28 天时出现临床恶化，需要低流量吸氧。相比之下，大多数标准治疗组参与者在 9 天、14 天和 28 天时出现临床恶化。到第 9 天，标准治疗组 32.7%（110 例）患者已住院，无需补充氧气但需要持续医疗护理。到第 28 天，这一比例增至 37.5%（21 例）。此外，标准治疗组 20.8%（70 例）患者在第 9 天时需要低流量吸氧，12.5%（16 例）患者在第 28 天时需要无创或机械通气。所有治疗组在第 9 天、14 天和 28 天时与标准治疗组均有显著差异（p < 0.0001）。同样，到第 28 天，三种两药联合治疗组明显优于氟伏沙明组（p < 0.0001）。任何研究组均未发生死亡。与标准治疗相比，联合用药治疗的参与者早在治疗第 3 天病毒载量就显著降低（p < 0.0001），早在治疗第 5 天血清细胞因子白细胞介素 -6（IL -6）、肿瘤坏死因子 -α（TNF -α）和白细胞介素 -1β（IL -1β）水平降低，治疗第 7 天白细胞介素 -8（IL -8）水平降低（p < 0.0001），且 COVID -19 急性后遗症（PASC）症状发生率较低（p < 0.0001）。标准治疗组发生了 23 例严重不良事件，而氟伏沙明组仅报告了 1 例严重不良事件，其他组未发生严重不良事件。
门诊诊断为 COVID- 19 的患者早期使用这些联合药物治疗与临床恶化可能性较低相关，且病毒载量和血清细胞因子显著快速降低，PASC 症状负担较低。在症状出现后很快开始使用这些 repurposed 药物，有很大潜力预防接种和未接种疫苗的 COVID-19 患者的临床恶化和死亡。
泰国 Ped Thai Su Phai（泰国鸭战危险）社会捐赠团体。
