Sirima Sodiomon B, Tiono Alfred B, Gansané Adama, Diarra Amidou, Ouédraogo Amidou, Konaté Amadou T, Kiechel Jean René, Morgan Caroline C, Olliaro Piero L, Taylor Walter R J
Centre National de Recherche et de Formation sur le Paludisme (CNRFP), BP 2208, Ouagadougou, Burkina Faso.
Malar J. 2009 Mar 16;8:48. doi: 10.1186/1475-2875-8-48.
Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested.
A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety.
Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7-94.7) vs. AS+AQ = 313/340 (95% CI: 88.6-94.7). Non-inferiority was demonstrated at two-sided alpha = 0.05: Delta (AS+AQ - AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Delta = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients.
Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring.
Current Controlled Trials ISRCTN07576538.
青蒿琥酯（AS）加阿莫地喹（AQ）是世界卫生组织推荐的一种用于治疗恶性疟原虫疟疾的青蒿素联合疗法（ACT）。固定剂量的AS/AQ是新的，但迄今为止其安全性和疗效未经测试。
开展了一项随机、开放标签试验，比较固定（F）剂量AS（25毫克）/AQ（67.5毫克）与松散（L）AS（50毫克）+AQ（153毫克）对布基纳法索750名年龄在6个月至5岁的恶性疟原虫感染儿童的疗效（非劣效性设计）和安全性。根据年龄给药。主要疗效终点是第28天经PCR校正的寄生虫学治愈率。接受挽救治疗的患者计为治疗失败，新感染计为治愈。记录的常见毒性标准（CTC）分级不良事件（AE）定义安全性。
招募的儿童和可评估儿童分别为750名（每组375名）和682名（90.9%）。有8名（AS/AQ组）和6名（AS+AQ组）早期治疗失败，1名第7天治疗失败（AS+AQ组）。每组分别有16名（AS/AQ组）和12名（AS+AQ组）患者出现复发性寄生虫血症（PCR新感染分别为10例和6例）。每组有14名患者因呕吐/吐出研究药物而需要挽救治疗。两组的有效率均为92.1%：AS/AQ组=315/342（95%CI：88.7-94.7），AS+AQ组=313/340（95%CI：88.6-94.7）。在双侧α=0.05时证明了非劣效性：差值（AS+AQ-AS/AQ）=0.0%（95%CI：-4.1%至4.0%）。第28天，Kaplan Meier经PCR校正的治愈率（所有随机分组儿童）相似：AS/AQ组为93.7%，AS+AQ组为93.2%，差值=-0.5（95%CI-4.2至3.0%）。到第2天，两组均有快速的寄生虫清除（F组和L组，97.8%无寄生虫血症）和发热清除（F组97.2%，L组96.0%无发热）。两种治疗耐受性均良好。固定剂量组和松散剂量组药物引起的呕吐分别为8/375（2.1%）和6/375（1.6%）（p=0.59）。1例患者出现无症状的CTC分级4级肝炎（AST 1052，ALT 936）。技术困难妨碍了对所有患者的中性粒细胞减少症的评估和风险评估。
固定剂量的AS/AQ有效且耐受性良好。这些数据支持使用这种新的固定剂量联合疗法治疗恶性疟原虫疟疾，并持续进行安全性监测。
当前对照试验ISRCTN07576538。
