Edward Hines Jr Veterans Administration Hospital, Hines, IL, USA.
Department of Internal Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Clinical Trials Centre Cologne, University of Cologne, Cologne, Germany.
Lancet Infect Dis. 2019 Mar;19(3):265-274. doi: 10.1016/S1473-3099(18)30614-5. Epub 2019 Jan 29.
Cadazolid is a novel quinoxolidinone antibiotic developed for treating Clostridium difficile infection. We aimed to investigate the safety and efficacy of cadazolid compared with vancomycin in patients with C difficile infection.
IMPACT 1 and IMPACT 2 were identically designed, multicentre, double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. IMPACT 1 was done in Australia, Brazil, Canada, France, Germany, Italy, the Netherlands, Peru, Poland, Romania, Spain, and the USA, and IMPACT 2 was done in Argentina, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Greece, Hungary, Israel, Romania, Slovakia, South Korea, the UK, and the USA. Patients (aged 18 years or older) with mild-to-moderate or severe C difficile infection (diarrhoea with positive glutamate dehydrogenase and toxin A or B enzyme immunoassays) were randomly assigned (1:1) with a randomisation list stratified by centre and C difficile infection episode type (block size of four), and allocation was masked to investigators and participants. Patients received either oral cadazolid 250 mg twice daily with vancomycin-matching placebo capsule four times daily or oral vancomycin 125 mg four times a day with cadazolid-matching placebo suspension twice daily for 10 days, with 30 days of follow-up. The primary efficacy outcome was non-inferiority (margin -10%) of cadazolid versus vancomycin for clinical cure in the modified intention-to-treat and per-protocol populations. Clinical cure was defined as resolution of diarrhoea with no additional treatment for C difficile infection. These trials are registered with ClinicalTrials.gov, numbers NCT01987895 (IMPACT 1) and NCT01983683 (IMPACT 2).
Between March 28, 2014, and March 24, 2017, for IMPACT 1, and Dec 13, 2013, and May 2, 2017, for IMPACT 2, 1263 participants were randomly assigned to receive cadazolid (306 in IMPACT 1 and 298 in IMPACT 2) or vancomycin (326 in IMPACT 1 and 311 in IMPACT 2). In the modified intention-to-treat population in IMPACT 1, 253 (84%) of 302 had clinical cure in the cadazolid group versus 271 (85%) of 318 in the vancomycin group. In IMPACT 2, 235 (81%) of 290 versus 258 (86%) of 301 had clinical cure. In the per-protocol population, 247 (88%) of 282 versus 264 (92%) of 288 had clinical cure in IMPACT 1 and 214 (87%) of 247 versus 237 (92%) of 259 in IMPACT 2. Non-inferiority for clinical cure to vancomycin was shown in IMPACT 1 but not in IMPACT 2 (IMPACT 1 treatment difference: -1·4 [95% CI -7·2 to 4·3] for modified intention to treat and -4·1 [-9·2 to 1·0] for per protocol; IMPACT 2: -4·7 [-10·7 to 1·3] for modified intention to treat and -4·9 [-10·4 to 0·6] for per protocol). The safety and tolerability profiles of the two antibiotics were similar.
Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely.
Actelion Pharmaceuticals.
卡他唑是一种新型的醌诺酮类抗生素，用于治疗艰难梭菌感染。我们旨在研究卡他唑与万古霉素相比在艰难梭菌感染患者中的安全性和疗效。
IMPACT 1 和 IMPACT 2 是完全相同的设计、多中心、双盲、安慰剂对照、非劣效性、随机 3 期临床试验。IMPACT 1 在澳大利亚、巴西、加拿大、法国、德国、意大利、荷兰、秘鲁、波兰、罗马尼亚、西班牙和美国进行，IMPACT 2 在阿根廷、比利时、巴西、加拿大、智利、克罗地亚、捷克共和国、希腊、匈牙利、以色列、罗马尼亚、斯洛伐克、韩国、英国和美国进行。年龄在 18 岁或以上的轻度至中度或重度艰难梭菌感染（谷氨酸脱氢酶和毒素 A 或 B 酶免疫测定阳性的腹泻）患者，按中心和艰难梭菌感染类型（块大小为 4 个）进行随机分组（1:1），并向研究者和参与者屏蔽分配。患者接受每日两次口服卡他唑 250mg 与万古霉素匹配安慰剂胶囊 4 次/天，或每日 4 次口服万古霉素 125mg 与卡他唑匹配安慰剂混悬液 2 次/天，共 10 天，随访 30 天。主要疗效终点是在改良意向治疗和方案人群中卡他唑与万古霉素的非劣效性（差值为-10%）临床治愈率。临床治愈率定义为腹泻缓解，无其他艰难梭菌感染治疗。这些试验在 ClinicalTrials.gov 上注册，编号为 NCT01987895（IMPACT 1）和 NCT01983683（IMPACT 2）。
在 2014 年 3 月 28 日至 2017 年 3 月 24 日期间，IMPACT 1 进行了 1263 名参与者的随机分组，分别接受卡他唑（IMPACT 1 中 306 名，IMPACT 2 中 298 名）或万古霉素（IMPACT 1 中 326 名，IMPACT 2 中 311 名）治疗。在 IMPACT 1 的改良意向治疗人群中，卡他唑组 302 名患者中有 253 名（84%）达到临床治愈率，万古霉素组 318 名患者中有 271 名（85%）。在 IMPACT 2 中，290 名患者中有 235 名（81%）达到临床治愈率，301 名患者中有 258 名（86%）。在方案人群中，282 名患者中有 247 名（88%）达到临床治愈率，288 名患者中有 264 名（92%）。在 IMPACT 1 中，卡他唑的临床治愈率优于万古霉素，IMPACT 2 则不优于万古霉素（IMPACT 1 治疗差异：改良意向治疗为-1.4[95%CI-7.2 至 4.3]，方案为-4.1[-9.2 至 1.0]；IMPACT 2：改良意向治疗为-4.7[-10.7 至 1.3]，方案为-4.9[-10.4 至 0.6]）。两种抗生素的安全性和耐受性相似。
卡他唑安全且耐受良好，但在 2 项艰难梭菌感染 3 期临床试验中均未达到优于万古霉素的临床治愈率的主要终点。因此，卡他唑进一步用于艰难梭菌感染的商业开发不太可能。
Actelion 制药公司。
