Dubberke Erik R, Orenstein Robert, Khanna Sahil, Guthmueller Beth, Lee Christine
Washington University School of Medicine, St. Louis, MO, USA.
, 660 S Euclid, Box 8051, St. Louis, MO, 63110, USA.
Infect Dis Ther. 2023 Feb;12(2):703-709. doi: 10.1007/s40121-022-00744-3. Epub 2022 Dec 21.
Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24 months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented.
The PUNCH CD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase 2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at least 18 years of age and had at least three episodes of CDI and at least two rounds of standard antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Patients were randomized 1:1:1 to group A, two doses of RBX2660; group B, two doses of placebo; or group C, one dose of RBX2660 and one dose of placebo; all administered 7 ± 2 days apart. Treatment success was prevention of recurrence, defined as absence of diarrhea and no re-treatment for CDI any time after the first dose until 8 weeks after the second dose of the study treatment. Safety was assessed by reports of adverse events and symptoms. The final efficacy and safety are reported for data available through 24 months.
For the primary endpoint, treatment success at 8 weeks, 56.8% (25/45) of participants who received one dose of RBX2660 + one dose of placebo, 55.6% (25/45) of participants who received two doses of RBX2660, and 43.2% (19/44) of participants who received two doses of placebo in the final intention-to-treat (ITT) population were responders (both p = 0.2 vs placebo). In the per-protocol population, 87.5% (21/24) of participants who received one dose of RBX2660 + one dose of placebo and 58.1% (18/31) of those who received two doses of placebo had treatment success (p = 0.017; treatment difference, 29.4 [95% CI 7.6, 51.3]); 75.0% (21/28) of participants in the PP population who received two doses of RBX2660 were responders (p = 0.17 vs placebo). The safety profile of RBX2660, whether delivered as one or two doses, was similar to the placebo group.
While the phase 2b PUNCH CD2 clinical trial did not meet its pre-defined primary endpoint of treatment success at 8 weeks after two doses of RBX2660 vs two doses of placebo, clinically meaningful data were obtained to justify proceeding with the single dose regimen in the phase 3 clinical trial, PUNCH CD3, now complete. To date, the cumulative data for RBX2660 demonstrate consistent efficacy and safety outcomes for reduction of CDI recurrence in adults.
ClinicalTrials.gov: NCT02299570.
迫切需要针对复发性艰难梭菌感染（rCDI）的有效治疗方法。RBX2660是一种基于微生物群的研究性活菌生物疗法，用于降低rCDI患者在接受标准护理抗生素治疗后CDI的复发率。在此，我们报告了长达24个月随访期的最终安全性数据以及最终疗效数据，这些数据与预先指定的统计分析计划定义相符。
PUNCH CD2临床试验是一项前瞻性、多中心、随机、双盲、安慰剂对照的三臂2b期研究，旨在评估RBX2660与安慰剂相比在降低rCDI方面的疗效和安全性。符合条件的患者年龄至少为18岁，至少有3次CDI发作且至少接受过两轮标准抗生素治疗，或至少有2次导致住院的严重CDI发作。患者按1:1:1随机分为A组，接受两剂RBX2660；B组，接受两剂安慰剂；或C组，接受一剂RBX2660和一剂安慰剂；所有给药间隔均为7±2天。治疗成功的定义为预防复发，即从第一剂给药后直至第二剂研究治疗后8周内任何时间均无腹泻且无需再次治疗CDI。通过不良事件和症状报告评估安全性。报告了截至24个月的可用数据的最终疗效和安全性。
对于主要终点，即8周时的治疗成功率，在最终意向性分析（ITT）人群中，接受一剂RBX2660 + 一剂安慰剂的参与者中有56.8%（25/45）、接受两剂RBX2660的参与者中有55.6%（25/45）、接受两剂安慰剂的参与者中有43.2%（19/44）为治疗成功的反应者（与安慰剂相比，p均 = 0.2）。在符合方案人群中，接受一剂RBX2660 + 一剂安慰剂的参与者中有87.5%（21/24）以及接受两剂安慰剂的参与者中有58.1%（18/31）治疗成功（p = 0.017；治疗差异为29.4 [95% CI 7.6, 51.3]）；在符合方案人群中，接受两剂RBX2660的参与者中有75.0%（21/28）为反应者（与安慰剂相比，p = 0.17）。RBX2660无论是一剂还是两剂给药，其安全性概况与安慰剂组相似。
虽然2b期PUNCH CD2临床试验未达到其预先定义的主要终点，即两剂RBX2660与两剂安慰剂相比在8周时的治疗成功率，但获得了具有临床意义的数据，证明在现已完成的3期临床试验PUNCH CD3中采用单剂量方案是合理的。迄今为止，RBX2660的累积数据表明其在降低成人CDI复发方面具有一致的疗效和安全性结果。
ClinicalTrials.gov：NCT02299570。
