Tebipenem-pivoxil as an Alternative to Ceftriaxone for Clinically Non-responding Children With Shigellosis: a Randomized Non-inferiority Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 132
- 试验地点
- 2
- 主要终点
- Clinical failure at Day 3
研究概览
简要总结
Background (brief):
Shigellosis is the second leading cause of death due to diarrheal diseases worldwide (>200,000 deaths/year). Though the mortality rate associated with Shigellosis has decreased, the fact that the bacteria have acquired resistance to multiple antibiotics, is a cause for major concern. Oral azithromycin and intravenous ceftriaxone are the recommend first and second line therapies, respectively in Bangladesh. Approximately 20% of Shigella isolates are resistant to azithromycin suggesting that a substantial number of children will require second-line therapy. While resistance to ceftriaxone in shigellosis is low in Bangladesh at 5%, the potential for rapid emergence of antibiotic resistance to this third-generation cephalosporin and ceftriaxone's resource-intensive delivery method, underscore the need for evidence-based alternative antibiotic regimens for multidrug resistant Shigella infections
Hypothesis:
Children treated with tebipenem-pivoxil will have no worse clinical and microbiologic failure rates compared to ceftriaxone.
Primary Aim To determine whether tebipenem-pivoxil is clinically non-inferior to the currently WHO-recommended second line Shigella therapy (ceftriaxone) 3 days after treatment initiation.
Hypothesis: Children randomized to tebipenem-pivoxil experience no more clinical failures than children treated with ceftriaxone 3 days after treatment initiation.
Secondary Aim:
To determine whether tebipenem-pivoxil is clinically non-inferior to the currently WHO-recommended second line Shigella therapy (ceftriaxone) 7 and 30 days after treatment initiation.
To determine whether tebipenem-pivoxil is microbiologically non-inferior to the currently WHO-recommended second line Shigella therapy (ceftriaxone) 7 and 30 days after treatment initiation.
Describe the number of adverse events, between children with shigellosis treated with oral tebipenem-pivoxil or IV ceftriaxone.
Compare the prevalence of ceftriaxone and carbapenam resistance, as well as ESBL-and carbapenemase-producing Escherichia coli, in children treated with tebipenem-pivoxil or ceftriaxone 7 and 30-days after initiation of second-line therapy.
Methods:
Investigators propose a phase IIb randomized controlled trial (RCT) to determine the efficacy and safety of oral tebipenem-pivoxil, compared to IV ceftriaxone, for children with Shigella infections unresponsive to first-line antibiotic therapy. Bangladeshi children aged 24 to 59 months with suspected Shigella infections and no clinical improvement within 48 hours of first-line therapy will be randomized to a 3-day course of oral tebipenem-pivoxil (4 mg/kg 3x daily) or 3-days of IV ceftriaxone (50 mg/kg 1x daily). The children will be evaluated for key clinical, microbiologic, and safety outcomes during the subsequent 30-day period. Additionally, investigators propose a lead in study of 15 patients to confirm the safety profile and pharmacokinetics and efficacy of tebipenem in the study population. During this pharmacokinetic study period investigators will compare 15 children with oral Tebipenem randomizing with 15 children with oral Azithromycin arm. Investigators will also check invitro susceptibility of Tebipenem-pivoxil in 200 shigella isolates prior to the clinical trial in collaboration with Infectious Diseases Division, icddr,b.
Randomization Block randomization (1:1) in random sized blocks of will be used to assign treatment groups at study enrollment by an independent statistician. Treatment allocation (once assigned) will be known to the managing clinician and the participant due to the differing drug delivery mechanisms of the two antibiotics (oral vs. injectable). However, the team conducting the statistical analyses will be blinded to treatment allocation (allocation will appear A and B).
详细描述
Background of the Project including Preliminary Observations:
Shigellosis is the second leading cause of death due to diarrheal diseases worldwide (>200,000 deaths/year). Among children under 5 years, 60,000 deaths and 74,000,000 cases of diarrhoea were attributed to Shigella in 2016, approximately 20% of which occurred in South Asia. In its severe form, Shigella invades the intestinal tissue resulting in the clinical manifestation of dysentery, blood or mucoid stool. The World Health Organization (WHO) recommends antibiotic therapy for children with Shigella dysentery based on evidence from randomized trials demonstrating clinical and microbiologic benefit of antibiotics for dysentery (>60% of which is caused by Shigella infections). Oral ciprofloxacin and intravenous (IV) or intramuscular (IM) ceftriaxone are the recommend first and second line therapies, respectively. In Bangladesh, based on the prevalence of Shigella isolates with resistance to ciprofloxacin (~70%), the macrolide antibiotic azithromycin is used as a first line therapy with ceftriaxone (second-line) reserved for the most severe cases. Approximately 20% of Shigella isolates are resistant to azithromycin suggesting a substantial number of children will require second-line therapy (Dhaka hospital, data unpublished). While a study conducted at icddrb showed resistance to ceftriaxone in shigellosis is low in Bangladesh at 2-5%, but Dhaka hospital surveillance system identified around 10% ceftriaxone resistance in under 5 children with shigellosis in recent years (from unpublished data), the potential for rapid emergence of antibiotic resistance to this third-generation cephalosporin and ceftriaxone's resource-intensive delivery method, underscore the need for evidence-based alternative antibiotic regimens for multidrug resistant Shigella infections.
In a patency document regarding the dosage of oral tebipenem pivoxil, it was reported that the drug is effective against a number a Gram negative bacteria, including Shigella. To evaluate the susceptibility of Tebipenem -pivoxil among Bangladeshi shigella isolates, investigators will perform in vitro susceptibility testing with previously collected 200 isolates in collaboration with Infectious Diseases Division of icddr,b. Assessing the need for new therapeutic regimes to counter the growing threat of development of antimicrobial resistance and development of multi-drug resistant strains, Investigators propose a phase IIb randomized controlled trial (RCT) to determine the efficacy and safety of oral tebipenem-pivoxil, compared to IV ceftriaxone, for children with Shigella infections unresponsive to first-line antibiotic therapy. Bangladeshi children aged 24 to 59 months with suspected Shigella infections and no clinical improvement within 48 hours of first-line therapy will be randomized to a 3-day course of oral tebipenem-pivoxil (4 mg/kg 3x daily) or 3-days of IV ceftriaxone (50 mg/kg 1x daily). The children will be evaluated for key clinical, microbiologic, and safety outcomes during the subsequent 30-day period. Additionally, investigators will monitor the acquisition of antibiotic resistance, including ESBL- and carbapenemase-producing E. coli, among enrolled children to determine the clinical and public health risk of using carbapenem antibiotics in this context. Furthermore, a lead in study of 15 patients is proposed to confirm the safety profile and pharmacokinetics of tebipenem in the study population. In parallel investigators will enroll another 15 children in Azithromycin arm. At the end of study, investigators will compare the two drugs in terms of safety and efficacy both clinically and microbiologically against shigellosis in children.
Research Design and Methods
Pilot study for efficacy and pharmacokinetics for Tebipenem:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 24 Months 至 59 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children aged 24-59 months with suspected Shigella infection (clinical features of fever, mucus and/or blood in stools, tenesmus, and RBC and leucocytes >10 per hpf)
排除标准
- •Child received study antibiotics (azithromycin, ceftriaxone, and/or tebipenem) for the illness prior to presentation (as confirmed by bottle or prescription)
- •Severe acute malnutrition (SAM), defined as weight-for-height z-score less than -3 or mid-upper arm circumference less than 115mm, and/or other signs of infections requiring antibiotics
- •Patients with other infectious foci who are potentially unresponsive to treatment with orally administered medication
- •Patients in whom the efficacy and safety of the study drug is difficult to determine because of a progressive, complicated, or severe underlying disease believed to critically influence the onset of the infection, its clinical course, and therapeutic efficacy
- •Patients with convulsive disorders, such as epilepsy, as an underlying disease
- •Patients with a known lipid metabolism disorder or congenital carnitine deficiency
- •Patients with severe hepatic or renal dysfunction
- •Patients with a history of allergy to β-lactam antibiotics (e.g., carbapenems, penicillin, and cephems)
- •Patients who have received other antibiotics for the illness and exhibited improvements
- •Patients deemed inappropriate for this study by the attending physician
- •Clinically improved after first-line therapy
- •Unable to provide a stool sample at enrolment
研究组 & 干预措施
Azithromycin arm (Pilot study)
Oral Azithromycin in children with shigellosis
干预措施: Azithromycin (Drug)
Ceftriaxone arm (Main trial)
Intravenous Ceftriaxone in children with shigellosis
干预措施: Ceftriaxon (Drug)
Tebipenem-pivoxil arm (Pilot study)
Oral Tebipenem-pivoxil in children with shigellosis
干预措施: Tebipenem Pivoxil (Drug)
Tebipenem-pivoxil arm (Main trial)
Oral Tebipenem-pivoxil in children with shigellosis
干预措施: Tebipenem Pivoxil (Drug)
结局指标
主要结局
Clinical failure at Day 3
时间窗: 3 days
Clinical Failure at Day 3 will be defined as presence of fever (axillary temperature ≥38°C), diarrhoea (3 or more abnormally loose or watery stools in the last 24 hours), blood in stool, or abdominal pain/tenderness (defined by localization of pain by a child in response to query of parent/caregiver or an examination during palpation there is any facial expression during compression of any part of abdomen) at Day 3 of follow-up or a death or hospitalization prior to Day 3.
次要结局
- Clinical failure at Day 7 & Day 30(7 days & 30 days)
- Adverse events(day 30)
- Carbapenem-resistant and cephalosporin resistant Shigella and Enterobacteriaceae coli isolates.(day 0, 7, & 30)
- Change in mid-upper arm circumference(day 7 & 30)
- Microbiological Failure(7 days & 30 days)
- ESBL-producing Shigella and Enterobacteriaceae coli isolates(day 0, 7, & 30)
- Change in length-for-age z-score(day 7 & 30)