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).
started
Aug 18, 2022
primary completion
Mar 15, 2025
completion
Aug 17, 2026
last updated
Aug 19, 2025
detailed description
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.
official title
Tebipenem-pivoxil as an Alternative to Ceftriaxone for Clinically Non-responding Children With Shigellosis: a Randomized Non-inferiority Trial
sourced from ClinicalTrials.gov · pharmadog mirrors structured fields, not the full protocol
Research Design and Methods
Pilot study for efficacy and pharmacokinetics for Tebipenem:
After consent is received, children will be screened in Dhaka Hospital, icddr,b after admission and eligible children with suspected shigella infection (clinical features of fever, mucus and/or blood in stools, tenesmus and RBC and leucocytes \>10 per hpf in stool) will be randomized local standard antibiotic azithromycin 10 mg/kg once daily for 5 days or oral tebipenem-pivoxil (4 mg/kg TID x 3 days).
Purposive sampling will be done for pilot study with 15 children in arm. Those who do not respond to treatment within 48 hours or whose symptoms worsen will be switched to IV ceftriaxone. The point of randomization will be considered Day 0; 3, 7, and 30 days after randomization into the trial, children will be assessed clinically by a physical exam. Anthropometric measurements will be taken from children at initiation of first line therapy and at day 3, 7, and 30 of follow-up.
Stool samples will be collected from children at prior to randomization and at day 3, day 7, and day 30 of follow-up. Stool samples will be divided into three equal parts, part 1 used for microbiologic culture and parts 2 and 3 stored at -80°C. For the first stool sample an additional portion of the stool sample will be used for microscopy and fecal leukocyte determination. Microbiologic culture (for isolation of Shigella and E. coli and antibiotic susceptibility testing \[AST\]) will be performed on fresh stool on day 0, day 3, day 7, and day 30. Quantitative PCR to detect the presence of DNA of Shigella through the identification of the ipaH gene will be performed on day 0, day 3 and day 7 frozen stool samples in a single batch at the end of the study. Culture-results will not be considered as confirmed Shigella infection as previous reports indicate that that approximately 60% of clinically relevant Shigella infections are missed by culture.
3 ml of blood will be collected on day 3 to assess AST, ALT, serum creatinine, and serum carnitine levels by ELISA) and to assess drug exposure (if possible). In addition, 3 ml of blood will be collected from participants at Day 0, Day 7 and Day 30 of follow-up for the isolation of peripheral blood mononuclear cells, which will be subsequently cryopreserved for future immunological studies.To confirm the tebipenem pharmacokinetic and safety profile in the patient population, a lead in study will be performed with the first 15 participants enrolled in the tebipenem-pivoxil arm. The 15 children will have additional 0.5 ml blood samples (one tenth tsf) collected via traditional method at time points distributed over days 0-3 to evaluate tebipenem pharmacokinetics.
As investigators have targeted to evaluate the pharmacokinetics of Tebipenem in shigellosis of 15 children. It will not be possible to have culture report before 48 hours, so investigators planned to evaluate 15 children with Tebipenem arm among those at least 50% children should have confirmed shigella infection in culture.
Assessment of efficacy trial:
The decision will be to progress to the main study if the proportion of clinical successes in the Tebipenem arm is greater than or equal to the number of successes in the Azithromycin arm among shigella confirmed cases.
Objective At the end, investigators might only get a conclusion whether Tebipenem as treatment of Shigella is somewhat better than Azithromycin based on clinical improvement and microbiological results.
Main trial:
Study procedure:
After consent is received, children will be screened and monitored in the study in hospital despite not yet being randomized (Day -2). Children will be immediately started on first-line antibiotic therapy according to the local standard of care (azithromycin 10 mg/kg once daily for 5 days). At or within 48 hours of treatment initiation, the study physician will examine the child and determine whether or not the child is considered to have clinical failure with first-line therapy (presence of fever, clinical deterioration, blood in stool, ≥3 loose/watery stool 48 hours after initiation of therapy). Children who have clinically failed at 48-hours since 1st line therapy initiation will be randomized to one of the two treatment arms: oral tebipenem-pivoxil (4 mg/kg TID x 3 days) or IV ceftriaxone (50 mg/kg QD x 3 days). Children randomized to tebipenem-pivoxil that do not respond to treatment within 48 hours or whose symptoms worsen will be switched to IV ceftriaxone. The point of randomization will be considered Day 0; 3, 7, and 30 days after randomization into the trial, children will be assessed clinically by a physical exam. Anthropometric measurements will be taken from children at initiation of first line therapy, randomization (enrolment in the RCT), and at day 3, 7, and 30 of follow-up.
Stool samples will be collected from children at Day -2 (prior to starting first-line therapy) and among those randomized, prior to administration of the first dose of second-line therapy (day 0), at day 3, day 7, and day 30 of follow-up. In the main clinical trial, we will additionally collect a flocked rectal swab at day-2, day 0 (before randomization), day 3, day 7 and day 30 for storage and eventual biomarker assessment. A series of inflammatory biomarker assays will be conducted on whole stool and rectal swab samples to determine markers of Shigella detection and treatment response upon the availability of funds. Stool samples will be divided into three equal parts, part 1 used for microbiologic culture and parts 2 and 3 stored at -80°C. For the first stool sample (at Day -2) an additional portion of the stool sample will be used for microscopy and fecal leukocyte determination. Microbiologic culture (for isolation of Shigella and E. coli and antibiotic resistance testing \[AST\]) will be performed on fresh stool on day -2, day 0, day 3, day 7, and day 30. Quantitative PCR to detect the presence of DNA of Shigella through the identification of the ipaH gene, will be performed on day -2, day 0, day 3 and day 7 frozen stool samples in a single batch at the end of the study. Culture-results will not be considered as confirmed Shigella infection as previous reports indicate that that approximately 60% of clinically relevant Shigella infections are missed by culture.
Blood collection at Day 3 to assess AST, ALT, serum creatinine, serum carnitine levels and at Day 0, 7, and 30 to perform any future immunological studies will be done in the pilot phase of the project only, it will not be repeated in the main trial.
Sample Size To the best of our knowledge, no randomized clinical trials have compared treatment options for clinically non-responding children with shigellosis or children with drug resistant (or presumed drug-resistant) Shigella. Therefore, the sample size estimation was derived from the most recent of the three trials of IV/IM ceftriaxone for shigellosis which compared a 3-day course of oral ciprofloxacin to IM ceftriaxone in Israeli children with invasive diarrhea (73 of whom had Shigella) and found 97% microbiologic success and 100% clinical success on day 5. We therefore assumed a clinical and microbiologic success rate of 97%. We chose an absolute 10% non-inferiority margin as the maximum risk difference in clinical success between tebipenem-pivoxil or ceftriaxone that would be clinically acceptable, by consultation with infectious disease and paediatric clinical specialists at the icddr,b.
Assuming an equal cure rate of 97% for both arms, an absolute 10% non-inferiority margin and a 2.5% one-sided alpha level, the study would require 46 confirmed Shigella patients per treatment arm to have 80% power. To achieve 92 children with Shigella-confirmed infection we will need to recruit 124 children in the RCT (approximately 75% of whom will have Shigella infection confirmed by PCR). We anticipate a low (5%) dropout rate because of the short follow-up time period for the primary outcome and the close monitoring of these children, requiring we enroll 132 children in the trial (66 in each arm).
