Tebipenem Trial in Children With Shigellosis

Summary

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).

Conditions

• Shigellosis

Interventions

DRUG

Tebipenem Pivoxil

Tebipenem (brand name: Orapenem) is a broad-spectrum orally administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics.

DRUG

Azithromycin

Oral Azithromycin antibiotic (Macrolides)

DRUG

Ceftriaxon

IV Ceftriaxone (Cephalosporin)

Sponsors & Collaborators

• University of Washington

  collaborator OTHER

• GlaxoSmithKline

  collaborator INDUSTRY

• Tres Cantos Open Lab Foundation

  collaborator UNKNOWN

• International Centre for Diarrhoeal Disease Research, Bangladesh

  lead OTHER

Principal Investigators

• Sharika Nuzhat, MBBS, DCH · International Centre for Diarrhoeal Disease Research, Bangladesh

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

24 Months

Max Age

59 Months

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2022-08-18

Primary Completion

2025-03-15

Completion

2026-08-17

Countries

• Bangladesh

Study Locations