Tebipenem Trial in Children With Shigellosis

NCT05121974 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: PR-21005
• Study Type: interventional
• Target: 132
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

Shigellosis; Tebipenem-pivoxil; Children; Randomized non-inferiority trial

Outcome Measures

Primary Outcomes (1)

• Clinical failure at Day 3

  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.

  3 days

Secondary Outcomes (7)

• Clinical failure at Day 7 & Day 30

  7 days & 30 days

• Microbiological Failure

  7 days & 30 days

• Adverse events

  day 30

• Carbapenem-resistant and cephalosporin resistant Shigella and Enterobacteriaceae coli isolates.

  day 0, 7, & 30

• ESBL-producing Shigella and Enterobacteriaceae coli isolates

  day 0, 7, & 30

Study Arms (4)

Tebipenem-pivoxil arm (Pilot study)

EXPERIMENTAL

Oral Tebipenem-pivoxil in children with shigellosis

Drug: Tebipenem Pivoxil

Azithromycin arm (Pilot study)

ACTIVE COMPARATOR

Oral Azithromycin in children with shigellosis

Drug: Azithromycin

Tebipenem-pivoxil arm (Main trial)

EXPERIMENTAL

Oral Tebipenem-pivoxil in children with shigellosis

Drug: Tebipenem Pivoxil

Ceftriaxone arm (Main trial)

ACTIVE COMPARATOR

Intravenous Ceftriaxone in children with shigellosis

Drug: Ceftriaxon

Interventions

Tebipenem Pivoxil DRUG

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

Also known as: Tebipenem (Orapenem)

Tebipenem-pivoxil arm (Main trial); Tebipenem-pivoxil arm (Pilot study)

Azithromycin DRUG

Oral Azithromycin antibiotic (Macrolides)

Also known as: Oral Azithromycin

Azithromycin arm (Pilot study)

Ceftriaxon DRUG

IV Ceftriaxone (Cephalosporin)

Also known as: Ceftriaxone

Ceftriaxone arm (Main trial)

Eligibility Criteria

• Age: 24 Months - 59 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• International Centre for Diarrhoeal Disease Research, Bangladesh: lead
• University of Washington: collaborator
• GlaxoSmithKline: collaborator
• Tres Cantos Open Lab Foundation: collaborator

Study Sites (1)

International Centre for Diarrhoeal Disease Research, Bangladesh

Dhaka, 1212, Bangladesh

Location

Related Publications (1)

• Nuzhat S, Islam MR, Das S, Bashar SJ, Pavlinac PB, Arnold SL, Newlands A, Gibson R, Alvaro EF, Addo J, Khanam F, Ahmed D, Chisti MJ, Qadri F, Ahmed T. Tebipenem pivoxil as an alternative to ceftriaxone for clinically non-responding children with shigellosis: a randomised non-inferiority trial protocol. BMJ Open. 2025 Feb 25;15(2):e088449. doi: 10.1136/bmjopen-2024-088449.

  PMID: 40000088 DERIVED

MeSH Terms

Conditions

Dysentery, Bacillary

Interventions

L 084; tebipenem; Azithromycin; Ceftriaxone

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Dysentery; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Sharika Nuzhat, MBBS, DCH

  International Centre for Diarrhoeal Disease Research, Bangladesh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Pilot study for efficacy and pharmacokinetics for Tebipenem: Two arms for children (24-59 months) with shigellosis 1. Oral Tebipenem-pivoxil 2. Oral Azithromycin Main trial: Two arms for children (24-59 months) with shigellosis: 1. Oral Tebipenem-pivoxil 2. IV Ceftriaxone

Study Record Dates

• First Submitted: October 31, 2021
• First Posted: November 16, 2021
• Study Start: August 18, 2022
• Primary Completion: March 15, 2025
• Study Completion (Estimated): August 17, 2026
• Last Updated: August 19, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

BA (1)