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Clinical Trial 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. Objectives: Primary objective: The proposed study involves aims to determine whether tebipenem-pivoxil is non-inferior to the currently WHO-recommended second line Shigella therapy (ceftriaxone). Secondary objectives: To describe the number of adverse events, between children with shigellosis treated with oral tebipenem-pivoxil or IV ceftriaxone. To compare the prevalence of ceftriaxone and tebipenem-pivoxil resistance, as well as ESBL- and carbapenemase-producing E. coli, in children treated with tebipenem-pivoxil or ceftriaxone 4- and 30-days after initiation of second-line therapy. Methods: We 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, we 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 we will compare 15 children with oral Tebipenem randomizing with 15 children with oral Azithromycin arm. We 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. Outcome measures/variables: - Clinical and microbiologic success as defined by the absence of both clinical and microbiologic failure at Day 7 - Clinical failure of test drugs as defined by the presence of fever (axillary temperature ≥38°C), diarrhoea (3 or more abnormally loose or watery stools in the last 24 hours), or blood in stool, at Day 7 of follow-up or a death prior to Day 7 - Microbiological failure as defined by the presence of Shigella in culture or Shigella DNA at quantities equal to or higher than enrolment values or Shigella isolated by microbiologic culture at Day 7.


Clinical Trial Description

Specific Objectives: Primary objective To determine whether tebipenem-pivoxil is non-inferior to the currently WHO-recommended second line Shigella therapy (ceftriaxone) Secondary objectives: - Describe the number of adverse events, between children with shigellosis treated with oral tebipenem-pivoxil or IV ceftriaxone. - Compare the prevalence of ceftriaxone and tebipenem-pivoxil resistance, as well as ESBL-and carbapenemase-producing Escherichia coli, in children treated with tebipenem-pivoxil or ceftriaxone 4- and 30-days after initiation of second-line therapy. 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, we 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, we 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, we 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 we will enroll another 15 children in Azithromycin arm. At the end of study, we will compare the two drugs in terms of safety and efficacy both clinically and microbiologically against shigellosis in children. Research Design and Methods In-vitro Susceptibility test: For invitro susceptibility MIC testing will be carried for Tebipenem against ~200 Shigella isolates in liquid media. For this we will test ~220 stored strains to revive ~200 strains. The test will be carried out in Mucosal Immunology and Vaccinology Laboratory, Infectious Diseases Division of icddr,b. 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. If possible, we will do platelet count on 7 day follow up. 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. Due to the established Azithromycin dosing regimen and safety profile, enrolment in the azithromycin arm will continue throughout the study. Blood collection limits by weight, age inclusive of all blood draws within the last 30 days, will be strictly followed. As we 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 we 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, we 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-hours7 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. 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 culture33. 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. If possible, we will do platelet count on 7 day follow up. 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. Due to the established ceftriaxone dosing regimen and safety profile, enrolment in the ceftriaxone arm will continue throughout the study. Blood collection limits by weight, age inclusive of all blood draws within the last 30 days, will be strictly followed. Sample Size Calculation and Outcome (Primary and Secondary) Variable(s) 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 shigellosis34-36 which compared a 3-day course of oral ciprofloxacin to IM ceftriaxone in Israeli children with invasive diarrhoea (73 of whom had Shigella) and found 97% microbiologic success and 100% clinical success on day 5 36. We therefore assumed a clinical and microbiologic success rate of 97%. We chose a 10% non-inferiority margin as the maximum risk difference in clinical and microbiologic 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, a 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 enrol 132 children in the trial (66 in each arm). There are three major aims of this trial; each aim along with the concurrent expected outcome has been described below: Aim 1: To determine whether tebipenem-pivoxil is non-inferior to the currently WHO-recommended 2nd line Shigella therapy (ceftriaxone). Here, clinical failure 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), or blood in stool, at Day 7 of follow-up or a death prior to Day 7. Microbiological failure will be defined as the presence of Shigella DNA at the same or higher quantities at Day 7 than at enrolment or Shigella isolated by microbiologic culture at Day 7. Clinical and microbiologic success is therefore defined as the absence of both clinical and microbiologic failure at Day 7. Change in length-for-age z-score (LAZ) and change in mid-upper arm circumference (MUAC) will be defined as the difference in LAZ and MUAC between enrolment and follow-up time points. Aim 2: Describe the number of adverse events, between children with shigellosis treated with oral tebipenem-pivoxil or IV ceftriaxone. Adverse events will be ascertained by caregiver report or identified by the study clinicians during clinical exams in hospital, at scheduled follow-up visits or during unscheduled visits. Severity (grades 1-5) will be defined according to 2014 Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events by the clinical team. Aim 3: Compare the prevalence of ceftriaxone and tebipenem-pivoxil resistance, as well as ESBL-and carbapenemase-producing Escherichia coli, in children treated with tebipenem-pivoxil or ceftriaxone 4- and 30-days after initiation of second-line therapy. Resistance cut-offs will be determined using Clinical and Laboratory Standards Institute (CLSI) 2021 Standards. Accordingly, ceftriaxone resistance will be defined as MIC ≥4 as per CLSI guidelines. ESBL will be detected by Vitek 2 system which is an automated bacterial identification and susceptibility testing system. Carbapenemase resistance will be defined as resistance to any of the following: meropenem (MIC ≥4), imipenem (MIC ≥4) or ertapenem (MIC ≥2). MIC cut-offs have not been established for tebipenem-pivoxil in E. coli and therefore will be analysed as a continuous variable. Pharmacokinetic study: Dose Administration The study drug in this study will be tebipenem pivoxil administered orally as the pediatric formulation, Orapenem (10% fine granules). Proposed dosing will be based on the following weight bands: 3-5.9 kg: 18 mg TID x 3 days (54 mg total daily dose) 6-9.9 kg: 32 mg TID x 3 days (66 mg total daily dose) 10-13.9 kg: 48 mg TID x 3 days (144 mg total daily dose) 14-19.9 kg: 68 mg TID x 3 days (204 mg total daily dose) 20-24.9 kg: 90 mg TID x 3 days (270 mg total daily dose) 25-34.9 kg: 120 mg TID x 3 days (360 mg total daily dose) Tebipenem pivoxil will be administered in 3 separate doses throughout the day for 3 consecutive days. If clinical research staff members discover that a dose was not administered on time, it should be administered immediately, and the actual time noted. The following/subsequent dose should not be given any sooner than 4 hours after the "late" dose. If the "missed/late" dose is within an hour of the next dose, then the missed dosed will be skipped and the next dose will be given as scheduled (i.e., the subject will have 2 doses rather than 3 in that 24-hour period). If a child vomits within 30 minutes of drug administration, the dose will be repeated. PK Sampling Schedule Plasma PK Sampling Schedule Below is a proposed sample schedule for PK study that will be done on the first 15 patients. However, the final schedule will be modified to confirm to all blood collection limits by weight, age inclusive of all blood draws within the last 30 days. We plan to have sparse sampling for each participant in the trial. Blood samples will be collected for determination of tebipenem concentrations and PK parameters are shown below. Time of study drug administration, time of nutritional supplement administration, PK blood sampling time, and meal timing will be collected. Day 1 of tebipenem dosing: Pre-Dose 1: 0 hours Post-Dose 1: 0.5 hours (±6 minutes) 1 hours (±6 minutes) 4 hours (±24 minutes) Post-dose 2: 1-2 hours post-dose 2 Post-dose 3: 1-2 hours post-dose 3 Day 2 of tebipenem dosing: Pre-Dose 1: 0 hours Post-Dose 2: 1-2 hours post-dose 2 Post-Dose 3: 1-2 hours post-dose 3 Day 3 of tebipenem dosing: Pre-Dose 1: 0 hours Post-Dose 1: 0.5 hours (±6 minutes) 1 hours (±6 minutes) 4 hours (±24 minutes) Post-dose 2: 1-2 hours post-dose 2 Post-dose 3: 1-2 hours post-dose 3 Data Analysis The primary analysis will be limited to children in whom Shigella was identified by PCR or culture at enrolment in the RCT (Day 0). Secondary analyses will include all children enrolled in the RCT (some of whom may not have molecularly confirmed Shigella infections but may have other inflammatory enteric bacteria, such as Campylobacter). Deaths due to non-Shigella related causes will be excluded as treatment failure. - Primary analyses will be intention-to-treat (ITT) based on randomization allocation to the 3-day course of tebipenem-pivoxil or ceftriaxone with randomization group included as the only covariate in models. - All investigators, statisticians, and laboratory personnel will be blinded to randomization arm. However, due to the difference in administration of the two drugs, oral vs. IV, study clinicians and local investigators will not be blinded. Clinical outcomes will be determined using standardized questionnaires and measures (observed stool frequency, stool appearance, and axillary temperature) so as to limit potential bias in clinical outcomes. - The primary outcome will be a combined outcome of clinical and microbiologic success at day 7. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT05121974
Study type Interventional
Source International Centre for Diarrhoeal Disease Research, Bangladesh
Contact M.A Salam Khan
Phone +880-2-9827001-10
Email [email protected]
Status Not yet recruiting
Phase Phase 2
Start date December 2021
Completion date December 2024

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