A Randomized, Doubleâ€blind, Doubleâ€dummy, Activeâ€controlled, Multiâ€centre Trial to Compare the Efficacyand Safety of CSEâ€1034 (Ceftriaxone+ Sulbactam+ EDTA) with Meropenem in Infections Caused by β –Lactamase (ESBL and MBL) producing Gram Negative Bacteria

Protocol Title: A Randomized, Doubleâ€blind, Doubleâ€dummy, Activeâ€controlled, Multiâ€centre Trial to Compare the Efficacy and Safety of CSEâ€1034 (Ceftriaxone + Sulbactam + EDTA) with Meropenem in Infections Caused by β – Lactamase (ESBL and MBL) producing Gram Negative Bacteria. Primary Objective: To evaluate the efficacy of CSEâ€1034 compared to meropenem in patients suffering from pneumonia (moderate to severe community acquired pneumonia, hospital acquired pneumonia and health care associated pneumonia) and complicated urinary tract infections caused by β – lactamase producing gramâ€negative bacteria. Secondary Objective: •    To evaluate the occurrence of relapse •    To evaluate the occurrence of superinfection •    To evaluate the efficacy of CSEâ€1034 in ESBL/MBL producing gram negative bacterial infection. •    Evaluation of Pharmacoeconomic analysis in the clinical efficacy evaluable (CEE) and the successfully treated patients. Safety Objectives: Safety and tolerability will be assessed by recording incidence of adverse events and serious adverse events, lab parameters which includes hematology, clinical biochemistry, vitals and clinical examinations, ECG during the study period. Primary Endpoints: Primary efficacy endpoints of this study have been presented separately to satisfy varying regulatory guidelines of FDA and EMA. The FDA co-primary endpoints are defined as: •    Proportion of patients with symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/ flank pain / suprapubic pain) at the TOC visit in the mMITT analysis set •    Proportion of patients with both a per-patient microbiological eradication and symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/ flank pain / suprapubic pain) at the TOC visit in the mMITT analysis set EMA primary endpoint is defined as: •    Proportion of patients with a favorable per-patient microbiological response at the TOC visit in the mMITT analysis set. Secondary Endpoints: •    Proportion of patients with a favorable per-patient microbiological response at the EOT, TOC, and LFU visits in the mMITT, ME, and extended ME analysis sets •    Proportion of patients with symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/ flank pain / suprapubic pain) at the EOT, TOC and LFU visits in the mMITT, ME, extended ME, and CE analysis set •    Proportion of favorable per-pathogen microbiological response at the EOT, TOC, and LFU visits in the mMITT, ME, and extended ME analysis sets •    Proportion of patients with an investigator-determined clinical cure at the EOT, TOC, and LFU visits in the mMITT, ME, extended ME, and CE analysis sets •    Proportion of patients with favorable investigator clinical response assessment and/ separately, favorable per-patient microbiological response at the TOC visit for patients infected with a Meropenem-resistant pathogen in the extended ME analysis sets •    Proportion of patients with symptomatic resolution (as defined in the co-primary variables) at TOC for patients infected with a Meropenem-resistant pathogen in the extended ME analysis set •    Time to first defervescence while on IV study therapy in patients in the mMITT, ME, extended ME, and CE analysis sets who have fever at study entry •    Number of deaths due to cUTI with more than 5 days of treatment till TOC visit. •    Total duration of treatment in the ME, and CE analysis sets. •    To measure the difference change in Subject Quality of life using MOS–SF–36 scale. •    Pharmacoeconomic data of CSE–1034 versus the comparator will be analyzed (The cost of medications; hospitalization charges; cost of interventions done for source control (e.g., chest X–ray, cultures, interventions, lab investigations, etc.). Safety End Points: •    Proportion of patients with any treatmentâ€emergent adverse event (TEAE) •    Proportion with any TEAE resulting in discontinuation of study drug therapy •    Proportion with serious adverse events (SAEs) during study drug therapy Criteria for evaluation of clinical assessment Clinical cure: All or most pre-therapy signs and symptoms of the index infection have improved or resolved such that no additional antibiotics are required Clinical failure: Patients who meet any one of the criteria below will be considered as failure: •    Death related to targeted infection •    No apparent response to treatment; persistence or progression of most or all pre-therapy signs and symptoms or use of additional antibiotics for the current infection •    Patient previously met criteria for failure (not applicable for the EOT visit) Indeterminate: Study data are not available for evaluation of efficacy for any reason, including: •    Patient lost to follow-up or assessment not undertaken such that a determination of clinical response cannot be made at either the EOT, TOC, or LFU visit •    Death where targeted infection is clearly noncontributory •    Circumstances that preclude classification as a cure or failure Criteria for evaluation of microbiological assessment Eradication: A specimen culture taken within 48 hours prior to randomization and compared with the culture from the EOT visit or compared with the culture from the TOC or LFU visit shows that the culture obtained at the relevant visit demonstrates <104 CFU/mL of the original pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved) Indeterminate: Study data are not available for evaluation of efficacy, for any reason including: •    Patient is lost to follow-up or an assessment is not undertaken such that no urine culture was obtained (or culture results could not be interpreted for any reason) at either the EOT, the TOC, or the LFU visit •    Death where targeted infection is clearly noncontributory •    Circumstances that preclude classification as an eradication or persistence Failure: Persistence: •    A pathogen present at Screening grew at ≥104 CFU/mL at EOT or TOC •    Death related to targeted infection Superinfection: A urine culture grew ≥105 CFU/mL of a pathogen other than a baseline pathogen during the course of active treatment with study therapy along with worsening signs and symptoms of infection or the emergence during treatment with study therapy of a new pathogen. New infection: A pathogen other than an original pathogen found at Screening at a level of ≥105 CFU/mL any time after treatment has finished. If any pathogen was isolated from a site distant to the primary infection after treatment with study therapy had been completed, this will also be designated as a new infection. STUDY ANALYSIS SET Microbiological modified intent-to-treat analysis set The mMITT analysis set includes all patients who: − •    Had clinical evidence of a targeted infecion and a positive study entry urine culture defined as ≥105 CFU/mL of a Gram-negative pathogen susceptible to both the drugs. •    Had no more than 2 microorganisms identified in the study entry culture regardless of colony count. Any patient with a Gram-positive pathogen, or a bacterial species typically not expected to respond to both study drugs will be excluded. Microbiologically evaluable analysis sets at the EOT and TOC visits The ME analysis set at the EOT and TOC visits include all patients meeting the following criteria: •    Were included in the mMITT analysis set •    Either Received therapy for ≥48 hours, with ≥80% of the scheduled drug administered over the number of days administered or Received therapy <48 hours before discontinuing treatment due to an AE •    Had no important protocol deviations that would affect the assessment of efficacy •    Had a microbiological assessment at the EOT or TOC visits, respectively, with a microbiological response other than indeterminate, including a quantitative urine culture •    Did not receive any antibiotic therapy with potential activity against the baseline pathogen collected at Screening between the time of the baseline culture and the EOT or TOC culture, respectively (other than protocol defined study therapy). Study therapy is defined as blinded IV study drug. This does not include antibiotic therapy taken for the treatment of targeted infection by patients who were considered failures •    Had a study entry urine culture obtained ≤48 hours before the start of treatment with IV study therapy •    Had 1 or at most 2 baseline pathogens susceptible to both IV study therapies Microbiologically evaluable analysis set at the LFU visit The ME analysis set at the LFU visit includes all patients meeting the following criteria: •    Were included in the ME analysis set at the TOC visit •    Had a microbiological assessment at the LFU visit, with a microbiological response other than indeterminate, including an interpretable quantitative urine culture •    Had no confounding events since the TOC visit, defined as any events that could impact the assessment of the microbiologic responses. An example of confounding event is a deviation in study procedures •    Did not receive any antibiotic therapy with potential activity against the baseline pathogen since the TOC visit. This does not include antibiotic therapy taken for the treatment of targeted infection by patients who were considered failures Extended microbiological evaluable analysis set The extended ME analysis set at the EOT, TOC, and LFU visits includes patients meeting the criteria for the ME analysis set, with the exception that baseline pathogens need not be susceptible to either study therapy. Clinically evaluable analysis set at the EOT and TOC visits The CE analysis set at the EOT and TOC visits includes all patients meeting the following criteria: •    Were included in the mMITT analysis set •    Either Received therapy for ≥48 hours, with ≥80% of the scheduled drug administered over the number of days administered or Received therapy <48 hours before discontinuing treatment due to an AE •    Had no important protocol deviations that would affect the assessment of efficacy •    Had a clinical outcome assessment of clinical cure or failure (and not indeterminate) at the EOT or TOC visits, respectively •    Did not receive antibiotic therapy with potential activity against the baseline pathogen between the time of the baseline culture and the EOT or TOC culture, respectively (other than protocol-defined study therapy). Study therapy is defined as blinded IV study drug. This does not include antibiotic therapy taken for the treatment of targeted infection by patients who were considered failures. •    Had the study entry urine culture obtained ≤48 hours before the start of treatment with IV study therapy Clinically evaluable analysis set at the LFU visit The CE analysis set at the LFU visit includes all patients meeting the following criteria: •    Were included in the CE analysis set at the TOC visit •    Had a clinical outcome assessment of clinical cure or failure (and not indeterminate) at the at the LFU visit •    Had no important protocol deviations that would affect the assessment of efficacy •    Did not receive any antibiotic therapy with potential activity against the baseline pathogen since the TOC visit. This does not include antibiotic therapy taken for the treatment of targeted infection by patients who were considered failures. Safety Analysis Set All randomized patients will be considered in safety analysis set. Determination of sample size Assuming both treatments had an underlying true response of > 96% for each co-primary endpoint and that mMITT analysis set included 60% of randomized patients, a sample size of 228 patients was required. For each primary endpoint, non-inferiority of CSE-1034 versus Meropenem was considered demonstrated if the lower limit of the 2-sided 95%confidence interval around the treatment difference was greater than 15% (sponsor) or greater than 10% (FDA and EMA) The sample size across the combined study database ensured >85% power for a 10% non-inferiority margin and >98% power for 15% non-inferiority margin. The sponsor will conclude non-inferiority if the lower limit of the 95% CI (corresponding to a 97.5% 1-sided lower bound) is greater than –15% for co-primary outcome variables; however, non-inferiority may be assessed using a 10% margin in regions where this is a regulatory requirement. A sensitivity analysis will also be performed for the co-primary outcome variables for both the EOT and TOC visits and also separately for the components of the second co-primary variable, i.e., per patient microbiological eradication and symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/dysuria/suprapubic pain/flank pain) at TOC as part of the secondary efficacy variables assessment in the mMITT analysis set. The analysis for the co-primary outcome variables and, as part of the secondary efficacy variable assessment, their components (as specified previously) will be performed and presented by subgroups. The subgroups to be analyzed will include, but not be limited to, type of infection, baseline pathogens, age, and sex. Synthesis of historical trials has indicated that a 15% margin is appropriate for assessment of non-inferiority in cUTI trials; however, there are regional variations in the regulatory requirements for non-inferiority trials. To meet these requirements globally, this trial has been sized to provide 85% power for a 10% non-inferiority margin, required in some regions (therefore providing >98% power to assess non-inferiority using a 15% margin).