Randomized, Double-blind, Double-dummy, Active-controlled, Multi-centre Trial to Compare the Efficacy and Safety of CSE-1034 (Ceftriaxone+ Sulbactam+ EDTA) With Meropenem in Infections Caused by β-Lactamase (ESBL and MBL) Producing Gram-Negative Bacteria
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 230
- 试验地点
- 17
- 主要终点
- 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 Microbiological Modified Intent-To-Treat (mMITT) analysis set
研究概览
简要总结
The purpose of this study is to evaluate the effects of CSE-1034 (Ceftriaxone+ Sulbactam+ EDTA) compared to Meropenem for treating hospitalized patients with complicated urinary tract infections, including acute pyelonephritis caused by β-lactamase producing gram-negative bacteria
详细描述
cUTIs are mostly caused by gram-negative bacteria, including Enterobacteriaceae (particularly Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis) and Pseudomonas aeruginosa, and often possess mechanisms leading to multidrug resistance. These mechanisms primarily consist of ESBLs (extended-spectrum beta-lactamases) that can hydrolyse cephalosporins, penicillins and aztreonam, and are encoded on mobile genes. This has led to increased risk of failure with first-line antibiotics and increased the usage of last line drugs like carbapenems. However, over the past decade, with the emergence of carbapenem-resistant infections caused by gram-negative pathogens like CRE (carbapenem-resistant Enterobacteriaceae), CRAB (carbapenem-resistant Acinetobacter baumannii) and CRPA (carbapenem-resistant Pseudomonas aeruginosa), there is a major threat looming on the effectiveness of these last resort drugs, warranting the discovery of newer and alternate agents.
To this end, the concept of using Antibiotic Resistance Breakers (ARBs) to revive the potency of existing antibiotics has been widely discussed in the recent literature. ARBs, sometimes referred as antibiotic adjuvants, are non-antibiotic moieties which do not have any antimicrobial activity on its own, but, in combination with antibiotics enhance their antimicrobial activity and help overcome resistance barriers. Most beta lactamase inhibitors (BLIs) can be thought of as ARBs that do not have any significant antimicrobial activity when used alone, but in combination with a beta-lactam antibiotic, help restore the activity against beta-lactamase producing organisms.
CSE-1034 is a novel combination of Ceftriaxone (third generation beta-lactam cephalosporin), Sulbactam (beta-lactamase inhibitor) and Disodium EDTA (Class 1 Antibiotic Resistance Breaker), and it restores the in vitro activity of Ceftriaxone against ESBL/MBL producing gram-negative bacteria, including enzyme families that belong to Ambler class A (TEM, SHV, CTX-M), class B (NDM, VIM, IMP), class C (some variants of AmpC), and class D (OXA ESBLs); it is not active against serine carbapenemases (higher variants of KPC, OXA carbapenemases). CSE-1034 also has proven in vitro activity against multiple resistance mechanisms including efflux pumps, bacterial biofilms, membrane permeability, and transfer of resistance by means of conjugation.
Since CSE-1034 has shown its efficacy in ESBL producing Escherichia coli, Klebsiella species, Pseudomonas aeruginosa and Acinetobacter species in various in vitro and in vivo studies, therefore, to meet regulatory expectations, non-inferiority of CSE-1034 in comparison to Meropenem (drug of choice in ESBL producing pathogens) is under study in this phase-3 clinical trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients willing to provide informed consent and who are willing to or likely to comply with all study requirements
- •Patients of either gender must have age ≥ 18 years
- •Patients with suspected cUTI based on clinical signs and symptoms
- •Urine culture results confirm bacterial urinary tract infection caused by β-lactamase producing gram- negative bacteria requiring intravenous therapy
- •Patients with indwelling catheters should have the catheter removed or replaced (if removal is not clinically acceptable) before or as soon as possible, but not longer than 12 hours, after randomization
- •Obstructive uropathy, where the obstruction is likely to be relieved by stent or nephrostomy tube no later than 24 hours after randomization
- •Patients having received antibiotics for complicated urinary tract infection only if the duration of therapy was ≤ 24 hours within 72 hr of enrollment
- •Patients having received prior antibiotics and not showing any clinically significant improvement irrespective of duration of therapy
- •Females of childbearing potential require a negative urine pregnancy test and must agree to abstinence or to use an effective method of contraception
排除标准
- •Patients with clinically significant cardiovascular, renal, hepatic, gastrointestinal conditions, neurological, psychiatric, respiratory, other severely immunocompromised, haematological, or malignant disease and other condition which may interfere with the assessment. History of uncontrolled diabetes mellitus, HIV and hepatitis B were excluded.
- •Patients with history of resistance to any of the investigational drugs were excluded from the study
- •Patients with history of hypersensitivity or allergic response, any contra-indications to penicillin, cephalosporin groups of drugs
- •Patients with creatinine clearance below 30 mL/min
- •Patients having abnormal laboratory parameters which in the opinion of PI are clinically significant enough to pose any undue safety concern for the patient or can interfere with patient's assessment
- •Perinephritic abscess or renal corticomedullary abscess, polycystic kidney disease, only one functional kidney, chronic vesicoureteral reflux
- •Uncomplicated UTI
- •Previous or planned renal transplantation or cystectomy
- •Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery to relieve obstruction, to place a stent or nephrostomy)
- •Patients with a Body Mass Index ≥ 35 kg/m^2
- •Pregnant or lactating women
- •Participation in any clinical study within the previous 6 months
研究组 & 干预措施
CSE-1034 (Ceftriaxone + Sulbactam + EDTA)
CSE-1034 (Ceftriaxone + Sulbactam + EDTA) was an Experimental drug in this study and is a combination of Ceftriaxone 1000mg, Sulbactam 500mg and EDTA 37mg available as dry powder for reconstitution. It was administered twelve hourly through intravenous route as infusion over 30 minutes. The duration of the active treatment was for 5-14 days depending upon the severity of the disease, which was determined by the Principal Investigator (PI).
Interventions:
- Drug: CSE-1034 (Ceftriaxone + Sulbactam + EDTA)
- Drug: Matching Placebo
干预措施: CSE-1034 (Ceftriaxone + Sulbactam + EDTA) (Drug)
Meropenem
Meropenem was the active comparator in the study. It was also available as dry powder for reconstitution and contained active ingredient Meropenem 1000mg. It was administered eight hourly through intravenous route as infusion over 30 minutes.The duration of the active treatment was for 5-14 days depending upon the severity of the disease, which was determined by the PI.
Interventions:
- Drug: Meropenem
- Drug: Matching Placebo
干预措施: Meropenem (Drug)
结局指标
主要结局
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 Microbiological Modified Intent-To-Treat (mMITT) analysis set
时间窗: TOC visit (16 to 25 days after randomization)
This was the first co-primary outcome measure for the Food and Drug Administration (FDA). For this outcome measure, success was achieved with a clinical outcome of Cure at the Test of Cure (TOC) visit. Cure was defined as all or most pre-therapy signs and symptoms of the index infection had improved or resolved such that no additional antibiotics was required.
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
时间窗: TOC visit (16 to 25 days after randomization)
This was the second co-primary outcome measure for the Food and Drug Administration (FDA). For this composite outcome measure, overall success was achieved with a clinical outcome of Cure and microbiologic outcome of Eradication at TOC visit. Cure was defined as all or most pre-therapy signs and symptoms of the index infection had improved or resolved such that no additional antibiotics was required. Eradication was defined using the FDA's colony-forming units per millilitre (CFU/mL) criteria that the bacterial pathogen(s) found at baseline was/were reduced to \<10\^4 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture).
Proportion of patients with a favorable per-patient microbiological response at the TOC visit in the mMITT analysis set
时间窗: TOC visit (16 to 25 days after randomization)
This was the primary outcome measure for the European Medicines Agency (EMA). For this measure, a microbiologic outcome of Eradication was defined using the EMA's CFU/mL criteria: bacterial pathogen(s) found at baseline was reduced to \<10\^3 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture).
次要结局
- Proportion of patients with symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/ flank pain / suprapubic pain) in the extended ME analysis set(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of patients with a favorable per-patient microbiological response in the mMITT analysis set(EOT (6 to 15 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of patients with a favorable per-patient microbiological response in the Microbiological Evaluable (ME) analysis set(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of patients with a favorable per-patient microbiological response in the extended ME analysis set(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of patients with symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/ flank pain / suprapubic pain) in the mMITT analysis set(EOT (6 to 15 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of patients with symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/ flank pain / suprapubic pain) in the CE analysis set(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of favorable per-pathogen microbiological response in the mMITT analysis set(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of favorable per-pathogen microbiological response in the ME analysis set(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of favorable per-pathogen microbiological response in the extended ME analysis set(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Proportion of patients with symptomatic resolution (as defined in the co-primary variables) for patients infected with a Meropenem -resistant pathogen in the extended ME analysis set(TOC visit (16 to 25 days after randomization))
- Proportion of patients with favorable per-patient microbiological response for patients infected with a Meropenem-resistant pathogen in the extended ME analysis sets(TOC visit (16 to 25 days after randomization))
- Time to first defervescence while on IV study therapy in patients in the mMITT analysis set who had fever at study entry(EOT (6 to 15 days after randomization))
- Time to first defervescence while on IV study therapy in patients in the ME analysis set who had fever at study entry(EOT (6 to 15 days after randomization))
- Time to first defervescence while on IV study therapy in patients in the extended ME analysis set who had fever at study entry(EOT (6 to 15 days after randomization))
- Time to first defervescence while on IV study therapy in patients in the CE analysis set who had fever at study entry(EOT (6 to 15 days after randomization))
- Number of deaths due to cUTI with more than 5 days of treatment till TOC visit(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization))
- Total duration of treatment in the ME analysis sets(EOT (6 to 15 days after randomization))
- Total duration of treatment in the CE analysis sets(EOT (6 to 15 days after randomization))
- To measure the difference change in Patient Quality of life using Medical Outcome Study (MOS)-Short Form Survey (SF-36) scale(EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization))
- Analysis of pharmacoeconomic data of CSE-1034 versus the comparator for mMITT population(EOT (6 to 15 days after randomization))
- Analysis of pharmacoeconomic data of CSE-1034 versus the comparator for CE population(EOT (6 to 15 days after randomization))