Clinical trial NCT03477422: CSE-1034 (Ceftriaxone+ Sulbactam+ EDTA) Compared to Meropenem in Complicated Urinary Tract Infections (cUTIs) Caused by ESBL Producing Gram Negative Bacteria
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Urinary Tract Infection Complicated
Acute Pyelonephritis
Keywords: CSE-1034 Double Blind Study
Elores
Meropenem
PLEA-CT
Bacterial Infections
ESBL
MBL
beta-lactamase
Anti-Infective Agents, Urinary
Anti-Infective Agents
Urinary Tract Infections
Pyelonephritis
Infection
Sulbactam
EDTA
Disodium EDTA
Antibiotic Adjuvant Entity
Antibiotic Resistance Breaker
Lead sponsor: Venus Remedies Limited
Sponsor class: INDUSTRY
First posted: 2018-03-26
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Patients willing to provide informed consent and who are willing to or likely to comply with all study requirements
2. Patients of either gender must have age ≥ 18 years
3. Patients with suspected cUTI based on clinical signs and symptoms
4. Urine culture results confirm bacterial urinary tract infection caused by β-lactamase producing gram- negative bacteria requiring intravenous therapy
5. 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
6. Obstructive uropathy, where the obstruction is likely to be relieved by stent or nephrostomy tube no later than 24 hours after randomization
7. Patients having received antibiotics for complicated urinary tract infection only if the duration of therapy was ≤ 24 hours within 72 hr of enrollment
8. Patients having received prior antibiotics and not showing any clinically significant improvement irrespective of duration of therapy
9. Females of childbearing potential require a negative urine pregnancy test and must agree to abstinence or to use an effective method of contraception

Exclusion Criteria:

1. 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.
2. Patients with history of resistance to any of the investigational drugs were excluded from the study
3. Patients with history of hypersensitivity or allergic response, any contra-indications to penicillin, cephalosporin groups of drugs
4. Patients with creatinine clearance below 30 mL/min
5. 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
6. Perinephritic abscess or renal corticomedullary abscess, polycystic kidney disease, only one functional kidney, chronic vesicoureteral reflux
7. Uncomplicated UTI
8. Previous or planned renal transplantation or cystectomy
9. 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)
10. Patients with a Body Mass Index ≥ 35 kg/m\^2
11. Pregnant or lactating women
12. Participation in any clinical study within the previous 6 months

Primary outcomes:
measure: 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
timeFrame: TOC visit (16 to 25 days after randomization)
measure: 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
timeFrame: TOC visit (16 to 25 days after randomization)
measure: Proportion of patients with a favorable per-patient microbiological response at the TOC visit in the mMITT analysis set
timeFrame: TOC visit (16 to 25 days after randomization)
Secondary outcomes:
measure: Proportion of patients with a favorable per-patient microbiological response in the mMITT analysis set
timeFrame: EOT (6 to 15 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: Proportion of patients with a favorable per-patient microbiological response in the Microbiological Evaluable (ME) analysis set
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: Proportion of patients with a favorable per-patient microbiological response in the extended ME analysis set
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: 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
timeFrame: EOT (6 to 15 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: 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
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: 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
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: Proportion of favorable per-pathogen microbiological response in the mMITT analysis set
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: Proportion of favorable per-pathogen microbiological response in the ME analysis set
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: Proportion of favorable per-pathogen microbiological response in the extended ME analysis set
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: 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
timeFrame: TOC visit (16 to 25 days after randomization)
measure: Proportion of patients with favorable per-patient microbiological response for patients infected with a Meropenem-resistant pathogen in the extended ME analysis sets
timeFrame: TOC visit (16 to 25 days after randomization)
measure: Time to first defervescence while on IV study therapy in patients in the mMITT analysis set who had fever at study entry
timeFrame: EOT (6 to 15 days after randomization)
measure: Time to first defervescence while on IV study therapy in patients in the ME analysis set who had fever at study entry
timeFrame: EOT (6 to 15 days after randomization)
measure: Time to first defervescence while on IV study therapy in patients in the extended ME analysis set who had fever at study entry
timeFrame: EOT (6 to 15 days after randomization)
measure: Time to first defervescence while on IV study therapy in patients in the CE analysis set who had fever at study entry
timeFrame: EOT (6 to 15 days after randomization)
measure: Number of deaths due to cUTI with more than 5 days of treatment till TOC visit
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization)
measure: Total duration of treatment in the ME analysis sets
timeFrame: EOT (6 to 15 days after randomization)
measure: Total duration of treatment in the CE analysis sets
timeFrame: EOT (6 to 15 days after randomization)
measure: To measure the difference change in Patient Quality of life using Medical Outcome Study (MOS)-Short Form Survey (SF-36) scale
timeFrame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization) & LFU Visit (23 to 32 days after randomization)
measure: Analysis of pharmacoeconomic data of CSE-1034 versus the comparator for mMITT population
timeFrame: EOT (6 to 15 days after randomization)
measure: Analysis of pharmacoeconomic data of CSE-1034 versus the comparator for CE population
timeFrame: EOT (6 to 15 days after randomization)
Other outcomes:
measure: Safety endpoints-Incidence of Treatment Emergent Adverse Events (TEAE) in Safety Population
timeFrame: First infusion to Day 32
measure: Safety endpoints-Incidence of TEAE resulting in discontinuation of study drug therapy in Safety Population
timeFrame: From first infusion to last infusion of study therapy. Duration of study therapy was 1 to 14 days.
measure: Safety endpoints-Incidence of Serious Adverse Events (SAEs) in Safety Population
timeFrame: First infusion to Day 32
Locations:
city: Srinagar
country: India
facility: Sher-i-Kashmir Institute of Medical Sciences (SKIMS)
state: Jammu & Kashmir
city: Bangalore
country: India
facility: Sapthagiri Institute of Medical Sciences and Research Center
state: Karnataka
city: Belgaum
country: India
facility: KLES, Dr Prabhakar Kore Hospital and Medical Centre , , India
state: Karnataka
city: Pune
country: India
facility: Deenanath Mangeshkar Hospital and Research Centre
state: Maharashtra
city: Ludhiana
country: India
facility: Christian Medical College & Hospital
state: Punjab
city: Bikaner
country: India
facility: S.P. Medical College
state: Rajasthan
city: Alīgarh
country: India
facility: J. N. Medical College, Aligarh Muslim University
state: Uttar Pradesh
city: Lucknow
country: India
facility: King George's Medical University (KGMU), -, India
state: Uttar Pradesh
city: Lucknow
country: India
facility: M.V. Hospital and Research Centre
state: Uttar Pradesh
city: Lucknow
country: India
facility: Ajanta Hospital & Research Centre, 765, ABC Complex, Kanpur Road, Alambagh, -, , India.
state: Uttar Pradesh
city: Varanasi
country: India
facility: Trimurti Hospital
state: Uttar Pradesh
city: Varanasi
country: India
facility: Sudbhawana Hospital
state: Uttar Pradesh
city: Varanasi
country: India
facility: Om Surgical Centre and Maternity Home
state: Uttar Pradesh
city: Chandigarh
country: India
facility: P. G. I. M. E. R., Sector 12, - India
city: New Delhi
country: India
facility: PGIMER Dr. RML Hospital
city: New Delhi
country: India
facility: All India Institute of Medical Science
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
Study officials:
affiliation: PGIMER Dr. RML Hospital, Baba Kharak Singh Marg, Connaught Place, New Delhi- 110001, India
name: Rajeev Sood
role: PRINCIPAL_INVESTIGATOR
affiliation: Christian Medical College & Hospital, Ludhiana, Punjab-141008, India
name: Kim Mammen
role: PRINCIPAL_INVESTIGATOR
affiliation: S.P. Medical College, Bikaner- 334003, Rajasthan, India
name: R.P Agrawal
role: PRINCIPAL_INVESTIGATOR
affiliation: Sapthagiri Institute of Medical Sciences and Research Center, #15, Chikkasandra, Hesaragatta Main Road, Bangalore-560 090, Karnataka, India
name: Manjunath M
role: PRINCIPAL_INVESTIGATOR
affiliation: Deenanath Mangeshkar Hospital and Research Centre, Erandwane, Pune - 411004
name: Pratibha Phadke
role: PRINCIPAL_INVESTIGATOR
affiliation: Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi- 110060, India
name: Sudhir Chadha
role: PRINCIPAL_INVESTIGATOR
affiliation: Sudbhawana Hospital, B 31/8023-B, Bhogabir, Lanka, Varanasi- 221005, India
name: A.K. Deb
role: PRINCIPAL_INVESTIGATOR
affiliation: M.V. Hospital and Research Centre, 314/30, Mirza Mandi, Chowk, Lucknow- 226003, India
name: Dharamraj Maurya
role: PRINCIPAL_INVESTIGATOR
affiliation: Ajanta Hospital & Research Centre, 765, ABC Complex, Kanpur Road, Alambagh, Lucknow-Uttar Pradesh, 226005, India.
name: Deepak Dewan
role: PRINCIPAL_INVESTIGATOR
affiliation: Om Surgical Centre and Maternity Home, SA 17/3, P-4, Sri Krishna Nagar, Paharia, Ghazipur Road, Varanasi- 221007, India
name: Shalini Srivastava
role: PRINCIPAL_INVESTIGATOR
affiliation: Trimurti Hospital, Gilat Bazaar, Varanasi- 221002, India
name: Ram Murti Singh
role: PRINCIPAL_INVESTIGATOR
affiliation: King George's Medical University (KGMU), Lucknow-226003, India
name: Rahul Janak Sinha
role: PRINCIPAL_INVESTIGATOR
affiliation: KLES, Dr Prabhakar Kore Hospital and Medical Centre, Nehru Nagar, Belagavi- 590010, Belgaum, Karnataka, India
name: Madhav Prabhu
role: PRINCIPAL_INVESTIGATOR
affiliation: J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
name: Mohd. Shameem
role: PRINCIPAL_INVESTIGATOR
affiliation: All India Institute of Medical Science, Ansari Nagar, New Delhi- 110029, India
name: Prem Nath Dogra
role: PRINCIPAL_INVESTIGATOR
affiliation: P. G. I. M. E. R., Sector 12, Chandigarh-160012, India
name: Ravimohan S Mavuduru
role: PRINCIPAL_INVESTIGATOR
affiliation: SKIMS, Srinagar, Jammu & Kashmir- 190011, India
name: Parvaiz Koul
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mir MDA, Chaudhary S, Payasi A, Sood R, Mavuduru RS, Shameem M. CSE (Ceftriaxone+ Sulbactam+ Disodium EDTA) Versus Meropenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: PLEA, a Double-Blind, Randomized Noninferiority Trial. Open Forum Infect Dis. 2019 Oct 1;6(10):ofz373. doi: 10.1093/ofid/ofz373.