Urinary Tract Infection ComplicatedPhase 3PLEANCT03477422
CSE-1034 (Ceftriaxone+ Sulbactam+ EDTA) Compared to Meropenem in Complicated Urinary Tract Infections (cUTIs) Caused by ESBL Producing Gram Negative Bacteria
A Phase 3 study testing CSE-1034 (Ceftriaxone + Sulbactam + EDTA) and Meropenem in people with Urinary Tract Infection Complicated and Acute Pyelonephritis, run by Venus Remedies Limited at 17 sites in India.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Urinary Tract Infection Complicated, Acute Pyelonephritis
- What is being tested?
- CSE-1034 (Ceftriaxone + Sulbactam + EDTA) and Meropenem
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 230 participants
- Where
- 17 sitesIndia
- Study dates
- 11 Jan 2014to 8 May 2017
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
17 sites in 1 country.
17 sites in 1 country
India17 sites
J. N. Medical College, Aligarh Muslim University
Aligarh, Uttar Pradesh, 202002
Sapthagiri Institute of Medical Sciences and Research Center
Bangalore, Karnataka, 560 090
KLES, Dr Prabhakar Kore Hospital and Medical Centre , , India
Belagavi, Karnataka, 590010
S.P. Medical College
Bikaner, Rajasthan, 334003
P. G. I. M. E. R., Sector 12, - India
Chandigarh, 160012
King George's Medical University (KGMU), -, India
Lucknow, Uttar Pradesh, 226003
M.V. Hospital and Research Centre
Lucknow, Uttar Pradesh, 226003
Ajanta Hospital & Research Centre, 765, ABC Complex, Kanpur Road, Alambagh, -, , India.
Lucknow, Uttar Pradesh, 226005
Christian Medical College & Hospital
Ludhiana, Punjab, 141008
PGIMER Dr. RML Hospital
New Delhi, 110001
All India Institute of Medical Science
New Delhi, 110029
Sir Ganga Ram Hospital
New Delhi, 110060
Deenanath Mangeshkar Hospital and Research Centre
Pune, Maharashtra, 411004
Sher-i-Kashmir Institute of Medical Sciences (SKIMS)
Srinagar, Jammu and Kashmir, 190011
Trimurti Hospital
Varanasi, Uttar Pradesh, 221002
Sudbhawana Hospital
Varanasi, Uttar Pradesh, 221005
Om Surgical Centre and Maternity Home
Varanasi, Uttar Pradesh, 221007
About this study
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
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
Read the 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.
- Being tested
- CSE-1034 (Ceftriaxone + Sulbactam + EDTA), Meropenem
- 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
- Medical subject headings
- Bacterial Infections, Urinary Tract Infections, Pyelonephritis, Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CSE-1034 (Ceftriaxone + Sulbactam + EDTA)Drug
Also called Elores
CSE-1034 (Ceftriaxone + Sulbactam + EDTA) was Experimental in this study and is a combination of Ceftriaxone 1000mg, Sulbactam 500mg and EDTA 37mg available as dry powder for reconstitution. Patients were given either CSE-1034 or placebo through IV route four times daily, strictly adhering to the time interval. Time of the first dose (Drug) was considered 0th hr, the second dose (Placebo) was given at 8th hour from first dose, third dose (Drug) at 12th hour from first dose and the fourth dose (Placebo) at 16th hour from first dose. The infusion was initiated within ± 30 min of schedule time.
MeropenemDrug
Also called Meronem
Meropenem was the Comparator in the study. It was also available as dry powder for reconstitution and contained active ingredient Meropenem 1000mg.Patients were given either Meropenem or placebo through IV route four times daily, strictly adhering to the time interval. Time of the first dose (Drug) was considered 0th hr, the second dose (Drug) was given at 8th hour from first dose, third dose (Placebo) at 12th hour from first dose and the fourth dose (Drug) at 16th hour from first dose. The infusion was initiated within ± 30 min of schedule time.
| Study group | Role | What they receive |
|---|---|---|
| CSE-1034 (Ceftriaxone + Sulbactam + EDTA) | Experimental | 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 Receives: Drug: CSE-1034 (Ceftriaxone + Sulbactam + EDTA) |
| Meropenem | Active comparator | 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 Receives: Drug: Meropenem |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
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.
Measured: TOC visit (16 to 25 days after randomization)
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
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).
Measured: TOC visit (16 to 25 days after randomization)
Proportion of patients with a favorable per-patient microbiological response at the TOC visit in the mMITT analysis set
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).
Measured: TOC visit (16 to 25 days after randomization)
Secondary outcomes (21)
Proportion of patients with a favorable per-patient microbiological response in the mMITT analysis set
This secondary outcome measure focused on the microbiological success in the mMITT population at the End of Treatment (EOT), and Late Follow-Up (LFU) visits. A microbiologic outcome of Eradication was met if urine culture obtained at the relevant visit demonstrates <10^4 CFU/mL (for FDA) or < 10^3 CFU/mL (for EMA) of the original uro-pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved)
Measured: 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
This secondary outcome measure focused on the microbiological success in the ME population at the EOT, TOC, and LFU visits. A microbiologic outcome of Eradication was met if urine culture obtained at the relevant visit demonstrates <10^4 CFU/mL (for FDA) or < 10^3 CFU/mL (for EMA) of the original uro-pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved)
Measured: 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
This secondary outcome measure focused on the microbiological success in the extended ME population at the EOT, TOC, and LFU visits. A microbiologic outcome of Eradication was met if urine culture obtained at the relevant visit demonstrates <10^4 CFU/mL (for FDA) or < 10^3 CFU/mL (for EMA) of the original uro-pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved)
Measured: 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
This secondary outcome measure focused on a clinical outcome of Cure in the mMITT analysis set. For this outcome measure, success was achieved with a clinical outcome of Cure at the EOT, and LFU visit for mMITT population. 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.
Measured: 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
This secondary outcome measure focused on a clinical outcome of Cure in the Clinical Evaluable (CE) analysis sets. For this outcome measure, success was achieved with a clinical outcome of Cure at the EOT, TOC, and LFU visit for CE population. 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.
Measured: 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 extended ME analysis set
This secondary outcome measure focused on a clinical outcome of Cure in the extended ME analysis set. For this outcome measure, success was achieved with a clinical outcome of Cure at the EOT, TOC, and LFU visit for extended ME population. 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.
Measured: 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
This secondary outcome measure focused on the per-pathogen (Enterobacter species, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Acinetobacter baumannii) microbiological outcome of Eradication in the m-MITT population at EOT, TOC, and LFU visit. A microbiologic outcome of Eradication was met if urine culture obtained at the relevant visit demonstrates <10^4 CFU/mL (for FDA) or < 10^3 CFU/mL (for EMA) of the original uro-pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved)
Measured: 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
This secondary outcome measure focused on the per-pathogen (Enterobacter species, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Acinetobacter baumannii) microbiological outcome of Eradication in the ME population at EOT, TOC, and LFU visit. A microbiologic outcome of Eradication was met if urine culture obtained at the relevant visit demonstrates <10^4 CFU/mL (for FDA) or < 10^3 CFU/mL (for EMA) of the original uro-pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved)
Measured: 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
This secondary outcome measure focused on the per-pathogen (Enterobacter species, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Acinetobacter baumannii) microbiological outcome of Eradication in the extended ME population at EOT, TOC, and LFU visit. A microbiologic outcome of Eradication was met if urine culture obtained at the relevant visit demonstrates <10^4 CFU/mL (for FDA) or < 10^3 CFU/mL (for EMA) of the original uro-pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved)
Measured: 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
This secondary outcome measure focused on a clinical outcome of Cure in the patients infected with a Meropenem resistant pathogen in the extended ME analysis set. For this outcome measure, success was achieved with a clinical outcome of Cure at the TOC visit in extended ME population. 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.
Measured: 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
This secondary outcome measure focused on the microbiological success in the patients infected with a Meropenem-resistant pathogen in the extended ME analysis population at the TOC visit. A microbiologic outcome of Eradication was met if urine culture obtained at the relevant visit demonstrates <10^4 CFU/mL (for FDA) or < 10^3 CFU/mL (for EMA) of the original uro-pathogen, and the patient was not bacteremic (if the patient was bacteremic at Screening, the bacteremia has resolved)
Measured: 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
This secondary outcome measure focused on the time to first defervescence in patients having fever study entry. Time to first defervescence was calculated for patients with a fever (>38°C) at Baseline. Defervescence (<37.8°C) was defined as absence of fever based on the highest temperature within a 24-hour period. Time to first defervescence while on IV study therapy (days) in the mMITT analysis set for patients who have fever at study entry was defined as the time from the first dose of IV study therapy to the first absence of fever.
Measured: 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
This secondary outcome measure focused on the time to first defervescence in patients having fever study entry. Time to first defervescence was calculated for patients with a fever (>38°C) at Baseline. Defervescence (<37.8°C) was defined as absence of fever based on the highest temperature within a 24-hour period. Time to first defervescence while on IV study therapy (days) in the ME analysis set for patients who have fever at study entry was defined as the time from the first dose of IV study therapy to the first absence of fever.
Measured: 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
This secondary outcome measure focused on the time to first defervescence in patients having fever study entry. Time to first defervescence was calculated for patients with a fever (>38°C) at Baseline. Defervescence (<37.8°C) was defined as absence of fever based on the highest temperature within a 24-hour period. Time to first defervescence while on IV study therapy (days) in the extended ME analysis set for patients who have fever at study entry was defined as the time from the first dose of IV study therapy to the first absence of fever.
Measured: 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
This secondary outcome measure focused on the time to first defervescence in patients having fever study entry. Time to first defervescence was calculated for patients with a fever (>38°C) at Baseline. Defervescence (<37.8°C) was defined as absence of fever based on the highest temperature within a 24-hour period. Time to first defervescence while on IV study therapy (days) in the CE analysis set for patients who have fever at study entry was defined as the time from the first dose of IV study therapy to the first absence of fever.
Measured: EOT (6 to 15 days after randomization)
Number of deaths due to cUTI with more than 5 days of treatment till TOC visit
This secondary outcome measure focused on the number deaths from day 01 dosing to TOC visit due to cUTI in patients received more than 5 days of treatment.
Measured: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization)
Total duration of treatment in the ME analysis sets
This secondary outcome measure focused on the number of days IV therapy was used for management of patients with cUTI including acute pyelonephritis
Measured: EOT (6 to 15 days after randomization)
Total duration of treatment in the CE analysis sets
This secondary outcome measure focused on the number of days IV therapy was used for management of patients with cUTI including acute pyelonephritis
Measured: 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
This secondary outcome measure focused on the MOS-SF-36 scale questionnaire. It was evaluated using the RAND methodology that measures the results based on eight different scales, namely - Physical functioning, Role limitations due to physical health, Role Limitations due to emotional problems, Energy/Fatigue, Emotional well-being, General Health, Health change, Pain and Social functioning. Broadly, the QoL scales are divided into two main sub-groups that provide a summary of the physical functioning and the mental functioning of the patient. Scores represent the percentage of the total possible score achieved, 100 being the highest score possible (denoting best outcome) and 0 being the lowest (denoting worst outcome)
Measured: 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
This secondary outcome measure focused on Pharmacoeconomics data of CSE-1034 versus the Meropenem. The difference in cost incurred in management of cUTI (medications cost + hospitalization charges + cost of interventions and cost of laboratory investigations) were analyzed for mMITT population at EOT for CSE-1034 versus the comparator .
Measured: EOT (6 to 15 days after randomization)
Analysis of pharmacoeconomic data of CSE-1034 versus the comparator for CE population
This secondary outcome measure focused on Pharmacoeconomics data of CSE-1034 versus the Meropenem. The difference in cost incurred in management of cUTI (medications cost + hospitalization charges + cost of interventions and cost of laboratory investigations) were analyzed for CE population at EOT for CSE-1034 versus the comparator .
Measured: EOT (6 to 15 days after randomization)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Mar 2018
- Study start11 Jan 2014
- Primary completion8 May 2017
- Study completion8 May 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Urinary Tract Infection ComplicatedStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 230 participants (actual)
Sponsor and investigators
- Lead sponsor
- Venus Remedies Limited
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Rajeev Sood, Principal investigator, PGIMER Dr. RML Hospital, Baba Kharak Singh Marg, Connaught Place, New Delhi- 110001, IndiaKim Mammen, Principal investigator, Christian Medical College & Hospital, Ludhiana, Punjab-141008, IndiaR.P Agrawal, Principal investigator, S.P. Medical College, Bikaner- 334003, Rajasthan, IndiaManjunath M, Principal investigator, Sapthagiri Institute of Medical Sciences and Research Center, #15, Chikkasandra, Hesaragatta Main Road, Bangalore-560 090, Karnataka, IndiaPratibha Phadke, Principal investigator, Deenanath Mangeshkar Hospital and Research Centre, Erandwane, Pune - 411004Sudhir Chadha, Principal investigator, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi- 110060, IndiaA.K. Deb, Principal investigator, Sudbhawana Hospital, B 31/8023-B, Bhogabir, Lanka, Varanasi- 221005, IndiaDharamraj Maurya, Principal investigator, M.V. Hospital and Research Centre, 314/30, Mirza Mandi, Chowk, Lucknow- 226003, India
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03477422
- Sponsor's protocol ID
- VRL/CSE-1034/05/2012
- Other IDs
- CTRI/2013/11/004133
- Acronym
- PLEA
- Status last verified
- Aug 2019
- First submitted
- 9 Mar 2018
- Last updated
- 29 Aug 2019
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 31433059
Study at a glance
From the registry record, last updated by the sponsor on 29 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03477422
- Acronym / sponsor ID
- PLEA / VRL/CSE-1034/05/2012
- Keywords
- CSE-1034 Double Blind Study, Elores, Meropenem, PLEA-CT, Bacterial Infections, ESBL, MBL, beta-lactamase
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 230 participants (actual)
- Lead sponsor
- Venus Remedies LimitedIndustry (pharma, biotech, devices)
- Study start
- 11 Jan 2014 (actual)
- Primary completion
- 8 May 2017 (actual)
- Study completion
- 8 May 2017 (actual)
- First posted
- 26 Mar 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| CSE-1034 (Ceftriaxone + Sulbactam + EDTA) | Experimental | Drug: 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 |
| Meropenem | Active comparator | Drug: MeropenemMeropenem 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CSE-1034 (Ceftriaxone + Sulbactam + EDTA)Also: EloresCSE-1034 (Ceftriaxone + Sulbactam + EDTA) was Experimental in this study and is a combination of Ceftriaxone 1000mg, Sulbactam 500mg and EDTA 37mg available as dry powder for reconstitution. Patients were given either CSE-1034 or placebo through IV route four times daily, strictly adhering to the time interval. Time of the first dose (Drug) was considered 0th hr, the second dose (Placebo) was given at 8th hour from first dose, third dose (Drug) at 12th hour from first dose and the fourth dose (Placebo) at 16th hour from first dose. The infusion was initiated within ± 30 min of schedule time. | Drug | CSE-1034 (Ceftriaxone + Sulbactam + EDTA) |
| MeropenemAlso: MeronemMeropenem was the Comparator in the study. It was also available as dry powder for reconstitution and contained active ingredient Meropenem 1000mg.Patients were given either Meropenem or placebo through IV route four times daily, strictly adhering to the time interval. Time of the first dose (Drug) was considered 0th hr, the second dose (Drug) was given at 8th hour from first dose, third dose (Placebo) at 12th hour from first dose and the fourth dose (Drug) at 16th hour from first dose. The infusion was initiated within ± 30 min of schedule time. | Drug | Meropenem |
Primary outcome
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
Time frame: 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
Time frame: 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
Time frame: 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).
21 secondary outcomes
Proportion of patients with a favorable per-patient microbiological response in the mMITT analysis set
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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 extended ME analysis set
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: EOT (6 to 15 days after randomization)
Number of deaths due to cUTI with more than 5 days of treatment till TOC visit
Time frame: EOT (6 to 15 days after randomization), TOC (16 to 25 days after randomization)
Total duration of treatment in the ME analysis sets
Time frame: EOT (6 to 15 days after randomization)
Total duration of treatment in the CE analysis sets
Time frame: 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
Time frame: 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
Time frame: EOT (6 to 15 days after randomization)
Analysis of pharmacoeconomic data of CSE-1034 versus the comparator for CE population
Time frame: EOT (6 to 15 days after randomization)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Aug 2019.
- Results publication: PubMed 31433059Mir 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rajeev Sood principal investigator
PGIMER Dr. RML Hospital, Baba Kharak Singh Marg, Connaught Place, New Delhi- 110001, India
Kim Mammen principal investigator
Christian Medical College & Hospital, Ludhiana, Punjab-141008, India
R.P Agrawal principal investigator
S.P. Medical College, Bikaner- 334003, Rajasthan, India
17 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing CSE-1034 (Ceftriaxone + Sulbactam + EDTA) and Meropenem in people with Urinary Tract Infection Complicated and Acute Pyelonephritis, run by Venus Remedies Limited at 17 sites in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: TOC visit (16 to 25 days after randomization)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03477422, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Aug 2019.