CSE-1034 (Ceftriaxone+ Sulbactam+ EDTA) Compared to Meropenem in Complicated Urinary Tract Infections (cUTIs) Caused by ESBL Producing Gram Negative Bacteria

NCT03477422 | Completed Phase 3

• 2 other identifiers: VRL/CSE-1034/05/2012CTRI/2013/11/004133
• Study Type: interventional
• Target: 230
• Locations: 1 country
• Sites: 17

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

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

Outcome Measures

Primary Outcomes (3)

• 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.

  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).

  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).

  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

  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)

Other Outcomes (3)

• Safety endpoints-Incidence of Treatment Emergent Adverse Events (TEAE) in Safety Population

  First infusion to Day 32

• Safety endpoints-Incidence of TEAE resulting in discontinuation of study drug therapy in Safety Population

  From first infusion to last infusion of study therapy. Duration of study therapy was 1 to 14 days.

• Safety endpoints-Incidence of Serious Adverse Events (SAEs) in Safety Population

  First infusion to Day 32

Study Arms (2)

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

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

Drug: Meropenem

Interventions

CSE-1034 (Ceftriaxone + Sulbactam + EDTA) DRUG

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.

Also known as: Elores

CSE-1034 (Ceftriaxone + Sulbactam + EDTA)

Meropenem DRUG

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.

Also known as: Meronem

Meropenem

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Venus Remedies Limited: lead

Study Sites (17)

Sher-i-Kashmir Institute of Medical Sciences (SKIMS)

Srinagar, Jammu and Kashmir, 190011, India

Location

Sapthagiri Institute of Medical Sciences and Research Center

Bangalore, Karnataka, 560 090, India

Location

KLES, Dr Prabhakar Kore Hospital and Medical Centre , , India

Belagavi, Karnataka, 590010, India

Location

Deenanath Mangeshkar Hospital and Research Centre

Pune, Maharashtra, 411004, India

Location

Christian Medical College & Hospital

Ludhiana, Punjab, 141008, India

Location

S.P. Medical College

Bikaner, Rajasthan, 334003, India

Location

J. N. Medical College, Aligarh Muslim University

Aligarh, Uttar Pradesh, 202002, India

Location

King George's Medical University (KGMU), -, India

Lucknow, Uttar Pradesh, 226003, India

Location

M.V. Hospital and Research Centre

Lucknow, Uttar Pradesh, 226003, India

Location

Ajanta Hospital & Research Centre, 765, ABC Complex, Kanpur Road, Alambagh, -, , India.

Lucknow, Uttar Pradesh, 226005, India

Location

Trimurti Hospital

Varanasi, Uttar Pradesh, 221002, India

Location

Sudbhawana Hospital

Varanasi, Uttar Pradesh, 221005, India

Location

Om Surgical Centre and Maternity Home

Varanasi, Uttar Pradesh, 221007, India

Location

P. G. I. M. E. R., Sector 12, - India

Chandigarh, 160012, India

Location

PGIMER Dr. RML Hospital

New Delhi, 110001, India

Location

All India Institute of Medical Science

New Delhi, 110029, India

Location

Sir Ganga Ram Hospital

New Delhi, 110060, India

Location

Related Publications (1)

• 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.

  PMID: 31433059 RESULT

MeSH Terms

Conditions

Bacterial Infections; Urinary Tract Infections; Pyelonephritis; Infections

Interventions

Ceftriaxone; Sulbactam; Edetic Acid; Meropenem

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Nephritis, Interstitial; Nephritis; Kidney Diseases; Pyelitis

Intervention Hierarchy (Ancestors)

Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Penicillins; Ethylenediamines; Diamines; Polyamines; Amines; Acetates; Acids, Acyclic; Carboxylic Acids; Thienamycins; Carbapenems

Study Officials

• Rajeev Sood

  PGIMER Dr. RML Hospital, Baba Kharak Singh Marg, Connaught Place, New Delhi- 110001, India

  PRINCIPAL INVESTIGATOR

• Kim Mammen

  Christian Medical College & Hospital, Ludhiana, Punjab-141008, India

  PRINCIPAL INVESTIGATOR

• R.P Agrawal

  S.P. Medical College, Bikaner- 334003, Rajasthan, India

  PRINCIPAL INVESTIGATOR

• Manjunath M

  Sapthagiri Institute of Medical Sciences and Research Center, #15, Chikkasandra, Hesaragatta Main Road, Bangalore-560 090, Karnataka, India

  PRINCIPAL INVESTIGATOR

• Pratibha Phadke

  Deenanath Mangeshkar Hospital and Research Centre, Erandwane, Pune - 411004

  PRINCIPAL INVESTIGATOR

• Sudhir Chadha

  Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi- 110060, India

  PRINCIPAL INVESTIGATOR

• A.K. Deb

  Sudbhawana Hospital, B 31/8023-B, Bhogabir, Lanka, Varanasi- 221005, India

  PRINCIPAL INVESTIGATOR

• Dharamraj Maurya

  M.V. Hospital and Research Centre, 314/30, Mirza Mandi, Chowk, Lucknow- 226003, India

  PRINCIPAL INVESTIGATOR

• Deepak Dewan

  Ajanta Hospital & Research Centre, 765, ABC Complex, Kanpur Road, Alambagh, Lucknow-Uttar Pradesh, 226005, India.

  PRINCIPAL INVESTIGATOR

• Shalini Srivastava

  Om Surgical Centre and Maternity Home, SA 17/3, P-4, Sri Krishna Nagar, Paharia, Ghazipur Road, Varanasi- 221007, India

  PRINCIPAL INVESTIGATOR

• Ram Murti Singh

  Trimurti Hospital, Gilat Bazaar, Varanasi- 221002, India

  PRINCIPAL INVESTIGATOR

• Rahul Janak Sinha

  King George's Medical University (KGMU), Lucknow-226003, India

  PRINCIPAL INVESTIGATOR

• Madhav Prabhu

  KLES, Dr Prabhakar Kore Hospital and Medical Centre, Nehru Nagar, Belagavi- 590010, Belgaum, Karnataka, India

  PRINCIPAL INVESTIGATOR

• Mohd. Shameem

  J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

  PRINCIPAL INVESTIGATOR

• Prem Nath Dogra

  All India Institute of Medical Science, Ansari Nagar, New Delhi- 110029, India

  PRINCIPAL INVESTIGATOR

• Ravimohan S Mavuduru

  P. G. I. M. E. R., Sector 12, Chandigarh-160012, India

  PRINCIPAL INVESTIGATOR

• Parvaiz Koul

  SKIMS, Srinagar, Jammu & Kashmir- 190011, India

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 9, 2018
• First Posted: March 26, 2018
• Study Start: January 11, 2014
• Primary Completion: May 8, 2017
• Study Completion: May 8, 2017
• Last Updated: August 29, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

IN (17)