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

NCT ID: NCT03477422

Last Updated: 2019-08-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 230 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-01-11
• Study Completion Date: 2017-05-08

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.

Conditions

Urinary Tract Infection Complicated; Acute Pyelonephritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

CSE-1034 (Ceftriaxone + Sulbactam + EDTA)

Intervention Type: 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.

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

Group Type: ACTIVE_COMPARATOR

Meropenem

Intervention Type: 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.

Interventions

CSE-1034 (Ceftriaxone + Sulbactam + EDTA)

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.

Intervention Type: DRUG

Meropenem

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.

Intervention Type: DRUG

Other Intervention Names

Elores; Meronem

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Venus Remedies Limited

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rajeev Sood

Role: PRINCIPAL_INVESTIGATOR

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

Kim Mammen

Role: PRINCIPAL_INVESTIGATOR

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

R.P Agrawal

Role: PRINCIPAL_INVESTIGATOR

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

Manjunath M

Role: PRINCIPAL_INVESTIGATOR

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

Pratibha Phadke

Role: PRINCIPAL_INVESTIGATOR

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

Sudhir Chadha

Role: PRINCIPAL_INVESTIGATOR

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

A.K. Deb

Role: PRINCIPAL_INVESTIGATOR

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

Dharamraj Maurya

Role: PRINCIPAL_INVESTIGATOR

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

Deepak Dewan

Role: PRINCIPAL_INVESTIGATOR

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

Shalini Srivastava

Role: PRINCIPAL_INVESTIGATOR

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

Ram Murti Singh

Role: PRINCIPAL_INVESTIGATOR

Trimurti Hospital, Gilat Bazaar, Varanasi- 221002, India

Rahul Janak Sinha

Role: PRINCIPAL_INVESTIGATOR

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

Madhav Prabhu

Role: PRINCIPAL_INVESTIGATOR

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

Mohd. Shameem

Role: PRINCIPAL_INVESTIGATOR

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

Prem Nath Dogra

Role: PRINCIPAL_INVESTIGATOR

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

Ravimohan S Mavuduru

Role: PRINCIPAL_INVESTIGATOR

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

Parvaiz Koul

Role: PRINCIPAL_INVESTIGATOR

SKIMS, Srinagar, Jammu & Kashmir- 190011, India

Locations

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

Srinagar, Jammu and Kashmir, India

Sapthagiri Institute of Medical Sciences and Research Center

Bangalore, Karnataka, India

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

Belagavi, Karnataka, India

Deenanath Mangeshkar Hospital and Research Centre

Pune, Maharashtra, India

Christian Medical College & Hospital

Ludhiana, Punjab, India

S.P. Medical College

Bikaner, Rajasthan, India

J. N. Medical College, Aligarh Muslim University

Aligarh, Uttar Pradesh, India

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

Lucknow, Uttar Pradesh, India

M.V. Hospital and Research Centre

Lucknow, Uttar Pradesh, India

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

Lucknow, Uttar Pradesh, India

Trimurti Hospital

Varanasi, Uttar Pradesh, India

Sudbhawana Hospital

Varanasi, Uttar Pradesh, India

Om Surgical Centre and Maternity Home

Varanasi, Uttar Pradesh, India

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

Chandigarh, , India

PGIMER Dr. RML Hospital

New Delhi, , India

All India Institute of Medical Science

New Delhi, , India

Sir Ganga Ram Hospital

New Delhi, , India

Countries

India

References

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.

Reference Type: RESULT

PMID: 31433059 (View on PubMed)

Other Identifiers

CTRI/2013/11/004133

Identifier Type: REGISTRY

Identifier Source: secondary_id

VRL/CSE-1034/05/2012

Identifier Type: -

Identifier Source: org_study_id