A Clinical Trial to Evaluate the Safety and Efficacy of Sulbactam-ETX2514, a new drug, for the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis

Phase 1

Conditions: Complicated Urinary Tract Infection including Acute Pyelonephritis
MedDRA version: 20.0Level: PTClassification code 10037597Term: Pyelonephritis acuteSystem Organ Class: 10021881 - Infections and infestations
MedDRA version: 20.0Level: HLTClassification code 10046577Term: Urinary tract infectionsSystem Organ Class: 100000005053
Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Registration Number: EUCTR2017-002608-29-BG

Lead Sponsor: Entasis Therapeutics

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 80

Inclusion Criteria

1. A signed informed consent form (ICF). If a study patient is unable to provide informed consent due to their medical condition, the patient’s legally authorized representative may consent on behalf of the study patient as permitted by local law and institutional Standard Operating Procedures;
2. Male or female, 18 to 90 years of age, inclusive;
3. Expectation, in the judgment of the Investigator, that the patient’s cUTI would require initial hospitalization and treatment with intravenous (IV) antibiotics;
4.Documented or suspected cUTI or AP, as defined below:
o cUTI
?Signs or symptoms evidenced by at least 2 of the following:
- Documented fever accompanied by chills, rigors, or warmth;
- Nausea or vomiting within 24 hours of Screening, as reported by the patient;
- Dysuria, increased urinary frequency, or urinary urgency; or
- Lower abdominal pain, pelvic pain, or suprapubic tenderness on physical examination;
?And urine specimen with evidence of pyuria:
- Positive leukocyte esterase on urinalysis; or
- White blood cell count =10 cells/mm3 in unspun urine; or
- White blood cell count =10 cells/high-power field (hpf) in urine sediment;
?And at least 1 of the following associated risks:
- Use of intermittent bladder catheterization or presence of an indwelling bladder catheter;
- Current known functional or anatomical abnormality of the urogenital tract, including anatomic malformations or neurogenic bladder, or with a post-void residual urine volume of =100 mL;
- Complete or partial obstructive uropathy (eg, nephrolithiasis, tumor, fibrosis, urethral stricture) that is expected to be medically or surgically treated during study drug therapy (prior to End of Treatment [EOT]);
- Azotemia, defined as blood urea nitrogen >20 mg/dL, blood urea >42.8 mg/dL, or serum creatinine >1.4 mg/dL, due to known prior intrinsic renal disease; or
- Chronic urinary retention in men (eg, previously diagnosed benign prostatic hypertrophy);
o AP
?Signs or symptoms evidenced by at least 2 of the following:
- Documented fever accompanied by chills, rigors, or warmth;
- Nausea or vomiting within 24 hours of Screening, as reported by the patient;
- Dysuria, increased urinary frequency, or urinary urgency; or
- Acute flank pain (onset within 7 days prior to randomization) or costo-vertebral angle tenderness on physical examination;
?And urine specimen with evidence of pyuria:
- Positive leukocyte esterase on urinalysis; or
- White blood cell count =10 cells/mm3 in unspun urine; or
- White blood cell count =10 cells/hpf in urine sediment;
5. Have a baseline urine culture specimen obtained within 48 hours prior to randomization;
6. Expectation, in the judgment of the Investigator, that any implanted urinary instrumentation (eg, nephrostomy tubes, ureteric stents) will be surgically removed or replaced before or within 24 hours after randomization, unless removal or replacement is considered unsafe or contraindicated;
7. Expectation, in the judgment of the Investigator, that the patient will survive with effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study;
8. Women of childbearing potential (ie, not post-menopausal or surgically sterilized) must have a negative pregnancy test (serum or urine) before randomization. Participating women of childbearing potential must be willing to consistently use 2 highly effective methods of contraception (ie, condom plus spermicide, combined oral

Exclusion Criteria

1. Presence of any known or suspected disease or condition that, in the opinion of the Investigator, may confound the assessment of efficacy, including but not limited to the following:
o Perinephric abscess;
o Renal corticomedullary abscess;
o Uncomplicated urinary tract infection (UTI);
o Any recent history of trauma to the pelvis or urinary tract;
o Polycystic kidney disease;
o Chronic vesicoureteral reflux;
o Previous or planned renal transplantation;
o Patients receiving dialysis, including hemodialysis, peritoneal dialysis, or continuous veno-venous hemofiltration;
o Previous or planned cystectomy or ileal loop surgery; and
o Known or suspected infection that is caused by a pathogen(s) that is known to be resistant to imipenem or ß-lactam/ß-lactamase inhibitor combinations, including infection caused by fungi (eg, candiduria) or mycobacteria (eg, urogenital tuberculosis);
2. Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
3. Gross hematuria requiring intervention other than administration of study drug or removal or exchange of a urinary catheter;
4. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required to relieve an obstruction or place a stent or nephrostomy prior to EOT);
5. Renal function at Screening as estimated by creatinine clearance <70 mL/min using the Cockcroft-Gault formula and serum creatinine value obtained from a local laboratory;
6. Known non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization that would interfere with evaluation of response to the study antibiotics;
7. Any signs of severe sepsis, including but not limited to the following:
o Shock or profound hypotension defined as systolic blood pressure <90 mmHg or a decrease of >40 mmHg from baseline (if known) that is not responsive to fluid challenge; or
o Disseminated intravascular coagulation as evidenced by prothrombin time or partial thromboplastin time ?=2 x the upper limit of normal (ULN) or <50,000 platelets/mm3 at Screening in patients in whom severe sepsis is suspected;
8. Pregnant or breastfeeding women;
9. Known seizure disorder requiring current treatment with anti-seizure medication which, in the opinion of the Investigator, would prohibit the patient from complying with the protocol. Patients with a history of epilepsy or who are on stable treatment (ie, no change in therapy within 30 days) with well controlled seizure disorder (ie, no recurrent episodes in the past 30 days) may be considered for enrollment in the study;
10. Treatment within 30 days prior to randomization with any cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation;
11. Patient requires continuing treatment with probenecid, methotrexate, ganciclovir, valproic acid, or divalproex sodium during the study;
12. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy;
13. Aspartate aminotransferase or alanine aminotransferase >3 x ULN or total bilirubin >2 x ULN at Screening;
14. Receipt of a single dose of a long-acting, potentially-effective systemic antibiotic with activity against Gram-negative uropathogens for more than 24

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the safety profile of ETX2514SUL versus placebo in patients with cUTI, including AP;Secondary Objective: • To evaluate the efficacy of ETX2514SUL in patients with cUTI, including AP, in the microbiologically modified Intent-to-Treat (m-MITT) Population;<br>• To compare the clinical cure rate in the 2 treatment groups in the modified Intent-to-Treat (MITT), m-MITT, Clinical Evaluable (CE), and Microbiological Evaluable (ME) Populations at the Test-of-Cure (TOC) Visit; and<br>• To compare the microbiological eradication rate in the m-MITT and ME Populations at the TOC Visit.<br>;Primary end point(s): The proportion of patients with an overall success (clinical cure and microbiologic eradication) in the m-MITT Population at the TOC Visit;Timepoint(s) of evaluation of this end point: Test of Cure Visits (7 days after the End of the Trial)

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Proportion of patients with a response of clinical cure in the Modified Intent-to-Treat (MITT), m-MITT, Clinical Evaluable (CE), and Microbiologic Evaluable (ME) Populations at the TOC Visit; and<br>• Proportion of patients with a response of microbiologic eradication in the m-MITT and ME Populations at the TOC Visit.<br>;Timepoint(s) of evaluation of this end point: Test of Cure Visits (7 days after the End of the Trial)