Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous Ertapenem in Patients With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)

• Status: Completed
• Trial end date: 2020-05-27
• Target enrollment: 0
• Participant gender: All

Summary

The key purpose of this study is to evaluate the efficacy, safety and pharmacokinetics (PK) of TBPM-PI-HBr compared to IV ertapenem, in subjects with Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP).

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Spero Therapeutics
• Treatments: Ertapenem

Criteria

Inclusion Criteria

1. Male and female subjects at least 18 years of age

2. Able to provide informed consent

3. Able to ingest oral tablets for the anticipated treatment duration

4. Have a diagnosis of cUTI or AP as defined below:

a. cUTI definition:

At least Two of the following signs and symptoms:

i. Chills, rigors, or fever; fever must be observed and documented by a health care provider (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F])

ii. Dysuria, urgency to void, or increased urinary frequency

iii. Nausea or vomiting, as reported by the subject

iv. Lower abdominal, suprapubic, or pelvic pain

And at least One of the following risk factors for cUTI:

i. Implanted urinary tract instrumentation (e.g., nephrostomy tube, ureteric stents, or other urinary tract prosthetic material), ongoing intermittent bladder catheterization, or presence of an indwelling bladder catheter (Note: bladder catheters that have been in place for >24 hours prior to Screening must be removed or replaced prior to collection of the Screening urine for urinalysis and culture, unless removal or replacement is considered unsafe or contraindicated)

ii. Current known functional or anatomical abnormality of the urogenital tract, including anatomic abnormalities of the urinary tract, neurogenic bladder, or post-void residual urine volume of ≥ 100 mL within the past 6 months

iii. Complete or partial obstructive uropathy (e.g., nephrolithiasis, tumor, fibrosis, urethral stricture) that is expected to be medically or surgically treated during study drug therapy (prior to EOT)

iv. Known intrinsic renal disease with blood urea nitrogen (BUN) >20 mg/deciliter (dL), or blood urea >42.8 mg/dL, or serum creatinine (Cr) >1.4 mg/dL

v. Urinary retention, including urinary retention in men due to previously diagnosed benign prostatic hyperplasia (BPH)

b. AP definition: Acute flank pain (onset within 7 days prior to randomization) or costovertebral angle tenderness on physical examination.

And at least One of the following signs and symptoms:

i. Chills, rigors, or fever; fever must be observed and documented by a health care provider (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F])

ii. Peripheral white blood cell count (WBC) >10,000/mm3 or bandemia (≥15% immature polymorphonuclear neutrophils (PMNs), regardless of WBC count)

iii. Nausea or vomiting, as reported by the subject

iv. Dysuria, urgency to void, or increased urinary frequency

Note: Subjects who meet the definition for cUTI (Inclusion Criterion 4a) and also have flank pain or costovertebral tenderness should be randomized as cUTI rather than AP.

5. Have an adequate urine specimen for evaluation and culture obtained within 24 h prior to randomization with evidence of pyuria that includes at least one of the following:

1. At least 10 WBCs per high power field (hpf) in urine sediment

2. At least 10 WBCs per cubic millimeter (mm3) in unspun (non centrifuged) urine

3. Positive leukocyte esterase (LE) on urinalysis

Note: Subjects may be randomized and administered investigational product (IP) prior to knowledge of urine culture results.

6. Expectation, in the judgment of the Investigator, that the subject will survive with effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study

7. Willing to comply with all the study activities and procedures throughout the duration of the study

8. Subjects must agree to use a highly-effective method of birth control; male subjects must agree to use an effective barrier method of contraception from Screening through late follow-up (LFU) and for 90 days following the last dose if sexually active with a female of childbearing potential (FOCP); female subjects must not be pregnant or nursing, and must commit to either sexual abstinence or use at least two medically accepted, effective methods of birth control (e.g., condom, spermicidal gel, oral contraceptive, indwelling intrauterine device, hormonal implant/patch, injections, approved cervical ring) from Screening through LFU and for 90 days following the last dose.

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:

1. Perinephric or renal corticomedullary abscess

2. Uncomplicated urinary tract infection (uUTI) - (acute cystitis that does not meet the cUTI disease definition, see Inclusion Criterion 4a)

3. Polycystic kidney disease

4. Recent history of trauma to the pelvis or urinary tract

5. Confirmed or suspected acute or chronic bacterial prostatitis, orchitis, or epididymitis

6. Chronic vesicoureteral reflux

7. Previous or planned renal transplantation

8. Previous or planned cystectomy or ileal loop surgery

9. Known or suspected non-renal source of infection (e.g., infective endocarditis, osteomyelitis, meningitis, pneumonia)

10. Confirmed or suspected infection that is caused by a pathogen that is resistant to either IP (e.g., carbapenem-resistant pathogen), including infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis)

2. Gross hematuria requiring intervention other than administration of IP or removal/placement of urinary tract instrumentation

3. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required relieving an obstruction or placing urinary tract instrumentation)

4. Creatinine clearance (CrCl) of <50 mL/min, as estimated by the Cockcroft-Gault formula:

estimated Creatinine Clearance (eC_Cr) [mL/min]=((140-Age [yrs]) × Body Weight [kg] × [0.85 if Female])/(72 × Serum Creatinine [mg⁄dL])

5. Anticipated concomitant use of non-study antibacterial drug therapy between randomization and the LFU Visit that would potentially effect outcome evaluations of cUTI/ AP, including but not limited to antibacterials with potential activity versus uropathogens, antibacterial drug prophylaxis, and antibacterial bladder irrigation

6. Anticipated concomitant use of gastric acid-reducing medications between randomization and end-of-treatment (EOT), including proton pump inhibitors, histamine-2 receptor antagonists, and antacids

7. Receipt of more than a single dose of a short-acting potentially effective antibiotic within 72 h prior to randomization; no more than 25% of subjects will be enrolled who meet the above criterion

Exception: Subjects who received more than a single dose of short-acting potentially effective antibiotic within 72 h prior to randomization may be eligible for enrollment if they meet all of the following criteria:

1. In the opinion of the Investigator they have failed the prior antibiotic therapy (e.g., have worsening signs and symptoms of cUTI/AP)

2. Have a documented uropathogen (growth in urine culture >105 CFU/mL) that is resistant to the prior antibiotic therapy

3. Have a documented uropathogen that is carbapenem-susceptible

4. Receives approval from the Medical Monitor to enroll the subject

8. Severe hepatic impairment at Screening, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5x upper limit of normal (ULN) or total bilirubin >3x ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, hepatic encephalopathy)

9. Any signs of severe sepsis, including shock or profound hypotension defined as systolic blood pressure <90 mmHg or a decrease of >40 mmHg from baseline that is not responsive to fluid challenge

10. Pregnant or breastfeeding women

11. History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures)

12. Receipt of any investigational medication during the last 30 days or 5 half-lives, whichever is longer, prior to randomization

13. Known history of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-defining illness, or known cluster of differentiation 4 (CD4) count <200/mm3 within the past year

14. Presence of immunodeficiency or an immunocompromised condition including neutropenia (<1,000 neutrophils/mm3 obtained from the local laboratory at Screening), hematologic malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as cancer chemotherapy, medications for the rejection of transplantation, and long term use of systemic corticosteroids (e.g., ≥20 mg/day of prednisone or systemic equivalent for at least 2 weeks)

15. A mean QT interval corrected using Fridericia's formula (QTcF) >480 msec based on triplicate ECGs at Screening

16. History of significant hypersensitivity or allergic reaction to β-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems), product excipients (Mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and Opadry) or any contraindication to the use of ertapenem

17. History of known genetic metabolism anomaly associated with carnitine deficiency (e.g., carnitine transporter defect, methylmalonic aciduria, propionic acidemia)

18. Requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT

19. Unable or unwilling to comply with the protocol

20. An employee of the Investigator or study center with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as a family member of the employee or the Investigator