Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous Ertapenem in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)
Condition: Complicated Urinary Tract Infection; Acute Pyelonephritis
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis
Intervention: TBPM-PI-HBr; Ertapenem; Dummy Infusion; Dummy tablets
Intervention description: TBPM-PI-HBr tablets administered orally.; Antibiotic Therapy for cUTI.; Dummy intravenous infusion.; Dummy tablets orally.
Intervention MeSH terms: Ertapenem
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1372.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Complicated Urinary Tract Infection; Acute Pyelonephritis

Summary:

      The key purpose of this study is to evaluate the efficacy, safety and pharmacokinetics (PK)
      of tebipenem pivoxil hydrobromide (TBPM-PI-HBr) compared to intravenous (IV) ertapenem, in
      participants with complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP).
    

Eligibility criteria:

        Inclusion Criteria

          1. Male and female participants at least 18 years of age.

          2. Able to provide informed consent.

          3. Able to ingest oral tablets for the anticipated treatment duration. If present at
             baseline, nausea and/or vomiting should have been mild or well-controlled with
             antiemetic therapy, in order to tolerate oral study drug.

          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 participants

             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 end of the treatment [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 participants.

             iv. Dysuria, urgency to void, or increased urinary frequency.

             Note: Participants 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: Participants could be
                  randomized and administered investigational product (IP) prior to knowledge of
                  urine culture results.

          6. Expectation, in the judgment of the Investigator, that the participant would 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. Participants were required to use a highly-effective method of birth control; male
             participants were required to use an effective barrier method of contraception from
             Screening through LFU and for 90 days following the last dose if sexually active with
             a female of childbearing potential (FOCP); female participants must not have been
             pregnant or nursing, and were required to 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 have confounded the assessment of efficacy, including but not
             limited to the following:

               1. Perinephric or renal corticomedullary abscess.

               2. Uncomplicated urinary tract infection (cUTI) - (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 ≤30 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
             started within 72 h prior to randomization.

             Exception: Participants 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. Had a documented uropathogen (growth in urine culture >10^5 CFU/mL) that is
                  resistant to the prior antibiotic therapy.

               3. Had a documented uropathogen that is carbapenem-susceptible.

               4. Received approval from the Medical Monitor to enroll the participants.

          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 and or acquired
             immunodeficiency syndrome (AIDS)-defining illness, or known history of HIV infection
             and known CD4 count <200/mm^3 within the past year.

         14. Presence of immunodeficiency or an immunocompromised condition including neutropenia
             (<1,000 neutrophils/mm^3 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.