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)

Spero Therapeutics1,372 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

1,372

Conditions

Complicated Urinary Tract Infection Acute Pyelonephritis

Interventions

TBPM-PI-HBr

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (96)

Medical Facility

La Mesa, California, United States

Medical Facility

Miami, Florida, United States

Medical Facility

Blagoevgrad, Bulgaria

Medical Facility

Dobrich, Bulgaria

Medical Facility

Rousse, Bulgaria

Medical Facility

Shumen, Bulgaria

Outcomes

Primary Outcomes

Overall Response (Combined Clinical Cure and Microbiological Eradication) at Test-of-Cure (TOC) in Micro Intent-to-Treat Population

Overall response is participants with combined clinical cure and microbiological eradication. Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 colony forming unit/milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.

Time frame: Day 19 (TOC)

Number of Participants With Treatment Emergent Adverse Events (TEAEs) in The Safety Population

An Adverse Event (AE) was defined as any untoward medical occurrence in a subject or clinical investigation participant administered a pharmaceutical product, which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational/experimental) product, whether or not related to this product.

Time frame: From the first dose of administration up to Day 25 post-treatment ± 2 days (up to approximately 27 days)

Secondary Outcomes

Overall Response (Combined Clinical Cure Plus Microbiological Eradication) At Test-Of-Cure (TOC) In The Microbiologically Evaluable (ME) - TOC Population

Overall response is participants with combined clinical cure and microbiological eradication. Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of cUTI or acute pyelonephritis (AP) that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.

Time frame: Day 19 (TOC)

Clinical Cure at End-of-Treatment (EOT), TOC, and Sustained Clinical Cure at Late Follow-Up (LFU) Days in the Micro-ITT Populations

Clinical cure is defined as number of participants with complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted. Sustained clinical cure is defined as participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.

Time frame: Days 15 (EOT), Day 19 (TOC) and Day 25 (LFU)

Clinical Cure at EOT Days the Clinically Evaluable (CE-EOT) Populations

Time frame: Day 15 (EOT)

Clinical Cure at TOC in the CE-TOC Populations

Time frame: Day 19 (TOC)

Sustained Clinical Cure at LFU in the CE-LFU Populations

Clinical cure is defined as number of participants with complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted. Sustained clinical cure is defined as number of participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.

Time frame: Day 25 (LFU)

Clinical Cure at EOT in the ME-EOT Populations

Time frame: Day 15 (EOT)

Clinical Cure at TOC Days in the ME-TOC Populations

Time frame: Day 19 (TOC)

Sustained Clinical Cure at LFU in the ME-LFU Population

Time frame: Day 25 (LFU)

By-Patient Microbiological Eradication at EOT, TOC, and Sustained Microbiological Eradication at LFU Days in the Micro-ITT Population

Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication is defined as number of participants with reduction of Baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline. Sustained Microbiological Eradication is defined as number of participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL.

Time frame: Days 15 (EOT), 19 (TOC) and 25 (LFU)

By-Pathogen Microbiological Eradication Rate at EOT in the Micro-ITT Population

Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.

Time frame: Days 15 (EOT)

By-Pathogen Microbiological Eradication Rate at TOC in the Micro-ITT Population

Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.

Time frame: Day 19 (TOC)

By-Pathogen Sustained Microbiological Eradication Rate at LFU in the Micro-ITT Population (m-ITT)

Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined as microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogen analyzed.

Time frame: Day 25 (LFU)

By-Patient Microbiological Eradication at EOT in the ME-EOT Populations

Time frame: Day 15 (EOT)

By-Patient Microbiological Eradication at TOC in the ME-TOC Population

Time frame: Day 15 (TOC)

By-Patient Sustained Microbiological Eradication at LFU Days in the ME-LFU Populations

Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to \<10\^3 colony forming unit/milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL.

Time frame: Day 25 (LFU)

By-pathogen Microbiological Eradication Rate in Participants at EOT in the ME-EOT Populations

Time frame: Day 15 (EOT)

By-pathogen Microbiological Eradication Rate in Participants at TOC in the ME-TOC Populations

Time frame: Day 19 (TOC)

By-pathogen Sustained Microbiological Eradication Rate in Participants at LFU in the ME-LFU Populations

Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL.Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogen analyzed.

Time frame: Day 25 (LFU)

Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) In Subgroup Including: Stratified Infection Category

Overall response rate is percentage of participants with combined clinical cure plus microbiological eradication. Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 colony forming unit/milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.

Time frame: Day 19 (TOC)

Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Stratified Age Category

Overall response rate is percentage of participants with combined clinical cure plus microbiological eradication. Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.

Time frame: Day 19 (TOC)

Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Including Region

Time frame: Day 25 (LFU)

Time (Days) to Resolution or Improvement of Signs and Symptoms of cUTI and AP Present a Baseline in the Micro-ITT Populations

Time (days) to resolution or improvement of signs and symptoms of cUTI and AP present at baseline was defined as follows: date of the first visit at which all baseline signs/symptoms have improved by at least 1 grade with worsening of none and development of no new signs/symptoms of the index infection minus the date of randomization.

Time frame: Day 25 (LFU)

Time (Days) to Defervescence in Micro-ITT Population With a Documented Fever at Screening or Day 1

Time to Defervescence (days) = date of first post-baseline temperature measure with maximum daily Temperature ≤38°C at the date of randomization.

Time frame: Day 25 (LFU)

Rate of Clinical Relapse at the LFU Days in the Micro-ITT Population

Clinical relapse is participants who met criteria for clinical cure at TOC, but new signs and symptoms of cUTI or AP are present at the LFU Visit and the subject requires antibiotic therapy for the cUT. Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted.

Time frame: Day 25 (LFU)

Rates Of Superinfection And New Infection In The Micro-ITT Population

Superinfection was isolation of a new uropathogen at ≥105 CFU/mL (other than the original Baseline pathogen\[s\] from blood and/or urine) from a urine culture that was accompanied by clinical signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., the participant was assessed by the investigator as a clinical failure) during the period up to and including EOT. New infection was isolation of a new uropathogen at ≥105 CFU/mL (other than the original baseline pathogen\[s\] from blood and/or urine) from a urine culture that was accompanied by clinical signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., the participant was assessed by the Investigator as a clinical failure) in the period after EOT.

Time frame: Day 25 (LFU)

Apparent Volume of Distribution (Vss) at Steady State in TBPM-PI-HBr Recipients in the Pharmacokinetic (PK) Population