Phase 3 Randomized Study of Tebipenem Pivoxil Hydrobromide vs. Imipenem-Cilastatin in Complicated Urinary Tract Infection and Acute Pyelonephritis
- Trial ID
- 2023-503785-22-00
- Protocol
- SPR994-305
- Sponsor
- Spero Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of oral tebipenem pivoxil hydrobromide (TBP-PI-HBr) compared to intravenous (IV) imipenem-cilastatin in terms of overall response, which includes both clinical cure and microbiological eradication, at the Test-of-Cure (TOC) visit in hospitalized adult patients with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP). This is clinically relevant as it aims to determine the effectiveness of an oral treatment option, potentially offering a more convenient and less invasive alternative to IV therapy for these conditions.
Secondary objectives include:
- Assessing the efficacy of oral TBP-PI-HBr compared to IV imipenem-cilastatin with respect to overall response rates at the End-of-Treatment (EOT) and Late Follow-up (LFU) visits in patients with cUTI/AP.
- Evaluating the clinical response rates at EOT, TOC, and LFU visits.
- Assessing microbiological response rates at EOT, TOC, and LFU visits.
- Evaluating the efficacy in patients with cUTI/AP infected with drug-resistant Enterobacterales uropathogens, such as extended spectrum β-lactamase (ESBL)-producing, fluoroquinolone-nonsusceptible (FQ-NS), and/or trimethoprim-sulfamethoxazole-resistant (TMP-SMX-R) strains.
- Assessing the safety and tolerability of oral TBP-PI-HBr compared to IV imipenem-cilastatin.
- Providing TBP plasma concentration data to characterize the pharmacokinetics (PK) of TBP in the target population using PK modeling.
- Exploring the efficacy of oral TBP-PI-HBr compared to IV imipenem-cilastatin with respect to clinical and microbiological response at Day 5, time to defervescence, rates of superinfection and new infection, urine concentration data relative to patient outcomes, and patient outcomes using a Desirability of Outcome Ranking (DOOR) ordinal endpoint.
Participants
The clinical trial involves a total of **1315 participants** who are adult patients aged 18 years and older, with a specific age cap of 90 years for those enrolled in India. The study population includes both **male and female** subjects, and does not involve any vulnerable populations. Participants are required to have a diagnosis of either **complicated urinary tract infection (cUTI)** or **acute pyelonephritis (AP)**. The selection criteria ensure that participants are capable of providing informed consent and can ingest oral tablets for the treatment duration. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants are expected to comply with all study activities and procedures, and those of childbearing potential must adhere to strict contraceptive measures throughout the study duration. The trial population was selected based on their medical condition and ability to meet the study's inclusion criteria, ensuring a focus on the efficacy of the treatment under investigation.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, double-dummy, multicenter, multinational study** to evaluate the efficacy and safety of orally administered **tebipenem pivoxil hydrobromide** compared to intravenously administered **imipenem-cilastatin** in patients with **complicated urinary tract infection (cUTI) or acute pyelonephritis (AP)**. The trial aims to assess the overall response, which includes both clinical cure and microbiological eradication, at the Test-of-Cure (TOC) visit. The study is expected to commence recruitment on February 1, 2024, and conclude by September 19, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, ability to provide informed consent, and diagnosis of cUTI or AP. The trial will include follow-up visits to monitor the participants' response to treatment and any adverse events. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.
The expected duration of participant involvement is approximately 10 days, corresponding to the maximum treatment period. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will ensure that all participants are monitored closely throughout the study to maintain the integrity of the data and the safety of the participants.
Treatment
The clinical trial involves the administration of **Tebipenem pivoxil** as the experimental medication. Tebipenem pivoxil is provided in the form of a **film-coated tablet** and is administered orally. The active substance in this medication is **tebipenem pivoxil hydrobromide**, a chemical compound. The maximum daily dose is 2400 mg, with a total maximum dose of 24000 mg over a treatment period of up to 10 days. The medication is produced by Spero Therapeutics Inc and is identified by the sponsor product code SPR994. Participant compliance with the dosing schedule is monitored throughout the trial.
As a comparator treatment, the trial utilizes **Imipenem and Cilastatin**, which is administered via **intravenous administration**. This medication is provided as a powder for solution for infusion, with each dose containing 500 mg of imipenem anhydrate and 500 mg of cilastatin. The maximum daily dose is 2000 mg, with a total maximum dose of 20000 mg over a 10-day treatment period. The active substances, imipenem anhydrate and cilastatin, are of chemical origin.
The trial also includes the use of a **placebo** to match Tebipenem pivoxil, provided in tablet form. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is designed to be indistinguishable from the active medication in appearance and administration.
Additionally, **Sodium Chloride** is used as a non-experimental treatment in the form of a **solution for infusion**. It serves as a standard-of-care therapy to maintain fluid balance in participants receiving intravenous treatments. The maximum daily dose is 4 units, with a total maximum dose of 40 units over the course of the trial. Sodium chloride is of chemical origin and is not the primary focus of the study but is used to support the administration of the comparator treatment.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the overall response, which is defined as a combination of clinical cure and favorable microbiological response at the Test-of-Cure (TOC) visit. This assessment will be conducted in the micro-ITT Population. The primary endpoint focuses on this overall response at the TOC visit. Secondary endpoints include the overall response at the TOC visit in the ME Population, as well as the overall response at the End-of-Treatment (EOT) and Long-term Follow-up (LFU) visits in both the micro-ITT and ME Populations. Additionally, clinical and microbiological responses will be evaluated at the EOT, TOC, and LFU visits across various populations, including the micro-ITT, Clinically Evaluable (CE), and ME Populations.
Exploratory endpoints will further assess clinical and microbiological responses at Day 5 in the micro-ITT Population, the time to defervescence in patients with documented fever at Screening or Day 1, and the occurrence of superinfection and new infection in the micro-ITT Population. The trial will also explore the concentration of TBP or imipenem in urine within the Urine PK Population subgroup and a composite ordinal endpoint (DOOR) at TOC and LFU in the micro-ITT Population. These assessments will be conducted using validated scales and laboratory tests at specified timepoints, ensuring a comprehensive evaluation of the efficacy of orally administered **tebipenem pivoxil hydrobromide** compared to intravenously administered imipenem-cilastatin in patients with complicated urinary tract infection or acute pyelonephritis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- male and female patients at least 18 years of age, patients enrolled in India must be ≤90 years of age
- able to provide informed consent
- able to ingest oral tablets for the anticipated treatment duration. If present at Baseline, nausea and/or vomiting should be mild or well controlled with antiemetic therapy
- have a diagnosis of cUTI or AP as defined below: a. cUTI definition: at least TWO of the following signs and symptoms: • chills, rigors, or fever (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F]); fever must be observed and documented by a health care provider • dysuria, urgency to void, or increased urinary frequency • nausea or vomiting, as reported by the patient • lower abdominal pain, suprapubic pain, pelvic pain or flank pain/costovertebral angle tenderness. AND at least ONE of the following risk factors for cUTI: • 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 h 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) • 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 milliliters (mL) within the past 6 months • 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 visit) • 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 • 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: • chills, rigors, or fever (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F]); fever must be observed and documented by a health care provider • peripheral white blood cell count (WBC) >10,000/cubic millimeter (mm3) or bandemia (>15% immature polymorphonuclear neutrophils [PMNs], regardless of WBC count) • nausea or vomiting, as reported by the patient • dysuria, urgency to void, or increased urinary frequency.
- 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: • at least 10 WBCs per high power field (HPF) in urine sediment • at least 10 WBCs per mm3 in unspun urine • positive leukocyte esterase (LE) on urinalysis. Note: Patients may be randomized and administered study drug prior to knowledge of urine culture results, but pyuria must be documented
- expectation, in the judgment of the Investigator, that the patient will survive with effective antimicrobial therapy and appropriate supportive care for the anticipated duration of the study
- willing to comply with all the study activities and procedures throughout the duration of the study
- willing to agree to use a highly effective method of birth control; male patients must agree to not engage in sexual activity with a female partner that could lead to pregnancy (i.e., heterosexual vaginal intercourse) or must agree to use an effective barrier method of contraception from Screening through the LFU visit and for 90 days following the last dose; females of childbearing potential (FOCP) must have a negative pregnancy test at Screening and agree to abstain from sexual activity that could lead to pregnancy (i.e., heterosexual vaginal intercourse or in vitro fertilization) from the time of Screening through the EOT visit, or agree to use a highly effective method of contraception from the time of Screening throughout the study (through the LFU visit). Highly effective methods of birth control include one or more of the following: • an approved hormonal contraceptive associated with inhibition of ovulation including oral, implantable, transdermal, injectable, intravaginal contraceptive used consistently for at least 1 month prior to study drug dosing • an intrauterine device or intrauterine hormone-releasing system • male sexual partner who has been vasectomized for at least 3 months prior to Screening and who has obtained a follow-up negative sperm count
- female of nonchildbearing potential based on at least 1 of the following criteria: • post-menopausal status defined as amenorrhea for at least 12 months prior to randomization • Follicle Stimulating Hormone (FSH) levels in the laboratory defined post-menopausal range; in the absence of amenorrhea for at least 12 months prior to randomization, at least two FSH measurements demonstrating levels in the post-menopausal range are required • patient report of surgical sterilization (i.e., bilateral tubal ligation, hysterectomy, bilateral oophorectomy/salpingectomy) at least 6 weeks prior to randomization
Exclusion Criteria
- presence of any known or suspected disease or condition that may confound the assessment of efficacy, including but not limited to the following: • perinephric or renal corticomedullary abscess • uncomplicated urinary tract infection (uUTI [acute cystitis that does not meet the cUTI disease definition; refer to Inclusion Criterion 4.a]) • polycystic kidney disease • recent history of trauma to the pelvis or urinary tract • confirmed or suspected acute or chronic bacterial prostatitis, orchitis, or epididymitis • chronic vesicoureteral reflux • previous or planned renal transplantation • previous or planned cystectomy or ileal loop surgery • known or suspected non-renal source of infection (e.g., infective endocarditis, osteomyelitis, meningitis, pneumonia) • confirmed or suspected infection that is caused by a pathogen that is resistant to either study drug (e.g., carbapenem-resistant pathogen), including infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis) or an intrinsically resistant bacterial species not expected to respond to oral IP or comparator IV (e.g., Pseudomonas species)
- history of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures)
- history of proven or suspected Clostridioides difficile associated diarrhea
- gross hematuria requiring intervention other than administration of study drug or removal/placement of urinary tract instrumentation
- urine Gram stain (if performed by site) fails to demonstrate a Gram negative bacillus (i.e., negative Gram stain or Gram stain demonstrating only a Gram-positive organism) Note: Urine Gram stain should be performed, if possible, to inform eligibility but is not mandatory for Screening
- urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required for relieving an obstruction or placing urinary tract instrumentation)
- creatinine clearance (CrCl) of ≤30 mL/min
- anticipated concomitant use of non-study antimicrobial drug therapy between randomization and the LFU visit that would potentially effect outcome evaluations of cUTI/AP, including but not limited to antimicrobials with potential activity against Gram-negative pathogens, antimicrobial drug prophylaxis, and antimicrobial bladder irrigation
- receipt of a potentially effective antimicrobial within 72 h prior to study randomization
- severe hepatic impairment at Screening, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>5×upper limit of normal (ULN) or total bilirubin >3×ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, hepatic encephalopathy)
- pregnant or lactating women
- receipt of any investigational device or investigational medication during the last 30 days or 5 half-lives, whichever is longer, prior to randomization
- known history of human immunodeficiency virus (HIV) infection with known CD4 count <200/mm3 or acquired immunodeficiency syndrome (AIDS)-defining illness within the past year
- 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)
- QT interval corrected using Fridericia’s formula (QTcF) >480 msec based on screening electrocardiogram (ECG)
- history of significant hypersensitivity or allergic reaction to β-lactam antimicrobials (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 imipenem-cilastatin
- history of known genetic metabolism anomaly associated with carnitine deficiency (e.g., carnitine transporter defect, methylmalonic aciduria, propionic acidemia)
- requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT
- unable or unwilling to comply with the protocol
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 01 Feb 2024 | 394 |
 Croatia | Not Recruiting | 01 Feb 2024 | 125 |
 Estonia | Not Recruiting | 01 Feb 2024 | 126 |
 Greece | Not Recruiting | 01 Feb 2024 | 138 |
 Hungary | Not Recruiting | 01 Feb 2024 | 104 |
 Latvia | Not Recruiting | 01 Feb 2024 | 105 |
 Poland | Not Recruiting | 01 Feb 2024 | 147 |
 Romania | Not Recruiting | 01 Feb 2024 | 210 |
 Slovakia | Not Recruiting | 01 Feb 2024 | 105 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Tebipenem pivoxil | Test | FILM-COATED TABLET | ORAL USE | 2400 | 10 | PRD7709263 |
SODIUM CHLORIDE | Placebo | — | SOLUTION FOR INFUSION | 4 | 10 | SUB12581MIG |
IMIPENEM AND CILASTATIN | Comparator | PHF00230MIG | INTRAVENOUS ADMINISTRATION | 2000 | 10 | SCP28152028 |
Placebo to match Tebipenem pivoxil, tablet | Placebo | N/A | — | — | — | N/A |