A Phase 3 study to assess efficacy and safety of oral tebipenem compared to IV imipenem-cilastatin in adults with cUTI/AP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Spero Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

25 Mar 2024 → 29 May 2025

Decision date (initial)

2024-02-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Spero Therapeutics, Inc.

External identifiers

EU CT number

2023-503785-22-00

WHO UTN

U1111-1289-9311

ClinicalTrials.gov

NCT06059846

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to the overall response (combined clinical cure plus microbiological eradication) at the Test-of-Cure (TOC) visit in hospitalized adult patients (≥18 years of age) with cUTI/AP

Secondary objectives 12

1. To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to overall response rates at the TOC visit in patients with cUTI/AP in the Microbiologically Evaluable (ME) Population.
2. To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to overall response rates at End-of- Treatment (EOT) and Late Follow-up (LFU) visits in patients with cUTI/AP.
3. To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to clinical response rates at EOT, TOC, and LFU visits in patients with cUTI/AP.
4. To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to microbiological response rates at EOT, TOC, and LFU visits in patients with cUTI/AP
5. To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to overall, clinical and microbiological response rates at TOC, EOT and LFU visits among cUTI/AP patients infected with drug-resistant Enterobacterales uropathogens, e.g., extended spectrum β-lactamase (ESBL)-producing, fluoroquinolone-nonsusceptible (FQ-NS), and/or trimethoprimsulfamethoxazole- resistant (TMP-SMX-R) strains
6. To assess the safety and tolerability of oral TBP-PI-HBr as compared to IV imipenem-cilastatin in patients with cUTI/AP
7. To provide tebipenem (TBP) plasma concentration data to characterize the pharmacokinetics (PK) of TBP in the target population using PK modelling
8. Exploratory: To explore the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to clinical response and microbiological response at Day 5 in patients with cUTI/AP
9. Exploratory: To explore the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to the time to defervescence in patients with a documented fever at Screening or Day 1 in patients with cUTI/AP
10. Exploratory: To explore the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to rates of superinfection and new infection in patients with cUTI/AP
11. Exploratory: To explore the concentration data of TBP or imipenem in urine for an assessment of the urine concentrations relative to patient outcomes
12. Exploratory: To explore the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to patient outcomes using a Desirability of Outcome Ranking (DOOR) ordinal endpoint in patients with cUTI/AP

Conditions and MedDRA coding

complicated urinary tract infection (cUTI) or acute pyelonephritis (AP)

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. male and female patients at least 18 years of age, patients enrolled in India must be ≤90 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 be mild or well controlled with antiemetic therapy
4. 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.
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: • 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
6. 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
7. willing to comply with all the study activities and procedures throughout the duration of the study
8. 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
9. 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 20

1. 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)
2. history of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures)
3. history of proven or suspected Clostridioides difficile associated diarrhea
4. gross hematuria requiring intervention other than administration of study drug or removal/placement of urinary tract instrumentation
5. 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
6. 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)
7. creatinine clearance (CrCl) of ≤30 mL/min
8. 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
9. receipt of a potentially effective antimicrobial within 72 h prior to study randomization
10. 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)
11. pregnant or lactating women
12. receipt of any investigational device or 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 with known CD4 count <200/mm3 or acquired immunodeficiency syndrome (AIDS)-defining illness 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. QT interval corrected using Fridericia’s formula (QTcF) >480 msec based on screening electrocardiogram (ECG)
16. 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
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall response (combined per-patient clinical cure and favorable microbiological response) at the TOC visit in the micro-ITT Population

Secondary endpoints 12

1. Overall response at the TOC visit in the ME Population
2. Overall response at the EOT and LFU visits in the micro-ITT and ME Populations
3. Clinical response at the EOT, TOC and LFU visits in the micro-ITT, Clinically Evaluable (CE) and ME Populations
4. Microbiological response at the EOT, TOC and LFU visits in the micro-ITT and ME Populations
5. Overall, Clinical and Microbiological response at the TOC, EOT and LFU visits in the micro-ITT and ME Populations in patients with drug resistant Enterobacterales
6. Treatment-emergent AEs (TEAEs) and SAEs and change from Baseline results for clinical laboratory tests, ECGs, and vital sign measurements in the Safety Population
7. TBP plasma concentration in the TBP PK Population
8. Exploratory: Clinical response and Microbiological response at Day 5 in the micro-ITT Population
9. Exploratory: Time (days) to defervescence in patients with a documented fever at Screening or Day 1 in the micro-ITT Population
10. Exploratory: Occurrence of superinfection and new infection in the micro-ITT Population
11. Exploratory: TBP or imipenem concentration in urine in the Urine PK Population subgroup
12. Exploratory: Composite ordinal endpoint (DOOR) at TOC and LFU in the micro-ITT Population

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Spero Therapeutics Inc.

Sponsor organisation

Spero Therapeutics Inc.

Address

675 Massachusetts Avenue

City

Cambridge

Postcode

02139-3309

Country

United States

Scientific contact point

Organisation

Spero Therapeutics Inc.

Contact name

David Hong

Public contact point

Organisation

Spero Therapeutics Inc.

Contact name

David Hong

Third parties 14

Locations

9 EU/EEA countries · 67 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 34 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications