Clinical trial NCT03788967: 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)
Official title: A Phase 3, Randomized, Double-blind, Double-dummy, Multicenter, Prospective 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complicated Urinary Tract Infection
Acute Pyelonephritis
Keywords: Complicated Urinary Tract Infection
Acute Pyelonephritis
Lead sponsor: Spero Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-12-28
Enrollment: 1372
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Overall Response (Combined Clinical Cure and Microbiological Eradication) at Test-of-Cure (TOC) in Micro Intent-to-Treat Population
timeFrame: Day 19 (TOC)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) in The Safety Population
timeFrame: From the first dose of administration up to Day 25 post-treatment ± 2 days (up to approximately 27 days)
Secondary outcomes:
measure: Overall Response (Combined Clinical Cure Plus Microbiological Eradication) At Test-Of-Cure (TOC) In The Microbiologically Evaluable (ME) - TOC Population
timeFrame: Day 19 (TOC)
measure: Clinical Cure at End-of-Treatment (EOT), TOC, and Sustained Clinical Cure at Late Follow-Up (LFU) Days in the Micro-ITT Populations
timeFrame: Days 15 (EOT), Day 19 (TOC) and Day 25 (LFU)
measure: Clinical Cure at EOT Days the Clinically Evaluable (CE-EOT) Populations
timeFrame: Day 15 (EOT)
measure: Clinical Cure at TOC in the CE-TOC Populations
timeFrame: Day 19 (TOC)
measure: Sustained Clinical Cure at LFU in the CE-LFU Populations
timeFrame: Day 25 (LFU)
measure: Clinical Cure at EOT in the ME-EOT Populations
timeFrame: Day 15 (EOT)
measure: Clinical Cure at TOC Days in the ME-TOC Populations
timeFrame: Day 19 (TOC)
measure: Sustained Clinical Cure at LFU in the ME-LFU Population
timeFrame: Day 25 (LFU)
measure: By-Patient Microbiological Eradication at EOT, TOC, and Sustained Microbiological Eradication at LFU Days in the Micro-ITT Population
timeFrame: Days 15 (EOT), 19 (TOC) and 25 (LFU)
measure: By-Pathogen Microbiological Eradication Rate at EOT in the Micro-ITT Population
timeFrame: Days 15 (EOT)
measure: By-Pathogen Microbiological Eradication Rate at TOC in the Micro-ITT Population
timeFrame: Day 19 (TOC)
measure: By-Pathogen Sustained Microbiological Eradication Rate at LFU in the Micro-ITT Population (m-ITT)
timeFrame: Day 25 (LFU)
measure: By-Patient Microbiological Eradication at EOT in the ME-EOT Populations
timeFrame: Day 15 (EOT)
measure: By-Patient Microbiological Eradication at TOC in the ME-TOC Population
timeFrame: Day 15 (TOC)
measure: By-Patient Sustained Microbiological Eradication at LFU Days in the ME-LFU Populations
timeFrame: Day 25 (LFU)
measure: By-pathogen Microbiological Eradication Rate in Participants at EOT in the ME-EOT Populations
timeFrame: Day 15 (EOT)
measure: By-pathogen Microbiological Eradication Rate in Participants at TOC in the ME-TOC Populations
timeFrame: Day 19 (TOC)
measure: By-pathogen Sustained Microbiological Eradication Rate in Participants at LFU in the ME-LFU Populations
timeFrame: Day 25 (LFU)
measure: Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) In Subgroup Including: Stratified Infection Category
timeFrame: Day 19 (TOC)
measure: Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Stratified Age Category
timeFrame: Day 19 (TOC)
measure: Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Including Region
timeFrame: Day 25 (LFU)
measure: Time (Days) to Resolution or Improvement of Signs and Symptoms of cUTI and AP Present a Baseline in the Micro-ITT Populations
timeFrame: Day 25 (LFU)
measure: Time (Days) to Defervescence in Micro-ITT Population With a Documented Fever at Screening or Day 1
timeFrame: Day 25 (LFU)
measure: Rate of Clinical Relapse at the LFU Days in the Micro-ITT Population
timeFrame: Day 25 (LFU)
measure: Rates Of Superinfection And New Infection In The Micro-ITT Population
timeFrame: Day 25 (LFU)
measure: Apparent Volume of Distribution (Vss) at Steady State in TBPM-PI-HBr Recipients in the Pharmacokinetic (PK) Population
timeFrame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
measure: Cmax in TBPM-PI-HBr Recipients in the PK Population
timeFrame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
measure: Area Under Curve (AUC 0-24) in TBPM-PI-HBr Recipients in the PK Population
timeFrame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
measure: Minimum Concentration (Cmin) in TBPM-PI-HBr Recipients in the PK Population
timeFrame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
measure: Systemic Clearance (CL) in TBPM-PI-HBr Recipients in the PK Population
timeFrame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Other outcomes:
Locations:
city: La Mesa
country: United States
facility: Medical Facility
state: California
city: Miami
country: United States
facility: Medical Facility
state: Florida
city: Blagoevgrad
country: Bulgaria
facility: Medical Facility
city: Dobrich
country: Bulgaria
facility: Medical Facility
city: Ruse
country: Bulgaria
facility: Medical Facility
city: Shumen
country: Bulgaria
facility: Medical Facility
city: Sofia
country: Bulgaria
facility: Medical Facility
city: Sofia
country: Bulgaria
facility: Medical Facility
city: Veliko Tarnovo
country: Bulgaria
facility: Medical Facility
city: Karlovy Vary
country: Czechia
facility: Medical Facility
city: Liberec
country: Czechia
facility: Medical Facility
city: Prague
country: Czechia
facility: Medical Facility
city: Zlin
country: Czechia
facility: Medical Facility
city: Ústí Nad Labem
country: Czechia
facility: Medical Facility
city: Kohtla-Jarve
country: Estonia
facility: Medical Facility
city: Tallinn
country: Estonia
facility: Medical Facility
city: Voru
country: Estonia
facility: Medical Facility
city: Tbilisi
country: Georgia
facility: Medical Facility
city: Tbilisi
country: Georgia
facility: Medical Facility
city: Tbilisi
country: Georgia
facility: Medical Facility
city: Tbilisi
country: Georgia
facility: Medical Facility
city: Zestap'oni
country: Georgia
facility: Medical Facility
city: Budapest
country: Hungary
facility: Medical Facility
city: Budapest
country: Hungary
facility: Medical Facility
city: Nagykanizsa
country: Hungary
facility: Medical Facility
city: Nyíregyháza
country: Hungary
facility: Medical Facility
city: Tatabánya
country: Hungary
facility: Medical Facility
city: Riga
country: Latvia
facility: Medical Facility
city: Riga
country: Latvia
facility: Medical Facility
city: Valmiera
country: Latvia
facility: Medical Facility
city: Chisinau
country: Moldova, Republic of
facility: Medical Facility
city: Chisinau
country: Moldova, Republic of
facility: Medical Facility
city: Katowice
country: Poland
facility: Medical Facility
city: Kraków
country: Poland
facility: Medical Facility
city: Oswiecim
country: Poland
facility: Medical Facility
city: Wrocław
country: Poland
facility: Medical Facility
city: Łódź
country: Poland
facility: Medical Facility
city: Bucharest
country: Romania
facility: Medical Facility
city: Bucharest
country: Romania
facility: Medical Facility
city: Bucharest
country: Romania
facility: Medical Facility
city: Craiova
country: Romania
facility: Medical Facility
city: Iaşi
country: Romania
facility: Medical Facility
city: Oradea
country: Romania
facility: Medical Facility
city: Arkhangelsk
country: Russian Federation
facility: Medical Facility
city: Lomonosov
country: Russian Federation
facility: Medical Facility
city: Penza
country: Russian Federation
facility: Medical Facility
city: Pyatigorsk
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical Facility
city: Saint Petersburg
country: Russian Federation
facility: Medical facility
city: Smolensk
country: Russian Federation
facility: Medical Facility
city: Smolensk
country: Russian Federation
facility: Medical Facility
city: Vsevolozhsk
country: Russian Federation
facility: Medical Facility
city: Yaroslavl
country: Russian Federation
facility: Medical Facility
city: Belgrade
country: Serbia
facility: Medical Facility
city: Belgrade
country: Serbia
facility: Medical Facility
city: Kragujevac
country: Serbia
facility: Medical Facility
city: Novi Sad
country: Serbia
facility: Medical Facility
city: Vršac
country: Serbia
facility: Medical Facility
city: Bratislava
country: Slovakia
facility: Medical Facility
city: Galanta
country: Slovakia
facility: Medical Facility
city: Lučenec
country: Slovakia
facility: Medical Facility
city: Martin
country: Slovakia
facility: Medical Facility
city: Poprad
country: Slovakia
facility: Medical Facility
city: Svidník
country: Slovakia
facility: Medical Facility
city: Benoni
country: South Africa
facility: Medical Facility
city: Chatsworth
country: South Africa
facility: Medical Facility
city: Durban
country: South Africa
facility: Medical Facility
city: Johannesburg
country: South Africa
facility: Medical Facility
city: Middelburg
country: South Africa
facility: Medical Facility
city: Pretoria
country: South Africa
facility: Medical Facility
city: Cherkasy
country: Ukraine
facility: Medical Facility
city: Chernihiv
country: Ukraine
facility: Medical Facility
city: Dnipro
country: Ukraine
facility: Medical Facility
city: Ivano-Frankivs'k
country: Ukraine
facility: Medical Facility
city: Ivano-Frankivs'k
country: Ukraine
facility: Medical Facility
city: Kharkiv
country: Ukraine
facility: Medical Facility
city: Kharkiv
country: Ukraine
facility: Medical Facility
city: Lviv
country: Ukraine
facility: Medical Facility
city: Lviv
country: Ukraine
facility: Medical Facility
city: Mykolaiv
country: Ukraine
facility: Medical Facility
city: Odesa
country: Ukraine
facility: Medical Facility
city: Odesa
country: Ukraine
facility: Medical Facility
city: Uzhhorod
country: Ukraine
facility: Medical Facility
city: Vinnytsia
country: Ukraine
facility: Medical Facility
city: Zaporizhia
country: Ukraine
facility: Medical Facility
city: Zhytomyr
country: Ukraine
facility: Medical Facility
Study officials:
affiliation: Spero Therapeutics Inc
name: David Melnick, MD
role: STUDY_DIRECTOR
References:
citation: Eckburg PB, Muir L, Critchley IA, Walpole S, Kwak H, Phelan AM, Moore G, Jain A, Keutzer T, Dane A, Melnick D, Talley AK. Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection. N Engl J Med. 2022 Apr 7;386(14):1327-1338. doi: 10.1056/NEJMoa2105462.