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)

NCT ID: NCT03788967

Last Updated: 2022-07-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1372 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-03
• Study Completion Date: 2020-05-27

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).

Conditions

Complicated Urinary Tract Infection; Acute Pyelonephritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

TBPM-PI-HBr 600 mg

TBPM-PI-HBr 600 mg (300 mg×2 ) film-coated tablets, administered orally three times per day (every 8 hours \[q8h\] ± 0.5 h) plus a single dummy IV infusion over 30 minutes (min) once daily (every 24 hours \[q24h\] ± 0.5 h) up to Day 15; participants with moderate renal insufficiency (creatinine clearance \[CrCl\] \>30 to ≤50 mL/min) required TBPM-PI-HBr dosage adjustment to 300 mg (one tablet) q8h ± 0.5 h.

Group Type: EXPERIMENTAL

TBPM-PI-HBr

Intervention Type: DRUG

TBPM-PI-HBr tablets administered orally.

Dummy Infusion

Intervention Type: DRUG

Dummy intravenous infusion.

Ertapenem 1 g

Ertapenem for IV injection, administered as a 1-gram IV infusion over 30 min once daily (q24h ± 0.5 h) plus dummy placebo tablets administered orally q8h (±0.5 h) up to Day 14; no dose adjustment of ertapenem was required for participants with renal insufficiency.

Group Type: ACTIVE_COMPARATOR

Ertapenem

Intervention Type: DRUG

Antibiotic Therapy for cUTI.

Dummy tablets

Intervention Type: DRUG

Dummy tablets orally.

Interventions

TBPM-PI-HBr

TBPM-PI-HBr tablets administered orally.

Intervention Type: DRUG

Ertapenem

Antibiotic Therapy for cUTI.

Intervention Type: DRUG

Dummy Infusion

Dummy intravenous infusion.

Intervention Type: DRUG

Dummy tablets

Dummy tablets orally.

Intervention Type: DRUG

Other Intervention Names

SPR994

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Spero Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Melnick, MD

Role: STUDY_DIRECTOR

Spero Therapeutics Inc

Locations

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

Medical Facility

Sofia, , Bulgaria

Medical Facility

Sofia, , Bulgaria

Medical Facility

Veliko Tarnovo, , Bulgaria

Medical Facility

Karlovy Vary, , Czechia

Medical Facility

Liberec, , Czechia

Medical Facility

Prague, , Czechia

Medical Facility

Ústí nad Labem, , Czechia

Medical Facility

Zlín, , Czechia

Medical Facility

Kohtla-Järve, , Estonia

Medical Facility

Tallinn, , Estonia

Medical Facility

Võru, , Estonia

Medical Facility

Tbilisi, , Georgia

Medical Facility

Tbilisi, , Georgia

Medical Facility

Tbilisi, , Georgia

Medical Facility

Tbilisi, , Georgia

Medical Facility

Zestaponi, , Georgia

Medical Facility

Budapest, , Hungary

Medical Facility

Budapest, , Hungary

Medical Facility

Nagykanizsa, , Hungary

Medical Facility

Nyíregyháza, , Hungary

Medical Facility

Tatabánya, , Hungary

Medical Facility

Riga, , Latvia

Medical Facility

Riga, , Latvia

Medical Facility

Valmiera, , Latvia

Medical Facility

Chisinau, , Moldova

Medical Facility

Chisinau, , Moldova

Medical Facility

Katowice, , Poland

Medical Facility

Krakow, , Poland

Medical Facility

Lodz, , Poland

Medical Facility

Oświęcim, , Poland

Medical Facility

Wroclaw, , Poland

Medical Facility

Bucharest, , Romania

Medical Facility

Bucharest, , Romania

Medical Facility

Bucharest, , Romania

Medical Facility

Craiova, , Romania

Medical Facility

Iași, , Romania

Medical Facility

Oradea, , Romania

Medical Facility

Arkhangelsk, , Russia

Medical Facility

Lomonosov, , Russia

Medical Facility

Penza, , Russia

Medical Facility

Pyatigorsk, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical Facility

Saint Petersburg, , Russia

Medical facility

Saint Petersburg, , Russia

Medical Facility

Smolensk, , Russia

Medical Facility

Smolensk, , Russia

Medical Facility

Vsevolozhsk, , Russia

Medical Facility

Yaroslavl, , Russia

Medical Facility

Belgrade, , Serbia

Medical Facility

Belgrade, , Serbia

Medical Facility

Kragujevac, , Serbia

Medical Facility

Novi Sad, , Serbia

Medical Facility

Vršac, , Serbia

Medical Facility

Bratislava, , Slovakia

Medical Facility

Galanta, , Slovakia

Medical Facility

Lučenec, , Slovakia

Medical Facility

Martin, , Slovakia

Medical Facility

Poprad, , Slovakia

Medical Facility

Svidník, , Slovakia

Medical Facility

Benoni, , South Africa

Medical Facility

Chatsworth, , South Africa

Medical Facility

Durban, , South Africa

Medical Facility

Johannesburg, , South Africa

Medical Facility

Middelburg, , South Africa

Medical Facility

Pretoria, , South Africa

Medical Facility

Cherkasy, , Ukraine

Medical Facility

Chernihiv, , Ukraine

Medical Facility

Dnipro, , Ukraine

Medical Facility

Ivano-Frankivsk, , Ukraine

Medical Facility

Ivano-Frankivsk, , Ukraine

Medical Facility

Kharkiv, , Ukraine

Medical Facility

Kharkiv, , Ukraine

Medical Facility

Lviv, , Ukraine

Medical Facility

Lviv, , Ukraine

Medical Facility

Mykolaiv, , Ukraine

Medical Facility

Odesa, , Ukraine

Medical Facility

Odesa, , Ukraine

Medical Facility

Uzhhorod, , Ukraine

Medical Facility

Vinnytsia, , Ukraine

Medical Facility

Zaporizhia, , Ukraine

Medical Facility

Zhytomyr, , Ukraine

Countries

United States; Bulgaria; Czechia; Estonia; Georgia; Hungary; Latvia; Moldova; Poland; Romania; Russia; Serbia; Slovakia; South Africa; Ukraine

References

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.

Reference Type: DERIVED

PMID: 35388666 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-003671-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SPR994-301

Identifier Type: -

Identifier Source: org_study_id