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)

NCT03788967 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: SPR994-3012018-003671-35
• Study Type: interventional
• Target: 1,372
• Locations: 15 countries
• Sites: 96

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

Keywords

Complicated Urinary Tract Infection; Acute Pyelonephritis

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

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

Secondary Outcomes (30)

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

  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

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

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

  Day 15 (EOT)

• Clinical Cure at TOC in the CE-TOC Populations

  Day 19 (TOC)

• Sustained Clinical Cure at LFU in the CE-LFU Populations

  Day 25 (LFU)

Study Arms (2)

TBPM-PI-HBr 600 mg

EXPERIMENTAL

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.

Drug: TBPM-PI-HBr; Drug: Dummy Infusion

Ertapenem 1 g

ACTIVE COMPARATOR

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.

Drug: Ertapenem; Drug: Dummy tablets

Interventions

TBPM-PI-HBr DRUG

TBPM-PI-HBr tablets administered orally.

Also known as: SPR994

TBPM-PI-HBr 600 mg

Ertapenem DRUG

Antibiotic Therapy for cUTI.

Ertapenem 1 g

Dummy Infusion DRUG

Dummy intravenous infusion.

TBPM-PI-HBr 600 mg

Dummy tablets DRUG

Dummy tablets orally.

Ertapenem 1 g

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female participants at least 18 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 have been mild or well-controlled with antiemetic therapy, in order to tolerate oral study drug.
• 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.

You may not qualify if:

• 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:
• Perinephric or renal corticomedullary abscess.
• 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 IP (e.g., carbapenem-resistant pathogen), including infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis).
• Gross hematuria requiring intervention other than administration of IP or removal/placement of urinary tract instrumentation.
• 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).
• 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 \[mg⁄dL\]).
• 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.

Sponsors & Collaborators

• Spero Therapeutics: lead

Study Sites (96)

Medical Facility

La Mesa, California, 91942, United States

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Miami, Florida, 33144, United States

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Blagoevgrad, 2700, Bulgaria

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Dobrich, 9300, Bulgaria

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Rousse, 7000, Bulgaria

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Shumen, 9700, Bulgaria

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Sofia, 1431, Bulgaria

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Sofia, 1606, Bulgaria

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Veliko Tarnovo, 5000, Bulgaria

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Karlovy Vary, 360 66, Czechia

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Liberec, 460 63, Czechia

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Prague, 140 59, Czechia

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Ústí nad Labem, 401 13, Czechia

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Zlín, 762 75, Czechia

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Kohtla-Järve, 31025, Estonia

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Tallinn, 10617, Estonia

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Võru, 65526, Estonia

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Tbilisi, 0144, Georgia

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Tbilisi, 0159, Georgia

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Tbilisi, 0160, Georgia

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Tbilisi, 0172, Georgia

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Zestaponi, 2000, Georgia

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Budapest, H-1082, Hungary

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Budapest, H-1204, Hungary

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Nagykanizsa, H-8800, Hungary

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Nyíregyháza, 4400, Hungary

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Tatabánya, 2800, Hungary

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Riga, LV-1002, Latvia

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Riga, LV-1038, Latvia

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Valmiera, LV-4201, Latvia

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Chisinau, MD-2004, Moldova

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Chisinau, MD2025, Moldova

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Katowice, 40-211, Poland

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Krakow, 31-559, Poland

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Lodz, 90-153, Poland

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Oświęcim, 32-600, Poland

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Wroclaw, 51-162, Poland

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Bucharest, 020125, Romania

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Bucharest, 021494, Romania

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Bucharest, 050659, Romania

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Craiova, 200642, Romania

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Iași, 700503, Romania

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Oradea, 410469, Romania

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Arkhangelsk, 163001, Russia

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Lomonosov, 198412, Russia

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Penza, 440026, Russia

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Pyatigorsk, 357500, Russia

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Saint Petersburg, 191186, Russia

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Saint Petersburg, 193312, Russia

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Saint Petersburg, 194017, Russia

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Saint Petersburg, 194044, Russia

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Saint Petersburg, 194064, Russia

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Saint Petersburg, 195009, Russia

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Saint Petersburg, 195067, Russia

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Saint Petersburg, 196247, Russia

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Saint Petersburg, 197022, Russia

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Saint Petersburg, 197374, Russia

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Saint Petersburg, 198205, Russia

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Saint Petersburg, 199106, Russia

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Smolensk, 214019, Russia

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Smolensk, 214025, Russia

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Vsevolozhsk, 188643, Russia

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Yaroslavl, 150062, Russia

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Belgrade, 11 000, Serbia

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Belgrade, 11080, Serbia

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Kragujevac, 34 000, Serbia

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Novi Sad, 21 000, Serbia

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Vršac, 26300, Serbia

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Bratislava, 826 06, Slovakia

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Galanta, 924 22, Slovakia

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Lučenec, 984 01, Slovakia

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Martin, 03659, Slovakia

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Poprad, 05845, Slovakia

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Svidník, 089 01, Slovakia

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Benoni, 1500, South Africa

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Chatsworth, 4092, South Africa

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Durban, 4001, South Africa

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Johannesburg, 2013, South Africa

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Middelburg, 1050, South Africa

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Pretoria, 0001, South Africa

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Cherkasy, 18009, Ukraine

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Chernihiv, 14034, Ukraine

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Dnipro, 49027, Ukraine

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Ivano-Frankivsk, 76008, Ukraine

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Ivano-Frankivsk, 76018, Ukraine

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Kharkiv, 61037, Ukraine

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Kharkiv, 61103, Ukraine

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Lviv, 79010, Ukraine

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Lviv, 79059, Ukraine

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Mykolaiv, 54058, Ukraine

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Odesa, 65025, Ukraine

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Odesa, 65074, Ukraine

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Uzhhorod, 88000, Ukraine

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Vinnytsia, 21018, Ukraine

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Zaporizhia, 69600, Ukraine

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Zhytomyr, 10002, Ukraine

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Related Publications (1)

• 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.

  PMID: 35388666 DERIVED

MeSH Terms

Interventions

tebipenem; Ertapenem

Intervention Hierarchy (Ancestors)

Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Angela Talley
• Organization: Senior Vice President Clinical Development

atalley@sperotherapeutics.com

857-242-1575

Study Officials

• David Melnick, MD

  Spero Therapeutics Inc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2018
• First Posted: December 28, 2018
• Study Start: June 3, 2019
• Primary Completion: May 20, 2020
• Study Completion: May 27, 2020
• Last Updated: July 25, 2022
• Results First Posted: July 25, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

PL (5); BU (7); ES (3); HU (5); US (2); SE (5); SL (6); ZA (6); LA (3); GE (5); RO (6); RU (20); MO (2); CZ (5); UA (16)