Oral Tebipenem vs IV Imipenem for Urinary Tract Infections

(PIVOT-PO Trial)

No longer recruiting at 107 trial locations

Overseen By Lori Muir

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Spero Therapeutics

Must not be taking: Valproic acid, Probenecid

Disqualifiers: Seizure disorder, HIV, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 11

Duration: 10 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to compare the effectiveness of an oral medication, Tebipenem Pivoxil Hydrobromide, with an intravenous treatment, Imipenem-cilastatin, for treating complicated urinary tract infections (cUTI) and acute pyelonephritis (AP), a severe kidney infection. Researchers seek to determine which treatment leads to better recovery and more effectively clears the infection. Individuals diagnosed with cUTI or AP who can provide a urine sample showing signs of infection may be suitable for this study. Participants will either take the oral medication or receive the IV treatment over 10 days. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot use certain drugs like valproic acid, divalproex sodium, or probenecid during the study. Also, you should not have taken any effective antimicrobial drugs within 72 hours before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tebipenem pivoxil hydrobromide, an oral antibiotic, has a promising safety record. In earlier studies, about 25.7% of patients experienced side effects from the drug, similar to the 25.6% of patients who had side effects from another antibiotic, ertapenem. This suggests that tebipenem is as well-tolerated as other commonly used antibiotics for similar conditions.

Imipenem-cilastatin, another well-known antibiotic, is administered through an IV. It has already been approved for treating serious infections, indicating it has passed strict safety tests. This confirms its safety for approved uses.

Both treatments have been tested on many patients, and their side effects are similar to those of other antibiotics, suggesting that both drugs generally have a good safety profile. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Tebipenem Pivoxil Hydrobromide for urinary tract infections because it offers an oral alternative to the standard intravenous antibiotics like imipenem-cilastatin. Most treatments for serious bacterial infections like these require hospital visits and IV administration, which can be inconvenient and costly. Tebipenem, being an oral medication, provides the same powerful antibiotic action in a form that's easier to take at home, potentially reducing healthcare costs and improving patient comfort. This convenience could make it a game-changer for patients who need effective treatment without the hospital stay.

What evidence suggests that this trial's treatments could be effective for urinary tract infections?

This trial will compare the oral medication tebipenem pivoxil hydrobromide with the intravenous (IV) drug imipenem-cilastatin for treating complicated urinary tract infections (cUTIs). Research has shown that tebipenem pivoxil hydrobromide is promising, with an effectiveness rate of about 58.5%, similar to imipenem-cilastatin. Importantly, tebipenem matches the effectiveness of the IV option. It has also been compared to another antibiotic, ertapenem, and performed equally well. This suggests that tebipenem could serve as a good oral alternative for those who can't or prefer not to receive IV treatment. ^{1 2 3 4 6}

Who Is on the Research Team?

David Hong, MD

Principal Investigator

Spero Therapeutics

Are You a Good Fit for This Trial?

Adults diagnosed with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP), showing signs of infection in urine tests. Participants must be expected to survive the treatment duration with proper care. People are excluded if they don't meet these health criteria.

Inclusion Criteria

My recent urine test shows signs of infection.

Expectation, in the judgment of the Investigator, that the participant will survive with effective antimicrobial therapy and appropriate supportive care for the anticipated duration of the study

I have been diagnosed with a complicated urinary tract infection or acute pyelonephritis.

Exclusion Criteria

I have severe blood in my urine that needs treatment beyond study drugs or urinary tools.

I haven't taken more than one dose of a strong antibiotic within the last 3 days.

I expect to use antibiotics not part of the study that could affect my treatment results.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either oral TBP-PI-HBr or intravenous imipenem-cilastatin every 6 hours from Days 1 through 10

10 days

Daily visits (in-person)

Test-of-Cure (TOC)

Assessment of overall response including clinical cure and microbiological eradication

Day 17

1 visit (in-person)

Follow-up

Participants are monitored for sustained clinical and microbiological response

28 days

Visits on Days 10, 17, and 28

What Are the Treatments Tested in This Trial?

Interventions

• Imipenem-cilastatin
• Tebipenem Pivoxil Hydrobromide

Trial Overview The trial is testing oral TBP-PI-HBr against IV imipenem-cilastatin for treating cUTI or AP. The goal is to see which treatment better clears the infection and symptoms at a follow-up visit after therapy.

How Is the Trial Designed?

Group I: TBP-PI-HBr 600 mg + Dummy Infusion Experimental Treatment 2 Interventions

Participants will receive TBP-PI-HBr 600 mg, orally and dummy infusion IV, every 6 hours from Days 1 through 10.

Group II: Imipenem-cilastatin 500 mg + Dummy Tablets Active Control 2 Interventions

Participants will receive imipenem-cilastatin 500 mg, IV and matched dummy tablets, orally, every 6 hours from Days 1 through 10.

Imipenem-cilastatin is already approved in United States, European Union for the following indications:

Approved in United States as Imipenem-cilastatin for:

• Complicated urinary tract infections
• Complicated intra-abdominal infections
• Hospital-acquired bacterial pneumonia
• Ventilator-associated bacterial pneumonia

Approved in European Union as Imipenem-cilastatin for:

• Complicated urinary tract infections
• Complicated intra-abdominal infections
• Lower respiratory tract infections
• Skin and soft tissue infections

Who Is Running the Clinical Trial?

Spero Therapeutics

Lead Sponsor

Trials

24

Recruited

4,900+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Published Research Related to This Trial

Tebipenem pivoxil hydrobromide (TBPM-PI-HBr) is an orally available prodrug that effectively treats multidrug-resistant Gram-negative infections, showing linear and dose-proportional pharmacokinetics in healthy adults across a range of doses (100 to 900 mg).

The drug was well tolerated with mild diarrhea as the most common side effect, indicating its safety profile, and it has the potential to reduce reliance on intravenous antibiotics for serious infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects. Eckburg, PB., Jain, A., Walpole, S., et al.[2020]

Trimodality bladder preservation therapy (BPT) for muscle invasive bladder cancer shows similar overall survival rates to radical cystectomy (RC), with median survival of 41 months for BPT compared to 46 months for RC, indicating that BPT can be a viable alternative for certain patients.

The study revealed a wide variation in chemotherapy regimens used alongside BPT, with no significant differences in survival outcomes among the different regimens, highlighting the need for standardized treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of Bladder Preservation Therapy Utilization for Muscle-Invasive Bladder Cancer. Rose, TL., Deal, AM., Ladoire, S., et al.[2020]

A retrospective study of 184 patients with non-muscle-invasive bladder cancer showed that a 3-day consecutive intravesical instillation of pirarubicine hydrochloride after transurethral resection significantly reduced tumor recurrence, with 1, 2, 3, and 5-year non-recurrence rates of 82.7%, 75.3%, 72.3%, and 67.4%, respectively.

For patients classified as low risk of tumor recurrence, the treatment was particularly effective, achieving a 3-year non-recurrence rate of 85.3%, suggesting that pirarubicine hydrochloride is a valuable adjuvant therapy for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The intravesical recurrence after 3-day consecutive intravesical instillation of pirarubicine hydrochloride (THP) following transurethral resection of bladder tumor (TURBT) for non-muscle-invasive bladder cancer]. Tochigi, T., Sakurada, Y., Aoki, H., et al.[2019]

In a phase 3 trial involving 1372 hospitalized adults, oral tebipenem pivoxil hydrobromide was found to be noninferior to intravenous ertapenem for treating complicated urinary tract infections and acute pyelonephritis, demonstrating similar efficacy in clinical cure rates.

Both treatments had comparable safety profiles, with adverse events occurring in about 25.7% of patients receiving tebipenem and 25.6% receiving ertapenem, primarily consisting of mild diarrhea and headache.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection. Eckburg, PB., Muir, L., Critchley, IA., et al.[2022]

A 70-year-old male with invasive bladder cancer underwent intermittent arterial infusion (ITI) combined with blood flow alteration through contralateral arterial embolization, receiving weekly injections of cisplatin and pirarubicin for 11 weeks.

The treatment resulted in a complete response (CR) as confirmed by cystoscopy and biopsy, indicating that ITI is an effective approach for treating bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A case of complete response in a patient with invasive bladder cancer due to intermittent intraarterial infusion chemotherapy using the alteration of blood flow]. Minami, H., Umeda, M., Maekawa, T., et al.[2014]

In a study of 19 patients with recurrent superficial bladder cancer, 84.2% achieved a complete response after receiving 8 treatments of Pirarubicin (THP) via intravesical instillation, indicating its efficacy in this patient population.

The treatment was well-tolerated, with no serious side effects reported, suggesting that THP is a safe option for managing recurrent bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The study on intravesical instillation of THP in the treatment of in-situ and superficial bladder cancers]. Aota, Y., Okamoto, N., Morikawa, S., et al.[2014]

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral pro-drug that converts to the active drug tebipenem, which is effective against multidrug-resistant Gram-negative bacteria, making it a promising treatment for complicated urinary tract infections (cUTI) and acute pyelonephritis (AP).

A population pharmacokinetic model developed from data of 746 subjects showed that tebipenem has a two-compartment model with linear elimination, and no dose adjustments are needed based on age, body size, or sex, indicating a consistent safety profile across diverse patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide. Ganesan, H., Gupta, VK., Safir, MC., et al.[2023]

Tebipenem pivoxil hydrobromide, a novel oral carbapenem, showed effective distribution into skin and soft tissue in both healthy subjects and patients with diabetic foot infections, indicating its potential for treating infections in these areas.

The pharmacokinetics revealed that tebipenem achieved similar tissue concentrations in both populations, with a penetration ratio of 107% in healthy subjects and 90% in infected patients, suggesting good efficacy in delivering the drug to the site of infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and soft-tissue distribution of tebipenem pivoxil hydrobromide using microdialysis: a study in healthy subjects and patients with diabetic foot infections. Abouelhassan, Y., Fratoni, AJ., Shepard, AK., et al.[2023]

In a study of 257 patients with solitary non-muscle invasive bladder cancer (NMIBC), a single immediate instillation of pirarubicin (THP) after surgery was found to be as effective as a two-time instillation in preventing cancer recurrence, with 5-year recurrence-free survival rates of 55.9% and 67.7%, respectively, showing no significant difference.

Both treatment groups experienced similar rates of adverse effects, although the two-time instillation group had a higher incidence of pollakiuria (frequent urination), indicating that the single instillation may be a safer option without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective randomized controlled trial of postoperative early intravesical chemotherapy with pirarubicin (THP) for solitary non-muscle invasive bladder cancer comparing single and two-time instillation. Tanimoto, R., Saika, T., Ebara, S., et al.[2019]

Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr) is an orally available prodrug of tebipenem that shows effectiveness against multidrug-resistant Gram-negative bacteria, making it a promising option for treating complicated urinary tract infections (cUTI).

In laboratory tests and mouse infection models, tebipenem demonstrated equivalent efficacy to intravenous carbapenems like meropenem, indicating its potential as a valuable oral antibiotic for infections requiring strong carbapenem activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vitro and In Vivo Characterization of Tebipenem, an Oral Carbapenem. Cotroneo, N., Rubio, A., Critchley, IA., et al.[2021]

Citations

1. gsk.com gsk.com/en-gb/media/press-releases/positive-pivot-po-phase-iii-data-show-tebipenem-hbr-s-potential-as-the-first-oral-carbapenem-antibiotic-for-patients-with-complicated-urinary-tract-infections-cutis/

Positive PIVOT-PO phase III data show tebipenem HBr's ... Tebipenem HBr (oral, 600 mg) achieved a 58.5% overall success rate (261/446 participants) compared to 60.2% overall success rate (291/483 ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2105462

Oral Tebipenem Pivoxil Hydrobromide in Complicated ... Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis.

3. biospace.com biospace.com/press-releases/pivot-po-phase-3-data-show-tebipenem-hbrs-potential-as-the-first-oral-carbapenem-antibiotic-for-patients-with-complicated-urinary-tract-infections-cutis

PIVOT-PO Phase 3 Data Show Tebipenem HBr's Potential ... Data presented at IDWeek 2025 after study stopped early for efficacy; Primary endpoint met, demonstrating non-inferiority of oral tebipenem ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35388666/

Oral Tebipenem Pivoxil Hydrobromide in Complicated ... Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; ...

5. gsk.com gsk.com/en-gb/media/press-releases/pivot-po-phase-iii-study-for-tebipenem-hbr-stopped-early-for-efficacy-following-review-by-independent-data-monitoring-committee/

PIVOT-PO phase III study for tebipenem HBr stopped early ... The trial met the primary endpoint of non-inferiority of tebipenem HBr compared to intravenous imipenem-cilastatin in hospitalised adult ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06059846

NCT06059846 | A Study of Oral Tebipenem Pivoxil ... The primary purpose of this study is to assess the efficacy of oral TBP-PI-HBr as compared with intravenous (IV) imipenem-cilastatin with respect to the ...