Complicated Urinary Tract InfectionPhase 3ADAPT-PONCT03788967
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)
A Phase 3 study testing TBPM-PI-HBr, Ertapenem and Dummy Infusion in people with Complicated Urinary Tract Infection and Acute Pyelonephritis, run by Spero Therapeutics at 96 sites in 15 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Complicated Urinary Tract Infection, Acute Pyelonephritis
- What is being tested?
- TBPM-PI-HBr, Ertapenem and Dummy Infusion
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,372 participants
- Where
- 96 sitesin 15 countries
- Study dates
- 3 Jun 2019to 27 May 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
- cUTI definition:
- At least Two of the following signs and symptoms:
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- 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])
- Dysuria, urgency to void, or increased urinary frequency
- Nausea or vomiting, as reported by the participants
- Lower abdominal, suprapubic, or pelvic pain
- 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 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).
- 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.
- 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]).
- 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).
- 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; fever must be observed and documented by a health care provider (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F]).
- Peripheral white blood cell count (WBC) >10,000/mm3 or bandemia (≥15% immature polymorphonuclear neutrophils (PMNs), regardless of WBC count).
- Nausea or vomiting, as reported by the participants.
- 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.
- 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 cubic millimeter (mm3) in unspun (non-centrifuged) urine.
- Positive leukocyte esterase (LE) on urinalysis. Note: Participants could be randomized and administered investigational product (IP) prior to knowledge of urine culture results.
- 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.
- Willing to comply with all the study activities and procedures throughout the duration of the study.
- 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.
Who cannot join
- 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.
- Uncomplicated urinary tract infection (cUTI) - (acute cystitis that does not meet the cUTI disease definition, see Inclusion Criterion 4a).
- Polycystic kidney disease.
- Recent history of trauma to the pelvis or urinary tract.
- Confirmed or suspected acute or chronic bacterial prostatitis, orchitis, or epididymitis.
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- 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 (eCCr) [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.
- 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.
- 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:
- In the opinion of the Investigator they have failed the prior antibiotic therapy (e.g., have worsening signs and symptoms of cUTI/AP).
- Had a documented uropathogen (growth in urine culture >10^5 CFU/mL) that is resistant to the prior antibiotic therapy.
- Had a documented uropathogen that is carbapenem-susceptible.
- Received approval from the Medical Monitor to enroll the participants.
- 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).
- 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.
- Pregnant or breastfeeding women.
- History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures).
- Receipt of any investigational medication during the last 30 days or 5 half-lives, whichever is longer, prior to randomization.
- 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.
- 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).
- A mean QT interval corrected using Fridericia's formula (QTcF) >480 msec based on triplicate ECGs at Screening.
- 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.
- History of known genetic metabolism anomaly associated with carnitine deficiency (e.g., carnitine transporter defect, methylmalonic aciduria, propionic acidemia)
- Requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT.
- Unable or unwilling to comply with the protocol.
- 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.
Trial locations and contacts
96 sites in 15 countries.
96 sites in 15 countries
Russia20 sites
Medical Facility
Arkhangelsk, 163001
Medical Facility
Lomonosov, 198412
Medical Facility
Penza, 440026
Medical Facility
Pyatigorsk, 357500
Medical Facility
Saint Petersburg, 191186
Medical Facility
Saint Petersburg, 193312
Medical Facility
Saint Petersburg, 194017
Medical Facility
Saint Petersburg, 194044
Medical Facility
Saint Petersburg, 194064
Medical Facility
Saint Petersburg, 195009
Medical Facility
Saint Petersburg, 195067
Medical Facility
Saint Petersburg, 196247
Medical Facility
Saint Petersburg, 197022
Medical Facility
Saint Petersburg, 197374
Medical Facility
Saint Petersburg, 198205
Medical facility
Saint Petersburg, 199106
Medical Facility
Smolensk, 214019
Medical Facility
Smolensk, 214025
Medical Facility
Vsevolozhsk, 188643
Medical Facility
Yaroslavl, 150062
Ukraine16 sites
Medical Facility
Cherkasy, 18009
Medical Facility
Chernihiv, 14034
Medical Facility
Dnipro, 49027
Medical Facility
Ivano-Frankivsk, 76008
Medical Facility
Ivano-Frankivsk, 76018
Medical Facility
Kharkiv, 61037
Medical Facility
Kharkiv, 61103
Medical Facility
Lviv, 79010
Medical Facility
Lviv, 79059
Medical Facility
Mykolaiv, 54058
Medical Facility
Odesa, 65025
Medical Facility
Odesa, 65074
Medical Facility
Uzhhorod, 88000
Medical Facility
Vinnytsia, 21018
Medical Facility
Zaporizhia, 69600
Medical Facility
Zhytomyr, 10002
Bulgaria7 sites
Medical Facility
Blagoevgrad, 2700
Medical Facility
Dobrich, 9300
Medical Facility
Rousse, 7000
Medical Facility
Shumen, 9700
Medical Facility
Sofia, 1431
Medical Facility
Sofia, 1606
Medical Facility
Veliko Tarnovo, 5000
Romania6 sites
Medical Facility
Bucharest, 020125
Medical Facility
Bucharest, 021494
Medical Facility
Bucharest, 050659
Medical Facility
Craiova, 200642
Medical Facility
Iași, 700503
Medical Facility
Oradea, 410469
Slovakia6 sites
Medical Facility
Bratislava, 826 06
Medical Facility
Galanta, 924 22
Medical Facility
Lučenec, 984 01
Medical Facility
Martin, 03659
Medical Facility
Poprad, 05845
Medical Facility
Svidník, 089 01
South Africa6 sites
Medical Facility
Benoni, 1500
Medical Facility
Chatsworth, 4092
Medical Facility
Durban, 4001
Medical Facility
Johannesburg, 2013
Medical Facility
Middelburg, 1050
Medical Facility
Pretoria, 0001
Czechia5 sites
Medical Facility
Karlovy Vary, 360 66
Medical Facility
Liberec, 460 63
Medical Facility
Prague, 140 59
Medical Facility
Ústí nad Labem, 401 13
Medical Facility
Zlín, 762 75
Georgia5 sites
Medical Facility
Tbilisi, 0144
Medical Facility
Tbilisi, 0159
Medical Facility
Tbilisi, 0160
Medical Facility
Tbilisi, 0172
Medical Facility
Zestaponi, 2000
Hungary5 sites
Medical Facility
Budapest, H-1082
Medical Facility
Budapest, H-1204
Medical Facility
Nagykanizsa, H-8800
Medical Facility
Nyíregyháza, 4400
Medical Facility
Tatabánya, 2800
Poland5 sites
Medical Facility
Katowice, 40-211
Medical Facility
Krakow, 31-559
Medical Facility
Lodz, 90-153
Medical Facility
Oświęcim, 32-600
Medical Facility
Wroclaw, 51-162
Serbia5 sites
Medical Facility
Belgrade, 11 000
Medical Facility
Belgrade, 11080
Medical Facility
Kragujevac, 34 000
Medical Facility
Novi Sad, 21 000
Medical Facility
Vršac, 26300
Estonia3 sites
Medical Facility
Kohtla-Järve, 31025
Medical Facility
Tallinn, 10617
Medical Facility
Võru, 65526
Latvia3 sites
Medical Facility
Riga, LV-1002
Medical Facility
Riga, LV-1038
Medical Facility
Valmiera, LV-4201
United States2 sites
Medical Facility
La Mesa, California, 91942
Medical Facility
Miami, Florida, 33144
Moldova2 sites
Medical Facility
Chisinau, MD-2004
Medical Facility
Chisinau, MD2025
About this study
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)
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).
- Being tested
- TBPM-PI-HBr, Ertapenem, Dummy Infusion, Dummy tablets
- Keywords
- Complicated Urinary Tract Infection, Acute Pyelonephritis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TBPM-PI-HBrDrug
Also called SPR994
TBPM-PI-HBr tablets administered orally.
ErtapenemDrug
Antibiotic Therapy for cUTI.
Dummy InfusionDrug
Dummy intravenous infusion.
Dummy tabletsDrug
Dummy tablets orally.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Ertapenem; Drug: Dummy tablets |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
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 acute pyelonephritis (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 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.
Measured: 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
Clinical cure is defined as number of participants with 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. Sustained clinical cure is defined as participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.
Measured: Days 15 (EOT), Day 19 (TOC) and Day 25 (LFU)
Clinical Cure at EOT Days the Clinically Evaluable (CE-EOT) Populations
Clinical cure is defined as number of participants with 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.
Measured: Day 15 (EOT)
Clinical Cure at TOC in the CE-TOC Populations
Clinical cure is defined as number of participants with 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.
Measured: Day 19 (TOC)
Sustained Clinical Cure at LFU in the CE-LFU Populations
Clinical cure is defined as number of participants with 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. Sustained clinical cure is defined as number of participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.
Measured: Day 25 (LFU)
Clinical Cure at EOT in the ME-EOT Populations
Clinical cure is defined as number of participants with 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.
Measured: Day 15 (EOT)
Clinical Cure at TOC Days in the ME-TOC Populations
Clinical cure is defined as number of participants with 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.
Measured: Day 19 (TOC)
Sustained Clinical Cure at LFU in the ME-LFU Population
Clinical cure is defined as number of participants with 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. Sustained clinical cure is defined as participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.
Measured: Day 25 (LFU)
By-Patient Microbiological Eradication at EOT, TOC, and Sustained Microbiological Eradication at LFU Days in the Micro-ITT Population
Microbiological eradication is defined as reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication is defined as number of participants with reduction of Baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline. Sustained Microbiological Eradication is defined as number of participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10^5 CFU/mL.
Measured: Days 15 (EOT), 19 (TOC) and 25 (LFU)
By-Pathogen Microbiological Eradication Rate at EOT in the Micro-ITT Population
Microbiological eradication is defined as reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
Measured: Days 15 (EOT)
By-Pathogen Microbiological Eradication Rate at TOC in the Micro-ITT Population
Microbiological eradication is defined as reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
Measured: Day 19 (TOC)
By-Pathogen Sustained Microbiological Eradication Rate at LFU in the Micro-ITT Population (m-ITT)
Microbiological eradication is defined as reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined as microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10^5 CFU/mL. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogen analyzed.
Measured: Day 25 (LFU)
By-Patient Microbiological Eradication at EOT in the ME-EOT Populations
Microbiological eradication is defined as reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.
Measured: Day 15 (EOT)
By-Patient Microbiological Eradication at TOC in the ME-TOC Population
Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
Measured: Day 15 (TOC)
By-Patient Sustained Microbiological Eradication at LFU Days in the ME-LFU Populations
Microbiological eradication is defined as number of participants with 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. Sustained Microbiological Eradication is defined participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10^5 CFU/mL.
Measured: Day 25 (LFU)
By-pathogen Microbiological Eradication Rate in Participants at EOT in the ME-EOT Populations
Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
Measured: Day 15 (EOT)
By-pathogen Microbiological Eradication Rate in Participants at TOC in the ME-TOC Populations
Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of participants analyzed.
Measured: Day 19 (TOC)
By-pathogen Sustained Microbiological Eradication Rate in Participants at LFU in the ME-LFU Populations
Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10^5 CFU/mL.Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogen analyzed.
Measured: Day 25 (LFU)
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) In Subgroup Including: Stratified Infection Category
Overall response rate is percentage of participants with combined clinical cure plus 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.
Measured: Day 19 (TOC)
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Stratified Age Category
Overall response rate is percentage of participants with combined clinical cure plus 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 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.
Measured: Day 19 (TOC)
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Including Region
Overall response rate is percentage of participants with combined clinical cure plus 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. The point estimate and confidence interval (CI) is presented for Central and eastern Europe subgroup.
Measured: Day 25 (LFU)
Time (Days) to Resolution or Improvement of Signs and Symptoms of cUTI and AP Present a Baseline in the Micro-ITT Populations
Time (days) to resolution or improvement of signs and symptoms of cUTI and AP present at baseline was defined as follows: date of the first visit at which all baseline signs/symptoms have improved by at least 1 grade with worsening of none and development of no new signs/symptoms of the index infection minus the date of randomization.
Measured: Day 25 (LFU)
Time (Days) to Defervescence in Micro-ITT Population With a Documented Fever at Screening or Day 1
Time to Defervescence (days) = date of first post-baseline temperature measure with maximum daily Temperature ≤38°C at the date of randomization.
Measured: Day 25 (LFU)
Rate of Clinical Relapse at the LFU Days in the Micro-ITT Population
Clinical relapse is participants who met criteria for clinical cure at TOC, but new signs and symptoms of cUTI or AP are present at the LFU Visit and the subject requires antibiotic therapy for the cUT. 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.
Measured: Day 25 (LFU)
Rates Of Superinfection And New Infection In The Micro-ITT Population
Superinfection was isolation of a new uropathogen at ≥105 CFU/mL (other than the original Baseline pathogen[s] from blood and/or urine) from a urine culture that was accompanied by clinical signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., the participant was assessed by the investigator as a clinical failure) during the period up to and including EOT. New infection was isolation of a new uropathogen at ≥105 CFU/mL (other than the original baseline pathogen[s] from blood and/or urine) from a urine culture that was accompanied by clinical signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., the participant was assessed by the Investigator as a clinical failure) in the period after EOT.
Measured: Day 25 (LFU)
Apparent Volume of Distribution (Vss) at Steady State in TBPM-PI-HBr Recipients in the Pharmacokinetic (PK) Population
Measured: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Cmax in TBPM-PI-HBr Recipients in the PK Population
Measured: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Area Under Curve (AUC 0-24) in TBPM-PI-HBr Recipients in the PK Population
Measured: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Minimum Concentration (Cmin) in TBPM-PI-HBr Recipients in the PK Population
Measured: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Systemic Clearance (CL) in TBPM-PI-HBr Recipients in the PK Population
Measured: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2018
- Study start3 Jun 2019
- Primary completion20 May 2020
- Study completion27 May 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Complicated Urinary Tract InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,372 participants (actual)
Sponsor and investigators
- Lead sponsor
- Spero Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- David Melnick, MD, Study director, Spero Therapeutics Inc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03788967
- Sponsor's protocol ID
- SPR994-301
- Other IDs
- 2018-003671-35, 2018
- Acronym
- ADAPT-PO
- Status last verified
- Jun 2022
- First submitted
- 22 Dec 2018
- Last updated
- 25 Jul 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 35388666
Study at a glance
From the registry record, last updated by the sponsor on 25 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03788967
- Acronym / sponsor ID
- ADAPT-PO / SPR994-301
- Keywords
- Complicated Urinary Tract Infection, Acute Pyelonephritis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,372 participants (actual)
- Lead sponsor
- Spero TherapeuticsIndustry (pharma, biotech, devices)
- Study start
- 3 Jun 2019 (actual)
- Primary completion
- 20 May 2020 (actual)
- Study completion
- 27 May 2020 (actual)
- First posted
- 28 Dec 2018 (actual)
- Results
- Posted 25 Jul 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| TBPM-PI-HBr 600 mg | Experimental | Drug: TBPM-PI-HBr, Drug: Dummy InfusionTBPM-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. |
| Ertapenem 1 g | Active comparator | Drug: Ertapenem, Drug: Dummy tabletsErtapenem 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (30 listed)
- 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:
- 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.
Key exclusion criteria (36 listed)
- 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:
- 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 (eCCr) [mL/min]=((140-Age [yrs]) × Body Weight [kg] × [0.85 if Female])/(72 × Serum Creatinine [mg⁄dL]).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TBPM-PI-HBrAlso: SPR994TBPM-PI-HBr tablets administered orally. | Drug | TBPM-PI-HBr 600 mg |
| ErtapenemAntibiotic Therapy for cUTI. | Drug | Ertapenem 1 g |
| Dummy InfusionDummy intravenous infusion. | Drug | TBPM-PI-HBr 600 mg |
| Dummy tabletsDummy tablets orally. | Drug | Ertapenem 1 g |
Primary outcome
Overall Response (Combined Clinical Cure and Microbiological Eradication) at Test-of-Cure (TOC) in Micro Intent-to-Treat Population
Time frame: Day 19 (TOC)
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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) in The Safety Population
Time frame: From the first dose of administration up to Day 25 post-treatment ± 2 days (up to approximately 27 days)
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.
30 secondary outcomes
Overall Response (Combined Clinical Cure Plus Microbiological Eradication) At Test-Of-Cure (TOC) In The Microbiologically Evaluable (ME) - TOC Population
Time frame: 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
Time frame: Days 15 (EOT), Day 19 (TOC) and Day 25 (LFU)
Clinical Cure at EOT Days the Clinically Evaluable (CE-EOT) Populations
Time frame: Day 15 (EOT)
Clinical Cure at TOC in the CE-TOC Populations
Time frame: Day 19 (TOC)
Sustained Clinical Cure at LFU in the CE-LFU Populations
Time frame: Day 25 (LFU)
Clinical Cure at EOT in the ME-EOT Populations
Time frame: Day 15 (EOT)
Clinical Cure at TOC Days in the ME-TOC Populations
Time frame: Day 19 (TOC)
Sustained Clinical Cure at LFU in the ME-LFU Population
Time frame: Day 25 (LFU)
By-Patient Microbiological Eradication at EOT, TOC, and Sustained Microbiological Eradication at LFU Days in the Micro-ITT Population
Time frame: Days 15 (EOT), 19 (TOC) and 25 (LFU)
By-Pathogen Microbiological Eradication Rate at EOT in the Micro-ITT Population
Time frame: Days 15 (EOT)
By-Pathogen Microbiological Eradication Rate at TOC in the Micro-ITT Population
Time frame: Day 19 (TOC)
By-Pathogen Sustained Microbiological Eradication Rate at LFU in the Micro-ITT Population (m-ITT)
Time frame: Day 25 (LFU)
By-Patient Microbiological Eradication at EOT in the ME-EOT Populations
Time frame: Day 15 (EOT)
By-Patient Microbiological Eradication at TOC in the ME-TOC Population
Time frame: Day 15 (TOC)
By-Patient Sustained Microbiological Eradication at LFU Days in the ME-LFU Populations
Time frame: Day 25 (LFU)
By-pathogen Microbiological Eradication Rate in Participants at EOT in the ME-EOT Populations
Time frame: Day 15 (EOT)
By-pathogen Microbiological Eradication Rate in Participants at TOC in the ME-TOC Populations
Time frame: Day 19 (TOC)
By-pathogen Sustained Microbiological Eradication Rate in Participants at LFU in the ME-LFU Populations
Time frame: Day 25 (LFU)
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) In Subgroup Including: Stratified Infection Category
Time frame: Day 19 (TOC)
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Stratified Age Category
Time frame: Day 19 (TOC)
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Including Region
Time frame: Day 25 (LFU)
Time (Days) to Resolution or Improvement of Signs and Symptoms of cUTI and AP Present a Baseline in the Micro-ITT Populations
Time frame: Day 25 (LFU)
Time (Days) to Defervescence in Micro-ITT Population With a Documented Fever at Screening or Day 1
Time frame: Day 25 (LFU)
Rate of Clinical Relapse at the LFU Days in the Micro-ITT Population
Time frame: Day 25 (LFU)
Rates Of Superinfection And New Infection In The Micro-ITT Population
Time frame: Day 25 (LFU)
Apparent Volume of Distribution (Vss) at Steady State in TBPM-PI-HBr Recipients in the Pharmacokinetic (PK) Population
Time frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Cmax in TBPM-PI-HBr Recipients in the PK Population
Time frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Area Under Curve (AUC 0-24) in TBPM-PI-HBr Recipients in the PK Population
Time frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Minimum Concentration (Cmin) in TBPM-PI-HBr Recipients in the PK Population
Time frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Systemic Clearance (CL) in TBPM-PI-HBr Recipients in the PK Population
Time frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jul 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35388666Eckburg 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Melnick, MD study director
Spero Therapeutics Inc
96 sites in 15 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing TBPM-PI-HBr, Ertapenem and Dummy Infusion in people with Complicated Urinary Tract Infection and Acute Pyelonephritis, run by Spero Therapeutics at 96 sites in 15 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 30 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 96 sites in Russia, Ukraine, Bulgaria, Romania, Slovakia and 10 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Jul 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Response (Combined Clinical Cure and Microbiological Eradication) at Test-of-Cure (TOC) in Micro Intent-to-Treat Population (time frame: Day 19 (TOC)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03788967, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jul 2022.