| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract infection |
| Komplicirana infekcija mokraćnog sustava |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated urinary tract infection |
| Komplicirana infekcija mokraćnog sustava |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of sulopenem IV followed by oral sulopenem-etzadroxil plus probenecid with ertapenem IV followed by oral ciprofloxacin or amoxicillin-clavulanate for the treatment of complicated urinary tract infection at Day 21 (± 1 day; test of cure [TOC visit]). |
| Usporediti učinkovitost intravenske primjene sulopenema praćene oralnom primjenom sulopenem-etzadroksila s probenecidom u odnosu na intravensku primjenu ertapenema praćenu oralnom primjenom ciprofloksacina ili amoksicilin-klavulanata u liječenju kompliciranih infekcija mokraćnog sustava na posjetu 21. dan (± 1 dan; posjet za utvrđivanje izlječenja). |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the per-patient microbiologic response across treatment groups.
• To compare the efficacy outcomes at relevant time points.
• To assess the safety profile of treatment with each regimen.
• To assess the population PK profile of sulopenem and/or sulopenem-etzadroxil co-administered with probenecid. |
• Usporediti mikrobiološki odgovor po ispitaniku u skupinama liječenja.
• Usporediti ishode učinkovitosti u relevantnim vremenskim točkama.
• Procijeniti sigurnosni profil obje terapije.
• Procijeniti populacijski farmakokinetički profil sulopenema i/ ili sulopenem-etzadroksila primjenjivanog zajedno s probenecidom.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
POPULATION PK SUB-STUDY
Date and Version: June 4, 2018
Objectives:
This study will be conducted within the context of an ongoing Phase 3 sulopenem clinical trial in order to generate confirmatory data for the population PK profile of both the IV and oral pro-drug regimens of sulopenem.
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Farmakokinetičko podispitivanje
Datum i verzija: 4. lipnja 2018.
Cilj podispitivanje:
Ovo ispitivanje biti će provedeno unutar aktivnog ispitivanja Faze 3 sulopenema u svrhu generiranja potvrdnih podataka za PK profil populacije IV i peroralnih režima sulopenema. |
|
| E.3 | Principal inclusion criteria |
1. Adults ≥18 years of age with more than 24 hours of urinary symptoms attributable to a UTI
2. Patient or the patient’s legally acceptable representative able to provide a signed written informed consent prior to any study-specific procedures.
3. Clinically documented pyelonephritis or complicated urinary tract infection:
a) Pyelonephritis with normal anatomy, OR
b) Complicated UTI as defined by one or more of the following factors:
i. The presence of an indwelling urethral catheter
ii. >100 mL of residual urine after voiding
iii. Neurogenic bladder
iv. Obstructive uropathy due to nephrolithiasis, tumor or fibrosis
v. Azotemia (blood urea nitrogen [BUN] > 20 mg/dL and BUN/creatinine ratio <15) due to intrinsic renal disease
vi. Urinary retention in men possibly due to benign prostatic hypertrophy
vii. Surgically modified or abnormal urinary tract anatomy
4. At least two of the following signs or symptoms:
a) Rigors, chills or fever/hypothermia with temperature (oral, rectal, tympanic, temporal) >100.4ºF or 38ºC, or <95ºF or 35ºC
b) Flank pain or pelvic pain
c) Nausea or vomiting
d) Dysuria, urinary frequency or urinary urgency
e) Costovertebral angle tenderness on physical examination
5. A mid-stream urine specimen with:
a) a machine-read dipstick positive for nitrite AND
b) evidence of pyuria as defined by either:
i. a machine-read dipstick positive for leukocyte esterase AND/OR
ii. at least 10 white blood cells per cubic millimeter on microscopic analysis of unspun urine AND/OR
iii. White blood cell count ≥10 cells/HPF in urine sediment |
1. Odrasli ispitanici od ≥18 godina sa simptomima pripisivim infekciji mokraćnog sustava u trajanju duljem od 24 sata.
2. Ispitanik ili njegov zakonski zastupnik mogu potpisati pisani i Informirani pristanak prije provođenja bilo kojeg postupka specifičnog za ispitivanje.
3. Klinički dokumentiran pijelonefritis ili infekcija mokraćnog sustava:
a) pijelonefritis s normalnom anatomijom ili
b) komplicirana infekcija mokraćnog sustava definirana s jednim ili više sljedećih čimbenika:
i. postojanje ugrađenoga mokraćnoga katetera
ii. >100 ml rezidualne mokraće nakon mokrenja
iii. neurogeni mjehur
iv. opstruktivna uropatija zbog bubrežnih kamenaca, tumora ili fibroze
v. azotemija (dušična urea u krvi >20 mg/dl i omjer dušične uree u krvi i kreatinina <15) zbog intrinzične bolesti bubrega
vi. zadržavanje mokraće u muškaraca, moguće zbog benigne hipertrofije prostate
vii. kirurški promijenjena ili nenormalna anatomija mokraćnog sustava.
4. Najmanje dva od sljedećih znakova ili simptoma:
a) drhtavica, zimica ili vrućica/ pothlađenost s temperaturama (mjerenim oralno, rektalno, u zvukovodu ili na čelu) >100,4 ° F ili 38 ° C ili <95 ° F ili 35 ° C
b) bolovi u slabinama ili području zdjelice
c) mučnina ili povraćanje
d) dizurija, učestalo mokrenje ili učestalo tjeranje na mokrenje
e) bolovi u lumbalnom području na fizikalnom pregledu.
5. Uzorak mokraće iz srednjeg mlaza sa:
a) strojno očitanim mjernim štapićem pozitivnim na nitrite i
b) dokaz piurije definirane kao:
i. strojno očitan mjerni štapić pozitivan na leukocitnu esterazu i/ ili
ii. najmanje 10 bijelih krvnih zrnaca po kubičnom milimetru na mikroskopskoj analizi necentrifugirane mokraće i/ ili
iii. broj bijelih krvnih zrnaca ≥10 stanica u sedimentu mokraće u vidljivom polju pod velikim povećanjem.
|
|
| E.4 | Principal exclusion criteria |
1. Receipt of effective antibacterial drug therapy for cUTI for a continuous duration of more than 24 hours in the 72 hours prior to randomization. Patients who have objective documentation of clinical progression of cUTI while on antibacterial drug therapy, or patients who received antibacterial drugs for surgical prophylaxis and then develop cUTI, may be appropriate for enrollment.
2. Subjects with an organism isolated from the urine within the last year known to be resistant to ertapenem.
3. Severe structural or functional urinary tract abnormality responsible for an intractable infection which in the opinion of the investigator would require > 10 days of therapy or post-treatment prophylaxis (eg. patients with chronic vesiculo-ureteral reflux).
4. Uncomplicated UTI
5. Patients with paraplegia/quadriplegia
6. Hypotension with systolic blood pressure < 90 mm Hg
7. Complicated UTI associated with complete obstruction, emphysematous pyelonephritis, known or suspected renal or perinephric abscess or expected to require surgical intervention (not placement of catheters, stents or nephrostomy tubes) to achieve cure
8. Patients with a known history of myasthenia gravis
9. Patients who require concomitant administration of tizanidine or valproic acid
10. Patients with a history of allergy to carbapenems or quinolones or amoxicillin-clavulanate or other beta-lactams, or hypersensitivity to probenecid
11. Renal transplantation
12. Patients requiring hemodialysis, hemofiltration or peritoneal dialysis
13. Acute or chronic prostatitis
14. High risk for cUTI caused by Pseudomonas spp. (eg,. history of prior UTI due to Pseudomonas spp, recent steroid use (>40 mg/day equivalent prednisolone for 5 days or more in the 30 days prior to randomization), multiple sclerosis, chronic supra-pubic catheter)
15. Chronic indwelling catheters or stents (>2 weeks)
16. Ileal loops or vesico-ureteral reflux
17. Recent trauma to the pelvis or urinary tract within the prior 30 days
18. History of seizures
19. Patients with a history of blood dyscrasias
20. Patients with a history of uric acid kidney stones
21. Patients with acute gouty attack
22. Patients on chronic methotrexate therapy
23. Females of child-bearing potential who are unable to take adequate contraceptive precautions (refer to Section 4.4.1), have a positive pregnancy test result within 24 hours of study entry, are otherwise known to be pregnant, or are currently breastfeeding an infant.
24. Male subjects who do not agree to use an effective barrier method of contraception (refer to Section 4.4.2) during the study and for 28 days after dosing
25. Patient is known to have a history of liver disease or neutropenia as defined by the following laboratory criteria:
a. Alanine aminotransferase (ALT)or aspartate aminotransferase (AST) >3 X Upper Limit of Normal (ULN)
b. Total bilirubin >2 X ULN
c. Neutropenia (absolute neutrophil count <1000 cells/mm3)
26. Patients participating in any other clinical study that involved the administration of an investigational medication at the time of presentation, during the course of the study, or who had received treatment with an investigational medication in the 30 days prior to study enrollment, or had previously been randomized to this study or had been treated with sulopenem.
27. Patients immunocompromised as evidenced by any of the following:
a. Human immunodeficiency virus (HIV) infection, with either a recent (in the past 6 months) acquired immune deficiency syndrome-defining condition or a CD4 + T lymphocyte count <200/mm3
b. Systemic or hematological malignancy requiring chemotherapeutic or radiation/immunologic interventions within 6 weeks prior to randomization or anticipated to begin prior to completion of study
c. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40 mg/day equivalent prednisolone for 5 days or more in the 30 days prior to randomization).
28. Patient unlikely to comply with protocol e.g., uncooperative attitude, inability to return for follow-up visits, and unlikely to complete the study.
29. Patient considered unlikely to survive the 4-week study period or has a rapidly progressive or terminal illness, including septic shock that was associated with a high risk of mortality. |
1. Primanje učinkovitog antibakterijskog liječenja komplicirane infekcije mokraćnog sustava u kontinuiranom trajanju duljem od 24 sata u 72 sata prije randomizacije. Bolesnici koji imaju objektivno dokumentiranu kliničku progresiju komplicirane infekcije mokraćnog sustava tijekom terapije antibakterijskim lijekom ili bolesnici koji su antibakterijske lijekove primali radi profilakse zbog kirurškog zahvata, a zatim dobili kompliciranu infekciju mokraćnog sustava, mogu biti podobni za uključenje.
2. Bolesnici kojima je u zadnjih godinu dana u mokraći izoliran organizam otporan na ertapenem.
3. Ozbiljne strukturne ili funkcionalne abnormalnosti mokraćnog sustava odgovorne za intraktabilnu infekciju koja bi prema mišljenju ispitivača zahtijevala >10 dana terapije ili profilakse nakon terapije (na primjer, bolesnici s kroničnim vezikoureteralnim refluksom).
4. Nekomplicirana infekcija mokraćnog sustava.
5. Bolesnici s paraplegijom ili kvadriplegijom.
6. Nizak krvni tlak sa sistoličkim tlakom <90 mmHg.
7. Komplicirana infekcija mokraćnog sustava povezana s potpunom opstrukcijom, emfizematičnim pijelonefritisom, poznatim renalnim ili perinefričnim apscesom ili sumnjom na njega ili očekivani kirurški zahvat (osim postavljanja katetera, prohodnica ili cjevčica za nefrostomiju) da bi se došlo do izlječenja.
8. Bolesnici s poviješću mijastenije gravis.
9. Bolesnici kojima je potrebna popratna primjena tizanidina ili valproične kiseline.
10. Bolesnici s poviješću alergija na karbapeneme ili kinolone ili amoksicilin-klavulanate ili druge beta-laktame ili preosjetljivosti na probenecid.
11. Presađivanje bubrega.
12. Bolesnici kojima je potrebna hemodijaliza, hemofiltracija ili peritonealna dijaliza.
13. Akutna ili kronična upala prostate.
14. Visok rizik od komplicirane infekcije mokraćnog sustava izazvane bakterijama Pseudomonas spp. (na primjer, povijest infekcija mokraćnog sustava zbog bakterije Pseudomonas spp., nedavno korištenje steroida [>40 mg na dan ekvivalenta prednizolona tijekom 5 dana ili dulje u 30 dana prije randomizacije], multipla skleroza, trajni suprapubični kateter).
15. Trajni ugrađeni kateteri ili prohodnice (>2 tjedna).
16. Ilealne petlje ili vezikoureteralni refluks.
17. Trauma u području zdjelice ili mokraćnog sustava u prethodnih 30 dana.
18. Povijest napadaja.
19. Bolesnici s poviješću krvne diskrazije.
20. Bolesnici s poviješću bubrežnih kamenaca koje je stvorila mokraćna kiselina.
21. Bolesnici s akutnim napadom gihta.
22. Bolesnici na kroničnoj terapiji metotreksatom.
23. Bolesnice koje mogu zatrudnjeti koje nisu sposobne uzimati odgovarajuću kontracepciju (pogledati poglavlje 4.4.1), koje imaju pozitivan rezultat testa na trudnoću u 24 sata prije uključivanja u ispitivanje ili za koje se zna da su trudne ili trenutno doje novorođenče.
24. Bolesnici koji ne pristanu na korištenje učinkovite barijerne metode kontracepcije (pogledati poglavlje 4.4.2) tijekom ispitivanja i 28 dana nakon primanja lijeka.
25. Bolesnici koji imaju povijest bolesti jetre ili neutropeniju definiranu prema sljedećim rezultatima laboratorijskih testova:
a. alanin aminotransferaza (ALT) ili aspartat aminotransferaza (AST) > 3 x od gornje granice normalnih vrijednosti
b. ukupni bilirubin > 2 x od gornje granice normalnih vrijednosti
c. neutropenija (apsolutni broj neutrofila <1000 stanica/mm3).
26. Bolesnici koji sudjeluju u bilo kojem drugom kliničkom ispitivanju koje uključuje primjenu eksperimentalnog lijeka u trenutku prezentacije ili tijekom ispitivanja ili su primali liječenje eksperimentalnim lijekom u 30 dana prije uključivanja u ispitivanja ili su već bili randomizirani u ovo ispitivanje ili su već liječeni sulopenemom.
27. Imunokompromitirani bolesnici s dokazom bilo čega od sljedećeg:
a. infekcija virusom ljudske imunodeficijencije (HIV) s nedavnim (u zadnjih 6 mjeseci) stanjem stečenog sindroma imunodeficijencije ili s brojem CD4+ T limfocita <200/mm3
b. sistemska ili krvna zloćudna bolest koja zahtijeva liječenje kemoterapijom ili zračenjem ili imunološko liječenje u 6 tjedana prije randomizacije ili očekivanje da će takvo liječenje početi prije završetka ispitivanja
c. terapija imunosupresivima, uključujući održavanje terapije kortikosteroidima (>40 mg na dan ekvivalenta prednizolona tijekom 5 dana ili dulje u 30 dana prije randomizacije).
28. Vjerojatnost da bolesnik neće biti usklađen s planom ispitivanja, na primjer zbog nekooperativnog stava, nemogućnosti dolaska na posjete za praćenje i vjerojatnost da neće završiti s ispitivanjem.
29. Očekivanje da bolesnik neće preživjeti 4 tjedna razdoblja ispitivanja ili ima rapidno progresivnu ili terminalnu bolest, uključujući septički šok, povezanu s visokom stopom smrtnosti.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
A patient will be defined as a responder at Day 21 (± 1day; TOC) if the following criteria are met:
• The patient is alive
• Resolution of dysuria, urinary frequency, urinary urgency, suprapubic pain, and flank pain or pelvic pain if present at trial entry and no new symptoms per the patient’s questionnaire
- Baseline symptoms associated with anatomic abnormalities that predispose to cUTI (e.g., symptoms associated with the presence of an indwelling urinary catheter) do not need to be resolved.
• The patient has received no rescue therapy for cUTI
- If an antibiotic is given for other reasons then the patient will not be considered a non-responder for cUTI
• The bacterial pathogen found at ≥ 10*5 CFU/mL in the trial entry urine culture is reduced to <103 CFU/mL in the urine culture taken at the specified study visit and the blood culture is eradicated if one was present at baseline
All other patients will be considered non-responders unless data are unavailable to determine if the patient is a responder or non-responder. In this case, the patient will be considered as having an indeterminate response. Deaths not due to cUTI will also be considered indeterminate. Patients with an indeterminate response are included in the denominator for determination of the response rate in the ITT populations. |
Smatrati će se da je ispitanik odgovorio na terapiju na 21. dan (± 1 dan; posjet za utvrđivanje izlječenja) ako su ispunjeni sljedeći kriteriji:
• Ispitanik je živ
• Nema pojave disurije, učestalosti mokrenja, urinarne hitnosti, suprapubične boli i boli u bokovima ili zdjelične boli ako su prisutni na početku ispitivanja i nema novih simptoma po upitniku ispitanika
- Simptomi koji su bili prisutni na nultoj točki povezani s anatomskim abnormalnostima koje predisponiraju za cUTI (npr. Simptomi povezani s prisutnošću urinarnog katetera) ne moraju biti riješeni.
• Ispitanik nije primio terapiju spašavanja za cUTI
- Ako se antibiotik daje iz drugih razloga, ispitanik se neće smatrati neodgovarajućim za cUTI
• Bakterijski patogen koji se nalazi u kulturi urina na ulasku u ispitivanje smanjen je sa ≥ 10*5 CFU/mL na <103 CFU / mL na kulturu urina uzetog tijekom specificiranog studijskog posjeta, a kultura krvi se eliminira ako je bilo prisutno na "baseline" posjeti.
Svi ostali ispitanici smatrat će se nereceptivnima osim ako podaci nisu dostupni da bi se utvrdilo je li ispitanik odgovorio na terapiju ili nije. U tom slučaju, smatra se da ispitanik ima nedefiniran odgovor. Smrtni slučajevi koji nisu uzrokovani cUTI-om također će se smatrati nedefiniranima. Pacijenti s nedefiniranim odgovorom uključeni su u nazivnik za određivanje stope odgovora u ITT populacijama. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At Day 21 (± 1day; TOC) |
| Na 21. dan (± 1 dan; posjet za utvrđivanje izlječenja) |
|
| E.5.2 | Secondary end point(s) |
Microbiologic Response is assessed at Day 21 (± 1day; TOC) using the definitions listed below:
Eradication:
A urine culture taken within 48 hours prior to randomization (baseline) and compared with the culture from the Day 5 visit, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline) visit, or Day 21 (± 1day; TOC) visit showed that the urine culture obtained at the relevant visit demonstrated <103 CFU/mL of the original uropathogen. For patients with bacteremia at Baseline, the follow-up repeat blood cultures are sterile.
Persistence:
A uropathogen present at baseline grew at ≥103 CFU/mL at the time-point of analysis, i.e. Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline), or Day 21 (± 1day; TOC). For patients with bacteremia at Baseline, follow-up blood cultures after 72 hours of treatment show growth of baseline pathogen.
Persistence with increasing MIC:
A urine culture taken after at least 2 full days of treatment grew ≥103 CFU/mL of the original uropathogen species and displayed ≥4-fold higher MIC to study drug therapy after treatment with study therapy at Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline), or Day 21 (± 1day; TOC) respectively. For patients with bacteremia at Baseline, follow-up blood cultures after 72 hours of treatment show growth of baseline pathogen and displayed ≥4-fold higher MIC to study drug therapy.
Indeterminate:
Patient was lost to follow-up or an assessment was not undertaken such that no urine culture was obtained; culture is contaminated or culture results could not be interpreted for any reason, at either the Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline), or the Day 21 (± 1day; TOC) visit. |
Sekundarni ciljevi
• Usporediti mikrobiološki odgovor po ispitaniku u skupinama liječenja.
• Usporediti ishode učinkovitosti u relevantnim vremenskim točkama.
• Procijeniti sigurnosni profil obje terapije.
• Procijeniti populacijski farmakokinetički profil sulopenema i/ ili sulopenem-etzadroksila primjenjivanog zajedno s probenecidom.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At Day 21 (± 1day; TOC) |
| Na 21. dan (± 1 dan; posjet za utvrđivanje izlječenja) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Croatia |
| Czech Republic |
| Estonia |
| Georgia |
| Hungary |
| Latvia |
| Poland |
| Russian Federation |
| Serbia |
| Slovakia |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS |
| Posljednja posjeta posljednjeg ispitanika |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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