| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| complicated intra-abdominal infection in adults |
| Soggetti adulti con infezioni intra-addominali complicate |
|
| E.1.1.1 | Medical condition in easily understood language |
| Infection inside the abdomen (also known as an intra-abdominal infection). the abdomen might also be thought of as `belly` or `tummy` |
| infezione dentro l'addome (pancia). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056570 |
| E.1.2 | Term | Intra-abdominal infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 evaluate the safety and tolerability of GSK2251052 in the treatment of adult subjects with cIAI. To evaluate the clinical and microbiological efficacy of GSK2251052 in microbiologically evaluable adult subjects with cIAI. |
| Valutare la sicurezza e la tollerabilita' di GSK2251052 nel trattamento di soggetti adulti con cIAI. Valutare l`€™efficacia clinica e microbiologica di GSK2251052 in soggetti adulti con cIAI valutabili da un punto di vista microbiologico. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the clinical and microbiological efficacy of GSK2251052 to meropenem in microbiologically evaluable adult subjects with cIAI. To evaluate the pharmacokinetics of GSK2251052 and characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship in this study population |
| Confrontare l`€™efficacia clinica e microbiologica di GSK2251052 rispetto a meropenem in soggetti adulti con cIAI valutabili da un punto di vista microbiologico. Valutare la farmacocinetica di GSK2251052 e caratterizzare la relazione farmacocinetica/farmacodinamica (PK/PD) in questa popolazione in studio. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Adult subjects least 18 years of age. N.B. Females of non-childbearing or childbearing potential may be enrolled. It is not contraidicated to enrol females of childbearing potential; however, they must have a negative pregnancy test at study entry and must have practiced adequate contraception for at least 30 days prior to study entry. 2. Subject has evidence of a systemic inflammatory response believed to be related to an intra-abdominal infectious process with no evidence of another infectious source (e.g., catheter related, lung, urinary tract) 3. Subject has an abnormal white blood cell count (>12,000/µL or <4,000/µL or >10% bands) PLUS one or more of the following • Fever, defined as >38°C oral, >38.5°C tympanic or >39°C rectal, within the last 24 hours • Heart rate of more than 90 beats per minute • Respiratory rate of more than 20 breaths per minute or a PaCO2 level of less than 32 mm Hg • Altered mental status thought due to an infectious process 4. Subject is post-op and required surgery within the last 24 hours prior to first dose of study medication OR subject requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) within 24 hours of study entry with no more than one pre-surgical dose of an antibiotic given for pre-operative prophylaxis. 5. Subject has a known Gram-negative pathogen(s) isolated prior to study entry or a suspected Gram-negative post-operative infection or has failed a prior Gram negative treatment regimen A subject enrolled as a failure of a previous antibacterial treatment regimen has to have: • Required surgical intervention • Lack of improvement or worsening in signs and symptoms of infection, including continued or worsening peritoneal findings • A culture positive for a Gram-negative pathogen (from an intra-abdominal site) N.B. Such subjects may be enrolled before the results of the culture are known but if the culture is negative, the subject must be removed from study drug therapy. 6. Subject requires antibacterial therapy for an anticipated duration of 7 days or more, in addition to surgical intervention, for one of the following eligible diagnoses: • Cholecystitis (including gangrenous cholecystitis) with rupture, perforation or progression of the infection beyond the gallbladder wall • Diverticular disease with perforation or abscess • Appendiceal perforation with duration of symptoms `‰¥48 hours AND imaging that is strongly suggestive of free fluid or abscess • Acute gastric and duodenal perforations, only if operated more than 24 hours after perforation occurred • Traumatic perforation of the intestine only if operated more than 12 hours after perforation occurred • Peritonitis due to perforated viscus, post-operative, or other focus of infection (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites) • Inflammatory bowel disease or ischemic bowel disease with bowel perforation 7. If pre-operative, subject must have peritoneal findings highly suspicious for cIAI, defined as one or more of the following: • Abdominal pain and/or tenderness • Localized or diffuse abdominal wall rigidity • An imaging procedure, ie. ultrasound or CT scan showing evidence of IAI • Mass • Ileus QTcB or QTcF < 450 msec; or QTc < 480 msec in subject with Bundle Branch Block |
| 1.Soggetti adulti di almeno 18 anni di eta'. Le donne potenzialmente fertili possono essere arruolate ma devono avere un test di gravidanza negativo al momento dell`arruolamento e devono accettare di utilizzare i metodi di contraccezione descritti nel protocollo. 2. Soggetti con evidenza di risposta infiammatoria sistemica presumibilmente imputabile ad un processo infettivo intra-addominale in assenza di evidenza di altra fonte infettiva (ad esempio correlata a catetere, polmonare o del tratto urinario).3. Soggetti con conta leucocitaria alterata (bande >12,000/µL o <4,000/µL o >10%) ASSOCIATA A uno dei seguenti elementi: •Febbre, definita come >38°C misurata per via orale, >38.5°C per via timpanica, >39°C per via rettale, nelle 24 ore precedenti •Frequenza cardiaca superiore ai 90 battiti al minuto •Frequenza respiratoria superiore a 20 respiri al minuto oppure livello PaCO2 inferiore a 32 mm Hg •Stato mentale alterato che si ritiene causato da un processo infettivo 4.Soggetti in stato post-operatorio e per cui e' stato necessario un intervento chirurgico nelle 24 ore precedenti la prima dose di farmaco OPPURE soggetti che necessitano di intervento chirurgico (ad esempio, laparotomia, chirurgia laparoscopica o drenaggio percutaneo di un ascesso) entro 24 ore dall`€™ingresso in studio con non piu' di una dose di antibiotico pre-intervento somministrata come profilassi pre-operatoria. 5.Soggetti con patogeni Gram-negativi isolati prima dell`€™ingresso in studio o sospetta infezione post-operatoria Gram-negativa o per cui un precedente regime pre-operatorio Gram-negativo e' fallito. Un soggetto arruolato in base al fallimento di un precedente regime terapeutico antibatterico dovra' presentare i seguenti elementi: •Necessita' di un intervento chirurgico •Assenza di miglioramento o un peggioramento nei degli segni e sintomi di infezione, compresa la continuazione o il peggioramento degli esiti peritoneali •Coltura positiva per patogeni Gram-negativi (da un sito intra-addominale) 6.Soggetti che necessitano di una terapia antibatterica per una durata prevista di 7 o piu' giorni, oltre all`€™intervento chirurgico, per una delle seguenti diagnosi eleggibili: •Colecistite (inclusa la colecistite cancrenosa) con rottura, perforazione o progressione dell`€™infezione oltre la parete della colecisti •Patologia diverticolare con perforazione o ascesso •Perforazione appendicolare con durata dei sintomi `‰¥48 ore E indagine per immagini fortemente suggestiva di fluido libero o ascesso • Perforazioni gastriche o duodenali acute, solo se operate piu' di 24 ore dopo il verificarsi della perforazione • Perforazione traumatica dell`€™intestino, solo se operata piu' di 12 ore dopo il verificarsi della perforazione • Peritonite dovuta a viscero perforato, post-chirurgia o altro focolare di infezione (ma non peritonite batterica spontanea associata a cirrosi e ascite cronica) • Patologia infiammatoria intestinale o patologia ischemica intestinale con perforazione dell`€™intestino. 7. Se in fase pre-operatoria, i soggetti dovranno presentare esiti peritoneali fortemente sospetti per cIAI, definiti come uno dei seguenti elementi: • Dolore e/o sensibilita' addominale • Rigidita' localizzata o diffusa della parete addominale • Procedura per immagini, ossia ecografia o TAC, che mostra evidenza di IAI • Massa • Ileo QTcB o QTcF < 450 msec; o QTc < 480 msec in soggetti con blocco di branca |
|
| E.4 | Principal exclusion criteria |
| 1. Subject has a known or suspected diagnosis of the following: - Abdominal wall abscess - Small bowel obstruction or ischemic bowel disease without perforation - Traumatic bowel perforation with surgery within 12 hours - Perforation of gastroduodenal ulcer with surgery within 24 hours - Any other intra-abdominal processes in which the primary etiology is not likely to be infectious. - Simple cholecystitis - Gangrenous or suppurative cholecystitis without rupture or extension beyond the gallbladder wall - Simple appendicitis - Acute suppurative cholangitis - Infected, necrotizing pancreatitis, or pancreatic abscess 2. Subject must not be managed by staged abdominal repair or open abdominal technique 3. Subject is known at study entry, prior to randomization to study medication, to have a cIAI caused by a Gram-positive pathogen or a pathogen resistant to the study antimicrobial agent. 4. Subject has an APACHE II score >20. 5. Subject is considered unlikely to survive the 4 6 week study period or has any rapidly progressing disease or immediately life-threatening illness (including acute hepatic failure, respiratory failure or septic shock). 6. Subject requires treatment with concomitant systemic antibacterial agents other than vancomycin. 7. Subject has moderate to severe impairment of renal function including a calculated creatinine clearance (CrCl) less than or equal to 50 mL/min; requirement for peritoneal dialysis, hemodialysis, or hemofiltration; or oliguria (less than 20 mL urine output per hour over 24 hours). 8. Subject has a prior history of seizures or CNS abnormality and/or is using concomitant medications with seizure potential 9. Subject requires probenecid or valproic acid medications 10. Subject has evidence of known or pre-existing severe hepatic disease(Child-Pugh score of B or C) 11. Subject has a known baseline hemoglobin less than 10 g/dL ,hematocrit less than 30% and/or a known reticulocyte count of >5% (ie, reticulocytes >5% of total RBC mass) 12. Subject has known neutropenia or is anticipated to develop neutropenia during the course of the study (ie, new chemotherapy patient), with absolute neutrophil count less than 1000 cells/mm3 13. Subject has a known platelet count less than 75,000 cells /mm3 (subjects with platelet counts as low as 50,000 cells /mm3 are eligible if the reduction is historically stable) 14. Subject has an immunocompromising illness; including known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS),organ (including bone marrow) transplant recipients, and hematological malignancy, and immunosuppressive therapy , including high-dose corticosteroids (e.g., greater than 40mg prednisone or equivalent per day for greater than two weeks) 15. Subject has participated in any investigational drug or device study within 30 days of study entry or within 5 half-lives, whichever is longer. 16. Subject has had more than 24 hours of systemic antibacterial therapy for cIAI within the 48 hour period prior to first dose of IV study drug therapy, unless there is a documented lack of clinical response to such therapy 17. Subject has a history of moderate or severe hypersensitivity to Meropenem or to lactam antibiotics 18. Subject has previously received treatment with GSK2251052 19. Subject is pregnant or nursing 20. Subject, in the opinion of the investigator, may be significantly compromised by a potential drop in haemoglobin > equal to 2.5 g/dl which is not related to the condition under study. |
| 1. Soggetti con diagnosi nota o sospetta di uno dei seguenti elementi: - Ascesso della parete addominale - Ostruzione dell`€™intestino tenue o patologia ischemica dell`€™intestino senza perforazione - Perforazione intestinale traumatica con intervento entro 12 ore - Qualsiasi altro processo intra-addominale per cui non e' probabile che l`€™eziologia primaria sia di tipo infettivo - Colecistite semplice - Colecistite cancrenosa o suppurativa senza rottura o estensione oltre la parete della colecisti - Appendicite semplice - Colangite suppurativa acuta - Pancreatite infettiva, necrotizzante o ascesso pancreatico. 2. Soggetti sottoposti a tecniche di riparazione addominale con interventi in serie (STAR) o con tecniche ad addome aperto 3. Soggetti con cIAI nota, all`€™ingresso nello studio, prima della randomizzazione al trattamento in studio, causata da un patogeno Gram-positivo o da un patogeno resistente all`€™agente antimicrobico in studio 4. Soggetti con punteggio APACHE II >20 5. Soggetti con un`€™aspettativa di vita inferiore alle 4-6 sett del periodo di studio o con una patologia a rapida progressione o con malattia con immediato pericolo di vita (compresa insufficienza epatica acuta, insufficienza respiratoria o shock settico) 6. Soggetti che richiedono trattamento con agenti antibatterici sistemici diversi da vancomicina 7. Soggetti con deterioramento moderato o severo della funzione renale, inclusa clearance della creatinina (CrCl) calcolata < uguale a 50 mL/min; necessita' di dialisi peritoneale, emodialisi o emofiltrazione; od oliguria 8. Soggetti con anamnesi positiva per attacchi epilettici o anormalita' del sistema nervoso centrale e/o che utilizzano farmaci concomitanti potenzialmente causa di attacchi epilettici 9. Soggetti che richiedono il trattamento con probenecid o acido valproico 10. Soggetti con evidenza di patologia epatica grave nota o pregressa (punteggio Child-Pugh B o C) 11. Soggetti con nota emoglobina basale inferiore a 10 g/dL, ematocrito inferiore a 27% e/o conta reticolocitica > 5% (cioe',reticolociti > 5% della massa totale dei globuli rossi) 12. Soggetti con neutropenia nota o che per i quali si prevede che sviluppino neutropenia nel corso dello studio (cioe' nuovi pazienti in chemioterapia), con conta assoluta dei neutrofili inferiore a 1000 cell/mm3 13. Soggetti con conta piastrinica nota inferiore a 75.000 cellule/mm3 (i soggetti con conte piastriniche fino a 50.000 cell/mm3 sono eleggibili se la riduzione e' storicamente stabile) 14. Soggetti con malattia immuno-compromettente, comprese l`€™infezione nota da virus HIV o la sindrome da immunodeficienza acquisita (AIDS), sottoposti a trapianto d`€™organo (incluso il midollo osseo) e con patologia onco-ematologica, e pazienti in terapia immunosoppressiva, compresi i corticosteroidi ad alto dosaggio (ad es. prednisone a dosaggi superiori a 40 mg al giorno o farmaco equivalente per piu' di due settimane) 15. Soggetti che hanno partecipato a qualsiasi studio con un farmaco sperimentale o un dispositivo medico nei 30 giorni precedenti l`€™ingresso in studio o entro 5 emivite, a seconda di quale dei due periodi di tempo sia piu' lungo 16. Soggetti con terapia antibatterica sistemica per cIAI di durata superiore alle 24 ore nelle 48 ore precedenti la somministrazione della prima dose di terapia con il farmaco in studio per via endovenosa, a meno che non ci sia assenza documentata di risposta clinica a tale terapia 17. Soggetti con storia di ipersensibilita' moderata o severa a meropenem o agli antibiotici betalattamici 18. Soggetti precedentemente sottoposti a trattamento con GSK225105 19. SOggetti in gravidanza o allattamento. 20. Soggetti, che a giudizio dello sperimentatore, potrebbero essere significativamente compromessi da un abbassamento dell`emoglobina < uguale 2.5g/dl non correlata alla condizione in studio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Safety evaluation of data from clinical laboratory tests, spontaneous/elicited adverse. event reporting, ECGs and vital signs in all enrolled subjects who had at least one dose of study medication. - Efficacy outcome measure is the clinical response at the Test of Cure Visit in subjects who have a qualifying Gram-negative pathogen at Baseline and who have a minimum of 5 days of IV therapy. |
| Valutazioni di sicurezza dei dati degli esami clinici di laboratorio, notifiche spontanee dedotte degli eventi avversi, ECG e segni vitali per tutti i soggetti arruolati che hanno assunto almeno una dose di farmaco in studio. Per la misurazione dell`€™esito di efficacia si utilizzera' la risposta clinica alla Visita Test of Cure nei soggetti per i quali e' stato individuato un patogeno Gram-negativo alla visita basale e la cui terapia endovenosa ha una durata di almeno 5 giorni. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary end point is to be evaluated at the test of cure visit (5 to 9 days post IV treatment) |
| L`€™endpoint primario e' la risposta clinica (cura o fallimento) alla visita Test of Cure (5-9 giorni dopo l`€™ultima dose) |
|
| E.5.2 | Secondary end point(s) |
| • Microbiological response at the Test of Cure Visit • Clinical response at the End of IV Therapy Visit • Microbiological response at the End of IV Therapy Visit • Clinical response at the Late Follow-up Visit • Microbiological response at the Late Follow-up Visit • Therapeutic response (combined clinical and microbiological response) at the Test of Cure Visit, Late Follow-up Visit and End of IV Therapy Visit.) |
| • Risposta microbiologica alla Visita Test of Cure • Risposta clinica alla Visita di fine della terapia endovenosa • Risposta microbiologica alla Visita di fine della terapia endovenosa • Risposta clinica all`€™ultima visita di Follow-up • Risposta microbiologica all`€™ultima visita di Follow-up • Risposta terapeutica (risposta clinica e microbiologica combinate) alla Visita Test of Cure, all`€™ultima visita di Follow-up e alla Visita di fine della terapia endovenosa. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary end points are to be evaluated at the test of cure visit (5 to 9 days post IV treatment), End of IV therapy visit and Late follow-up visit (21 -28 days post IV treatment). |
| - visita Test of Cure (5-9 giorni dopo l`€™ultima dose) - visita di fine terapia endovenosa - 21-28 giorni dopo trattamento endovenoso |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| double-dummy |
| double-dummy, dose ranging |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 40 |
| 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 |
| Russian Federation |
| South Africa |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
