| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Intra-abdominal infections. |
|
| 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". |
|
| 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 | 14.0 |
| 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. |
|
| 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
French subjects:subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category
1-Adult subjects least 18 years of age
N.B. Females of non-childbearing or childbearing potential may be enrolled. It is not contraindicated 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. Additionally, the subject agrees to one of the methods listed in the protocol for avoidance of pregnancy during the entire study treatment period:
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 first dose of study medication 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 must:
• Show lack of improvement or worsening in signs and symptoms of infection, including continued or worsening peritoneal findings
• Require additional surgical intervention which must be performed within 24 hours of first dose of study medication with no more than one pre-surgical dose of an antibiotic given for pre-operative prophylaxis.
AND/OR
• Be post-op and have required surgery within 24 hours prior to first dose of study medication with no more than one pre-surgical dose of an antibiotic given for pre-operative prophylaxis.
• Have 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 subjects with Bundle Branch Block
|
|
| E.4 | Principal exclusion criteria |
French subjects: the French subject has participated in any study using an
investigational drug during the previous 30 days.
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) of ≤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 10g/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 β-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 ≥2.5g/dl which is not related to the condition under study. |
|
| 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. |
|
| 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) |
|
| 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.) |
|
| 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). |
|
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose ranging, double dummy |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Canada |
| India |
| Israel |
| 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 | 12 |
| 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 |
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