| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult patients with infections in the abdomen that requires surgical intervention and treatment with antibiotics. |
|
| 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 determine the PK of ATM-AVI and to assess the safety of ATM-AVI in the patient population |
|
| E.2.2 | Secondary objectives of the trial |
To assess the treatment outcome per patient at the test of cure (TOC) visit;
To assess the relationship between exposure and clinical cure for ATM-AVI |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study-specific procedures.
2. Male or female from 18 to 90 years of age inclusive.
3. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met
4. Diagnosis of cIAI
EITHER:
Intra-operative/postoperative enrolment with visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery. Specimens from the surgical intervention must be sent for culture. Patients who undergo a surgical procedure with complete fascial closure are appropriate for the trial. The skin incision may be left open for purposes of wound management as long as complete fascial closure is accomplished. The patient has at least 1 of the following diagnosed during the surgical intervention:
(a) Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall
(b) Diverticular disease with perforation or abscess
(c) Appendiceal perforation or peri-appendiceal abscess
(d) Acute gastric or duodenal perforations, only if operated on >24 hours after diagnosis
(e) Traumatic perforation of the intestines, only if operated on >12 hours after diagnosis
(f) Secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
(g) Intra abdominal abscess (including of liver or spleen provided that there is extension beyond the organ with evidence of intraperitoneal involvement)
OR
Preoperative enrollment where the following clinical criteria are met with confirmation of infection by surgical intervention within 24 hours of entry:
(a) Requirement for surgical intervention, defined per protocol as open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery
(b) Evidence of systemic inflammatory response, with at least one of the following:
Fever (defined as body temperature >38°C) or hypothermia with a core body temperature <35°C
Elevated white blood cells (>12000 cells/µL)
Systolic blood pressure <90 mmHg or mean arterial pressure <70 mmHg, or a systolic blood pressure decrease of >40 mmHg
Increased heart rate ( >90 bpm) and respiratory rate (>20 breaths/min)
Hypoxemia (defined as oxygen saturation < 95% by pulse oximetry)
Altered mental status.
(c) Physical findings consistent with intra-abdominal infection, such as:
Abdominal pain and/or tenderness, with or without rebound
Localized or diffuse abdominal wall rigidity
Abdominal mass.
(d) Supportive radiologic imaging findings of intra-abdominal infection such as perforated intraperitoneal abscess detected on computed tomography scan, magnetic resonance image, or ultrasound.
(e) Specimens from the surgical intervention will be sent for culture for isolation of both aerobic and anaerobic bacteria.
5. Patients who failed prior antibacterial treatment for their current cIAI can be enrolled but must:
• Have a known or suspected pathogen causing cIAI resistant to the prior therapy while assuming the organism is sensitive to ATM-AVI.
• Require surgical intervention.
Such patients can be enrolled before the results of the culture are known (see also exclusion criterion 10).
6. Patient must have or will have a surgical intervention within 24 hours (before or after) the administration of the first dose of study drug
|
|
| E.4 | Principal exclusion criteria |
1. Involvement in the planning and/or conduct of the study
2. Patient has been previously enrolled in this study, previously treated with ATM-AVI or previously participated in an investigation study containing AVI
3. Patient has participated or intends to participate in any other clinical study that involves the administration of an investigational medication at the time of presentation, during the course of the study, or during the 30 days prior to study start.
4. Patient has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem, monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the respective (investigational) medicinal products to be administered during the study
5. Patient has a diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery within 24 hours of diagnosis (these are considered situations of peritoneal soiling before infection has become established); another intra-abdominal process in which the primary etiology is not likely to be infectious
6. Patient has a simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess or ischaemic/necrotic intestine without perforation
7. Patient has a cIAI managed by staged abdominal repair (STAR), open abdomen technique or any situation where infection source control is not likely to be achieved or in whom the abdomen is left open, or those unlikely to solely respond to antimicrobial therapy
8. At screening, if it is known the patient has an infection due to a pathogen that is unlikely to respond to ATM-AVI plus metronidazole treatment
9. Patient has a rapidly progressive (expected to die in <30 days) or terminal illness, including acute hepatic failure, respiratory failure or septic shock with a high risk of mortality due to other causes than cIAI
10. Patient has received systemic antibacterial agents within the 72-hour period prior to study entry, unless either of the following pertains:
(a) Patient has a new infection (not considered a treatment failure) and the following is met:
• Patient received no more than 24 hours of total prior antibiotic therapy within the 72 hour period prior to study entry
(b) Patient is considered to have failed the previous treatment regimen
11. Patient has a concurrent infection that may interfere with the evaluation of clinical cure for the study therapy
12. Patient needs effective concomitant systemic antibacterials (oral, IV, or intramuscular) or antifungals in addition to the investigational product and metronidazole
13. Patient has creatinine clearance ≤50 ml/min. Note: following review of PK and safety data from the first 10 enrolled patients, and the confirmation of a provisional dose schedule, patients with a creatinine clearance of 31 – 50 mL/min may be included.
14. Patient has had acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis (any Child-Pugh class), acute hepatic failure, or acute decompensation of chronic hepatic failure
15. Presence of hepatic disease as indicated by aspartate aminotransferase (AST) or alanine transaminase (ALT) >3 × upper limit of normal (ULN) at Screening. Patients with AST and/or ALT >3 × ULN and < 5 × ULN are eligible if these elevations are acute, not accompanied by a total bilirubin ≥ 2xULN and documented by the investigator as being directly related to the infectious process being treated
16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert’s disease
17. Alkaline phosphatase (ALP) >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if this value is acute and directly related to the infectious process being treated.
18. Patients with an immunocompromising illness
19. Known active Clostridium difficile associated diarrhoea
20. Any other condition that, in the opinion of the investigator, may confound the results of the study or pose additional risks
21. Patient with a do not resuscitate order
22. Patient has an absolute neutrophil count <1000/µL
23. Patient has a hematocrit <25% or hemoglobin <8 gm/dL.
24. Patient has a platelet count <75,000/µL. Patients with a platelet as low as 50,000 /µL are permitted if the reduction is historically stable
25. Patient is currently receiving treatment with probenecid.
26. Patient is pregnant or breastfeeding or if of child bearing potential,
27. Patient is unlikely to comply with protocol,
28. Patient is currently receiving anti-convulsant therapy to prevent recurrence of a past history of seizures.
29. Patient has a prior liver, pancreas or small-bowel transplant.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Concentrations of ATM and AVI in plasma; concentration-time profile of ATM and AVI
The derived PK parameters Cmax, tmax, AUC(0-6), AUC(0-last), tlast, t1/2, Vss, Vz and CL for the patients undergoing intensive sampling on day 4;
2. Safety and tolerability as assessed by adverse events, physical examination, vital signs, ECGs, and laboratory assessments |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Sampling take Trough (within 10 min prior to IV infusion start), 0.5h 1, 2, 3 (within 15 minutes before IV infusion stop), 3.25, 3.5. 3.75, 4, 5, and 6 h after start of IV infusion on Day 4
2. AE, Physical exam, vital sign, ECG and laboratory assessments conducted from screening to last visit
|
|
| E.5.2 | Secondary end point(s) |
Proportion of patients with clinical cure at the TOC visit;
Correlation of derived PK parameters for ATM-AVI and clinical cure at TOC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at test of cure visit (Day 25 ± 3) |
|
| 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 | Yes |
| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| Last visit of last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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