A study to determine how the drug(ATM-AVI) is moved in your body and whether the drug is safe and tolerable for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults

• Register: EUCTR
• Last refreshed on: 29 January 2018
• Main ID: EUCTR2015-002726-39-DE
• Date of registration: 09/12/2015
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc.
• Public title: A study to determine how the drug(ATM-AVI) is moved in your body and whether the drug is safe and tolerable for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults
• Scientific title: A Phase IIa prospective, open-label, multicenter study to determine the pharmacokinetics (PK) and safety and tolerability of aztreonam-avibactam (ATM-AVI) for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults - REJUVENATE
• Date of first enrolment: 25/02/2016
• Target sample size: 40
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002726-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany, Spain

Contacts

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc.

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc.

Key inclusion & exclusion criteria

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)
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 ß-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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Product Name: AVIBACTAM
Product Code: AVI
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: avibactam sodium
CAS Number: 1192491-61-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 600-

Trade Name: AZACTAM 1 g vial
Product Code: J01DF01
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: aztreonam
CAS Number: 827611-49-4
Other descriptive name: AZTREONAM LYSINE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: Metronidazole 500 mg/ 100 ml intravenous infusion
Product Name: Metronidazole 500 mg/100 ml Intravenous
Product Code: SUB08922MIG
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: Metronidazole
CAS Number: 442-48-1
Current Sponsor code: Metronidazole
Other descriptive name: METRONIDAZOLE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Trade Name: AZACTAM 2 g
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: aztreonam
CAS Number: 827611-49-4
Other descriptive name: AZTREONAM LYSINE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 2-

Trade Name: AZACTAM 2 g
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: aztreonam
CAS Number: 827611-49-4
Other descriptive name: AZTREONAM LYSINE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 2-

Trade Name: AZACTAM 1 g
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: aztreonam
CAS Number: 827611-49-4
Other descriptive name: AZTREONAM LYSINE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: Aztreonam 1 g
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: aztreonam
CAS Number: 827611-49-4
Other descriptive name: AZTREONAM LYSINE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number:

Primary Outcome(s)

Main Objective: To determine the PK of ATM-AVI and to assess the safety of ATM-AVI in the patient population

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

Secondary Objective: 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

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

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: at test of cure visit (Day 25 ± 3)

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

Secondary ID(s)

D4910C00009/C3601001

NCT02655419

Source(s) of Monetary Support

Pfizer Inc.

IMI Combacte-Care consortium