Clinical trial NCT06462235: A Study to Learn About the Study Medicine Aztreonam-Avibactam (ATM-AVI) in Infants and Newborns Admitted in Hospitals With Bacterial Infection (CHERISH)
Official title: A PHASE 2A, 2-PART, OPEN-LABEL, NON-RANDOMIZED, MULTICENTER, SINGLE AND MULTIPLE DOSE TRIAL TO EVALUATE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF AZTREONAM AND AVIBACTAM ± METRONIDAZOLE IN NEONATES AND INFANTS FROM BIRTH TO LESS THAN 9 MONTHS OF AGE WITH SUSPECTED OR CONFIRMED INFECTIONS DUE TO GRAM-NEGATIVE PATHOGENS REQUIRING INTRAVENOUS ANTIBIOTIC TREATMENT
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Gram-negative Bacterial Infection
Keywords: gram-negative
aztreonam-avibactam
neonate
infant
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
First posted: 2024-06-17
Enrollment: 48
Sex: ALL
Maximum age (years): 39
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Non-randomized, 2-part with four age cohorts in each part
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to learn about the safety and effects of ATM-AVI for the possible treatment of infections caused by a type of bacteria called gram-negative bacteria.

The study medicine is a combination of an antibiotic, aztreonam (ATM), and another medicine, avibactam (AVI), which is used to help stop bacteria from being resistant to antibiotics. Antibiotics are medicines that fights bacteria and infections.

The study will include newborns and infants up to 9 months of age who are admitted in the hospital.

The study is conducted in 2 parts: Part A and Part B.

In Part A, all participants will receive a single intravenous (injected directly into a vein) infusion of ATM-AVI. This is to study the safety and effects of a single amount.

In Part B, all participants will receive multiple intravenous infusions of ATM-AVI as treatment for a possible or confirmed infection with gram-negative bacteria.

Detailed description: This is a 2-part Phase 2a, non-randomized, multicenter, open-label, single and multi-dose study to assess pharmacokinetics (PK), safety, and tolerability of ATM-AVI in hospitalized neonates and infants aged birth, including preterm birth, to \<9 months. A total of 48 participants will be enrolled in 4 age cohorts of 12 each, 6 Part A and 6 Part B. Part A will begin enrolling before Part B and no infant may participate in both parts. Cohort 1 will include full term infants age ≥13 weeks to \<39 weeks and preterm infants postmenstrual age ≥50 weeks to \<75 weeks. Cohort 2 will include full term infants age ≥28 weeks to \<13 weeks and preterm infants postmenstrual age ≥40 weeks to \<50 weeks and ≥28 days of age. Cohort 3 will include full term infants age birth to \<28 days. Cohort 4 will include preterm infants age birth to \<28 days or postmenstrual age \<40 weeks.

Participants in Part A must be hospitalized and receiving intravenous antibiotic treatment for a suspected or confirmed bacterial infection. Participants will receive a single 3 hour intravenous infusion of ATM-AVI and have 3 ATM-AVI blood level assessments during and up to 5 hour after the infusion. Participants will be observed for 48 hours following the infusion to assess safety and toleration and will have a final follow-up safety assessment which may be conducted by telephone 4-5 weeks following the infusion. The single infusion of ATM-AVI is administered to assess the safety, tolerability, and pharmacokinetics of a single dose of ATM-AVI and is not intended as treatment for the bacterial infection. The total duration of study participation in Part A is expected to be 5 weeks through the end of the final safety follow-up.

Participants in Part B must be hospitalized with suspected or confirmed aerobic gram-negative bacterial infection requiring intravenous antibacterial therapy. Part B participants will receive multiple 3 hour intravenous infusions of ATM-AVI every 6 hour (8 hours for preterm infants) for 3-14 days as treatment for their bacterial infection and to assess ATM-AVI pharmacokinetics, safety, tolerability, and efficacy. Participants with complicated intra-abdominal infection (cIAI) will also receive intravenous metronidazole and all participants will have the option to receive other intravenous antibiotic treatment for gram-positive bacteria, as appropriate. Participants who have a good clinical response after 72 hours of intravenous ATM-AVI treatment may be switched to a different orally administered antibiotic, if clinically appropriate. Part B participants will have a total of 5 ATM-AVI blood level assessments over the first 2 or more days following the start of ATM-AVI infusions and will have their clinical response assessed at the End of Treatment (intravenous and oral, if applicable), and at a Test-of-Cure (TOC) evaluation 7 to 14 days after the last antibiotic treatment (intravenous or oral). A final safety assessment which may be conducted by telephone will occur 4-5 weeks after the last dose of ATM-AVI. The total duration of study participation in Part B is expected to be up to 7 weeks through the end of the final safety follow-up.

Additional safety monitoring will be provided by an independent external Data Monitoring Committee (DMC). Enrollment for the study will begin with Part A, single dose, cohorts 1-3. Part A Cohort 4 (preterm neonates) will commence enrollment after sponsor and DMC review of plasma drug levels and safety for a least 2 participants in Part A Cohort 3 and review of ATM-AVI safety and tolerability for all participants enrolled at that time. Enrollment in the multidose Part B cohorts will be delayed until preliminary information is obtained regarding ATM-AVI multidose safety, tolerability, and drug levels for the participants 9 months to 2 years of age in the separate ongoing ATM-AVI pediatric study C3601008 \[NCT05639647\].

Eligibility criteria: Inclusion Criteria

Participants must meet the following key inclusion criteria to be eligible for enrollment into the study:

1. Hospitalized with age from birth \<9 months, including preterm birth
2. Part A: Receiving IV antibiotics for treatment of suspected or confirmed bacterial infection, including but not limited to cIAI, cUTI, HAP/VAP, BSI, or sepsis.
3. Part B: Suspected or confirmed gram-negative bacterial infection requiring IV antibiotics, including but not limited to cIAI, cUTI, HAP/VAP, BSI, or sepsis.

Participants with any of the following characteristics/conditions will be excluded:

1. Received any other investigational medicinal product within the longer of 30 days or 5 half-lives before enrollment.
2. Any medical or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
3. Severe renal impairment or known significant renal disease, as evidenced by elevated serum creatinine at screening, or urinary output \<0.5 mL/kg/h for 6 consecutive hours or requirement for dialysis.
4. Part B Only: Received \>24 hours of systemic antibiotic treatment for gram-negative organisms at time of enrollment, unless documented treatment failure or lack of improvement in at least one objective sign or symptom of infection after ≥48 hours of antibiotics.

Primary outcomes:
measure: Maximum Predicted Plasma Concentration (Cmax) of ATM and AVI
timeFrame: Up to Day 15
measure: Area under the Concentration-Time Curve (AUC) of ATM-AVI
timeFrame: Up to Day 15
measure: Plasma Elimination Half-Life (t1/2)
timeFrame: Up to Day 15
measure: Apparent Clearance (CL)
timeFrame: Up to Day 15
measure: Plasma concentrations of ATM and AVI by nominal sampling time
timeFrame: Up to Day 15
measure: Proportion of Participants reporting Adverse Events (AE)
timeFrame: Baseline up to Day 50
measure: Proportion of Participants reporting Serious Adverse Events (SAE)
timeFrame: Baseline up to Day 50
measure: Proportion of Participants reporting AEs leading to discontinuation of study drug
timeFrame: Baseline up to Day 50
measure: Proportion of Participants reporting AEs resulting in death
timeFrame: Baseline up to Day 50
measure: Proportion of Participants reporting liver injury and acute kidney injury
timeFrame: Baseline up to Day 50
Secondary outcomes:
measure: Part B: Proportion of participants with each clinical outcome and with a favorable clinical outcome at end of IV study treatment (EOIV)
timeFrame: Up to 15 days after start of IV study treatment
measure: Part B: Proportion of participants with each clinical outcome and with a favorable clinical outcome at end of treatment (EOT)
timeFrame: Within 48 hours after last dose of oral switch treatment
measure: Part B: Proportion of participants with each clinical outcome and with a favorable clinical outcome at test of cure (TOC)
timeFrame: 7-14 days after the last study treatment
measure: Part B: Proportion of participants with a favorable microbiological response at TOC
timeFrame: 7-14 days after the last study treatment
measure: Part B: Counts and proportions of pathogens with each per-pathogen microbiological response at EOIV/EOT
timeFrame: Up to 15 days after start of IV study treatment
measure: Part B: Counts and proportions of pathogens with each per-pathogen microbiological response at TOC
timeFrame: 7-14 days after the last study treatment
measure: Part B: Counts and proportions of participants with emergent infections (new infections or superinfections) during the study
timeFrame: Through study completion, up to Day 50
Other outcomes:
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Indianapolis
country: United States
facility: Riley Hospital for Children at Indiana University Health
state: Indiana
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: Louisville
country: United States
facility: Novak Center for Children's Health
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville, Norton Children's Research Institute
state: Kentucky
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: New Brunswick
country: United States
facility: Bristol Myers Squibb Children's Hospital at Robert Wood Johnson University Hospital
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers University
state: New Jersey
city: Houston
country: United States
facility: Memorial Hermann Hospital - Texas Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Surat
country: India
facility: Nirmal Hospital Pvt Ltd.
state: Gujarat
city: Bengaluru
country: India
facility: RajaRajeswari Medical College and Hospital
state: Karnataka
city: Lucknow
country: India
facility: Medanta Hospital Lucknow
state: Uttar Pradesh
city: Kolkata
country: India
facility: Institute of Child Health
state: WEST Bengal
city: Petah-Tikva
country: Israel
facility: Schneider Children's Medical Center
state: Hamerkaz
city: Haifa
country: Israel
facility: Rambam Health Care Campus
state: Hatsafon
city: Hsinchu City
country: Taiwan
facility: Hsinchu Municipal Mackay Children's Hospital
state: Hsinchu
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Medical Foundation-Linkou Branch
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: