A phase 2A multicenter, observer-blinded, randomized 2 arm Study to investigate pharmacokinetics, safety, tolerability and efficacy of intravenous Aztreonam-Avibactam ± Metronidazole compared to Best Available Therapy (BAT) in pediatric participants 9 months to less than 18 years of age with serious gram-negative bacterial Infections including complicated intra-abdominal Infection
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Pfizer Inc
- 入组人数
- 48
- 试验地点
- 5
- 主要终点
- (2)Minimum Predicted Trough Plasma Concentration (Cmin) of ATM & AVI
研究概览
简要总结
The purpose of this study is to evaluate the PK, safety, tolerability and efficacy of intravenous ATM-AVI in participants 9 months to less than 18 years of age for the indications in which ATM-AVI is being studied in adults: cIAI, cUTI, HAP/VAP, and BSI. This study is being conducted in fulfillment of requirements in the ATM-AVI PIP1 submitted to the EMA and the ATM-AVI PSP2 submitted to the FDA.
The study is open-label with a blinded observer due to the complicated dosing regimens of the investigational product and the serious nature of the infections. Single blind study observer is a well-accepted study design in a pediatric population. Children are a vulnerable population and need close clinical monitoring by unblinded observers to interject when needed whilst the blinded observer will assess the safety and the clinical cure without bias. Given the risk to participants and severity of disease, a placebo controlled study would not be ethically appropriate. The rationale for the study design is that it provides comparative data in an open setting.
研究设计
- 研究类型
- Interventional
入排标准
- 年龄范围
- 9.00 Month(s) 至 18.00 Year(s)（—）
- 性别
- All
入选标准
- •Participants are eligible to be included in the study only if all of the following criteria apply: Age and Sex:
- •Participants ≥9 months to <18 years of age at Screening a) Refer below for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
- •Female (post-pubertal) participants must have a negative serum/urine pregnancy test (β-hCG sensitivity ≥25 mIU/mL), Disease Characteristics:
- •Suspected/confirmed cIAI, cUTI, HAP/VAP, or BSI with gram-negative pathogens,
- •Require hospitalization and IV antibiotic treatment.
- •Male Participant Reproductive Inclusion Criteria: Male participants are eligible to participate if they agree to the following requirements during the intervention period and for at least 7 days after the last dose of study intervention, which corresponds to the time needed to eliminate reproductive safety risk of the study intervention(s):
- •Refrain from donating sperm.
- •PLUS either:
- •Be abstinent from heterosexual intercourse with a female of childbearing potential as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.
- •OR 3) Must agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
- •Female Participant Reproductive Inclusion Criteria: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: 1) Is not a WOCBP (Woman of Childbearing Potential) OR 2) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), as described below, during the intervention period and for at least 28 days after the last dose of study intervention, which corresponds to the time needed to eliminate any reproductive safety risk of the study intervention(s).
- •If a highly effective method that is user dependent is chosen, a second effective method of contraception, as described below, must also be used.
- •The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
- •The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
排除标准
- •Participants are excluded from the study if any of the following criteria apply:
- •Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
- •Gram-negative species not expected to respond to ATM-AVI ≤14 days
- •Pregnant or breastfeeding; fertile male/female unwilling/unable to use effective contraception for at ≥7 days (males) or ≥28 days (females) after last ATM-AVI infusion.
- •HAP/VAP only
- •Microbiologically known or high likelihood of monomicrobial infection with a gram-positive organism, lung abscess, pleural empyema, or post-obstructive pneumonia, lung or heart transplant.
- •Current use of any prohibited concomitant medication(s) or participants unwilling/unable to use a permitted concomitant medication(s).
- •Prior and Concomitant Therapy.
- •Received >24 hours of systemic antibiotics (abx) for ≤48hr before randomization, except if; a.
- •Failed systemic abx for >48hr.
- •Not taking protocol prohibited medications, Prior/Concurrent Clinical Study Experience: Previous administration with an investigational product (drug or vaccine) within 30 days(or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).Diagnostic Assessments:
- •CrCL ≤15 mL/min/1.73 m2 (eGFR calculation based on age).
- •Non-infectious related screening ALT or AST >3 x ULN, ALP >3 x ULN and/orTBili >2 x ULN (> 3 x ULN for Gilbert’s syndrome), Other Exclusions:
- •Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
结局指标
主要结局
(2)Minimum Predicted Trough Plasma Concentration (Cmin) of ATM & AVI
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(3)Area under the Concentration-Time Curve (AUC) of ATM-AVI
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(4)Plasma Decay Half-Life (t1/2)
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(5)Apparent Clearance (CL)
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(8)Proportion of Participants reporting AEs leading to discontinuation
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(1)Maximum Predicted Plasma Concentration (Cmax) of ATM & AVI
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(6)Proportion of Participants reporting AE
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(7)Proportion of Participants reporting SAE
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
(9)Proportion of Participants reporting AEs resulting in death
时间窗: (1) Time Frame: Up to 15 Days | (2) Time Frame: Up to 15 Days | (3) Time Frame: Up to 15 Days | (4) Time Frame: Up to 15 Days | (5) Time Frame: Up to 15 Days | (6) Time Frame: Baseline up to Day 50 | (7) Time Frame: Baseline up to Day 50 | (8) Time Frame: Baseline up to Day 50 | (9) Time Frame: Baseline up to Day 50 | treatment of serious gram-negative bacterial infections in participants of 9 months to 18 years of age.
次要结局
- 1) Describe the efficacy of ATM-AVI and BAT(for the treatment of serious gram-negative)