P1, SAD & MAD PK & Safety Study of Xeruborbactam Oral Prodrug in Combo With Ceftibuten in Renal Impairment Pts

Study Overview
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Brief Summary
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A Phase 1, open-label, single-dose study to determine the safety and pharmacokinetics of ORAvance (ceftibuten/xeruborbactam oral prodrug [QPX7831]) in participants with renal impairment

Detailed Description
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Qpex Biopharma, Inc. is developing an oral dosage form that delivers Xeruborbactam, a new boron-based beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases, for oral treatment in combination with a beta-lactam antibiotic. Ceftibuten is a cephalosporin antibiotic approved in the US for acute exacerbations of chronic bronchitis, acute bacterial otitis media and pharyngitis/ tonsillitis. This is a Phase 1 open-label, single-dose study to assess the safety, tolerability, and PK, of ceftibuten and xeruborbactam oral prodrug given in combination to participants with varying degrees of renal impairment as compared to participants with normal renal function. Objectives: The objectives of the study are: To assess the PK of ceftibuten and xeruborbactam oral prodrug given in combination in participants with varying degrees of renal impairment. To evaluate the safety and tolerability of ceftibuten and xeruborbactam oral prodrug given in combination in participants with varying degrees of renal impairment.

Official Title
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A Phase 1, Open-label, Single-dose Study to Determine the Safety and Pharmacokinetics of ORAvance (Ceftibuten/Xeruborbactam Oral Prodrug [QPX7831]) in Participants With Renal Impairment

Conditions
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Bacterial Infections

Intervention / Treatment
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* Drug: Xeruborbactam Oral Prodrug
* Drug: Ceftibuten


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Participants: Able to understand the study conduct and tasks required of the participants, sign the informed consent form and willing to cooperate with all tests and examinations required by the protocol. Males and females 18 through 80 years of age, inclusive, at the time of screening. If male, agree to be sexually abstinent or to use 2 approved methods of contraception as detailed in the study protocol when engaging in sexual activity from study check-in through 30 days following the last administration of the study drug, and to refrain from donating sperm during this same period of time. If the sexual partner is surgically sterile, contraception is not necessary. Females of childbearing potential must either be sexually abstinent for 14 days prior to Day 1 and remain so through 30 days following the last administration of the study drug, OR have been using (or agree to use) acceptable methods of birth control as detailed in the study protocol. Females of non-childbearing potential must either be postmenopausal (defined as 12 months spontaneous amenorrhea) with a serum follicle stimulating hormone (FSH) level in the laboratory defined postmenopausal range or have undergone 1 of the sterilization procedures detailed in the study protocol at least 6 months prior to Day 1. Have a BMI ≥ 18.5 kg/m2 and ≤ 40 kg/m2, inclusive. Have sufficient peripheral vascular access, based on the investigator's assessment, for PK blood sample collection. Have a sitting pulse rate ≥ 45 beats per minute (bpm) and ≤ 110 bpm during the vital sign assessment at screening. Willing to abstain from alcohol for 48 hours prior to dosing through discharge from the Phase 1 unit on Day 6 or Day 4 (depending on Group assigned). Participants with Renal Impairment: Have an eGFR < 90 mL/min calculated using the CKD-EPI equation. Have negative test results for hepatitis B surface antigen (HBsAg), anti Hepatitis C virus (HCV) antibody and anti-human immunodeficiency virus (HIV) antibody. Participants with renal impairment with a positive HCV antibody result will be included at the investigator's discretion if all liver enzyme parameters are within the normal range. Participants with Normal Renal Function: Have an eGFR ≥ 90 mL/min calculated using the CKD-EPI equation. Have negative test results for HBsAg, anti HCV antibody and anti-HIV antibody. Exclusion Criteria: Participants must not meet any of the following exclusion criteria to be eligible to participate in the study. All Participants: Have unstable or new medical conditions (eg, cardiovascular, respiratory, hepatic, renal, gastrointestinal, autoimmune, endocrine, or neurological disorders) which have occurred in the 3 months prior to the first dose of study drug and which are capable of altering the distribution, metabolism, or elimination of drugs or, in the opinion of the investigator, constitute a risk factor to participating in the study and/or receiving study drug. Documented hypersensitivity reaction or anaphylaxis to any medication, including ceftibuten or other beta-lactam antibiotics (eg, cephalosporins, penicillins, carbapenems, or monobactams) or any excipients used in this formulation. History of clinically significant seizures, head injury, or meningitis. Current evidence or history of malignancy, except squamous cell carcinoma or basal cell carcinoma of the skin, in the 2 years prior to Day -1 with no evidence of recurrence. Females who are pregnant, lactating, or have a positive pregnancy test at the Screening Visit or Day -1. Previously received any dose of ORAvance (ceftibuten/xeruborbactam oral produg). Received any investigational drug within 30 days or 5 half-lives, whichever is longer, prior to Day 1 of the current study. Current participation in another investigational study within 30 days prior to the Screening Visit. Blood donation or significant blood loss (ie, > 500 mL) within 56 days prior to Day 1. Plasma or platelet donation within 14 days prior to Day -1. Any acute illness requiring antibiotic drug therapy within 30 days prior to Day 1 or a febrile illness within 7 days prior to Day 1. Vigorous exercise from 48 hours prior to Day -1 until the day of discharge from the study. Positive drug test at the Screening Visit or Day -1 unless results can be explained by a prescription medication. Recent history (ie, within 6 months prior to Day 1) of abuse of prescription or illicit drugs as detailed in the study protocol. Positive alcohol test at the Screening Visit or Day 1. Recent history (ie, within 6 months prior to Day 1) of excessive alcohol intake as defined in the study protocol. Concurrent use of medications known to affect the elimination of serum creatinine and competitors of renal tubular secretion within 30 days prior to the first dose of study drug or anticipated need for these therapies through the last PK sample. Employees of the investigative site involved in this study . Unable or unwilling to adhere to the study-specified procedures and restrictions. QTcF interval > 500 msec, previous history or family history of prolonged QT syndrome at screening or Day -1. Use of products containing alcohol, caffeine, xanthine, or ephedrine within 24 hours before dosing. Have any clinically significant abnormalities in laboratory values at screening or check-in (Day -1), defined in the study protocol. Liver function abnormalities at screening or check-in (Day -1) (defined by an elevation in bilirubin, aspartate aminotransferase, or alanine transaminase, > upper limit of normal range for participants based on age and sex). Use of any other prescription or nonprescription drugs, vitamins, grapefruit or grapefruit juice, or dietary or herbal supplements within 14 days prior to Day -1. Concomitant medications required to treat underlying renal disease or medical conditions related to renal disease are permitted. Oral contraceptives are permitted for birth control. Doses of concomitant medications (except hormonal contraceptives, hormone replacement therapy for females, and insulin) must be stable for 3 weeks prior to dosing on Day 1. Minor dose changes consistent with treatment practices may be permitted at the discretion of the Sponsor's Medical Monitor. Acetaminophen (≤ 2 g/day) and low dose acetylsalicylic acid (ie, ≤ 325 mg per day) are permitted. Participants with Renal Impairment: Abnormal and clinically significant findings on physical examination, medical history, serum chemistry, hematology, or urinalysis per investigator discretion. Participants in the renal impairment group will have consideration for the degree of renal impairment and presence of comorbidities. 22. Have a sitting systolic BP > 180 mm Hg or < 90 mm Hg or have a sitting diastolic BP > 110 mm Hg or < 50 mm Hg at the Screening Visit or Day -1. Participants with Normal Renal Function: 23. Abnormal and clinically significant findings on physical examination, medical history, serum chemistry, hematology, or urinalysis per investigator discretion. 24. Have a sitting systolic BP > 150 mm Hg or < 90 mm Hg or have a sitting diastolic BP > 90 mm Hg or < 50 mm Hg at the Screening Visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Open-label, single dose design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label, Single Dose Combination of Ceftibuten & Xeruborbactam oral prodrug<br>32 participants will be enrolled with varying degrees of renal impairment as well as participants with normal renal function (NRF). 8 participants will be enrolled in each group based on estimated glomerular filtration rate at screening: Group 1: Mild renal impairment (eGFR 60 to 89 mL/min/1.73m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation) Group 2: Moderate renal impairment (eGFR 30 to < 60 mL/min/1.73m2 calculated using the CKD-EPI equation) Group 3: Severe renal impairment (eGFR < 30 mL/min/1.73m2 calculated using the CKD-EPI equation) not receiving HD therapy Group 4: Healthy participants with NRF matched to patients in Groups 1, 2 and 3 based on age, gender and BMI All subjects will receive a single dose of ceftibuten & QPX7831 on Day 1. Participants will remain in the clinic until completion of the post-dose procedures on Day 6. Participants will be contacted by phone between Days 8-10 for follow-up. | Drug: Xeruborbactam Oral Prodrug<br>* Experimental<br>* Other names: QPX7831;Drug: Ceftibuten<br>* Experimental<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent adverse events by subject and by group | Number of patients with Treatment-Emergent Adverse Events by subject, by group, severity and relationship to treatment | 10 days | 
| Number of patients with changes from baseline in safety parameters | Number of patients with changes in safety parameters before and after dosing by subject and group | 10 days | 
| Peak plasma Concentration measurements by subject and by group (Cmax) | Comparison will be performed between the groups for concentration measurements (Cmax). Mean graphical presentation of the data will be reported. Statistical analysis of exposure parameters will be performed. | 10 days | 
| Time concentration data measurements by subject and by group (Tmax) | Comparison will be performed between the groups for time concentration data measurements (Tmax) | 10 days | 
| Area under the plasma concentration versus time curve (AUC) between groups | Comparison will be performed between the groups for area under the plasma concentration versus time curve (AUC) Mean graphical presentation of the data will be reported. Statistical analysis of exposure parameters will be performed. | 10 days | 
| Urine Pharmacokinetic (PK) amount excreted by subject and by group | Urine Pharmacokinetic (PK) parameters such as amount excreted will be calculated from urinary excretion data | 10 days | 
| Urine Pharmacokinetic (PK) % dose excreted by subject and by group | Urine Pharmacokinetic (PK) parameters such as amount of % dose excreted will be calculated from urinary excretion data | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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beta-lactamase inhibitor