A Study to Learn About the Study Medicine Called CTB+AVP in Healthy Adult People.

Study Overview
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Brief Summary
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The purpose of this clinical trial is to learn about the pharmacokinetics, safety and tolerability of various single- and multiple-doses of CTB+AVP in healthy adult participants. CTB+AVP is a study medicine that is being developed to treat people with complicated urinary tract infections. This study is seeking healthy adult male and female participants, 18-60 years of age, with a body weight > 50 kg and a BMI of 17.5 to 30.5 kg/m2. Participants in Part-1 of the study will receive increasing single doses of CTB and/or AVP. Participants in Part-2 will receive increasing multiple doses of CTB+AVP three times a day for 7 days. The study team will monitor how each participant is doing with the study treatments via close monitoring in an in-patient setting. Experiences of people receiving CTB+AVP will be compared to those of people who do not. This will help determine if CTB+AVP is safe and well-tolerated at each dose of the study medicine. Participants will take part in this study for a maximum of 12 weeks for Part-1 (up to 4 weeks for screening, up to 3 weeks of taking study medicine and up to 5 weeks for safety follow-up visit) and for a maximum of 10 weeks for Part-2 (up to 4 weeks for screening, up to 1 week of taking study medicine and up to 5 weeks for safety follow-up visit). During the duration of the study, blood samples for study medicine levels, and various measures for monitoring safety such as blood samples for clinical laboratory measurements, electrocardiograms and vital sign measurements will be taken.

Detailed Description
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This is a 2-part study in healthy male and female adult participants. Part-1 is to evaluate safety, tolerability and pharmacokinetics (PK) of 3 planned and 2 optional doses in 8 participants, in a 5-period sequential single dose design. Part-2 is to evaluate safety, tolerability and PK of 1 planned and 2 optional cohorts in 8 participants each, in a multiple dose sequential design, with 7 days of repeated every 8 hours (q8h) dosing in each cohort. In addition, 2 optional cohorts in 6 participants each of Japanese descent and Chinese descent will also receive multiple doses of CTB+AVP repeated every 8 hours (q8h) for 7 days.

Official Title
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A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED, SINGLE AND MULTIPLE-DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP]) IN HEALTHY ADULT PARTICIPANTS

Conditions
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Healthy

Intervention / Treatment
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* Drug: Placebo
* Drug: PF-07612577
* Drug: PF-06264006


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb) For optional Japanese cohort only: Japanese participants who have 4 Japanese biologic grandparents who were born in Japan For optional Chinese cohort only: Chinese participants who were born in mainland China, and both parents are of Chinese descent. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing) Known allergy to the cephalosporin group of antibiotics History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality [or other conditions or situations related to COVID-19 pandemic (eg, Contact with positive case, residence, or travel to an area with high incidence)] that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study A positive urine drug test Positive test result for SARS-CoV-2 infection at the time of screening or Day -1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07612577<br>Part-1: Dose 1, Dose 2, Dose 4, Dose 5 Part-2: Cohort 2-5 | Drug: PF-07612577<br>* PF-07612577<br>* Other names: CTB+AVP;|
| Placebo Comparator: Placebo<br>Part-1: Dose 1-5 Part-2: Cohort 2-4 | Drug: Placebo<br>* Placebo<br>* Other names: Placebo comparator;|
| Experimental: PF-06264006<br>Part-1: Dose 3, Dose 5 | Drug: PF-06264006<br>* PF-06264006<br>* Other names: ceftibuten (CTB);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Time to Cmax (Tmax) of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Dose-Normalized Maximum Observed Plasma Concentration [Cmax(dn)] of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Dose-Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUClast(dn)] of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Dose-Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf(dn)] of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Terminal Elimination Half-Life (t1/2) of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Apparent Oral Volume of Distribution (Vz/F) of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Apparent Oral Clearance (CL/F) of cis-CTB, AVP, AVI and HPA |  | Part-1: pre-dose to 24 hours post-dose for every period; Part-2: pre-dose to 8 hours post-dose on Day 1 and Day 6, and to 24 hours post-dose on Day 7 for each cohort | 
| Frequency of treatment-emergent adverse events (TEAEs) |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 
| Severity of treatment-emergent adverse events (TEAEs) |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 
| Causality of treatment-emergent adverse events (TEAEs) |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 
| Withdrawals due to treatment-emergent adverse events (TEAEs) |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 
| Frequency of abnormal laboratory findings |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 
| Magnitude of abnormal laboratory findings |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 
| Change from baseline in vital sign measurements |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 
| Change from baseline in 12-lead ECG parameters |  | Part-1: 0 hours up to 8 weeks; Part-2: 0 hours up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of unchanged drug excreted in urine within dosing interval of 8 hours for cis-CTB, AVP, AVI, and HPA (Ae,tau) |  | Part-2: Day 6 only, pre-dose to 8 hours post-dose | 
| Amount of unchanged drug excreted in urine within dosing interval of 8 hours as a percent of the administered dose for cis-CTB, AVP, AVI, and HPA (Ae,tau,%) |  | Part-2: Day 6 only, pre-dose to 8 hours post-dose | 
| Renal clearance of cis-CTB, AVP, AVI and HPA (CLr) |  | Part-2: Day 6 only, pre-dose to 8 hours post-dose |