A Study to Evaluate the Pharmacodynamic Effects of Single Oral Doses of PF-06648671 on β-Amyloid (Aβ) Concentrations in Cerebrospinal Fluid (CSF)

Study Overview
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Brief Summary
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This is phase 1 investigator-and-subject blind, sponsor open, randomized, placebo controlled, parallel study in healthy subjects to evaluate the pharmacodynamics effect of single oral doses of PF-06648671 on CSF Aβ concentrations using serial CSF sampling methodology.

Detailed Description
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This study is investigator-and-subject blind, sponsor open, randomized, placebo-controlled, parallel study in healthy subjects to evaluate central (CSF) and peripheral (plasma) pharmacodynamics effects (Abeta) over 36 hours post single doses of PF-06648671. Two cohorts will be run in sequential. the first cohort is to evaluate the Abeta effect at top dose of 300 mg PF-06648671 and second cohort is to evaluate the Abeta effect at top dose (if more subjects are required) and/or 1-2 lower doses

Official Title
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A Phase 1 Investigator-and-subject Blind, Randomized, Placebo Controlled, Parallel Study In Healthy Subjects To Evaluate The Pharmacodynamic Effects Of Single Oral Doses Of Pf-06648671 On Aβ Concentrations In Cerebrospinal Fluid Using Serial Sampling Methodology

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: PF-06648671
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female subjects of non childbearing potential BMI of 17.5 to 30.5 kg/m2 and a total body weight >50 kg (110 lbs) Evidence of a personally signed and dated informed consent document indicating that subject has been informed of all pertinent aspects of the study. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated asymptomatic, seasonal allergies at the time of dosing) Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study medication (whichever is longer) Subjects with a history of significant active bleeding, coagulation disorder or clinically significant finding on prothrombin time/ partial thromboplastin time/International Normalized Ratio (PT/PTT/INR) at Screening Subjects with lower spinal malformations (on physical examination), local spinal infection, or other abnormalities that would exclude puncture (LP) Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06648671 High dose group<br>subjects receive a single oral dose of PF-06648671 at 300 mg | Drug: PF-06648671<br>* Experimental Pfizer compound which will be dosed as oral suspension, single dose at 300 mg and/or 1-2 lower doses<br>|
| Experimental: PF-06648671 Low dose group<br>Subjects receive a single oral dose of PF-06648671 lower than 300 mg dose | Drug: PF-06648671<br>* Experimental Pfizer compound which will be dosed as oral suspension, single dose at 300 mg and/or 1-2 lower doses<br>|
| Placebo Comparator: Placebo group<br>Subjects receive matching placebo | Drug: Placebo<br>* Placebo which will be dosed as oral suspension, single doses to match PF-06648671<br>|
| Experimental: PF-06648671 Low dose group (2)<br>Optional arm. Subjects receive a single oral dose of PF-06648671 at second lower dose if 300 mg dose is not repeated in cohort 2 | Drug: PF-06648671<br>* Experimental Pfizer compound which will be dosed as oral suspension, single dose at 300 mg and/or 1-2 lower doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CSF Aβ40 and Aβ42 concentration at maximum change from baseline |  | 0-36 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with AEs and SAEs | Counts of participants who have TEAEs, defined as newly occuring or worsening after first dose. Relatedness to PF-06648671 will be assessed by the investigator (Yes/No). Participants with multiple occurrence of an AE within a category will be counted once within the category | 0-2 weeks | 
| supine vital sign | Measurement of supine vital signs | 0-2 weeks | 
| Electrocardiogram (ECG) | Measurement of standard 12-lead ECG (single) | 0-2 weeks | 
| Maximum Observed Plasma Concentration (Cmax) |  | 0-72 hours postdose | 
| Area Under the Curve from Time Zero to Last Quantifiable Plasma Concentration (AUClast) |  | 0-72 hours postdose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time in Plasma (AUCinf) |  | 0-72 hours postdose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 0-72 hours postdose | 
| Plasma Decay Half-life (t1/2) |  | 0-72 hours postdose | 
| Apparent Oral Clearance (CL/F) |  | 0-72 hours postdose | 
| Apparent Volume of Distribution (Vz/F)) |  | 0-72 hours postdose | 
| Maximum Observed CSF Concentration (CSF Cmax) |  | 0-36 hours postdose | 
| Area Under the Curve from Time Zero to Last Quantifiable Concentration in CSF (CSF AUClast) |  | 0-36 hours postdose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time in CSF (CSF AUCinf) |  | 0-36 hours postdose | 
| CSF Decay Half-life (CSF t1/2) |  | 0-36 hours postdose | 
| Plasma Aβ40, Aβ42 and Aβtotal | Plasma Aβ40, Aβ42 and Aβtotal if possible | 0-72 hours postdose | 
| CSF Aβ37, Aβ38 and Aβtotal Concentration |  | 0-36 hours postdose | 
| Number of participants with lab test values of potential clinical importance | Pre-defined criteria were established for each lab test to identify potential clinical importance | 0-2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Double blind, Placebo-Controlled, Parallel Design, CSF Aβ Concentrations, PF-06648671