Clinical trial NCT02407353: A Study to Evaluate the Pharmacodynamic Effects of Single Oral Doses of PF-06648671 on β-Amyloid (Aβ) Concentrations in Cerebrospinal Fluid (CSF)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: Phase 1
Double blind
Placebo-Controlled
Parallel Design
CSF Aβ Concentrations
PF-06648671
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2015-04-02
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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

Eligibility criteria: 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

Primary outcomes:
measure: CSF Aβ40 and Aβ42 concentration at maximum change from baseline
timeFrame: 0-36 hours postdose
Secondary outcomes:
measure: Number of participants with AEs and SAEs
timeFrame: 0-2 weeks
measure: supine vital sign
timeFrame: 0-2 weeks
measure: Electrocardiogram (ECG)
timeFrame: 0-2 weeks
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 0-72 hours postdose
measure: Area Under the Curve from Time Zero to Last Quantifiable Plasma Concentration (AUClast)
timeFrame: 0-72 hours postdose
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time in Plasma (AUCinf)
timeFrame: 0-72 hours postdose
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: 0-72 hours postdose
measure: Plasma Decay Half-life (t1/2)
timeFrame: 0-72 hours postdose
measure: Apparent Oral Clearance (CL/F)
timeFrame: 0-72 hours postdose
measure: Apparent Volume of Distribution (Vz/F))
timeFrame: 0-72 hours postdose
measure: Maximum Observed CSF Concentration (CSF Cmax)
timeFrame: 0-36 hours postdose
measure: Area Under the Curve from Time Zero to Last Quantifiable Concentration in CSF (CSF AUClast)
timeFrame: 0-36 hours postdose
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time in CSF (CSF AUCinf)
timeFrame: 0-36 hours postdose
measure: CSF Decay Half-life (CSF t1/2)
timeFrame: 0-36 hours postdose
measure: Plasma Aβ40, Aβ42 and Aβtotal
timeFrame: 0-72 hours postdose
measure: CSF Aβ37, Aβ38 and Aβtotal Concentration
timeFrame: 0-36 hours postdose
measure: Number of participants with lab test values of potential clinical importance
timeFrame: 0-2 weeks
Other outcomes:
Locations:
city: Glendale
country: United States
facility: California Clinical Trials Medical Group, Inc.
state: California
city: Glendale
country: United States
facility: Glendale Adventist Medical Center
state: California
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Ahn JE, Carrieri C, Dela Cruz F, Fullerton T, Hajos-Korcsok E, He P, Kantaridis C, Leurent C, Liu R, Mancuso J, Mendes da Costa L, Qiu R. Pharmacokinetic and Pharmacodynamic Effects of a gamma-Secretase Modulator, PF-06648671, on CSF Amyloid-beta Peptides in Randomized Phase I Studies. Clin Pharmacol Ther. 2020 Jan;107(1):211-220. doi: 10.1002/cpt.1570. Epub 2019 Sep 11.