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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: PF-06648671; Drug: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Glendale Adventist Medical Center
    • Glendale, California, United States, 91206
      • California Clinical Trials Medical Group, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-06648671 High dose group; subjects receive a single oral dose of PF-06648671 at 300 mg	Drug: PF-06648671; Experimental Pfizer compound which will be dosed as oral suspension, single dose at 300 mg and/or 1-2 lower doses
Experimental: PF-06648671 Low dose group; Subjects receive a single oral dose of PF-06648671 lower than 300 mg dose	Drug: PF-06648671; Experimental Pfizer compound which will be dosed as oral suspension, single dose at 300 mg and/or 1-2 lower doses
Placebo Comparator: Placebo group; Subjects receive matching placebo	Drug: Placebo; Placebo which will be dosed as oral suspension, single doses to match PF-06648671
Experimental: PF-06648671 Low dose group (2); 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; Experimental Pfizer compound which will be dosed as oral suspension, single dose at 300 mg and/or 1-2 lower doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• 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.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: March 25, 2015
• First Submitted That Met QC Criteria: March 30, 2015
• First Posted (Estimate): April 2, 2015

Study Record Updates

• Last Update Posted (Estimate): March 22, 2016
• Last Update Submitted That Met QC Criteria: March 21, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Phase 1; Placebo-Controlled; Double blind; PF-06648671; Parallel Design; CSF Aβ Concentrations
• Other Study ID Numbers: B7991003