PF 06412562 in Subjects With Advanced Stage Parkinson's Disease

A Phase Ib Safety, Tolerability, and Efficacy Study of Two Days of Oral Split Dose (25/20 mg) Administration of PF 06412562 in Subjects With Advanced Stage Parkinson's Disease

The purpose of this study is to test the safety and tolerability of the investigational drug PF-06412562 compared to the current medical standard of care medication for Parkinson's disease, carbidopa/levodopa. This research also is being done to find out if the investigational drug PF-06412562 can help improve the motor (movement) function, alertness, and cognitive (thinking) skills of people who are considered to be in the advanced-stage of Parkinson's disease. In this study, PF06412562 is 'investigational,' which means that it is experimental and has not been approved by the US Food and Drug Administration (FDA), but can be used in clinical research studies such as this one.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: PF-06412562; Drug: Standard of Care Placebo

Detailed Description

The investigators are conducting a randomized, double-blind, carbidopa/levodopa-controlled crossover safety, tolerability, and efficacy study of the investigational compound, PF-06412562, in advanced Parkinson's patients. The primary purpose of this study is to test the safety and tolerability of the investigational drug PF-06412562 compared to the current medical standard of care medication for Parkinson's disease, carbidopa/levodopa, in these patients. This secondary purpose of this research is to find out if the investigational drug PF-06412562 can help improve the motor (movement) function, alertness, and cognitive (thinking) skills of people who are considered to be in the advanced-stage of Parkinson's disease. This study will inform the field as to whether PF-06412562 is safe and well-tolerated in advanced Parkinson's patients, and also may provide preliminary data on its efficacy in several domains.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of classic PD with history of clinically meaningful response to levodopa
• Disease duration >15 years since diagnosis
• Hoehn & Yahr stage >IV "on" or "off" levodopa
• Consent signed by subject, if possible
• If subject is cognitively impaired, consent signed by power of attorney or legally authorized subject representative
• Assent from the study subject, if possible
• Stable dose of all medications for 60 days prior to Day 1 of first week of study

Exclusion Criteria:

• Atypical parkinsonian syndrome (e.g., never responded to levodopa, and/or atypical signs)
• Acute or unstable medical condition such as heart disease, kidney and liver failure
• History of HIV, hepatitis B and C
• Use of moderate to strong CYP 3A4 modulators (see both inhibitors and inducers in Appendix BB)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-06412562; Subjects will receive 25 mg of PF-06412562 twice daily on study Days 2 and 3, along with placebo carbidopa/levodopa dosed at these times. Additional carbidopa/levodopa placebo capsules also will be administered according to the subject's home regimen.	Drug: PF-06412562; PF-06412562 is a dopamine agonist developed by Pfizer Inc. into a tablet form for oral usage. It will be provided as 5 mg tablets. Thus, to administer the 25 mg dose, 5 x 5 mg tablets will be given; and to administer the 20 mg dose, 4 x 5 mg tablets will be administered.
Active Comparator: Standard of Care carbidopa/levodopa; Subjects will take placebo tablets for the PF-06412562 twice daily on study Days 2 and 3, along with active carbidopa/levodopa (25/100 mg) administered at these times. Additional active carbidopa/levodopa capsules also will be administered according to the subject's home regimen.	Drug: Standard of Care Placebo; 25/100 mg tablet(s) of carbidopa/levodopa will be encapsulated and administered according to the subject's home regimen.; Other Names: Sinemet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of PF-06412562 assessed by blood sample results	NA (mmol/L), K(mmol/L), HCO3(mmol/L)	Day 1
Safety and tolerability of PF-06412562 assessed by blood sample results	Ca (mg/dL), Mg (mg/dL), BUN( mg/dL), Creatinine (mg/dL), Bilirubin (mg/dL)	Day 1
Safety and tolerability of PF-06412562 assessed by blood sample results	AST (U/L), ALT (U/L)	Day 1
Safety and tolerability of PF-06412562 assessed by blood sample results	white blood cell count (K/uL), platelets (K/uL)	Day 1
Safety and tolerability of PF-06412562 assessed by blood sample results	Hematocrit (%)	Day 1
Safety and tolerability of PF-06412562 assessed by blood sample results	hemoglobin (g/dL)	Day 1
Safety and tolerability of PF-06412562 assessed by blood sample results	NA (mmol/L), K(mmol/L), HCO3(mmol/L)	Day 4
Safety and tolerability of PF-06412562 assessed by blood sample results	Ca (mg/dL), Mg (mg/dL), BUN (mg/dL), creatinine (mg/dL), bilirubin (mg/dL)	Day 4
Safety and tolerability of PF-06412562 assessed by blood sample results	AST (U/L), ALT (U/L)	Day 4
Safety and tolerability of PF-06412562 assessed by blood sample results	white blood cell count (K/uL), platelets (K/uL)	Day 4
Safety and tolerability of PF-06412562 assessed by blood sample results	hematocrit (%)	Day 4
Safety and tolerability of PF-06412562 assessed by blood sample results	hemoglobin (g/dL)	Day 4
Safety and tolerability of PF-06412562 assessed by blood sample results	Red blood cell count (M/uL)	Day 4
Safety and tolerability of PF-06412562 assessed by vital signs	height (inches)	Time Frame: Vital signs: X2 on Day 1
Safety and tolerability of PF-06412562 assessed by vital signs	weight (lbs)	X2 on Day 1
Safety and tolerability of PF-06412562 assessed by vital signs	blood pressure (mmHg)	X2 on Day 1
Safety and tolerability of PF-06412562 assessed by vital signs	heart rate (bpm)	X2 on Day 1
Safety and tolerability of PF-06412562 assessed by vital signs	respiratory rate (breathes/min)	X2 on Day 1
Safety and tolerability of PF-06412562 assessed by vital signs	temperature (F)	X2 on Day 1
Safety and tolerability of PF-06412562 assessed by vital signs	height (inches)	X3 on Days 2
Safety and tolerability of PF-06412562 assessed by vital signs	blood pressure (mmHg)	X3 on Days 2
Safety and tolerability of PF-06412562 assessed by vital signs	heart rate (bpm)	X3 on Days 2
Safety and tolerability of PF-06412562 assessed by vital signs	respiratory rate (breathes/min)	X3 on Days 2
Safety and tolerability of PF-06412562 assessed by vital signs	temperature (F)	X3 on Days 2
Safety and tolerability of PF-06412562 assessed by vital signs	height (inches)	X3 on Days 3
Safety and tolerability of PF-06412562 assessed by vital signs	weight (lbs)	X3 on Days 3
Safety and tolerability of PF-06412562 assessed by vital signs	blood pressure (mmHg)	X3 on Days 3
Safety and tolerability of PF-06412562 assessed by vital signs	heart rate (bpm)	X3 on Days 3
Safety and tolerability of PF-06412562 assessed by vital signs	respiratory rate (breathes/min)	X3 on Days 3
Safety and tolerability of PF-06412562 assessed by vital signs	temperature (F)	X3 on Days 3
Safety and tolerability of PF-06412562 assessed by vital signs	height (inches)	X2 on Day 4
Safety and tolerability of PF-06412562 assessed by vital signs	weight (lbs)	X2 on Day 4
Safety and tolerability of PF-06412562 assessed by vital signs	blood pressure (mmHg)	X2 on Day 4
Safety and tolerability of PF-06412562 assessed by vital signs	heart rate (bpm)	X2 on Day 4
Safety and tolerability of PF-06412562 assessed by vital signs	respiratory rate (breathes/min)	X2 on Day 4
Safety and tolerability of PF-06412562 assessed by vital signs	temperature (F)	X2 on Day 4
Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function	Blood pressure (mmHg), cold pressor test measuring blood pressure (mmHg)	X1 on Day 1 over 15 min
Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function	heart rate (beats/min), sinus arrhythmia (beats/min)	X1 on Day 1 over 15 min
Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function	Blood pressure (mmHg), cold pressor test measuring blood pressure (mmHg)	X3 on Days 2 over 15 min each time
Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function	heart rate (beats/min), sinus arrhythmia (beats/min)	X3 on Days 2 over 15 min each time
Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function	Blood pressure (mmHg), cold pressor test measuring blood pressure (mmHg)	X3 on Days 3 over 15 min each time
Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function	heart rate (beats/min), sinus arrhythmia (beats/min)	X3 on Days 3 over 15 min each time
Safety and tolerability of PF-06412562 assessed by UPDRS-IV	UPDRS-IV (United Parkinson's Disease Rating Scale): each questions scored on scale of 0 to 4, where 0= not present, 4= severe; subscales are summed to yield a total score, min total score:0, max total score:81; higher score corresponds to increased disease severity	X3 on Days 2
Safety and tolerability of PF-06412562 assessed by UPDRS-IV	UPDRS-IV (United Parkinson's Disease Rating Scale): each questions scored on scale of 0 to 4, where 0= not present, 4= severe; subscales are summed to yield a total score, min total score:0, max total score:81; higher score corresponds to increased disease severity	X3 on Days 3
Safety and tolerability of PF-06412562 assessed by Columbia Suicide Rating	C-SSRS measures suicidal ideation and/or behavior. Rated from Category 1-10 with Category 1 being the least severe, and Category 10 representing the most severe, i.e. completing suicide.	X1 on Day 1
Safety and tolerability of PF-06412562 assessed by Columbia Suicide Rating	C-SSRS measures suicidal ideation and/or behavior. Rated from Category 1-10 with Category 1 being the least severe, and Category 10 representing the most severe, i.e. completing suicide.	X1 on Day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pilot data on potential efficacy of PF-06412562 compared to the standard of care treatment (i.e., carbidopa/levodopa) on overall signs and quality of life in subjects with advanced PD	• Clinician Global Impression of Change score: measures change in disease symptoms per clinician's judgement. Each item rated 1-7, 1=marked improvement, 7= marked worsening; min Caregiver perception of change interview: interviews with participants' caregiver(s). Open-ended questions elicit open-ended answers about subject's behavior, appearance, cognition, etc. over the study	Global Impression of Change: X3 on Days 2 and 3; Caregiver Perception of Change: X1 on Day 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pilot data on potential efficacy of PF 06412562 on individual domains of alertness	Glasgow Coma scale (GCS): records consciousness; each item rated 1-6; score range: 3-14, where 3=deep unconsciousness, 15=totally alert Stanford Sleepiness Scale (SSS): measure of alertness; rated 1-7, 1=fully alert, 7=almost asleep, min total score=1, max total score=7	Once before and X2 after drug administration on Days 2 & 3
Pilot data on potential efficacy of PF 06412562 on individual domains of cogitation	a. Severe Impairment Battery (SIB): evaluates cognition; min total score=0, max total score=100, higher score=lower cognition COGNISTAT: cognitive screening that assesses different domains of cognition Frontal Assessment Battery (FAB): used to assess different types of dementias. Min total score=0, max total score=18, higher scores=better performance	Once before and X2 after drug administration on Days 2 & 3
Pilot data on potential efficacy of PF 06412562 on individual domains of motor	MDS-UPDRS-motor (III) (United Parkinson's Disease Rating Scale): each question scored on scale of 0 to 4, where 0= not present, 4= severe; min total score:0, max total score:81; higher score corresponds to increased disease severity	Once before and X2 after drug administration on Days 2 & 3
Pilot data on potential efficacy of PF 06412562 on individual domains of sleep	8 hour overnight polysomnography (PSG): sleep study monitoring body functions, brain activity (EEG), eye movements (EOG), muscle activity (EMG), and heart rhythm (ECG) Qualitative caregiver interview: (see outcome 2 description)	PSG sleep study: Days 1-3 at bedtime

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Collaborators: Pfizer
• Investigators: Principal Investigator: Xuemei Huang, MD, PhD, Milton S. Hershey Medical Center

Publications and helpful links

General Publications

• Fernandez-Mendoza J, Puzino K, Amatrudo G, Bourchtein E, Calhoun SL, Plante DT, Kaplan K. The Hypersomnia Severity Index: reliability, construct, and criterion validity in a clinical sample of patients with sleep disorders. J Clin Sleep Med. 2021 Nov 1;17(11):2249-2256. doi: 10.5664/jcsm.9426.
• Huang X, Lewis MM, Van Scoy LJ, De Jesus S, Eslinger PJ, Arnold AC, Miller AJ, Fernandez-Mendoza J, Snyder B, Harrington W, Kong L, Wang X, Sun D, Delnomdedieu M, Duvvuri S, Mahoney SE, Gray DL, Mailman RB. The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson's Disease: A Feasibility Study. J Parkinsons Dis. 2020;10(4):1515-1527. doi: 10.3233/JPD-202188.

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2018
• Primary Completion (Actual): March 21, 2019
• Study Completion (Actual): April 21, 2019

Study Registration Dates

• First Submitted: August 1, 2018
• First Submitted That Met QC Criteria: September 7, 2018
• First Posted (Actual): September 11, 2018

Study Record Updates

• Last Update Posted (Actual): July 31, 2019
• Last Update Submitted That Met QC Criteria: July 30, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Parkinson's Disease; Parkinson Disease; Advanced Parkinson's Disease; End-Stage; Progressed; End-Stage Parkinson's Disease; Clinical intervention; Double-blind, randomized
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Dopamine Agonists; Dopamine Agents; Adjuvants, Immunologic; Antiparkinson Agents; Anti-Dyskinesia Agents; Carbidopa, levodopa drug combination
• Other Study ID Numbers: 9437

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No