Clinical trial NCT01280123: Pioglitazone in Early Parkinson's Disease
Official title: A Multi-Center, Double-Blind, Placebo-Controlled Phase II Study of Pioglitazone in Early Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson's Disease
Keywords: Parkinson's Disease
Biomarkers
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Michael J. Fox Foundation for Parkinson's Research
First posted: 2011-01-20
Enrollment: 210
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multi-center, double-blind, placebo controlled clinical trial of two dosages of oral pioglitazone (15 milligram(mg) and 45 milligram (mg)) for safety, tolerability, and futility.

Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day for at least 8 weeks but no more than 8 months, will be randomized to one of two dosages of oral pioglitazone (15 mg and 45 mg) or matching placebo.

The study will measure disease progression by the change in total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline visit and 44 weeks.

Detailed description: A Multi-Center, Double-Blind, Placebo-Controlled Phase II Study of Pioglitazone in Early Parkinson's Disease (PD). The patient population has early stage PD (\< 5 years from diagnosis), must be treated with 1 mg/day of rasagiline or 10 mg/day of selegiline for at least 8 weeks but not more than 8 months prior to enrollment.

The primary objective of this clinical trial is to assess the futility of pioglitazone on PD disease progression as measured by the change in total UPDRS score between the baseline visit and 44 weeks. The secondary objectives of the study are to collect additional efficacy and safety/tolerability data to be used in planning a subsequent Phase III trial of pioglitazone in early, treated PD. Measures of cognition, mood and blood- and urine-based biomarkers will also be explored. Subjects in this trial are randomly assigned in a 1:1:1 ratio to one of three study arms: 15 mg, 45 mg or placebo.

Eligibility criteria: Inclusion Criteria:

1. Willing and able to give informed consent.
2. Men and women with idiopathic PD of less than 5 years duration from diagnosis with a Hoehn and Yahr Stage \< 2.
3. On stable dosage of rasagiline 1 mg/day or selegiline 10 mg/day for at least 8 weeks but not more than 8 months prior to baseline. Expected to remain on stable dose of rasagiline or selegiline as the only treatment for their PD for the duration of the study (44 weeks).
4. Diagnosis must be confirmed by bradykinesia plus one of the other cardinal signs (resting tremor, rigidity) being present, without any other known or suspected cause of parkinsonism. The clinical signs must be asymmetric.
5. Subjects may be taking stable doses (30 days) of anticholinergics or creatine (\< 5gm/day) but must be expected to remain on the same dose.
6. Age \> 30 years.
7. Women who are not postmenopausal or surgically sterile must use a medically accepted contraceptive regimen for at least 60 days before the baseline visit, and agree to continue such use throughout the duration of the study and for 30 days after the final dose of study drug.

Exclusion Criteria:

1. Exposure to dopaminergic PD therapy or amantadine within 60 days prior to baseline visit or for 90 days or more at any point in the past
2. Use of any of the following drugs within 180 days prior to baseline: neuroleptics, metoclopramide, alpha-methyldopa, clozapine, olanzapine and flunarizine.
3. Use of any of the following drugs within 90 days prior to baseline: methylphenidate, cinnarizine, reserpine, tetrabenazine, amphetamine or monoamine oxidase (MAO)-A inhibitors (pargyline, phenelzine, and tranylcypromine).
4. Presence of drug-induced parkinsonism (e.g., metoclopramide, flunarizine), metabolic identified neurogenetic disorders (e.g., Wilson's disease), encephalitis, or other atypical Parkinsonian syndromes (e.g., progressive supranuclear palsy, multiple system atrophy).
5. Participation in other drug studies or receipt of other investigational drugs within 30 days prior to baseline or during the study.
6. Presence of freezing.
7. Any clinically significant psychiatric or medical condition or laboratory abnormality, which would in the judgment of the Investigator interfere with the subject's ability to participate.
8. History of stereotaxic brain surgery for PD
9. Clinically significant structural brain disease that the investigator believes would interfere with study evaluations.
10. History of congestive heart failure.
11. Use of pioglitazone or rosiglitazone within 90 days before randomization.
12. Known intolerance to pioglitazone or rosiglitazone.
13. Allergy to rasagiline or selegiline, or contraindication to rasagiline or selegiline use.
14. Type I or Type II diabetes mellitus.
15. HgbA1C greater than or equal to 6% at Screening.
16. Known liver disease or elevation of AST or ALT greater than 2.5 times the upper limit of normal.
17. Known history of osteoporosis. All women ≥ 65 years of age or men and woman at high risk of osteoporosis should have documented evidence of screening for osteoporosis. Factors associated with high risk of osteoporosis include: previous non traumatic fracture, chronic glucocorticoid use, body weight under 58 kg, family history of hip fracture, current cigarette smoking, and excessive alcohol intake.
18. Drug or alcohol use or dependence that, in the opinion of the Investigator, would interfere with the safe conduct of the study.
19. Significant peripheral edema (2+ or more) of the extremities of any etiology.
20. Current or planned use of gemfibrozil or rifampin during the trial.
21. History of bladder cancer.
22. Evidence of hematuria which has not been evaluated for evidence of bladder cancer. (Documentation of work up or a repeat urine test that was negative for hematuria and the primary care physician or urologist does not feel that further work up is required.)
23. History of macular edema.

Primary outcomes:
measure: Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to 44 Weeks
timeFrame: 44 weeks
Secondary outcomes:
measure: Change in Ambulatory Capacity From Baseline to 44 Weeks
timeFrame: 44 weeks
measure: Change in Schwab and England Scale From Baseline to 44 Weeks
timeFrame: 44 weeks
measure: Change in Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 44 Weeks
timeFrame: 44 weeks
measure: Change in the Mattis Dementia Rating Scale (DRS-2)From Baseline to 44 Weeks
timeFrame: 44 weeks
measure: Change in the 15-item Geriatric Depression Scale (GDS-15)From Baseline to 44 Weeks
timeFrame: 44 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univeristy of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Fountain Valley
country: United States
facility: The Parkinson's & Movement Disorder Institute
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Fransisco
country: United States
facility: University of California San Fransisco
state: California
city: Aurora
country: United States
facility: Univeristy of Colorado Denver
state: Colorado
city: Gainsville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: University of Florida, Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Honolulu
country: United States
facility: Pacific Health Research & Education Institute
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Shreveport
country: United States
facility: LSU Health Science Center Shreveport
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Golden Valley
country: United States
facility: Struthers Parkinson's Center
state: Minnesota
city: St Louis
country: United States
facility: Washington University
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: Manhasset
country: United States
facility: North Shore - LIJ Health System
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: Northwestern University
name: Tanya Simuni, MD
role: STUDY_DIRECTOR
affiliation: University of Rochester
name: Karl Kieburtz, MD MPH
role: STUDY_DIRECTOR
References:
citation: NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators. Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 2015 Aug;14(8):795-803. doi: 10.1016/S1474-4422(15)00144-1. Epub 2015 Jun 23.
citation: Carta AR, Simuni T. Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson's disease. Expert Opin Investig Drugs. 2015 Feb;24(2):219-27. doi: 10.1517/13543784.2015.963195. Epub 2014 Sep 17.