Pioglitazone in Early Parkinson's Disease

Parkinson's Disease Clinical Trial

Official title:

A Multi-Center, Double-Blind, Placebo-Controlled Phase II Study of Pioglitazone in Early Parkinson's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01280123
• Other study ID #: FS-ZONE
• Secondary ID: 5U01NS043128-12
• Status: Completed
• Phase: Phase 2
• First received: December 3, 2010
• Last updated: September 15, 2015
• Start date: March 2011
• Est. completion date: May 2014

Study information

• Verified date: September 2013
• Source: University of Rochester
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Parkinson Disease
• Parkinson's Disease

Intervention

Drug:
• Pioglitazone
Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated.
• placebo
Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Medical College of Georgia	Augusta	Georgia
United States	Univeristy of Colorado Denver	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	Univeristy of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	SUNY Downstate Medical Center	Brooklyn	New York
United States	University of Vermont	Burlington	Vermont
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	Michigan State University	East Lansing	Michigan
United States	The Parkinson's & Movement Disorder Institute	Fountain Valley	California
United States	University of Florida	Gainsville	Florida
United States	Struthers Parkinson's Center	Golden Valley	Minnesota
United States	Pacific Health Research & Education Institute	Honolulu	Hawaii
United States	University of Florida, Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky	Lexington	Kentucky
United States	University of Southern California	Los Angeles	California
United States	North Shore - LIJ Health System	Manhasset	New York
United States	University of Miami	Miami	Florida
United States	Vanderbilt University	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	University of California San Fransisco	San Fransisco	California
United States	LSU Health Science Center Shreveport	Shreveport	Louisiana
United States	Washington University	St Louis	Missouri
United States	University of South Florida	Tampa	Florida

Sponsors (3)

Lead Sponsor	Collaborator
University of Rochester	Michael J. Fox Foundation for Parkinson's Research, National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. Epu — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to 44 Weeks	Change in total UPDRS score from baseline to 44 weeks (in subjects treated with rasagiline 1 mg/day or selegiline 10 mg/day).; The Total UPDRS is the sum of parts I, II, and III. The possible range of the total UPDRS is from 0-176. Higher values indicate worse outcomes.; The change is 44 weeks - baseline.	44 weeks	No
Secondary	Change in Ambulatory Capacity From Baseline to 44 Weeks	This is the sum of the 5 UPDRS questions regarding ambulatory capacity: falling, freezing, walking, gait, postural stability.; Ambulatory Capacity is calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson's Disease Rating Scale (UPDRS). It ranges from 0-20. Higher scores are worse. Change is 44 weeks - baseline.	44 weeks	No
Secondary	Change in Schwab and England Scale From Baseline to 44 Weeks	The modified Schwab and England Activities of Daily Living is a single question ranging from 0-100% with anchors for each 10% interval. Higher scores are better (100% completely independent- 0% vegetative).	44 weeks	No
Secondary	Change in Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 44 Weeks	The Parkinson's Disease Questionnaire (PDQ-39) is a short, 39 item measure of quality of life in subjects with Parkinson's disease. The questionnaire covers 8 aspects of quality of life: mobility, activities of daily living, emotional well-being, stigma, social support, cognitions, communication and bodily discomfort.; The total score ranges from 0 (never have difficulty) to 100 (always have difficulty). Lower scores reflect better quality of life.	44 weeks	No
Secondary	Change in the Mattis Dementia Rating Scale (DRS-2)From Baseline to 44 Weeks	The Mattis dementia rating scale is a psychometric instrument designed to assess the extent and nature of dementia. Mattis Dementia Rating scale (DRS-2) raw score is the sum of 5 raw sub-scores (attention has possible 37 points, initiation/perseveration has possible 37 points, construction has possible 6 points, conceptualization has possible 39 points, memory has possible 25 points). Total range is 0-144. Higher scores are better.	44 weeks	No
Secondary	Change in the 15-item Geriatric Depression Scale (GDS-15)From Baseline to 44 Weeks	The Geriatric Depression Scale - 15 is a short 15 yes or no question instrument for assessing depression in the elderly. It has been found to be particularly useful in assessing depression in Parkinson's Disease. A score of 0 to 5 is normal. A score greater than 5 suggests depression.	44 weeks	No