Parkinson's Disease
Conditions
Keywords
Parkinson's Disease, Biomarkers
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.
Interventions
DRUGplacebo
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.
DRUGPioglitazone
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.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Michael J. Fox Foundation for Parkinson's Research
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to 44 Weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Ambulatory Capacity From Baseline to 44 Weeks | 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. |
| Change in Schwab and England Scale From Baseline to 44 Weeks | 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). |
| Change in Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 44 Weeks | 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. |
| Change in the Mattis Dementia Rating Scale (DRS-2)From Baseline to 44 Weeks | 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. |
| Change in the 15-item Geriatric Depression Scale (GDS-15)From Baseline to 44 Weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 15 mg Pioglitazone 15 mg pioglitazone
Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo
44 weeks: 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 begin randomized dose of study drug. 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. Subjects will be followed on study drug for 44 weeks. | 72 |
| 45 mg Pioglitazone 45 mg pioglitazone
Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo
44 weeks: 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 begin randomized dose of study drug. 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. Subjects will be followed on study drug for 44 weeks. | 67 |
| Matching Placebo Placebo
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. | 71 |
| Total | 210 |
Baseline characteristics
| Characteristic | 45 mg Pioglitazone | Total | Matching Placebo | 15 mg Pioglitazone |
|---|---|---|---|---|
| Age, Continuous | 58.8 years STANDARD_DEVIATION 9.2 | 59.7 years STANDARD_DEVIATION 9.9 | 59.0 years STANDARD_DEVIATION 9.9 | 61.3 years STANDARD_DEVIATION 10.6 |
| Ambulatory capacity | 0.8 units on a scale STANDARD_DEVIATION 0.8 | 1.0 units on a scale STANDARD_DEVIATION 0.9 | 1.1 units on a scale STANDARD_DEVIATION 0.9 | 1.1 units on a scale STANDARD_DEVIATION 0.9 |
| Duration of PD symptoms (years) | 2.0 years STANDARD_DEVIATION 1.2 | 2.2 years STANDARD_DEVIATION 1.9 | 2.3 years STANDARD_DEVIATION 2.3 | 2.3 years STANDARD_DEVIATION 1.9 |
| Geriatric Depression Scale (GDS) | 1.1 units on a scale STANDARD_DEVIATION 1.3 | 1.4 units on a scale STANDARD_DEVIATION 1.6 | 1.8 units on a scale STANDARD_DEVIATION 1.9 | 1.4 units on a scale STANDARD_DEVIATION 1.4 |
| Mattis-Dementia Rating scale | 138.8 units on a scale STANDARD_DEVIATION 10.2 | 138.4 units on a scale STANDARD_DEVIATION 9.9 | 138 units on a scale STANDARD_DEVIATION 11.4 | 138.6 units on a scale STANDARD_DEVIATION 8.2 |
| Parkinson's Disease Questionnaire 39 (PDQ-39) Summary Index | 8.1 units on a scale STANDARD_DEVIATION 5.9 | 9.1 units on a scale STANDARD_DEVIATION 7.4 | 10.6 units on a scale STANDARD_DEVIATION 7.9 | 8.5 units on a scale STANDARD_DEVIATION 8.1 |
| Race/Ethnicity, Customized Non-Latino whites | 63 participants | 184 participants | 63 participants | 58 participants |
| Race/Ethnicity, Customized Racial/Ethnic Minority | 4 participants | 26 participants | 8 participants | 14 participants |
| rasagiline/selegiline use rasagiline use | 57 participants | 177 participants | 60 participants | 60 participants |
| rasagiline/selegiline use selegiline use | 10 participants | 33 participants | 11 participants | 12 participants |
| Right-handed No | 5 participants | 24 participants | 9 participants | 10 participants |
| Right-handed Yes | 62 participants | 186 participants | 62 participants | 62 participants |
| Schwab and England Activities of Daily Living scale (SEADL) | 94.1 units on a scale STANDARD_DEVIATION 5 | 93.9 units on a scale STANDARD_DEVIATION 4.9 | 93.9 units on a scale STANDARD_DEVIATION 5 | 93.8 units on a scale STANDARD_DEVIATION 4.9 |
| Sex/Gender, Customized Females | 20 participants | 62 participants | 23 participants | 19 participants |
| Sex/Gender, Customized Males | 47 participants | 148 participants | 48 participants | 53 participants |
| Time since PD diagnosis (years) | 0.7 years STANDARD_DEVIATION 0.7 | 0.7 years STANDARD_DEVIATION 0.7 | 0.8 years STANDARD_DEVIATION 0.7 | 0.8 years STANDARD_DEVIATION 0.7 |
| Total Unified Parkinson's Disease Rating Scale (UPDRS) | 21.2 units on a scale STANDARD_DEVIATION 8.8 | 22.2 units on a scale STANDARD_DEVIATION 9.2 | 21.7 units on a scale STANDARD_DEVIATION 8.7 | 23.8 units on a scale STANDARD_DEVIATION 9.9 |
| UPDRS ADL | 5.5 units on a scale STANDARD_DEVIATION 2.9 | 5.6 units on a scale STANDARD_DEVIATION 3 | 5.5 units on a scale STANDARD_DEVIATION 3 | 5.9 units on a scale STANDARD_DEVIATION 3.2 |
| UPDRS mental | 0.8 units on a scale STANDARD_DEVIATION 0.9 | 0.8 units on a scale STANDARD_DEVIATION 1 | 0.9 units on a scale STANDARD_DEVIATION 1.1 | 0.8 units on a scale STANDARD_DEVIATION 0.9 |
| UPDRS motor | 15.0 units on a scale STANDARD_DEVIATION 7.1 | 15.8 units on a scale STANDARD_DEVIATION 7.1 | 15.3 units on a scale STANDARD_DEVIATION 6.5 | 17.7 units on a scale STANDARD_DEVIATION 7.7 |
| Years of education | 16.2 years STANDARD_DEVIATION 3.3 | 16.7 years STANDARD_DEVIATION 3.1 | 16.8 years STANDARD_DEVIATION 3 | 17.1 years STANDARD_DEVIATION 3.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 63 / 72 | 51 / 67 | 59 / 71 |
| serious Total, serious adverse events | 6 / 72 | 9 / 67 | 3 / 71 |
Outcome results
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.
Time frame: 44 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 15 mg Pioglitazone | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to 44 Weeks | 4.42 units on a scale | Standard Error 0.95 |
| 45 mg Pioglitazone | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to 44 Weeks | 5.13 units on a scale | Standard Error 0.99 |
| Matching Placebo | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to 44 Weeks | 6.25 units on a scale | Standard Error 0.96 |
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.
Time frame: 44 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 15 mg Pioglitazone | Change in Ambulatory Capacity From Baseline to 44 Weeks | 0.39 units on a scale |
| 45 mg Pioglitazone | Change in Ambulatory Capacity From Baseline to 44 Weeks | 0.38 units on a scale |
| Matching Placebo | Change in Ambulatory Capacity From Baseline to 44 Weeks | 0.4 units on a scale |
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.
Time frame: 44 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 15 mg Pioglitazone | Change in Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 44 Weeks | 2.03 units on a scale |
| 45 mg Pioglitazone | Change in Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 44 Weeks | 2.08 units on a scale |
| Matching Placebo | Change in Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 44 Weeks | 0.08 units on a scale |
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).
Time frame: 44 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 15 mg Pioglitazone | Change in Schwab and England Scale From Baseline to 44 Weeks | -2.12 units on a scale |
| 45 mg Pioglitazone | Change in Schwab and England Scale From Baseline to 44 Weeks | -2.52 units on a scale |
| Matching Placebo | Change in Schwab and England Scale From Baseline to 44 Weeks | -1.84 units on a scale |
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.
Time frame: 44 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 15 mg Pioglitazone | Change in the 15-item Geriatric Depression Scale (GDS-15)From Baseline to 44 Weeks | 0.13 units on a scale |
| 45 mg Pioglitazone | Change in the 15-item Geriatric Depression Scale (GDS-15)From Baseline to 44 Weeks | 0.38 units on a scale |
| Matching Placebo | Change in the 15-item Geriatric Depression Scale (GDS-15)From Baseline to 44 Weeks | 0.18 units on a scale |
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.
Time frame: 44 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 15 mg Pioglitazone | Change in the Mattis Dementia Rating Scale (DRS-2)From Baseline to 44 Weeks | 1.16 units on a scale |
| 45 mg Pioglitazone | Change in the Mattis Dementia Rating Scale (DRS-2)From Baseline to 44 Weeks | 2.11 units on a scale |
| Matching Placebo | Change in the Mattis Dementia Rating Scale (DRS-2)From Baseline to 44 Weeks | 3.16 units on a scale |