Parkinson's Disease
Conditions
Keywords
SURE-PD3, Parkinson's disease, PD, Inosine, Urate, Parkinson Study Group (PSG)
Brief summary
A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial to determine whether oral inosine dosed to moderately elevate serum urate (from ≤5.7 mg/dL to 7.1-8.0 mg/dL) over 2 years slows clinical decline in early PD. Clinical decline will be assessed as change in the primary outcome variable of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), a composite scale comprising patient- and clinician-reported outcomes.
Detailed description
Capsules containing 500 mg of inosine (active drug) or \ 500 mg of lactose (placebo) will be taken orally up to two capsules three times per day (i.e., up to 3 g/day) for 24 months. In the inosine-treated group the number of capsules taken per day will be titrated to serum urate levels - measured at trough at study visits no more than three months apart - in order to achieve concentrations of 7.1-8.0 mg/dL. Initial dosing will be tailored to individualized factors including gender and pretreatment serum urate, and then advanced gradually toward the projected target dose. Adjustments in dosing of placebo capsules in the control arm will be algorithm-based to match dosing of inosine capsules in the active drug arm. Following study drug discontinuation all subjects will be followed during a 3-month wash-out period by telephone calls and a final study visit. All study visits after screening will include measurement of the primary outcome variable (MDS-UPDRS) and most will include secondary outcome variables: adverse events, dose adjustments, disability warranting initiation of dopaminergic therapy, Quality of Life in Neurological Disorders (Neuro-QOL), 39-item Parkinson's Disease Questionnaire (PDQ-39), Schwab & England Activities of Daily Living (S&E ADL) scale, Montreal Cognitive Assessment (MoCA), and orthostatic vital signs.
Interventions
DRUGInosine
capsules containing 500 mg of inosine
DRUGPlacebo
capsules containing \ 500 mg of lactose and appearing indistinguishable from inosine capsules
Sponsors
The Parkinson Study Group
Michael J. Fox Foundation for Parkinson's Research
University of Rochester
National Institute of Neurological Disorders and Stroke (NINDS)
Michael Alan Schwarzschild
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Study subjects meeting all of the following criteria will be allowed to enroll in the study: 1. Willingness and ability to give written informed consent and to comply with trial procedures. 2. Fulfillment of diagnostic criteria for idiopathic PD with at least two of the cardinal signs of PD (resting tremor, bradykinesia, rigidity) present at 2nd screening and baseline evaluations, as assessed by the Site Investigator. 3. Absence of current or imminent (within 90 days of enrollment) PD disability requiring dopaminergic therapy, as assessed by the Site Investigator. 4. Modified Hoehn and Yahr Scale Stage 1 to 2.5 inclusive. 5. Age 30 or older at the time of PD diagnosis. 6. Diagnosis of PD made within 3 years prior to 1st Screening Visit. 7. Non-fasting serum urate ≤ 5.7 mg/dL at 1st Screening Visit (SC1). 8. If the subject is female, then: 1. Being surgically sterile (hysterectomy or tubal ligation), or 2. Being postmenopausal (last menstruation was two years or more prior to 2nd Screening Visit), or 3. For those of childbearing potential * Using a reliable form of contraception for 60 days or more prior to Baseline Visit and agreeing to continue such use for 30 days post last dose of study drug. Reliable forms of contraception include: abstinence; implanted, injected or oral contraceptives (birth control pills), intrauterine device in place for at least 3 months prior to Baseline Visit, vaginal ring with spermicide, barrier with spermicide such as male or female condom, diaphragm or cervical cap, transdermal patch; male partner with vasectomy. * And having a negative pregnancy test at the 2nd Screening Visit. \[Note that a urine pregnancy test will be performed at screening on all women who are not at least two years postmenopausal or surgically sterile.\]
Exclusion criteria
Study subjects meeting any of the following criteria during screening evaluations will be excluded from entry into the study: 1. Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease. 2. Dopamine transporter (DAT) brain scan without evidence of dopamine deficit. 3. History of gout. 4. History of uric acid or urate urolithiasis, or recurrent urolithiasis all of unknown type. 5. A screening test positive for uric acid crystalluria, urine pH ≤ 5.0, or an estimated glomerular filtration rate \< 60 ml/min/1.73 m2. 6. History of myocardial infarction or stroke. 7. Symptomatic congestive heart failure with a documented ejection fraction below 45%. 8. History of severe chronic obstructive pulmonary disease. 9. Mini Mental State Exam score \< 25; i.e., a score of 0 to 24. 10. Use of any anti-parkinsonian medication (including levodopa, dopamine agonists, amantadine, entacapone and the anticholinergic agents trihexyphenidyl and benztropine) other than monoamine oxidase-B inhibitors within 60 days of Baseline, or in excess of 90 days. 11. Change in the dosage of (or initiation of) a monoamine oxidase-B (MAO-B) inhibitor within 90 days prior to Baseline, i.e., entry on a MAO-B inhibitor requires a stable dosage for the 90 days prior to Baseline. 12. Use of the following within 30 days prior to the Baseline Visit: inosine, allopurinol, febuxostat, probenecid, more than 50 IU of vitamin E daily, or more than 300 mg of vitamin C daily (though a daily standard multivitamin such as Bayer One-A-Day® or Centrum® is permissible), reserpine, methylphenidate, amphetamines, cinnarizine, monoamine oxidase-A inhibitors, tetrabenazine, neuroleptics or other dopamine blocking drugs. 13. Use of the following within 90 days prior to the DAT neuroimaging screening evaluation: modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, or amphetamine derivative. 14. Unstable dosing of a thiazide -- such as hydrochlorothiazide (e.g., Esidrex), chlorothiazide (e.g., Diuril), chlorthalidone (e.g., Hygroton), indapamide (e.g., Lozol), metolazone (e.g., Zaroxolyn), which are permissible as long as the subject is on a stable dose from 1 week prior to the 1st Screening Visit through the Baseline Visit. 15. Known unstable medical or psychiatric condition that may compromise participation in the study. (Note that difficulty swallowing large capsules might preclude participation due to the size of the study drug capsules.) 16. Clinically serious abnormality in the screening visit laboratory studies or ECG, as determined by the Site Investigator. 17. Participation in another investigational treatment study within 30 days prior to the Baseline Visit. 18. Known hypersensitivity or intolerability to inosine. 19. Known hypersensitivity to DaTscan (either the active substance of ioflupane I-123 or to any of the excipients).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Clinical Decline | two years | The primary outcome of the trial is rate of change in the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) I-III total score over 24 months estimated from a shared-baseline, random-slopes mixed model, censoring follow-up of subjects after initiation of dopaminergic therapy. Parts I-III of the MDS-UPDRS include ratings of non-motor experiences of daily living, motor experiences of daily living, and a motor examination. The MDS-UPDRS is assessed on a 5-point Likert scale ranging from 0 to 4 where higher scores imply worse symptoms. Parts I-III contain 59 total questions (13 in Part I, 13 in Part II, and 33 in Part III). Total scores for Parts I-III are calculated as simple sums of component items with mean imputation by Part if no more than 1, 2, or 7 items are missing for Parts I through III, respectively. Total scores may range from 0 to 236, with 0 meaning no symptoms and 236 meaning worse symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Developing Adverse Effects | two years | Safety of oral inosine titrated to elevate trough serum urate to 7.1 - 8.0 mg/dL will be evaluated by comparing active vs. placebo treatment with respect to the percentage of subjects experiencing individual types of AE, as classified by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and system organ class. |
| Percentage of Subjects Tolerant of the Treatment | three months; two years | Tolerability of a treatment will be defined as a percentage of all subjects in a treatment group who are tolerant of the treatment at 12 weeks (short-term tolerability) and 24 months (long-term tolerability). A subject who is tolerant of treatment will be defined as one who remains on-study and on the assigned treatment without one or more dose reductions lasting more than 4 weeks cumulative due to AEs. A treatment will be declared tolerable if the percentage who are tolerant is significantly greater than 50% by one-tailed testing at p \< 0.05. |
| Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | two years | The percentage of participants with disability warranting the initiation of dopaminergic therapy in each treatment group at time from baseline visit (in 180 day increments). |
| Clinical Efficacy: Rate of Change in Parkinson's Disease Questionnaire - 39 Item Version (PDQ-39) Scale | two years | Rate of change in Parkinson's Disease Questionnaire - 39 item version (PDQ-39) scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. The PDQ-39 asks 39 questions organized over eight domains (scales): mobility (10 items), activities of daily living (6 items), emotional well-being (6 items), stigma (4 items), social support (3 items), cognition (4 items), communication (3 items), and bodily discomfort (3 items). Each item has five possible ordinal responses, from never to always, depending on frequency of the symptom over the preceding month. The eight scales' scores are generated by Likert's method of summated ratings and then transformed to a single figure that ranges from 0 to 100. Higher scores are associated with more symptoms. |
| Rate of Developing Adverse Effects | two years | Safety also will be evaluated by comparing active vs. placebo treatment with respect to overall adverse event (AE) and serious AE (SAE) rate. |
| Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) Depression Module | two years | Rate of change in Quality of Life in Neurological Disorders (Neuro-QOL) depression module scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related quality of life (HRQoL) of people with neurological disorders. Higher raw scores are associated with more of the concept being measured. The depression module score ranges from 8 to 40. |
| Clinical Efficacy: Rate of Change in Schwab and England Scale | two years | Rate of change in percentage points on the Schwab and England scale for functional disability (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. The Schwab and England scale is a Site Investigator and subject assessment of the subject's level of independence. The subject will be scored on a percentage scale reflective of his/her ability to perform acts of daily living. Printed scores with associated descriptors range from 0% to 100% in increments of 5%, with higher percentages associated with more independence. A score of 0% implies vegetative functions such as swallowing, bladder and bowel functions are not functioning; bedridden. A score of 100% implies subject has full ability and is completely independent; essentially normal. |
| Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA) | two years | Rate of change in points on the Montreal Cognitive Assessment (MoCA) scale (for cognition; over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. The MoCA assesses attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Points are awarded for the correct completion of MoCA tasks. Scores for each task are summed for a total score (range 0-30). Higher scores indicate greater cognitive capacity. |
| Symptomatic Effects | three months (after both initiation and discontinuation of study drug) | Symptomatic effects will be estimated by changes in motor and other features (e.g., as assessed by short-term change in Movement Disorders Society Unified PD Rating Scale \[MDS-UPDRS\] I-III total score) during the first 3 months of wash-in at the start of period 1 and during the 3-month wash-out of period 2. The MDS-UPDRS includes ratings of non-motor experiences of daily living, motor experiences of daily living, and a motor examination. The MDS-UPDRS is assessed on a 5-point Likert scale ranging from 0 to 4 where higher scores imply worse features. Parts I-III contain 59 total questions (13 in Part I, 13 in Part II, and 33 in Part III). Total scores are calculated as simple sums of component items with mean imputation by Part if no more than 1, 2, or 7 items are missing for Parts I through III, respectively. Total scores may range from 0 to 236, with 0 meaning no symptoms and 236 meaning worse symptoms. |
| Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | two years | Rate of change in Quality of Life in Neurological Disorders (Neuro-QOL) scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related quality of life (HRQoL) of people with neurological disorders. It comprises 17 domains of HRQL covering physical, psychological and social health. Domains tested include anxiety, cognitive function, communication, depression, emotional and behavioral dyscontrol, fatigue, lower extremity function- mobility, positive affect and well- being, stigma, upper extremity function- fine motor and ADL, sleep disturbance, satisfaction with social roles and activities, and ability to participate in social roles and activities. Higher raw scores are associated with more of the concept being measured. All scales range from 8 to 40 except for Positive Affect and Well-Being which ranges from 9 to 45. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inosine Inosine will be dosed by titrating the number of capsules taken daily to achieve an elevation of serum urate to trough levels of 7.1 to 8.0 mg/dL.
Inosine: capsules containing 500 mg of inosine | 149 |
| Placebo Placebo will be dosed to match the capsule titrations of the inosine group.
Placebo: capsules containing \
500 mg of lactose and appearing indistinguishable from inosine capsules | 149 |
| Total | 298 |
Baseline characteristics
| Characteristic | Inosine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 73 Participants | 74 Participants | 147 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 75 Participants | 151 Participants |
| Age, Continuous | 63.0 years STANDARD_DEVIATION 9.7 | 63.6 years STANDARD_DEVIATION 9.4 | 63.3 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 144 Participants | 145 Participants | 289 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 143 Participants | 145 Participants | 288 Participants |
| Region of Enrollment Puerto Rico | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 148 participants | 149 participants | 297 participants |
| Sex: Female, Male Female | 80 Participants | 67 Participants | 147 Participants |
| Sex: Female, Male Male | 69 Participants | 82 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 147 | 0 / 149 |
| other Total, other adverse events | 125 / 147 | 135 / 149 |
| serious Total, serious adverse events | 16 / 147 | 21 / 149 |
Outcome results
Primary
Rate of Clinical Decline
The primary outcome of the trial is rate of change in the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) I-III total score over 24 months estimated from a shared-baseline, random-slopes mixed model, censoring follow-up of subjects after initiation of dopaminergic therapy. Parts I-III of the MDS-UPDRS include ratings of non-motor experiences of daily living, motor experiences of daily living, and a motor examination. The MDS-UPDRS is assessed on a 5-point Likert scale ranging from 0 to 4 where higher scores imply worse symptoms. Parts I-III contain 59 total questions (13 in Part I, 13 in Part II, and 33 in Part III). Total scores for Parts I-III are calculated as simple sums of component items with mean imputation by Part if no more than 1, 2, or 7 items are missing for Parts I through III, respectively. Total scores may range from 0 to 236, with 0 meaning no symptoms and 236 meaning worse symptoms.
Time frame: two years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inosine | Rate of Clinical Decline | 11.116 score per year |
| Placebo | Rate of Clinical Decline | 9.860 score per year |
p-value: 0.18395% CI: [-0.594, 3.106]Mixed Models Analysis
Secondary
Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA)
Rate of change in points on the Montreal Cognitive Assessment (MoCA) scale (for cognition; over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. The MoCA assesses attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Points are awarded for the correct completion of MoCA tasks. Scores for each task are summed for a total score (range 0-30). Higher scores indicate greater cognitive capacity.
Time frame: two years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inosine | Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA) | 0.186 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA) | 0.226 score per year |
p-value: 0.75895% CI: [-0.295, 0.215]Mixed Models Analysis
Secondary
Clinical Efficacy: Rate of Change in Parkinson's Disease Questionnaire - 39 Item Version (PDQ-39) Scale
Rate of change in Parkinson's Disease Questionnaire - 39 item version (PDQ-39) scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. The PDQ-39 asks 39 questions organized over eight domains (scales): mobility (10 items), activities of daily living (6 items), emotional well-being (6 items), stigma (4 items), social support (3 items), cognition (4 items), communication (3 items), and bodily discomfort (3 items). Each item has five possible ordinal responses, from never to always, depending on frequency of the symptom over the preceding month. The eight scales' scores are generated by Likert's method of summated ratings and then transformed to a single figure that ranges from 0 to 100. Higher scores are associated with more symptoms.
Time frame: two years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inosine | Clinical Efficacy: Rate of Change in Parkinson's Disease Questionnaire - 39 Item Version (PDQ-39) Scale | 0.686 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Parkinson's Disease Questionnaire - 39 Item Version (PDQ-39) Scale | 0.756 score per year |
p-value: 0.85695% CI: [-0.825, 0.685]Mixed Models Analysis
Secondary
Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL)
Rate of change in Quality of Life in Neurological Disorders (Neuro-QOL) scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related quality of life (HRQoL) of people with neurological disorders. It comprises 17 domains of HRQL covering physical, psychological and social health. Domains tested include anxiety, cognitive function, communication, depression, emotional and behavioral dyscontrol, fatigue, lower extremity function- mobility, positive affect and well- being, stigma, upper extremity function- fine motor and ADL, sleep disturbance, satisfaction with social roles and activities, and ability to participate in social roles and activities. Higher raw scores are associated with more of the concept being measured. All scales range from 8 to 40 except for Positive Affect and Well-Being which ranges from 9 to 45.
Time frame: two years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Communication | 0.055 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Positive Affect and Well-Being | -0.240 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Emotional and Behavioral Dyscontrol | -0.229 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Stigma | -0.060 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Upper Extremity Function | -0.026 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Fatigue | -0.049 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Sleep Disturbance | 0.091 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Anxiety | -0.397 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Satisfaction with Social Roles and Activities | -0.387 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Lower Extremity Function | -0.092 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Participation in Social Roles and Activities | -0.382 score per year |
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Cognitive Function | 0.014 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Participation in Social Roles and Activities | -0.130 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Cognitive Function | -0.282 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Communication | -0.201 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Anxiety | -0.473 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Emotional and Behavioral Dyscontrol | -0.324 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Fatigue | -0.040 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Lower Extremity Function | -0.261 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Positive Affect and Well-Being | 0.094 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Stigma | 0.021 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Upper Extremity Function | -0.238 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Sleep Disturbance | 0.020 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) | Satisfaction with Social Roles and Activities | -0.381 score per year |
Comparison: Anxietyp-value: 0.73695% CI: [-0.368, 0.521]Mixed Models Analysis
Comparison: Cognitive Functionp-value: 0.16795% CI: [-0.124, 0.714]Mixed Models Analysis
Comparison: Communicationp-value: 0.02295% CI: [0.038, 0.474]Mixed Models Analysis
Comparison: Emotional and Behavioral Dyscontrolp-value: 0.58495% CI: [-0.245, 0.435]Mixed Models Analysis
Comparison: Fatiguep-value: 0.97395% CI: [-0.56, 0.541]Mixed Models Analysis
Comparison: Lower Extremity Functionp-value: 0.21495% CI: [-0.098, 0.437]Mixed Models Analysis
Comparison: Positive Affect and Well-Beingp-value: 0.27195% CI: [-0.931, 0.262]Mixed Models Analysis
Comparison: Stigmap-value: 0.56695% CI: [-0.355, 0.194]Mixed Models Analysis
Comparison: Upper Extremity Functionp-value: 0.1395% CI: [-0.063, 0.487]Mixed Models Analysis
Comparison: Sleep Disturbancep-value: 0.72395% CI: [-0.325, 0.468]Mixed Models Analysis
Comparison: Satisfaction with Social Roles and Activitiesp-value: 0.98495% CI: [-0.592, 0.579]Mixed Models Analysis
Comparison: Participation in Social Roles and Activitiesp-value: 0.42695% CI: [-0.877, 0.371]Mixed Models Analysis
Secondary
Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) Depression Module
Rate of change in Quality of Life in Neurological Disorders (Neuro-QOL) depression module scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related quality of life (HRQoL) of people with neurological disorders. Higher raw scores are associated with more of the concept being measured. The depression module score ranges from 8 to 40.
Time frame: two years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inosine | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) Depression Module | -0.023 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) Depression Module | 0.083 score per year |
p-value: 0.45495% CI: [-0.382, 0.171]Mixed Models Analysis
Secondary
Clinical Efficacy: Rate of Change in Schwab and England Scale
Rate of change in percentage points on the Schwab and England scale for functional disability (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group. The Schwab and England scale is a Site Investigator and subject assessment of the subject's level of independence. The subject will be scored on a percentage scale reflective of his/her ability to perform acts of daily living. Printed scores with associated descriptors range from 0% to 100% in increments of 5%, with higher percentages associated with more independence. A score of 0% implies vegetative functions such as swallowing, bladder and bowel functions are not functioning; bedridden. A score of 100% implies subject has full ability and is completely independent; essentially normal.
Time frame: two years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inosine | Clinical Efficacy: Rate of Change in Schwab and England Scale | -0.833 score per year |
| Placebo | Clinical Efficacy: Rate of Change in Schwab and England Scale | -0.880 score per year |
p-value: 0.9195% CI: [-0.764, 0.858]Mixed Models Analysis
Secondary
Percentage Developing Adverse Effects
Safety of oral inosine titrated to elevate trough serum urate to 7.1 - 8.0 mg/dL will be evaluated by comparing active vs. placebo treatment with respect to the percentage of subjects experiencing individual types of AE, as classified by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and system organ class.
Time frame: two years
Population: Only 147 of 149 participants in the inosine group were analyzed because 2 participants never initiated study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inosine | Percentage Developing Adverse Effects | 129 Participants |
| Placebo | Percentage Developing Adverse Effects | 137 Participants |
p-value: 0.00495% CI: [1.046, 1.273]Poisson Regression
Secondary
Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time
The percentage of participants with disability warranting the initiation of dopaminergic therapy in each treatment group at time from baseline visit (in 180 day increments).
Time frame: two years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inosine | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 180 Days | 30.81 percentage of participants |
| Inosine | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 540 Days | 72.21 percentage of participants |
| Inosine | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 360 Days | 59.01 percentage of participants |
| Inosine | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 720 Days | 84.57 percentage of participants |
| Inosine | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 0 Days | 0 percentage of participants |
| Placebo | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 720 Days | 88.27 percentage of participants |
| Placebo | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 0 Days | 0 percentage of participants |
| Placebo | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 180 Days | 32.42 percentage of participants |
| Placebo | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 360 Days | 56.32 percentage of participants |
| Placebo | Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time | 540 Days | 78.55 percentage of participants |
p-value: 0.497Log Rank
Secondary
Percentage of Subjects Tolerant of the Treatment
Tolerability of a treatment will be defined as a percentage of all subjects in a treatment group who are tolerant of the treatment at 12 weeks (short-term tolerability) and 24 months (long-term tolerability). A subject who is tolerant of treatment will be defined as one who remains on-study and on the assigned treatment without one or more dose reductions lasting more than 4 weeks cumulative due to AEs. A treatment will be declared tolerable if the percentage who are tolerant is significantly greater than 50% by one-tailed testing at p \< 0.05.
Time frame: three months; two years
Population: Only 147 of 149 participants in the inosine group were analyzed because 2 participants never initiated study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inosine | Percentage of Subjects Tolerant of the Treatment | 12 weeks | 93.2 percentage of subjects |
| Inosine | Percentage of Subjects Tolerant of the Treatment | 12 months | 76.1 percentage of subjects |
| Inosine | Percentage of Subjects Tolerant of the Treatment | 24 months | 50.3 percentage of subjects |
| Placebo | Percentage of Subjects Tolerant of the Treatment | 12 weeks | 98.7 percentage of subjects |
| Placebo | Percentage of Subjects Tolerant of the Treatment | 12 months | 91.3 percentage of subjects |
| Placebo | Percentage of Subjects Tolerant of the Treatment | 24 months | 70.8 percentage of subjects |
p-value: 0.002Log Rank
Secondary
Rate of Developing Adverse Effects
Safety also will be evaluated by comparing active vs. placebo treatment with respect to overall adverse event (AE) and serious AE (SAE) rate.
Time frame: two years
Population: Only 147 of 149 participants in the inosine group were analyzed because 2 participants never initiated study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inosine | Rate of Developing Adverse Effects | 354.05 Events per 100 patient-years |
| Placebo | Rate of Developing Adverse Effects | 327.73 Events per 100 patient-years |
p-value: 0.12495% CI: [0.979, 1.192]Poisson Regression
Secondary
Symptomatic Effects
Symptomatic effects will be estimated by changes in motor and other features (e.g., as assessed by short-term change in Movement Disorders Society Unified PD Rating Scale \[MDS-UPDRS\] I-III total score) during the first 3 months of wash-in at the start of period 1 and during the 3-month wash-out of period 2. The MDS-UPDRS includes ratings of non-motor experiences of daily living, motor experiences of daily living, and a motor examination. The MDS-UPDRS is assessed on a 5-point Likert scale ranging from 0 to 4 where higher scores imply worse features. Parts I-III contain 59 total questions (13 in Part I, 13 in Part II, and 33 in Part III). Total scores are calculated as simple sums of component items with mean imputation by Part if no more than 1, 2, or 7 items are missing for Parts I through III, respectively. Total scores may range from 0 to 236, with 0 meaning no symptoms and 236 meaning worse symptoms.
Time frame: three months (after both initiation and discontinuation of study drug)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Inosine | Symptomatic Effects | Period 1: BL to V03 | -1.509 score per period |
| Inosine | Symptomatic Effects | Period 2: V10 to SV | -2.729 score per period |
| Placebo | Symptomatic Effects | Period 1: BL to V03 | -1.301 score per period |
| Placebo | Symptomatic Effects | Period 2: V10 to SV | -0.328 score per period |
Comparison: BL to V01p-value: 0.79695% CI: [-1.783, 1.367]Mixed Models Analysis
Comparison: V10 to SVp-value: 0.48695% CI: [-9.156, 4.355]Mixed Models Analysis