Study of Urate Elevation in Parkinson's Disease, Phase 3

A Randomized, Double-blind, Placebo-controlled Trial of Urate-elevating Inosine Treatment to Slow Clinical Decline in Early Parkinson's Disease

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.

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.

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).