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

Parkinson's Disease Clinical Trial

— SURE-PD3  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02642393
• Other study ID #: INO-PD-P3-2014
• Secondary ID: 1U01NS090259-01A
• Status: Completed
• Phase: Phase 3
• Start date: June 2016
• Est. completion date: June 2019

Study information

• Verified date: July 2020
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 298
• Est. completion date: June 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Parkinson Disease
• Parkinson's Disease

Intervention

Drug:
• Inosine
capsules containing 500 mg of inosine
• Placebo
capsules containing ~500 mg of lactose and appearing indistinguishable from inosine capsules

Locations

Country	Name	City	State
Puerto Rico	University of Puerto Rico	San Juan
United States	Albany Medical College	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland, Baltimore	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston University Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	SUNY Downstate Medical Center	Brooklyn	New York
United States	The 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 Cincinnati/Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	Wesley Neurology Clinic, PC	Cordova	Tennessee
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	Michigan State University	East Lansing	Michigan
United States	Rocky Mountain Movement Disorder Center	Englewood	Colorado
United States	Baylor College of Medicine	Houston	Texas
United States	University of Texas Houston Medical School	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California San Diego	La Jolla	California
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	University of Southern California	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	University of Tennessee Health Science Center	Memphis	Tennessee
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Oschner Clinic Foundation	New Orleans	Louisiana
United States	Weill Cornell Medical Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health & Sciences University	Portland	Oregon
United States	Butler Hospital	Providence	Rhode Island
United States	VCU Parkinson's & Movement Disorder Center (McGuire Veterans Hospital)	Richmond	Virginia
United States	University of California Davis	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California San Francisco	San Francisco	California
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Inland Northwest Research	Spokane	Washington
United States	Northwest Neurological PLLC	Spokane	Washington
United States	Overlook Medical Center, Atlantic Neuroscience Institute	Summit	New Jersey
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	SUNY Upstate Medical University	Syracuse	New York
United States	University of South Florida	Tampa	Florida
United States	Baylor Scott & White Health	Temple	Texas
United States	Hartford HealthCare Movement Disorders Center	Vernon	Connecticut
United States	Sentara Neurology Specialists	Virginia Beach	Virginia
United States	Henry Ford Health System	West Bloomfield	Michigan
United States	Neurosciences Institute at Central DuPage Hospital	Winfield	Illinois

Sponsors (5)

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

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (1)

Parkinson Study Group SURE-PD Investigators, Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014 Feb;71(2):141-50. doi: 10.1001/jamaneurol.2013.5528. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	two years
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.	two years
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.	two years
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.	three months; two years
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).	two years
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.	two years
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.	two years
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.	two years
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".	two years
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.	two years
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.	three months (after both initiation and discontinuation of study drug)

External Links

•   Not-for-profit scientific network of Parkinson centers in North America