SURE-PD3: Study of Urate Elevation in Parkinson's Disease, Phase 3

• Sponsor: Michael Alan Schwarzschild (Other)
• Overall Status: Completed
• CT.gov ID: NCT02642393
• Collaborator: The Parkinson Study Group (Other), Michael J. Fox Foundation for Parkinson's Research (Other), University of Rochester (Other), National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 298
• Locations: 62
• Arms: 2
• Actual Duration (Months): 36
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: Inosine; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 298 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A Randomized, Double-blind, Placebo-controlled Trial of Urate-elevating Inosine Treatment to Slow Clinical Decline in Early Parkinson's Disease
• Actual Study Start Date: Jun 1, 2016
• Actual Primary Completion Date: Jun 1, 2019
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Inosine; capsules containing 500 mg of inosine; Other Names: hypoxanthine 9-β-D-ribofuranoside
Placebo Comparator: Placebo Placebo will be dosed to match the capsule titrations of the inosine group.	Drug: Placebo; capsules containing ~500 mg of lactose and appearing indistinguishable from inosine capsules; Other Names: inactive agent

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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).

5. 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.

6. 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.

7. 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.

8. 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".

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts 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:

9. Being surgically sterile (hysterectomy or tubal ligation), or

10. Being postmenopausal (last menstruation was two years or more prior to 2nd Screening Visit), or

11. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Barrow Neurological Institute	Phoenix	Arizona	United States	85013
3	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85259
4	Banner Sun Health Research Institute	Sun City	Arizona	United States	85351
5	University of California San Diego	La Jolla	California	United States	92093
6	University of Southern California	Los Angeles	California	United States	90033
7	University of California Davis	Sacramento	California	United States	95817
8	University of California San Francisco	San Francisco	California	United States	94143
9	University of Colorado	Aurora	Colorado	United States	80045
10	Rocky Mountain Movement Disorder Center	Englewood	Colorado	United States	80113
11	Hartford HealthCare Movement Disorders Center	Vernon	Connecticut	United States	06066
12	University of South Florida	Tampa	Florida	United States	33613
13	Emory University	Atlanta	Georgia	United States	30329
14	Augusta University	Augusta	Georgia	United States	30912
15	Northwestern University	Chicago	Illinois	United States	60611
16	Rush University Medical Center	Chicago	Illinois	United States	60612
17	Neurosciences Institute at Central DuPage Hospital	Winfield	Illinois	United States	60190
18	Indiana University	Indianapolis	Indiana	United States	46202
19	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
20	University of Louisville	Louisville	Kentucky	United States	40202
21	Oschner Clinic Foundation	New Orleans	Louisiana	United States	70121
22	University of Maryland, Baltimore	Baltimore	Maryland	United States	21201
23	Johns Hopkins University	Baltimore	Maryland	United States	21287
24	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
25	Boston University Medical Center	Boston	Massachusetts	United States	02118
26	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
27	University of Michigan	Ann Arbor	Michigan	United States	48105
28	Michigan State University	East Lansing	Michigan	United States	48824
29	Henry Ford Health System	West Bloomfield	Michigan	United States	48322
30	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
31	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
32	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada	United States	89106
33	Overlook Medical Center, Atlantic Neuroscience Institute	Summit	New Jersey	United States	07901
34	Albany Medical College	Albany	New York	United States	12208
35	SUNY Downstate Medical Center	Brooklyn	New York	United States	11203
36	Weill Cornell Medical Center	New York	New York	United States	10021
37	SUNY Upstate Medical University	Syracuse	New York	United States	13210
38	Duke University	Durham	North Carolina	United States	27705
39	University of Cincinnati/Cincinnati Children's Hospital	Cincinnati	Ohio	United States	45219
40	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
41	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
42	Ohio State University	Columbus	Ohio	United States	43221
43	Oregon Health & Sciences University	Portland	Oregon	United States	97239
44	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19107
45	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
46	Butler Hospital	Providence	Rhode Island	United States	02906
47	Medical University of South Carolina	Charleston	South Carolina	United States	29403
48	Wesley Neurology Clinic, PC	Cordova	Tennessee	United States	38018
49	University of Tennessee Health Science Center	Memphis	Tennessee	United States	38163
50	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
51	UT Southwestern Medical Center	Dallas	Texas	United States	75390-9036
52	Baylor College of Medicine	Houston	Texas	United States	77030
53	University of Texas Houston Medical School	Houston	Texas	United States	77030
54	Baylor Scott & White Health	Temple	Texas	United States	76508
55	The University of Vermont	Burlington	Vermont	United States	05405
56	University of Virginia	Charlottesville	Virginia	United States	22908
57	VCU Parkinson's & Movement Disorder Center (McGuire Veterans Hospital)	Richmond	Virginia	United States	23230
58	Sentara Neurology Specialists	Virginia Beach	Virginia	United States	23456
59	Inland Northwest Research	Spokane	Washington	United States	99202
60	Northwest Neurological PLLC	Spokane	Washington	United States	99202
61	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
62	University of Puerto Rico	San Juan		Puerto Rico	935

Sponsors and Collaborators

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

Investigators

• Study Chair: Michael A Schwarzschild, MD, PhD, Massachusetts General Hospital (PI of Clinical Coordinating Center), PSG (Chair, SURE-PD3 Steering Committee)
• Study Director: Alberto Ascherio, MD, DrPH, Harvard School of Public Health, PSG (Co-Chair, SURE-PD3 Steering Committee)
• Study Director: David Oakes, PhD, University of Rochester (PI of Data Coordinating Center), PSG (Study Statistician/Member, SURE-PD3 Steering Committee)
• Study Director: Eric A Macklin, PhD, Massachusetts General Hospital, PSG (Study Statistician/Member, SURE-PD3 Steering Committee)

Study Documents (Full-Text)

• Statistical Analysis Plan - Sep 5, 2019
• Study Protocol - Nov 28, 2017

More Information

Additional Information:

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

Publications

• 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.

• Responsible Party: Michael Alan Schwarzschild, Chair, SURE-PD3 Steering Committee, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02642393
• Other Study ID Numbers: INO-PD-P3-2014; 1U01NS090259-01A1
• First Posted: Dec 30, 2015
• Last Update Posted: Jul 28, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Michael Alan Schwarzschild, Chair, SURE-PD3 Steering Committee, Massachusetts General Hospital: SURE-PD3; Parkinson's disease; PD; Inosine; Urate; Parkinson Study Group (PSG)
• Additional relevant MeSH terms: Parkinson Disease

Study Results

Participant Flow

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	149	149
COMPLETED	50	57
NOT COMPLETED	99	92

Baseline Characteristics

Arm/Group Title	Inosine	Placebo	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	149	149	298
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	76 51%	75 50.3%	151 50.7%
>=65 years	73 49%	74 49.7%	147 49.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.0 (9.7)	63.6 (9.4)	63.3 (9.5)
Sex: Female, Male (Count of Participants)
Female	80 53.7%	67 45%	147 49.3%
Male	69 46.3%	82 55%	151 50.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 3.4%	4 2.7%	9 3%
Not Hispanic or Latino	144 96.6%	145 97.3%	289 97%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 1.3%	1 0.7%	3 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 1.3%	0 0%	2 0.7%
White	143 96%	145 97.3%	288 96.6%
More than one race	1 0.7%	1 0.7%	2 0.7%
Unknown or Not Reported	1 0.7%	2 1.3%	3 1%
Region of Enrollment (participants) [Number]
Puerto Rico	1 0.7%	0 0%	1 0.3%
United States	148 99.3%	149 100%	297 99.7%

Outcome Measures

1. Primary Outcome

Title	Rate of Clinical Decline
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
Mean (95% Confidence Interval) [score per year]	11.116	9.860

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.183
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	1.256
	Confidence Interval	(2-Sided) 95%; -0.594 to 3.106
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.943
	Estimation Comments

2. Secondary Outcome

Title	Rate of Developing Adverse Effects
Description	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

Outcome Measure Data

Analysis Population Description

Only 147 of 149 participants in the inosine group were analyzed because 2 participants never initiated study drug.

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	147	149
Number (95% Confidence Interval) [Events per 100 patient-years]	354.05	327.73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	Poisson Regression
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.080
	Confidence Interval	(2-Sided) 95%; 0.979 to 1.192
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage Developing Adverse Effects
Description	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

Outcome Measure Data

Analysis Population Description

Only 147 of 149 participants in the inosine group were analyzed because 2 participants never initiated study drug.

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	147	149
Count of Participants [Participants]	129 86.6%	137 91.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Poisson Regression
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.154
	Confidence Interval	(2-Sided) 95%; 1.046 to 1.273
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Subjects Tolerant of the Treatment
Description	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

Outcome Measure Data

Analysis Population Description

Only 147 of 149 participants in the inosine group were analyzed because 2 participants never initiated study drug.

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	147	149
12 weeks	93.2	98.7
12 months	76.1	91.3
24 months	50.3	70.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
0 Days	0 0%	0 0%
180 Days	30.81 20.7%	32.42 21.8%
360 Days	59.01 39.6%	56.32 37.8%
540 Days	72.21 48.5%	78.55 52.7%
720 Days	84.57 56.8%	88.27 59.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.497
	Comments
	Method	Log Rank
	Comments

6. Secondary Outcome

Title	Clinical Efficacy: Rate of Change in Parkinson's Disease Questionnaire - 39 Item Version (PDQ-39) Scale
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
Mean (95% Confidence Interval) [score per year]	0.686	0.756

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.856
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.070
	Confidence Interval	(2-Sided) 95%; -0.825 to 0.685
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.385
	Estimation Comments

7. Secondary Outcome

Title	Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
Anxiety	-0.397	-0.473
Cognitive Function	0.014	-0.282
Communication	0.055	-0.201
Emotional and Behavioral Dyscontrol	-0.229	-0.324
Fatigue	-0.049	-0.040
Lower Extremity Function	-0.092	-0.261
Positive Affect and Well-Being	-0.240	0.094
Stigma	-0.060	0.021
Upper Extremity Function	-0.026	-0.238
Sleep Disturbance	0.091	0.020
Satisfaction with Social Roles and Activities	-0.387	-0.381
Participation in Social Roles and Activities	-0.382	-0.130

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Anxiety
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.736
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.076
	Confidence Interval	(2-Sided) 95%; -0.368 to 0.521
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.226
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Cognitive Function
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.167
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.295
	Confidence Interval	(2-Sided) 95%; -0.124 to 0.714
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.213
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Communication
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.256
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.474
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.111
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Emotional and Behavioral Dyscontrol
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.584
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.095
	Confidence Interval	(2-Sided) 95%; -0.245 to 0.435
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.173
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Fatigue
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.973
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.010
	Confidence Interval	(2-Sided) 95%; -0.560 to 0.541
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.280
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Lower Extremity Function
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.214
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.169
	Confidence Interval	(2-Sided) 95%; -0.098 to 0.437
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Positive Affect and Well-Being
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.334
	Confidence Interval	(2-Sided) 95%; -0.931 to 0.262
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.304
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Stigma
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.566
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.080
	Confidence Interval	(2-Sided) 95%; -0.355 to 0.194
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.140
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Upper Extremity Function
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.130
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.212
	Confidence Interval	(2-Sided) 95%; -0.063 to 0.487
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.140
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Sleep Disturbance
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.723
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.072
	Confidence Interval	(2-Sided) 95%; -0.325 to 0.468
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.202
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Satisfaction with Social Roles and Activities
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.984
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.006
	Confidence Interval	(2-Sided) 95%; -0.592 to 0.579
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.298
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	Participation in Social Roles and Activities
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.253
	Confidence Interval	(2-Sided) 95%; -0.877 to 0.371
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.317
	Estimation Comments

8. Secondary Outcome

Title	Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) Depression Module
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
Mean (95% Confidence Interval) [score per year]	-0.023	0.083

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.454
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.106
	Confidence Interval	(2-Sided) 95%; -0.382 to 0.171
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

9. Secondary Outcome

Title	Clinical Efficacy: Rate of Change in Schwab and England Scale
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
Mean (95% Confidence Interval) [score per year]	-0.833	-0.880

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.910
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; -0.764 to 0.858
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.413
	Estimation Comments

10. Secondary Outcome

Title	Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
Mean (95% Confidence Interval) [score per year]	0.186	0.226

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.758
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.040
	Confidence Interval	(2-Sided) 95%; -0.295 to 0.215
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

11. Secondary Outcome

Title	Symptomatic Effects
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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	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
Measure Participants	149	149
Period 1: BL to V03	-1.509	-1.301
Period 2: V10 to SV	-2.729	-0.328

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	BL to V01
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.796
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.208
	Confidence Interval	(2-Sided) 95%; -1.783 to 1.367
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.803
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inosine, Placebo
	Comments	V10 to SV
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.486
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-2.400
	Confidence Interval	(2-Sided) 95%; -9.156 to 4.355
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.443
	Estimation Comments

Adverse Events

Time Frame	27 months
Adverse Event Reporting Description	Only 147 of 149 participants in the inosine group were analyzed because 2 participants never initiated study drug.
Arm/Group Title	Inosine		Placebo
Arm/Group Description	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		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
All Cause Mortality
	Inosine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/147 (0.7%)		0/149 (0%)
Serious Adverse Events
	Inosine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/147 (10.9%)		21/149 (14.1%)
Cardiac disorders
Atrial fibrillation	0/147 (0%)	0	2/149 (1.3%)	2
Cardiomyopathy	0/147 (0%)	0	1/149 (0.7%)	1
Gastrointestinal disorders
Abdominal pain	0/147 (0%)	0	1/149 (0.7%)	1
Abdominal pain upper	1/147 (0.7%)	1	0/149 (0%)	0
Constipation	0/147 (0%)	0	1/149 (0.7%)	1
Gastric ulcer	0/147 (0%)	0	1/149 (0.7%)	1
Hiatus hernia	0/147 (0%)	0	1/149 (0.7%)	1
Intestinal obstruction	0/147 (0%)	0	1/149 (0.7%)	1
Small intestinal obstruction	0/147 (0%)	0	1/149 (0.7%)	1
General disorders
Chest pain	0/147 (0%)	0	2/149 (1.3%)	2
Death	1/147 (0.7%)	1	0/149 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	0/147 (0%)	0	1/149 (0.7%)	1
Infections and infestations
Cellulitis	0/147 (0%)	0	1/149 (0.7%)	1
Corona virus infection	0/147 (0%)	0	1/149 (0.7%)	1
Diverticulitis	1/147 (0.7%)	1	0/149 (0%)	0
Extradural abscess	0/147 (0%)	0	1/149 (0.7%)	1
Gastroenteritis	0/147 (0%)	0	1/149 (0.7%)	1
Pneumonia	0/147 (0%)	0	1/149 (0.7%)	1
Urinary tract infection	1/147 (0.7%)	1	0/149 (0%)	0
Injury, poisoning and procedural complications
Concussion	0/147 (0%)	0	1/149 (0.7%)	1
Hip fracture	1/147 (0.7%)	1	0/149 (0%)	0
Procedural pain	0/147 (0%)	0	1/149 (0.7%)	1
Spinal compression fracture	0/147 (0%)	0	1/149 (0.7%)	1
Investigations
Blood sodium decreased	1/147 (0.7%)	1	0/149 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/147 (0%)	0	1/149 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile duct cancer	0/147 (0%)	0	1/149 (0.7%)	1
Prostate cancer	1/147 (0.7%)	1	0/149 (0%)	0
Transitional cell carcinoma	1/147 (0.7%)	1	0/149 (0%)	0
Nervous system disorders
Encephalopathy	1/147 (0.7%)	1	0/149 (0%)	0
Syncope	1/147 (0.7%)	1	2/149 (1.3%)	3
Transient ischaemic attack	0/147 (0%)	0	1/149 (0.7%)	1
Renal and urinary disorders
Nephrolithiasis	6/147 (4.1%)	6	0/149 (0%)	0
Urinary retention	0/147 (0%)	0	1/149 (0.7%)	1
Reproductive system and breast disorders
Testicular mass	1/147 (0.7%)	1	0/149 (0%)	0
Surgical and medical procedures
Hip arthroplasty	0/147 (0%)	0	2/149 (1.3%)	2
Knee arthroplasty	1/147 (0.7%)	1	0/149 (0%)	0
Vascular disorders
Hypotension	0/147 (0%)	0	1/149 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Inosine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	125/147 (85%)		135/149 (90.6%)
Gastrointestinal disorders
Constipation	7/147 (4.8%)	7	16/149 (10.7%)	16
Diarrhoea	9/147 (6.1%)	11	9/149 (6%)	12
Nausea	22/147 (15%)	25	20/149 (13.4%)	31
General disorders
Fatigue	8/147 (5.4%)	9	11/149 (7.4%)	11
Infections and infestations
Nasopharyngitis	12/147 (8.2%)	14	10/149 (6.7%)	13
Sinusitis	10/147 (6.8%)	11	7/149 (4.7%)	9
Upper respiratory tract infection	7/147 (4.8%)	8	13/149 (8.7%)	16
Urinary tract infection	17/147 (11.6%)	24	10/149 (6.7%)	16
Investigations
Blood creatinine increased	13/147 (8.8%)	13	3/149 (2%)	3
Crystal urine present	8/147 (5.4%)	9	7/149 (4.7%)	9
Mean cell volume increased	12/147 (8.2%)	13	7/149 (4.7%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	9/147 (6.1%)	9	13/149 (8.7%)	13
Back pain	18/147 (12.2%)	19	10/149 (6.7%)	12
Muscle spasms	9/147 (6.1%)	10	7/149 (4.7%)	7
Pain in extremity	9/147 (6.1%)	9	21/149 (14.1%)	25
Nervous system disorders
Dizziness	14/147 (9.5%)	16	16/149 (10.7%)	22
Headache	8/147 (5.4%)	9	14/149 (9.4%)	16
Somnolence	4/147 (2.7%)	4	8/149 (5.4%)	9
Psychiatric disorders
Insomnia	9/147 (6.1%)	9	6/149 (4%)	6
Renal and urinary disorders
Haematuria	13/147 (8.8%)	13	12/149 (8.1%)	12
Nephrolithiasis	12/147 (8.2%)	12	4/149 (2.7%)	4
Proteinuria	9/147 (6.1%)	9	12/149 (8.1%)	14

Limitations/Caveats

A prespecified interim analysis determined futility for demonstrating the hypothesized inosine effect of a slower rate of change in the primary outcome and prompted early completion of the trial after an average study drug exposure of 17 months.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.