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

NCT02642393 | Completed Phase 3 Results DMC

• 2 other identifiers: INO-PD-P3-20141U01NS090259-01A1
• Study Type: interventional
• Target: 298
• Locations: 2 countries
• Sites: 62

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.

Conditions

Parkinson's Disease

Keywords

SURE-PD3; Parkinson's disease; PD; Inosine; Urate; Parkinson Study Group (PSG)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Rate of Developing Adverse Effects

  two years

• Percentage Developing Adverse Effects

  two years

• Percentage of Subjects Tolerant of the Treatment

  three months; two years

• Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time

  two years

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

  two years

Study Arms (2)

Inosine

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Placebo will be dosed to match the capsule titrations of the inosine group.

Drug: Placebo

Interventions

Inosine DRUG

capsules containing 500 mg of inosine

Also known as: hypoxanthine 9-β-D-ribofuranoside

Inosine

Placebo DRUG

capsules containing \~500 mg of lactose and appearing indistinguishable from inosine capsules

Also known as: inactive agent

Placebo

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Study subjects meeting all of the following criteria will be allowed to enroll in the study:
• Willingness and ability to give written informed consent and to comply with trial procedures.
• 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.
• Absence of current or imminent (within 90 days of enrollment) PD disability requiring dopaminergic therapy, as assessed by the Site Investigator.
• Modified Hoehn and Yahr Scale Stage 1 to 2.5 inclusive.
• Age 30 or older at the time of PD diagnosis.
• Diagnosis of PD made within 3 years prior to 1st Screening Visit.
• Non-fasting serum urate ≤ 5.7 mg/dL at 1st Screening Visit (SC1).
• If the subject is female, then:
• Being surgically sterile (hysterectomy or tubal ligation), or
• Being postmenopausal (last menstruation was two years or more prior to 2nd Screening Visit), or
• 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. \[Note that a urine pregnancy test will be performed at screening on all women who are not at least two years postmenopausal or surgically sterile.\]

You may not qualify if:

• Study subjects meeting any of the following criteria during screening evaluations will be excluded from entry into the study:
• Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease.
• Dopamine transporter (DAT) brain scan without evidence of dopamine deficit.
• History of gout.
• History of uric acid or urate urolithiasis, or recurrent urolithiasis all of unknown type.
• A screening test positive for uric acid crystalluria, urine pH ≤ 5.0, or an estimated glomerular filtration rate \< 60 ml/min/1.73 m2.
• History of myocardial infarction or stroke.
• Symptomatic congestive heart failure with a documented ejection fraction below 45%.
• History of severe chronic obstructive pulmonary disease.
• Mini Mental State Exam score \< 25; i.e., a score of 0 to 24.
• 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.
• 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.
• 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.
• Use of the following within 90 days prior to the DAT neuroimaging screening evaluation: modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, or amphetamine derivative.
• 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.

Sponsors & Collaborators

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

Study Sites (62)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

Mayo Clinic Arizona

Scottsdale, Arizona, 85259, United States

Location

Banner Sun Health Research Institute

Sun City, Arizona, 85351, United States

Location

University of California San Diego

La Jolla, California, 92093, United States

Location

University of Southern California

Los Angeles, California, 90033, United States

Location

University of California Davis

Sacramento, California, 95817, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Rocky Mountain Movement Disorder Center

Englewood, Colorado, 80113, United States

Location

Hartford HealthCare Movement Disorders Center

Vernon, Connecticut, 06066, United States

Location

University of South Florida

Tampa, Florida, 33613, United States

Location

Emory University

Atlanta, Georgia, 30329, United States

Location

Augusta University

Augusta, Georgia, 30912, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Neurosciences Institute at Central DuPage Hospital

Winfield, Illinois, 60190, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Oschner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

University of Maryland, Baltimore

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston University Medical Center

Boston, Massachusetts, 02118, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Michigan State University

East Lansing, Michigan, 48824, United States

Location

Henry Ford Health System

West Bloomfield, Michigan, 48322, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Cleveland Clinic Lou Ruvo Center for Brain Health

Las Vegas, Nevada, 89106, United States

Location

Overlook Medical Center, Atlantic Neuroscience Institute

Summit, New Jersey, 07901, United States

Location

Albany Medical College

Albany, New York, 12208, United States

Location

SUNY Downstate Medical Center

Brooklyn, New York, 11203, United States

Location

Weill Cornell Medical Center

New York, New York, 10021, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

University of Cincinnati/Cincinnati Children's Hospital

Cincinnati, Ohio, 45219, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State University

Columbus, Ohio, 43221, United States

Location

Oregon Health & Sciences University

Portland, Oregon, 97239, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19107, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Butler Hospital

Providence, Rhode Island, 02906, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29403, United States

Location

Wesley Neurology Clinic, PC

Cordova, Tennessee, 38018, United States

Location

University of Tennessee Health Science Center

Memphis, Tennessee, 38163, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390-9036, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Texas Houston Medical School

Houston, Texas, 77030, United States

Location

Baylor Scott & White Health

Temple, Texas, 76508, United States

Location

The University of Vermont

Burlington, Vermont, 05405, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

VCU Parkinson's & Movement Disorder Center (McGuire Veterans Hospital)

Richmond, Virginia, 23230, United States

Location

Sentara Neurology Specialists

Virginia Beach, Virginia, 23456, United States

Location

Inland Northwest Research

Spokane, Washington, 99202, United States

Location

Northwest Neurological PLLC

Spokane, Washington, 99202, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

University of Puerto Rico

San Juan, Massachusetts, 935, Puerto Rico

Location

Related Publications (4)

• 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.

  PMID: 24366103 BACKGROUND

• Di Luca DG, Macklin EA, Hodgeman K, Lopez G, Pothier L, Callahan KF, Lowell J, Chan J, Videnovic A, Lungu C, Lang AE, Litvan I, Schwarzschild MA, Simuni T. Enrollment of Participants From Marginalized Racial and Ethnic Groups: A Comparative Assessment of the STEADY-PD III and SURE-PD3 Trials. Neurol Clin Pract. 2023 Feb;13(1):e200113. doi: 10.1212/CPJ.0000000000200113. Epub 2023 Jan 18.

  PMID: 36865634 DERIVED

• Parkinson Study Group SURE-PD3 Investigators; Schwarzschild MA, Ascherio A, Casaceli C, Curhan GC, Fitzgerald R, Kamp C, Lungu C, Macklin EA, Marek K, Mozaffarian D, Oakes D, Rudolph A, Shoulson I, Videnovic A, Scott B, Gauger L, Aldred J, Bixby M, Ciccarello J, Gunzler SA, Henchcliffe C, Brodsky M, Keith K, Hauser RA, Goetz C, LeDoux MS, Hinson V, Kumar R, Espay AJ, Jimenez-Shahed J, Hunter C, Christine C, Daley A, Leehey M, de Marcaida JA, Friedman JH, Hung A, Bwala G, Litvan I, Simon DK, Simuni T, Poon C, Schiess MC, Chou K, Park A, Bhatti D, Peterson C, Criswell SR, Rosenthal L, Durphy J, Shill HA, Mehta SH, Ahmed A, Deik AF, Fang JY, Stover N, Zhang L, Dewey RB Jr, Gerald A, Boyd JT, Houston E, Suski V, Mosovsky S, Cloud L, Shah BB, Saint-Hilaire M, James R, Zauber SE, Reich S, Shprecher D, Pahwa R, Langhammer A, LaFaver K, LeWitt PA, Kaminski P, Goudreau J, Russell D, Houghton DJ, Laroche A, Thomas K, McGraw M, Mari Z, Serrano C, Blindauer K, Rabin M, Kurlan R, Morgan JC, Soileau M, Ainslie M, Bodis-Wollner I, Schneider RB, Waters C, Ratel AS, Beck CA, Bolger P, Callahan KF, Crotty GF, Klements D, Kostrzebski M, McMahon GM, Pothier L, Waikar SS, Lang A, Mestre T. Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):926-939. doi: 10.1001/jama.2021.10207.

  PMID: 34519802 DERIVED

• Mestre TA, Macklin EA, Ascherio A, Ferreira JJ, Lang AE, Schwarzschild MA; Parkinson Study Group SURE-PD3 Investigators. Expectations of Benefit in a Trial of a Candidate Disease-Modifying Treatment for Parkinson Disease. Mov Disord. 2021 Aug;36(8):1964-1967. doi: 10.1002/mds.28630. Epub 2021 May 4.

  PMID: 33942376 DERIVED

Related Links

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

MeSH Terms

Conditions

Parkinson Disease

Interventions

Inosine

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Limitations and 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.

Results Point of Contact

• Title: Dr. Michael Schwarzschild
• Organization: Massachusetts General Hospital

michaels@helix.mgh.harvard.edu

617-724-9611

Study Officials

• Michael A Schwarzschild, MD, PhD

  Massachusetts General Hospital (PI of Clinical Coordinating Center), PSG (Chair, SURE-PD3 Steering Committee)

  STUDY CHAIR

• 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 DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chair, SURE-PD3 Steering Committee

Study Record Dates

• First Submitted: December 19, 2015
• First Posted: December 30, 2015
• Study Start: June 1, 2016
• Primary Completion: June 1, 2019
• Study Completion: June 1, 2019
• Last Updated: July 28, 2020
• Results First Posted: July 28, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share

Locations

US (61); PR (1)