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

NCT ID: NCT02642393

Last Updated: 2020-07-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 298 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2019-06-30

Brief Summary

A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial to determine whether oral inosine dosed to moderately elevate serum urate (from ≤5.7 mg/dL to 7.1-8.0 mg/dL) over 2 years slows clinical decline in early PD.

Clinical decline will be assessed as change in the primary outcome variable of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), a composite scale comprising patient- and clinician-reported outcomes.

Detailed Description

Capsules containing 500 mg of inosine (active drug) or ~500 mg of lactose (placebo) will be taken orally up to two capsules three times per day (i.e., up to 3 g/day) for 24 months. In the inosine-treated group the number of capsules taken per day will be titrated to serum urate levels - measured at trough at study visits no more than three months apart - in order to achieve concentrations of 7.1-8.0 mg/dL. Initial dosing will be tailored to individualized factors including gender and pretreatment serum urate, and then advanced gradually toward the projected target dose. Adjustments in dosing of placebo capsules in the control arm will be algorithm-based to match dosing of inosine capsules in the active drug arm.

Following study drug discontinuation all subjects will be followed during a 3-month wash-out period by telephone calls and a final study visit. All study visits after screening will include measurement of the primary outcome variable (MDS-UPDRS) and most will include secondary outcome variables: adverse events, dose adjustments, disability warranting initiation of dopaminergic therapy, Quality of Life in Neurological Disorders (Neuro-QOL), 39-item Parkinson's Disease Questionnaire (PDQ-39), Schwab & England Activities of Daily Living (S&E ADL) scale, Montreal Cognitive Assessment (MoCA), and orthostatic vital signs.

Conditions

Parkinson's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Inosine

Intervention Type: DRUG

capsules containing 500 mg of inosine

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

Inosine

capsules containing 500 mg of inosine

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

hypoxanthine 9-β-D-ribofuranoside; inactive agent

Eligibility Criteria

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).

• Minimum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Parkinson Study Group

NETWORK

Sponsor Role: collaborator

Michael J. Fox Foundation for Parkinson's Research

OTHER

Sponsor Role: collaborator

University of Rochester

OTHER

Sponsor Role: collaborator

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Michael Alan Schwarzschild

OTHER

Sponsor Role: lead

Responsible Party

Michael Alan Schwarzschild

Chair, SURE-PD3 Steering Committee

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Michael A Schwarzschild, MD, PhD

Role: STUDY_CHAIR

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

Alberto Ascherio, MD, DrPH

Role: STUDY_DIRECTOR

Harvard School of Public Health, PSG (Co-Chair, SURE-PD3 Steering Committee)

David Oakes, PhD

Role: STUDY_DIRECTOR

University of Rochester (PI of Data Coordinating Center), PSG (Study Statistician/Member, SURE-PD3 Steering Committee)

Eric A Macklin, PhD

Role: STUDY_DIRECTOR

Massachusetts General Hospital, PSG (Study Statistician/Member, SURE-PD3 Steering Committee)

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Barrow Neurological Institute

Phoenix, Arizona, United States

Mayo Clinic Arizona

Scottsdale, Arizona, United States

Banner Sun Health Research Institute

Sun City, Arizona, United States

University of California San Diego

La Jolla, California, United States

University of Southern California

Los Angeles, California, United States

University of California Davis

Sacramento, California, United States

University of California San Francisco

San Francisco, California, United States

University of Colorado

Aurora, Colorado, United States

Rocky Mountain Movement Disorder Center

Englewood, Colorado, United States

Hartford HealthCare Movement Disorders Center

Vernon, Connecticut, United States

University of South Florida

Tampa, Florida, United States

Emory University

Atlanta, Georgia, United States

Augusta University

Augusta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

Neurosciences Institute at Central DuPage Hospital

Winfield, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Louisville

Louisville, Kentucky, United States

Oschner Clinic Foundation

New Orleans, Louisiana, United States

University of Maryland, Baltimore

Baltimore, Maryland, United States

Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Boston University Medical Center

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Michigan State University

East Lansing, Michigan, United States

Henry Ford Health System

West Bloomfield, Michigan, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Cleveland Clinic Lou Ruvo Center for Brain Health

Las Vegas, Nevada, United States

Overlook Medical Center, Atlantic Neuroscience Institute

Summit, New Jersey, United States

Albany Medical College

Albany, New York, United States

SUNY Downstate Medical Center

Brooklyn, New York, United States

Weill Cornell Medical Center

New York, New York, United States

SUNY Upstate Medical University

Syracuse, New York, United States

Duke University

Durham, North Carolina, United States

University of Cincinnati/Cincinnati Children's Hospital

Cincinnati, Ohio, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Oregon Health & Sciences University

Portland, Oregon, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Butler Hospital

Providence, Rhode Island, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Wesley Neurology Clinic, PC

Cordova, Tennessee, United States

University of Tennessee Health Science Center

Memphis, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

University of Texas Houston Medical School

Houston, Texas, United States

Baylor Scott & White Health

Temple, Texas, United States

The University of Vermont

Burlington, Vermont, United States

University of Virginia

Charlottesville, Virginia, United States

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

Richmond, Virginia, United States

Sentara Neurology Specialists

Virginia Beach, Virginia, United States

Inland Northwest Research

Spokane, Washington, United States

Northwest Neurological PLLC

Spokane, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

University of Puerto Rico

San Juan, Massachusetts, Puerto Rico

Countries

United States; Puerto Rico

References

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.

Reference Type: BACKGROUND

PMID: 24366103 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36865634 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34519802 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33942376 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Related Links

http://www.parkinson-study-group.org/

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

Other Identifiers

1U01NS090259-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

INO-PD-P3-2014

Identifier Type: -

Identifier Source: org_study_id