Clinical trial NCT02642393: Study of Urate Elevation in Parkinson's Disease, Phase 3
Official title: A Randomized, Double-blind, Placebo-controlled Trial of Urate-elevating Inosine Treatment to Slow Clinical Decline in Early Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Parkinson's Disease
Keywords: SURE-PD3
Parkinson's disease
PD
Inosine
Urate
Parkinson Study Group (PSG)
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: The Parkinson Study Group
name: Michael J. Fox Foundation for Parkinson's Research
name: University of Rochester
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2015-12-30
Enrollment: 298
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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).

Primary outcomes:
measure: Rate of Clinical Decline
timeFrame: two years
Secondary outcomes:
measure: Rate of Developing Adverse Effects
timeFrame: two years
measure: Percentage Developing Adverse Effects
timeFrame: two years
measure: Percentage of Subjects Tolerant of the Treatment
timeFrame: three months; two years
measure: Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time
timeFrame: two years
measure: Clinical Efficacy: Rate of Change in Parkinson's Disease Questionnaire - 39 Item Version (PDQ-39) Scale
timeFrame: two years
measure: Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL)
timeFrame: two years
measure: Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) Depression Module
timeFrame: two years
measure: Clinical Efficacy: Rate of Change in Schwab and England Scale
timeFrame: two years
measure: Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA)
timeFrame: two years
measure: Symptomatic Effects
timeFrame: three months (after both initiation and discontinuation of study drug)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Englewood
country: United States
facility: Rocky Mountain Movement Disorder Center
state: Colorado
city: Vernon
country: United States
facility: Hartford HealthCare Movement Disorders Center
state: Connecticut
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Winfield
country: United States
facility: Neurosciences Institute at Central DuPage Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Oschner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland, Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: West Bloomfield
country: United States
facility: Henry Ford Health System
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: Summit
country: United States
facility: Overlook Medical Center, Atlantic Neuroscience Institute
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati/Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Butler Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Cordova
country: United States
facility: Wesley Neurology Clinic, PC
state: Tennessee
city: Memphis
country: United States
facility: University of Tennessee Health Science Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: University of Texas Houston Medical School
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Health
state: Texas
city: Burlington
country: United States
facility: The University of Vermont
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: VCU Parkinson's & Movement Disorder Center (McGuire Veterans Hospital)
state: Virginia
city: Virginia Beach
country: United States
facility: Sentara Neurology Specialists
state: Virginia
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
city: Spokane
country: United States
facility: Northwest Neurological PLLC
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico
Study officials:
affiliation: Massachusetts General Hospital (PI of Clinical Coordinating Center), PSG (Chair, SURE-PD3 Steering Committee)
name: Michael A Schwarzschild, MD, PhD
role: STUDY_CHAIR
affiliation: Harvard School of Public Health, PSG (Co-Chair, SURE-PD3 Steering Committee)
name: Alberto Ascherio, MD, DrPH
role: STUDY_DIRECTOR
affiliation: University of Rochester (PI of Data Coordinating Center), PSG (Study Statistician/Member, SURE-PD3 Steering Committee)
name: David Oakes, PhD
role: STUDY_DIRECTOR
affiliation: Massachusetts General Hospital, PSG (Study Statistician/Member, SURE-PD3 Steering Committee)
name: Eric A Macklin, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.