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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2016 by Massachusetts General Hospital
Sponsor:
Collaborators:
The Parkinson Study Group
Michael J. Fox Foundation for Parkinson's Research
University of Rochester
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Michael Alan Schwarzschild, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT02642393
First received: December 19, 2015
Last updated: September 20, 2016
Last verified: September 2016
  Purpose

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 Intervention Phase
Parkinson's Disease
Drug: Inosine
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: A Randomized, Double-blind, Placebo-controlled Trial of Urate-elevating Inosine Treatment to Slow Clinical Decline in Early Parkinson's Disease

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Rate of clinical decline [ Time Frame: two years ] [ Designated as safety issue: No ]
    The primary outcome of the trial is rate of change in 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.


Secondary Outcome Measures:
  • Rate of developing adverse effects [ Time Frame: two years ] [ Designated as safety issue: Yes ]
    Safety also will be evaluated by comparing active vs. placebo treatment with respect to overall adverse event (AE) and serious AE (SAE) rate.

  • Proportion developing adverse effects [ Time Frame: two years ] [ Designated as safety issue: Yes ]
    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 proportions of subjects experiencing individual types of AE, as classified by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and system organ class.

  • Proportion of subjects tolerant of the treatment [ Time Frame: three months; two years ] [ Designated as safety issue: Yes ]
    Tolerability of a treatment will be defined as a proportion 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 proportion who are tolerant is significantly greater than 50% by one-tailed testing at p < 0.05.

  • Time to disability warranting dopaminergic therapy [ Time Frame: two years ] [ Designated as safety issue: No ]
    Secondary efficacy outcomes will include time from baseline visit to disability warranting the initiation of dopaminergic therapy in each treatment group.

  • Clinical efficacy: Rate of change in PDQ-39 [ Time Frame: two years ] [ Designated as safety issue: No ]
    Rate of change in 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.

  • Clinical efficacy: Rate of change in Neuro-QOL [ Time Frame: two years ] [ Designated as safety issue: No ]
    Rate of change in 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.

  • Clinical efficacy: Rate of change in Neuro-QOL depression module [ Time Frame: two years ] [ Designated as safety issue: No ]
    Rate of change in 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.

  • Clinical efficacy: Rate of change in Schwab and England scale [ Time Frame: two years ] [ Designated as safety issue: No ]
    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.

  • Clinical efficacy: Rate of change in Montreal Cognitive Assessment (MoCA) [ Time Frame: two years ] [ Designated as safety issue: No ]
    Rate of change in points on the 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.

  • Clinical efficacy: Proportion of subjects having developed disability warranting dopaminergic therapy [ Time Frame: up to 27 months ] [ Designated as safety issue: No ]
    Determinations of disability warranting initiation of dopaminergic therapy will be made every three months during period 1 (24 months on study drug) and monthly during period 2 (following study drug discontinuation, between months 24 and 27) for subjects who have not previously reached this level of disability. Analysis of measures that are equally evaluable at the end of both periods (such as proportion of subjects having developed disability warranting dopaminergic therapy), will be conducted as a three-part test: a) of significantly slower worsening during period 1, b) of non-inferior rates of worsening during period 2, and c) of a significant net benefit at the end of period 2. It could provide evidence of disease modification if all three evaluations were favorable.

  • Symptomatic effects [ Time Frame: three months (after both initiation and discontinuation of study drug) ] [ Designated as safety issue: No ]
    Symptomatic effects will be estimated by changes in motor and other features (e.g., as assess by short-term change in total MDS-UPDRS 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.


Estimated Enrollment: 270
Study Start Date: June 2016
Estimated Study Completion Date: August 2020
Estimated Primary Completion Date: February 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: inactive agent

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

Ages Eligible for Study:   30 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02642393

Contacts
Contact: Sheehan F Wheeler 617-726-5714 SFWheeler@mgh.harvard.edu

  Show 59 Study Locations
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)
  More Information

Additional Information:
Publications:
Responsible Party: Michael Alan Schwarzschild, Chair, SURE-PD3 Steering Committee, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT02642393     History of Changes
Other Study ID Numbers: INO-PD-P3-2014  1U01NS090259-01A1 
Study First Received: December 19, 2015
Last Updated: September 20, 2016
Health Authority: United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: De-identified data; per policies of NIH/NINDS and the PSG (Parkinson Study Group)

Keywords provided by Massachusetts General Hospital:
SURE-PD3
Parkinson's disease
PD
Inosine
Urate
Parkinson Study Group (PSG)

Additional relevant MeSH terms:
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Uric Acid
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 23, 2016