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N-Acetylcysteine for Neuroprotection in Parkinson's Disease (NAC for PD)

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ClinicalTrials.gov Identifier: NCT01470027
Recruitment Status : Completed
First Posted : November 10, 2011
Results First Posted : April 18, 2018
Last Update Posted : April 18, 2018
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Dikoma C. Shungu, Weill Medical College of Cornell University

Brief Summary:
The overall objective of this developmental/exploratory study is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to assess (a) whether brain levels of the antioxidant glutathione (GSH) are decreased in vivo, as has been found in postmortem brain, in 30 patients with Parkinson's disease (PD) compared to matched controls; (b) whether GSH levels in PD brain increase significantly following 30 days of daily supplementation with 1800mg or 3600mg of N-acetylcysteine (NAC) compared to placebo and to baseline, and (c) whether any such increases in brain GSH would be dose-dependent and be associated with a change in the participants' oxidative stress profiles. In addition, a clinical assessment battery, including quantitative tests of motor function, will be performed to investigate potential associations between the NAC intervention, brain GSH levels, oxidative stress markers, and clinical presentation. If successful, this study will represent the first objective documentation of whether there is a GSH deficit in living PD brain that dietary NAC supplementation can mitigate, thereby providing a compelling justification for investigating such neuroprotective strategies in larger controlled clinical trials.

Condition or disease Intervention/treatment Phase
Parkinson Disease Drug: N-acetylcysteine Drug: Placebo Phase 1 Phase 2

Detailed Description:
Parkinson's disease (PD) is a neurodegenerative disorder in which deficits of the primary intracellular antioxidant, glutathione (GSH), are postulated to mediate increased oxidative stress and mitochondrial dysfunction in the pathogenic cascade leading up to the loss of nigrostriatal dopaminergic neurons that is the hallmark of the disorder. Therefore, there is currently great interest in treatment strategies that can maintain, restore and/or elevate intracellular GSH levels. However, GSH does not readily cross the blood-brain barrier or the membranes of most cells, including neurons, so that direct dietary supplementation of the antioxidant has not proved viable in increasing its intracellular concentration. On the other hand, since the bioavailability of cysteine, which does cross both the blood-brain barrier and most cell membranes, is rate-limiting in the GSH synthesis pathway, this amino acid and its non-toxic derivatives, such as N-acetylcysteine (NAC), are being investigated as potential precursors that can be supplied through dietary means to spur in situ synthesis and elevation of brain GSH. The overall objective of this Exploratory/Developmental (R21) study is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to determine (a) whether levels of GSH are decreased in vivo in the brain of 30 patients with Parkinson's disease (PD) compared to matched controls, as has been found in postmortem brain; (b) whether GSH levels in PD brain increase significantly following 30 days of daily supplementation with 1800mg or 3600mg of NAC compared to baseline and placebo, and (c) whether any such increases in brain GSH would be dose-dependent and be associated with a change in the participants' oxidative stress profiles. Additionally, a clinical assessment battery, including quantitative tests of motor function, will be performed to investigate potential associations between the NAC intervention, brain GSH levels, oxidative stress markers, and clinical presentation. If successful, this study will represent the first objective documentation of whether there is a GSH deficit in living PD brain that dietary NAC supplementation can mitigate, thereby providing a compelling justification for investigating such neuroprotective strategies in larger controlled clinical trials.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: N-Acetylcysteine for Neuroprotection in Parkinson's Disease
Study Start Date : January 2012
Actual Primary Completion Date : August 2016
Actual Study Completion Date : August 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: N-acetylcysteine 1800mg
N-acetylcysteine 1800mg/day for 30 days
Drug: N-acetylcysteine
900mg NAC effervescent tablets
Other Name: NAC
Active Comparator: N-acetylcysteine 3600mg
N-acetylcysteine 3600mg daily for 30 days
Drug: N-acetylcysteine
900mg NAC effervescent tablets
Other Name: NAC
Placebo Comparator: Placebo
Placebo effervescent tablets daily for 30 days
Drug: Placebo
effervescent tablets



Primary Outcome Measures :
  1. Change of Cerebral Glutathione Levels as Measured by Proton Magnetic Resonance Spectroscopy [ Time Frame: at baseline and 4 weeks after intervention start ]

    In vivo brain GSH measured with 1H MRS in the unmedicated patients with idiopathic PD and in sex- and age-matched healthy controls prior to and following 4 weeks supplementation with either placebo, 1800mg/day or 3600 mg/day of NAC. Striatal and occipital cortex glutathione levels as measured in vivo by 1H MRS at baseline and following 4 weeks of treatment with placebo, 1800mg NAC/day and 3600mg NAC/day.

    The area under the GSH spectral peak was obtained by frequency-domain fitting of the GSH resonance in the edited spectrum to a pseudo-Voigt lineshape function using a robust and highly optimized public-domain Levenberg-Marquardt nonlinear least-squares minimization routine. The resulting peak areas were then expressed as ratios relative to the synchronously acquired and similarly fitted unsuppressed voxel water signal.



Secondary Outcome Measures :
  1. Unified Parkinson's Disease Rating Scale (UPDRS) Parts I-V (Total Score Reported) [ Time Frame: at baseline and 4 weeks after intervention start ]

    The UPDRS is considered the gold standard for determining disease severity and progression in patients with Parkinson's disease. It consists of the following five elements:

    1. Evaluation of mentation, behavior and mood.
    2. Self evaluation of the activities of daily living (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, etc.
    3. Motor evaluation by a clinician.
    4. Hoehn and Yahr scale (Hoehn 1967) for the description of the overall disease severity in PD with 8 stages.
    5. Schwab and England activities of daily living scale (Schwab and England 1969) for the estimation of the general abilities in PD patients. The Schwab and England ADL scale is graduated in 10% steps with 100% indicating complete independence and 0% indicating an individual in whom the vegetative functions are completely impaired.

    A total of 199 points are possible for UPDRS, with 199 representing the worst disability and 0 no disability.


  2. Mini Mental State Examination (MMSE) [ Time Frame: at baseline and 4 weeks after intervention start ]
    The MMSE is a brief questionnaire-based test that is used to screen for cognitive impairment. Domains tested are orientation to time and place, registration, attention and calculation, recall, language, repetition and complex commands. Scores lower than 25/30 points indicate mild (21-24 points), moderate (10-20 points) or severe (<10 points) cognitive impairment, but scores may need to be corrected for educational attainment, age and interfering impairments such as motor deficits that affect drawing skills.

  3. Hamilton Depression Rating Scale (HAM-D) [ Time Frame: at baseline and 4 weeks after intervention start ]

    The Hamilton Depression Rating Scale (HAM-D) is a 21-item instrument designed to measure the severity of illness in adults already diagnosed as having depression. The Hamilton Depression Rating Scale (HAM-D) has proven useful for many years as a way of determining a patient's level of depression before, during, and after treatment. It is clinician-administered and requires 15 to 20 minutes complete the interview and score the results. Although the HAM-D form lists 21 items, the scoring is based on the first 17. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2.

    The minimum score is 0 and maximum score is 50. The scale has been widely used in clinical practice and become a standard in pharmaceutical trials.

    HAM-D Scoring Instructions are following:

    0-7 = Normal; 8-13 = Mild Depression; 14-18 = Moderate Depression; 19-22 = Severe Depression;

    ≥ 23 = Very Severe Depression.


  4. 9-Hole Peg Board Test (9-HPT) [ Time Frame: at baseline and 4 weeks after intervention start ]
    The 9-HPT is a standardized, quantitative timed test of upper extremity motor function. Individuals are asked to place and remove nine pegs, one at a time, from nine holes in a board as quickly as possible. The task is performed twice with the dominant and twice with the non-dominant hand, and the average time to complete the task once is calculated for each hand. The 9-HPT has a high inter- and intra-rater reliability, is validated and is sensitive to detect minor impairments of hand function.

  5. 10-Meter Walk Test [ Time Frame: at baseline and 4 weeks after intervention start ]

    The 10-meter walk test is a standardized, quantitative timed test of lower body motor function. The maximal gait speed is measured during a 10-meter walk. The task will be performed three times and the average time to complete the task once will be recorded. The 10-meter walk test is a reliable and sensitive measure of gait function in elderly individuals and PD patients.

    Cut-off values:

    < 0.4 m/s more likely to be household ambulators; 0.4 - 0.8 m/s limited community ambulators; > 0.8 m/s community ambulators.


  6. Beck Anxiety Inventory [ Time Frame: at baseline and 4 weeks after intervention start ]

    The Beck Anxiety Inventory (BAI) is a clinician-administered and validated instrument to discriminate anxiety from depression. The standardized BAI cutoffs are:

    0-9: minimal anxiety; 10-16: mild anxiety; 17-29: moderate anxiety; 30-63: severe anxiety.


  7. Parkinson's Disease Quality of Life Questionnaire (PDQLQ) [ Time Frame: at baseline and 4 weeks after intervention start ]

    The Parkinson's Disease Quality of Life Questionnaire is a self completion PRO designed to address aspects of functioning and well-being for those affected by Parkinson's disease.

    The Parkinson's Disease Quality of Life Questionnaire is coded on a scale of 0 to 185, with 185 indicating perfect health and 0 indicating very poor health.




Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Diagnosis of idiopathic PD according to the United Kingdom Parkinson's Disease Society Brain Bank criteria (UKPDSBB) criteria (only for PD group
  • Age 50 to 75 years
  • Able to give informed consent for study participation
  • Not on any medication for PD (anticholinergic agents allowed)

Exclusion Criteria:

  • Unable to give informed consent
  • Unable to undergo a brain MRI
  • PD duration ≥15 years
  • Receiving dopamine receptor blocking agents, including typical neuroleptics, prochlorperazine, and metoclopramide
  • Diagnosis of major depression or other axis I psychopathology
  • Modified Mini-Mental Status Exam (MMSE) ≤ 24/30
  • Diagnosis of chronic or persistent illnesses that could affect oxidative stress status, such as diabetes or congestive heart failure
  • Significant concomitant medical disease limiting life expectancy to less than 12 months from study inclusion
  • Diagnosis of primary mitochondrial disorder, epilepsy, stroke, multiple sclerosis or other neurodegenerative diseases such as Alzheimer's disease or ALS

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01470027


Locations
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10021
Sponsors and Collaborators
Weill Medical College of Cornell University
National Institute on Aging (NIA)
Investigators
Principal Investigator: Dikoma C. Shungu, Ph.D. Weill Medical College of Cornell University

Responsible Party: Dikoma C. Shungu, Professor of Physics in Radiology, Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT01470027     History of Changes
Other Study ID Numbers: 1109011912
1R21AG041509 ( U.S. NIH Grant/Contract )
First Posted: November 10, 2011    Key Record Dates
Results First Posted: April 18, 2018
Last Update Posted: April 18, 2018
Last Verified: March 2018

Keywords provided by Dikoma C. Shungu, Weill Medical College of Cornell University:
magnetic resonance spectroscopy
N-acetylcysteine
antioxidant
glutathione

Additional relevant MeSH terms:
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes