Convection-Enhanced Delivery to Study the Pathophysiology Underlying the Clinical Features of Parkinson s Disease

NCT00921128 | Withdrawn Phase 1

• 2 other identifiers: 09016009-N-0160
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Background:

• Parkinson s disease (PD) is a progressive neurodegenerative disorder that affects the brain cells that make the chemical dopamine. The primary medical treatment for PD has been to use medications to replace the dopamine that is missing from the brain. These medications can be effective at first, but after many years side effects and tolerance develop.
• Surgery can treat basic PD symptoms and complications. Deep brain stimulation (DBS) offers a safer alternative as the therapy can be adjusted and reversed to minimize side effects and optimize beneficial effects. DBS treats the symptoms of PD but does not alter its course.
• Infusions of neurochemicals or medications are another PD treatment method. NIH researchers have developed the technique of convection-enhanced delivery, which very precisely and consistently delivers infusions of many types into the brain. This project will allow researchers to infuse a medication, Muscimol, into the subthalamic region of the brain to see if it is as safe and effective as DBS. Objectives:
• To determine whether an infusion of Muscimol into the brain is safe and relieves the symptoms of Parkinson s disease.
• To demonstrate that the infusion can be monitored with magnetic resonance imaging (MRI) using gadolinium. Eligibility:
• Patients 18 years of age and older who have Parkinson s disease and are preparing for bilateral subthalamic nucleus (STN) DBS surgery.
• Patients will be divided into two groups. One group of patients will have a partial infusion of Muscimol into the STN, and the second group of patients will have complete infusion of Muscimol into the STN. Design:
• This study will begin 5 days before the patient undergoes bilateral subthalamic DBS surgery.
• On Day 1 of the study, small thin tubes (microcatheters) will be inserted into the STN through the same incision and burr holes that are used for DBS. Two infusion studies of Muscimol will be performed on successive days: the first without PD medication (Day 3 of study) and the second with PD medication (Day 4 of study).
• Each infusion will be monitored in the MRI suite, and researchers will perform clinical examinations of patients PD symptoms.
• Following the study experiments, a second surgery will be performed to remove the microcatheters and to place DBS electrodes in the standard fashion.

Conditions

Parkinson's Disease

Keywords

Muscimol; Convection-Enhanced Delivery; Parkinson's Disease; Deep Brain Stimulation; Parkinson Disease; PD

Outcome Measures

Primary Outcomes (1)

• Determine potential effectiveness of PD symptom reversal by muscimol infusion. Effectiveness will be determined by improvements in (off) and (on) scale UPDRS scores (motor subsection), pegboard testing of bradykinesia and TGUG gait assessment.

Secondary Outcomes (1)

• Determine feasibilty of distributing muscimol by CED in the STN of PD patients. This endpoint will be the MR-imaging confirmation of distribution.

Interventions

Muscimol DRUG

Eligibility Criteria

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

You may qualify if:

• Diagnosed with idiopathic PD by UK criteria:
• Bradykinesia: At least one of the following:
• Muscular rigidity
• Hz resting tremor
• Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction
• Three or more required in addition to above for the diagnosis of idiopathic PD:
• Unilateral onset
• Rest tremor present
• Progressive disorder
• Persistent asymmetry affecting side of onset most
• Excellent response (70-100%) to levodopa
• Severe levodopa-induced chorea
• Levodopa response for 5 years or more
• Clinical course of ten years or more
• The above clinical features must not be due to trauma, brain tumor, infection, cerebrovascular disease, other known neurological disease (e.g., multiple system atrophy, progressive supranuclear palsy, striatonigral degeneration, Huntington s disease, Wilson s disease, hydrocephalus) or due to known drugs, chemicals or toxicants.

You may not qualify if:

• Presence of prominent oculomotor palsy, cerebellar signs, vocal cord paresis, orthostatic hypotension (\> 20 mm Hg drop on standing), pyramidal tract signs or amyotrophy.
• Presence of dementia (Clinical Dementia Rating Scale score \> 1.0 or Mini Mental Status Examination Score \< 25).
• Presence or history of psychosis, including if induced by anti-PD medications.
• Presence of untreated or suboptimally treated depression (Hamilton Depression Scale score \>10) or a history of a serious mood disorder (for example, requiring psychiatric hospitalization or a prior suicide attempt).
• Presence of substance (drug, alcohol) abuse.
• Presence of hypointensity in the striatum on T2-weighted MR-imaging.
• Contraindication to MR-imaging and/or gadolinium.
• Coagulopathy, anticoagulant therapy, low platelet count, or inability to temporarily stop any antithrombotic medication.
• Prior brain surgery, including gene therapy, radiofrequency ablation or deep brain stimulation.
• Male or female with reproductive capacity who is unwilling to use contraception throughout the study.
• History of stroke or poorly controlled cardiovascular disease.
• Uncontrolled hypertension or diabetes or any other acute or chronic medical condition that would increase the risks of a neurosurgical procedure.
• Clinically active infection, including acute or chronic scalp infection.
• Received investigational agent within 12 weeks prior to screening.
• Unable to comply with the procedures of the protocol, including frequent and prolonged follow-up.

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Related Publications (3)

• Baraldi M, Grandison L, Guidotti A. Distribution and metabolism of muscimol in the brain and other tissues of the rat. Neuropharmacology. 1979 Jan;18(1):57-62. doi: 10.1016/0028-3908(79)90009-1. No abstract available.

  PMID: 418955 BACKGROUND

• Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990 Sep 21;249(4975):1436-8. doi: 10.1126/science.2402638.

  PMID: 2402638 BACKGROUND

• Bergman H, Wichmann T, Karmon B, DeLong MR. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol. 1994 Aug;72(2):507-20. doi: 10.1152/jn.1994.72.2.507.

  PMID: 7983515 BACKGROUND

MeSH Terms

Conditions

Parkinson Disease

Interventions

Muscimol

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)

Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Mycotoxins; Toxins, Biological; Biological Factors

Study Officials

• Kareem A Zaghloul, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2009
• First Posted: June 16, 2009
• Study Start: June 2, 2009
• Study Completion: September 1, 2016
• Last Updated: October 6, 2017

Record last verified: 2016-09-01