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

This study has suspended participant recruitment.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
ClinicalTrials.gov Identifier:
NCT00921128
First received: June 13, 2009
Last updated: March 14, 2014
Last verified: January 2014
  Purpose

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.

Condition Intervention Phase
Parkinson's Disease
Drug: Muscimol
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Convection Enhanced Delivery of Muscimol to Study the Pathophysiology Underlying the Clinical Features of Parkinson's Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

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

Estimated Enrollment: 8
Study Start Date: June 2009
Intervention Details:
    Drug: Muscimol
    N/A
Detailed Description:

Objective: The objectives of this pilot study are to gain insight into the safety, feasibility and clinical effects of infusion of a temporary acting GABAA agonist (muscimol) by convection-enhanced delivery into the subthalamic nuclei (STN) of Parkinson s disease (PD) patients undergoing deep brain stimulation (DBS) surgery.

Study population: Eight adult male and female patients with medically-intractable PD who are preparing to undergo DBS surgery and who meet all Inclusion and Exclusion Criteria will be enrolled. Six subjects will be treated (2 may be screening failures).

Design: We propose a single center pilot study of infusion of muscimol into the bilateral STN of PD patients that will undergo DBS. Subjects will be enrolled into 1 of 2 cohorts. Both cohorts will contain 3 patients each (total of 6 patients). Patients in both cohorts will undergo pre-, intra- and post-operative PD assessments. The first cohort will undergo bilateral perfusion of half of the volume (infusion of 8 microliters)of the STN with muscimol (8.8 mM) and gadolinium-DTPA ([1 mM] in off and on medication states on sequential days). The second cohort will undergo bilateral perfusion of the entire of the volume (infusion of 16 microliters) of the STN with muscimol (8.8 mM) and gadolinium-DTPA ([1 mM] in off and on medication states on sequential days). Distribution of muscimol using a surrogate imaging tracer (gadolinium-DPTA) will be tracked using real-time MR-imaging and correlated to clinical effect. After the infusions are completed, the catheters will be removed and patients will undergo placement of bilateral STN DBS. Patients will be evaluated using standard PD rating scales to determine the effects to STN neuronal suppression and to compare the effects of muscimol pharmacologic neuronal suppression to DBS effects.

Outcome measures: To determine the distribution of muscimol in the STN and to provide an anatomic correlate for clinical effects of neuronal suppression, real-time 3D-volumetric MR-imaging will be used during infusions. To assess safety, tolerability and clinical effects of muscimol infusion, standard PD rating scales (motor subsection of the Unified PD Rating Scale, timed-up-and-go gait assessment and peg board bradykinesia testing) will be performed following infusion and correlated to real-time infusion MR-imaging studies. To compare the effects of muscimol infusion to STN DBS, the assessments obtained during infusion will be compared to the similar assessment 6 months after DBS placement.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Diagnosed with idiopathic PD by UK criteria:

Bradykinesia: At least one of the following:

  1. Muscular rigidity
  2. 4-6 Hz resting tremor
  3. 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:

  1. Unilateral onset
  2. Rest tremor present
  3. Progressive disorder
  4. Persistent asymmetry affecting side of onset most
  5. Excellent response (70-100%) to levodopa
  6. Severe levodopa-induced chorea
  7. Levodopa response for 5 years or more
  8. 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.

    Disability present despite optimal antiparkinsonian medication therapy.

    Unequivocal responsiveness to levodopa, based on the single-dose levodopa test (as described in the CAPIT and CAPSIT guidelines). In addition to a 33% or greater improvement in one of the timed tasks, a 30% or greater improvement in the UPDRS total motor score will be required to establish unequivocal responsiveness to levodopa.

    Patients must demonstrate at least 6 hours of non-on time and medication side-effects such as levodopa-induced dyskinesias or motor fluctuations.

    Neuropsychological evaluation does not indicate substantial depression or cognitive dysfunction.

    Able to provide proper Informed Consent.

    EXCLUSION CRITERIA:

    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.

    Baseline hematology, chemistry or coagulation values out of normal range unless not clinically significant with respect to surgery.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00921128

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Kareem A Zaghloul, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
ClinicalTrials.gov Identifier: NCT00921128     History of Changes
Other Study ID Numbers: 090160, 09-N-0160
Study First Received: June 13, 2009
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Muscimol
Convection-Enhanced Delivery
Parkinson's Disease
Deep Brain Stimulation
Parkinson Disease
PD

Additional relevant MeSH terms:
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Muscimol
Ibotenic Acid
GABA-A Receptor Agonists
GABA Agonists
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Excitatory Amino Acid Agonists
Excitatory Amino Acid Agents

ClinicalTrials.gov processed this record on April 15, 2014