A Pilot Trial of Lithium in Subjects With Progressive Supranuclear Palsy or Corticobasal Degeneration - Full Text View

Sponsor:	Westat
Collaborator:	National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by:	Westat
ClinicalTrials.gov Identifier:	NCT00703677

Purpose

The goal of this trial is to evaluate the safety and tolerability of lithium in people with progressive supranuclear palsy or corticobasal degeneration.

Condition	Intervention	Phase
Progressive Supranuclear Palsy Corticobasal Degeneration	Drug: Lithium	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Pilot Trial of Lithium in Subjects With Progressive Supranuclear Palsy or Corticobasal Degeneration

Resource links provided by NLM:

Genetics Home Reference related topics: familial paroxysmal nonkinesigenic dyskinesia progressive external ophthalmoplegia progressive supranuclear palsy

MedlinePlus related topics: Paralysis Progressive Supranuclear Palsy

Drug Information available for: Lithium carbonate Lithium citrate

U.S. FDA Resources

Further study details as provided by Westat:

Primary Outcome Measures:

Ability to Tolerate Lithium Carbonate [ Time Frame: 28 weeks ] [ Designated as safety issue: Yes ]
The ability to complete the study period on lithium at a serum concentration of at least 0.4 mEq/L.

Secondary Outcome Measures:

Study Drug Compliance [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
Subjects receiving 80% or more of the prescribed doses between study visits were considered compliant.
Changes in Amount of Tau and Phosphorylated Tau in Cerebral Spinal Fluid (CSF) [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are characterized by hyperphosphorylation of tau. Lithium inhibits one of the kinases (GSK-3 beta) that phosphorylates tau; levels of tau phosphorylation will be measured at baseline and at Week 28.
Change in Brain-Derived Neurotrophic Factor (BDNF) in CSF [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
With inhibition of Glycogen Synthase Kinase (GSK)-3 beta, levels of BDNF may increase. BDNF levels will be measured at baseline and at Week 28.
Change in Glycogen Synthase Kinase (GSK)-3 Beta Activity [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
Levels of beta-catenin and the ratio of phosphorylated GSK-3 beta to total GSK-3 beta will be measured at baseline and at Week 28
PSP Rating Scale Score: Change From Baseline [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
The PSP Rating Scale is a 28-item scale designed to assess the disability associated with PSP. The six functional categories assessed are: daily activities, behavior, bulbar function, oculomotor function, limb motor function, and gait/midline function. Subjects will be assessed at baseline and Weeks 12, 20, and 28.
Unified Parkinson Disease Rating Scale (UPDRS) Motor Subscale Score: Change From Baseline [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
The UPDRS is a commonly used clinical rating scale to assess motor function in patients with parkinsonism. Subjects will be assessed at baseline and Weeks 5, 12, 20, and 28.
PSP-Quality of Life Scale (QoL):Change From Baseline [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
The PSP-QoL Scale is an instrument designed to assess mental and physical aspects of quality of life specifically in patients with PSP. Subjects will be assessed at baseline and Weeks 12, 20, and 28.
Frontal Assessment Battery (FAB): Change From Baseline [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
The FAB is a brief, 6-item instrument designed to assess executive function. Subjects will be assessed at baseline and at Week 28.
Geriatric Depression Scale(GDS)-15:Change From Baseline [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
The GDS-15 is a 15-item instrument used to screen for depression in the elderly. Subjects will be assessed at the Screening Visit and at Week 28.

Enrollment:	17
Study Start Date:	September 2008
Study Completion Date:	January 2010
Primary Completion Date:	January 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1 All participants will receive lithium. The dosage will be titrated over a 5-week period. Participants will then be followed prospectively for 6 months. Participants will be evaluated at the screening visit, baseline visit, and weeks 2 and 5 during the titration phase. Clinic study visits will then occur on alternate months through week 28. Telephone visits will occur between clinic study visits.	Drug: Lithium All participants will receive lithium. The dosage will be titrated over a 5-week period and then continued for an additional 6 months.

Arms

Assigned Interventions

1

All participants will receive lithium. The dosage will be titrated over a 5-week period. Participants will then be followed prospectively for 6 months. Participants will be evaluated at the screening visit, baseline visit, and weeks 2 and 5 during the titration phase. Clinic study visits will then occur on alternate months through week 28. Telephone visits will occur between clinic study visits.

Drug: Lithium

All participants will receive lithium. The dosage will be titrated over a 5-week period and then continued for an additional 6 months.

Detailed Description:

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are progressive, adult-onset neurodegenerative disorders characterized by the accumulation of hyperphosphorylated tau. Symptomatic treatment is of minimal benefit to individuals with PSP or CBD, and there are no effective disease modifying agents.

Tau phosphorylation is regulated in part by the enzyme GSK-3β (glycogen synthase kinase-3 beta ). Inhibition of this enzyme may benefit individuals with PSP or CBD by decreasing the levels of phosphorylated tau. Lithium is known to inhibit GSK-3β and, thus, may be a rational therapeutic approach.

The primary objective of this study is to determine the safety and tolerability of lithium in people with PSP or CBD. Additionally, this study will evaluate potential biomarkers and clinical outcome measures as well as assess study drug compliance.

In this multicenter, open label study, 45 eligible participants with PSP or CBD will receive the study drug, lithium. The dosage of lithium will be titrated over a 5-week period, and participants will then be followed prospectively for 6 months. Participants will be evaluated at the screening visit, baseline visit, and weeks 2 and 5 during the titration phase. Clinic study visits will then occur on alternate months through week 28. Telephone visits will occur between clinic study visits.

Eligibility

Ages Eligible for Study:	40 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Able to give informed consent
Able to comply with the study protocol, including ability to attend follow-up study visits for the duration of the study
Diagnosis of PSP or CBD based on the following criteria:
1. Probable PSP:
  - Gradually progressive akinetic disorder
  - Unequivocal and prominent slowing of vertical saccades or vertical supranuclear gaze palsy
  - Early prominent postural instability or early falls
  - Poor or absent response to levodopa
2. Probable CBD:
  - Chronic progressive course
  - Asymmetric onset
  - Presence of higher cortical dysfunction (apraxia, apraxia of speech, non-fluent aphasia, cortical sensory loss, or alien limb)
  - Movement disorder: rigid/akinetic syndrome resistant to levodopa and either dystonic limb posturing or focal myoclonus in limb (spontaneous or stimulus sensitive)
If psychotropic or anti-parkinsonian medications are taken (e.g., anxiolytics, hypnotics, benzodiazepines, antidepressants, levodopa, amantadine), the dosage must be stable for 28 days prior to the screening visit and should be maintained at constant dosages throughout the study, as possible
If NSAIDs, ACE-Is, ARBs, thiazide diuretics, COX-2 inhibitors or theophylline are taken by the subject, the dosage must be stable for 28 days prior to the screening visit and should be maintained at constant dosages throughout the study, as possible.
Creatinine clearance > 50 ml/min
Able to take oral medication
Women must not be able to become pregnant (e.g., post menopausal, surgically sterile or using adequate birth control methods for the duration of the study.)
Able to identify a study partner

Exclusion Criteria:

Evidence of other diseases that could explain the clinical presentation
History of known sensitivity or intolerability to lithium or to other known ingredients in the study drug
Exposure to any investigational agent within 28 days of the screening visit
Clinically significant cardiac disease or EKG findings
Other serious illness, including psychiatric illness ("serious illness" is defined as an illness that is unstable enough that it might jeopardize the subject's ability to complete the study)
Moderate to severe ongoing depression
Family history of "PSP" or "CBS"
Clinically significant abnormalities on the screening visit laboratory results
Any AE ≥ Grade 3 as listed on the CTCAE, version 3.0
Women who are pregnant or breastfeeding
History of brain surgery
Use of other potential GSK-3β inhibitors (e.g., valproic acid)
Use of iodide salts [e.g., calcium iodide, hydrogen iodide (hydriodic acid), iodide, iodinated glycerol (Organidin), iodine, potassium iodide (SSKI), and sodium iodide]
Previous use of lithium
Use of Coenzyme Q10 at a dosage greater than 600 mg a day or NanoQuinon at a dosage greater than 150mg a day or 2.5 mg/kg a day
Active psoriasis

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00703677

Locations

United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Kentucky
University of Louisville
Louisville, Kentucky, United States, 40202
United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
United States, New Jersey
UMDNJ Robert Wood Johnson Medical School
New Brunswick, New Jersey, United States, 08901
United States, New York
Beth Israel Medical Center
New York, New York, United States, 10003
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239-3098
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29401
United Kingdom
Newcastle University
Newcastle upon Tyne, United Kingdom, NE4 5PL

Sponsors and Collaborators

Westat

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

Principal Investigator:

Renè Gonin, PhD

(Math. Stats.), Westat

More Information

No publications provided

Responsible Party:	Renè Gonin, Ph.D. (Math. Stats.), Principal Investigator, and Senior Biostatistician, Westat
ClinicalTrials.gov Identifier:	NCT00703677 History of Changes
Other Study ID Numbers:	NPTUNE_PSP_CBD, HHSN265200423611C
Study First Received:	June 20, 2008
Results First Received:	April 30, 2010
Last Updated:	June 18, 2010
Health Authority:	United States: Federal Government United States: Institutional Review Board

Keywords provided by Westat:

progressive supranuclear palsy
corticobasal degeneration
PSP

CBD
lithium
tau

Additional relevant MeSH terms:

Supranuclear Palsy, Progressive
Paralysis
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Ophthalmoplegia
Ocular Motility Disorders
Cranial Nerve Diseases
Tauopathies
Neurodegenerative Diseases
Neurologic Manifestations
Eye Diseases
Signs and Symptoms

Lithium
Lithium Carbonate
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Antimanic Agents
Antidepressive Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2012