Clinical trial NCT00703677: A Pilot Trial of Lithium in Subjects With Progressive Supranuclear Palsy or Corticobasal Degeneration
Official title: A Pilot Trial of Lithium in Subjects With Progressive Supranuclear Palsy or Corticobasal Degeneration
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Progressive Supranuclear Palsy
Corticobasal Degeneration
Keywords: progressive supranuclear palsy
corticobasal degeneration
PSP
CBD
lithium
tau
Lead sponsor: Westat
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2008-06-23
Enrollment: 17
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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 criteria: Inclusion Criteria:

1. Able to give informed consent
2. Able to comply with the study protocol, including ability to attend follow-up study visits for the duration of the study
3. 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)
4. 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
5. 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.
6. Creatinine clearance \> 50 ml/min
7. Able to take oral medication
8. 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.)
9. Able to identify a study partner

Exclusion Criteria:

1. Evidence of other diseases that could explain the clinical presentation
2. History of known sensitivity or intolerability to lithium or to other known ingredients in the study drug
3. Exposure to any investigational agent within 28 days of the screening visit
4. Clinically significant cardiac disease or EKG findings
5. 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)
6. Moderate to severe ongoing depression
7. Family history of "PSP" or "CBS"
8. Clinically significant abnormalities on the screening visit laboratory results
9. Any AE ≥ Grade 3 as listed on the CTCAE, version 3.0
10. Women who are pregnant or breastfeeding
11. History of brain surgery
12. Use of other potential GSK-3β inhibitors (e.g., valproic acid)
13. Use of iodide salts \[e.g., calcium iodide, hydrogen iodide (hydriodic acid), iodide, iodinated glycerol (Organidin), iodine, potassium iodide (SSKI), and sodium iodide\]
14. Previous use of lithium
15. 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
16. Active psoriasis

Primary outcomes:
measure: Ability to Tolerate Lithium Carbonate
timeFrame: 28 weeks
Secondary outcomes:
measure: Study Drug Compliance
timeFrame: 28 weeks
measure: Changes in Amount of Tau and Phosphorylated Tau in Cerebral Spinal Fluid (CSF)
timeFrame: 28 weeks
measure: Change in Brain-Derived Neurotrophic Factor (BDNF) in CSF
timeFrame: 28 weeks
measure: Change in Glycogen Synthase Kinase (GSK)-3 Beta Activity
timeFrame: 28 weeks
measure: PSP Rating Scale Score: Change From Baseline
timeFrame: 28 weeks
measure: Unified Parkinson Disease Rating Scale (UPDRS) Motor Subscale Score: Change From Baseline
timeFrame: 28 weeks
measure: PSP-Quality of Life Scale (QoL):Change From Baseline
timeFrame: 28 weeks
measure: Frontal Assessment Battery (FAB): Change From Baseline
timeFrame: 28 weeks
measure: Geriatric Depression Scale(GDS)-15:Change From Baseline
timeFrame: 28 weeks
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: New Brunswick
country: United States
facility: UMDNJ Robert Wood Johnson Medical School
state: New Jersey
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle University
Study officials:
affiliation: (Math. Stats.), Westat
name: Renè Gonin, PhD
role: PRINCIPAL_INVESTIGATOR
References: