A Pilot Trial of Lithium in Subjects With Progressive Supranuclear Palsy or Corticobasal Degeneration

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

Study Overview

• Status: Completed
• Conditions: Corticobasal Degeneration; Progressive Supranuclear Palsy
• Intervention / Treatment: Drug: Lithium

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability to Tolerate Lithium Carbonate	The ability to complete the study period on lithium at a serum concentration of at least 0.4 mEq/L.	28 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study Drug Compliance	Subjects receiving 80% or more of the prescribed doses between study visits were considered compliant.	28 weeks
Changes in Amount of Tau and Phosphorylated Tau in Cerebral Spinal Fluid (CSF)	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.	28 weeks
Change in Brain-Derived Neurotrophic Factor (BDNF) in CSF	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.	28 weeks
Change in Glycogen Synthase Kinase (GSK)-3 Beta Activity	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	28 weeks
PSP Rating Scale Score: Change From Baseline	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.	28 weeks
Unified Parkinson Disease Rating Scale (UPDRS) Motor Subscale Score: Change From Baseline	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.	28 weeks
PSP-Quality of Life Scale (QoL):Change From Baseline	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.	28 weeks
Frontal Assessment Battery (FAB): Change From Baseline	The FAB is a brief, 6-item instrument designed to assess executive function. Subjects will be assessed at baseline and at Week 28.	28 weeks
Geriatric Depression Scale(GDS)-15:Change From Baseline	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.	28 weeks

Collaborators and Investigators

• Sponsor: Westat
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Renè Gonin, PhD, (Math. Stats.), Westat

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: June 20, 2008
• First Submitted That Met QC Criteria: June 20, 2008
• First Posted (Estimate): June 23, 2008

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: June 9, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: tau; lithium; PSP; CBD; progressive supranuclear palsy; corticobasal degeneration
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Tauopathies; Cranial Nerve Diseases; Ocular Motility Disorders; Ophthalmoplegia; Paralysis; Supranuclear Palsy, Progressive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Antimanic Agents; Lithium Carbonate
• Other Study ID Numbers: NPTUNE_PSP_CBD; HHSN265200423611C (Other Grant/Funding Number: NIH Contract)