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

Progressive Supranuclear Palsy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00703677
• Other study ID #: NPTUNE_PSP_CBD
• Secondary ID: HHSN265200423611
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: June 20, 2008
• Last updated: June 9, 2015
• Start date: September 2008
• Est. completion date: January 2010

Study information

• Verified date: June 2015
• Source: Westat
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: January 2010
• Est. primary completion date: January 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

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-3ß 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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Corticobasal Degeneration
• Progressive Supranuclear Palsy
• Supranuclear Palsy, Progressive

Intervention

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.

Locations

Country	Name	City	State
United Kingdom	Newcastle University	Newcastle upon Tyne
United States	University of Maryland	Baltimore	Maryland
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Louisville	Louisville	Kentucky
United States	UMDNJ Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Beth Israel Medical Center	New York	New York
United States	Oregon Health & Science University	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
Westat	National Institute of Neurological Disorders and Stroke (NINDS)

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Study Drug Compliance	Subjects receiving 80% or more of the prescribed doses between study visits were considered compliant.	28 weeks	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No