Corticobasal Degeneration, Progressive Supranuclear Palsy
Conditions
Keywords
progressive supranuclear palsy, corticobasal degeneration, PSP, CBD, lithium, tau
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.
Interventions
DRUGLithium
All participants will receive lithium. The dosage will be titrated over a 5-week period and then continued for an additional 6 months.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Westat
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ability to Tolerate Lithium Carbonate | 28 weeks | The ability to complete the study period on lithium at a serum concentration of at least 0.4 mEq/L. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Study Drug Compliance | 28 weeks | 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) | 28 weeks | 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 | 28 weeks | 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 | 28 weeks | 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 | 28 weeks | 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 | 28 weeks | 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 | 28 weeks | 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 | 28 weeks | 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 | 28 weeks | 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. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
The protocol was open for recruitment between September 2008 and August 24, 2009 at neurology clinics affiliated with university hospitals.
Participants by arm
| Arm | Count |
|---|---|
| Lithium Carbonate All participants will receive lithium in this open label study (single arm). Dosages will be determined in advance to achieve serum concentrations of 0.4-0.6, 0.6-0.8, 0.8-1.0, and 1.0-1.2 mEq/L. | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Dropout-withdrawal not related to drug | 3 |
Baseline characteristics
| Characteristic | Lithium Carbonate |
|---|---|
| Age, Customized 40 - 49 years | 0 participants |
| Age, Customized 50 - 59 years | 2 participants |
| Age, Customized 60 - 69 years | 9 participants |
| Age, Customized 70 - 79 years | 6 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 4 / 17 |
Outcome results
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.
Time frame: 28 weeks
Population: One subject completed the full 28 week course of study drug; 13 subjects stopped drug early due to intolerability.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lithium Carbonate | Ability to Tolerate Lithium Carbonate | 1 Subject |
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.
Time frame: 28 weeks
Population: Due to the very small number of samples collected, samples were not analyzed
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
Time frame: 28 weeks
Population: Due to the very small number of samples collected, samples were not analyzed.
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.
Time frame: 28 weeks
Population: Due to the very small number of samples collected, samples were not analyzed
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.
Time frame: 28 weeks
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.
Time frame: 28 weeks
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.
Time frame: 28 weeks
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.
Time frame: 28 weeks
Secondary
Study Drug Compliance
Subjects receiving 80% or more of the prescribed doses between study visits were considered compliant.
Time frame: 28 weeks
Population: All subjects were evaluated for compliance.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lithium Carbonate | Study Drug Compliance | 14 Subjects |
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.
Time frame: 28 weeks