Dementia With Lewy Bodies
Conditions
Brief summary
This study evaluates the effect of Bosutinib (Bosulif,Pfizer®) in the treatment of patients with Dementia with Lewy Bodies. Half participants will receive 100 mg of Bosutinib , while the other half will receive placebo.
Detailed description
This proposal will evaluate the effects of Bosutinib (Bosulif, Pfizer®) treatment - an FDA-approved tyrosine kinase inhibitor that targets c-Abelson (Abl) and Src tyrosine kinases- in patients with DLB. Investigators have demonstrated safety and efficacy of this compound in pre-clinical animal models and others have shown similar benefits of Bosutinib on inflammation and neurotoxic protein clearance in neurodegeneration. Investigators have demonstrated that Bosutinib enters the brain (5% CSF:plasma ratio) and inhibits Abl at lower doses (5mg/kg) than the cancer dose (80mg/kg) in animals. Bosutinib also reduces the levels of neurotoxic proteins including alpha-synuclein, tau and beta-amyloid and improves motor and cognitive behavior in models of neurodegeneration. The use of Bosutinib is a novel strategy that promotes autophagy to clear neurotoxic protein aggregates in neurons. Bosutinib is FDA-approved for the treatment of chronic myelogenous leukemia (CML) at an oral dose of 400-600 mg daily. Based on our preclinical evidence, investigators used allometric conversion to extrapolate animal to human dose and estimated a human equivalent dose daily dose of 100mg Bosutinib in this clinical study to determine the safety and tolerability, pharmacokinetics and pharmacodynamics in patients with mild to moderate DLB.
Interventions
DRUGPlacebo Oral Tablet
Fifteen (15) patients in group 1 will receive the matching placebo("sugar pill") one (1) tablet orally once daily for 3 months (90 days) .
DRUGBosutinib Oral Tablet
Fifteen (15) patients in group 1 will receive the 100 mg of Bosutinib one (1) tablet orally once daily for 3 months (90 days) .
Sponsors
Georgetown University
Alzheimer's Association
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants will be randomized by a Biostatistician by an internet based randomization module into two groups. The researchers include : Primary investigator , Sub-Investigators ,Clinical Coordinators, Nurse Practitioners , and Clinical Reseach unit staff. The investigators will be blinded to the dosage. Medications for any patient will be labeled by the CRU with a package medical identification number (Med. Id). A patient specific patient identification number (Pat. Id.) will be assigned to each patient. The investigator will have to note the Pat.Id on the designated medication package number after randomization.
Intervention model description
We will evaluate the effects of 100 mg Bosutinib versus matching placebo taken daily by mouth for 12 weeks, followed by a 4 week wash-out period in individuals diagnosed with DLB. We will perform physiologically-based population pharmacokinetics (popPK) using a seamless random single dose (RSD) of Bosutinib, where participants (n=30) will be randomized to 3 groups (n=10) and take a single oral dose of 100mg, 200mg, Bosutinib or placebo (1;1;1) open label. Lumbar puncture will be performed between 1-4 hours after dosing. Participants will then be randomized double-blinded into 2 groups 1;1 using placebo(n=15) and 100mg (n=15) for 3 months. Randomization and Registration will be performed by an internet based randomization module. Randomization of the subjects to the 2 treatment groups will be performed in a stratified manner. The chance for randomization to the groups is 1:1 for placebo: 100 mg Bosutinib.
Eligibility
Sex/Gender
ALL
Age
25 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent 2. Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative (LAR) 3. Age of 25-90 years, medically stable 4. Clinical diagnosis of DLB according to McKeith et al (7) with both dementia MoCA≥18 and Parkinsonian defined as bradykinesia in combination with rest tremor, rigidity or both UPDRS I-III ≤ 50 and UPDRS-III between 20-40. 5. Dementia and Parkinsonism must be present with at least one other symptom such as fluctuation, visual hallucinations or REM sleep behavioral disorder (RBD) 6. Abnormal DaTScan 7. Stable on Levodopa no more than 800mg daily, acetylcholinesterase inhibitors, dopamine agonists for at least 6 weeks 8. Stable on monoamine oxidase inhibitors (MOA-B) for at least 4 weeks before enrollment 9. Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI 10. QTc interval 350-480 ms, inclusive 11. Participants must be willing to undergo LP at baseline and 3 months after treatment.
Exclusion criteria
1. Medical history of liver or pancreatic disease, GI ulcers and Chron's disease, kidney, GI, or blood problems 2. Abnormal liver function defined as AST and/or ALT \> 100% the upper limit of the normal 3. Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal or proteinuria 4. History of HIV, clinically significant chronic hepatitis, or other active infection 5. hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥480 ms or concomitant drugs known to prolong the QTc interval and history of any cardiovascular disease, including myocardial infarction or cardiac failure, angina, arrhythmia 6. History or presence of significant cardiac conditions including: cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable angina, or stroke), congestive heart failure, first, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances, any history of Torsade de Pointes. 7. Treatment with any of the following drugs at the time of screening or the preceding 30 days, and/or planned use over the course of the trial: Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine), treatment with QT prolonging drugs (www.crediblemeds.org)- excluding SSRIs (e.g. Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, Trazodone, etc.), Strong CYP3A4 inhibitors (including grapefruit juice). The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) must be avoided. Should treatment with any of these agents be required, therapy with Bosutinib should be interrupted. Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin, xeralto, etc. St. John's Wort and the concomitant use of strong other CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) must be avoided since these agents may reduce the concentration of Bosutinib 8. Females must not be lactating, pregnant or with possible pregnancy 9. Clinical signs indicating syndromes other than DLB including, Alzheimer's Disease (AD) idiopathic PD, corticobasal degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of frontal dementia, history of stroke, head injury or encephalitis, cerebellar signs, early severe autonomic involvement, Babinski sign 10. Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any active major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse 11. Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory abnormality. 12. Active neoplastic disease, history of cancer five years prior to screening, including breast cancer (history of skin melanoma or stable prostate cancer are not exclusionary) 13. Contraindications to LP: prior lumbosacral spine surgery, severe degenerative joint disease or deformity of the spine, platelets \< 100,000, use of Coumadin/warfarin, or history of a bleeding disorder. 14. Must not be on any immunosuppressant medications 15. Must not be enrolled as an active participant in another clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability Go/NoGo (25% Discontinuations) Will be Determined Based on Any Emergent Adverse Events. | 12 weeks | We will determine safety and tolerability using the occurrence of adverse events (AEs) of interest, including myelosuppression, urinary, pancreatic and hepatic disorders, QTc prolongation as per Bosutinib IB. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine Changes in Absorbance Levels (ABS) in DLB Related CSF and Plasma Tyrosine Kinases | Change between baseline (BSL) and Week-12 | Phospho-ABL(PanTyr) and phospho-SRC(Y416) are critical drivers in the pathogenesis of various neurodegenerative diseases. We will examine the changes in CSF and Plasma phospho-ABL(PanTyr) and phospho-SRC(Y416) absorbance (ABS) levels at baseline and 3 months. The magnitude of the absorbance is proportional to the quantity of tyrosine-phosphorylated protein. |
| Determine the Maximum Concentration (Cmax) (ng/ml) of Bosutinib in the CSF and Plasma. | 12 weeks | To determine the Cmax (ng/ml), we will measure Bosutinib in both the CSF and Plasma using Liquid chromatography-tandem mass spectrometry (LC-MS/MS) |
| Determine the Maximum Concentration (Cmax) (nM) of Bosutinib in the CSF and Plasma. | 12 weeks | To determine the Cmax (nM), we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS) |
| Determine the Maximum Time (Tmax) Bosutinib Peaks in CSF and Plasma. | 12 weeks | To determine the Tmax, we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS) |
| Determine the Area Under the Curve (AUC) (ng/ml*Hours) for Bosutinib in CSF and Plasma. | 12 weeks | To determine the AUC (ng/ml\*hours) , we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS) |
| Determine the Area Under the Curve (AUC) (nM*Hours) for Bosutinib in CSF and Plasma. | 12 weeks | To determine the AUC (nM\*hours) , we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS) |
| Changes in Dementia Lewy Body (DLB) Related CSF and Plasma Biomarkers | Change between baseline (BSL) and Week-12 | We will examine the changes in CSF and Plasma Abeta40, Abeta42, total tau, ptau181 and total and oligomeric alpha-synuclein at baseline, week-12, and the change between baseline and week-12. |
| Change in Ratios in Dementia Lewy Body (DLB) Related CSF and Plasma Biomarkers | 12 weeks | We will examine the ratio changes in CSF and Plasma AB42 to AB40, ptau(181 )to AB42, pTau(181) to tTau, aggregated a-syn to total a-syn at baseline, 12 weeks, and between baseline and week-12. |
| Measure HVA and DOPAC in CSF and Plasma | 12 weeks | We will measure the levels of DOPAC AND Homovanillic Acid (HVA) using liquid-liquid extraction and Liquid chromatography-tandem mass spectrometry (LC-MS/MS) in CSF and plasma samples at baseline (BSL), 12 weeks, and between baseline and 12 weeks (WK12). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORFernando L Pagan, MD
Georgetown Univeristy
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 24 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 74.45 years STANDARD_DEVIATION 8.22 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 6 / 13 | 6 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
None listed