Impact of Bosutinib on Safety, Tolerability, Biomarkers and Clinical Outcomes in Dementia With Lewy Bodies

NCT03888222 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: IRB#: STUDY00000017
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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.

Conditions

Dementia With Lewy Bodies

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability Go/NoGo (25% discontinuations) will be determined based on any emergent adverse events.

  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.

  3 Months

Secondary Outcomes (2)

• We will determine Bosutinib levels in CSF and plasma.

  3 Months

• We will determine changes in DLB related CSF and plasma biomarkers

  3 Months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Thirty (30) participants will be recruited and randomized into 2 groups (arms) (1:1) .Fifteen (15) patients in group 1 will receive the matching placebo("sugar pill") one (1) capsule orally once daily for 3 months (90 days).

Drug: Placebo Oral Tablet

100 mg of Bosutinib

ACTIVE COMPARATOR

Thirty (30) participants will be recruited and randomized into 2 groups (arms) (1:1) .Fifteen (15) patients in group 2 will receive the 100 mg of Bosutinib one (1) capsule orally once daily for 3 months (90 days).

Drug: Bosutinib Oral Tablet

Interventions

Placebo Oral Tablet DRUG

Fifteen (15) patients in group 1 will receive the matching placebo("sugar pill") one (1) tablet orally once daily for 3 months (90 days) .

Also known as: Placebo

Placebo

Bosutinib Oral Tablet DRUG

Fifteen (15) patients in group 1 will receive the 100 mg of Bosutinib one (1) tablet orally once daily for 3 months (90 days) .

Also known as: Bosutinib(Bosulif®, SKI-606, Pfizer)

100 mg of Bosutinib

Eligibility Criteria

• Age: 25 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative (LAR)
• Age of 25-90 years, medically stable
• 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.
• Dementia and Parkinsonism must be present with at least one other symptom such as fluctuation, visual hallucinations or REM sleep behavioral disorder (RBD)
• Abnormal DaTScan
• Stable on Levodopa no more than 800mg daily, acetylcholinesterase inhibitors, dopamine agonists for at least 6 weeks
• Stable on monoamine oxidase inhibitors (MOA-B) for at least 4 weeks before enrollment
• Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI
• QTc interval 350-480 ms, inclusive
• Participants must be willing to undergo LP at baseline and 3 months after treatment.

You may not qualify if:

• Medical history of liver or pancreatic disease, GI ulcers and Chron's disease, kidney, GI, or blood problems
• Abnormal liver function defined as AST and/or ALT \> 100% the upper limit of the normal
• Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal or proteinuria
• History of HIV, clinically significant chronic hepatitis, or other active infection
• 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
• 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.
• 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
• Females must not be lactating, pregnant or with possible pregnancy
• 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
• 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
• 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.
• 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.
• Must not be on any immunosuppressant medications
• Must not be enrolled as an active participant in another clinical study.

Sponsors & Collaborators

• Georgetown University: lead
• Alzheimer's Association: collaborator

Study Sites (1)

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

Related Publications (1)

• Hebron ML, Lonskaya I, Olopade P, Selby ST, Pagan F, Moussa CE. Tyrosine Kinase Inhibition Regulates Early Systemic Immune Changes and Modulates the Neuroimmune Response in alpha-Synucleinopathy. J Clin Cell Immunol. 2014 Sep 30;5:259. doi: 10.4172/2155-9899.1000259.

  PMID: 25635231 RESULT

Related Links

• https://sites.google.com/a/georgetown.edu/moussa-lab/lab-members

MeSH Terms

Conditions

Lewy Body Disease

Interventions

bosutinib

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Fernando L Pagan, MD

  Georgetown Univeristy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor Of Neurology , Director of Movement Disorder Program, Medical Director of NPF COE at GUH , Fellowship Director

Model Details: 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.

Study Record Dates

• First Submitted: March 13, 2019
• First Posted: March 25, 2019
• Study Start: April 23, 2019
• Primary Completion: August 27, 2021
• Study Completion: August 27, 2021
• Last Updated: April 5, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)