Study for the Use of TKIs for Treatment of Cognitive Decline Due to Degenerative Dementias
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|ClinicalTrials.gov Identifier: NCT02921477|
Recruitment Status : Enrolling by invitation
First Posted : October 3, 2016
Last Update Posted : December 4, 2019
|First Submitted Date ICMJE||September 28, 2016|
|First Posted Date ICMJE||October 3, 2016|
|Last Update Posted Date||December 4, 2019|
|Actual Study Start Date ICMJE||September 2016|
|Estimated Primary Completion Date||December 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Number of patients who are discontinued due to tolerability issues related to treatment [ Time Frame: 1 year ]
Outcome goal to determine safety and tolerability of study medication
|Original Primary Outcome Measures ICMJE
||Number of patients who are discontinued due to tolerability issues related to treatment [ Time Frame: 1 year ]|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Study for the Use of TKIs for Treatment of Cognitive Decline Due to Degenerative Dementias|
|Official Title ICMJE||Open Label Study for the Use of Tyrosine Kinase Inhibitors for Treatment of Cognitive Decline Due to Degenerative Dementias|
The present study is designed as an open label study of patients with mild cognitive impairment or dementia to evaluate longer term tolerability and potential efficacy of tyrosine kinase inhibitors. Baseline and outcome measures in this study utilize validated tests that are appropriate for repeated measures which are not affected by practice effects. Advantages of this study include the fact that the neuropsychological testing instruments and advanced MRI imaging protocols that have been in routine clinical deployment provide for a high degree of availability and reliability for diagnosis and for monitoring change of status. Quality assurance is tightly controlled. The study population is sufficiently broad and the conditions of interest are sufficiently prevalent so that recruitment of the projected numbers of subjects is not a limiting factor.
For a Phase I trial there is a proposed 20 patient sample to determine the frequency of common side effects in the population that is being studied. Subjects will be administered the initial dose of bosutinib, with dosage progressively increased over the course of the study. The initial dose of bosutinib is 100 mg tablet, once per day. The dose will be increased as tolerated up to 300 mg per day.
All subjects will be started at 100 mg/day and the dose will be increased by 100 mg each month if the lower dose is tolerated without significant side effects. That is to say, the subject will take 100 mg/day every day for the first month, 200 mg/day every day for the second month, and 300 mg/day every day for the third month and for the remainder of the study, provided that adverse reactions do not prohibit continuation at this dosage. The investigators will be using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 to monitor, evaluate, and report adverse reactions on an ongoing basis. Stopping and dose reduction rules for reported adverse reactions have been taken from the package insert of bosutinib.
In order for a subject to be considered for this study, the following criterion is required:
• Cognitive decline with mild cognitive impairment (Clinical Dementia Rating Stage 0.5) through moderate dementia (CDR Stages 1 and 2)
All patients, according to routine best practices will have an evaluation including neurological interview and examination to screen for reversible causes of cognitive change such as depression, substance abuse, vitamin deficiency and systemic illness. All patients will have a Beck Depression scale and blood tests for B12 and thyroid hormone. Patients will have an EKG, in particular to screen for QT prolongation which is a relative counterindication for use of tyrosine kinase inhibitor therapy.
According to the package insert for bosutinib, the investigators are proposing to use an age range and dosage route that is comparable and overlapping with routine application of this drug. In addition, the investigators are proposing dosage ranges that are substantially lower than usually recommended for treatment of leukemia.
The QDRS scale will be given to all patients; a cut off score of 1.5 has been used qualify patients with a dementia score (CDR) of 0.5 (ref 19).
All patients will have a lumbar puncture for ABeta 42 and Tau proteins for Alzheimer's Spectrum. This spinal fluid examination has been shown to be both sensitive and specific for Alzheimer's disease (ref 20). Cerebrospinal fluid (CSF) tau levels are also elevated in alpha synucleinopathy and frontotemporal lobar degeneration (ref 21). The lumbar puncture is performed once at entry.
All patients will have an advanced MRI of the brain to include volume measurement of the hippocampus (ref 22), arterial spin labeling (ASL) perfusion scan (ref 23) and MRS of prefrontal, precuneus, hippocampus and occipital lobe. Patients with cognitive decline have decreased perfusion in temporal parietal or frontal regions of the brain with ASL perfusion, or show characteristic change in MRS or volumetric evaluation compared to aged matched control subjects. MRI will also demonstrate if patients have tumors, hydrocephalus, subdural hematomas and other structural etiologies of cognitive decline.
On entry, patients will have CDR stage of at least 0.5 and at least one abnormal imaging biomarker and none of the exclusion criteria below. Baseline, six months, twelve months, eighteen months and two year (completion) testing will include the Quick Dementia Rating System (QDRS) for staging and the following battery of tests:
The rationale behind this criterion is supported by the importance that the subject is cognitively able to effectively speak, listen, and read in English, and has the cognitive capacity to give informed consent.
All subjects will be started at 100 mg/day and the dose will be increased by 100 mg each month if the lower dose is tolerated without significant side effects. Adverse reactions will be scaled according to the CTCAE v.4. If the subject experiences severe adverse reactions at any dose, or if the subject requires dose reduction for toxicity from a dose of 100 mg/day, the subject will be removed from the study. If the subject experiences moderate adverse reactions at a dose >100 mg/day, the dose will be reduced by 100 mg and maintained at the lower dose for 1 month. If the subject experiences moderate or severe adverse reactions at this lower dose, the subject will be removed from the study. After 1 month, the dose will again be increased by 100 mg. If the subject does not experience any adverse reactions at this elevated dose, he/she will resume with the original up-titration schedule (i.e. increase by 100 mg every month up to 300 mg/day). If the subject experiences moderate symptoms at this elevated dose, the dose will again be reduced by 100 mg and will be maintained at this lower dose as the maximally tolerated dose.
The duration of treatment is 1 year. To minimize risk, subjects will be seen weekly for toxicity monitoring during the first month of treatment, and biweekly during the second month of treatment. On weeks when the subject is not in for a visit, subject status will be assessed on the basis of phone calls with the respective care taker. The care taker will be determined during the QDRS staging at the time of the initial consultation. The care taker is an individual who is intimately familiar and in close contact with the subject. After the first two months, visits will be on a monthly basis. Mild, moderate, and severe adverse reactions will be reported on an ongoing basis. The rationale for such extended administration is to allow for a more reliable assessment of tolerability. The primary endpoint in evaluating tolerability will be how many of the initial 20 subjects are discontinued due to adverse reactions. Subjects will be discontinued if they have moderate or severe adverse reaction ratings according to the CTCAE, which are not remediable by dosage reduction.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1|
|Study Design ICMJE||Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: bosutinib
|Study Arms ICMJE||Experimental: Bosutinib Treatment Arm
Subjects will be administered the initial dose of bosutinib, with dosage progressively increased over the course of the study. The initial dose of bosutinib is 100 mg tablet, once per day. The dose will be increased as tolerated up to 300 mg per day. The dose will be increased by 100 mg each month if the lower dose is tolerated without significant side effects. That is to say, the subject will take 100 mg/day every day for the first month, 200 mg/day every day for the second month, and 300 mg/day every day for the third month and for the remainder of the study, provided that adverse reactions do not prohibit continuation at this dosage. Stopping and dose reduction rules for reported adverse reactions have been taken from the package insert of bosutinib. The duration of treatment is 1 year.
Intervention: Drug: bosutinib
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Enrolling by invitation|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||December 2021|
|Estimated Primary Completion Date||December 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||45 Years to 89 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT02921477|
|Other Study ID Numbers ICMJE||062016|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||
|Responsible Party||Sheldon Jordan, Neurological Associates of West Los Angeles|
|Study Sponsor ICMJE||Neurological Associates of West Los Angeles|
|PRS Account||Neurological Associates of West Los Angeles|
|Verification Date||December 2019|
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