Forty five (45) participants will be recruited and randomized into 3 arms (1:1:1). Fifteen (15) patients in arm 1 (group 1) will receive the matching placebo (8 x Placebo capsules) ("sugar pill") orally once daily for 12 weeks (90 days).

Forty five (45) participants will be recruited and randomized into 3 arms (1:1:1) .Fifteen (15) patients in arm 2 (group 2) will receive the 96 mg of K0706 (4 x 24 mg K0706 and 4 Placebo capsules) orally once daily for 12 weeks (90 days).

Forty five (45) participants will be recruited and randomized into 3 arms (1:1:1) .Fifteen (15) patients in arm 3 (group 3) will receive 192 mg of K0706 (8 x 24 mg K0706 capsules) orally once daily for 12 weeks(90 days).

Dementia With Lewy Bodies

Fifteen (15) patients in group 1 will receive the matching placebo ("sugar pill") eight (8) capsule orally daily for 12 weeks (90 days) without food.

Placebo oral capsule

Fifteen (15) patients in group 2 will receive the 96 mg of K0706 (4 x 24 mg of K0706) orally and four placebo capsules daily for 12 weeks (90 days) without food.

96 mg of K0706

Fifteen (15) patients in group 3 will receive the 192 mg of K0706 (8 x 24 mg of K0706) orally daily for 12 weeks (90 days) without food.

192 mg K0706

https://sites.google.com/a/georgetown.edu/moussa-lab/home3

MedStar Georgetown University Hospital

K0706 for Patients Diagnosed With Dementia With Lewy Bodies

A Randomized, Double Blind, Placebo-controlled Study to Evaluate the Impact of K0706 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics and Clinical Outcomes in Dementia With Lewy Bodies (DLB)

The investigators will determine safety and tolerability by using the occurrence of adverse events (AEs) of interest, including myelosuppression, urinary, pancreatic and hepatic disorders, gastrointestinal (GI), kidney disorders, Corrected QT-interval (QTc)prolongation as per SPARC Ltd Investigator Brochure (IB).

Concentration of K0706 will be measured in the plasma

Concentration of K0706 will be measured in the CSF

Concentration of DLB related plasma biomarkers, including HVA, DOPAC, Abeta40/42, total tau, ptau231/181 and total and oligomeric alpha-synuclein will be measured.

Concentration of DLB related CSF biomarkers, including HVA, DOPAC, Abeta40/42, total tau, ptau231/181 and total and oligomeric alpha-synuclein will be measured.

The MoCA is designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains, including attention and concentration, executive functions, memory, language, visuo-constructional skills, conceptual thinking, calculations and orientation. Scores range between 0 and 30 where 30 is the highest score and 0 is the lowest score.

The Trail Making Test (TMT) is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. The time to complete the test is measured.

ADAS-cog aims to evaluate cognitive impairment in Alzheimer's disease. ADAS-cog was included in this LBD study to better capture potential changes in activities of daily living (ADL) and non-ADLs and severity of cognitive impairment. Points for errors in each task are added up and the greater the dysfunction, the greater the score.

ADCS-ADL is an activity of daily living inventory to assess functional performance. Using a structured interview format, study partners are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. The ADCS-ADL includes some items from traditional basic ADL tests as well as instrumental (complex) activities of daily living. It is a 23 item scale that provide a total score from 0-78 with a lower score indicating greater severity.

The NPI is a multi-item instrument to assess psychopathology in Azheimer's disease based on interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric disturbances. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously) as well as severity (1=mild, 2=moderate, 3=severe). The overall score and the score for each subscale are the product of severity and frequency.

The CAF consists of seven items of confusional behavior (falls, fluctuation, drowsiness, attention, disorganized thinking, altered level of consciousness, communication), scores for which are summed to provide a severity score for fluctuating confusion ranging from 0 to 21.

The IAS measures apathy and irritability in patients with dementia. The IAS is a 28-item self-administered questionnaire collecting information about different aspects of irritability and apathy utilizing a 0-3 scale for each item to indicate severity. Both a patient and a study partner version can be administered. The IAS will be completed separately by Subjects and Study Partners. A higher total score indicates higher severity.

PBA-s is a structured interview in which a trained interviewer rates the frequency and severity of neuropsychiatric symptoms through observation and the reporting of the Subject and Study Partner. Symptoms rated include depressed mood, suicidal ideation, anxiety, irritability, angry or aggressive behavior, apathy, perseverative thinking or behavior, obsessive-compulsive behaviors, delusional or paranoid thinking, hallucinations, and disoriented behavior. Each behavioral problem is rated for both severity and frequency on a 0-4- point scale; severity and frequency ratings are then multiplied to provide an overall score for each symptom.

UPDRS-I-III is used to follow the longitudinal course of Parkinson's disease. The UPDRS is made up of these sections: Part I: evaluation of mentation, behavior, and mood. Part II: self-evaluation of the activities of daily life (ADLs) Part III: clinician-scored monitored motor evaluation. Part IV: complications of therapy. Part V: Hoehn and Yahr staging of severity of Parkinson's disease. Part VI: Schwab and England ADL scale.

Timed Up and Go (TUG) is an assessment of mobility, balance, walking ability, and fall risk. It measures the time that a person takes to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down.

Fernando Pagan MD

Associate Professor Of Neurology , Director of Movement Disorder Program, Medical Director of NPF COE at GUH , Fellowship Director

Georgetown University

Sun Pharma Advanced Research Company Limited

The effects of 92mg of K0706 versus 196mg of K0706 versus matching placebo taken daily by mouth for 12 weeks, followed by a 4 week wash-out period in individuals diagnosed with DLB will be evaluated.

Participants will be randomized by a Biostatistician by an internet based randomization module into three groups. The researchers include : Primary investigator , Sub-Investigators ,Clinical Coordinators, Nurse Practitioners, and Clinical Research unit (CRU) 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.

The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125 mg twice/daily, the target dose will be 25mg twice daily (50 mg/day) and participants will take 50 mg/day carvedilol for 6 months.Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.

REM Sleep Behavior Disorder

Pre-motor Parkinson Disease

Symptomatic Parkinson Disease

At the end of Baseline visit, carvedilol 3.125 twice daily will be initiated and maintained for 1 week, increased to 6.25twice daily (dispensed at week 1visit), to 12.5mg twice daily (dispensed at week 2) and a max dose of 25mg twice daily (dispensed at week 4 visit), as tolerated. A subject that cannot tolerate at least a 25 mg daily dose will be excluded from the study. Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose. The project will include a washout period at study end.

Carvedilol

Cedars Sinai Medical Center

Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease

The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease

123I-MIBG reuptake will be measured by early and late Heart to Mediastinal ratio (H/M) and Washout ratio (WR) which will be calculated using the following formula: [(early heart counts/pixel - early mediastinum counts/pixel) - (late heart counts/pixel decay-corrected - late mediastinum counts/pixel decay-corrected)]/(early heart counts/pixel - early mediastinum counts/pixel). Care will be taken to exclude lung or liver from the myocardial and large vessels and lung from the mediastinum region of interest. MIBG abnormality cutoffs will be set for values of late H/M <2.2 and WR >30%.

Safety will be monitored collecting the type and frequency of adverse events, including clinical symptoms, changes in vital signs, clinical laboratory measures and EKG abnormalities.

Twenty-four-hour Holter monitoring of all patients will be conducted at two points during the study: 1) After MIBG and prior to the administration of the study drug and 2) within one week of the end of the six-month treatment trial. Two-channel Holter recordings will obtained and analyzed on a commercially available scanner in the cardiac laboratory at Cedars Sinai Medical Center, according to published guidelines.

The Movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS) Part III will be administered at baseline and 26 weeks after study medication titration. Each item of the MDS-UPDRS has a possible rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.Clinical scales will be performed OFF medication in those subjects that might be receiving dopaminergic drugs

RBD questionnaire (RBDSQ) changes from Screening at 26 weeks after study drug titration

University of Pennsylvania Smell Identification Test (UPSIT) changes from screening at 26 weeks after study medication titration

Functional constipation will be assessed at screening and at 26 weeks after study medication titration using a questionnaire based on modified ROME III diagnostic criteria, which focuses on symptoms including straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction or blockage, manual maneuvers to facilitate evacuation, and two or fewer bowel movements per week. This questionnaire is based on a six item self-report measures with a three point summated rating scale. The total score has a range of 0 to 12, with scores > 4 identifying functional constipation.

Color vision changes will be assessed using HRR Pseudochromatic Plates from screening at 26 weeks after study medication titration

DaT/SPECT uptake at baseline will be quantified at baseline and 26 weeks after study medication titration

The NMSS measures non-motor symptoms over the previous month. Each symptom is scored with respect to: Severity: 0 = None, 1 = Mild; 2 = Moderate; 3 = Severe and Frequency: 1 = Rarely (<1/wk); 2 = Often (1/wk); 3 = Frequent (several times per week); 4 = Very Frequent (daily or all the time).

The SCOPA-AUT scale consists of 25 items assessing autonomic symptoms in the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction.

Peripheral IR will be defined by testing for fasting plasma insulin (FPI), fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) from baseline at 26 weeks after study medication titration. HOMA index will be calculated by the formula: HOMA-IR = (FPI x FPG)/405. [A cutoff HOMA index of 2.0, equivalent to <50% sensitivity, will be used to define IR. Subjects were considered to have IR if they either had a HOMA≥2.0 and/or HbA1c≥5.7.

Measures of insulin sensitivity in neuronal-origin enriched plasma EVs (central IR) will be used to test the association of changes in such sensitivity to changes in MIBG uptake and clinical scores from baseline to 26 weeks after carvedilol titration. For that purpose, plasma samples will be collected and stored and -80oC to allow for isolation of neuronal origin EVs at the completion of the study.

Michele Tagliati, MD

Professor of Neurology, Director of Movement Disorders

Treatment: carvedilol titration; Experimental treatment with carvedilol will be offered at stabilized medical treatment. The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125mg twice daily and will be doubled every week according to patient tolerability, as measured by subjective complaints, arterial blood pressure and heart rate. The target dose will be 25mg twice daily (50 mg/day). Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.

Patients with iatrogenic chronic autonomic failure (CAF) (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies)

Patients with Parkinson's disease (PD) without orthostatic hypotension (PD no OH)

Healthy Volunteers with genetic risk of PD

Includes patients with orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (nOH), and people with multiple system atrophy (MSA).

Parkinson's Disease

Multiple System Atrophy

Autonomic Failure

18F-DOPA is a positron-emitting analog of the catechol amino acid, levodopa (L-DOPA, Ldihydroxyphenylalanine). 18F-DOPA PET scanning is used to visualize catecholamine terminals in the brain.

18F-Dopa

11C-MRB may be injected IV for visualizing sites of neuronal uptake of norepinephrine in the brain or periphery by PET scanning.

11C-methylreboxetine

13N-labeled ammonia is a perfusion imaging agent used to obtain perfusion-corrected values for 18F-dopamine-derived radioactivity in the heart and other organs.

13N-Ammonia

18F-Dopamine is a positron-emitting analog of the catecholamine, dopamine. 18F- Dopamine positron emission tomographic (PET) scanning may be used to visualize sympathetic innervation.

18F-Dopamne

Desipramine (DMI) is an approved tricyclic antidepressant. The drug inhibits neuronal uptake of catecholamines. DMI treatment is used to test for effects of NET inhibition on results of 11C-MRB or 18F-dopamine PET scans. The subject receives a single dose of DMI by mouth (about 125 mg per 70 kg body mass) about 2-3 hours before the subject receives the PET imaging agent.

Desipramine (DMI)

National Institutes of Health Clinical Center

Clinical Laboratory Evaluation of Chronic Autonomic Failure

Neuroimaging data are from MRI and from 18F-DOPA and 18F-dopamine PET scanning. Neurochemical data are from assays of catechols in plasma and cerebrospinal fluid. Immunofluorescence microscopy data are from analyses of immunoreactive tyrosine hydroxylase and AS in skin biopsy samples. Neurobehavioral rating scale data are from the University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform Parkinson s Disease Rating Scale (UPDRS).

Estimated extraneuronal binding of 11C-methylreboxetine is based on studies of patients with iatrogenic CAF and desipramine-treated HVs

National Institute of Neurological Disorders and Stroke (NINDS)

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.

synucleinopathies/tyrosine

K0706 for Patients Diagnosed With Dementia With Lewy Bodies

Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease

Clinical Laboratory Evaluation of Chronic Autonomic Failure

Study for the Use of TKIs for Treatment of Cognitive Decline Due to Degenerative Dementias

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