PROSEEK: A Phase 2 Study In Early Parkinson's Disease Patients Evaluating The Safety And Efficacy Of Abl Tyrosine Kinase Inhibition Using K0706

Study Overview
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Brief Summary
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This study consists of 2 parts. Part 1 of the study is conducted to evaluate the efficacy, safety, and tolerability of two doses of K0706 compared to placebo in subjects with early Parkinson's Disease who are not receiving dopaminergic therapy. Part 2 is an optional long term extension study for subjects who have completed week 40 of Part 1

Detailed Description
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This study is designed to assess the ability of K0706 to slow the progression of PD. Preclinical animal model data have already demonstrated that K0706 has neuroprotective activity, but further development will require human clinical experience. This study will also allow determination of safety and tolerability of K0706 over many months in subjects with PD.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of K0706 in Subjects With Early Parkinson's Disease

Conditions
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Early Parkinson Disease

Intervention / Treatment
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* Drug: K0706
* Drug: K0706
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Part 1: Inclusion criteria: Males or females aged ≥ 50 years; Body mass index (BMI) greater than 18.5 kg/m2 and less than 45 kg/m2; Diagnosed with Clinically Probable PD according to the MDS clinical diagnostic criteria, with documented diagnosis of PD per treating physician's records within three years of the Screening visit. Disease severity according to modified Hoehn & Yahr stage ≤ 2; Projected to not required to start dopaminergic therapy within 9 months from Baseline; Exclusion criteria: Current, or within 60 days of Screening, use of any prescription, investigational, or over the counter medication for the symptomatic treatment of PD or to slow the progression of PD. Treatment with Monoamine Oxidase B (MAOB) inhibitors will be allowed if the dose is stable for at least 30 days prior to Screening and subjects agree to remain on it for the duration of the study; Prior use of dopaminergic therapy (e.g., levodopa, dopamine agonist, amantadine) for 30 or more days any time in the past; A diagnosis of a significant central or peripheral nervous system disease affecting the subject's cognition or motor function at any time, such as another neurodegenerative disorder, multiple sclerosis or stroke. This does not include transient neurological deficits such as transient ischemic attacks or migraine aura; A diagnosis of a medical condition that could interfere with interpretation of the MDS-UPDRS during the trial (e.g., musculoskeletal disorders); Contraindications to receiving an MRI; Contraindications to receiving a DaT SPECT scan (e.g., hypersensitivity to the active substance, any of the excipients, or iodine) if a new DaT SPECT scan is required for the study; Most recent DaT SPECT scan not compatible with PD (i.e., Scans Without Evidence of Dopaminergic Deficit [SWEDD]) based on a central reading by a study physician; MRI of the brain performed after onset of PD suggestive of secondary Parkinsonism (e.g., subdural hematoma, normal pressure hydrocephalus, or infarcts of the basal ganglia); Severe tremors as defined by a score of severe on any of the MDS-UPDRS Parts 2 or 3 tremor severity (not constancy) items; Montreal cognitive assessment score < 25 History of any surgery on the brain itself including deep brain stimulation for PD (note this does not include surgeries on the skull that do not affect the brain, e.g., small meningioma removal); History of hypersensitivity (e.g., bronchospasm, anaphylaxis, serious drug rash) to contents of the study drug or other tyrosine kinase inhibitors; Recent use of medications that can cause Parkinsonism and suspicion of the investigator that it could have worsened the subject's Parkinsonism. This includes neuroleptics (e.g., olanzapine, risperidone, haloperidol), some anti-nausea medications (e.g., prochlorperizine, metoclopramide) and others (e.g., flunarizine, methyldopa) Use of medications that affect the dopaminergic system within 60 days of Screening. This includes stimulants (e.g., methylphenidate, amphetamine derivatives, modafinil) and Monoamine Oxidase A (MAOA) inhibitors (e.g., phenelzine, and tranylcypromine). Note that antidepressants are acceptable as long as the subject has remained on them at a stable dose for over 60 days prior to Screening and plans to remain on them through the study; Any malignant disease (other than basal cell carcinoma of the skin) with evidence of disease within the past 5 years and with the potential for recurrence Part 2: Inclusion criteria: Subject has completed part 1 of the study. Subject projected not to need dopaminergic treatment except for treatment with Monoamine Oxidase B (MAOB) inhibitors. MAOB inhibitors will be allowed if the patient was already taking the same during part 1 of the study. Subject has received K0706/placebo, as appropriate, within 4 weeks prior to end of part 1 of the study. Male subjects enrolled in the study should not father a child and are advised to prevent the passage of semen to their sexual partner during intercourse using an effective method, as judged by the Investigator, for the duration of the study and for 3 months after the last dose of study drug Exclusion criteria: Clinically significant or unstable psychiatric or medical condition, vital sign, or laboratory abnormality that in the opinion of the investigator interferes with participation in the study Any condition that in the opinion of the Investigator represents an obstacle for study conduct and/or represents a potential unacceptable risk for the subject. Subject has any concurrent medical condition or uncontrolled, clinically significant systemic disease (e.g., renal failure, heart failure, hypertension, liver disease, diabetes, or anemia) that, in the opinion of the Investigator, could cause continued treatment to be detrimental to the subject

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: K0706, low dose<br> | Drug: K0706<br>* low dose, orally, once-daily<br>|
| Experimental: K0706, high dose<br> | Drug: K0706<br>* high dose, orally, once-daily<br>|
| Placebo Comparator: Placebo<br> | Other: placebo<br>* placebo, orally, once-daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the sum of MDS-UPDRS Parts 2 and 3 |  | Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the movement disorder society - unified Parkinson's disease rating scale |  | Week 40 | 
| Time from Baseline to initiation of symptomatic medication |  | Week 40 | 
| Change in health related quality of life as measured by the European quality of life questionnaire 5 level version |  | Week 40 | 
| Change in Clinician global impression severity |  | Week 40 | 
| Change in the scales for outcomes in Parkinson's disease - autonomic questionnaire |  | Week 40 | 
| Level of K0706 |  | Week 40 |