BTRX-246040 Study in Subjects With Parkinson's Disease With Motor Fluctuations

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety, tolerability, pharmacokinetics and efficacy of BTRX-246040 in subjects with PD who have motor fluctuations and predictable early morning off periods.

Detailed Description
-----------------
Study treatment is 1 day and total duration of the study is up to 36 days, including an approximate 28-day screening period. The study will consist of 4 sequential, ascending dose cohorts of 8 subjects each with a 6:2 randomization to BTRX-246040 or placebo. The planned dosing for each cohort will be 40, 80,120 and 160 mg. After enrollment of the first cohort has been completed, doses for subsequent cohorts may be modified based on review of the available data (safety, tolerability, efficacy, and PK) by an unblinded Dosing Review Committee (DRC). A similar review and determination of dosing for the subsequent cohort will be performed after completion of each cohort and based on all data available from previous cohorts. Subjects who meet entry criteria assessed at the screening visit (up to 28 days prior to Day 1) will present to the clinic on the morning of Day 1 (treatment day) in the practically defined OFF state (having withheld anti-parkinsonian medications after 10:00 PM the evening prior). Subjects will be dosed with study drug and remain on site for an 8-hour observation period with UPDRS Part III motor response, dyskinesia rating and ON/OFF status assessed pre-dose, every 30 minutes for 4 hours post-dose, and then hourly for 4 additional post-dose hours (i.e., 8 hours total post-dose) prior to being discharged. Blood for pharmacokinetics will be collected 6 times at scheduled intervals within the 8-hour observation period. A follow-up safety visit is scheduled 7 days later.

Official Title
-----------------
Phase 2A, Double-blind, Placebo-controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of BTRX-246040 in Parkinson's Disease Subjects With Motor Fluctuations

Conditions
-----------------
Parkinson Disease, Motor Disorder

Intervention / Treatment
-----------------
* Drug: BTRX-246040
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with Parkinson's disease (consistent with the UK PD Society Brain Bank Criteria for the Diagnosis of PD) Men or women ≥ 30 years old and ≤ 76 years old Female subjects must be either surgically sterilized or 2 years post menopausal at screening Modified Hoehn and Yahr Staging ≤ 3 in the ON state Montreal Cognitive Assessment (MoCA) Score ≥ 26 Currently has a clear and decisive response to levodopa, and receiving a stable dose of levodopa (at least 4 doses per day of levodopa or ≥ 3 doses per day of RytaryTM (Carbidopa and levodopa Extended-Release Capsules) for at least four weeks prior to screening) Experiencing motor fluctuations during waking hours with at least 2 hours of OFF periods each day, including predictable early morning OFF periods, based on subject assessment Able to participate in the study in the practically defined OFF state All anti-parkinsonian medications maintained at a stable dose for at least 4 weeks prior to the initial Screening Visit with the exception of MAO-B inhibitors, which must be maintained at a stable level for at least 8 weeks prior to the screening visit Approved by a central Enrollment Authorization Committee as meeting entry criteria and being a suitable candidate for the study Male subjects agree to use a reliable method of birth control during the study and for at least 90 days following the last dose of BTRX-246040 or placebo. Informed and given ample time and opportunity to think about his/her participation in this study and has given his/her written informed consent on an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved consent form. Judged to be reliable and able to keep all appointments for clinic visits, tests, and procedures, including venipuncture, and examinations required by the protocol. Exclusion Criteria: Diagnosis of secondary or an atypical Parkinsonian syndrome Severe disabling dyskinesia Clinically significant psychosis or hallucinations or history of psychosis in past 6 months History of previous neurosurgery for PD Currently or previously on Duopa/Duodopa Currently taking apomorphine Has a diagnosis or history of a substance related disorder per DSM-V criteria (including alcohol but excluding nicotine and caffeine), during the 12 months prior to the Screening Visit. Medical or recreational use of marijuana in the 6 months prior to the Screening Visit Has tested positive at the Screening Visit for drugs of abuse (opiates, cannabinoids, methadone, cocaine, and amphetamines [including ecstasy]) Active suicidal ideation within one year prior to the Screening Visit as evidenced by answering yes to Questions 4 or 5 on the suicidal ideation portion of the Columbia- Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 1 year Current major depressive episode or a Beck Depression Inventory-II (BDI-II) score above the protocol-defined threshhold. Subjects receiving treatment for depression with antidepressants may be enrolled if they have been on a stable daily dose for at least 8 weeks before the Screening Visit and are clinically stable in the opinion of the PI Currently or within 8 weeks of screening receiving bupropion Exposure to neuroleptics (antipsychotic drugs) for more than 1 month within the past 2 years, or any exposure within the past year Any malignancy in the 5 years prior to randomization (excluding successfully treated basal cell carcinoma of the skin or cervical carcinoma in situ) Current or previous diagnosis of malignant melanoma or the presence of any suspicious skin lesion based on physical exam findings. Any other clinically significant medical condition or circumstance prior to randomization that, in the opinion of the Investigator, could affect subject safety, preclude evaluation of response, interfere with the ability to comply with study procedures, or prohibit completion of the study (e.g., uncontrolled diabetes mellitus, renal or hepatic impairment, coronary artery disease, evidence of significant active cardiac, respiratory, or hematologic disease, cancer with < 5 year remission (excluding successfully treated basal cell carcinoma of the skin or cervical carcinoma in situ), chronic pain, fibromyalgia or gastric bypass). Prior seizures (other than childhood febrile seizure) or other condition that would place the subject at increased risk of seizures or is taking anticonvulsants for seizure control. History of serious head injury (e.g., skull fracture, cerebral contusion, or trauma resulting in prolonged unconsciousness), intracranial neoplasm or hemorrhage. Orthostatic hypotension that is symptomatic or requires medication Participation in another study of an IMP or medical device currently or in the last 30 days or within 5 half-lives of the IMP (whichever is longer) prior to Screening Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 2x upper limit of normal (ULN) or glomerular filtration rate ≤ 60 mL/min at Visit 1 (screening) Nephritic syndrome, end-stage renal disease (and using renal replacement therapy such as hemodialysis or peritoneal dialysis), or a serum creatinine ≥ 2 mg/dL (≥ 172 μmol/L) at the Screening Visit Any other clinically significant abnormalities (i.e., laboratory deviations requiring acute medical intervention or further medical evaluation) in laboratory results at screening including clinical chemistries, hematology, and urinalysis, that, in the judgment of the Investigator, should preclude a subject's participation at study entry. ECG abnormalities at Visit 1 (screening) or Visit 2 that, in the judgment of the Investigator, are clinically significant related to the subject's participation Using the following concomitant medications (contact the Sponsor-designated medical monitor to determine eligibility when in doubt): proton pump inhibitors within 5 half-lives of Screening fluoxetine and irreversible monoamine oxidase inhibitors within 4 weeks of Screening Currently taking or have taken, within 5 half-lives of Screening, any medications or supplements that are strong inhibitors or inducers of CYP3A4. A known hypersensitivity to gelatin capsules. Investigator site personnel directly affiliated with this study, and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. Employees of the Sponsor or of any third-party organizations involved in study who require exclusion of their employees. Have participated in a clinical trial or any other type of medical research judged by the Investigator to be scientifically or medically incompatible with this study within 30 days prior to Visit 1 (screening). Contact the Sponsor-designated medical monitor to determine eligibility when in doubt. Previous completion or withdrawal from this study or any other study investigating BTRX-246040 (previously called LY2940094).

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 76 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will consist of 3 sequential, single ascending dose cohorts of 8 subjects each with a 6:2 randomization to BTRX-246040 or placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BTRX-246040 Cohort 1<br>BTRX-246040 will be administered orally 40 mg (1capsule) in Cohort 1 | Drug: BTRX-246040<br>* oral capsule 40 mg<br>|
| Experimental: BTRX-246040 Cohort 2<br>BTRX-246040 will be administered orally 80 mg (2 capsules) in Cohort 2 | Drug: BTRX-246040<br>* oral capsule 40 mg<br>|
| Experimental: BTRX-246040 Cohort 3<br>BTRX-246040 will be administered orally120 mg (3 capsules) in Cohort 3 | Drug: BTRX-246040<br>* oral capsule 40 mg<br>|
| Placebo Comparator: Placebo Cohorts 1-3<br>Placebo will be administered orally at the same number of capsules as active drug at each Cohort. Placebo capsules will consist of inactive ingredients and look identical to BTRX-246040. | Drug: Placebo<br>* oral capsule matching BTRX-246040 40 mg capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Motor Function | The Unified Parkinson's Disease Rating Scale (UPDRS) Part III is a 14-item rating scale, which consists of the motor examination. Each item is scored from 0 (Normal) to 4 (Most severe). | from pre-dose to post-dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of ON time on Day 1 | The Unified Parkinson's Disease Rating Scale (UPDRS) Part III is a 14-item rating scale, which consists of the motor examination. Each item is scored from 0 (Normal) to 4 (Most severe). | from pre-dose to post-dose on Day 1 | 
| Percentage of subjects that turn ON on Day 1 | The Unified Parkinson's Disease Rating Scale (UPDRS) Part III is a 14-item rating scale, which consists of the motor examination. Each item is scored from 0 (Normal) to 4 (Most severe). | from pre-dose to post-dose on Day 1 | 
| Time to ON on Day 1 | The Unified Parkinson's Disease Rating Scale (UPDRS) Part III is a 14-item rating scale, which consists of the motor examination. Each item is scored from 0 (Normal) to 4 (Most severe). | from pre-dose to post-dose on Day 1 | 
| Area under the curve for UPDRS Part III during the 8 hours of assessment on Day 1 | The Unified Parkinson's Disease Rating Scale (UPDRS) Part III is a 14-item rating scale, which consists of the motor examination. Each item is scored from 0 (Normal) to 4 (Most severe). | from pre-dose to post-dose on Day 1 | 
| Change from pre-dose UPDRS dyskinesia score | The Unified Parkinson's Disease Rating Scale (UPDRS) Part III is a 14-item rating scale, which consists of the motor examination. Each item is scored from 0 (Normal) to 4 (Most severe). | from pre-dose to post-dose on Day 1 |