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

Phase 2

Completed

Conditions: Motor Disorder
Parkinson Disease

Interventions: Drug: BTRX-246040
Drug: Placebo

Registration Number: NCT03608371

Lead Sponsor: BlackThorn Therapeutics, Inc.

Brief Summary: The purpose of this study is to assess the safety, tolerability, pharmacokinetics and efficacy of BTRX-246040 in participants with Parkinson's Disease 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 consists of 3 sequential, ascending dose cohorts of 8 participants each with a 6:2 randomization to BTRX-246040 or placebo. The planned dosing for each cohort is 40, 80, and 120 mg. After enrollment of the first cohort is completed, doses for subsequent cohorts may be modified based on review of the available data (safety, tolerability, efficacy, and pharmacokinetics) by an unblinded Dosing Review Committee (DRC). A similar review and determination of dosing for the subsequent cohort is to be performed after completion of each cohort and based on all data available from previous cohorts.

Participants who meet entry criteria assessed at the screening visit (up to 28 days prior to Day 1) 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). Participants are to be dosed with study drug and remain on site for an 8-hour observation period with Unified Parkinson's Disease Rating Scale (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 are to be collected 6 times at scheduled intervals within the 8-hour observation period. A follow-up safety visit is scheduled 7 days later.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

Inclusion Criteria

Diagnosed with Parkinson's disease (PD), consistent with the United Kingdom PD Society Brain Bank Criteria for the Diagnosis of PD
Men or women ≥ 30 years old and ≤ 76 years old
Female participants 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 4 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 participant 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 monoamine oxidase B (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 participants 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 Diagnostic and Statistical Manual of Mental Disorders V edition (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 1 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 19. Participants 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 Principal Investigator
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 participant 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 participant 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 investigational medicinal product (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 participant's participation at study entry
Electrocardiogram (ECG) abnormalities at Visit 1 (screening) or Visit 2 that, in the judgment of the Investigator, are clinically significant related to the participant's participation
Using the following concomitant medications (contact the Sponsor-designated medical monitor to determine eligibility when in doubt):
1. proton pump inhibitors within 5 half-lives of Screening
2. 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)
Previous completion or withdrawal from this study or any other study investigating BTRX-246040 (previously called LY2940094)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
BTRX-246040 Cohort 1	BTRX-246040	BTRX-246040 40 mg administered orally
BTRX-246040 Cohort 2	BTRX-246040	BTRX-246040 80 mg administered orally
BTRX-246040 Cohort 3	BTRX-246040	BTRX-246040 120 mg administered orally
Placebo Cohorts 1-3	Placebo	Placebo is administered orally at the same number of capsules as active drug in each Cohort. Placebo capsules consist of inactive ingredients and look identical to BTRX-246040.

Primary Outcome Measures

Name	Time	Method
Maximal Change in UPDRS Part III From Predose to Postdose on Day 1	From pre-dose to 8 hours post-dose on Day 1	UPDRS = Unified Parkinson's Disease Rating Scale. 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). The score ranges from 0-56.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Turned ON on Day 1	From dose to 8 hours post-dose on Day 1	ON is the typical functional state when patients are receiving medication and have a good response. OFF is the typical functional state when patients have a poor response in spite of taking medications.
Time to ON on Day 1	From dose to 8 hours post-dose on Day 1	ON is the typical functional state when patients are receiving medication and have a good response. OFF is the typical functional state when patients have a poor response in spite of taking medications.
Area Under the Curve for UPDRS Part III During the 8 Hours of Assessment on Day 1	From pre-dose to 8 hours post-dose 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). UDPRS Part III was assessed pre-dose and every 30 minutes for 4 hours and then hourly for another 4 hours (i.e., 8 hours following study drug administration) on Day 1.
Duration of ON Time on Day 1	From dose to 8 hours post-dose on Day 1	ON is the typical functional state when patients are receiving medication and have a good response. OFF is the typical functional state when patients have a poor response in spite of taking medications.
Change From Pre-dose Dyskinesia Rating (From the UPDRS Part III Motor Response and Dyskinesia Assessment)	From pre-dose to 8 hours post-dose 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). An additional single item to rate dyskinesia was added to the UDPRS and was rated from 0 (no dyskinesia) to 4 (severe dyskinesia: maximal amplitude and present during most of the examinations).