Early Parkinson's Disease Monotherapy With CVN424

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, 12-week, placebo-controlled clinical trial of CVN424 150 milligrams (mg) tablets in early, untreated Parkinson's Disease (PD). Participants will be randomized in a 1:1 ratio to CVN424 150 mg or placebo at the Baseline Visit. The purpose of this study is to measure effect on motor features with CVN424 compared to placebo in early, untreated Parkinson's Disease (PD) and to evaluate the potential of CVN424 to improve motor and non-motor functions in participants with early PD who are not taking dopaminergic or anti-PD therapies.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Trial of CVN424 in Early Parkinson's Disease

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: CVN424 150 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of PD consistent with United Kingdom Brain Bank and Movement Disorder Society Research Criteria for the Diagnosis of PD; must include bradykinesia with sequence effect, and motor asymmetry if no PD-type rest tremor. Not receiving anti-parkinsonian therapy, and not expecting to require it for the duration of the study. Men or women of all races who are at least 30 years at Screening. Modified Hoehn and Yahr ≤ 2.5 at Screening. Montreal Cognitive Assessment (MoCA) ≥ 26. Freely ambulatory at time of Screening (with/without assistive device). Female participants of childbearing potential and male participants with female partners of childbearing potential must agree to either remain abstinent or use adequate and reliable contraception throughout the study and at least 30 days after the last dose of study drug has been taken. Able and willing to give written (signed and dated) informed consent approved by an institutional review board, and to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures to complete the study. Approved as an appropriate and suitable candidate by the Enrollment Authorization Committee (EAC). Exclusion Criteria: Diagnosis of secondary or atypical parkinsonism. Diagnosis of motor signs or symptoms ≥ 4 years before Screening Visit. Previous surgical procedure for PD. Prior treatment with a dopamine agonist, levodopa, adenosine A2A receptor antagonists for more than 28 total days at any time. Treatment with a dopamine agonist within 14 days of Screening. Treatment with an MAOB inhibitor within 90 days of Screening. Currently receiving or received within 28 days of Screening any antipsychotic, metoclopramide or reserpine. Current use of potent Cytochrome P450 (CYP) 3A4/5 inhibitors or inducers. Clinically significant orthostatic hypotension. Clinically significant hallucinations requiring antipsychotic use. Known autoimmune, malignancy (except basal cell carcinoma) or hematologic disease (prior or current). Any clinically significant medical, surgical, or psychiatric abnormality that, in the judgment of the Investigator, is likely to interfere with study compliance, the safe participation of the participant or the assessment of safety or efficacy. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2 times the upper limit of normal (ULN), and total bilirubin greater than 1.5 times ULN. Participants with Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided that direct bilirubin is 1.5 times ULN. Significant renal impairment as determined by creatinine clearance (CrCL) as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation of ≤ 50 milliliters per minutes (mL/min). Participant has an ECG or clinical evidence of potentially unstable heart disease, including the following: QT interval corrected using Fridericia's formula (QTcF) > 470 milliseconds (msec) for female participants; > 450 msec for male participants Complete right or left bundle branch block History or clinical evidence of coronary artery disease, ischemic cardiac disease or myocardial infarct Clinically significant atrial or ventricular dysrhythmia; the heart must be in predominantly normal sinus rhythm Second- or third-degree atrioventricular (AV) block History or clinical evidence of heart failure History or clinical evidence of cardiomyopathy or cardiac structural abnormality Any other cardiac condition that the Investigator feels may predispose the participant to ischemia or arrhythmia Current (or within past 12 months) diagnosis or history of substance abuse (excluding nicotine or caffeine) by Diagnostic and Statistical Manual of Mental Disorders 5 criteria. Positive urine drug screen for tetrahydrocannabinol or any drugs that may affect participant safety or interfere with efficacy assessments. Medical or recreational use of marijuana or cannabidiol (CBD) within 2 months of the Screening Visit. Currently active major depression as determined by Beck Depression Inventory (BDI)-II score of > 19. Active suicidal ideation within 1 year prior to Screening Visit as determined by a positive response to Question 4 or 5 on the C-SSRS. Currently lactating or pregnant, or planning to become pregnant during the study. Current participation in another investigational clinical study and/or receipt of any investigational drug within 90 days prior to Screening. Prior use of CVN424. Positive test for coronavirus disease 2019 (COVID-19) via polymerase chain reaction (PCR) test. Confirmatory test will be allowed at the discretion of the Investigator to rule out false positives. A participant who tests positive for COVID-19 will be eligible to be rescreened once result is negative. Positive test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) consistent with current infection.

Ages Eligible for Study
-----------------
Minimum Age: 30 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVN424 150 mg<br>Participants will be administered with CVN424 150 mg. | Drug: CVN424 150 mg<br>* Participants will receive 1 CVN424 tablet (150 mg) per day.<br>|
| Placebo Comparator: Placebo<br>Participants will be administered with placebo. | Drug: Placebo<br>* Participants will receive 1 matching placebo tablet per day.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 12 on the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (Motor Examination) | The MDS-UPDRS is a comprehensive 50-question assessment of both motor and non-motor symptoms associated with PD. It features sections that require independent completion by people with PD and their caregivers, and sections to be completed by the same clinician throughout the study. Part III consists of 33 scores based on 18 items, and each question is anchored with five response scale from 0 (normal) to 4(severe). A 0 means there is no disability, and the higher the score, the more the disability is reflected. The maximum score for Part III is 132. The total score is the sum of the numerical response values of the items. It is completed by a rater based on findings from the motor examination. | Baseline and Up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 12 on the Clinical Global Impression Scale - Severity (CGI-S) | The CGI-S is a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal/not at all ill) to 7 (amongst the most severely ill participants). This requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. Higher scores indicate worser the illness. | Baseline and Up to Week 12 | 
| Change from Baseline to Week 12 on the Patient Global Impression Scale - Severity (PGI-S) | The PGI-S is a participant-completed assessment rating PD severity on a scale of 1 to 7; 1 being normal/not at all ill and 7 being extremely severely ill. Higher scores indicate worser the illness. | Baseline and Up to Week 12 | 
| Change from Baseline to Week 12 on the MDS-UPDRS Part II | The MDS-UPDRS is a comprehensive 50-question assessment of both motor and non-motor symptoms associated with PD. It features sections that require independent completion by people with PD and their caregivers, and sections to be completed by the same clinician throughout the study. Part II assess motor experiences of daily living, motor aspects of experiences of daily living. This part has 13 items. It is a self-administered questionnaire completed by the participant, which can be reviewed by the Investigator to ensure all responses are completed. | Baseline and Up to Week 12 | 
| Change from Baseline to Week 12 on the MDS-UPDRS Part I | The MDS-UPDRS is a comprehensive 50-question assessment of both motor and non-motor symptoms associated with PD. It features sections that require independent completion by people with PD and their caregivers, and sections to be completed by the same clinician throughout the study. Part I assess non-motor experiences of daily living, non-motor aspects of experiences of daily living (6 items assessed by interview and 7 items by self-assessment). It has 13 items and is further grouped into two parts: Part IA has items associated with behaviors that are assessed and completed by the rater based on information provided by the participant and caregiver. Part IB is self-administered and completed by the participant with or without assistance or input from the caregiver, but independently of the rater. Responses to both IA and IB can be reviewed by the rater to ensure information accuracy and/or provide additional information or clarification of the test items, if necessary. | Baseline and Up to Week 12 | 
| Change from Baseline on the Epworth Sleepiness Scale (ESS) | The ESS is a participant self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0 to 3: would never doze, slight chance of dozing, moderate chance of dozing, and high chance of dozing), their usual chances of dozing off or falling asleep while engaged in eight different activities, such as sitting and reading, watching television, sitting in a public place, etc. Most people engage in those activities at least occasionally, although not necessarily every day. The ESS score (the sum of 8 item scores) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life, or their daytime sleepiness. The questionnaire takes no more than 2 or 3 minutes to answer. | Baseline and at Weeks 2, 4, 8 and 12 | 
| Change from Baseline on the Non-motor Symptoms Scale (NMSS) | The NMSS for Parkinson's Disease is a 30-item rater-based scale to assess the frequency and severity of NMSS in subjects across all stages of PD. The NMSS measures the severity and frequency of non-motor symptoms across 9 dimensions (cardiovascular, including falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal, urinary, sexual function, and miscellany). Responses are to quantify symptoms according to severity (using a scale of 0 to 3) and frequency (using a scale of 0 to 4). It is completed by a rater. | Baseline and at Weeks 4, 8 and 12 | 
| Change from Baseline on the total MDS-UPDRS | The MDS-UPDRS is a comprehensive 50-question assessment of both motor and non-motor symptoms associated with PD. It features sections that require independent completion by people with PD and their caregivers, and sections to be completed by the same clinician throughout the study. The total score of MDS-UPDRS is the sum of Parts I, II and III. | Baseline and at Weeks 2, 4, 8 and 14 | 
| Change from Baseline on the Parkinson's Disease Sleep Scale (PDSS-2) | The PDSS-2 is a 15-item participant-reported outcome measure to assess nocturnal disturbances in PD. It is a 5-point frequency scale (from very often [0] to never [4]), with a total score ranging from 0 to 60, where higher scores indicate greater impairment. | Baseline and at Weeks 4, 8 and 12 | 
| Change from Baseline to Week 12 on the Parkinson's Disease Patient Report of Problems (PD-PROP™) scale | The PD-PROP™ is a series of open-ended questions that asks individuals with PD to rank, in their own words, without restriction of content or length, up to 5 PD-related bothersome problems and their related effects on daily functioning. | Baseline and Up to Week 12 | 
| Change from Baseline to Week 12 on the Personal Wellbeing Patient Report of Problems (PWB-PROP™) scale | The PWB-PROP™ is a series of open-ended questions that asks individuals with PD to rank, in their own words, without restriction of content or length, up to 5 PD-related bothersome problems related to their day-to-day life or personal wellbeing, such as personal, family, financial, social, or other aspects and their related effects on daily functioning. | Baseline and Up to Week 12 | 
| Number of participants reporting treatment emergent adverse events (TEAEs), TEAEs related to moderate or severe intensity and leading to withdrawal of study drug |  | Up to Week 14 | 
| Number of participants reporting serious adverse events (SAEs) |  | Up to Week 14 | 
| Number of participants with clinically significant changes in physical examination, vital signs, electrocardiogram (ECG) finding, laboratory values and Columbia Suicide Severity Rating Scale (C-SSRS) |  | Up to Week 14 | 
| Number of participants reporting abuse related adverse events |  | Up to Week 14 | 
| Number of participants with occurrences of withdrawal symptoms recorded at the follow-up visit |  | At Week 14 | 
| Percentage of completers |  | Up to Week 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parkinson's Disease, CVN424, Progressive neurodegenerative disorder, Parkinson's disease monotherapy