Evaluation of Long-Term Safety and Tolerability of Tavapadon in Patients with Parkinson's Disease: A 58-Week Open-Label Multinational Study

The primary objective of this study is to evaluate the **safety** and **tolerability** of long-term administration of tavapadon in subjects with Parkinson's disease. This is clinically relevant as it aims to ensure that the investigational product can be safely used over an extended period, which is crucial for managing a chronic condition like Parkinson's disease.

Secondary objectives include:

• Evaluating the effects of tavapadon on Parkinson's disease symptoms during long-term treatment.
• Assessing the impact of tavapadon on L-Dopa usage.
• Evaluating speech and facial expression characteristics of subjects with Parkinson's disease at US sites only.

The clinical trial involves a total of **516 participants** diagnosed with **Parkinson's disease**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their completion of a prior 27-week double-blind treatment period in related trials, with a requirement to enter this trial within 72 hours of their last visit in the previous trial. The trial population includes individuals who are sexually active and agree to use effective birth control methods or remain abstinent during the study and for four weeks after the last dose. Participants are expected to comply with the trial's protocol, including refraining from any Parkinson's disease medications not permitted by the study. The trial also includes a vulnerable population, indicating that special considerations are in place to ensure their safety and compliance. The selection criteria emphasize the ability to understand the trial's nature and adhere to its requirements, ensuring a committed and informed participant group.

The clinical trial is designed to evaluate the long-term safety and tolerability of **tavapadon** in patients diagnosed with **Parkinson's disease**. This study is structured as an open-label trial, allowing for the observation of the investigational product's effects over a 58-week period. Participants who have completed a prior 27-week double-blind treatment period in related trials are eligible to enroll within 72 hours of their last visit in the previous study. The trial will involve oral administration of tavapadon in tablet form, with a maximum daily dose of 15 mg and a total dose not exceeding 6090 mg over the course of the study.

The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and a final end-of-study visit to assess overall outcomes. The primary endpoints focus on the safety and tolerability of tavapadon, including the nature and frequency of treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, and physical and neurological examinations. Secondary endpoints will assess the effects of tavapadon on Parkinson's disease symptoms, changes in L-Dopa usage, and exploratory analyses of speech and facial expression characteristics.

Participant involvement is expected to last for the full 58-week duration unless conditions arise that necessitate early termination, such as significant non-compliance with the protocol or the occurrence of serious adverse events. The trial is not categorized as low intervention and is classified as a phase III study. The estimated recruitment start date was June 23, 2021, with an anticipated end date of December 12, 2025. Participants are required to adhere to specific protocol requirements, including the use of acceptable birth control methods and refraining from non-permitted Parkinson's disease medications throughout the trial.

The clinical trial involves the administration of **Tavapadon**, a chemical compound developed by Cerevel Therapeutics, LLC. Tavapadon is provided in the form of a **tablet** and is intended for **oral use**. The active substance in Tavapadon is chemically synthesized and is identified by the synonyms PF-06649751 and (-)-1,5-DIMETHYL-6-(2-METHYL-4-((3-(TRIFLUOROMETHYL)-2-PYRIDINYL)OXY)PHENYL)-2,4(1H,3H)-PYRIMIDINEDIONE. The maximum daily dose of Tavapadon is 15 mg, with a total maximum dose of 6090 mg over the course of the trial. The treatment period extends up to 58 weeks, during which the safety and tolerability of long-term administration in subjects with Parkinson's Disease will be evaluated.

Participants in the trial will receive Tavapadon tablets, which are not formulated for pediatric use. The trial does not involve any orphan drug designation. The administration schedule requires participants to adhere to the prescribed dosage and frequency, with compliance monitored throughout the study. No additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. The trial's primary objective is to assess the safety and tolerability of Tavapadon in the target population.

The efficacy of Tavapadon in the treatment of **Parkinson's Disease** will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on evaluating the safety and tolerability of long-term administration of Tavapadon. This includes monitoring the nature, frequency, and temporality of treatment-emergent adverse events (TEAEs), both non-serious and serious, as well as abuse-related adverse events and those related to mental health issues (MHIs). Additional primary endpoints include the frequency of discontinuations, assessments using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP RS), the Epworth Sleepiness Scale (ESS), the Columbia-Suicide Severity Rating Scale (C-SSRS), and the Subjective Mental Well-being Questionnaire (SMWQ). Clinical laboratory evaluations, vital signs, physical and neurological examinations, and electrocardiograms (ECGs) will also be conducted.

Secondary endpoints aim to evaluate the effects of Tavapadon on Parkinson's Disease symptoms during long-term treatment. This will be measured by changes from baseline in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I, II, and III scores, and changes in the Hauser diary for subjects requiring daily L-Dopa or equivalent therapy at enrollment. Additionally, changes from baseline in the EQ-5D-5L index and visual analog scale (VAS) scores will be assessed. The trial will also evaluate the effects of Tavapadon on L-Dopa usage by measuring changes from baseline in L-Dopa usage. Exploratory analyses of speech and facial expression characteristics will be conducted using audio and video data collected from remote digital testing through an interactive application platform on the subject's personal mobile device.