Efficacy, Safety, and Tolerability of Continuous Subcutaneous ND0612 Infusion Versus Oral Immediate-Release Carbidopa-Levodopa in Parkinson's Disease with Motor Fluctuations

The primary objective of this study is to evaluate the effect of **ND0612** on daily "ON" time without troublesome dyskinesia in subjects with **Parkinson's disease** experiencing motor fluctuations. This is assessed using subject-completed "ON/OFF" diary assessments of motor function. The clinical relevance of this objective lies in its potential to improve the quality of life for patients by increasing periods of effective motor function without the burden of dyskinesia.

Secondary objectives include determining the effect of ND0612 on:

• Daily "OFF" time using subject-completed "ON/OFF" diary assessments.
• Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II (Motor Aspects of Experiences of Daily Living).
• Patient Global Impression of Change (PGIC).
• Clinical Global Impression of Improvement (CGI-I).
• MDS-UPDRS Part III (Motor Examination), measured in the "OFF" state or approximately 15 minutes before the next encapsulated oral dose.
• Daily "ON" time without dyskinesia using subject-completed "ON/OFF" diary assessments.
• Proportion of responders in "OFF" time.
• Parkinson's disease Quality of Life based on the 39-item PD Quality of Life questionnaire (PDQ-39).
• The Parkinson’s Disease Sleep Scale (PDSS-2).

The clinical trial involves a total of **225 participants** diagnosed with **Parkinson's disease**, aiming to evaluate the effect of ND0612 on daily "ON" time without troublesome dyskinesia. The study population includes both male and female subjects, aged 30 years and older, who are experiencing motor fluctuations. Participants were selected based on their ability to maintain accurate "ON/OFF" diaries of motor function, with a Mini Mental State Examination (MMSE) score of 24 or higher. The trial includes individuals who are not pregnant or lactating, and female participants are required to use effective contraception methods. Participants must have a study partner and demonstrate willingness and ability to comply with study requirements. The trial population is characterized by a diverse age range and includes individuals who are considered a vulnerable population. The selection criteria ensure that participants have a consistent diagnosis of Parkinson's disease according to the UK Brain Bank Criteria and experience significant motor fluctuations that cannot be further improved by adjusting anti-PD medications. Lifestyle considerations such as the ability to operate the pump system and adherence to medication regimens are also taken into account.

The clinical trial is designed as a **randomized**, **double-blind**, **double-dummy**, parallel group study to evaluate the efficacy, safety, and tolerability of continuous subcutaneous ND0612 infusion compared to oral IR-LD/CD in subjects with **Parkinson's disease** experiencing motor fluctuations. The trial is expected to run from February 2020 to May 2027, with the primary objective being to assess the effect of ND0612 on daily "ON" time without troublesome dyskinesia. The study involves multiple visits, starting with a screening visit to determine eligibility based on criteria such as age, ability to maintain accurate "ON/OFF" diaries, and a diagnosis consistent with the UK Brain Bank Criteria.

Participants will be involved in the study for a maximum treatment period of 59 weeks. The trial includes a baseline visit, followed by regular follow-up visits to monitor the primary and secondary endpoints, which include changes in "ON" and "OFF" times. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted. Conditions for early termination from the study include non-compliance with study requirements or adverse events that compromise participant safety.

The trial employs a **controlled** methodology, with participants receiving either the active treatment or a placebo, ensuring that neither the participants nor the investigators know which treatment is being administered. This design helps to eliminate bias and provides a robust comparison of the treatment's effects. The study's endpoints are measured using subject-completed "ON/OFF" diary assessments, which are crucial for evaluating the treatment's impact on motor function. Participants are required to have a study partner to assist with diary entries and ensure adherence to the study protocol.

The clinical trial involves the administration of **ND0612**, an experimental medication formulated as a **solution for infusion in an administration system**. This medication contains the active substances **carbidopa** and **levodopa**, both of which are of chemical origin. ND0612 is delivered via a **subcutaneous** route using an infusion pump system, which has been CE marked. The maximum daily dose of ND0612 is 720 mg, with a total maximum dose of 1,261,310 mg over a treatment period of up to 59 days. The infusion is continuous, ensuring a steady delivery of the medication to manage motor fluctuations in subjects with Parkinson's disease.

The study also includes a **placebo** for ND0612, which is a solution for infusion intended for subcutaneous use. The placebo contains sodium phosphate dibasic anhydrous, sodium phosphate monobasic dihydrate, L-arginine, and ascorbic acid. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment or the placebo.

Additionally, the trial utilizes **IR-LD/CD**, a comparator treatment in the form of a **tablet**. This medication also contains the active substances carbidopa and levodopa, and is administered orally. The IR-LD/CD serves as a standard-of-care therapy, providing a basis for comparison with the experimental ND0612 treatment. The maximum treatment period for IR-LD/CD is 18 days, and it is used to evaluate the efficacy and safety of ND0612 in comparison to traditional oral therapy.

Two types of **placebo capsules** are used in the study: one for LD/CD capsules (white) and another for LD/CD capsules (grey). The white placebo capsules are composed of a yellow placebo tablet and pharmacopeial grade microcrystalline cellulose (Avicel PH-102) filled into size DB AA white opaque gelatin capsules. The grey placebo capsules are composed of pharmacopoeia grade microcrystalline cellulose (Avicel PH-102) filled into size DB AA grey opaque capsules. These placebos are used to maintain the double-dummy design of the trial, ensuring that all participants receive both an infusion and an oral treatment, whether active or placebo, to preserve blinding and study integrity.

The efficacy of the clinical trial will be assessed by evaluating the effect of ND0612 on daily "ON" time without troublesome dyskinesia in subjects with Parkinson's disease experiencing motor fluctuations. The primary endpoint is the change from Baseline to the end of the Double-Blind Double-Dummy (DBDD) Maintenance Period in the mean daily "ON" time without troublesome dyskinesia, adjusted to the subject's waking hours and normalized to 16 waking hours. This assessment will be based on subject-completed "ON/OFF" diary entries over three consecutive days prior to the visit.

The key secondary efficacy endpoint involves measuring the change from Baseline to the end of the DBDD Maintenance Period (DB Week 12) in the mean daily "OFF" time, also adjusted to the subject's waking hours and normalized to 16 waking hours. This will similarly be based on "ON/OFF" diary assessments conducted over three consecutive days before the visits. These diary assessments are crucial tools for capturing the fluctuations in motor function experienced by subjects with Parkinson's disease.