A Clinical Study of Efficacy, Safety, Tolerability and PK of ND0612H in Subjects With Advanced Parkinson's Disease

Study Overview
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Brief Summary
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This is a multicenter, parallel-group, rater-blinded, randomized clinical study in subjects with advanced PD investigating the efficacy, PK, safety and tolerability of continuous SC infusion of 2 dosing regimens of ND0612H, a solution of LD/CD delivered via a pump system as a continuous SC infusion, compared to standard oral LD/CD. After screening, subjects will undergo 1 day of standard oral LD/CD inpatient dosing followed by 2 days of inpatient treatment with 1 of 2 randomly allocated (1:1 randomization ratio) dosing regimens of ND0612H continuous SC infusion. Subjects will then continue on a maintenance dose of the assigned ND0612H dosing regimen for the next 25 days. A safety visit will be performed 4 weeks after the last SC administration of the study drug for a total of about 2.5 months of participation for each subject enrolled into the trial.

Detailed Description
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This phase IIa randomized, controlled, parallel-group study will be conducted in 36 subjects with advanced PD who are treated with oral LD/CD at a stable dose and have predictable morning OFF periods and at least 2.5 hrs of daily OFF periods. The study will investigate the efficacy, PK, safety and tolerability of continuous SC infusion of 2 dosing regimens of ND0612H. Regimen 1 will employ continuous infusion for 24 hrs using a low infusion rate at night and a higher rate at daytime with supplemental administration of oral immediate release (IR) LD/CD in the mornings. During the inpatient period of about 3 days, the site staff will manage the administration and replacement of the infusions. On Day 4 subjects will be discharged home after they and their study partners have received training on the administration of the infusion. Subjects will then continue on a maintenance dose of the assigned ND0612 dosing regimen for the next 25 days. A safety visit will be performed 4 weeks after the last SC administration of the study drug.

Official Title
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A Multicenter, Parallel-group, Rater-blinded, Randomized Clinical Study Investigating the Efficacy, Safety, Tolerability and Pharmacokinetics of 2 Dosing Regimens of ND0612H [ ] in Subjects With Advanced Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: ND0612 (Levodopa/Carbidopa solution)
* Drug: ND0612 (Levodopa/Carbidopa solution) + morning oral IR-LD/CD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female PD subjects of any race aged 30 to 80 years who sign an Institutional Review Board/Ethics Committee (IRB/EC)-approved informed consent form (ICF). PD diagnosis consistent with the UK Brain Bank Criteria. Modified Hoehn & Yahr scale in ON state of stage ≤3. Taking at least 4 doses/day of LD (or at least 3 doses/day of Rytary) and taking, or have attempted to take, at least 2 other classes of anti-PD medications in a therapeutic dose for at least 30 consecutive days each. Subjects must be stable on their anti-PD medications for at least 30 days before Day 1. Subjects may have had prior exposure to SC apomorphine injections/infusion but must have stopped administration at least 4 weeks before the screening visit. Treatment with apomorphine is prohibited during the entire ND0612H treatment period. Must have a minimum of 2.5 hrs of OFF time per day with predictable early morning OFF periods as estimated by the subject. Must have predictable and well defined early morning OFF periods with a good response to LD for treatment of the early morning OFF in the judgement of the investigator. Mini Mental State Examination (MMSE) score >26. No clinically significant medical, psychiatric or laboratory abnormalities which the investigator judges would be unsafe or non-compliant in the study. Female subjects must be surgically sterile, postmenopausal (defined as cessation of menses for at least 1 year), or willing to practice a highly effective method of contraception. All female participants must be non-lactating and non-pregnant and have a negative urine pregnancy test at Screening and at Baseline. Female subjects of childbearing potential must practice a highly effective method of contraception (e.g., oral contraceptives, a barrier method of birth control [e.g., condoms with contraceptive foams, diaphragms with contraceptive jelly], intrauterine devices, partner with vasectomy), 1 month before enrollment, for the duration of the study, and 3 months after the last dose of study drug. Willingness and ability to comply with study requirements Exclusion Criteria: Atypical or secondary parkinsonism. Acute psychosis or hallucinations in past 6 months. Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the Investigator or the eligibility reviewer, makes the subject unsuitable for study entry or potentially unable to complete all aspects of the study. Prior neurosurgical procedure for PD, or duodopa treatment. Subjects with a history of drug abuse or alcoholism within the past 12 months. Clinically significant ECG rhythm abnormalities. Renal or liver dysfunction that may alter drug metabolism including: serum creatinine >1.3 mg/dL, serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit of normal (ULN), total serum bilirubin >2.5 mg/dL. Subjects who are not willing to operate the pump system.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 1<br>Dosing Regimen 1 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 24 hours. | Drug: ND0612 (Levodopa/Carbidopa solution)<br>* The total daily dose of levodopa/carbidopa 720/90 mg. Device: CRONO TWIN pump system.<br>* Other names: Regimen 1 - 24-hr infusion;|
| Experimental: ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 2<br>Dosing Regimen 2 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 14 hours. Infusion started at wake-up time supplemented with an oral IR LD/CD tablet. | Drug: ND0612 (Levodopa/Carbidopa solution) + morning oral IR-LD/CD<br>* The total daily dose levodopa/carbidopa from ND0612 538/67 mg. Morning dose of oral IR-LD/CD 150/15 mg. Device: CRONO TWIN pump system.<br>* Other names: Regimen 2 - 14-hr infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Daily OFF Time | Based on Parkinson's disease symptom assessment, ON time is when there is good response to medication and few symptoms. OFF time is when no there is no response to medication and significant motor symptoms. An ON/OFF Log was completed by a blinded rater starting before the first dose of LD/DDI and following the first dose at 30 min intervals for 8 hrs. The changes in OFF time as hours (normalized to 16 hrs of awake time) during the 8 hrs of data collection were estimated. Negative change from baseline for OFF time indicates improvement. | Baseline to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Subjects With Full ON at Approximately 08:00 and Approximately 09:00, as Determined by the Subject | Based on Parkinson's disease symptom assessment, ON time is when there is good response to medication and few symptoms. OFF time is when no there is no response to medication and significant motor symptoms. Subjects were asked to indicate when exactly in their opinion they had turned to full ON (i.e. an ON response comparable to the ON response to standard oral LD/DDI treatment). Higher percentage of subjects with full ON on Day 28 indicates improvement. | Baseline to Day 28 | 
| Change in Daily Good ON Time as Assessed by a Blinded Rater | Based on Parkinson's disease symptom assessment, ON time is when there is good response to medication and few symptoms. OFF time is when no there is no response to medication and significant motor symptoms. Good ON time means ON time without troublesome dyskinesia (involuntary muscle movement), defined as the sum of ON time without dyskinesia and ON time with non-troublesome dyskinesia. An ON/OFF Log was completed by a blinded rater starting before the first dose of LD/DDI and following the first dose at 30 min intervals for 8 hrs. Daily total scores were normalized to 16 hours of awake time. Positive change from baseline for ON time without dyskinesia and for Good ON time, and a negative change in ON time with moderate or severe (troublesome) dyskinesia indicates improvement. | Baseline to Day 28 | 
| Change in Morning UPDRS Part III (Motor) Scores | The Unified Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. UPDRS part III (motor) score is calculated as the sum of the individual UPDRS items 18-31, each of which are measured on a 5-point scale (i.e., 0 is normal and 4 indicates a severe abnormality). UPDRS part III was done as a motor examination on Day 1 before the first dose of standard oral LD/DDI and at the same time on Day 28. The range of score values is from 0 to 132. Higher scores correlate with greater motor impairment. | Baseline to Day 28 | 
| Change in UPDRS Part II (ADL) Scores | The Unified Parkinson's disease rating scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The UPDRS Part II (activity of daily living) score was calculated as the sum of the individual UPDRS items 5-17. The Part II score is the sum of the answers to the 13 questions that comprise Part II, each of which are measured on a 5-point scale (i.e., 0 is normal and 4 indicates a severe abnormality). The range of score values is from 0 to 52. Higher scores correlate with greater impairments for daily activities. | Baseline to Day 28 | 
| CGI-Improvement (CGI-I) Score as Assessed by Investigator | Global improvement was rated by the investigator or designee using Clinical Global Impression of Improvement (CGI-I). The CGI-I employs a 7-point scale with 1 being very much improved and 7 being very much worse for improvement rating. | Baseline to Day 28 | 
| Change in PDSS-2 Total Score | The quality of night sleep was rated by the subjects using the Parkinson's Disease Sleep Scale (PDSS)-2, which includes questions addressing 15 commonly reported symptoms associated with sleep disturbance in PD. Each question is assessed from 0 (Always) to 10 (Never). The total score values range from 0 to 150. Higher scores indicate a lower quality of sleep, i.e., a reduction in the score indicates an improvement in sleep quality. | Baseline to Day 27 | 
| Change in PDQ-39 Summary Index and the 8-dimension Scores | Subjects were requested to rate their quality of life using the Quality of Life in Parkinson's Disease (PDQ)-39, a 39-item, self-administered questionnaire with 8 discrete dimensions (mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort.). The PDQ-39 Summary Index is the sum of the dimension scores divided by the number of dimensions. The total score values range from 0 to 100%. Higher scores indicate a worse quality of life. | Baseline to Day 27 |