A Sequential Two-Part, Open-Label Study in Healthy Male and Female Subjects

Study Overview
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Brief Summary
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An Open-Label Study in Healthy Male and Female Subjects to Identify the Concentration that Provides Optimal Bioavailability of Levodopa Infused Subcutaneously via a Pump System; and to Compare the Bioavailability of Levodopa/Carbidopa Solution to that of Levodopa/Carbidopa Intestinal Gel (LCIG), Infused via a Naso-Jejunal Tube

Detailed Description
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Part 1: This is a single centre, open-label design with 2 study arms (ND0612H and ND0612L), in 24 subjects that will receive the ND0612L or ND0612H regimens. Part of the subjects will also participate in Part 2 of the study. Within each study arm, subjects will receive 3 doses of the investigational LD/CD solution for subcutaneous (SC) infusion. Study drug will be administered for 24 -30 hours as a subcutaneous (SC) infusion to the lower abdomen. Then subjects will be readmitted for Part 2. Part 2: This is a single centre, open-label design with 3 treatment arms to which 15 subjects who completed the ND0612H arm of Part 1 ND0612-005a will be allocated in a randomised manner. Within each treatment arm subjects will receive 2 out of 3 doses of LCIG infused for 16 hours directly to the jejunum. Subjects will be discharged from the clinic 24 hours after the end of the last infusion

Official Title
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1) To Identify the Concentration of CD That Provides Optimal Bioavailability of a Concomitant Fixed Concentration of LD Infused SC Continuously; 2) To Compare the Bioavailability of the Optimal LD/CD Solution to That of LD/CD Intestinal Gel

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: ND0612
* Drug: LCIG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria: Part 1 ND0612-005a: Healthy males or non-pregnant, non-lactating healthy females Age 40 to 65 years of age Body mass index of 18.0 to 32.0 kg/m2 or, if outside the range, considered not clinically significant by the investigator Must be willing and able to communicate and participate in the whole study (Part 1 only for subjects assigned to ND0612L and Part 1 and Part 2 for subjects assigned to ND0612H) Must provide written informed consent Area of administration to be evaluable for local skin reaction (normal skin without skin burns, scars or large tattoos in the area of administration) Must agree to use an adequate method of contraception Inclusion Criteria: Part 2 ND0612-005b: 1. Subjects who were dosed with ND0612H (any replacements subjects enrolled in Part 2 will be dosed with the optimal LD/CD concentration of ND0612H after completion of Part 2). Exclusion Criteria: Participation in a clinical research study within the previous 3 months Subjects who are study site employees, or immediate family members of a study site or sponsor employee Subjects who have previously been enrolled in this study History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine) Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening Females of childbearing potential who are pregnant or lactating (female subjects must have a negative urine pregnancy test at admission) Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1) Positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1) Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening History of cardiovascular, renal, hepatic, chronic respiratory or GI disease as judged by the investigator Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active Donation or loss of greater than 400 mL of blood within the previous 3 months Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than 4 g per day paracetamol, hormone replacement therapy and hormonal contraception) or herbal remedies in the 14 days before IMP administration (See Section 11.4). Exceptions may apply on a case by case basis if considered not to interfere with the objectives of the study as agreed by the PI and sponsor's medical monitor Use of any non-selective monoamine oxidase (MAO) inhibitors within 2 weeks of screening History or presence of glaucoma History or presence of suspicious undiagnosed skin lesions or a history of melanoma Any history of psychoses or seizure Known hypersensitivity to Sinemet® or domperidone or any of the excipients Any history or presence of Prolactin-releasing pituitary tumour (prolactinoma) Any medical history of GI haemorrhage, mechanical obstruction or perforation Any history of moderate or severe hepatic impairment Subjects with clinically significant liver function tests Subjects with QTc >450 ms at screening Subjects with significant electrolyte disturbances Subjects with any underlying cardiac disease Subjects who have received QT-prolonging drugs or potent cytochrome P450 (CYP) 3A4 inhibitors within 4 weeks of screening ND0612H arm only: Subjects who have sinus problems ND0612H arm only: Subjects who have regular heartburn and/or indigestion ND0612H arm only: Subjects who have had abdominal (bowel) surgery ND0612H arm only: Any clinically significant findings observed during naso-jejunal tube placement as determined by the endoscopist Failure to satisfy the investigator of fitness to participate for any other reason

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ND0612L (LD/CD solution)<br>3 doses of the investigational ND0612L (LD/CD solution) for subcutaneous (SC) infusion 0.24ml per hour. | Drug: ND0612<br>* Subcutaneous solution<br>* Other names: (Levodopa-Carbidopa solution);|
| Experimental: ND0612H (LD/CD solution)<br>3 doses of the investigational ND0612H (LD/CD solution) for subcutaneous (SC) infusion 0.64ml per hour. | Drug: ND0612<br>* Subcutaneous solution<br>* Other names: (Levodopa-Carbidopa solution);|
| Active Comparator: LCIG (Levodopa-carbidopa intestinal gel)<br>Active Comparator: LCIG subjects who completed the ND0612H arm will be administered with 3 doses of LCIG, directly to the jejunum. | Drug: LCIG<br>* Intrajejunal Gel<br>* Other names: (Levodopa-Carbidopa Intestinal Gel);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximal plasma concentration) of CD for different doses of CD | Pre-infusion and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 17, 20, 22, 24, 25, 26, 27, 28, 29, 30, 31, and 32 hours after commencing the ND0612 infusion on Days 1, 3 and 5. | 6 days | 
| AUC (area under the curve) of CD for different doses of CD | Pre-infusion and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 17, 20, 22, 24, 25, 26, 27, 28, 29, 30, 31, and 32 hours after commencing the ND0612 infusion on Days 1, 3 and 5. | 6 days | 
| Cmax (maximal plasma concentration) of LD and CD for ND0612 vs. LCIG | Pre-infusion and at 1, 2, 3, 4, 6, 9, 12, 14, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after commencing the LCIG infusion on Days 1 and 3. | 4 days | 
| AUC (area under the curve) of LD and CD for ND0612. LCIG | Pre-infusion and at 1, 2, 3, 4, 6, 9, 12, 14, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after commencing the LCIG infusion on Days 1 and 3. | 4 days |