| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10034005 |
| E.1.2 | Term | Parkinson's disease and parkinsonism |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess relative bioavailability of levodopa (LD) administered as ND0612,
infused subcutaneously (s.c.), with orally co-administered LD/CD (Test)
versus LD administered as carbidopa-levodopa enteral suspension (CLES),
infused via a permanent percutaneous endoscopic gastrostomy with jejunal
tube (PEG-J) or a naso-jejunal tube (Reference). |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of study treatments.
• To assess the pharmacokinetics (PK) of LD and carbidopa (CD) derived from ND0612 plus oral LD/CD or from CLES. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or non-pregnant, non-lactating female patient with idiopathic PD currently responding to LD therapy, aged ≥30 years.
2. Female patients must have a negative pregnancy test at screening and at admission.
3. Patients must have a body mass index (BMI) within the range of 18.5 – 35 kg/m2, where BMI = body weight (kg) / height (m2) at screening.
4. Must be willing and able to communicate and participate in the whole study.
5. Must provide written informed consent.
6. Area of administration to be evaluable for local skin reaction (normal skin without skin burns, scars or large tattoos in the area of administration).
7. Must agree to use an adequate method of contraception (per local independent ethics committee requirements).
For Cohort 1 only:
8. Currently treated with CLES via PEG-J at a dose of at least 800 mg LD/day and up to 2200 mg LD/day.
For Cohort 2 only:
8. Stable PD treatment for at least 30 days before screening with at least 4 doses/day of LD/DOPA-decarboxylase-inhibitor (or at least 3 doses/day of Rytary or Numient) or for whom the conversion to oral LD/CD IR tablets will lead to a LD dose between 800 and 2200 mg/day and according to Investigator judgment motor fluctuations cannot be further improved by adjusting oral LD medication.
9. Must have a minimum of 2 hours of “OFF” time per day as estimated by the patient. |
|
| E.4 | Principal exclusion criteria |
1. Previously unable to tolerate ND0612 and/or have experienced intolerable adverse drug reactions associated with its use or serious adverse reaction.
2. Atypical or secondary parkinsonism.
3. Acute psychosis or hallucinations within the past 6 months prior to screening.
4. Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the Investigator, makes the patient unsuitable for study entry or potentially unable to complete all aspects of the study.
5. Any malignancy in the 5 years prior to randomization (excluding basal cell carcinoma of the skin, transitional cell carcinoma in situ or cervical carcinoma in situ that have been successfully treated).
6. Positive serum serology for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV) at the screening visit.
7. Patients with a history of drug abuse or alcoholism within the past 12 months prior to screening or positive drugs of abuse or alcohol test result at the screening visit and/or on admission.
8. Routine 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).
9. Clinically significant electrocardiogram (ECG) rhythm abnormalities.
10.Renal or liver dysfunction that may alter drug metabolism including: serum creatinine >1.5 mg/dL, serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit of normal (ULN), total serum bilirubin >2.5 mg/dL.
11. Patients who have previously been enrolled in this study.
12. Patients who do not have suitable veins for multiple venipunctures / cannulation as assessed by the Investigator at the screening visit.
13. Psychiatric, neurological or behavioral disorders that may interfere with the conduct or interpretation of the study, including dementia, or patients who are considered to be violent or at suicidal risk by the Investigator.
14. Presence or history of clinically significant allergy requiring treatment, as judged by the Investigator or serious hypersensitivity to any drug or the formulation excipients. Hay fever is allowed unless it is active.
15.Blood loss of greater than 500 mL within the previous 3 months prior to first dosing.
16. Current use of the dopamine agonist pramipexole within 1 month before Day 1.
17. Intake of domperidone within 2 days before Day 1 or planned to be taken before last PK sampling.
18. Intake of
- Catechol-O-methyltransferase (COMT) inhibitors as entacapone, opicapone or agents including them (i.e. Stalevo)
- DDCI other than CD (i.e. beserazide, methyldopa [Aldomet, Aldoril, Dopamet, Dopegyt], DL-x-Difluoromethyl DOPA (DFMD), 3',4',5,7- Tetrahydroxy-8-methoxyisoflavone)
- Rytary or Numient within 2 days prior randomization. Patients who are taking any of these medications at screening should be converted to an equivalent dose of oral LD/CD IR tablets as detailed in Table 4).
19. Intake of donepezil (Aricept) within 14 days before Day 1.
20. Intake of trihexylphenidyl (benzhexole) within 2 days before Day 1.
21. Intake of multivitamins with iron (e.g. Pimavanserin) within 8 hours prior to start of study treatment on Day 1
22. Intake of calcium carbonate, sodium carbonate, aluminum hydroxide, aluminum carbonate, magnesium hydroxide or magnesium oxide within 8 hours prior to start of study treatment on Day 1
23.Current participation in a clinical study with an investigational compound or past participation within the last 30 days or within less than 5 times the half-life of the investigational product administered in the clinical research study, whichever is longer.
24.Any PD-related feature or symptom that could interfere with the study conduct and results as assessed by the Investigator.
25.History or presence of narrow-angle glaucoma.
26.Any history or presence of prolactin-releasing pituitary tumor (prolactinoma).
27. Patients who are not willing to adhere to the protocol-prescribed study
restrictions.
28. Patients who are employees of a study site or Sponsor, or immediate family members thereof.
29. The patient is a vulnerable patient, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
Cohort 2 only:
30.Contraindications for insertion of a naso-jenunal tube, e.g. recent nasal surgery, nasal fractures, upper gastrointestinal obstruction, esophageal atresia/stenosis, history of significant upper gastrointestinal bleeding,
esophageal varices or coagulation abnormalities.. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For LD:
• Cmax and AUC24 the concentrations measured with the following 24-hours periods will be included into the calculation of AUC24:
for ND0612 16-hours regimen (Test 1): from start of dosing until 24 hours post start of dosing (06:00 to 06:00);
for ND0612 24-hours regimen (Test 2): from start of second low rate period until end of third high rate period (20:00 to 20:00);
for CLES regimen: from start of dosing until 24 hours post start of dosing (06:00 to 06:00) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For LD:
• Cmax and AUC24 the concentrations measured with the following 24-hours periods will be included into the calculation of AUC24:
for ND0612 16-hours regimen (Test 1): from start of dosing until 24 hours post start of dosing (06:00 to 06:00);
for ND0612 24-hours regimen (Test 2): from start of second low rate period until end of third high rate period (20:00 to 20:00);
for CLES regimen: from start of dosing until 24 hours post start of dosing (06:00 to 06:00) |
|
| E.5.2 | Secondary end point(s) |
For LD:
• AUC16 (i.e. 6:00-22:00 for CLES and ND0612 16-hours and 6:00-22:00 last day of administration for ND0612 24-hours)
• Cavg, (AUCt/t represents the mean concentration within the dosing period)
• End points assessing the variability of the concentrations: these endpoints will be assessed both during the expected stable phase as defined in the SAP. For the piecewise approach, the end points are calculated separately for the 2 or 3 hour periods, as defined in the SAP.
o Fluctuation Index (FI; ([Cmax-Cmin])/[Cavg])
o Peak to Trough (PtT = Cmax/Cmin)
o Swing ([Cmax-Cmin]/[Cmin])
• t1/2 (if data permit)
• lambda z (if data permit)
• tmax
• Ctrough (last planned PK sample in a period)
For CD:
• Cmax
• AUC24
• Ctrough (last planned PK sample in a period)
For 3-OMD:
• Cmax
• AUC24
• Ctrough (last planned PK sample in a period) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For LD:
• AUC16 (i.e. 6:00-22:00 for CLES and ND0612 16-hours and 6:00-22:00 last day of administration for ND0612 24-hours)
• Cavg, (AUCt/t within the dosing period)
• End points assessing the variability of the concentrations: these endpoints will be assessed both during the expected stable phase as defined in the SAP. For the piecewise approach, the end points are calculated separately for the 2 or 3 hour periods, as defined in the SAP.
• Ctrough (last planned PK sample in a period)
For CD:
• Cmax
• AUC24
• Ctrough (last planned PK sample in a period)
For 3-OMD:
• Cmax
• AUC24
• Ctrough (last planned PK sample in a period) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| France |
| Italy |
| Netherlands |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS, completion of the last patient’s 4-weeks’ return
visit (follow-up visit) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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