| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| 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 |
| The primary objective of the study is to determine the effect of ND0612 on daily “ON” time without troublesome dyskinesia (defined as the sum of "ON" time without dyskinesia and “ON” time with non-troublesome dyskinesia) using subject-completed “ON/OFF” diary assessments of motor function in subjects with Parkinson’s disease (PD) experiencing motor fluctuations. |
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| E.2.2 | Secondary objectives of the trial |
| Key secondary objective of the study is to determine the effect of ND0612 on daily “OFF” time in subjects with PD experiencing motor fluctuations using subject-completed “ON/OFF” diary assessments of motor function. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| There is an optional pharmacogenetics sub study |
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| E.3 | Principal inclusion criteria |
1. Male and female subjects with PD of any race at least 30 years of age who sign an Institutional Review Board/Ethics Committee–approved informed consent form (ICF).
2. Parkinson’s disease diagnosis consistent with the UK Brain Bank Criteria.
3. Modified Hoehn and Yahr scale in “ON” stage ≤ 3.
4. Subjects must experience motor fluctuations and experience an average of at least 2.5 hours daily (with a minimum of 2 hours every day) in the “OFF” state during the waking hours as confirmed by an adequately completed “ON/OFF” diary over 3 days.
5. Subject treatment should be at least 4 doses/day of LD/ Dopa Decarboxylase Inhibition (DDI) (or at least 3 doses/day of extended release LD/DDI, e.g., Rytary) and at least 400 mg/day of LD, or equivalent according to the conversion table, and, according to the Investigator’s judgement, the subject experiences motor fluctuations that cannot be further improved by adjusting anti-PD medications.
6. Subjects and/or study partners have no impediment that may prevent them from operating the pump system.
7. Subjects and/or study partners must demonstrate ability to keep accurate diary entries of PD symptoms (“ON/OFF” diaries) with at least 75% concordance with the Blinded Efficacy Rater by the end of the diary training session during the Screening Period, including at least 1 "OFF" assessment.
8. Mini Mental State Examination (MMSE) score ≥ 24.
9. Female subjects must be surgically sterile (hysterectomy, bilateral oophorectomy, or tubal ligation); postmenopausal (defined as cessation of menses for at least 1 year); or willing to practice a highly effective method of contraception. All female subjects must be non-lactating and not pregnant and have a negative urine pregnancy test at Screening and at Enrollment (IR1 D1). Female subjects of childbearing potential must practice a highly effective method of contraception (such methods include combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation: oral / intravaginal; transdermal / progestogen-only hormonal contraception associated with inhibition of ovulation: oral / injectable; implantable / intrauterine device [IUD] / intrauterine hormone-releasing system [IUS]/ bilateral tubal occlusion / vasectomized partner/ sexual abstinence) from 1 month before Enrollment (IR D1/V2) until 1 month after the last dose of study treatment. Alternatively, true abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, the subject and sexual partner must comply with the contraceptive requirements detailed above.
10. Willingness and ability to comply with study requirements.
11. Subjects must have a named study partner that signed the ICF.
12. Approval for entry into the study by an independent EAC. |
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| E.4 | Principal exclusion criteria |
1. Atypical or secondary Parkinsonism.
2. Acute psychosis or troublesome hallucinations in the past 6 months.
3. Subjects with clinically significant or unstable medical, surgical, or psychiatric condition or laboratory abnormalities which, in the opinion of the Investigator or the EAC, represents a safety risk, makes the subject unsuitable for study entry, or potentially unable to complete all aspects of the study.
4. Clinically significant ECG abnormalities.
5. Renal or liver dysfunction that may alter drug metabolism including Screening Visit serum levels of creatinine > 1.5 mg/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 × upper limit of normal, and total bilirubin > 2.5 mg/dL.
6. Any malignancy in the 5 years before enrollment, except basal cell carcinoma of the skin, squamous cell carcinoma in situ, or cervical carcinoma in situ that have been successfully treated.
7. Use of subcutaneous (SC) apomorphine injections, sublingual apomorphine, or inhaled LD within 4 weeks before the enrollment.
8. Concomitant therapy or within 28 days before enrollment with: metoclopramide, reserpine, methylphenidate, or amphetamines, well as neuroleptics; exception in case of Quetiapine and Pimavanserin use: (1) allowed only in case it had been used for a period of at least 3 months before enrollment, (2) subject is on stable therapy for at least 3 months (3) underlying psychosis to be under control and anticipating no changes to the dosage of the medication throughout the study.
9. Subjects with a history of alcohol or substance abuse within the past 12 months.
10. Subjects who have taken experimental medications within 30 days before enrollment.
11. Subjects who have previously participated in studies ND0612H-006 and/or ND0612H-012.
12. Subjects who have previously undergone treatment for PD with a surgical intervention (e.g., pallidotomy, thalamotomy, transplantation, deep brain stimulation procedures), gene therapy, Duodopa®/Duopa®, or continuous dopaminergic or apomorphine infusion. Subjects who have discontinued Duodopa®/Duopa® treatment at least 6 months before enrollment and have undergone stoma closure surgery at least 6 months before enrollment, may be included in this study. Subjects who are planning to undergo treatment for PD with a surgical intervention will be enrolled at the Investigator’s discretion.
13. Subjects with severe disabling dyskinesias, based on Investigator's discretion.
14. History of significant skin conditions or disorders (e.g., psoriasis, atopic dermatitis, etc.) or evidence of different lesions (e.g., sunburn, acne, scar tissue, tattoo, open wound, branding, or pigmentation) that, in the Investigator's opinion, would interfere with the infusion of the study drug or could interfere with study assessments.
15. Subjects who do not have sufficient SC tissue for SC infusion treatment.
16. Use of non-selective monoamine oxidase inhibitors (e.g., phenelzine, isocarboxazid, tranylcypromine) within 4 weeks before enrollment.
17. Use of monoamine-depleting agents (e.g., reserpine, tetrabenazine, deutetrabenazine, valbenazine, xenazine) within 4 weeks before enrollment.
18. Current or previous diagnosis of Dopamine Dysregulation Syndrome or Impulse Control Disorder.
19. Impulse control disorder within the past 2 years, if considered clinically significant by the investigator.
20. Subjects who answered "yes" to questions 4 or 5 of the C-SSRS within the last 5 years.
21. Known allergy to the study drug or placebo or any of their excipients.
22. Subjects with narrow angle glaucoma |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change from Baseline to the end of the DBDD Maintenance Period (DB W12) in the mean daily "ON" time without troublesome dyskinesia ("GOOD ON") adjusted to subject's waking hours and normalized to 16 waking hours, based on subject's "ON/OFF" diary assessments on the 3 consecutive days before the visit. "GOOD ON" is defined as the sum of "ON" time without dyskinesia and "ON" time with non-troublesome dyskinesia. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of the DBDD Maintenance Period (DB W12) |
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| E.5.2 | Secondary end point(s) |
| The key secondary efficacy endpoint is the change from Baseline to the end of the DBDD Maintenance Period (DB W12) in the mean daily “OFF” time adjusted to subject’s waking hours and normalized to 16 waking hours, based on subject's “ON/OFF” diary assessments on the 3 consecutive days before the visits. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of the DBDD Maintenance Period (DB W12) |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Israel |
| Russian Federation |
| Serbia |
| Ukraine |
| United States |
| Austria |
| Belgium |
| France |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Slovakia |
| Spain |
| United Kingdom |
| Czechia |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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