E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with advanced Parkinson's disease |
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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 assess the long term safety (systemic and local) and tolerability of continuous SC infusion of ND0612. Assessment will be based on adverse events (AEs), with a focus on adverse events of special interest (AESI), i.e., infusion site reactions, cases of hypersensitivity, polyneuropathy.
Tolerability will be assessed based on percentage of subjects that complete the 12 month treatment period of the study and the percentage of subjects who discontinue from the 12-month treatment period due to an AE. |
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E.2.2 | Secondary objectives of the trial |
Further Safety Objectives: (assessed based on 12 month data):
- To further assess the safety and tolerability of ND0612 including suicidality (Columbia – Suicide Severity Rating Scale [C-SSRS]), Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP RS), excessive daytime sleepiness (Epworth Sleepiness Scale [ESS]), vital signs, laboratory tests and electrocardiogram (ECG) data.
Further Safety Objectives assessed based on data up to 60 months:
- To assess the long-term safety (systemic and local) and tolerability of continuous SC infusion of ND0612. Assessment will be based on AEs, with a focus on AESI, i.e., infusion site reactions, cases of hypersensitivity, polyneuropathy. |
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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 |
Pharmacokinetic sub-study for a clinical study protocol titled: A
multicenter, international, open-label, safety study of ND0612, a solution
of levodopa/carbidopa, delivered via a pump system as a continuous
subcutaneous infusion in subjects with advanced Parkinson's Disease
(BeyoND)
Core Protocol Version: 7.0
Date of PK sub-study Protocol: 04-Mar-2019 |
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E.3 | Principal inclusion criteria |
To be eligible for study entry subjects in Cohort 1 (previously completed the treatment period in protocol ND0612H-006 within one month prior to enrolling to ND0612H-012) must satisfy all of the following criteria:
1.Subject is able to, and has signed an Institutional Review Board/Ethics Committee (IRB/EC)-approved informed consent form (ICF).
2.Subject has completed the treatment period of study ND0612H-006 not more than one month prior to enrolling in ND0612H-012.
3.Willing and able to administer the SC infusion alone or with the assistance of a study partner and able to comply with the study specific procedures.
To be eligible for study entry subjects in Cohort 2 (ND0612 naïve subjects and subjects who completed treatment in a ND0612 clinical study more than one month before screening) must satisfy all of the following criteria:
1.Male and female PD subjects of any race aged at least 30 years who sign an IRB/EC-approved ICF.
2.PD diagnosis consistent with the UK Brain Bank Criteria.
3.Modified Hoehn & Yahr scale in “ON” state of stage ≤3.
4.Taking at least 4 doses/day of LD/DDI (or at least 3 doses/day of Rytary) and taking, or have attempted to take, at least one other PD treatment for at least 30 days.
5.Subjects must be stable on their anti-PD medications for at least 30 days before Day 1.
6.Subjects may have had prior exposure to SC apomorphine injections/infusion but must have stopped continuous apomorphine administration at least 4 weeks before the screening visit. Treatment with apomorphine is prohibited during the entire ND0612 treatment period.
7.Must have a minimum of 2 hrs of “OFF” time per day with predictable early morning “OFF” periods as estimated by the subject.
8.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.
9.Mini Mental State Examination (MMSE) score ≥ 26.
10.No clinically significant medical, psychiatric or laboratory abnormalities which the investigator judges would be unsafe or non-compliant in the study.
11.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 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, 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. 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.
12.Willing and able to administer the SC infusion alone or with the assistance of a study partner after a screening period up to 40 days and willing and able to comply with study requirements.
13. Subjects should have a named study partner. |
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E.4 | Principal exclusion criteria |
Subjects in Cohort 1 and Cohort 2 will be excluded from the study if one or more of the following criteria listed below are applicable.
1.Previously unable to tolerate ND0612 and/or have experienced intolerable adverse drug reactions associated with its use, regardless of the dosing regimen administered.
For Cohort 2 the following exclusion criteria apply:
1.Atypical or secondary parkinsonism.
2.Acute psychosis or hallucinations in past 6 months.
3.Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the Investigator makes the subject unsuitable for study entry or potentially unable to complete all aspects of the study.
4. Any malignancy in the 5 years prior to randomization (excluding basal cell carcinoma of the skin or cervical carcinoma in situ that have been successfully treated treatment.
5. Positive serum serology for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV) at the screening visit.
6. Prior neurosurgical procedure for PD, or Duodopa treatment
7. Subjects with a history of drug abuse or alcoholism within
the past 12 months.
8. Clinically significant ECG rhythm abnormalities.
9. 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.
10. Current participation in a clinical trial with an investigational product or past participation within the last 30 days before Day 1.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in this study is a safety endpoint assessing the long-term safety (systemic and local) and tolerability of continuous SC infusion of ND0612 throughout the 12-month treatment period.
Assessments, which constitute the primary endpoint of this study, will be based on AEs, with a focus on AESI, which will include infusion site reactions, hypersensitivity and polyneuropathy. Visual Analogue Scale (VAS) for pain assessment will also be used as primary measure. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary safety endpoints to be assessed for the 12-month treatment period include:
•Assessment of suicidal behavior and ideation (C-SSRS responses, including the number of subjects experiencing at least 1 event of suicidal ideation, at least 1 event of suicidal behavior, at least 1 event of suicidal ideation or behavior and self-injurious behavior without suicidal intent, changes from Baseline in C-SSRS categories (No Suicidal Ideation or
Behavior, Suicidal Ideation and Suicidal Behavior) and changes from Baseline in C-SSRS suicidal ideation)
•Assessment of impulsive compulsive behavior (QUIP RS total scores)
•Epworth Sleepiness Scale (ESS total score)
•Vital signs with a focus on orthostatic BP (possible dopaminergic side effect)
•Laboratory data (hematology and biochemistry), including dipstick urinalysis results evaluation
•12-lead ECG parameters, including ECG interpretation of clinical significance
•Physical examination
•Prior and concomitant medications
The exploratory efficacy endpoints assessed for 12 months of Treatment are:
•Change in daily "ON" time without troublesome dyskinesia (defined as the sum of "ON" time without dyskinesia and "ON" time with non-troublesome dyskinesia) based on home "ON-OFF" diaries
•Change in daily "OFF" time from Baseline to the 12-month visit, based on home "ON/OFF" diaries
• Change in total daily dose of oral LD/DDI from baseline to the 12 month visit
•Proportion of responders at the 12-month visit based on daily "OFF" time recorded in home "ON/OFF" diaries. A responder is defined as a subject that experiences ≥ 50% reduction in "OFF" time from Baseline.
•Change in daily "ON" time with troublesome dyskinesia in a subset of subjects who had more than 1 hour of troublesome dyskinesia at Baseline, based on home "ON/OFF" diaries from Baseline to the 12-month visit.
•Change in PDQ-39 scores from Baseline to the 12 month visit
•Change in EQ-5D-5L scores from Baseline to the 12 month visit
•Change in UPDRS Part II (ADL) from Baseline to the 12 month visit
•Change in CGI-Severity and CGI-Improvement from Baseline to the 12 month visit
•Change in SGI-Improvement from Baseline to the 12 month visit
•Change in PDSS total score from Baseline to the 12 month visit
•Change in UPDRS Part III (motor score) from Baseline to the 12 month visit
•Change from baseline to month 12 in percentage of "OFF" time and percentage of 'Good' ON during the first 3 hours since the subject is awake after 06:00 (6 am)
•Change from baseline to month 12 in ND0612 total dose
•Proportion of patients who reduced ND0612 total dose at any time during the study |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | Yes |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
2 dosages of IMP will be studied: Regimen 1 (720 LD/90 CD mg) vs Regimen 3 (720 LD / 90 CD mg) |
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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 | 20 |
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 |
United States |
Austria |
France |
Poland |
Czechia |
Italy |
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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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |