| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of levodopa-responsive Parkinson's subjects with severe motor fluctuations. |
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| E.1.1.1 | Medical condition in easily understood language |
Advanced Parkinson's Disease
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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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013113 |
| E.1.2 | Term | Disease Parkinson's |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the longterm safety and tolerability of LCIG over 12 months in subjects with advanced levodopa-responsive PD and severe motor-fluctuations despite optimized treatment with available PD medications. |
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| E.2.2 | Secondary objectives of the trial |
A secondary objective will be to assess the long-term maintenance of efficacy and health-related outcome measures as measured by change from Baseline to Endpoint using the following assessments:
● "Off" time as measured by the Parkinson's Disease Diary©14
● "On" time without troublesome dyskinesia as measured by the Parkinson's
Disease Diary©
● Parkinson's Disease Diary©
● UPDRS Parts I, II, III, and IV
● CGI-I
● PDQ-39
● EQ-5D
● Caregiver burden (ZBI)
● Emp I and Emp II |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of idiopathic PD according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria;.
2. The subjects' advanced PD must be the Levodopalevodopa-responsive type as judged by the Investigator. Additionally, subjects will need to demonstrate severe motor fluctuations in spite of individually optimized available treatment, and where other therapy options are indicated;.
3. Subjects have had optimal treatment with available PD medication as defined by local standards of care and, based upon the judgment of the Investigator, and their symptoms are judged inadequately controlled on this optimized treatment. Optimized treatment is defined as the maximum therapeutic effect obtained with pharmacological antiparkinsonian therapies when no further improvement is expected regardless of any additional manipulations of Levodopalevodopa and/or other antiparkinsonian medication; this. This will be based on the Investigator's best clinical judgment;.
4. Presence of a recognizable "offOff" and "onOn" state (motor fluctuations) as confirmed by the symptom diaryParkinson's Disease Diary© at baseline (diaries are collected for the 3 days preceding the Baseline visit);.
5. Subjects (or subject's proxy) must be able to keep a subject diaryParkinson's Disease Diary© of "offOff" time and dyskinesia;. Subjects' entries may be entered by the caregiver.
6. Subjects must be experiencing a minimum of 3 hours per day of "offOff" time, as estimated by the Investigator and supported by the UPDRS and the diariesParkinson's Disease Diary©. The "offOff" time must occur during a continuous 16-hour interval, including the portion of the day during which the subject is awake the majority of the time (e.g., 5 AM to 9 PM, 7 AM to 11 PM);.
7. The subject must be able to understand the nature of the study and must provide written informed consent prior to the conduct of any study procedures (including any changes occurring in the subject's current therapeutic regimen);.
8. Subjects must be able to speak, read, understand and possess the ability to respond to and follow simple instructions. For a subject to be eligible all required documents, including the informed consent, must be available in a language which is understandable to the subject;.
9. Male or female subjects aged at least 30 years; of age.
10. Females who are not breast-feeding or are of non-childbearing potential. All females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-HCG) test prior to study entry.
Non-childbearing is defined as:
● last natural menstruation at least 24 months prior to Baseline or
● surgically sterilized (i.e., tubal sterilization) at least 3 months prior to Baseline or
● total hysterectomy at least 3 months prior to Baseline.
11. A female subject of childbearing potential may be enrolled provided that she is maintained on one of the following medically acceptable methods of birth control (a stable dose of contraceptive drug for at least 3 months or barrier methods: intra uterine device, diaphragm, combination of a condom and spermicide).
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the exclusion criteria listed below either at screening and/or baseline must be excluded from participation in the study.
1. PD diagnosis is unclear or a suspicion of other parkinsonianParkinsonian syndromes exists, such as secondary parkinsonismParkinsonism (caused by drugs, toxins, infectious agents, vascular disease, trauma, brain neoplasm), Parkinson's-plus syndromes (e.g., multiple system atrophy, progressive supranuclear palsy) or other neurodegenerative diseases;.
2. Subjects who have undergone surgery for the treatment of PD (e.g., pallidotomy, deep brain stimulation, fetal tissue transplantation);.
3. Subjects with any neurological deficit that might interfere with the study assessments (e.g., hemiparesis); and/or any subjects diagnosed with an acute stroke within the 6 months prior to Baseline;.
4. Known hypersensitivity to Levodopa, Carbidopalevodopa, carbidopa or radiopaque material;.
5. Contraindications to Levodopa,levodopa such as narrow angle glaucoma, pheochromocytoma, Cushing's syndrome andor history of malignant melanoma;.
6. Subjects who are experiencing sleep attacks or who exhibit clinically significant impulsive behavior (e.g., pathological gambling, hypersexuality) at any point during the 3 months prior to the screening evaluation;.
7. Current diagnosis or history of drug or alcohol abuse (Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV-TR criteria) within 12 months prior to the Screening visit;.
8. Current primary psychiatric diagnosis of acute psychotic disorder or other primary psychiatric diagnoses (e.g., such as bipolar disorder or major depressive disorder (per DSM IV-TR criteria);.
9. Psychiatric, neurological or behavioral disorders that may interfere with the ability of subjects to give informed consent, or interfere with the conduct or interpretation of the study; troublesome. Troublesome hallucinations would also be included under this category;.
10. Alzheimer's disease; or other conditions including significant cognitive impairment or dementia (defined as MMSE < 24);.
11. Clinically significant abnormal laboratory data (e.g., aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥ 3 × ULN) or any other abnormal laboratory value that could interfere with the assessment of safety. in the judgment of the Investigator;.
12. Current evidence of clinically significant hematological, autoimmune, endocrine, cardiovascular, renal or gastrointestinal disorder that would possibly interfere with the subject's participation in the study (e.g., treated, controlled and thus stable hypertension is not considered an exclusion criterion);.
13. A history of, or a known current gastrointestinal, liver, kidney or other known condition, which may interfere with the absorption, distribution, metabolism or excretion of the study drug and/or assessments, or interfere with the insertion of the tubing system (e.g., subjects who have undergone gastric or intestinal surgery other than, for instance, appendectomy or cholecystectomy);.
14. Any malignant disease or a history of neoplasms, other than carcinoma in situ of the cervix or basal cell carcinoma of the skin, within the past 5 years prior to screening. Additionally, subjects with prostate cancer may be considered for enrollment in the study following a comprehensive assessment and a discussion between the Investigator and the Medical Monitor regarding the appropriateness of the subject for the study;.
15. Medical, laboratory or surgical issues deemed by the Investigator to be clinically significant;.
16. A planned surgical procedure scheduled for when a subject would be participating in the study (subjects may later be considered for inclusion following full recuperation from the surgical procedure);.
17. Exposure to any investigational drug within 30 days prior to Baseline (Visit 2);.
18. Prior exposure to LCIG;.
19. Uncooperative attitude or reasonable likelihood for non-compliance with the protocol;, study procedures or treatments.
20. Site personnel and their immediate families defined as spouse, parent, child, grandparent or grandchild;.
21. Subjects who will not provide written informed consent for participation in the study;.
22. Subjects for whom placement of a PEG-J tube for LCIG treatment is contraindicated, or that the subject would be considered a high risk for the PEG-J procedure according to the Gastroenterologist's/Surgeongastroenterologist's/surgeon's evaluation. Contraindications for PEG-J tube placement include, but are not limited to, the following conditions: e.g., pathological changes of the gastric wall, inability to bring the gastric wall and abdominal wall together, blood coagulation disorders, peritonitis, acute pancreatitis, and paralytic ileus.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The safety and tolerability of LCIG will be assessed by the following assessments:
● Physical examination, including weight
● Vital signs (systolic/diastolic blood pressure, pulse rate and temperature), including orthostatic vital signs (supine and standing [after 2 minutes])
● Neurological Examination
● Clinical laboratory assessments including biochemistry, hematology and, urinalysis, thyroid function studies and special labs to monitor for vitamin deficiency
● Resting 12-lead electrocardiograms (ECGs)
● Concomitant medication usage
● Adverse event monitoring (including the development of sleep attacks, for the development of melanoma, or excessive impulsive behavior)
● Abnormal Involuntary Movement Scale (AIMS)
● Monitoring complications of the infusion device
● Tolerability assessed by number of subjects who complete the study in each group.
The pharmacokinetic objectives are to estimate the population mean values of pharmacokinetic parameters of Levodopalevodopa following administration of LCIG in subjects with PD.
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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) |
●"Off" time as measured by the Parkinson's Disease Diary©14
● "On" time without troublesome dyskinesia as measured by the Parkinson's
Disease Diary©
● Parkinson's Disease Diary©
● UPDRS Parts I, II, III, and IV
● CGI-I
● PDQ-39
● EQ-5D
● Caregiver burden (ZBI)
● Emp I and Emp II
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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 | 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| Canada |
| Czech Republic |
| Finland |
| Germany |
| Israel |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Thailand |
| United Kingdom |
| United States |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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