| 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 | 14.0 |
| 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 this study will be to demonstrate the superiority of treatment with Levodopa-Carbidopa Intestinal Gel (LCIG) over treatment with optimized oral Levodopa-Carbidopa during 12 weeks of treatment |
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| E.2.2 | Secondary objectives of the trial |
| “On” time without troublesome dyskinesia (“On” time without dyskinesia or with non-troublesome dyskinesia) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects with PD who experience motor complications despite optimized available therapy are eligible to participate and must also meet the following criteria in order to participate in this study.
1. Diagnosis of idiopathic Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria;
2. The subject’s Parkinson’s disease is Levodopa-responsive and subjects must demonstrate some identifiable “On response”, as established through observation by the Investigator. Additionally, subjects will need to demonstrate severe motor fluctuations in spite of individually optimized treatment, and where other therapy should be considered.
3. The subject’s history of anti PD therapy must include the following:
•Must have demonstrated a significant response to Levodopa
•Must have had an adequate trial of immediate-release Levodopa- decarboxylase inhibitor (e.g., Sinemet®) or controlled-release Levodopa-decarboxylase inhibitor (e.g., Sinemet®-CR) administered at a daily dose equivalent to a dose of ≥ 400 mg levodopa
•Must have had an adequate trial of a dopaminergic agonist administered concomitantly with Levodopa-decarboxylase inhibitor
•Must have had an adequate trial of a catechol O methyl transferase (COMT) inhibitor (i.e., entacapone or tolcapone) OR an adequate trial of a monoamine oxidase (MAO) –B inhibitor
An “adequate trial” is defined as a therapeutic attempt in which the patient failed to achieve the therapeutic benefit for reason of either efficacy or tolerability. The patient must have:
o Been treated for a minimum period of two weeks at a minimal dose of at least 33% of the maximally recommended dose in the approved label; or
o Had to discontinue the drug either because of an adverse reaction or intolerability following the dosing regimen in the approved label.
4. The presence of a recognizable “Off” and “On” state (motor fluctuations), as confirmed by the Parkinson’s Disease Diary recordings prior to the PEG-J procedure. Parkinson’s Disease Diaries are collected and evaluated prior to the PEG-J placement procedure.
5. Subjects must be experiencing a minimum of three hours of “Off” time confirmed by the Parkinson’s Disease Diary for each of the three consecutive. The “Off” 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).
6. Subject (or subject’s proxy/caregiver) must be able to complete both the Daily Dosing Diary and the Parkinson’s Disease Diary of “Off” time. The subject or caregiver must also be able to demonstrate the ability to operate, manipulate, and care for the infusion pump and tubing.
7. Subject must demonstrate a 75% concordance with the Investigator’s or qualified designee’s assessment of symptoms on the Parkinson’s Disease Diary following training. Subject must also have a 75% or greater compliance rate on the diary completion to qualify for randomization.
8. 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).
9. Subjects must be able to speak, read, understand and possess the ability to respond to and follow simple instructions. For the subject to be eligible all required documents, including the informed consent, must be available in a language that is understandable to the subject
10. Male or female subjects aged at least 30 years.
11. Females who are not breast-feeding
12. An independent physician attested that treatment with LCIG, including PEG-J placement, is suitable for the subject (Germany only).
13. Female subjects of non-childbearing potential either postmenopausal for at least 2 years or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy). Postmenopausal subjects should be amenorrheic for at least 24 months prior to Screening.
14. Female subjects of childbearing potential practicing at least one of the following methods of birth control throughout the study:
o Total abstinence from intercourse;
o Vasectomized partner(s);
o Intrauterine device (IUD);
o Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal foam/gel/film/cream/suppository). Diaphragm must be used with spermicidal foam or jelly. The combination of diaphragm and spermicidal substance counts as a single barrier;
o Using oral, injected, or implanted methods of hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration and the partner should also use a barrier method (e.g. condom) with spermicidal foam/gel/cream/suppository during this study and for 90 days after study drug completion. |
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the exclusion criteria listed below either at screening and/or prior to randomization must be excluded from participation in the study.
1. The PD diagnosis is unclear or a suspicion of other Parkinsonian syndromes exist, such as secondary Parkinsonism (e.g., caused by drugs, toxins, infectious agents, vascular disease, trauma, brain neoplasm), Parkinson-plus syndromes (e.g., multiple system atrophy, progressive supranuclear palsy) or other neurodegenerative diseases.
2. Subject has undergone neurosurgery for the treatment of PD.
3. Current enrollment in another clinical study.
4. Subjects with any neurological deficit that might interfere with the study assessments (e.g. hemiparesis); and/or any subjects who have had an acute stroke diagnosed within the six months prior to baseline.
5. Known hypersensitivity to Levodopa, Carbidopa, or radiopaque material.
6. Contraindications to levodopa, (e.g., narrow angle glaucoma, pheochromocytoma, Cushing’s syndrome or history of malignant melanoma).
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 screening visit.
8. Current primary psychiatric diagnosis of acute psychotic disorder or other primary psychiatric diagnoses, (e.g., bipolar disorder or major depressive disorder per (DSM-IV-TR criteria).
9. Subject experiencing sleep attacks (see Section 11.3.2) or exhibiting clinically significant impulsive behavior (e.g., pathological gambling, hypersexuality at any point during the three months prior to the screening evaluation).
10. 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.
11. Troublesome hallucinations not controlled by allowed concomitant therapy.
12. Significant cognitive impairment that, in the opinion of the Investigator, would impact the subject’s ability to participate in the trial;
o Mimi-Mental State Examination score of < 24
o Alzheimer’s disease or other dementia
13. Clinically significant abnormal laboratory data (e.g., alanine aminotransferase [SLT] or aspartate aminotransferase [AST] 3 x the upper limit of normal [ULN]), or any abnormal laboratory value that could interfere with the assessment of safety.
14. 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).
15. Subjects who in the judgment of the investigator would not be likely to complete the study.
16. A history of, or a known current gastrointestinal, liver, kidney or other condition, which may interfere with the absorption, distribution, metabolism or excretion of the study drug, assessments or amy interfere with the insertion of the PEG-J tube (e.g., subjects who have undergone gastric or intestinal surgery other than appendectomy or cholecystectomy).
17. Any malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma of the skin within the past five years prior to screening. Subjects with prostrate cancer or completely excised squamous cell carcinoma of the skin without reoccurrence within 2 years prior to Screening may be permitted to enroll following Investigator and Medical Monitor discussion and documentation of approval.
18. Medical, laboratory, or surgical issues deemed by the investigator to be clinically significant.
19. 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).
20. Exposure to any investigational drug within 30 days prior to Study Day 1.
21. Prior exposure to LCIG.
22. Uncooperative attitude or reasonable likelihood for non-compliance with the protocol, study procedures or treatments.
23. Site personnel and their immediate families defined as spouse, parent, child, grandparent or grandchild.
24. Subject for whom the 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 evaluation. Contraindication for PEG-J tube placement includes but is 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 change from baseline in mean daily “Off” time (hours), based on the 3 consecutive day average of “Off” time for the Parkinson’s Disease Diary at Study Week 12 (endpoint). The Baseline value is defined as the values collected on the Parkinson’s Disease Diary before the PEG-J procedure |
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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) |
o “On” time without troublesome dyskinesia (“On” time without dyskinesia or with non-troublesome dyskinesia)
Other Secondary Variables:
o PDQ-39
o CGI-I
o UPDRS Part II
o UPDRS Part III
o EQ-5D
o Caregiver Burden (ZBI)
All assessments related to the evaluation of Primary and Secondary Variables should be performed during the subject’s “On” time.
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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 | No |
| E.6.9 | Dose response | Yes |
| 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 |
|
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
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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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 |
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