Open-Label, 12- Month Safety and Efficacy Study of Levodopa – Carbidopa Intestinal Gel in Levodopa-Responsive Subjects with Advanced Parkinson's Disease and Severe MotorFluctuations Despite Optimized Treatment with Available Parkinson’s Disease Medications

An Open-Label, 12-Month Safety and Efficacy Study of Levodopa – Carbidopa Intestinal Gel in Levodopa-Responsive. • Primary Objective Evaluate the long-term safety and tolerability of Levodopa-Carbidopa Intestinal Gel (LCIG) over 12 months in subjects with advanced levodopa-responsive PD and severe motor fluctuations despite optimized treatment with available PD medications, Subjects with Advanced Parkinson's Diseaseand Severe Motor-Fluctuations.Despite Optimized Treatment with Available Parkinson’s Disease Medications. • Secondary Objective Assess the long-term maintenance of efficacy in the treatment of severe motorfluctuations, dyskinesia and mobility using: • Change from baseline in mean daily “off” time using self administered home diary (Hauser) • Change from baseline in diary assessment of On time with and without troublesome dyskinesias • Clinical Global Impression improvement (CGI-I) • UPDRS total score and subscore parts I-III and IV (dyskinesia) • Change form baseline PDQ-30. • Safety Objectives – Physical exam, Vital signs including orthostatics, Clinical laboratory assessments and Resting ECG – Concomitant medications – AE monitoring (including sleep attacks, melanoma and impulsive behavior) – Abnormal Involuntary Movement Scale (AIMS) – Device complications – Tolerability Study Objectives Pharmacokinetic Objective The pharmacokinetic objective is to estimate the population mean values of pharmacokinetic parameters of levodopa following administration of LCIG in subjects with Parkinson’s disease. Study Design • Open-Label • Phase III • Multicenter Approximately 100 sites in 15 Countries worldwide • 250 subjects enrolled • 12 months treatment with Levodopa-Carbidopa Intestinal Gel. Summary of Study Periods Screening • Up to 28 days • Baseline assessment • Diary training Nasojejunal test period • 2 to 14 days • Hospitalization up to 14 days • Dose titration • Safety and efficacy assessment. Summary of Study Periods PEG-J Surgery • 2 days, may be extended to 14 days • Hospitalization • PEG-J surgery • Optimization of Levodopa-Carbidopa Intestinal Gel dosing Post PEG-J long term treatment • 10 Outpatient visits • + 1 Follow-up visit Summary of Study Periods • Screening • Up to 28 days • Baseline assessments • Diary training Nasojejunal Test Period • 2 to 14 days • Hospitalization up to 14 days - Dose titration - Safety and efficacy assessments Screening Period • Inclusion / Exclusion criteria assessed - Neurologist and Gastroenterologist must evaluate subject to confirm inclusion / exclusion criteria - Gastroenterologist must examine and evaluate subject and asses suitability to undergo PEG-J procedure Screening Period Assessments - Physical Examination - Vital signs, temperature, height and weight - Labs, 12 Lead ECGs - Dermatology exam: Melanoma Check - Mini Mental State Exam (MMSE) - Assessment for presence of sleep attacks (sleep questionnaire) - Minnesota Impulsive Disorder Interview (MID) for the assessment of impulsive behavior - Quality of Life rating scales (PDQ-39) - Subject to complete the Hauser symptom diary daily for the 3 days prior to baseline Inclusion Criteria 1. Diagnosis of idiopathic PD according to the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria 2. The subject’s advanced PD must be the levodopa-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 levodopa and/or other antiparkinsonian medication; this will be based on the Investigator’s best clinical judgment 4. Presence of a recognizable “off” and “on” state (motor fluctuations) as confirmed by the symptom diary at baseline (diaries are collected for the three days preceding the baseline visit) 5. Subjects (or subject’s proxy) must be able to keep a subject diary of “off” time and dyskinesia 6. Subjects must be experiencing a minimum of three hours per day of “off” time, as estimated by the Investigator and supported by the UPDRS and the diaries The “off” time must occur during a continuous 16-hour interval, including the portion of the day 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 10. Females who are not breast-feeding or are of non-childbearing potential All females of child bearing potential must have a negative serum beta-human chorionic gonadotropin (−CG) test prior to study entry 11. A female subject of child-bearing 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 three months or barrier methods: intrauterine device, diaphragm, combination of a condom and spermicide) Exclusion Criteria 1. PD diagnosis is unclear or a suspicion of other parkinsonian syndromes exists, such as secondary parkinsonism (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 subject diagnosed with an acute stroke within the six months prior to Baseline 4. Known hypersensitivity to levodopa, carbidopa or radiopaque material 5. Contraindications to levodopa, such as narrow angle glaucoma, pheochromocytoma, Cushing’s syndrome and history of malignant melanoma 6. Subjects who are experiencing sleep attacks (Section 8.1.1.1); or who exhibit clinically significant impulsive behavior (e.g. pathological gambling, hypersexuality) during the three 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, such as bipolar disorder or major depressive disorder (DSMIV 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 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. 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 hallucinations would also be included under this category 12. Clinically significant abnormal laboratory data (e.g., aspartate aminotransferase [AST] or alanine aminotransferase [ALT] 3 x ULN) or any other abnormal laboratory value that could interfere with the assessment of safety in the judgment of the Investigator 13. 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) 14. 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) 15. 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 five 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 16. Medical, laboratory or surgical issues deemed by the Investigator to be clinically significant 17. 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) 18. Exposure to any investigational drug within 30 days prior to baseline (Visit 2) 19. Prior exposure to Levodopa-Carbidopa Intestinal Gel (LCIG) 20. Uncooperative attitude or reasonable likelihood for non-compliance with the protocol 21. Site personnel and their immediate families defined as spouse, parent, child, grandparent or grandchild 22. Subjects who will not provide written informed consent for participation in the study 23. 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/surgeon’s evaluation Contraindications for PEG-J tube placement include, but are not limited to, the following conditions: 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 24.