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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
No full textAn 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
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