Open Label Continuation Treatment Study With Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease

Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) which started on or after the date of the first LCIG Infusion in this study and within 30 days of the date of the last PEG-J exposure.

At least possibly drug-related is defined as TEAEs assessed as having a "Possible" or "Probable" or missing relationship to study drug.

Serious AEs included any untoward medical occurrence that:

• Resulted in death
• Was life-threatening
• Required inpatient hospitalization or prolongation of an existing hospitalization
• Resulted in persistent or significant disability/incapacity
• was a congenital anomaly/birth defect

The severity of all AEs was characterized as mild, moderate or severe according to the following definitions:

• Mild: usually transient and do not interfere with daily activities.
• Moderate: low level of inconvenience or concern to the subject, may interfere with daily activities.
• Severe: events interrupt the subject's usual daily activity.

Device complications include complications with the pump, intestinal tube, PEG-J or stoma.

Participants were asked whether they experienced any events in which they fell asleep suddenly or unexpectedly, including while engaged in some activity (e.g., eating/drinking, speaking, or driving) or at rest, with or without any previous warning of sleepiness. If yes, participants were asked if they suffered any "bad" outcome or problem from the falling asleep event.

To monitor for the development of intense impulsive behavior the Minnesota Impulsive Disorder Interview (MIDI) was administered. The MIDI is a semi-structured clinical interview assessing pathological gambling, trichotillomania, kleptomania, pyromania, intermittent explosive disorder, compulsive buying, and compulsive sexual behavior.

A comprehensive assessment for the presence of melanoma was performed at least once a year by a dermatologist.

Adverse events of special interest (AESIs) were identified using standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (SMQ) or company MedDRA queries (CMQs). The AESI in the following categories were identified on the basis of review of the clinical program and postmarketing observations where the treatment system is commercially available.

• Procedure and device associated events
• Polyneuropathy, included preferred terms in either the peripheral neuropathy or GuillainBarre syndrome standardized MedDRA query (narrow search), such as polyneuropathy, decreased vibratory sense, peripheral neuropathy, peripheral sensory neuropathy, neuralgia, demyelinating polyneuropathy, and sensory disturbance
• Weight loss
• Cardiovascular fatalities
• Respiratory tract aspiration including aspiration pneumonia/pneumonitis.

The Columbia-Suicide Severity Rating Scale (C-SSRS) was implemented with Protocol Amendment 3 (20 March 2012) in order to assess suicidal behavior and ideation.

Suicidal ideation includes the wish to be dead, nonspecific active suicidal thoughts, active ideation without intent to act, active ideation with some intent to act, and active ideation with specific plan or intent. Suicidal behavior includes actual attempts, interrupted attempts, aborted attempts, completed suicide, and preparatory acts or behaviors.

The number of participants with affirmative responses on the C-SSRS at any time during the treatment period is reported.

A vital sign value was considered potentially clinically significant if it satisfied the pre-specified criteria presented in the table and was also more extreme than the participant's corresponding Baseline value.

A laboratory value was considered potentially clinically significant if it satisfied the pre-specified criteria presented in the table and was also more extreme than the participant's corresponding Baseline value.

A laboratory value was considered potentially clinically significant if it satisfied the pre-specified criteria presented in the table and was also more extreme than the participant's corresponding baseline value.

ULN = upper limit of normal

Special tests for vitamin deficiencies (folic acid, vitamin B6, vitamin B12, methylmalonic acid [MMA], and homocysteine) were implemented with Protocol Amendment 2 (27 July 2011). The number of participants with vitamin levels outside of the normal range at any time post-baseline is reported for each vitamin tested.

Participants could use oral levodopa-carbidopa for scheduled or supplemental bedtime/overnight doses after the pump was disconnected for the night, or as rescue medication in case of acute deterioration caused by failure of the LCIG system such as tubes and/or the pump or the onset of an acute illness.

The initiation of additional concomitant PD medication was allowed at the discretion of the Investigator if medically indicated.

The PD symptom diary asks participants (or their caregivers) to indicate their status upon waking and every 30 minutes during their normal waking time according to the following categories: asleep, "off", "on" without dyskinesia, "on" with non-troublesome dyskinesia, or "on" with troublesome dyskinesia.

"Off" time was defined as time when medication had worn off and was no longer providing benefit with regard to mobility, slowness, and stiffness.

PD diary times were normalized to a 16-hour waking day and averaged for the 3 days prior to each study visit.

A negative change for "off" time indicates improvement. The PD diary assessment was implemented with Protocol amendment 4 (December 2013) for participants at United States (US) sites only.

The PD diary asks participants (or their caregivers) to indicate their status upon waking and every 30 minutes during their normal waking time according to the following categories: asleep, "off", "on" without dyskinesia, "on" with non-troublesome dyskinesia, or "on" with troublesome dyskinesia.

"On" time is when medication is providing benefit with regard to mobility, slowness and stiffness. Dyskinesia is involuntary twisting, turning movements which are an effect of medication and occur during "on" time. Non-troublesome dyskinesia does not interfere with function or cause meaningful discomfort.

"On" time without troublesome dyskinesia is the sum of "on" time without dyskinesia and "on" time with non-troublesome dyskinesia. PD diary times were normalized to a 16-hour waking day and averaged for the 3 days prior to each study visit. A positive change indicates improvement.

The PD diary was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The PD diary asks participants (or their caregivers) to indicate their status upon waking and every 30 minutes during their normal waking time according to the following categories: asleep, "off", "on" without dyskinesia, "on" with non-troublesome dyskinesia, or "on" with troublesome dyskinesia.

"On" time is when medication is providing benefit with regard to mobility, slowness and stiffness. Dyskinesia is involuntary twisting, turning movements which are an effect of medication and occur during "on" time. Troublesome dyskinesia interferes with function or causes meaningful discomfort.

PD diary times were normalized to a 16-hour waking day and averaged for the 3 days prior to each study visit. A positive change indicates improvement.

The PD diary was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The UPDRS is an Investigator-used rating tool to follow the longitudinal course of PD. It is made up of the following sections:

I) Mentation, Behavior, and Mood;

II) Activities of Daily Living;

III) Motor Examinations;

IV) Complications of Therapy sections (including dyskinesias).

The Part I Score is the sum of the answers to the 4 questions that comprise Part I, each of which are measured on a 5-point scale (0-4). The Part I score ranges from 0-16 and higher scores are associated with more disability. A negative change from Baseline indicates improvement.

The UPDRS was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The UPDRS is an Investigator-used rating tool to follow the longitudinal course of PD. It is made up of the following sections:

I) Mentation, Behavior, and Mood;

II) Activities of Daily Living;

III) Motor Examinations;

IV) Complications of Therapy sections (including dyskinesias).

The Part II score is the sum of the answers to the 13 questions that comprise Part II, each of which are measured on a 5-point scale (0-4). The Part II score ranges from 0-52 and higher scores are associated with more disability. A negative change from Baseline indicates improvement.

The UPDRS was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The UPDRS is an Investigator-used rating tool to follow the longitudinal course of PD. It is made up of the following sections:

I) Mentation, Behavior, and Mood;

II) Activities of Daily Living;

III) Motor Examinations;

IV) Complications of Therapy sections (including dyskinesias).

UPDRS Part III consists of 14 questions. Questions 20 - 26 are multi-part questions in that they are evaluated separately for multiple body parts. Counting each of these assessments leads to a total of 27 answers for Part III. The UPDRS Part III score is the sum of the 27 answers provided to the 14 Part III questions, each of which are measured on a 5-Point scale (0-4). The Part III score ranges from 0-108 and higher scores are associated with more disability. A negative change from Baseline indicates improvement.

The UPDRS was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The UPDRS is an Investigator-used rating tool to follow the longitudinal course of PD. It is made up of the following sections:

I) Mentation, Behavior, and Mood;

II) Activities of Daily Living;

III) Motor Examinations;

IV) Complications of Therapy sections (including dyskinesias).

The UPDRS total score is the sum of the responses to the 31 questions (44 answers) that comprise Parts I - III of the scale. The total score ranges from 0 - 176 with 176 representing the worst (total) disability, and 0 no disability. A negative change from Baseline indicates improvement.

The UPDRS was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The UPDRS is an Investigator-used rating tool to follow the longitudinal course of PD. It is made up of the following sections:

I) Mentation, Behavior, and Mood;

II) Activities of Daily Living;

III) Motor Examinations;

IV) Complications of Therapy sections (including Dyskinesias).

The UPDRS Part IV Score is the sum of all answers to the 11 questions that comprise Part IV, 4 of which are measured on a 5-point scale (0 - 4) and 7 which are measured on a 2-point scale (0 - 1). The Part IV score ranges from 0 - 23 with higher scores associated with more disability. A negative change from Baseline indicates improvement.

The UPDRS was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The UPDRS is an Investigator-used rating tool to follow the longitudinal course of PD. It is made up of the following sections:

I) Mentation, Behavior, and Mood; II) Activities of Daily Living; III) Motor Examinations; IV) Complications of Therapy sections (including Dyskinesias); and

The UPDRS Part IV dyskinesia Score is the sum of Questions 32 (What proportion of the waking day are dyskinesias present?), 33 (How disabling are the dyskinesias? ), and 34 (How painful are the dyskinesias?) on UPDRS Part IV, each of which are measured on a 5-point scale (0-4). The Part IV dyskinesia score ranges from 0 - 12 and higher scores are associated with more disability. A negative change from Baseline indicates improvement.

The UPDRS was implemented with Protocol amendment 4 (December 2013) for participants at US sites only.

The PDQ-39 is a self-administered questionnaire that comprises 39 items addressing the following eight domains of health that patients consider to be adversely affected by the disease:

• Mobility (e.g., fear of falling when walking) - 10 questions
• Activities of daily living (e.g., difficulty cutting food) - 6 questions
• Emotional well-being (e.g., feelings of isolation) - 6 questions
• Stigma (e.g., social embarrassment) - 4 questions
• Social support - 3 questions
• Cognition - 4 questions
• Communication - 3 questions
• Bodily discomfort - 3 questions

Each question is answered on a 5-point scale from 0 (Never) to 4 (Always / Cannot Do At All). Scores are calculated by summing the answers to the questions in the domain and converting to a scale from 0 to 100. Higher scores are associated with the more severe symptoms of the disease such as tremor and stiffness. The PDQ-39 summary index (range 0-100) includes responses to all 39 items. A negative change indicates improvement.