A Study to Examine the Effect of Levodopa-Carbidopa Intestinal Gel (LCIG) Therapy Relative to That of Optimized Medical Treatment (OMT) on Non-motor Symptoms (NMS) Associated With Advanced Parkinson's Disease (PD)

Study Overview
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Brief Summary
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The primary objective of this study is to examine the effect of LCIG relative to that of OMT on NMS associated with PD.

Detailed Description
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The study will consist of 3 sequential parts: Part 1: Screening period. The screening period will consist of 3 visits, Visit 1 (V1), Visit 2 ([V2] [optional]) and the Randomization Visit (V3) in which the participant will be assessed to determine eligibility. The duration of the Screening Period can be between 30 to 67 days to accommodate the required procedures, training and collection of diaries, and to allow for stabilization of anti-PD medications and medications to treat NMS. All anti-PD medications and medications to treat NMS are required to be stable for a minimum of 30 days prior to randomization. Part 2: Treatment period. Those participants randomized to OMT at the end of V3 will remain on their current optimized regimen. The day after randomization will be considered Day 1 of their treatment period and participants will have study visits at the end of Weeks 2, 6, 12, and 26. All participants randomized to the LCIG group should have all anti-PD medications, with the exception of levodopa formulations, tapered off within 14 days after randomization. Optional nasojujunal (NJ) and/or percutaneous endoscopic gastrostomy with a jejunal tube (PEG-J) placement will then occur. After that, the participant may begin initiation and titration of LCIG infusion to be adjusted to obtain the optimal clinical response. The day of initial NJ or PEG-J placement will be considered Day 1 for participants in the LCIG group. Study visits happen at the end of Weeks 2, 6, 12, and 26. Part 3: Extension/Transition Period. Eligible participants who complete the 26 week study may continue into the Extension Period of the study. Participants in the LCIG arm will have study drug dispensation every 4 weeks and will have study visits every 6 months. Participants from the OMT arm will undergo the NJ (optional) and PEG-J procedures, titration, plus have visits at 2 weeks, 6 weeks, 3 months and 6 months post NJ or PEG-J. Participants will then continue to receive study drug every 4 weeks and will have study visits every 6 months until Duodopa is commercially available. Transition to a Post-Trial Access protocol will be possible if Duodopa does not become commercially available in a location.

Official Title
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An Open-label, Randomized 26-Week Study Comparing Levodopa-Carbidopa INteStInal Gel (LCIG) THerapy to Optimized Medical Treatment (OMT) on Non-Motor Symptoms (NMS) in Subjects With Advanced Parkinson's Disease - INSIGHTS Study

Conditions
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Advanced Parkinson's Disease

Intervention / Treatment
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* Drug: Optimized Medical Treatment
* Drug: Levodopa-Carbidopa Intestinal Gel
* Device: Nasojejunal (NJ) tube
* Device: Percutaneous endoscopic gastrostomy with a jejunal (PEG-J) tube


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant(s) must have a diagnosis of idiopathic Parkinson's disease according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria. Participant(s) demonstrates persistent motor fluctuations in spite of individually optimized treatment. The participant's Parkinson's disease is levodopa-responsive. Participant(s) has had optimized treatment with available anti-PD medication and their motor 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 clinical judgment. Male or female participant(s) must be at least 30 years of age. Minimum Parkinson's Disease Sleep Scale 2 (PDSS-2) total score of 18 at Baseline assessment. Exclusion Criteria: Participant's PD diagnosis is unclear or there is a suspicion that the subject has a parkinsonian syndrome such as secondary parkinsonism (e.g. caused by drugs, toxins, infectious agents, vascular disease, trauma, brain neoplasm), parkinson-plus syndrome (e.g. Multiple System Atrophy, Progressive supranuclear Palsy, Diffuse Lewy Body disease) or other neurodegenerative disease that might mimic the symptoms of PD. Participant(s) has undergone neurosurgery for the treatment of Parkinson's disease. Known hypersensitivity to levodopa, carbidopa or radiopaque material. Participant(s) has contraindications to levodopa (e.g. narrow angle glaucoma, malignant melanoma). Participant(s) experiencing clinically significant sleep attacks or clinically significant impulsive behavior (e.g. pathological gambling, hypersexuality) at any point during the three months prior to the Screening evaluation as judged by the Principal Investigator.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Optimized Medical Treatment (OMT)<br>Participants randomized to continue OMT remain on their current optimized regimen. During the 26-week treatment phase, changes to anti-PD and NMS medications are to remain stable and can only be made if medically indicated. Eligible participants may elect to enter an extension/transition follow-up period to receive an individually optimized LCIG dose (after NJ and/or PEG-J placement), in order to transition to commercially available LCIG. | Drug: Optimized Medical Treatment<br>* Oral, sublingual or transdermal anti-PD medications and medications to treat NMS per Investigator discretion and/or in accordance with approved product label of the prescribed medications.<br>Drug: Levodopa-Carbidopa Intestinal Gel<br> <br> * Other names: LCIG;Device: Nasojejunal (NJ) tube<br>* optional prior to PEG-J placement<br>Device: Percutaneous endoscopic gastrostomy with a jejunal (PEG-J) tube<br> <br> |
| Experimental: Levodopa-Carbidopa Intestinal Gel (LCIG)<br>Participants randomized to LCIG at an individually optimized dose (after NJ and/or PEG-J placement), in accordance with the LCIG approved product label for countries participating in the study. During the 26-week treatment phase, changes to anti-PD and NMS medications are to remain stable and can only be made if medically indicated. The total daily dose of LCIG was composed of 3 components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. The continuous infusion is expected to run over a period of 16 consecutive hours each day. Eligible participants may elect to enter an extension/transition follow-up period to receive an individually optimized LCIG dose, in order to transition to commercially available LCIG. | Drug: Levodopa-Carbidopa Intestinal Gel<br> <br> * Other names: LCIG;Device: Nasojejunal (NJ) tube<br>* optional prior to PEG-J placement<br>Device: Percutaneous endoscopic gastrostomy with a jejunal (PEG-J) tube<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in the NMSS Total Score | The NMSS consists of 30 questions in 9 domains (cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, GI tract, urinary, sexual function, miscellaneous). Score of each question is calculated by multiplying severity*frequency. Severity and frequency are rated using a scale ranging from 0 (none) to 3 (severe) for severity and from 1 (rarely) to 4 (very frequent) for frequency. Total score is the sum of 9 domains, and ranges from 0 to 360, with a lower value indicating a more desirable outcome. Repeated-measure analysis. | Baseline, Week 26 | 
| Change From Baseline to Week 26 in the Modified PDSS-2 Total Score | The PDSS-2 addresses PD-specific sleep disturbances such as restless leg syndrome (RLS), morning akinesia, pain, and sleep apnea. The frequency is assessed for the 15 sleep problems based on a 5-point Likert-type scale (ranging from 0 [never] to 4 [very often]). Scores are calculated for each of the 3 domains (motor symptoms at night, PD symptoms at night, and disturbed sleep) as well as a total score. The PDSS-2 domain scores range from 0 to 20 and the total score is a sum of the 3 domains and ranges from 0 to 60. Repeated measure analysis. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in Parkinson's Disease Questionnaire (PDQ-8) Summary Index Score | The PDQ-8 is a disease-specific instrument designed to measure aspects of health relevant to PD. Eight questions including the mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort are assessed on a 5-point scale: 0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always (or cannot do at all, if applicable). Summary index score is the sum of each question divided by 32 and multiplied by 100. Scores range from 0 to 100 with lower values desirable. | Baseline, Week 26 | 
| Clinical Global Impression of Change (CGI-C) Final Score | CGI-C score is a clinician's impression of a subject's change in status on a 7-point scale (1 = very much improved, 2 = much improved, 3 = minimally Improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse). Scores range from 1 to 7, with lower score desirable. | End of Treatment Period (up to Week 26) | 
| Change From Baseline at Week 26 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score | UPDRS is an investigator-used rating tool to follow the longitudinal course of Parkinson's disease of 42 total questions. Part I (Questions 1 - 4), Part II (Questions 5 - 17), Part III (Questions 18 - 31), and Part IV (Questions 32 - 42). Questions 35 - 38 and 40 - 42 are 2-point (0 and 1), all other questions are 5-point (0 - 4). Part II scores range from 0 to 52 with lower value desirable. | Baseline, Week 26 | 
| Change From Baseline to Week 26 in the NMSS Domain Scores | The NMSS consists of 30 questions in 9 domains. Score of each question is calculated by multiplying severity*frequency. Severity and frequency are rated using a scale ranging from 0 (none) to 3 (severe) for severity and from 1 (rarely) to 4 (very frequent) for frequency. Cardiovascular/falls scores range from 0 - 24 with lower value desirable. Sleep/fatigue scores range from 0 - 48 with lower value desirable. Mood/cognition scores range from 0 - 72 with lower value desirable. Perceptual problems/hallucinations scores range from 0 - 36 with lower value desirable. Attention/memory scores range from 0 - 36 with lower value desirable. Gastrointestinal tract scores range from 0 - 36 with lower value desirable. Urinary scores range from 0 - 36 with lower value desirable. Sexual function scores range from 0 - 24 with lower value desirable. Miscellaneous scores range from 0 - 48 with lower value desirable. Repeated-measure analysis. | Baseline, Week 26 | 
| Change From Baseline to Week 26 in the Modified PDSS-2 Domain Scores | The PDSS-2 addresses PD-specific sleep disturbances such as restless leg syndrome (RLS), morning akinesia, pain, and sleep apnea. The frequency is assessed for the 15 sleep problems based on a 5-point Likert-type scale (ranging from 0 [never] to 4 [very often]). Scores are calculated for each of the 3 domains (motor symptoms at night, PD symptoms at night, and disturbed sleep) as well as a total score. The PDSS-2 domain scores range from 0 to 20 and the total score is a sum of the 3 domains and ranges from 0 to 60. Repeated measure analysis. | Baseline, Week 26 | 
| Change From Baseline at Week 26 in UPDRS Parts I, III, and IV Score | UPDRS is an investigator-used rating tool to follow the longitudinal course of Parkinson's disease of 42 total questions. Part I (Questions 1 - 4), Part II (Questions 5 - 17), Part III (Questions 18 - 31), and Part IV (Questions 32 - 42). Questions 35 - 38 and 40 - 42 are 2-point (0 and 1), all other questions are 5-point (0 - 4). Part I is the sum of Questions 1 - 4; scores range from 0 to 16 with lower value desirable. Part III is the sum of Questions 18 - 31 (Questions 20 - 26 apply to multiple body parts, resulting in 27 answers total); scores range from 0 to 108 with lower value desirable. Part IV is the sum of Questions 32 - 42; scores range from 0 to 23 with lower value desirable. | Baseline, Week 26 | 
| Change From Baseline at Week 26 in Parkinson's Anxiety Scale (PAS) Total Score | PAS is a 12-item scale developed specifically to measure severity in anxiety in Parkinson's disease for the following items: Feeling anxious or nervous; Feeling tense or stressed; Being unable to relax; Excessive worrying about everyday matters; Fear of something bad, or even the worst, happening; Panic or intense fear; Shortness of breath; Heart palpitations or heart beating fast; Fear of losing control; Social situations; Public settings; Specific objects or situations. Severity for each item is rated as: 0, Never; 1 Rarely; 2, Sometimes; 3, Often; 4, Nearly always. Total score is the sum of the12 item scores, with a range of 0 to 48; a lower value is desirable. | Baseline, Week 26 | 
| Change From Baseline at Week 26 in Geriatric Depression Scale (GDS-15) Score | The GDS-15 is a short, self-report reliable and valid screening instrument for depression in the elderly of 15 yes/no questions: 1) Satisfied with life 2) Dropped many activities and interests 3) Life is empty 4) Often get bored 5) In good spirits most of the time 6) Afraid that something bad is going to happen 7) Feel happy most of the time 8) Often feel helpless 9) Prefer to stay at home, rather than going out and doing things 10) Feel that have more problems with memory than most 11) Think it is wonderful to be alive now 12) Feel worthless 13) Feel full of energy 14) Situation is hopeless 15) Most subjects are better off. Answers of 'yes' to questions 2, 3, 4, 6, 8, 9, 10, 12, 14, 15 are scored 1 point. Answers of 'no' to questions 1, 5, 7, 11, 13 are scored 1 point. The 15 items are summed and scores range from 0 - 15 with lower value desirable. | Baseline, Week 26 | 
| Change From Baseline at Week 26 in King's PD Pain Scale (KPPS) Score | The KPPS score is a clinical PD-specific pain scale of 14 items addressing the following 7 domains: musculoskeletal pain, chronic pain, fluctuation-related pain, nocturnal pain, orofacial pain, neuropathic pain, radicular pain. Each domain item is scored by severity (0, none to 3, very severe) multiplied by frequency (0, never to 4, all the time) resulting in a subscore of 0 - 12 (with lower value desirable), the sum of the 14 items gives the total score with a range from 0 to 168 with lower value desirable. | Baseline, Week 26 | 
| Patient Global Impression of Change (PGIC) Final Score | The PGIC is a 7-point response scale. The participant was asked by the Investigator or qualified designee to rate their change in status using the following 7-point scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. PGIC score ranges from 1 to 7 with lower score desirable. | End of Treatment Period (up to Week 26) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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levodopa-carbidopa intestinal gel, levodopa, carbidopa, Advanced Parkinson's Disease, Non-Motor Symptom Scale NMSS, Parkinson's Disease Sleep Scale PDSS-2, efficacy