A Study Comparing Efficacy of Levodopa-Carbidopa Intestinal Gel/Carbidopa-Levodopa Enteral Suspension and Optimized Medical Treatment on Dyskinesia in Subjects With Advanced Parkinson's Disease (DYSCOVER)

Study Overview
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Brief Summary
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The primary objective of this study was to examine the effect of levodopa-carbidopa intestinal gel (LCIG) compared with optimized medical treatment (OMT) on dyskinesia in participants with advanced Parkinson's disease (PD).

Detailed Description
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This was a Phase 3b, open-label, randomized, multicenter, 12-week study. The study consisted of 3 sequential periods: Screening, Treatment, and Follow-Up. The OMT group had the same schedule of visits/procedures throughout the study as the LCIG treatment group, except for visits related to nasojejunal (NJ)/percutaneous endoscopic gastrostomy (PEG) procedures, titration of LCIG, and follow-up period.

Official Title
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An Open-label, Randomized 12 Week Study Comparing Efficacy of Levodopa-Carbidopa Intestinal Gel/Carbidopa-Levodopa Enteral Suspension and Optimized Medical Treatment on Dyskinesia in Subjects With Advanced Parkinson's Disease DYSCOVER (DYSkinesia COmparative Interventional Trial on Duodopa VERsus Oral Medication)

Conditions
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Parkinson's Disease (PD)

Intervention / Treatment
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* Drug: Optimized antiparkinsonian treatment
* Drug: Levodopa-Carbidopa Intestinal Gel (LCIG)
* Device: CADD-Legacy ambulatory infusion pump
* Device: Percutaneous endoscopic gastrostomy tube
* Device: Jejunal extension tube


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a diagnosis of idiopathic Parkinson's disease (PD) according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria Participants with advanced levodopa-responsive PD and persistent motor fluctuations who have not been controlled with optimized medical treatment (OMT: the maximum therapeutic effect obtained with pharmacological antiparkinsonian therapies when no further improvement is expected with regard to any additional manipulations of levodopa and/or other antiparkinsonian medication based on the Investigator's clinical judgment) Unified Dyskinesia Rating Scale (UDysRs) Total score ≥ 30 at Visit 3 Exclusion Criteria: Participant(s) treated with levodopa-carbidopa intestinal gel (LCIG) previously 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. 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 OMT continued their current anti Parkinson's disease (anti-PD) medication regimen for the duration of the study. All anti-PD medications and medications to treat dyskinesia must have remained stable for the duration of the study unless adjustments were medically indicated. The Investigator provided the prescription for continued OMT. | Drug: Optimized antiparkinsonian treatment<br>* Dose levels of prescribed antiparkinsonian medications were individually optimized to their maximum therapeutic effect.<br>|
| Experimental: Levodopa-Carbidopa Intestinal Gel (LCIG)<br>The total daily dose of infusion LCIG was composed of three components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. A temporary nasojejunal (NJ) tube may have been used initially with the infusion pump to determine a participant's response to this method of treatment and to optimize the dose of LCIG before treatment with a permanent percutaneous endoscopic gastrostomy - with jejunal extension (PEG-J) tube was started. Following optional NJ and/or PEG-J placement and, at the investigator's discretion, the participant may have begun initiation and titration of LCIG infusion on Day 1 once tube placement was confirmed. The dose of LCIG was adjusted to obtain the optimal clinical response. The rate of LCIG infusion is typically within the range of 1 to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period of 16 consecutive hours each day. | Drug: Levodopa-Carbidopa Intestinal Gel (LCIG)<br>* Dose levels were individually optimized.<br>* Other names: DUODOPA;Device: CADD-Legacy ambulatory infusion pump<br>* (manufactured by Smiths Medical)<br>Device: Percutaneous endoscopic gastrostomy tube<br>* (PEG tube)<br>Device: Jejunal extension tube<br>* (J-tube)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score | The Unified Dyskinesia Rating Scale (UDysRS) is a tool used to assess dyskinesia in Parkinson's disease (PD) and contains both self-evaluation questions and items that are assessed directly by the physician to objectively rate the abnormal movements associated with PD. Part 1 contains 11 questions about the ON time dyskinesia and the impact of ON-dyskinesia on experiences of daily living. Part 2 contains 4 questions about OFF-dystonia rating. Part 3 contains 7 questions about objective evaluation of dyskinesia impairment and Part 4 contains 4 questions regarding dyskinesia disability. Each question is scored with respect to severity, which is rated on a scale where 0 = normal, 1 = slight, 2 = mild, 3= moderate and 4 = severe. The UDysRS total score is obtained by summing the item scores, ranging from 0 to 104. Higher scores are associated with more disability. Negative changes from baseline indicate improvement. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Week 12 in ON Time Without Troublesome Dyskinesia | The Parkinson's Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study visits. It reflects both time awake and time asleep. Daily totals are normalized to a 16-hour scale (i.e., 16 hours of awake time). The normalized totals for the 3 days prior to the visit are averaged for the analysis. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Positive change from baseline for ON time without troublesome dyskinesia indicates improvement. | Baseline, Week 12 | 
| Mean Change From Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index | The Parkinson's Disease Questionnaire-8 (PDQ-8) is a disease-specific instrument designed to measure aspects of health that are relevant to participants with PD, and which may not be included in general health status questionnaires. The PDQ-8 is a self-administered questionnaire. Each item is scored on the following 5-point scale: 0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always (or cannot do at all, if applicable). Higher scores are consistently associated with the more severe symptoms of the disease such as tremors and stiffness. The results are presented as a summary index. The PDQ-8 summary index ranges from 0 to 100, where lower scores indicate a better perceived health status. Negative changes from baseline indicate improvement. | Baseline, Week 12 | 
| Mean Clinical Global Impression of Change (CGI-C) Score at Week 12 | The Clinical Global Impression of Change (CGI-C) score is a clinician's rating scale for assessing Global Improvement of Change. The CGI-C rates improvement by 7 categories: very much improved (1), much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7). The CGI-C score ranges from 1 to 7, with lower scores indicating improvement. | Baseline, Week 12 | 
| Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living) | The Unified Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The Part II score is the sum of the answers to the 13 questions related to Activities of Daily Living, and ranges from 0-52. Higher scores are associated with more disability. Negative values indicate improvement from baseline. | Baseline, Week 12 | 
| Mean Change From Baseline to Week 12 in OFF Time | The Parkinson's Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study visits. It reflects both time awake and time asleep. Daily totals are normalized to a 16-hour scale (i.e., 16 hours of awake time). The normalized totals for the 3 days prior to the visit are averaged for the analysis. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Negative change from baseline for OFF time indicates improvement. | Baseline, Week 12 | 
| Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination) | The Unified Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The Part III score is the sum of the 27 answers related to Motor Examination, and ranges from 0-108. Higher scores are associated with more disability. Negative values indicate improvement from baseline. | Baseline, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carbidopa, Levodopa, Efficacy, Levodopa-carbidopa intestinal gel, Advanced Parkinson's Disease