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)

Phase 3

Completed

Conditions: Parkinson's Disease (PD)

Interventions: 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

Registration Number: NCT02799381

Lead Sponsor: AbbVie

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Optimized Medical Treatment (OMT)	Optimized antiparkinsonian treatment	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.
Levodopa-Carbidopa Intestinal Gel (LCIG)	Levodopa-Carbidopa Intestinal Gel (LCIG)	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.
Levodopa-Carbidopa Intestinal Gel (LCIG)	CADD-Legacy ambulatory infusion pump	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.
Levodopa-Carbidopa Intestinal Gel (LCIG)	Percutaneous endoscopic gastrostomy tube	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.
Levodopa-Carbidopa Intestinal Gel (LCIG)	Jejunal extension tube	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.

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score	Baseline, Week 12	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.

Secondary Outcome Measures

Name	Time	Method
Mean Clinical Global Impression of Change (CGI-C) Score at Week 12	Baseline, 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.
Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living)	Baseline, Week 12	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.
Mean Change From Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index	Baseline, Week 12	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.
Mean Change From Baseline to Week 12 in OFF Time	Baseline, Week 12	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.
Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination)	Baseline, Week 12	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.
Mean Change From Baseline to Week 12 in ON Time Without Troublesome Dyskinesia	Baseline, Week 12	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.

Trial Locations

Locations (28): Oulun yliopistollinen sairaala /ID# 150947
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Oulu, Finland
A.O. Univ. Ospedali Riuniti /ID# 150853
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Ancona, Marche, Italy
Policlinico Universitario Campus Bio-Medico /ID# 150846
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Rome, Lazio, Italy
Pecsi Tudomanyegyetem Klinikai Kozpont I. sz. Belgyogyaszati Klinika /ID# 170116
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Pécs, Pecs, Hungary
University General Hospital of Heraklion "PA.G.N.I" /ID# 150956
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Heraklion, Greece
Seconda Universita' di Napoli /ID# 150851
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Naples, Italy
Parkinson's Disease Treatment Center of Southwest Florida /ID# 150095
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Port Charlotte, Florida, United States
Univerzitna nemocnica L. Pasteura /ID# 150146
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Košice - Západ, Kosicky Kraj, Slovakia
Univerzitna Nemocnica Bratislava /ID# 150144
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Bratislava, Slovakia
Azienda USL Toscana Centro /ID# 150770
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Florence, Italy
Hospital Universitario Cruces /ID# 203807
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Barakaldo, Spain
Central Texas Neurology Consul /ID# 150088
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Round Rock, Texas, United States
Szegedi Tudomanyegyetem /ID# 170115
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Szeged, Hungary
Mediterraneo Hospital /ID# 150955
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Glyfada, Greece
Hospital Univ Ramon y Cajal /ID# 150152
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Madrid, Spain
Semmelweis Egyetem /ID# 170117
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Budapest, Hungary
Hospital General Univ de Elche /ID# 150154
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Elche, Spain
Univerzitna nemocnica Martin /ID# 150145
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Martin, Zilinsky Kraj, Slovakia
Policlinico Tor Vergata /ID# 151167
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Rome, Italy
Hospital Universitario Infanta /ID# 159696
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Madrid, Spain
Hospital Regional Universitari /ID# 171485
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Málaga, Malaga, Spain
Hospital Virgen de la Salud /ID# 166297
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Toledo, Spain
Hospital Universitario Virgen Macarena /ID# 158861
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Sevilla, Spain
Helsinki Univ Central Hospital /ID# 151214
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Helsinki, Finland
University Hospital of Ioannin /ID# 150954
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Ioannina, Greece
Univerzitna Nemocnica Bratislava /ID# 150171
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Bratislava, Slovakia
Hospital General Universitario Gregorio Maranon /ID# 150155
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Madrid, Spain
Hospital Univ de la Princesa /ID# 150157
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Madrid, Spain