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

Study Overview
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Brief Summary
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The primary objective of this study will be to provide further evidence of the long-term safety and tolerability of levodopa-carbidopa intestinal gel (Duodopa®) over 12-months in participants with advanced Parkinson's disease (PD) and severe motor fluctuations.

Detailed Description
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The study was composed of a screening period followed by 3 sequential on-treatment periods, as follows: Screening Period (up to 28 days): determination of eligibility and discontinuation of antiparkinsonian disease medications other than levodopa-carbidopa immediate release (LC-oral) prior to nasojejunal (NJ) tube placement. NJ Test Period (2 to 14 days): first hospitalization period, Baseline assessments, placement of NJ tube, and optimization of levodopa-carbidopa intestinal gel (LCIG) treatment via NJ tube and infusion pump (participant was hospitalized for NJ tube placement but hospitalization was not required for entire duration of LCIG treatment optimization). PEG-J Period (2 to 14 days): second hospitalization period; placement of PEG-J tube; further optimization of LCIG treatment. Post PEG-J Long-Term Treatment Period (Day 28 to Day 378): LCIG administration via a permanent PEG-J tube and infusion pump, with dosage adjusted according to clinical condition.

Official Title
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An Open-Label, 12-Month Safety and Efficacy Study of Levodopa - Carbidopa Intestinal Gel in Levodopa-Responsive Subjects With Advanced Parkinson's Disease and Severe Motor Fluctuations Despite Optimized Treatment With Available Parkinson's Disease Medications

Conditions
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Advanced Parkinson's Disease

Intervention / Treatment
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* Drug: Levodopa-carbidopa intestinal gel
* Device: CADD-Legacy® 1400 ambulatory infusion pump
* Device: PEG tube
* Device: J-tube


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Idiopathic Parkinson's disease (PD) according to United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria Levodopa-responsive with severe motor fluctuations Recognizable off and on state (motor fluctuations) confirmed by diary Exclusion Criteria: Diagnosis is unclear or a suspicion of other parkinsonian syndromes exists such as secondary parkinsonism Undergone surgery for the treatment of PD Contraindications to levodopa (such as narrow angle glaucoma)

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levodopa-Carbidopa Intestinal Gel (LCIG)<br>All participants were to receive LCIG, via the NJ tube during the nasojejunal (NJ) Test Period and delivered to the proximal small intestine via percutaneous endoscopic gastrostomy - with jejunal extension tube (PEG-J) during the Post-PEG-J Long-Term Treatment Period. The starting dose was individually determined based on the daily dose of oral levodopa prior to study enrollment. The infusion dose was individually optimized for each participant on the basis of response and potential adverse events. During the Post-PEG-J Long-Term Treatment Period, LCIG was expected to be infused continuously over approximately 16 hours daily with a rate of infusion ranging from 1 to 10 mL/hour (20 to 200 mg of levodopa/hour), in most instances. | Drug: Levodopa-carbidopa intestinal gel<br>* Infusion should be kept within a range of 0.5-10 mL/hour (10-200 mg levodopa/hour) and is usually 2-6 mL/hour (40-120 mg levodopa/hour).<br>Device: CADD-Legacy® 1400 ambulatory infusion pump<br> <br> Device: PEG tube<br>* percutaneous endoscopic gastrostomy tube<br>Device: J-tube<br>* jejunal tube<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths and Discontinuations Due to AEs | AE=any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that: results in death; is life-threatening (an event in which the subject was at risk of death at the time of the event); requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events. Treatment-emergent events (TEAE or TESAE)=those starting after the first dose of study drug. Severe=severity reported as 'severe' or missing. Possibly or Probably Treatment Related=drug-event relationship reported as 'possible', 'probable' or missing. Death=a fatal outcome of an SAE or AE. | Screening through Day 378 + 30 days | 
| Number of Participants With Device Complications During the Nasojejunal (NJ) Test Period | Complications of the infusion device were collected during the NJ Test period. Pump, intestinal tube, NJ tube, and other complications included (but were not limited to) device breakage, device leakage, device malfunction, device misuse, device occlusion, intentional and unintentional device removal by participant, complication of device insertion, device dislocation, device breakage, device dislocation, and post-procedural hemorrhage. | NJ Test Period (from 2 to 14 days) | 
| Number of Participants With Device Complications During the Percutaneous Endoscopic Gastrostomy - With Jejunal Extension Tube (PEG-J) Surgery and Post-PEG Long Term Treatment Periods | Complications of the infusion device were collected during the PEG-J Surgery and Post-PEG Long-Term Treatment periods. Pump, PEG-J, stoma, and other complications included (but were not limited to) device breakage, device leakage, device malfunction, device misuse, device occlusion, intentional and unintentional device removal by participant, complication of device insertion, device dislocation, device breakage, device dislocation, and post-procedural hemorrhage. | PEG-J Surgery Period (from 2 to 14 days) through the Long Term Treatment Period (Day 28 to Day 378) | 
| Number of Participants With Potentially Clinically Significant Values for Hematology Parameters | Potentially clinically significant values for red blood cells (RBCs), hemoglobin, and hematocrit are specified for females (f) and males (m) separately in the category rows. | Screening through Day 378 | 
| Number of Participants With Potentially Clinically Significant Values for Clinical Chemistry Parameters | Terms abbreviated in the table include aspartate aminotransferase (AST), upper limit of normal (ULN), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), female (f), and male (m). | Screening through Day 378 | 
| Number of Participants With Potentially Clinically Significant Vital Sign Parameters | Terms abbreviated in the table include supine systolic blood pressure (SuSBP), standing systolic blood pressure (StSBP), orthostatic systolic blood pressure (OSBP), supine diastolic blood pressure (SuDBP), standing diastolic blood pressure (StDBP), orthostatic diastolic blood pressure (ODBP), supine pulse (SuP) in beats per minute (bpm), standing pulse (StP), and body temperature (Temp). Increase and decrease are signified by ↑ and ↓, respectively. | up to 56 weeks | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Parameters | Terms abbreviated in the table include heart rate (HR) in beats per minute (bpm), PR interval (PRI), QT interval corrected for heart rate using Bazett's formula (QTcB), and QT interval corrected for heart rate using Fridericia's formula (QTcF). Increase and decrease are signified by ↑ and ↓, respectively. | Screening through Day 378 | 
| Number of Participants With Sleep Attacks at Baseline | To prospectively monitor for the possible development of sleep attacks, participants were asked if they had 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. Those participants who reported 1 or more sleep attacks were asked to report the number of sleep attacks they experienced, whether they experienced sleepiness or drowsiness prior to the sleep attack, whether they experienced a 'bad' outcome or problem due to a sleep attack, and if so, how many 'bad' outcomes or problems they experienced. | Baseline | 
| Number of Participants With Sleep Attacks During the Post-PEG Long-Term Treatment Period | To prospectively monitor for the possible development of sleep attacks, participants were asked if they had 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. Those participants who reported 1 or more sleep attacks were asked to report the number of sleep attacks they experienced, whether they experienced sleepiness or drowsiness prior to the sleep attack, whether they experienced a 'bad' outcome or problem due to a sleep attack, and if so, how many 'bad' outcomes or problems they experienced. | During the Post-PEG Long-Term Treatment Period (Day 28 through Day 378) | 
| Summary of Minnesota Impulsive Disorder Interview (MIDI) Assessment of Intense Impulsive Behavior at Baseline (BL) and During the Post-PEG Long-term Treatment (PPLT) Period | The MIDI is a validated assessment of impulsive behavior consisting of a semistructured clinical interview assessing pathological gambling, trichotillomania (compulsive hair-pulling), kleptomania (compulsive stealing), pyromania (compulsive fire setting), intermittent explosive disorder, compulsive buying, and compulsive sexual behavior. | Baseline, during the Post-PEG Long-term Treatment Period (Day 28 through Day 378) | 
| Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score at Endpoint | The AIMS is an investigator-completed rating scale that has a total of 12 items rating involuntary movements of various areas of the participant's body. Items 1 through 10 are rated on a 5-point scale of severity from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe), and items 11 and 12 are yes/no questions regarding issues with teeth or dentures. The total AIMS score was calculated by summing items 1-10, with a possible range of 0-40; a negative change indicates improvement. The AIMS was to be performed at consistent times, when the subject was experiencing his/her worst On time (dyskinesia [involuntary muscle movement]). | Baseline, Endpoint (last Post-PEG Long-Term Period visit up to Day 378) | 
| Number of Participants With Confirmed Cases of Melanoma | A comprehensive assessment for the presence of melanoma was performed during the screening period and at early termination or end of study by a dermatologist experienced with the diagnosis of the condition. If a suspicious lesion was present, a biopsy was obtained for proper diagnosis. | Screening up to Day 378 | 
| Number of Participants Taking at Least 1 Concomitant Medication During the Study | Concomitant medications include those started on or after the first open-label LCIG infusion as well as medications started prior to the first open-label infusion but continued during the study. | Screening up to Day 378 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Daily Off Time at Endpoint | Based on the Parkinson's Disease Symptom Diary. On time is when PD symptoms are well controlled by the drug. Off time is when PD symptoms are not adequately controlled by the drug. The diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected clinic 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. Negative change from baseline for off time indicates improvement. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Average Daily Normalized On Time With Troublesome Dyskinesia at Endpoint | Based on the Parkinson's Disease Symptom Diary. On time is when PD symptoms are well controlled by the drug. Off time is when PD symptoms are not adequately controlled by the drug. The diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected clinic 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. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Average Daily On Time Without Troublesome Dyskinesia at Endpoint | Based on the Parkinson's Disease Symptom Diary. On time is when PD symptoms are well controlled by the drug. Off time is when PD symptoms are not adequately controlled by the drug. On time without troublesome dyskinesia (involuntary muscle movement) is defined as on time without dyskinesia and on time with non-troublesome dyskinesia. The diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected clinic 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. Positive change from Baseline for on time without troublesome dyskinesia indicates improvement. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Clinical Global Impression - Status (CGI-S) Score at Baseline and Clinical Global Impression - Improvement (CGI-I) Score at Endpoint | The CGI-S is a global assessment by the Investigator of current symptomatology and impact of illness on functioning. The ratings of the CGI-S are as follows: 1 = normal, 2 = borderline ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, and 7 = among the most extremely ill. The CGI-I is a global assessment by the Investigator of the change in clinical status since the start of treatment. The CGI-I ratings are as follows: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Part I Score at Month 12 | The UPDRS is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. 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. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score at Endpoint | The 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 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. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score at Endpoint | The 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 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. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Total Score at Endpoint | The UPDRS is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The 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 will range from 0-176, with 176 representing the worst (total) disability, and 0 representing no disability. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Part IV Score at Endpoint | The UPDRS is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The Part IV Score is the sum of the answers to the 11 questions that comprise Part IV, each of which are measured on a 5-point scale (0-4) or a 2-point scale (0 or 1). The Part IV score ranges from 0-23 and higher scores are associated with more disability. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Summary Index at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. These include: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. The PDQ-39 Summary Index is the sum of all answers divided by the highest score possible (i.e. number of answers multiplied by 4) which is multiplied by 100 to put the score on a 0-100 scale. Higher scores are associated with more severe symptoms. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Mobility Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Mobility (e.g., fear of falling when walking) includes 10 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Activities of Daily Living Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Activities of Daily Living (e.g., difficulty cutting food) includes 6 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Emotional Well-Being Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Emotional Well-being (e.g., feelings of isolation) includes 6 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Stigma Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Stigma (e.g., social embarrassment) consists of 4 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Social Support Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Social Support includes 3 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Cognition Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Cognition includes 4 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Communication Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Communication includes 3 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Parkinson's Disease Questionnaire (PDQ-39) Bodily Discomfort Domain Score at Endpoint | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients. The PDQ-39 Domain: Bodily Discomfort includes 3 questions, each answered on a 5-point scale. The domain scores are calculated by first summing the answers to the questions in the domain. The sum is divided by the highest score possible (i.e., number of answers multiplied by 4) and the quotient is multiplied by 100 to put the score on a scale from 0 to 100, where lower scores indicate a better perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in EuroQol Quality of Life Scale (EQ-5D) Summary Index at Endpoint | The EQ-5D is a participant answered questionnaire scoring 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by applying a formula that essentially attaches values (also called QOL weights or QOL utilities) to each of the levels in each dimension. EQ-5D Summary Index values range from -0.11 to 1.00 with positive change indicating improvement. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in EuroQol Quality of Life Scale (EQ-5D) Visual Analogue Scale (VAS) at Endpoint | The EQ-5D VAS records the participant's self-rated health on a scale from 0-100 where 100 is the 'best imaginable health state' and 0 is the 'worst imaginable health state'. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 
| Change From Baseline in Zarit Burden Interview (ZBI) Total Score at Endpoint | The ZBI is a 22-item questionnaire regarding the caregiver/subject relationship and evaluates the caregiver's health condition, psychological well-being, finances and social life. Each question is answered on a 5-point scale (0=never, 1=rarely, 2=sometimes, 3=quite frequently, and 4=nearly always). The caregiver burden is evaluated by the total score (Range 0 to 88) obtained from the sum of the answers to the 22 questions. Higher scores are associated with a higher level of burden for the caregiver. | Baseline, Endpoint (last post-baseline visit up to Day 378) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe motor fluctuations, levodopa, levodopa/carbidopa intestinal gel, efficacy, dyskinesia, Parkinson's Disease, carbidopa, DUOPA