Safety/Efficacy Study of Levodopa-Carbidopa Intestinal Gel in Parkinson's Subjects

Study Overview
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Brief Summary
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Long term safety and efficacy (12 months) of levodopa-carbidopa intestinal gel.

Detailed Description
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Study S187.3.003 (NCT00360568) is a Phase 3, 12-month, open-label, multicenter continuation treatment study of the safety, tolerability, and efficacy of levodopa-carbidopa intestinal gel (LCIG) in the treatment of participants with levodopa-responsive Parkinson's disease (PD) with persistent motor fluctuations despite optimized treatment with available PD medications. All participants received LCIG. Only participants who completed 12 weeks of double-blind, double-dummy treatment in Study S187.3.001 or S187.3.002 (NCT00357994/ NCT00660387) qualified for enrollment in this 12-month continuation treatment study.

Official Title
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Open-Label, 12-Month Safety and Efficacy Study of Levodopa - Carbidopa Intestinal Gel in Levodopa-Responsive Parkinson's Disease Subjects

Conditions
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Dyskinesias, Parkinson's Disease, Severe Motor Fluctuations

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 Kingdon Parkinson's Disease Society (UKPDS) Brain Bank Criteria Levodopa-responsive with severe motor fluctuations Completion of protocol S187.3.001 (NCT00357994) or S187.3.002 (NCT00660387) and continue to meet the inclusion criteria for the preceding study Exclusion Criteria: Patients with medically relevant abnormal findings (labs, electrocardiogram [ECG], physical examination, adverse events, psychiatric, neurological or behavioral disorders, etc.) at end of the double-blind phase (Week 12) of Study S187.3.001 (NCT00357994) or Study S187.3.002 (NCT00660387)

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 received LCIG, delivered through a percutaneous endoscopic gastrostomy with jejunal extension (PEG-J), administered for up to 12 months (52 weeks). Starting dose of LCIG was based on the participant's optimized oral levodopa-carbidopa dose that the subject was receiving just prior to randomization in Study S187.3.001 (NCT00357994) or Study S187.3.002 (NCT00660387), administered in the morning of the first day following Study Day 86 of either of these 2 previous studies. The LCIG infusion was expected to infuse over approximately16 hours each day with a rate of infusion within the range of 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 AEs (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. | From study enrollment to the end of study or early termination of treatment, including the removal of PEG-J, plus 30 days. | 
| Number of Participants With Device Complications | Complications of the infusion device were collected. Pump, intestinal tube, PEG, 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 device site reaction. | 12 months | 
| Number of Participants With Potentially Clinically Significant Values for Hematology Parameters | Terms abbreviated in the table include females (f) and males (m). | 12 months | 
| Number of Participants With Potentially Clinically Significant Values for Clinical Chemistry Parameters | Terms abbreviated in the table include upper limit of normal (ULN), male (m), and female (f). | 12 months | 
| 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. | 12 months | 
| 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. | 12 months | 
| Number of Participants With Sleep Attacks at Baseline and Endpoint | 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. | Baseline, Endpoint (Month 12 or last post-baseline visit) | 
| Summary of Minnesota Impulsive Disorder Interview (MIDI) Assessment of Intense Impulsive Behavior at Baseline (BL) and Post-baseline (PBL) | 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, Post-baseline (up to Month 12) | 
| 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 concerning problems 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 (Month 12 or last post-baseline visit) | 
| 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/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. | up to Month 12 | 
| Number of Participants With Clinically Significant Neurological Examination Findings | The neurologic examination was to be done during On time. The neurological examination assessed: cranial nerves - assessment of cranial nerves II - XII, excluding fundoscopic examination; motor system - assessment of tone, strength, and abnormal movements; sensory system - including light touch, pinprick, joint position, and vibratory sense; reflexes - assessment of deep tendon reflexes and plantar responses (Babinski sign); coordination - assessment of upper and lower extremities; gait - assessment of base and tandem gait; station - assessment of posture and stability. | up to 12 months | 
| Columbia-Suicide Severity Rating Scale (C-SSRS) Findings | The Columbia-Suicide Severity Rating Scale (C-SSRS) is a systematically administered instrument developed to track suicidal adverse events across a treatment study. The instrument is designed to assess suicidal behavior and ideation, track and assess all suicidal events, as well as the lethality of attempts. Suicidal ideation categories include the following: wish to be dead; nonspecific active suicidal thoughts; active suicidal ideation without intent to act; active suicidal ideation with some intent to act but no plan; active suicidal ideation with plan and intent. Suicidal behavior categories include the following: actual attempt; interrupted attempt; aborted attempt; preparatory acts or behavior; suicidal behavior; completed suicide. | up to 12 months | 
| Number of Participants Taking at Least 1 Concomitant Medication During the Study | Concomitant medications include medications 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. | 12 months | 

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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| Change From Baseline in Average Daily On Time Without Troublesome Dyskinesia at Month 12 | 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Part I Score at Endpoint | 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 or last post-baseline visit) | 
| 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 (Month 12 months or last post-baseline visit) | 

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