A Study to Assess the Efficacy, Safety and Tolerability of ABT-SLV187 Monotherapy in Subjects With Advanced Parkinson's Disease (PD) and Persistent Motor Complications, Despite Optimized Treatment With Available Anti-Parkinsonian Medications

Study Overview
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Brief Summary
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The primary objective of this study is to measure the efficacy of ABT-SLV187 in subjects with advanced Parkinson's disease.

Detailed Description
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The study was composed of a screening period followed by 2 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 (N-J) tube placement. N-J Test Period (2 to 14 days): first hospitalization period, Baseline assessments, placement of N-J tube, and optimization of levodopa-carbidopa intestinal gel (LCIG) treatment via N-J tube and infusion pump (participant was hospitalized for N-J tube placement but hospitalization was not required for entire duration of LCIG treatment optimization). PEG-J Period (12 weeks): second hospitalization period; placement of PEG-J tube; further optimization of LCIG treatment.

Official Title
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An Open-Label, Single-Arm, Baseline-Controlled, Multicenter Study to Evaluate the Efficacy, Safety and Tolerability of ABT-SLV187 Monotherapy in Subjects With Advanced Parkinson's Disease and Persistent Motor-Complications Despite Optimized Treatment With Available Anti-Parkinsonian Medication

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: Diagnosis of idiopathic Parkinson's disease according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria. Subjects have 4 or 5 in modified Hohn and Yahr (H & Y) classification of disease severity at Off state determined by the UPDRS Part V at Screening Visit 1. The subject's advanced Parkinson's disease must be levodopa-responsive as judged by the Investigator. Subjects have had optimal treatment with available Parkinson's disease medication as defined by local standards of care and, based upon the judgment of the Investigator, and their symptoms are judged inadequately controlled on this optimized treatment. Optimized treatment is defined as the maximum therapeutic effect obtained with available anti-parkinsonian pharmacological therapy when no further improvement is expected regardless of any additional manipulations of levodopa and/or other anti parkinsonian medication; this will be based on the Investigator's best clinical judgment. Presence of a recognizable Off and On state (motor fluctuations) as confirmed by UPDRS Part III (in both On and Off states), and by the Parkinson's Disease Diary© which must be observed and confirmed at Screening Visit 1. Subjects must be experiencing a minimum of 3 hours per day of Off time, as estimated by the Investigator and supported by the UPDRS at Screening Visit 1 and the Parkinson's Disease Diaries at baseline. The Off time must occur during a continuous 16-hour interval, including the portion of the day during which the subject is awake the majority of the time (e.g., 5 AM to 9 PM, 7 AM to 11 PM). Exclusion Criteria: Parkinson's disease diagnosis is unclear or a suspicion of other parkinsonian syndromes exists, such as secondary Parkinsonism (caused by drugs, toxins, infectious agents, vascular disease, trauma, brain neoplasm), Parkinson's-plus syndromes (e.g., multiple system atrophy, progressive supranuclear palsy) or the other neurodegenerative diseases that might mimic the symptoms of Parkinson's disease . Subjects who have undergone neurosurgery for the treatment of Parkinson's disease . Current primary psychiatric diagnosis of acute psychotic disorder or other uncontrolled primary psychiatric diagnoses, (e.g., bipolar disorder or major depressive disorder per Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria. Alzheimer's disease; or other significant cognitive impairment or dementia (defined as Mini-Mental State Examination (MMSE) total score < 24). Subject has significant current suicidal ideation within the previous year as evidenced by answering yes to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at Screening or any history of suicide attempts. A low B12 level or low-normal B12 level (less than 300 pg/mL) with elevated methylmalonic acid (MMA). Note: Abnormal Vitamin B12 of questionable clinical significance (i.e., indeterminate or low normal results) prior to or at Screening Visit 2 require appropriate interpretation in conjunction with MMA and homocysteine laboratory values prior to proceeding further into the study.

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 via the N-J tube during the nasojejunal (N-J) 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 PEG-J 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). | Drug: Levodopa-carbidopa intestinal gel<br>* Dose levels will be individually optimized. 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>* Other names: LCIG;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 |
| --- | --- | --- |
| Average Daily Normalized Off Time: Change From Baseline To The Final PEG-J Visit | 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 (end of screening period) and Final PEG-J Visit (up to week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Daily Normalized On Time Without Troublesome Dyskinesia: Change From Baseline To The Final PEG-J Visit | 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. Positive change from baseline for on time indicates improvement. | Baseline (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Parkinson's Disease Questionnaire (PDQ-39) Summary Index: Change From Baseline To The Final PEG-J Visit | 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 (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Clinical Global Impression - Change (CGI-I) Score at the Final PEG-J Visit | 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. | Final PEG-J Visit (up to week 12) | 
| Patient Global Impression of Change (PGI-C) Score at the Final PEG-J Visit | The PGI-C is a 7-point response scale. The subjects were to rate their change in status from Screening Visit 1 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. The responses of Minimally improved, Much improved, and Very much improved on the PGI-C were used to define responders. | Final PEG-J Visit (up to week 12) | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score: Change From Baseline To The Final PEG-J Visit | 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 (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Part IIl Score: Change From Baseline To The Final PEG-J Visit | 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 (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Average Daily Normalized On Time With Troublesome Dyskinesia: Change From Baseline To The Final PEG-J Visit | 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. Positive change from baseline for on time indicates improvement. | Baseline (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Number of Participants With Potentially Clinically Significant Values for 12-lead Electrocardiogram (ECG) | 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), QT interval corrected for heart rate using Fridericia's formula (QTcF), and baseline (BL). Increase and decrease are signified by ↑ and ↓, respectively. n = the number of participants with available data at each time point. | From Baseline (end of screening period) to Final PEG-J Visit (up to week 12) | 
| Parkinson's Disease Questionnaire (PDQ-39) Mobility, Emotional Well-Being, Stigma, Social Support, Cognition, Communication, and Bodily Discomfort Domain Scores: Change From Baseline To The Final PEG-J Visit | The PDQ-39 is a self-administered questionnaire which comprises 39 items (each question answered on a 5-point scale) addressing 8 domains of health in Parkinson's disease patients: Mobility (e.g., fear of falling when walking) includes 10 questions; Emotional Well-being (e.g., feelings of isolation) includes 6 questions; Stigma (e.g., social embarrassment) includes 4 questions; Social Support includes 3 questions; Cognition includes 4 questions; Communication includes 3 questions; and Bodily Discomfort includes 3 questions. 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 (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Total Score: Change From Baseline To The Final PEG-J Visit | 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 to176, with 176 representing the worst (total) disability, and 0 representing no disability. | Baseline and Final PEG-J Visit (up to Week 12) | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Part I Score: Change From Baseline To The Final PEG-J Visit | 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 to 16 and higher scores are associated with more disability. | Baseline (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Part IV Score: Change From Baseline To The Final PEG-J Visit | 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 to 23 and higher scores are associated with more disability. | Baseline (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Average Daily Normalized Off Time Excluding Subjects Who Did Not Receive LCIG During the Entire PEG-J Period: Change From Baseline To The Final PEG-J Visit | 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 (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Average Daily Normalized Off Time Including All PD Diaries Regardless if They Were Completed After the Subject Had Used a Concomitant Anti-Parkinsonian Medication: Change From Baseline To The Final PEG-J Visit | 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 (end of screening period) and Final PEG-J Visit (up to week 12) | 
| Average Daily Normalized Off Time at Baseline and Each Visit: Change From Baseline To The Final PEG-J Visit | 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. n= the number of participants with available data at each time point. | Baseline (end of screening period) and Weeks 2, 4, 6, 8, 10, and 12 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) is any untoward medical occurrence in a participant which does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent AEs (TEAEs) are defined as any event that began or worsened in severity after N-J placement. The investigator assessed the relationship of each event to the use of study drug as Reasonable Possibility or No Reasonable Possibility. For more details on adverse events please see the AE section below. | From N-J placement to the end of study or early termination of treatment, including the removal of PEG-J (up to 17 weeks), plus 30 days. | 
| 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), body temperature (Temp), and baseline (BL). Increase and decrease are signified by ↑ and ↓, respectively. | From Baseline (end of screening period) to Final PEG-J Visit (up to week 12) | 
| Number of Participants With Potentially Clinically Significant Values for Hematology Parameters | Terms abbreviated in the table include females (f), males (m), and femtoliters (fL). | From Baseline (end of screening period) to Final PEG-J Visit (up to week 12) | 
| 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). | From Baseline (end of screening period) to Final PEG-J Visit (up to week 12) | 

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