Study of Safety, Tolerability, Pharmacokinetics, and Efficacy of ABT-SLV187 in Subjects With Advanced Parkinson's Disease

Study Overview
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Brief Summary
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To explore the safety, tolerability, pharmacokinetics and efficacy of ABT-SLV187 in advanced Parkinson's disease (PD) patients with severe motor complications. The complications of medical devices for the naso-jejunum (NJ) infusion system of ABT-SLV187 will also be investigated.

Official Title
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An Open-Label, Single-Arm, Baseline-Controlled, Multicenter Study to Explore the Safety, Tolerability, Pharmacokinetics, and Efficacy of ABT-SLV187 in Subjects With Advanced Parkinson's Disease

Conditions
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Advanced Parkinson's Disease

Intervention / Treatment
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* Drug: ABT-SLV187
* Drug: Oral Levodopa/Carbidopa
* Device: Infusion Pump: CADD-Legacy® 1400 Pump
* Device: NJ-Tube: Silicon ED Tube
* Device: Adaptor: Hakko Adaptor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Idiopathic PD according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank criteria PD stage corresponds to 4 or 5 in the 'off' state according to the modified Hoehn & Yahr (H & Y) classification of disease severity Levodopa-responsive subjects demonstrate some identifiable 'ON response' established by observation by Investigator and demonstrate severe motor fluctuations in spite of individually optimized treatment and where therapy options are indicated 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 Subjects with any neurological deficit that may interfere with the study assessments

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 99 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<br>Following a 28-day Run-in Period where participants are switched from prior anti-PD medications to monotherapy with an oral 100 mg levodopa/10 mg carbidopa tablet (optimized every 3rd hour during waking hours), participants receive ABT-SLV187 (levodopa-carbidopa intestinal gel), administered over 16 hours a day with an infusion pump directly into the proximal jejunum by an NJ tube, for 3 weeks. The individually-adjusted infusion dose (composed of the morning dose, the continuous maintenance dose, and the extra dose) is optimized by the Investigator for each participant during the study based on the participant's symptoms. | Drug: ABT-SLV187<br> <br> * Other names: Levodopa-carbidopa intestinal gel (LCIG);Drug: Oral Levodopa/Carbidopa<br>* Tablet; contains 100 mg levodopa and 10 mg carbidopa<br>Device: Infusion Pump: CADD-Legacy® 1400 Pump<br>* General infusion pump, manufactured by Smiths Medical (US)<br>Device: NJ-Tube: Silicon ED Tube<br>* Device used to deliver nutrition/drug to stomach/intestine or to aspirate stomach fluid, manufactured by Create Medic Co., Ltd. (Japan)<br>Device: Adaptor: Hakko Adaptor<br>* Accessory set for fluid infusion set, consisting of caps, connectors and adapters, etc, manufactured by Hakko Medical (Japan)<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), and AEs Leading to Discontinuation During the Run-in Period | AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with this treatment. SAE: an event that results in the death of a subject, is life threatening, results in hospitalization or prolongation of hospitalization, is a congenital anomaly, results in persistent or significant disability/incapacity, or other important medical event. Severity was rated as mild, moderate, or severe. AEs of special interest included: device-associated gastrointestinal disorders; cardiovascular fatalities; aspiration including aspiration pneumonia; a diagnosis of peripheral polyneuropathy (axonal, demyelinating or mixed type); possible symptoms of peripheral polyneuropathy; clinically significant weight loss. 'AEs at least possibly related' are defined as those that were assessed by investigator as probably related or possibly related. | During the Run-in period (up to approximately 28 days) | 
| Number of Participants With AEs, SAEs, and AEs Leading to Discontinuation During the ABT-SLV187 Treatment Period | AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with this treatment. SAE: an event that results in the death of a subject, is life threatening, results in hospitalization or prolongation of hospitalization, is a congenital anomaly, results in persistent or significant disability/incapacity, or other important medical event. Severity was rated as mild, moderate, or severe. AEs of special interest included: device-associated gastrointestinal disorders; cardiovascular fatalities; aspiration including aspiration pneumonia; a diagnosis of peripheral polyneuropathy (axonal, demyelinating or mixed type); possible symptoms of peripheral polyneuropathy; clinically significant weight loss. 'AEs at least possibly related' are defined as those that were assessed by investigator as probably related or possibly related. | From NJ placement to end of ABT-SLV187 Treatment Period (Day 21) +30 days | 
| Number of Participants With Potentially Clinically Significant (PCS) Hematology Results During the ABT-SLV187 Treatment Period | M=male, F=female, MCV=mean corpuscular volume, MCH=mean corpuscular hemoglobin, MCHC=mean corpuscular hemoglobin concentration. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Number of Participants With PCS Blood Biochemistry Results During the ABT-SLV187 Treatment Period | M=male, F=female, γ-GTP=gamma-glutamyl transpeptidase. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Number of Participants With PCS Values in Special Laboratory Parameters During the ABT-SLV187 Treatment Period | M=male, F=female | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Number of Participants With Potentially Clinically Significant Urinalysis Results During the ABT-SLV187 Treatment Period |  | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Number of Participants With Potentially Clinically Significant (PCS) Vital Signs Results During the ABT-SLV187 Treatment Period | ↓=decrease, ↑=increase, BL=baseline, temp.=temperature, SBP=systolic blood pressure, Sup.=supine, Sta.=standing, DBP=diastolic blood pressure. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Number of Participants With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Results During the ABT-SLV187 Treatment Period | High potentially clinically significant Bazett's heart rate-corrected QT interval (QTcB) values were: 450 msec for males / 470 msec for females. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Mean Change From Baseline to the End of Treatment in Percentage of Ratings in the Normal State on the Treatment Response Scale (TRS) I | Participants were video recorded a total of 10 times for 1 to 2 minutes every 60 minutes while performing a standardized sequence of motor tasks: rest, finger taps, rapid alternating movement of hands, arising from chair and gait, including confirmation of postural stability. Based on these video recordings, a Video Evaluation Committee consisting of 3 neurologists individually evaluated the following Video Assessment and Treatment Response Scale (TRS) under blinded conditions: Finger Taps, Rapid Alternating Movement of Hands, Arising from Chair, Gait, Body Bradykinesia and Hypokinesia, Dyskinesia. The average of the neurologists' evaluations was calculated as a percentage of ratings in the Normal state (ie, mild OFF to ON with mild dyskinesia) on the TRS I (total 10 assessments per day). | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to the End of Treatment in Percentage of Ratings in the OFF and Dyskinesia States on the TRS I and the Normal, OFF, and Dyskinesia States on the TRS II | Participants were video recorded a total of 10 times for 1 to 2 minutes every 60 minutes while performing a standardized sequence of motor tasks: rest, finger taps, rapid alternating movement of hands, arising from chair and gait, including confirmation of postural stability. Based on these video recordings, a Video Evaluation Committee consisting of 3 neurologists individually evaluated the following Video Assessment and TRS under blinded conditions: Finger Taps, Rapid Alternating Movement of Hands, Arising from Chair, Gait, Body Bradykinesia and Hypokinesia, Dyskinesia for TRS I, with the addition of Tremor at Rest and Postural Stability for TRS II. The average of the 3 neurologists' evaluations was calculated as a percentage of ratings in the Normal state (ie, mild OFF to ON with mild dyskinesia), the Off state (moderate OFF to severe OFF), and the Dyskinesia state (ON with moderate dyskinesia to ON with severe dyskinesia) on the TRS I or II. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Change From Baseline to the End of Treatment in Parkinson's Disease Diary Assessment | For each half hour period during 3 consecutive days prior to each assessment of the diary, participants (and/or their caregivers) entered into a diary whether they were asleep, in the ON motor state or in the OFF motor state in the following 5 grades: asleep, OFF, ON (no dyskinesia [D]), ON with non-troublesome dyskinesia (NTD), ON with troublesome dyskinesia (TD). 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. Dyskinetic time is time with involuntary muscle movement. The ON or OFF times were calculated as the average of 3 daily times from the diaries. w/o = without, w/ = with | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Baseline and Endpoint (End of Treatment) Video Scoring of Unified Parkinson's Disease Rating Scale (UPDRS) Items and Dyskinesia | Participants were video recorded a total of 10 times for 1 to 2 minutes every 60 minutes while performing a standardized sequence of motor tasks. Based on these video recordings, a Video Evaluation Committee consisting of 3 neurologists individually evaluated the video under blinded conditions using the following assessments: Tremor at Rest (UPDRS item #20), Finger Taps (UPDRS #23), Rapid Alternating Movement of Hands (UPDRS #25), Arising from Chair (UPDRS #27), Gait (UPDRS #29), Postural Stability (UPDRS #30), Body Bradykinesia and Hypokinesia (UPDRS #31), and Dyskinesia (evaluated with the Goetz Dyskinesia Rating Scale). The UPDRS score is the sum of the answers to individual questions, each of which are measured on a 5-point scale (0-4), with higher scores associated with more disability. The Goetz Dyskinesia Rating Scale is a 5-point scale of the severity of dyskinesias, from 0 (absent) to 4 (violent dyskinesias). | Baseline (Day -1), Endpoint (Day 21) | 
| Mean Change From Baseline to the End of Treatment in UPDRS Total Scores and Subscores | 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 ranges from 0-176, with 176 representing the worst (total) disability, and 0 no disability. The Part I Score is the sum of the answers to the 4 questions related to Mentation, Behavior and Mood, and ranges from 0-16. 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. The Part III score is the sum of the 27 answers related to Motor Examination, and ranges from 0-108. The Part IV Score is the sum of the answers to the 11 questions related to Complications of Therapy, and ranges from 0-23. The Part IV dyskinesia subscore ranges from 0-12. For each part of the UPDRS, higher scores are associated with more disability. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Change From Baseline to the End of Treatment in the Japanese Version of Parkinson's Disease Questionnaire 39 (PDQ-39) Total Score and Domain Scores | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health in Parkinson's disease patients, including Mobility, Activities of Daily Living, Emotional Well-being, Stigma, Social Support, Cognition, Communication, and Bodily Discomfort, as well as a Summary Index Total Score. Scores for each are 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 (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Modified Hoehn and Yahr Staging at Baseline and End of Treatment | Participant's ON and OFF states staged according to the Modified Hoehn and Yahr criteria, an 8-point scale for staging: 0, No signs of disease; 1, Unilateral disease; 1.5, Unilateral plus axial involvement; 2, Bilateral disease; 2.5, Mild bilateral disease; 3, Mild to moderate bilateral disease; 4, Severe disability; and 5, Wheelchair bound or bedridden unless aided. 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. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Schwab and England Activities of Daily Living Scale at Baseline and End of Treatment | The Schwab and England scale was used to rate the subject's activities of daily living by recording the percentage score, ranging between being completely independent (100%) and totally dependent (10%). | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Clinical Global Impression - Severity (CGI-S) Score at Baseline and Clinical Global Impression - Improvement (CGI-I) Score at Baseline and End of Treatment | 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: normal, borderline ill, mildly ill, moderately ill, markedly ill, severely ill, and 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: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Time to Reach Peak Plasma Concentration (Tmax) After Administration of Oral Levodopa/Carbidopa (L/C) Tablets and Intra-jejunal Administration of ABT-SLV187 | Tmax of levodopa, carbidopa, and its metabolite 3-O-methyldopa (3-OMD) after administration of oral L/C tablets and intra-jejunal administration of ABT-SLV187. | Baseline (Day -1): pre-dose; 15, 30, 45, 60 mins post-morning dose; every 30 mins thereafter for 12 hrs. Day 21: pre-dose; 15, 30, 45, 60 mins post-infusion; every 30 mins from hrs 1 to 12 post-infusion; every 2 hrs from 12 to 16 hrs post-infusion. | 
| Peak Plasma Concentration (Cmax), Average Plasma Concentration (Cavg), Trough Plasma Concentration (Cmin), and Cmin Within 2 and 12 Hours (Cmin [2-12 Hours]) After Administration of Oral L/C Tablets and Intra-jejunal Administration of ABT-SLV187 | Cmax, Cavg, Cmin, and Cmin (2-12 hours) of levodopa, carbidopa, and 3-OMD after administration of the oral L/C tablets (Day -1) and intra-jejunal administration of ABT-SLV187 (Day 21). Cmin values for levodopa and carbidopa during the 16 hours of infusion were observed either at time 0 or 15 min after start of the infusion and were a result of drug washout prior to establishment of infusion. | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| The Area Under the Concentrations-time Curve From 0 to 12 and 0 to 16 Hours (AUC0-12, AUC0-16) After Administration of Oral L/C Tablets and Intra-jejunal Administration of ABT-SLV187 | AUC0-12 and AUC0-16 of levodopa, carbidopa, and 3-OMD after administration of the oral L/C tablets (Day -1) and intra-jejunal administration of ABT-SLV187 (Day 21). | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| AUC0-12/Dose0-12, AUC0-16/Dose0-16 After Administration of Oral L/C Tablets and Intra-jejunal Administration of ABT-SLV187 | AUC0-12/Dose0-12 of levodopa, carbidopa, and 3-OMD after administration of the oral L/C tablets (Day -1) and intra-jejunal administration of ABT-SLV187 (Day 21). AUC0-16/Dose0-16 of levodopa, carbidopa, and 3-OMD after administration of intra-jejunal administration of ABT-SLV187 (Day 21). | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Degree of Fluctuation (2-12 Hours) After Administration of Oral L/C Tablets and Intra-jejunal Administration of ABT-SLV187 | Degree of Fluctuation (calculated as [Cmax - Cmin] / Cavg)) of levodopa, carbidopa, and 3-OMD after administration of the oral L/C tablets (Day -1) and intra-jejunal administration of ABT-SLV187 (Day 21). | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Ratio of Metabolite 3-OMD to Levodopa (M/P [AUC0-12]) After Administration of Oral L/C Tablets and Intra-jejunal Administration of ABT-SLV187 | M/P (AUC0-12) after administration of the oral L/C tablets (Day -1) and intra-jejunal administration of ABT-SLV187 (Day 21). | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 
| Number of Participants With Product Quality Complaints (PQC) During the ABT-SLV187 Treatment Period |  | Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Levodopa-carbidopa intestinal gel, Advanced Parkinson's disease, Severe motor fluctuations, Dyskinesia