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

This study has been completed.
Sponsor:
Collaborator:
Abbott Japan Co.,Ltd
Information provided by (Responsible Party):
AbbVie ( AbbVie (prior sponsor, Abbott) )
ClinicalTrials.gov Identifier:
NCT01479127
First received: September 26, 2011
Last updated: March 23, 2016
Last verified: March 2016
  Purpose
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.

Condition Intervention Phase
Advanced Parkinson's Disease
Drug: ABT-SLV187
Drug: Oral Levodopa/Carbidopa
Device: Infusion Pump: CADD-Legacy® 1400 Pump
Device: NJ-Tube: Silicon ED Tube
Device: Adaptor: Hakko Adaptor
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by AbbVie:

Primary Outcome Measures:
  • Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and AEs Leading to Discontinuation During the Run-in Period [ Time Frame: During the Run-in period (up to approximately 28 days) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With AEs, SAEs, and AEs Leading to Discontinuation During the ABT-SLV187 Treatment Period [ Time Frame: From NJ placement to end of ABT-SLV187 Treatment Period (Day 21) +30 days ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Potentially Clinically Significant (PCS) Hematology Results During the ABT-SLV187 Treatment Period [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: Yes ]
    M=male, F=female, MCV=mean corpuscular volume, MCH=mean corpuscular hemoglobin, MCHC=mean corpuscular hemoglobin concentration.

  • Number of Participants With PCS Blood Biochemistry Results During the ABT-SLV187 Treatment Period [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    M=male, F=female, γ-GTP=gamma-glutamyl transpeptidase.

  • Number of Participants With PCS Values in Special Laboratory Parameters During the ABT-SLV187 Treatment Period [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    M=male, F=female

  • Number of Participants With Potentially Clinically Significant Urinalysis Results During the ABT-SLV187 Treatment Period [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
  • Number of Participants With Potentially Clinically Significant (PCS) Vital Signs Results During the ABT-SLV187 Treatment Period [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    ↓=decrease, ↑=increase, BL=baseline, temp.=temperature, SBP=systolic blood pressure, Sup.=supine, Sta.=standing, DBP=diastolic blood pressure.

  • Number of Participants With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Results During the ABT-SLV187 Treatment Period [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    High potentially clinically significant Bazett's heart rate-corrected QT interval (QTcB) values were: 450 msec for males / 470 msec for females.

  • Mean Change From Baseline to the End of Treatment in Percentage of Ratings in the "Normal" State on the Treatment Response Scale (TRS) I [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • 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 [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to the End of Treatment in Parkinson's Disease Diary Assessment [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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 and Endpoint (End of Treatment) Video Scoring of Unified Parkinson's Disease Rating Scale (UPDRS) Items and Dyskinesia [ Time Frame: Baseline (Day -1), Endpoint (Day 21) ] [ Designated as safety issue: No ]
    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).

  • Mean Change From Baseline to the End of Treatment in UPDRS Total Scores and Subscores [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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.

  • Modified Hoehn and Yahr Staging at Baseline and End of Treatment [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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.

  • Schwab and England Activities of Daily Living Scale at Baseline and End of Treatment [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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%).

  • Clinical Global Impression - Severity (CGI-S) Score at Baseline and Clinical Global Impression - Improvement (CGI-I) Score at Baseline and End of Treatment [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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.

  • Time to Reach Peak Plasma Concentration (Tmax) After Administration of Oral Levodopa/Carbidopa (L/C) Tablets and Intra-jejunal Administration of ABT-SLV187 [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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).

  • AUC0-12/Dose0-12, AUC0-16/Dose0-16 After Administration of Oral L/C Tablets and Intra-jejunal Administration of ABT-SLV187 [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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).

  • Degree of Fluctuation (2-12 Hours) After Administration of Oral L/C Tablets and Intra-jejunal Administration of ABT-SLV187 [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    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).

  • 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 [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]
    M/P (AUC0-12) after administration of the oral L/C tablets (Day -1) and intra-jejunal administration of ABT-SLV187 (Day 21).

  • Number of Participants With Product Quality Complaints (PQC) During the ABT-SLV187 Treatment Period [ Time Frame: Baseline (Day -1), End of ABT-SLV187 Treatment Period (Day 21) ] [ Designated as safety issue: No ]

Enrollment: 8
Study Start Date: October 2011
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Levodopa-carbidopa intestinal gel

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
Other Names:
  • DUOPA™ (carbidopa and levodopa Enteral Suspension)
  • DUODOPA®
  • Levodopa-carbidopa intestinal gel (LCIG)
Drug: Oral Levodopa/Carbidopa
Tablet; contains 100 mg levodopa and 10 mg carbidopa
Device: Infusion Pump: CADD-Legacy® 1400 Pump
General infusion pump, manufactured by Smiths Medical (US)
Device: NJ-Tube: Silicon ED Tube
Device used to deliver nutrition/drug to stomach/intestine or to aspirate stomach fluid, manufactured by Create Medic Co., Ltd. (Japan)
Device: Adaptor: Hakko Adaptor
Accessory set for fluid infusion set, consisting of caps, connectors and adapters, etc, manufactured by Hakko Medical (Japan)

  Eligibility

Ages Eligible for Study:   30 Years to 99 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01479127

Sponsors and Collaborators
AbbVie (prior sponsor, Abbott)
Abbott Japan Co.,Ltd
Investigators
Study Director: Yukihiro Kumamoto, MS AbbVie Japan Co., Ltd
  More Information

Additional Information:
Responsible Party: AbbVie ( AbbVie (prior sponsor, Abbott) )
ClinicalTrials.gov Identifier: NCT01479127     History of Changes
Other Study ID Numbers: M12-925 
Study First Received: September 26, 2011
Results First Received: February 15, 2016
Last Updated: March 23, 2016
Health Authority: Japan: Ministry of Health, Labor and Welfare

Keywords provided by AbbVie:
Levodopa-carbidopa intestinal gel
Advanced Parkinson's disease
Severe motor fluctuations
Dyskinesia

Additional relevant MeSH terms:
Parkinson Disease
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Nervous System Diseases
Neurodegenerative Diseases
Parkinsonian Disorders
Carbidopa
Carbidopa, levodopa drug combination
Levodopa
Adjuvants, Immunologic
Anti-Dyskinesia Agents
Antiparkinson Agents
Central Nervous System Agents
Dopamine Agents
Dopamine Agonists
Enzyme Inhibitors
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on May 03, 2016