Parkinson's Disease (PD)
Conditions
Keywords
Carbidopa, Levodopa, Efficacy, Levodopa-carbidopa intestinal gel, Advanced Parkinson's Disease
Brief summary
The primary objective of this study was to examine the effect of levodopa-carbidopa intestinal gel (LCIG) compared with optimized medical treatment (OMT) on dyskinesia in participants with advanced Parkinson's disease (PD).
Detailed description
This was a Phase 3b, open-label, randomized, multicenter, 12-week study. The study consisted of 3 sequential periods: Screening, Treatment, and Follow-Up. The OMT group had the same schedule of visits/procedures throughout the study as the LCIG treatment group, except for visits related to nasojejunal (NJ)/percutaneous endoscopic gastrostomy (PEG) procedures, titration of LCIG, and follow-up period.
Interventions
DRUGOptimized antiparkinsonian treatment
Dose levels of prescribed antiparkinsonian medications were individually optimized to their maximum therapeutic effect.
Dose levels were individually optimized.
DEVICECADD-Legacy ambulatory infusion pump
(manufactured by Smiths Medical)
DEVICEPercutaneous endoscopic gastrostomy tube
(PEG tube)
DEVICEJejunal extension tube
(J-tube)
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have a diagnosis of idiopathic Parkinson's disease (PD) according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria * Participants with advanced levodopa-responsive PD and persistent motor fluctuations who have not been controlled with optimized medical treatment (OMT: the maximum therapeutic effect obtained with pharmacological antiparkinsonian therapies when no further improvement is expected with regard to any additional manipulations of levodopa and/or other antiparkinsonian medication based on the Investigator's clinical judgment) * Unified Dyskinesia Rating Scale (UDysRs) Total score ≥ 30 at Visit 3
Exclusion criteria
* Participant(s) treated with levodopa-carbidopa intestinal gel (LCIG) previously * Participant's PD diagnosis is unclear or there is a suspicion that the subject has a parkinsonian syndrome such as secondary parkinsonism (e.g. caused by drugs, toxins, infectious agents, vascular disease, trauma, brain neoplasm), parkinson-plus syndrome (e.g. Multiple System Atrophy, Progressive supranuclear Palsy, Diffuse Lewy Body disease) or other neurodegenerative disease that might mimic the symptoms of PD * Participant(s) has undergone neurosurgery for the treatment of Parkinson's disease. * Participant(s) has contraindications to levodopa (e.g. narrow angle glaucoma, malignant melanoma) * Participant(s) experiencing clinically significant sleep attacks or clinically significant impulsive behavior (e.g. pathological gambling, hypersexuality) at any point during the three months prior to the Screening evaluation as judged by the Principal Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score | Baseline, Week 12 | The Unified Dyskinesia Rating Scale (UDysRS) is a tool used to assess dyskinesia in Parkinson's disease (PD) and contains both self-evaluation questions and items that are assessed directly by the physician to objectively rate the abnormal movements associated with PD. Part 1 contains 11 questions about the ON time dyskinesia and the impact of ON-dyskinesia on experiences of daily living. Part 2 contains 4 questions about OFF-dystonia rating. Part 3 contains 7 questions about objective evaluation of dyskinesia impairment and Part 4 contains 4 questions regarding dyskinesia disability. Each question is scored with respect to severity, which is rated on a scale where 0 = normal, 1 = slight, 2 = mild, 3= moderate and 4 = severe. The UDysRS total score is obtained by summing the item scores, ranging from 0 to 104. Higher scores are associated with more disability. Negative changes from baseline indicate improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index | Baseline, Week 12 | The Parkinson's Disease Questionnaire-8 (PDQ-8) is a disease-specific instrument designed to measure aspects of health that are relevant to participants with PD, and which may not be included in general health status questionnaires. The PDQ-8 is a self-administered questionnaire. Each item is scored on the following 5-point scale: 0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always (or cannot do at all, if applicable). Higher scores are consistently associated with the more severe symptoms of the disease such as tremors and stiffness. The results are presented as a summary index. The PDQ-8 summary index ranges from 0 to 100, where lower scores indicate a better perceived health status. Negative changes from baseline indicate improvement. |
| Mean Clinical Global Impression of Change (CGI-C) Score at Week 12 | Baseline, Week 12 | The Clinical Global Impression of Change (CGI-C) score is a clinician's rating scale for assessing Global Improvement of Change. The CGI-C rates improvement by 7 categories: very much improved (1), much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7). The CGI-C score ranges from 1 to 7, with lower scores indicating improvement. |
| Mean Change From Baseline to Week 12 in ON Time Without Troublesome Dyskinesia | Baseline, Week 12 | The Parkinson's Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study 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. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Positive change from baseline for ON time without troublesome dyskinesia indicates improvement. |
| Mean Change From Baseline to Week 12 in OFF Time | Baseline, Week 12 | The Parkinson's Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study 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. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Negative change from baseline for OFF time indicates improvement. |
| Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination) | Baseline, Week 12 | The Unified Parkinson's Disease Rating Scale (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 related to Motor Examination, and ranges from 0-108. Higher scores are associated with more disability. Negative values indicate improvement from baseline. |
| Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living) | Baseline, Week 12 | The Unified Parkinson's Disease Rating Scale (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 related to Activities of Daily Living, and ranges from 0-52. Higher scores are associated with more disability. Negative values indicate improvement from baseline. |
Countries
Finland, Greece, Hungary, Italy, Slovakia, Spain, United States
Participant flow
Pre-assignment details
Safety Data Set: all participants randomized to OMT and all participants randomized to LCIG treatment who had a study tube (NJ or PEG-J) placement procedure. Two participants randomized to the LCIG arm did not have device placement for LCIG infusion and were not included in the safety data set.
Participants by arm
| Arm | Count |
|---|---|
| Optimized Medical Treatment (OMT) Participants randomized to OMT continued their current anti Parkinson's disease (anti-PD) medication regimen for the duration of the study. All anti-PD medications and medications to treat dyskinesia must have remained stable for the duration of the study unless adjustments were medically indicated. The Investigator provided the prescription for continued OMT. | 33 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) The total daily dose of infusion LCIG was composed of three components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. A temporary nasojejunal (NJ) tube may have been used initially with the infusion pump to determine a participant's response to this method of treatment and to optimize the dose of LCIG before treatment with a permanent percutaneous endoscopic gastrostomy - with jejunal extension (PEG-J) tube was started. Following optional NJ and/or PEG-J placement and, at the investigator's discretion, the participant may have begun initiation and titration of LCIG infusion on Day 1 once tube placement was confirmed. The dose of LCIG was adjusted to obtain the optimal clinical response. The rate of LCIG infusion is typically within the range of 1 to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period of 16 consecutive hours each day. | 28 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Participant did not take any study drug | 1 | 0 |
| Overall Study | Withdrew consent | 3 | 2 |
Baseline characteristics
| Characteristic | Optimized Medical Treatment (OMT) | Levodopa-Carbidopa Intestinal Gel (LCIG) | Total |
|---|---|---|---|
| Age, Continuous | 68.7 years STANDARD_DEVIATION 7.2 | 69.3 years STANDARD_DEVIATION 6.99 | 69.0 years STANDARD_DEVIATION 7.05 |
| Body Mass Index (BMI) | 25.2 kg/m^2 STANDARD_DEVIATION 4.42 | 24.5 kg/m^2 STANDARD_DEVIATION 4.24 | 24.9 kg/m^2 STANDARD_DEVIATION 4.32 |
| Parkinson's disease duration (years) < 10 years | 14 Participants | 7 Participants | 21 Participants |
| Parkinson's disease duration (years) ≥ 10 years | 19 Participants | 20 Participants | 39 Participants |
| Parkinson's disease duration (years) Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 33 Participants | 28 Participants | 61 Participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Male | 17 Participants | 12 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 33 |
| other Total, other adverse events | 15 / 28 | 4 / 33 |
| serious Total, serious adverse events | 2 / 28 | 0 / 33 |
Outcome results
Primary
Mean Change From Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score
The Unified Dyskinesia Rating Scale (UDysRS) is a tool used to assess dyskinesia in Parkinson's disease (PD) and contains both self-evaluation questions and items that are assessed directly by the physician to objectively rate the abnormal movements associated with PD. Part 1 contains 11 questions about the ON time dyskinesia and the impact of ON-dyskinesia on experiences of daily living. Part 2 contains 4 questions about OFF-dystonia rating. Part 3 contains 7 questions about objective evaluation of dyskinesia impairment and Part 4 contains 4 questions regarding dyskinesia disability. Each question is scored with respect to severity, which is rated on a scale where 0 = normal, 1 = slight, 2 = mild, 3= moderate and 4 = severe. The UDysRS total score is obtained by summing the item scores, ranging from 0 to 104. Higher scores are associated with more disability. Negative changes from baseline indicate improvement.
Time frame: Baseline, Week 12
Population: Intent-to-treat (ITT) population: all participants with available data who were randomized to the OMT and all participants who were randomized to LCIG treatment and received at least 1 dose of study drug following PEG-J placement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Optimized Medical Treatment (OMT) | Mean Change From Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score | -2.33 units on a scale | Standard Error 2.56 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) | Mean Change From Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score | -17.37 units on a scale | Standard Error 2.79 |
p-value: <0.000195% CI: [-21.47, -8.63]Mixed-effects model repeated measures
Secondary
Mean Change From Baseline to Week 12 in OFF Time
The Parkinson's Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study 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. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Negative change from baseline for OFF time indicates improvement.
Time frame: Baseline, Week 12
Population: Intent-to-treat (ITT) population: all participants with available data who were randomized to the OMT and all participants who were randomized to LCIG treatment and received at least 1 dose of study drug following PEG-J placement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Optimized Medical Treatment (OMT) | Mean Change From Baseline to Week 12 in OFF Time | 0.18 hours | Standard Error 0.49 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) | Mean Change From Baseline to Week 12 in OFF Time | -2.17 hours | Standard Error 0.53 |
Comparison: If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.p-value: =0.000295% CI: [-3.51, -1.19]Mixed-effects model repeated measures
Secondary
Mean Change From Baseline to Week 12 in ON Time Without Troublesome Dyskinesia
The Parkinson's Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study 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. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Positive change from baseline for ON time without troublesome dyskinesia indicates improvement.
Time frame: Baseline, Week 12
Population: Intent-to-treat (ITT) population: all participants with available data who were randomized to the OMT and all participants who were randomized to LCIG treatment and received at least 1 dose of study drug following PEG-J placement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Optimized Medical Treatment (OMT) | Mean Change From Baseline to Week 12 in ON Time Without Troublesome Dyskinesia | -0.12 hours | Standard Error 0.63 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) | Mean Change From Baseline to Week 12 in ON Time Without Troublesome Dyskinesia | 3.15 hours | Standard Error 0.69 |
Comparison: If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.p-value: <0.000195% CI: [1.71, 4.83]Mixed-effects model repeated measures
Secondary
Mean Change From Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index
The Parkinson's Disease Questionnaire-8 (PDQ-8) is a disease-specific instrument designed to measure aspects of health that are relevant to participants with PD, and which may not be included in general health status questionnaires. The PDQ-8 is a self-administered questionnaire. Each item is scored on the following 5-point scale: 0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always (or cannot do at all, if applicable). Higher scores are consistently associated with the more severe symptoms of the disease such as tremors and stiffness. The results are presented as a summary index. The PDQ-8 summary index ranges from 0 to 100, where lower scores indicate a better perceived health status. Negative changes from baseline indicate improvement.
Time frame: Baseline, Week 12
Population: Intent-to-treat (ITT) population: all participants with available data who were randomized to the OMT and all participants who were randomized to LCIG treatment and received at least 1 dose of study drug following PEG-J placement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Optimized Medical Treatment (OMT) | Mean Change From Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index | -4.95 units on a scale | Standard Error 3.11 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) | Mean Change From Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index | -21.62 units on a scale | Standard Error 3.47 |
Comparison: If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.p-value: <0.000195% CI: [-24.48, -8.85]Mixed-effects model repeated measures
Secondary
Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination)
The Unified Parkinson's Disease Rating Scale (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 related to Motor Examination, and ranges from 0-108. Higher scores are associated with more disability. Negative values indicate improvement from baseline.
Time frame: Baseline, Week 12
Population: Intent-to-treat (ITT) population: all participants with available data who were randomized to the OMT and all participants who were randomized to LCIG treatment and received at least 1 dose of study drug following PEG-J placement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Optimized Medical Treatment (OMT) | Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination) | -0.87 units on a scale | Standard Error 1.89 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) | Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination) | -4.93 units on a scale | Standard Error 2.08 |
Comparison: If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.p-value: =0.076295% CI: [-8.55, 0.44]Mixed-effects model repeated measures
Secondary
Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living)
The Unified Parkinson's Disease Rating Scale (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 related to Activities of Daily Living, and ranges from 0-52. Higher scores are associated with more disability. Negative values indicate improvement from baseline.
Time frame: Baseline, Week 12
Population: Intent-to-treat (ITT) population: all participants with available data who were randomized to the OMT and all participants who were randomized to LCIG treatment and received at least 1 dose of study drug following PEG-J placement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Optimized Medical Treatment (OMT) | Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living) | 0.21 units on a scale | Standard Error 1.16 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) | Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living) | -5.33 units on a scale | Standard Error 1.28 |
Comparison: If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.p-value: =0.000695% CI: [-8.59, -2.49]Mixed-effects model repeated measures
Secondary
Mean Clinical Global Impression of Change (CGI-C) Score at Week 12
The Clinical Global Impression of Change (CGI-C) score is a clinician's rating scale for assessing Global Improvement of Change. The CGI-C rates improvement by 7 categories: very much improved (1), much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7). The CGI-C score ranges from 1 to 7, with lower scores indicating improvement.
Time frame: Baseline, Week 12
Population: Intent-to-treat (ITT) population: all participants with available data who were randomized to the OMT and all participants who were randomized to LCIG treatment and received at least 1 dose of study drug following PEG-J placement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Optimized Medical Treatment (OMT) | Mean Clinical Global Impression of Change (CGI-C) Score at Week 12 | 4.58 units on a scale | Standard Error 0.25 |
| Levodopa-Carbidopa Intestinal Gel (LCIG) | Mean Clinical Global Impression of Change (CGI-C) Score at Week 12 | 2.48 units on a scale | Standard Error 0.28 |
Comparison: If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.p-value: <0.000195% CI: [-2.78, -1.44]Mixed-effects model repeated measures