Dyskinesia, Levodopa-Induced Dyskinesia (LID), Parkinson's Disease (PD)
Conditions
Keywords
Levodopa-Induced Dyskinesia, LID, Parkinsonism, Parkinson's Disease
Brief summary
This is a multi-center, randomized, double-blind, placebo-controlled, 2-arm, parallel group study to evaluate the efficacy and safety of ADS-5102 extended release (ER) capsules, an investigational formulation of amantadine, dosed once nightly at bedtime for the treatment of levodopa-induced dyskinesia (LID) in subjects with Parkinson's disease (PD). The novel pharmacokinetic profile of ADS-5102 is expected to achieve i) maximal concentrations in the early morning through mid-day, when LID can be troublesome, and ii) lower concentrations in the evening, potentially reducing the negative impact of amantadine on sleep. This pharmacokinetic profile could enable higher doses to be tolerated with a once-nightly ER formulation than can be tolerated with an immediate-release formulation. The once-nightly dosing regimen may also provide enhanced convenience and compliance. In a previous clinical study, ADS-5102 met its primary endpoint; LID was significantly reduced as measured by the change in UDysRS score over 8 weeks vs. placebo.
Interventions
DRUGADS-5102
Oral capsules to be administered once nightly at bedtime, for 13 weeks.
OTHERPlacebo
Oral capsules to be administered once nightly at bedtime, for 13 weeks.
Sponsors
Adamas Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Signed a current IRB/REB/IEC-approved informed consent form; * Parkinson's disease, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria; * On a stable regimen of antiparkinson's medications for at least 30 days prior to screening, including a levodopa preparation administered not less than three times daily, and willing to continue the same doses and regimens during study participation; * Following diary training, the subject is willing and able to understand and complete the 24-hour PD home diary (trained caregiver/study partner assistance allowed); * Any other current and allowed prescription/non-prescription medications and/or nutritional supplements taken regularly must have been at a stable dose and regimen for at least 30 days prior to screening, and subject must be willing to continue the same doses and regimens during study participation (this criterion does not apply to medications that are being taken pre-study only on an as-needed basis);
Exclusion criteria
* History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain stimulation); * History of seizures within 2 years prior to screening; * History of stroke or TIA within 2 years prior to screening; * History of cancer within 5 years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer, in situ cervical cancer, or other definitively treated cancer that is considered cured; * Presence of cognitive impairment, as evidenced by a Mini-Mental Status Examination (MMSE) score of less than 24 during screening; * If female, is pregnant or lactating; * If a sexually active female, is not surgically sterile or at least 2 years post-menopausal, or does not agree to utilize an effective method of contraception from screening through at least 4 weeks after the completion of study treatment, using one of the following: barrier methods (diaphragm or partner using condoms plus use of spermicidal jelly or foam, preferably double-barrier methods); oral or implanted hormonal contraceptive; intrauterine device (IUD); or vasectomized male partner; * Treatment with an investigational drug or device within 30 days prior to screening; * Treatment with an investigational biologic within 6 months prior to screening; * Current participation in another clinical trial;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Unified Dyskinesia Rating Scale (UDysRS) Total Score | Baseline to Week 12 | The UDysRS is a dyskinesia rating scale from 0-104; it evaluates involuntary movements associated with PD. A higher score indicates more severe PD. The UDysRS was measured at Baseline and Weeks 2, 4, 8, and 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) | Baseline to Week 12 | A PD home diary was used to score 5 different conditions in 30-minute intervals: ASLEEP, OFF, ON (ie, had adequate control of PD symptoms) without dyskinesia, ON with non-troublesome dyskinesia, and ON with troublesome dyskinesia. The results were based on 2 consecutive 24-hour diaries taken prior to the day of randomization and prior to the Week 2, 4, 8, and 12 visits. |
Countries
Austria, France, Germany, Spain, United States
Participant flow
Recruitment details
77 subjects with Parkinson's disease (PD) and Levodopa-induced Dyskinesia (LID) were randomized at 32 study sites in the United States, Germany, France, Spain, and Austria. The first subject was randomized on 23 October 2014 and the last subject completed on 10 March 2016.
Pre-assignment details
All randomized subjects who received ≥ 1 dose of study drug and provided ≥ 1 postbaseline efficacy assessment (75) were included in both the Safety Analysis Population and the Modified Intent-to-Treat (MITT) population (with 38 subjects in the placebo group and 37 in the ADS-5102 group).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: oral capsules administered once nightly at bedtime for 13 weeks | 38 |
| ADS-5102 (Amantadine HCl Extended Release) 340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 13 weeks | 37 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Did Not Receive Study Drug | 1 | 1 |
| Overall Study | Subject Unwilling to Proceed | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | ADS-5102 (Amantadine HCl Extended Release) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 44 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 31 Participants | 16 Participants |
| Age, Continuous | 64.9 years STANDARD_DEVIATION 9.08 | 64.8 years STANDARD_DEVIATION 9.31 | 64.7 years STANDARD_DEVIATION 9.66 |
| Duration of Levodopa Treatment | 8.54 years STANDARD_DEVIATION 4.845 | 8.12 years STANDARD_DEVIATION 4.493 | 7.69 years STANDARD_DEVIATION 4.121 |
| Duration of LID | 3.98 years STANDARD_DEVIATION 2.566 | 3.88 years STANDARD_DEVIATION 2.857 | 3.78 years STANDARD_DEVIATION 3.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 70 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hoehn and Yahr Stage | 2.4 units on a scale STANDARD_DEVIATION 0.55 | 2.2 units on a scale STANDARD_DEVIATION 0.59 | 2.1 units on a scale STANDARD_DEVIATION 0.6 |
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Combined Parts I, II, and III | 46.1 units on a scale STANDARD_DEVIATION 17 | 46.3 units on a scale STANDARD_DEVIATION 15.83 | 46.6 units on a scale STANDARD_DEVIATION 14.76 |
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I | 9.9 units on a scale STANDARD_DEVIATION 4.86 | 10.6 units on a scale STANDARD_DEVIATION 5.39 | 11.3 units on a scale STANDARD_DEVIATION 5.87 |
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II | 14.8 units on a scale STANDARD_DEVIATION 6.06 | 14.4 units on a scale STANDARD_DEVIATION 6.07 | 14.1 units on a scale STANDARD_DEVIATION 6.15 |
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III | 21.4 units on a scale STANDARD_DEVIATION 10.22 | 21.3 units on a scale STANDARD_DEVIATION 9.68 | 21.2 units on a scale STANDARD_DEVIATION 9.24 |
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV | 11.1 units on a scale STANDARD_DEVIATION 2.4 | 10.5 units on a scale STANDARD_DEVIATION 2.66 | 9.8 units on a scale STANDARD_DEVIATION 2.78 |
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, Item 4.1 | 2.8 units on a scale STANDARD_DEVIATION 0.94 | 2.5 units on a scale STANDARD_DEVIATION 0.92 | 2.2 units on a scale STANDARD_DEVIATION 0.81 |
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, Item 4.2 | 2.5 units on a scale STANDARD_DEVIATION 0.51 | 2.5 units on a scale STANDARD_DEVIATION 0.55 | 2.5 units on a scale STANDARD_DEVIATION 0.61 |
| PD Home Diary Asleep time | 8.21 hours STANDARD_DEVIATION 1.643 | 8.06 hours STANDARD_DEVIATION 1.572 | 7.91 hours STANDARD_DEVIATION 1.502 |
| PD Home Diary OFF time | 1.98 hours STANDARD_DEVIATION 1.687 | 2.30 hours STANDARD_DEVIATION 1.871 | 2.62 hours STANDARD_DEVIATION 2.015 |
| PD Home Diary ON time without troublesome dyskinesia | 7.79 hours STANDARD_DEVIATION 3.249 | 8.27 hours STANDARD_DEVIATION 2.909 | 8.77 hours STANDARD_DEVIATION 2.457 |
| PD Home Diary ON time with troublesome dyskinesia | 6.02 hours STANDARD_DEVIATION 3.353 | 5.37 hours STANDARD_DEVIATION 3.02 | 4.71 hours STANDARD_DEVIATION 2.509 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 38 Participants | 74 Participants | 36 Participants |
| Region of Enrollment Europe | 30 Participants | 52 Participants | 22 Participants |
| Region of Enrollment United States | 8 Participants | 23 Participants | 15 Participants |
| Sex: Female, Male Female | 18 Participants | 36 Participants | 18 Participants |
| Sex: Female, Male Male | 20 Participants | 39 Participants | 19 Participants |
| Subjects taking Antiparkinson Medication Anticholinergics | 2 Participants | 2 Participants | 0 Participants |
| Subjects taking Antiparkinson Medication COMT Inhibitors | 1 Participants | 4 Participants | 3 Participants |
| Subjects taking Antiparkinson Medication Dopamine Agonists | 25 Participants | 46 Participants | 21 Participants |
| Subjects taking Antiparkinson Medication Levodopa | 38 Participants | 75 Participants | 37 Participants |
| Subjects taking Antiparkinson Medication MAO Inhibitors | 20 Participants | 37 Participants | 17 Participants |
| Time Since PD Diagnosis | 10.71 years STANDARD_DEVIATION 4.265 | 10.55 years STANDARD_DEVIATION 4.669 | 10.40 years STANDARD_DEVIATION 5.105 |
| Unified Dyskinesia Rating Scale (UDysRS) Total Objective Score (Parts III, IV) | 15.9 units on a scale STANDARD_DEVIATION 7 | 17.0 units on a scale STANDARD_DEVIATION 7.53 | 18.1 units on a scale STANDARD_DEVIATION 7.99 |
| Unified Dyskinesia Rating Scale (UDysRS) Total Score | 41.2 units on a scale STANDARD_DEVIATION 10.32 | 40.7 units on a scale STANDARD_DEVIATION 11.68 | 40.2 units on a scale STANDARD_DEVIATION 13.06 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 37 |
| other Total, other adverse events | 19 / 38 | 31 / 37 |
| serious Total, serious adverse events | 0 / 38 | 4 / 37 |
Outcome results
Primary
Change in the Unified Dyskinesia Rating Scale (UDysRS) Total Score
The UDysRS is a dyskinesia rating scale from 0-104; it evaluates involuntary movements associated with PD. A higher score indicates more severe PD. The UDysRS was measured at Baseline and Weeks 2, 4, 8, and 12.
Time frame: Baseline to Week 12
Population: MITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in the Unified Dyskinesia Rating Scale (UDysRS) Total Score | -6.3 units on a scale | Standard Error 2.08 |
| ADS-5102 (Amantadine HCl Extended Release) | Change in the Unified Dyskinesia Rating Scale (UDysRS) Total Score | -20.7 units on a scale | Standard Error 2.2 |
Comparison: 32 subjects per treatment arm provided 90% power using a 2-sided test at 5% significance.p-value: <0.000195% CI: [-20.4, -8.3]Linear Mixed Model w/ Repeated Measures
Secondary
Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time)
A PD home diary was used to score 5 different conditions in 30-minute intervals: ASLEEP, OFF, ON (ie, had adequate control of PD symptoms) without dyskinesia, ON with non-troublesome dyskinesia, and ON with troublesome dyskinesia. The results were based on 2 consecutive 24-hour diaries taken prior to the day of randomization and prior to the Week 2, 4, 8, and 12 visits.
Time frame: Baseline to Week 12
Population: MITT population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) | Change in ON time without troublesome dyskinesia | 2.05 hours | Standard Error 0.526 |
| Placebo | Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) | Change in ON time with troublesome dyskinesia | -2.47 hours | Standard Error 0.436 |
| Placebo | Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) | Change in OFF time | 0.61 hours | Standard Error 0.313 |
| ADS-5102 (Amantadine HCl Extended Release) | Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) | Change in ON time without troublesome dyskinesia | 3.95 hours | Standard Error 0.562 |
| ADS-5102 (Amantadine HCl Extended Release) | Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) | Change in ON time with troublesome dyskinesia | -3.61 hours | Standard Error 0.468 |
| ADS-5102 (Amantadine HCl Extended Release) | Change in the Standardized PD Home Diary (ON Time Without Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) | Change in OFF time | -0.49 hours | Standard Error 0.336 |
p-value: 0.016895% CI: [0.35, 3.45]Linear Mixed Model w/ Repeated Measures
p-value: 0.085395% CI: [-2.42, 0.16]Linear Mixed Model w/ Repeated Measures
p-value: 0.019995% CI: [-2.02, -0.18]Linear Mixed Model w/ Repeated Measures