Parkinson Disease, Idiopathic Parkinson Disease, Idiopathic Parkinson's Disease
Conditions
Brief summary
This is a study of the efficacy and safety of preladenant in adult participants with moderate to severe Parkinson's Disease (PD). While on this study, participants will continue to take their usual, prescribed, stable regimen of levodopa (L-dopa) or L-dopa plus adjunct PD medications and will be randomized to receive 2 mg preladenant, 5 mg preladenant, or placebo, twice daily, for 12 weeks. After that, participants may choose to receive additional treatment with preladenant. The primary hypothesis is that at least the 5 mg twice daily dose of preladenant is superior to placebo as measured by the change from Baseline to Week 12 in the mean off time.
Interventions
DRUGPreladenant
Preladenant 2 mg or 5 mg oral tablet taken twice daily
DRUGPlacebo
Preladenant-matching placebo oral tablet taken twice daily
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Each participant must have a diagnosis of idiopathic Parkinson's disease. * Each participant must have received prior therapy with L-dopa for approximately 1 or more years immediately before Screening and must continue to have a beneficial clinical response to L-dopa. * Each participant must have been on a stable dopaminergic treatment regimen for at least the 5 weeks immediately before Randomization. Participants receiving other adjunctive treatments (eg, dopamine agonist, anticholinergics) are permitted to enroll in this trial. Participants taking only L-dopa are permitted to enroll in this trial. * Each participant must be experiencing motor fluctuations with or without dyskinesias within the 4 weeks immediately before Screening, must be experiencing a minimum of 2 hours/day of off time, and have a Hoehn & Yahr stage between 2.5 and 4 when in the on state. * Each participant, with or without the help of a caregiver, must be capable of maintaining an accurate and complete symptom diary and to adhere to dose and visit schedules. * Each participant must have results of Screening clinical laboratory tests drawn within 5 weeks prior to Randomization clinically acceptable to the investigator and not within the parameters specified for exclusion (below). * All participants who are sexually active or plan to be sexually active agree to use a highly effective method of birth control while in the study and for 2 weeks after the last dose of study drug. A male participant must also not donate sperm within 2 weeks after the last dose of study drug.
Exclusion criteria
* A participant must not have a form of drug induced or atypical parkinsonism, a cognitive impairment, bipolar disorder, untreated major depressive disorder, schizophrenia, or other psychotic disorder; history exposure to a known neurotoxin, or any neurological features not consistent with the diagnosis of PD as assessed by the investigator. * A participant must not have a history of repeated strokes or head injuries, or a stroke within 6 months of Screening; poorly controlled diabetes; abnormal renal function; or a severe or ongoing unstable medical condition. * A participant must not have had surgery for their PD. * A participant must not be at imminent risk of self-harm or harm to others. * A participant must not have a systolic blood pressure (BP) ≥150 mm Hg OR diastolic BP ≥95 mm Hg at Screening and at 2 BP rechecks prior to study start. * A participant must not have had any clinically significant cardiovascular event or procedure for 6 months prior to study start, including, but not limited to, myocardial infarction, angioplasty, unstable angina, or heart failure; and a participant must not have heart failure staged New York Heart Association Class III or IV. * A participant must not have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 x the upper limit of normal (ULN) or total bilirubin (T BIL) ≥1.5 x ULN. * A participant must not have a history of serologically confirmed hepatic dysfunction (defined as viral infection \[Hepatitis B, C, or E; Epstein-Barr virus (EBV); cytomegalovirus (CMV)\]) or a history of diagnosis of drug- or alcohol- induced hepatic toxicity or frank hepatitis. * A participant must not have a history within the past 5 years of a primary or recurrent malignant disease with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or in situ prostate cancer with a normal prostate-specific antigen (PSA) post resection. * A participant must not have received certain prespecified medications for a prespecified time window before the trial. * A participant must not have an average daily consumption of more than three 4 ounce glasses (118 mL) of wine or the equivalent. * A participant must not have a severe or ongoing unstable medical condition (eg, any form of clinically significant cardiac disease, symptomatic orthostatic hypotension, seizures, or alcohol/drug dependence). * A participant must not have allergy/sensitivity to investigational product(s) or its/their excipients. * A participant must not be breast-feeding, considering breast-feeding, pregnant, or intending to become pregnant. * A participant must not have used preladenant ever, or any investigational drugs within 90 days immediately before Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase | Up to Week 14 | The number of participants with Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg increase was reported. Participants lie supine at rest for 5 minutes, then have a single BP measurement taken (ie, 1 reading). Participants then stand for 3 minutes at rest, followed by a single BP measurement (1 reading) in the standing position. |
| Percentage of Participants With Suicidality | Up to Week 12 | The percentage of participants with suicidality using the Columbia - Suicide Severity Rating Scale (C-SSRS) was reported. The C-SSR was used in this study only for the purpose of safety monitoring by measuring the incidence of different types of suicidality categories during treatment. The assessment was done by the nature of the responses, not by a numbered scale. Participants who reported at least one occurrence of suicidal behavior or suicidal ideation were counted as having experienced suicidality. Suicidal behavior included suicide attempt, aborted attempt, interrupted attempt, or preparatory behavior. Suicidal ideation included a wish to die or active suicidal thought with or without method, intent or plan. |
| Change From Baseline in Total Epworth Sleepiness Scale (ESS) at Week 12 | Baseline and Week 12 | The ESS is a self-administered questionnaire providing a measure of a person's general level of daytime sleepiness, or their average sleep propensity in daily life. The scale consists of 8 situations in which the participant rates their tendency to become sleepy on a scale of 0=no chance of dozing to 3=high chance of dozing. The overall score is the sum of the scores for the 8 situations for a minimum of 0 and a maximum of 24 with a higher score indicating greater sleepiness. The mean change from baseline in total EES was based on a cLDA with treatment, time, and treatment-by-time interaction as fixed effects and subject as random effect. |
| Change From Baseline in Average Off Time (Hours Per Day) at Week 12 | Baseline and Week 12 | The on state is defined as the period of time during which a patient's symptoms of PD improve or disappear following treatment with L-dopa or dopamine agonists. The off state is defined as the period of time characterized by the return of symptoms (i..e. tremor, slowness, and rigidity) following treatment with L-dopa or dopamine agonists. Study participants reported their symptoms at half-hour intervals as off, on, or asleep on their daily diary for 3 days before randomization (baseline) and for the 3 days immediately before their Week 12 visit. The mean change from baseline in off time was based on a constrained longitudinal data analysis (cLDA) with treatment, time, and treatment-by-time interaction as fixed effects and subject as random effect. |
| Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase | Up to Week 14 | The number of participants with Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg increase was reported. Participants lie supine at rest for 5 minutes, then have a single BP measurement taken (ie, 1 reading). Participants then stand for 3 minutes at rest, followed by a single BP measurement (1 reading) in the standing position. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Average On Time (Hours Per Day) Without Troublesome Dyskinesia at Week 12 | Baseline and Week 12 | On time is when a PD participant's symptoms are improved. Mean on time without troublesome dyskinesias is derived from the available diary data collected for 3 days immediately prior to a clinic visit. On time without troublesome dyskinesia is the sum of on time without dyskinesia plus on time with non-troublesome dyskinesia as recorded in the diary. The mean change from baseline in on time was based on a cLDA with treatment, time, and treatment-by-time interaction as fixed effects and subject as random effect. |
| Percentage of Participants With >30% Change (Reduction) From Baseline at Week 12 in Mean Off Time | Baseline and Week 12 | A participant with at least a 30% reduction in mean off time from Baseline to End of Treatment (Week 12) is considered as responder. The on state is defined as the period of time during which a patient's symptoms of PD improve or disappear following treatment with L-dopa or dopamine agonists. The off state is defined as the period of time characterized by the return of symptoms (i..e. tremor, slowness, and rigidity) following treatment with L-dopa or dopamine agonists. Study participants reported their symptoms at half-hour intervals as off, on, or asleep on their daily diary for 3 days before randomization and for the 3 days immediately before their Week 12 visit. |
Participant flow
Recruitment details
Adult participants with a diagnosis of moderate to severe idiopathic Parkinson's disease were selected to participate in this study.
Pre-assignment details
After a Screening Period of up to 5 weeks, participants were randomized into 1 of 3 treatment groups (preladenant 2 or 5 mg twice daily or placebo) for 12 weeks. At the end of treatment, participants could choose to enter into an extension trial or return for a follow-up visit 2 weeks later.
Participants by arm
| Arm | Count |
|---|---|
| Preladenant 2 mg Participants received 2 mg as a single oral dose twice daily for 12 weeks. Participants could then enroll in an extension trial or return for a follow-up visit two (2) weeks later. | 157 |
| Preladenant 5 mg Participants received 5 mg as a single oral dose twice daily for 12 weeks. Participants could then enroll in an extension trial or return for a follow-up visit two (2) weeks later. | 157 |
| Placebo Participants received preladenant-matching placebo as a single oral dose twice daily for 12 weeks. Participants could then enroll in an extention trial or return for a follow-up visit two (2) weeks later. | 159 |
| Total | 473 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative | 1 | 0 | 2 |
| Overall Study | Adverse Event | 6 | 10 | 5 |
| Overall Study | Did Not Meet Protocol Eligibility | 0 | 0 | 1 |
| Overall Study | Did Not Receive Treatment | 1 | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 3 |
| Overall Study | Protocol Violation | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 7 | 3 |
Baseline characteristics
| Characteristic | Preladenant 2 mg | Preladenant 5 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 62.9 Years STANDARD_DEVIATION 9 | 64.2 Years STANDARD_DEVIATION 8.7 | 64.2 Years STANDARD_DEVIATION 8.9 | 63.8 Years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 49 Participants | 71 Participants | 64 Participants | 184 Participants |
| Sex: Female, Male Male | 108 Participants | 86 Participants | 95 Participants | 289 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 37 / 157 | 46 / 157 | 25 / 159 |
| serious Total, serious adverse events | 5 / 157 | 2 / 157 | 4 / 159 |
Outcome results
Primary
Change From Baseline in Average Off Time (Hours Per Day) at Week 12
The on state is defined as the period of time during which a patient's symptoms of PD improve or disappear following treatment with L-dopa or dopamine agonists. The off state is defined as the period of time characterized by the return of symptoms (i..e. tremor, slowness, and rigidity) following treatment with L-dopa or dopamine agonists. Study participants reported their symptoms at half-hour intervals as off, on, or asleep on their daily diary for 3 days before randomization (baseline) and for the 3 days immediately before their Week 12 visit. The mean change from baseline in off time was based on a constrained longitudinal data analysis (cLDA) with treatment, time, and treatment-by-time interaction as fixed effects and subject as random effect.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS): All randomized participants remaining after participants were excluded for failure to receive at least one dose of study treatment, lack of any post-randomization endpoint data subsequent to at least 1 dose of study treatment, or lack of Baseline data for those analyses requiring Baseline data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Preladenant 2 mg | Change From Baseline in Average Off Time (Hours Per Day) at Week 12 | -1.0 hours per day | Standard Error 0.2 |
| Preladenant 5 mg | Change From Baseline in Average Off Time (Hours Per Day) at Week 12 | -1.1 hours per day | Standard Error 0.2 |
| Placebo | Change From Baseline in Average Off Time (Hours Per Day) at Week 12 | -0.8 hours per day | Standard Error 0.19 |
p-value: 0.493395% CI: [-0.72, 0.35]cLDA
p-value: 0.236495% CI: [-0.86, 0.21]cLDA
Primary
Change From Baseline in Total Epworth Sleepiness Scale (ESS) at Week 12
The ESS is a self-administered questionnaire providing a measure of a person's general level of daytime sleepiness, or their average sleep propensity in daily life. The scale consists of 8 situations in which the participant rates their tendency to become sleepy on a scale of 0=no chance of dozing to 3=high chance of dozing. The overall score is the sum of the scores for the 8 situations for a minimum of 0 and a maximum of 24 with a higher score indicating greater sleepiness. The mean change from baseline in total EES was based on a cLDA with treatment, time, and treatment-by-time interaction as fixed effects and subject as random effect.
Time frame: Baseline and Week 12
Population: All Participants as Treated (APaT): All participants who received at least one (1) dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Preladenant 2 mg | Change From Baseline in Total Epworth Sleepiness Scale (ESS) at Week 12 | -0.4 Score on a Scale | Standard Error 0.28 |
| Preladenant 5 mg | Change From Baseline in Total Epworth Sleepiness Scale (ESS) at Week 12 | -0.0 Score on a Scale | Standard Error 0.29 |
| Placebo | Change From Baseline in Total Epworth Sleepiness Scale (ESS) at Week 12 | -0.2 Score on a Scale | Standard Error 0.28 |
p-value: 0.696895% CI: [-0.92, 0.61]cLDA
p-value: 0.614295% CI: [-0.57, 0.97]cLDA
Primary
Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase
The number of participants with Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg increase was reported. Participants lie supine at rest for 5 minutes, then have a single BP measurement taken (ie, 1 reading). Participants then stand for 3 minutes at rest, followed by a single BP measurement (1 reading) in the standing position.
Time frame: Up to Week 14
Population: All Participants as Treated (APaT): All participants who received at least one (1) dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Preladenant 2 mg | Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase | Supine | 1 Participants |
| Preladenant 2 mg | Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase | Standing | 7 Participants |
| Preladenant 5 mg | Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase | Supine | 2 Participants |
| Preladenant 5 mg | Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase | Standing | 3 Participants |
| Placebo | Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase | Supine | 3 Participants |
| Placebo | Number of Participants With Diastolic Blood Pressure (DBP) ≥105 mmHg and 15 mmHg Increase | Standing | 6 Participants |
Primary
Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase
The number of participants with Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg increase was reported. Participants lie supine at rest for 5 minutes, then have a single BP measurement taken (ie, 1 reading). Participants then stand for 3 minutes at rest, followed by a single BP measurement (1 reading) in the standing position.
Time frame: Up to Week 14
Population: All Participants as Treated (APaT): All participants who received at least one (1) dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Preladenant 2 mg | Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase | Supine | 0 Participants |
| Preladenant 2 mg | Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase | Standing | 1 Participants |
| Preladenant 5 mg | Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase | Supine | 1 Participants |
| Preladenant 5 mg | Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase | Standing | 0 Participants |
| Placebo | Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase | Supine | 0 Participants |
| Placebo | Number of Participants With Systolic Blood Pressure (SBP) ≥180 mmHg and 20 mmHg Increase | Standing | 0 Participants |
Primary
Percentage of Participants With Suicidality
The percentage of participants with suicidality using the Columbia - Suicide Severity Rating Scale (C-SSRS) was reported. The C-SSR was used in this study only for the purpose of safety monitoring by measuring the incidence of different types of suicidality categories during treatment. The assessment was done by the nature of the responses, not by a numbered scale. Participants who reported at least one occurrence of suicidal behavior or suicidal ideation were counted as having experienced suicidality. Suicidal behavior included suicide attempt, aborted attempt, interrupted attempt, or preparatory behavior. Suicidal ideation included a wish to die or active suicidal thought with or without method, intent or plan.
Time frame: Up to Week 12
Population: All Participants as Treated (APaT): All participants who received at least one (1) dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preladenant 2 mg | Percentage of Participants With Suicidality | 3 Percentage of participants |
| Preladenant 5 mg | Percentage of Participants With Suicidality | 4 Percentage of participants |
| Placebo | Percentage of Participants With Suicidality | 1 Percentage of participants |
Secondary
Change From Baseline in Average On Time (Hours Per Day) Without Troublesome Dyskinesia at Week 12
On time is when a PD participant's symptoms are improved. Mean on time without troublesome dyskinesias is derived from the available diary data collected for 3 days immediately prior to a clinic visit. On time without troublesome dyskinesia is the sum of on time without dyskinesia plus on time with non-troublesome dyskinesia as recorded in the diary. The mean change from baseline in on time was based on a cLDA with treatment, time, and treatment-by-time interaction as fixed effects and subject as random effect.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS): All randomized participants remaining after participants were excluded for failure to receive at least one dose of study treatment, lack of any post-randomization endpoint data subsequent to at least 1 dose of study treatment, or lack of Baseline data for those analyses requiring Baseline data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Preladenant 2 mg | Change From Baseline in Average On Time (Hours Per Day) Without Troublesome Dyskinesia at Week 12 | 0.6 hours per day | Standard Error 0.21 |
| Preladenant 5 mg | Change From Baseline in Average On Time (Hours Per Day) Without Troublesome Dyskinesia at Week 12 | 0.7 hours per day | Standard Error 0.21 |
| Placebo | Change From Baseline in Average On Time (Hours Per Day) Without Troublesome Dyskinesia at Week 12 | 0.5 hours per day | Standard Error 0.2 |
p-value: 0.77695% CI: [-0.47, 0.63]cLDA
p-value: 0.68395% CI: [-0.44, 0.67]cLDA
Secondary
Percentage of Participants With >30% Change (Reduction) From Baseline at Week 12 in Mean Off Time
A participant with at least a 30% reduction in mean off time from Baseline to End of Treatment (Week 12) is considered as responder. The on state is defined as the period of time during which a patient's symptoms of PD improve or disappear following treatment with L-dopa or dopamine agonists. The off state is defined as the period of time characterized by the return of symptoms (i..e. tremor, slowness, and rigidity) following treatment with L-dopa or dopamine agonists. Study participants reported their symptoms at half-hour intervals as off, on, or asleep on their daily diary for 3 days before randomization and for the 3 days immediately before their Week 12 visit.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS): All randomized participants remaining after participants were excluded for failure to receive at least one dose of study treatment, lack of any post-randomization endpoint data subsequent to at least one dose of study treatment, or lack of Baseline data for those analyses requiring Baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preladenant 2 mg | Percentage of Participants With >30% Change (Reduction) From Baseline at Week 12 in Mean Off Time | 37.1 Percentage of participants |
| Preladenant 5 mg | Percentage of Participants With >30% Change (Reduction) From Baseline at Week 12 in Mean Off Time | 36.9 Percentage of participants |
| Placebo | Percentage of Participants With >30% Change (Reduction) From Baseline at Week 12 in Mean Off Time | 30.5 Percentage of participants |
p-value: 0.24495% CI: [-4.17, 18.05]Mixed Models Analysis
p-value: 0.26295% CI: [-4.63, 17.61]Mixed Models Analysis