Parkinson's Disease
Conditions
Keywords
Parkinson's disease
Brief summary
This study is to evaluate the efficacy of a range of preladenant doses compared with placebo in participants with moderate to severe Parkinson's disease (PD) experiencing motor fluctuations and receiving a stable dose of levodopa (L-dopa), as measured by off time. Participants will continue to receive their stable regimen of L-dopa plus any adjunct medications during the study as prescribed by their physician. Several classes of adjunct medications may be used, including Amantadine, anticholinergics, dopa decarboxylase inhibitors, and dopamine agonists. Primary Hypothesis: At least the 10 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
2, 5, or 10 mg tablets taken orally twice daily (BID)
DRUGPlacebo tablet to match Preladenant
tablets taken orally BID
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Must have a diagnosis of idiopathic PD based on the United Kingdom Parkinson's Disease Society Brain Bank Criteria, judged to be moderate to severe * Must have received prior therapy with L-dopa for more than 1 year before Screening * Must have been on a stable, optimal dopaminergic treatment regimen, defined as maximum therapeutic effect achieved with available anti-Parkinsonian treatment, for at least the 4 weeks immediately before randomization * If receiving one or more of the following adjunctive treatments: amantadine, anticholinergics, catechol-O-methyltransferase inhibitors, dopa decarboxylase inhibitors, dopamine agonists, entacapone, L-dopa, must have been on a stable regimen of treatment for at least the 4 weeks immediately before randomization * Hoehn and Yahr stage must be ≥ 2.5 and ≤ 4 following optimum titration of treatment medications at Screening * Must be experiencing motor fluctuations with or without dyskinesias following optimum titration of treatment medications and within the 4 weeks immediately before Screening \- Must be experiencing a minimum of 2 hours/day of off time as estimated by the investigator and supported by the symptom diary (Daily Diary) at the Diary Training Visit \- With or without the help of a caregiver, must be capable of maintaining an accurate and complete symptom diary (Daily Diary) as assessed at the Diary Training Visit \- Must have results of Screening clinical laboratory tests (complete blood count \[CBC\], blood chemistries, and urinalysis) within normal limits or clinically acceptable to the investigator at Screening \- Must have results of a physical examination within normal limits or clinically acceptable limits to the investigator * Must be able to adhere to dose and visit schedules * Females of child-bearing potential must have a negative serum pregnancy test (human chorionic gonadotropin \[hCG\]) at Screening and must agree to use a medically accepted method of contraception while receiving protocol-specified medication and for 2 weeks after stopping the medication
Exclusion criteria
* Must not have a form of drug-induced or atypical parkinsonism, cognitive impairment, bipolar disorder, schizophrenia, or other psychotic disorder * Must not have had surgery for PD * Must not have an untreated major depressive disorder meeting Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM-IV-TR) criteria \- Must not be at imminent risk of self-harm or harm to others, in the investigator's opinion based on clinical interview * Must not have participated in any studies using preladenant * Must not have allergy/sensitivity to preladenant or any of its excipients * Must not have used any investigational drugs or participated in any other clinical trial within 90 days of Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean 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 participant's symptoms of PD improve or disappear following treatment with levodopa (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 with treatment, time, and treatment-by-time interaction as fixed effects, and an unstructured covariance matrix was used to model the correlation among repeated measurements. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to 14 weeks | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to 12 Weeks | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥30% Reduction in Off Time at Week 12 | Up to 12 Weeks | The proportion of responders (≥30% Reduction in Off Time at Week 12) was analyzed using a generalized linear mixed model with baseline mean OFF time (hours/day) as a covariate and treatment-by-time interaction as a fixed effect, and an unstructured covariance matrix was used to model the correlation among repeated measurements. Responder rates for each treatment arm are presented as are differences from placebo with 95% confidence interval. |
| Change From Baseline in Mean On Time Without Troublesome Dyskinesias (Hours Per Day) at Week 12 | Baseline and Week 12 | When a participant is on without dyskinesias, parkinsonian symptoms have dissipated and the participant is experiencing no uncontrollable extraneous movements. Study participants reported their parkinsonian symptoms at half-hour intervals as off, on without dyskinesia, on with non-troublesome dyskinesia, on with troublesome dyskinesia, or asleep on their daily diary for 3 days before randomization and for the 3 days immediately before their Week-12 visit. The mean change from baseline in on without troublesome dyskinesia time was based on a constrained longitudinal data analysis with treatment, time, and treatment-by-time interaction as fixed effects, and an unstructured covariance matrix was used to model the correlation among repeated measurements. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Preladenant 2 mg Participants received preladenant 2 mg taken orally twice daily (BID), one tablet in the morning and one tablet in the evening, for 12 weeks. | 111 |
| Preladenant 5 mg Participants received preladenant 5 mg taken orally BID, one tablet in the morning and one tablet in the evening, for 12 weeks. | 113 |
| Preladenant 10 mg Participants received preladenant 10 mg taken orally BID, one tablet in the morning and one tablet in the evening, for 12 weeks. | 113 |
| Placebo Participants received a placebo to preladenant tablet taken orally BID, one tablet in the morning and one tablet in the evening, for 12 weeks. | 113 |
| Total | 450 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 6 | 12 | 5 |
| Overall Study | Did Not Meet Protocol Eligibility | 2 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Non-compliance With Protocol | 0 | 1 | 1 | 0 |
| Overall Study | Subject Withdrew Consent | 2 | 2 | 2 | 11 |
Baseline characteristics
| Characteristic | Preladenant 2 mg | Preladenant 5 mg | Preladenant 10 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 68.0 Years STANDARD_DEVIATION 7.9 | 67.6 Years STANDARD_DEVIATION 8.3 | 67.8 Years STANDARD_DEVIATION 7.6 | 65.8 Years STANDARD_DEVIATION 9.1 | 67.3 Years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 54 Participants | 66 Participants | 69 Participants | 64 Participants | 253 Participants |
| Sex: Female, Male Male | 57 Participants | 47 Participants | 44 Participants | 49 Participants | 197 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 111 | 23 / 113 | 25 / 113 | 14 / 113 |
| serious Total, serious adverse events | 9 / 111 | 5 / 113 | 7 / 113 | 3 / 113 |
Outcome results
Primary
Change From Baseline in Mean Off Time (Hours Per Day) at Week 12
The on state is defined as the period of time during which a participant's symptoms of PD improve or disappear following treatment with levodopa (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 with treatment, time, and treatment-by-time interaction as fixed effects, and an unstructured covariance matrix was used to model the correlation among repeated measurements.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS) population, which consisted of all randomized participants who received at least one dose of study treatment; had endpoint data subsequent to at least one dose of study treatment; and had baseline data for those analyses requiring baseline data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Preladenant 2 mg | Change From Baseline in Mean Off Time (Hours Per Day) at Week 12 | -1.2 Hours/Day | Standard Deviation 2.3 |
| Preladenant 5 mg | Change From Baseline in Mean Off Time (Hours Per Day) at Week 12 | -1.0 Hours/Day | Standard Deviation 2.6 |
| Preladenant 10 mg | Change From Baseline in Mean Off Time (Hours Per Day) at Week 12 | -0.9 Hours/Day | Standard Deviation 2.2 |
| Placebo | Change From Baseline in Mean Off Time (Hours Per Day) at Week 12 | -0.5 Hours/Day | Standard Deviation 3 |
p-value: 0.056495% CI: [-1.37, 0.02]Constrained longitudinal data analysis
p-value: 0.184495% CI: [-1.16, 0.22]Constrained longitudinal data analysis
p-value: 0.338695% CI: [-1.04, 0.36]Constrained longitudinal data analysis
Primary
Number of Participants Who Discontinued Study Treatment Due to an AE
An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product.
Time frame: Up to 12 Weeks
Population: All Participants as Treated population, which included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preladenant 2 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 6 Participants |
| Preladenant 5 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 6 Participants |
| Preladenant 10 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 12 Participants |
| Placebo | Number of Participants Who Discontinued Study Treatment Due to an AE | 5 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product.
Time frame: Up to 14 weeks
Population: All Participants as Treated population, which included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preladenant 2 mg | Number of Participants Who Experienced an Adverse Event (AE) | 53 Participants |
| Preladenant 5 mg | Number of Participants Who Experienced an Adverse Event (AE) | 60 Participants |
| Preladenant 10 mg | Number of Participants Who Experienced an Adverse Event (AE) | 69 Participants |
| Placebo | Number of Participants Who Experienced an Adverse Event (AE) | 55 Participants |
Secondary
Change From Baseline in Mean On Time Without Troublesome Dyskinesias (Hours Per Day) at Week 12
When a participant is on without dyskinesias, parkinsonian symptoms have dissipated and the participant is experiencing no uncontrollable extraneous movements. Study participants reported their parkinsonian symptoms at half-hour intervals as off, on without dyskinesia, on with non-troublesome dyskinesia, on with troublesome dyskinesia, or asleep on their daily diary for 3 days before randomization and for the 3 days immediately before their Week-12 visit. The mean change from baseline in on without troublesome dyskinesia time was based on a constrained longitudinal data analysis with treatment, time, and treatment-by-time interaction as fixed effects, and an unstructured covariance matrix was used to model the correlation among repeated measurements.
Time frame: Baseline and Week 12
Population: FAS population, which consisted of all randomized participants who received at least one dose of study treatment; had endpoint data subsequent to at least one dose of study treatment; and had baseline data for those analyses requiring baseline data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Preladenant 2 mg | Change From Baseline in Mean On Time Without Troublesome Dyskinesias (Hours Per Day) at Week 12 | 1.3 Hours/Day | Standard Deviation 2.5 |
| Preladenant 5 mg | Change From Baseline in Mean On Time Without Troublesome Dyskinesias (Hours Per Day) at Week 12 | 1.0 Hours/Day | Standard Deviation 2.9 |
| Preladenant 10 mg | Change From Baseline in Mean On Time Without Troublesome Dyskinesias (Hours Per Day) at Week 12 | 1.0 Hours/Day | Standard Deviation 2.4 |
| Placebo | Change From Baseline in Mean On Time Without Troublesome Dyskinesias (Hours Per Day) at Week 12 | 0.5 Hours/Day | Standard Deviation 2.9 |
p-value: 0.050995% CI: [0, 1.43]Constrained longitudinal data analysis
p-value: 0.184795% CI: [-0.23, 1.19]Constrained longitudinal data analysis
p-value: 0.202195% CI: [-0.25, 1.19]Constrained longitudinal data analysis
Secondary
Percentage of Participants With ≥30% Reduction in Off Time at Week 12
The proportion of responders (≥30% Reduction in Off Time at Week 12) was analyzed using a generalized linear mixed model with baseline mean OFF time (hours/day) as a covariate and treatment-by-time interaction as a fixed effect, and an unstructured covariance matrix was used to model the correlation among repeated measurements. Responder rates for each treatment arm are presented as are differences from placebo with 95% confidence interval.
Time frame: Up to 12 Weeks
Population: Full Analysis Set (FAS) population, which consisted of all randomized participants who received at least one dose of study treatment; had endpoint data subsequent to at least one dose of study treatment; and had baseline data for those analyses requiring baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preladenant 2 mg | Percentage of Participants With ≥30% Reduction in Off Time at Week 12 | 34.5 Percentage of participants |
| Preladenant 5 mg | Percentage of Participants With ≥30% Reduction in Off Time at Week 12 | 34.6 Percentage of participants |
| Preladenant 10 mg | Percentage of Participants With ≥30% Reduction in Off Time at Week 12 | 24.6 Percentage of participants |
| Placebo | Percentage of Participants With ≥30% Reduction in Off Time at Week 12 | 28.9 Percentage of participants |
p-value: 0.40495% CI: [-7.75, 19]A generalized linear mixed model
p-value: 0.3995% CI: [-7.73, 18.81]A generalized linear mixed model
p-value: 0.50895% CI: [-17.78, 7.97]A generalized linear mixed model