Parkinson Disease
Conditions
Brief summary
This is a randomized, placebo-controlled, 3-period crossover, balanced, single-site, third party-blind study of preladenant (SCH 420814) in participants with Parkinson disease (PD) to be conducted in conformance with Good Clinical Practices. This trial will investigate the effects of single doses of preladenant and placebo on the dyskinesia and antiparkinsonian actions of a levodopa infusion. The study will examine 10 mg (low dose) or 100 mg (high dose) study drug, given as single, oral administrations in conjunction with intravenous (IV) levodopa infusion and oral carbidopa.
Interventions
DRUGSCH 420814 10 mg
one 10-mg capsule, orally, at hour 0 of treatment period
DRUGSCH 420814 100 mg
single oral dose of four SCH 420814 25-mg capsules at hour 0 of treatment period
DRUGPlacebo
Placebo capsule, oral, at hour 0 of treatment period
DRUGLevodopa
levodopa intravenous (IV) infusion (1 mg/kg body weight) was beginning 1 hour after study drug administration and continued for 2 hours
DRUGCarbidopa
one 25-mg table, orally, at hours 0, 2 and 4 of each treatment period
Sponsors
Oregon Health and Science University
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have a diagnosis of idiopathic PD based on history, exam and any relevant laboratory tests * Participants must have been treated with levodopa for one or more years * Participants must have motor fluctuations that can be measured as a 10% change in tapping speed between on and off and concurrent motor Unified PD Rating Scale (UPDRS) must also show a 20% improvement when on * Participants must have dyskinesia when on measured as at least 2 in one or more body parts on scale using 0 (absent) to 4 (severe) for four limbs, trunk, neck and face (total 7 body parts and 28 points) * Participant must be free of any clinically significant disease that would interfere with the study evaluations * Female participants must be postmenopausal and/or surgically sterilized and have a negative serum pregnancy test at the screening visit and a negative urine or serum pregnancy test upon each admission to the study center * Premenopausal, unsterilized female participants have to agree to use a medically accepted method of contraception * Male participants must agree to use a medically accepted method of contraception as or abstain from sexual intercourse during the trial and for 2 months after stopping the medication.
Exclusion criteria
* Female participants who are pregnant, intend to become pregnant (within 3 months of ending the study), or are lactating * Participants with dementia (mini-mental state examination \[MMSE\] \<23), hallucinations, confusion, major psychiatric disorders, and unstable medical conditions * Participants with any stable surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of any drug * Participants with a positive screen for drugs of abuse * Participants who are positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV) * Participants who are currently participating in another medical interventional clinical study or have participated in a medical interventional clinical study within 30 days and who have previously received this compound.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Peak Dyskinesia Score | Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period | Dyskinesia was scored on a scale of 0 (absent), 1 (mild) , 2 (moderate), 3 (severe) and 4 (incapacitating) for seven body parts (face, neck, trunk, each arm and each leg) based on the worse dyskinesia noted during the entire measurement time. Scores were assessed at Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0. The dyskinesia score was the sum of the scores for the seven body parts. The peak dyskinesia score was recorded for each participant regardless of what timepoint the score was achieved. The total possible score for an individual at each timepoint could range from 0 to 28 with higher scores indicating greater effects of the dyskinesia. The mean peak dyskinesia score was calculated using the individual peak values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Peak Finger Tapping Score | Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period | Tapping was measured with two manual counters with keys that were depressed to register a count. The participant alternately tapped each counter using the index finger of the more affected hand for 60 seconds and was not allowed to use more than one finger to tap. The participant was instructed to tap as rapidly as possible while being timed for 60 seconds. The counts were recorded for the two counters at Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0. The peak tapping score was recorded for each participant regardless of what timepoint the score was achieved. The mean peak finger tapping score was calculated using the individual peak values. |
| Mean Peak Tremor Score | Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period | Tremor was scored on a scale of 0 (absent), 1 (mild, 2 (moderate), 3 (severe) and 4 (incapacitating) for seven body parts (face, neck, trunk, each arm and each leg) based on the worse tremor observed during the time spent with participant while taking other study measurements(vital signs, drawing samples, performing the tapping and walking tasks). Scores were assessed at Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0. The tremor score was the sum of scores for seven body parts. The peak tremor score was recorded for each participant regardless of what timepoint the score was achieved. The total possible score for an individual at each timepoint could range from 0 to 28 with higher scores indicating more effects of the tremors. The mean peak tremor score was calculated using the individual peak values. |
| Mean Peak Walking Speed | Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period | Walking speed assessment began with the participant being seated in an armless chair. Then while being timed, the participant stood up with their arms crossed on their chest and walked 6 meters, turned around, returned to the chair and sat. Timing was stopped when the participant's buttocks hit the chair and the total time was recorded. If the participant could not arise in 60 seconds, 60 seconds was entered in this line of the report form and the participant was tested again but allowed to push off to get out of the chair. Sixty seconds was the maximum time allowed to complete the walking assessment, thus 60 seconds was recorded as the time if they could not complete the task within this time limit. Walking speed was assessed at Hours 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7.0 and 8. The peak walking speed was recorded for each participant regardless of what timepoint the score was achieved. The mean peak walking speed was calculated using the individual peak values. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SCH 420814 10 mg→SCH 420814 100 mg→Placebo Participants were to receive their assigned experimental treatment based on randomly assigned treatment sequence at Hour 0 following an overnight withdrawal of their antiparkinsonian medications of each treatment period. The levodopa infusion was to be started at Hour 1 and was to run for 2 hours. The participants were to also receive 25 mg of carbidopa at the following times: Hours 0, 2, and 4. Treatment periods were to be separated by at least 7 days but not more than 28 days washout between each dose. | 2 |
| SCH 420814 100 mg→Placebo→ SCH 420814 10 mg Participants were to receive their assigned experimental treatment based on randomly assigned treatment sequence at Hour 0 following an overnight withdrawal of their antiparkinsonian medications of each treatment period. The levodopa infusion was to be started at Hour 1 and was to run for 2 hours. The participants were to also receive 25 mg of carbidopa at the following times: Hours 0, 2, and 4. Treatment periods were to be separated by at least 7 days but not more than 28 days washout between each dose. | 2 |
| Placebo→SCH 420814 10 mg→SCH 420814 100 mg Participants were to receive their assigned experimental treatment based on randomly assigned treatment sequence at Hour 0 following an overnight withdrawal of their antiparkinsonian medications of each treatment period. The levodopa infusion was to be started at Hour 1 and was to run for 2 hours. The participants were to also receive 25 mg of carbidopa at the following times: Hours 0, 2, and 4. Treatment periods were to be separated by at least 7 days but not more than 28 days washout between each dose. | 2 |
| SCH 420814 10 mg→ Placebo→ SCH 420814 100 mg Participants were to receive their assigned experimental treatment based on randomly assigned treatment sequence at Hour 0 following an overnight withdrawal of their antiparkinsonian medications of each treatment period. The levodopa infusion was to be started at Hour 1 and was to run for 2 hours. The participants were to also receive 25 mg of carbidopa at the following times: Hours 0, 2, and 4. Treatment periods were to be separated by at least 7 days but not more than 28 days washout between each dose. | 2 |
| SCH 420814 100 mg→ SCH 420814 10 mg→Placebo Participants were to receive their assigned experimental treatment based on randomly assigned treatment sequence at Hour 0 following an overnight withdrawal of their antiparkinsonian medications of each treatment period. The levodopa infusion was to be started at Hour 1 and was to run for 2 hours. The participants were to also receive 25 mg of carbidopa at the following times: Hours 0, 2, and 4. Treatment periods were to be separated by at least 7 days but not more than 28 days washout between each dose. | 2 |
| Placebo→ SCH 420814 100 mg→SCH 420814 10 mg Participants were to receive their assigned experimental treatment based on randomly assigned treatment sequence at Hour 0 following an overnight withdrawal of their antiparkinsonian medications of each treatment period. The levodopa infusion was to be started at Hour 1 and was to run for 2 hours. The participants were to also receive 25 mg of carbidopa at the following times: Hours 0, 2, and 4. Treatment periods were to be separated by at least 7 days but not more than 28 days washout between each dose. | 2 |
| Total | 12 |
Baseline characteristics
| Characteristic | SCH 420814 10 mg→SCH 420814 100 mg→Placebo | SCH 420814 100 mg→Placebo→ SCH 420814 10 mg | Placebo→SCH 420814 10 mg→SCH 420814 100 mg | SCH 420814 10 mg→ Placebo→ SCH 420814 100 mg | SCH 420814 100 mg→ SCH 420814 10 mg→Placebo | Placebo→ SCH 420814 100 mg→SCH 420814 10 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.5 Years STANDARD_DEVIATION 4.9 | 59.5 Years STANDARD_DEVIATION 3.5 | 65.0 Years STANDARD_DEVIATION 4.2 | 63.5 Years STANDARD_DEVIATION 6.4 | 68.5 Years STANDARD_DEVIATION 13.4 | 57.5 Years STANDARD_DEVIATION 3.5 | 61.9 Years STANDARD_DEVIATION 6.7 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 6 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 | 5 / 12 | 4 / 12 | 4 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Mean Peak Dyskinesia Score
Dyskinesia was scored on a scale of 0 (absent), 1 (mild) , 2 (moderate), 3 (severe) and 4 (incapacitating) for seven body parts (face, neck, trunk, each arm and each leg) based on the worse dyskinesia noted during the entire measurement time. Scores were assessed at Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0. The dyskinesia score was the sum of the scores for the seven body parts. The peak dyskinesia score was recorded for each participant regardless of what timepoint the score was achieved. The total possible score for an individual at each timepoint could range from 0 to 28 with higher scores indicating greater effects of the dyskinesia. The mean peak dyskinesia score was calculated using the individual peak values.
Time frame: Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period
Population: All participants who received at least 1 dose of study drug and had available data for endpoint. Results pooled by study drug and not by randomly assigned sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 420814 10 mg | Mean Peak Dyskinesia Score | 11.00 Score on a scale | Standard Deviation 5.15 |
| SCH 420814 100 mg | Mean Peak Dyskinesia Score | 11.42 Score on a scale | Standard Deviation 5.81 |
| Placebo | Mean Peak Dyskinesia Score | 8.50 Score on a scale | Standard Deviation 3.92 |
Secondary
Mean Peak Finger Tapping Score
Tapping was measured with two manual counters with keys that were depressed to register a count. The participant alternately tapped each counter using the index finger of the more affected hand for 60 seconds and was not allowed to use more than one finger to tap. The participant was instructed to tap as rapidly as possible while being timed for 60 seconds. The counts were recorded for the two counters at Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0. The peak tapping score was recorded for each participant regardless of what timepoint the score was achieved. The mean peak finger tapping score was calculated using the individual peak values.
Time frame: Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period
Population: All participants who received at least 1 dose of study drug and had available data for endpoint. Results pooled by study drug and not by randomly assigned sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 420814 10 mg | Mean Peak Finger Tapping Score | 44.33 taps per 60 seconds | Standard Deviation 27.76 |
| SCH 420814 100 mg | Mean Peak Finger Tapping Score | 41.58 taps per 60 seconds | Standard Deviation 22.31 |
| Placebo | Mean Peak Finger Tapping Score | 45.75 taps per 60 seconds | Standard Deviation 28.26 |
Secondary
Mean Peak Tremor Score
Tremor was scored on a scale of 0 (absent), 1 (mild, 2 (moderate), 3 (severe) and 4 (incapacitating) for seven body parts (face, neck, trunk, each arm and each leg) based on the worse tremor observed during the time spent with participant while taking other study measurements(vital signs, drawing samples, performing the tapping and walking tasks). Scores were assessed at Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0. The tremor score was the sum of scores for seven body parts. The peak tremor score was recorded for each participant regardless of what timepoint the score was achieved. The total possible score for an individual at each timepoint could range from 0 to 28 with higher scores indicating more effects of the tremors. The mean peak tremor score was calculated using the individual peak values.
Time frame: Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period
Population: All participants who received at least 1 dose of study drug and had available data for endpoint. Results pooled by study drug and not by randomly assigned sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 420814 10 mg | Mean Peak Tremor Score | 3.5 Score on a scale | Standard Deviation 4.76 |
| SCH 420814 100 mg | Mean Peak Tremor Score | 3.33 Score on a scale | Standard Deviation 4.66 |
| Placebo | Mean Peak Tremor Score | 4.42 Score on a scale | Standard Deviation 5.3 |
Secondary
Mean Peak Walking Speed
Walking speed assessment began with the participant being seated in an armless chair. Then while being timed, the participant stood up with their arms crossed on their chest and walked 6 meters, turned around, returned to the chair and sat. Timing was stopped when the participant's buttocks hit the chair and the total time was recorded. If the participant could not arise in 60 seconds, 60 seconds was entered in this line of the report form and the participant was tested again but allowed to push off to get out of the chair. Sixty seconds was the maximum time allowed to complete the walking assessment, thus 60 seconds was recorded as the time if they could not complete the task within this time limit. Walking speed was assessed at Hours 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7.0 and 8. The peak walking speed was recorded for each participant regardless of what timepoint the score was achieved. The mean peak walking speed was calculated using the individual peak values.
Time frame: Hours 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0 and 8.0 of each treatment period
Population: All participants who received at least 1 dose of study drug and had available data for endpoint. Results pooled by study drug and not by randomly assigned sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 420814 10 mg | Mean Peak Walking Speed | 16.64 Seconds | Standard Deviation 18.98 |
| SCH 420814 100 mg | Mean Peak Walking Speed | 14.45 Seconds | Standard Deviation 15.73 |
| Placebo | Mean Peak Walking Speed | 20.00 Seconds | Standard Deviation 20.64 |