Dyskinesia in Parkinson's Disease (Study P04501)

Parkinson Disease Clinical Trial

Official title:

A Phase 2, 12-Week, Double-Blind, Dose-Finding, Placebo-Controlled Study to Assess the Efficacy and Safety of a Range of SCH 420814 Doses in Subjects With Moderate to Severe Parkinson's Disease Experiencing Motor Fluctuations and Dyskinesias

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00406029
• Other study ID #: P04501
• Secondary ID: MK-3814-013
• Status: Completed
• Phase: Phase 2
• Start date: November 20, 2006
• Est. completion date: November 3, 2008

Study information

• Verified date: October 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to assess the efficacy and safety of a range of doses of SCH 420814 (preladenant) when used together with a stable dose of L-dopa/dopa decarboxylase inhibitor to treat Parkinson's disease. In this study, we will be comparing 3 doses (1 mg, 2 mg, and 5 mg taken twice a day) of preladenant with placebo (sugar pill). Following an Interim Analysis (temporary hold for new enrollment-ongoing subjects will continue on treatment) to review drug safety, a new dose group of 10 mg (taken twice a day) may be added.

Approximately 160 participants will be randomized in this study in approximately 22 study centers worldwide for the first part of this study. Following the Interim Analysis, 40 new participants may be added, for a total of 200 participants. The study is double blind, which means neither you nor your study doctor will know whether you are receiving the study medication or placebo.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 253
• Est. completion date: November 3, 2008
• Est. primary completion date: October 5, 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years and older

Eligibility

Inclusion Criteria:

• Participants must be 30 years of age, of either sex and of any race, with a diagnosis of moderate to severe idiopathic Parkinson's disease for at least 5 years.

• Women of childbearing potential must have a negative serum pregnancy test at Visit 2 (Week -1). If participant is postmenopausal (not surgically induced), she must be postmenopausal by history for at least 2 years before study entry. If not, proper birth control must be used.

Note: Acceptable methods of birth control include oral or injectable hormonal contraceptive, medically prescribed intrauterine device (IUD), and double-barrier method (eg, condom in combination with spermicide). Bilateral tubal ligation is an acceptable method of birth control for this study.

• Participants' clinical laboratory tests (complete blood count [CBC], blood chemistries, and urinalysis) must be within normal limits or clinically acceptable to the investigator/sponsor.

Exclusion Criteria:

• Participants with any form of drug-induced or atypical parkinsonism, cognitive impairment (Mini-Mental State Examination [MMSE] score <=23), a history of Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV) diagnosed major depression, unstable mild depression or psychosis, or participants taking tolcapone will be excluded. (Participants with mild depression who are well controlled on a stable dose of an antidepressant medication for at least 4 weeks before screening will be eligible.)

• All participants with a severe or ongoing unstable medical condition will be excluded including those with a history of poorly controlled diabetes, obesity associated with metabolic syndrome, uncontrolled hypertension, cerebrovascular disease, or any form of clinically significant cardiac disease, symptomatic orthostatic hypotension, renal failure, history of abnormal renal function, seizures, alcohol/drug dependence, or previous surgery for Parkinson's disease.

• Average daily consumption of more than two 4-oz (120 mL) glasses of wine or their equivalent.

• Because it is not known whether preladenant passes into breast milk and because the effects, if any, of preladenant on the developing human are unknown, women who are breastfeeding or who are considering breastfeeding are excluded from this trial.

• Participants with allergy/sensitivity to study drug or its excipients.

• Participants with any clinically significant condition or situation, other than the condition being studied that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study.

• Participants who have used any other investigational drugs within 30 days of Screening.

• Participants who are participating in any other clinical study.

Related Conditions & MeSH terms

• Brain Diseases
• Central Nervous System Diseases
• Dyskinesias
• Movement Disorders
• Nervous System Diseases
• Neurodegenerative Diseases
• Parkinson Disease

Intervention

Drug:
• Preladenant
1 mg BID capsules
• Preladenant
2 mg BID capsules
• Preladenant
5 mg BID capsules
• Preladenant
10 mg BID capsules
• Placebo
BID capsules
• L-dopa
Participants must receive L-dopa as part of their usual ongoing treatment for Parkinson's Disease. L-dopa is often administered concomitantly with a dopa decarboxylase inhibitor (e.g., carbidopa).
• Other Parkinson's Disease treatments
Participants may also receive other drugs as part of their usual ongoing treatment for Parkinson's Disease, such as dopamine agonists (e.g., pramipexole) and/or the catechol-O-methyl transferase (COMT) inhibitor entacapone.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Endpoint of 12 Weeks in the 3-day Average of Awake Time Per Day Spent in the "Off" State	"Off" time refers to periods of inadequate control of Parkinson disease symptoms (worsening or presence of symptoms). For baseline and the 12 weeks treatment period, hours spent in the "off" state during awake time were recorded in half-hour time intervals using a daily diary at least 3 full days before scheduled visits. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For endpoint, the 24-hour average was derived for the last available 3 consecutive days with postbaseline data available during the treatment period. Change from baseline in least squares (LS) means and pooled standard deviation (SD) were obtained from an analysis of covariance (ANCOVA) model with effect for treatment and baseline covariate. A negative change from baseline signifies less time spent in the "off" state.	Baseline (Week -1) and up to 12 weeks
Secondary	Change From Baseline in Awake Time Per Day Spent in the "Off" State at Each Visit	"Off" time refers to periods of inadequate control of Parkinson disease symptoms (worsening or presence of symptoms). Hours spent in the "off" state during awake time were recorded in half-hour time intervals using a daily diary at least 3 full days before scheduled visits. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For treatment period visits, the 24-hour average was derived for the final 3 consecutive days with data available for the particular visit. Change from baseline in LS means and pooled SD were obtained from an ANCOVA model with treatment effect and baseline covariate. A negative change from baseline signifies less time spent in the "off" state.	Baseline (Week -1) and Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in Awake Time Per Day Spent in the "on" State	"On" time refers to periods of adequate control of Parkinson disease symptoms (symptoms better or absent). Hours spent in the "on" state during awake time were recorded in half-hour time intervals using a daily diary at least 3 full days before scheduled visits. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For endpoint, the 24-hour average was derived for the last available 3 consecutive days with postbaseline data available during the treatment period. For treatment period visits, the 24-hour average was derived for the final 3 consecutive days with data available for the particular visit. Change from baseline in LS means and pooled SD were obtained from an ANCOVA model with effect for treatment and baseline covariate. A positive (+) change from baseline signifies more time spent in the "on" state.	Baseline (Week -1) and Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in Awake Time Per Day Spent in the "on" State (no Dyskinesias)	"On" time refers to periods of adequate control of Parkinson disease symptoms (better/absent). Dyskinesias refers to maintenance therapy (e.g., L-dopa) side effects of chorea, dystonia, or in combination. Hours spent in the "on" state with no dyskinesias during awake time were recorded in half-hour time intervals using a daily diary at least 3 full days before scheduled visits. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For endpoint, the 24-hour average was derived for the last available 3 consecutive days with postbaseline data available during the treatment period. For treatment period visits, the 24-hour average was derived for the final 3 consecutive days with data available for the particular visit. Change from baseline in LS means & pooled SD were obtained from an ANCOVA model with effect for treatment & baseline covariate. A (+) change from baseline signifies more time spent in the "on" state (no dyskinesias).	Baseline (Week -1) and Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in Awake Time Per Day Spent in the "on" State (With Troublesome Dyskinesias)	"On" time refers to periods of adequate control of Parkinson disease symptoms (better/absent). Troublesome dyskinesias refers to maintenance therapy side effects of chorea, dystonia, or in combination that impair function. Hours spent in the "on" state with troublesome dyskinesias during awake time were recorded in half-hour time intervals using a daily diary at least 3 full days before scheduled visits. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For endpoint, the 24-hour average was derived for the last available 3 consecutive days with postbaseline data available during the treatment period. For treatment period visits, the 24-hour average was derived for the final 3 consecutive days with data available for the particular visit. Change from baseline in LS means & pooled SD were obtained using ANCOVA with treatment effect & baseline covariate. A (+) change from baseline signifies more time spent in the "on" state (troublesome dyskinesias).	Baseline (Week -1) and Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in Awake Time Per Day Spent in the "on" State (Without Troublesome Dyskinesias)	"On" time refers to periods of adequate control of Parkinson disease symptoms (better/absent). Troublesome dyskinesias refers to maint. therapy side effects of chorea, dystonia, or in combination that impair function. Hours spent in the "on" state without troubles. dyskinesias during awake time were recorded in half-hour time intervals using a daily diary at least 3 full days before scheduled visits. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For endpoint, the 24-hour average was derived for the last available 3 consecutive days with postbaseline data available during the treatment period. For treatment period visits, the 24-hour average was derived for the final 3 consecutive days with data available for the particular visit. Change from baseline in LS means & pooled SD were obtained using ANCOVA with treatment effect & baseline covariate. A (+) change from baseline signifies more time spent in the "on" state (without troubles. dyskinesias).	Baseline (Week -1) and Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in Absolute Duration of Dyskinesias	Dyskinesias refers to maintenance therapy side effects of chorea, dystonia, or in combination (that occur in the ON time). Hours spent with dyskinesias (troublesome and not troublesome) were recorded in half-hour time intervals using a daily diary at least 3 full days before scheduled visits. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For endpoint, the 24-hour average was derived for the last available 3 consecutive days with postbaseline data available during the treatment period. For treatment period visits, the 24-hour average was derived for the final 3 consecutive days with data available for the particular visit. Change from baseline in LS means & pooled SD were obtained using ANCOVA with treatment effect & baseline covariate. A negative change from baseline signifies less time spent with dyskinesia.	Baseline (Week -1) and Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in Total Sleep Time	Hours spent in the sleep state were recorded using a daily diary at least 3 full days before scheduled visit. For baseline, the 24-hour average over 3 consecutive days was derived for Week -1. For endpoint, the 24-hour average was derived for the last available 3 consecutive days with postbaseline data available during the treatment period. For treatment period visits, the 24-hour average was derived for the final 3 consecutive days with data available for the particular visit. Change from baseline in LS means & pooled SD were obtained using ANCOVA with treatment effect & baseline covariate. A positive change from baseline means more time asleep and a negative change means less time asleep.	Baseline (Week -1) and Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in Frequency of Sleep Attacks at Week 2	Sleep attacks are uncontrollable episodes of sleep that occur during the daytime lasting a few seconds to several minutes. A questionnaire to determine sleep attacks over the prior 2 week period was administered at baseline and at 2-week intervals during the treatment period. Frequency of sleep attacks over the two-week treatment period intervals were tabulated in relation to the baseline assessment. Results are presented as participants showing the respective change in frequency of sleep attacks at baseline to the week of assessment (Week 2) (as reported by the participant). For example, someone who had >2 sleep attacks at BL who had a decrease of 1-2 by Week 2 would be reported as BL >2 to WK2 1-2. BL = baseline. WK = week.	Baseline (predose Day 1) and 2 hours postdose at Week 2
Secondary	Change From Baseline in Frequency of Sleep Attacks at Week 4	Sleep attacks are uncontrollable episodes of sleep that occur during the daytime lasting a few seconds to several minutes. A questionnaire to determine sleep attacks over the prior 2 week period was administered at baseline and at 2-week intervals during the treatment period. Frequency of sleep attacks over the two-week treatment period intervals were tabulated in relation to the baseline assessment. Results are presented as participants showing the respective change in frequency of sleep attacks at baseline to the week of assessment (Week 4) (as reported by the participant). For example, someone who had >2 sleep attacks at BL who had a decrease of 1-2 by Week 4 would be reported as BL >2 to WK4 1-2. BL = baseline. WK = week.	Baseline (predose Day 1) and 2 hours postdose at Week 4
Secondary	Change From Baseline in Frequency of Sleep Attacks at Week 6	Sleep attacks are uncontrollable episodes of sleep that occur during the daytime lasting a few seconds to several minutes. A questionnaire to determine sleep attacks over the prior 2 week period was administered at baseline and at 2-week intervals during the treatment period. Frequency of sleep attacks over the two-week treatment period intervals were tabulated in relation to the baseline assessment. Results are presented as participants showing the respective change in frequency of sleep attacks at baseline to the week of assessment (Week 6) (as reported by the participant). For example, someone who had >2 sleep attacks at BL who had a decrease of 1-2 by Week 6 would be reported as BL >2 to WK6 1-2. BL = baseline. WK = week.	Baseline (predose Day 1) and 2 hours postdose at Week 6
Secondary	Change From Baseline in Frequency of Sleep Attacks at Week 8	Sleep attacks are uncontrollable episodes of sleep that occur during the daytime lasting a few seconds to several minutes. A questionnaire to determine sleep attacks over the prior 2 week period was administered at baseline and at 2-week intervals during the treatment period. Frequency of sleep attacks over the two-week treatment period intervals were tabulated in relation to the baseline assessment. Results are presented as participants showing the respective change in frequency of sleep attacks at baseline to the week of assessment (Week 8) (as reported by the participant). For example, someone who had >2 sleep attacks at BL who had a decrease of 1-2 by Week 8 would be reported as BL >2 to WK8 1-2. BL = baseline. WK = week.	Baseline (predose Day 1) and 2 hours postdose at Week 8
Secondary	Change From Baseline in Frequency of Sleep Attacks at Week 10	Sleep attacks are uncontrollable episodes of sleep that occur during the daytime lasting a few seconds to several minutes. A questionnaire to determine sleep attacks over the prior 2 week period was administered at baseline and at 2-week intervals during the treatment period. Frequency of sleep attacks over the two-week treatment period intervals were tabulated in relation to the baseline assessment. Results are presented as participants showing the respective change in frequency of sleep attacks at baseline to the week of assessment (Week 10) (as reported by the participant). For example, someone who had >2 sleep attacks at BL who had a decrease of 1-2 by Week 10 would be reported as BL >2 to WK10 1-2. BL = baseline. WK = week.	Baseline (predose Day 1) and 2 hours postdose at Week 10
Secondary	Change From Baseline in Frequency of Sleep Attacks at Week 12	Sleep attacks are uncontrollable episodes of sleep that occur during the daytime lasting a few seconds to several minutes. A questionnaire to determine sleep attacks over the prior 2 week period was administered at baseline and at 2-week intervals during the treatment period. Frequency of sleep attacks over the two-week treatment period intervals were tabulated in relation to the baseline assessment. Results are presented as participants showing the respective change in frequency of sleep attacks at baseline to the week of assessment (Week 12) (as reported by the participant). For example, someone who had >2 sleep attacks at BL who had a decrease of 1-2 by Week 12 would be reported as BL >2 to WK12 1-2. BL = baseline. WK = week.	Baseline (predose Day 1) and 2 hours postdose at Week 12
Secondary	Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Part 1	The UPDRS is a frequently used multi-item 4-part questionnaire designed to assess various aspects of Parkinson's disease severity. A total of 42 items are assessed divided across Parts 1 to 4. Part 1 assesses mentation (4 items scored from 0 [best] to 4 [worst]; total range 0-16). Assessments were obtained at baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, and 12. For endpoint, the last postbaseline visit while on study medication was used. Change from baseline in LS means and pooled SD were obtained from an ANCOVA model with effect for treatment and baseline covariate. Negative change from baseline indicates a decrease in severity.	Baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in UPDRS Part 2	The UPDRS is a frequently used multi-item 4-part questionnaire designed to assess various aspects of Parkinson's disease severity. A total of 42 items are assessed divided across Parts 1 to 4. Part 2 assesses daily living (13 items scored from 0 [best] to 4 [worst]; total range 0-52). Assessments were obtained at baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, and 12. For endpoint, the last postbaseline visit while on study medication was used. Change from baseline in LS means and pooled SD were obtained from an ANCOVA model with effect for treatment and baseline covariate. Negative change from baseline indicates a decrease in severity.	Baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in UPDRS Part 3 (1 Hour Post-dose)	The UPDRS is a frequently used multi-item 4-part questionnaire designed to assess various aspects of Parkinson's disease severity. A total of 42 items are assessed divided across Parts 1 to 4. The Part 3 subscale assesses motor function across 14 categories for 27 items. Scores for each item range from 0 (best) to 4 (worst) with a total range of 0-108. Assessments were obtained at baseline (predose Day 1) and 1 hour postdose at Weeks 2, 4, 6, 8, 10, and 12. For endpoint, the last postbaseline visit while on study medication was used. Change from baseline in LS means and pooled SD were obtained from an ANCOVA model with effect for treatment and baseline covariate. Negative change from baseline indicates a decrease in severity.	Baseline (predose Day 1) and 1 hour postdose at Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in UPDRS Part 3 (2 Hours Post-dose)	The UPDRS is a frequently used multi-item 4-part questionnaire designed to assess various aspects of Parkinson's disease severity. A total of 42 items are assessed divided across Parts 1 to 4. The Part 3 subscale assesses motor function across 14 categories for 27 items. Scores for each item range from 0 (best) to 4 (worst) with a total range of 0-108. Assessments were obtained at baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, and 12. For endpoint, the last postbaseline visit while on study medication was used. Change from baseline in LS means and pooled standard deviation were obtained from an ANCOVA model with effect for treatment and baseline covariate. Negative change from baseline indicates a decrease in severity.	Baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, 12
Secondary	Change From Baseline in UPDRS Part 4	The UPDRS is a frequently used multi-item 4-part questionnaire designed to assess various aspects of Parkinson's disease severity. A total of 42 items are assessed divided across Parts 1 to 4. The Part 4 subscale assesses complications of therapy over the past week for a total of eleven question items. The first three questions and question 8 are rated from 0 (best) to 4 (worst), and the remaining seven questions are simple no (0) / yes (1) questions. The total subscale score ranges from 0 to 23. Assessments were obtained at baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, and 12. For endpoint, the last postbaseline visit while on study medication was used. Change from baseline in LS means and pooled SD were obtained from an ANCOVA model with effect for treatment and baseline covariate. Negative change from baseline indicates a decrease in severity.	Baseline (predose Day 1) and 2 hours postdose at Weeks 2, 4, 6, 8, 10, 12