Clinical trial NCT01155466: A Placebo- and Active Controlled Study of Preladenant in Subjects With Moderate to Severe Parkinson's Disease (P04938)
Official title: A Phase 3, 12-Week, Double-Blind, Double-Dummy, Placebo- and Active-Controlled Efficacy and Safety Study of Preladenant in Subjects With Moderate to Severe Parkinson's Disease (Phase 3;Protocol No. P04938)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Parkinson Disease
Keywords: Idiopathic Parkinson Disease
Idiopathic Parkinson's Disease
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2010-07-01
Enrollment: 778
Sex: ALL
Minimum age (years): 30
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: When a patient with Parkinson's disease (PD) is initially treated with L-dopa or dopamine agonists, the symptoms of PD improve or disappear. After several years of taking L dopa or dopamine agonists, patients notice that their PD medications wear off sooner than when they first started taking them. This "wearing off" is characterized by the return of symptoms (i.e., tremor, slowness, and rigidity) and may occur over the course of a few minutes to an hour. When a patient's PD symptoms have returned, the patient is said to be in the "off" state. When the patient takes another dose of medication, and his/her PD symptoms improve or resolve, the patient is said to be in the "on" state. Antagonism of adenosine Type 2a receptors (A2a) may provide relief of PD symptoms. This trial will test the hypothesis that A2a receptor antagonism can lead to improvement in the function of PD participants taking a stable dose of L-dopa, as measured by a reduction in "off" time.


Eligibility criteria: Inclusion Criteria:

* Must have a diagnosis of moderate to severe idiopathic Parkinson's disease.
* 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
* 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 agonists, anticholinergics, entacapone) or taking only L dopa are permitted, provided the treatment regimen has been taken for at least 5 weeks prior to randomization
* 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
* Must be capable of maintaining an accurate and complete symptom diary and to adhere to dose and visit schedules with or without the help of a caregiver
* Must have results of a physical examination and screening clinical laboratory tests clinically acceptable to the investigator
* If 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. Males must also not donate sperm during the trial within 2 weeks after the last dose of study drug

Exclusion Criteria:

* 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 of exposure to a known neurotoxin, or any neurological features not consistent with the diagnosis of PD as assessed by the investigator
* Must not have a history of repeated strokes or head injuries, or a stroke within 6 months of Screening
* Must not have poorly-controlled diabetes or abnormal renal function
* Must not have had surgery for their PD
* Must not be at imminent risk of self-harm or harm to others
* Must not have sleep attacks or compulsive behavior that would interfere with the integrity of the trial or would pose a risk to the subject in participating in the trial
* Must not have a systolic blood pressure (BP) ≥150 mm Hg OR diastolic BP ≥95 mm Hg at Screening
* 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 must not have heart failure staged New York Heart Association Class III or IV
* Must not have an alanine aminotransferase (ALT) or aspartate amino transferase (AST) ≥3 x the upper limit of normal (ULN) or total bilirubin (T-BIL) ≥1.5 x ULN
* Must not have a history of serologically confirmed hepatic dysfunction (defined as viral infection \[Hepatitis B or C; Epstein Barr virus (EBV); cytomegalovirus (CMV)\]) or a history of diagnosis of drug or alcohol induced hepatic toxicity or frank hepatitis
* 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
* Must not have received certain prespecified medications or ingested high tyramine-containing aged cheeses (eg, Stilton) for a prespecified time window before the trial, during the trial, and for 2 weeks after the trial
* Must not have an average daily consumption of more than three 4 ounce glasses (118 mL) of wine or the equivalent
* 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)
* Must not have allergy/sensitivity to investigational product(s) or its/their excipients
* A female subject must not be breast-feeding, considering breast-feeding, pregnant, or intending to become pregnant
* Must not have used preladenant ever, or any investigational drugs within 90 days immediately before Screening

Primary outcomes:
measure: Change From Baseline in Mean "Off" Time
timeFrame: Baseline and Week 12
measure: Numberof Participants With Systolic Blood Pressure >=180 mm Hg
timeFrame: Up to Week 14
measure: Number of Participants With Diastolic Blood Pressure >=105 mm Hg
timeFrame: Up to Week 14
measure: Number of Participants With Alanine Aminotransferase >=3 Times the Upper Limit of Normal
timeFrame: Up to Week 14
measure: Number of Participants With Aspartate Aminotransferase >=3 Times the Upper Limit of Normal
timeFrame: Up to Week 14
measure: Percentage of Participants With Suicidality
timeFrame: Up to Week 12
measure: Change From Baseline at Week 12 in Epworth Sleepiness Scale (ESS)
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Percentage of Participants With >30% Change (Reduction) From Baseline at Week 12 in Mean "Off" Time
timeFrame: Baseline and Week 12
measure: Change From Baseline at Week 12 in Mean "On" Time Without Troublesome Dyskinesia
timeFrame: Baseline and Week 12
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Hauser RA, Stocchi F, Rascol O, Huyck SB, Capece R, Ho TW, Sklar P, Lines C, Michelson D, Hewitt D. Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned. JAMA Neurol. 2015 Dec;72(12):1491-500. doi: 10.1001/jamaneurol.2015.2268.