Excessive Daytime Sleepiness, Hypopnea Syndrome, Sleep Apnea, Obstructive
Conditions
Brief summary
The purpose of this study is to determine the safety and efficacy of MK0249 in treating refractory excessive daytime sleepiness (EDS) in patients with Obstructive Sleep Apnea/Hypopnea Syndrome (OSA/HS) using nasal continuous positive airway pressure (nCPAP) therapy.
Interventions
DRUGComparator: MK0249
Patients will be assigned to receive MK0249 film coated tablet (FCT). The doses of MK0249 that are included for possible investigation (depending upon an adaptive allocation process) are 3 mg, 5 mg, 8 mg, 10 mg, and 12 mg. Study medication will be taken for 14 days, during each of the 3 treatment periods, by mouth (po) once a day (qd).
DRUGComparator: placebo
Placebo; Patients will be assigned to receive placebo, across 3 treatment periods. Study medication will be taken for 14 days, during each of the 3 treatment periods, po qd.
DRUGComparator: modafinil
Patients will be assigned to receive modafinil 200mg oral compressed tablet (OCT), across 3 treatment periods. Study medication will be taken for 14 days, during each of the 3 treatment periods, po qd.
Sponsors
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 64 Years
Healthy volunteers
No
Inclusion criteria
* Patient is male or female and is at least 18 years old and less than 65 years old * Patient must have a diagnosis of Obstructive Sleep Apnea/Hypopnea Syndrome * Patient has been using nCPAP treatment for at least 2 months prior to Visit 1 * Patient is willing to stay at a sleep laboratory for 4 full days and nights for observation and assessments * Patient is willing to refrain from napping for the duration of the study
Exclusion criteria
* Patient is pregnant, breastfeeding, or planning to become pregnant within the next 4 months * Patient is or has participated in a study with an investigational compound or device within 30 days of signing the informed consent * Patient has had asthma-related visit to the emergency room or hospitalization within 6 months of Visit 1 * Patient has donated or received blood products within 8 weeks of signing consent or is planning on doing either for the duration of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean of Average Maintenance of Wakefulness Test Early for The Mode Dose of MK0249 Versus Placebo | At Week 2 | The Maintenance of Wakefulness Test (MWT) is an objective assessment of sleepiness that measures the ability of a patient to remain awake. The primary endpoint was the mean of sleep latency (average of the first 4 MWTs which were at 0900, 1100, 1300, and 1500), where latency for each MWT was defined as the time to onset of the first 16 continuous seconds of any stage of sleep; if no sleep was observed according to these rules, then latency was defined as 30 minutes. The comparison was for the mode dose of MK0249 versus placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean of Average Maintenance of Wakefulness Test Early for the Mode Dose of MK0249 Versus Modafinil | At Week 2 | The Maintenance of Wakefulness Test (MWT) is an objective assessment of sleepiness that measures the ability of a patient to remain awake. The primary endpoint was the mean of sleep latency (average of the first 4 MWTs which were at 0900, 1100, 1300, and 1500), where latency for each MWT was defined as the time to onset of the first 16 continuous seconds of any stage of sleep; if no sleep was observed according to these rules, then latency was defined as 30 minutes. The comparison was for the mode dose of MK0249 versus modafinil. |
| Mean of Average Maintenance of Wakefulness Test Early for Top 2 Doses Pooled of MK0249 Versus Modafinil | At Week 2 | The Maintenance of Wakefulness Test (MWT) is an objective assessment of sleepiness that measures the ability of a patient to remain awake. The primary endpoint was the mean of sleep latency (average of the first 4 MWTs which were at 0900, 1100, 1300, and 1500), where latency for each MWT was defined as the time to onset of the first 16 continuous seconds of any stage of sleep; if no sleep was observed according to these rules, then latency was defined as 30 minutes. The comparison was for the top 2 doses pooled of MK0249 versus modafinil. |
| Clinical Global Impressions Scale of Severity Score as it Relates to Excessive Daytime Sleepiness (CGIS-EDS) for the Mode Dose of MK0249 Versus Placebo | At Week 2 | Clinical Global Impressions Scale of Severity (CGI-S) is a subscale of the CGI which is a standard psychometric scale used to demonstrate changes and improvements in illness. CGI-S consists of a 7-point scale rated from 1 to 7. The investigator or sponsor-approved clinician judged how ill the patient was with respect to Excessive Daytime Sleepiness (EDS) at the time of the CGI-S rating (CGIS-EDS), with higher scores indicating more severe illness. |
| Epworth Sleepiness Scale (ESS) Score for the Mode Dose of MK0249 Versus Placebo | At Week 2 | The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire that provides subjective reports that equate with sleep propensity, not with 'subjective sleepiness'. Having a high sleep propensity means having a history of dozing in situations that have a relatively low soporific nature, in which normal subjects seldom doze. The ESS consists of eight items, which are rated from 0 (would never dose) to 3 (high chance of dozing). The ESS score is the total score of the 8 individual items; this total score ranges from 0 to 24 (higher total score is worse). |
Participant flow
Recruitment details
The majority of patients were recruited from investigators' own databases at 24 sites in the United States. The primary therapy period was 13-Mar-2008 to 25-Feb-2009.
Pre-assignment details
Participants maintained sleep and sleepiness diaries during a 7- to 10-day placebo run-in period. They used a nasal continuous positive airway pressure (nCPAP) device to monitor their CPAP use. At the end of the run-in period, participants stayed overnight at the clinic for nighttime polysomnography and if eligible, were randomized the next morning
Participants by arm
| Arm | Count |
|---|---|
| All Randomized Participants All participants randomized in study | 125 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Placebo Washout Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
| Placebo Washout Period 2 | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 | Adverse Event | 1 | 0 | 0 | 3 | 0 | 0 |
| Treatment Period 1 | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 | Withdrawal by Subject | 1 | 0 | 1 | 0 | 1 | 0 |
| Treatment Period 2 | Adverse Event | 0 | 3 | 0 | 0 | 2 | 0 |
| Treatment Period 2 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 3 | 0 |
| Treatment Period 3 | Adverse Event | 0 | 2 | 0 | 0 | 0 | 0 |
| Treatment Period 3 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Randomized Participants |
|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 8.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants |
| Race/Ethnicity, Customized Asian | 3 participants |
| Race/Ethnicity, Customized Black or African American | 19 participants |
| Race/Ethnicity, Customized White | 102 participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 41 / 117 | 6 / 10 | 7 / 25 | 16 / 46 | 25 / 39 | 38 / 111 |
| serious Total, serious adverse events | 2 / 117 | 0 / 10 | 0 / 25 | 0 / 46 | 0 / 39 | 0 / 111 |
Outcome results
Primary
Mean of Average Maintenance of Wakefulness Test Early for The Mode Dose of MK0249 Versus Placebo
The Maintenance of Wakefulness Test (MWT) is an objective assessment of sleepiness that measures the ability of a patient to remain awake. The primary endpoint was the mean of sleep latency (average of the first 4 MWTs which were at 0900, 1100, 1300, and 1500), where latency for each MWT was defined as the time to onset of the first 16 continuous seconds of any stage of sleep; if no sleep was observed according to these rules, then latency was defined as 30 minutes. The comparison was for the mode dose of MK0249 versus placebo.
Time frame: At Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients with patients excluded for failure to receive at least one dose of study treatment or lack of endpoint data. Patients with at least one dose and endpoint in at least one treatment period were included in the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean of Average Maintenance of Wakefulness Test Early for The Mode Dose of MK0249 Versus Placebo | 12.79 Minutes | Standard Error 0.75 |
| MK0249 Mode Dose | Mean of Average Maintenance of Wakefulness Test Early for The Mode Dose of MK0249 Versus Placebo | 13.34 Minutes | Standard Error 1.09 |
p-value: 0.615Mixed Models Analysis
Secondary
Clinical Global Impressions Scale of Severity Score as it Relates to Excessive Daytime Sleepiness (CGIS-EDS) for the Mode Dose of MK0249 Versus Placebo
Clinical Global Impressions Scale of Severity (CGI-S) is a subscale of the CGI which is a standard psychometric scale used to demonstrate changes and improvements in illness. CGI-S consists of a 7-point scale rated from 1 to 7. The investigator or sponsor-approved clinician judged how ill the patient was with respect to Excessive Daytime Sleepiness (EDS) at the time of the CGI-S rating (CGIS-EDS), with higher scores indicating more severe illness.
Time frame: At Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients with patients excluded for failure to receive at least one dose of study treatment or lack of an endpoint data. Patients with at least one dose and endpoint in at least one treatment period were included in the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impressions Scale of Severity Score as it Relates to Excessive Daytime Sleepiness (CGIS-EDS) for the Mode Dose of MK0249 Versus Placebo | 3.76 units on a scale | Standard Error 0.11 |
| MK0249 Mode Dose | Clinical Global Impressions Scale of Severity Score as it Relates to Excessive Daytime Sleepiness (CGIS-EDS) for the Mode Dose of MK0249 Versus Placebo | 3.43 units on a scale | Standard Error 0.18 |
p-value: 0.079Mixed Models Analysis
Secondary
Epworth Sleepiness Scale (ESS) Score for the Mode Dose of MK0249 Versus Placebo
The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire that provides subjective reports that equate with sleep propensity, not with 'subjective sleepiness'. Having a high sleep propensity means having a history of dozing in situations that have a relatively low soporific nature, in which normal subjects seldom doze. The ESS consists of eight items, which are rated from 0 (would never dose) to 3 (high chance of dozing). The ESS score is the total score of the 8 individual items; this total score ranges from 0 to 24 (higher total score is worse).
Time frame: At Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients with patients excluded for failure to receive at least one dose of study treatment or lack of an endpoint data. Patients with at least one dose and endpoint in at least one treatment period were included in the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Epworth Sleepiness Scale (ESS) Score for the Mode Dose of MK0249 Versus Placebo | 12.81 units on a scale | Standard Error 0.43 |
| MK0249 Mode Dose | Epworth Sleepiness Scale (ESS) Score for the Mode Dose of MK0249 Versus Placebo | 10.83 units on a scale | Standard Error 0.65 |
p-value: 0.003Mixed Models Analysis
Secondary
Mean of Average Maintenance of Wakefulness Test Early for the Mode Dose of MK0249 Versus Modafinil
The Maintenance of Wakefulness Test (MWT) is an objective assessment of sleepiness that measures the ability of a patient to remain awake. The primary endpoint was the mean of sleep latency (average of the first 4 MWTs which were at 0900, 1100, 1300, and 1500), where latency for each MWT was defined as the time to onset of the first 16 continuous seconds of any stage of sleep; if no sleep was observed according to these rules, then latency was defined as 30 minutes. The comparison was for the mode dose of MK0249 versus modafinil.
Time frame: At Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients with patients excluded for failure to receive at least one dose of study treatment or lack of an endpoint data. Patients with at least one dose and endpoint in at least one treatment period were included in the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean of Average Maintenance of Wakefulness Test Early for the Mode Dose of MK0249 Versus Modafinil | 13.34 Minutes | Standard Error 1.09 |
| MK0249 Mode Dose | Mean of Average Maintenance of Wakefulness Test Early for the Mode Dose of MK0249 Versus Modafinil | 17.45 Minutes | Standard Error 0.74 |
90% CI: [-5.92, -2.3]
Secondary
Mean of Average Maintenance of Wakefulness Test Early for Top 2 Doses Pooled of MK0249 Versus Modafinil
The Maintenance of Wakefulness Test (MWT) is an objective assessment of sleepiness that measures the ability of a patient to remain awake. The primary endpoint was the mean of sleep latency (average of the first 4 MWTs which were at 0900, 1100, 1300, and 1500), where latency for each MWT was defined as the time to onset of the first 16 continuous seconds of any stage of sleep; if no sleep was observed according to these rules, then latency was defined as 30 minutes. The comparison was for the top 2 doses pooled of MK0249 versus modafinil.
Time frame: At Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients with patients excluded for failure to receive at least one dose of study treatment or lack of an endpoint data. Patients with at least one dose and endpoint in at least one treatment period were included in the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean of Average Maintenance of Wakefulness Test Early for Top 2 Doses Pooled of MK0249 Versus Modafinil | 13.64 Minutes | Standard Error 0.85 |
| MK0249 Mode Dose | Mean of Average Maintenance of Wakefulness Test Early for Top 2 Doses Pooled of MK0249 Versus Modafinil | 17.45 Minutes | Standard Error 0.74 |
90% CI: [-5.23, -2.38]