Primary Insomnia, Sleep Disorder
Conditions
Keywords
insomnia, middle of the night, sleep maintenance
Brief summary
SKP-1041 is a new formulation of a marketed sleeping agent called zaleplon. Zaleplon is currently available as Sonata as well as several generic formulations. Sonata and its generics induce sleep soon after ingestion. SKP-1041, however, is a formulation that is designed to become active 2-3 hours after ingestion. It is intended for use in people who have no trouble falling to sleep but who often awaken in the middle of the night. This trial will determine the best dose to prevent those awakenings.
Detailed description
Patients will participate in the study for approximately 44 to 56 days, including a 14- to 21-day Screening Period, 4 Treatment Periods each followed by washout periods, and a final Follow-up Visit. Patients will receive their randomly assigned study medication and spend 2 nights in a sleep laboratory, subsequently returning home for a 4- to 7-day washout period between each treatment period. The fourth and final treatment period will include a third night at the site during which all patients will continue to receive the same study medication as on the first 2 nights of this treatment period. Blood will be drawn from all patients for pharmacokinetic analyses at specific time intervals. Patients will undergo final safety assessments 2 to 5 days after the last dose of study medication.
Interventions
DRUGplacebo
tablet at bedtime
DRUGSKP-1041 (experimental formulation of zaleplon)
tablet at bedtime
Sponsors
INC Research Limited
Somnus Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Primary insomnia characterized by chronic difficulty maintaining sleep
Exclusion criteria
* History of restless legs syndrome, sleep apnea, narcolepsy, or parasomnias; * Any clinically relevant acute or chronic diseases which could interfere with the patient's safety during this trial or with this tablet's absorption; * Pregnancy; * History of medication allergies; * Use of medication that might interfere with this study; * Recent travel across more than 3 time zones.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wake After Sleep Onset During Hours 3 to 7 Post-dose (WASO 3-7) | Hours 3-7 (inclusive) after tablet ingestion | Wake time After Sleep Onset hours 3-7 Pairwise comparisons of treatment group vs. placebo mean change from baseline in minutes per polysomnographic recording. Each patient receives baseline placebo and then each treatment dose at bedtime for two nights of sleep laboratory PSG measurements. The WASO3-7 mean of each two night visit is then used to compare placebo vs. treatment change from baseline minutes awake during hours 3 through 7 post-dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Sleep Time 3-7 Hours Post-dose | hours 3-7 (inclusive) post-dose | Total Sleep Time during hours 3-7 (inclusive) post-dose |
| Number of Awakenings After Sleep Onset During Hours 3 to 7 Post-dose (NAASO 3-7) | hours 3-7 (inclusive) post-dose | Number of Awakenings After Sleep Onset during hours 3-7 post-dose (inclusive) as measured with PSG (polysomnography) |
| Subjective Wake Time After Sleep Onset (sWASO) | 9 hours after tablet ingestion | Subjective wake time after sleep onset sourced from the Morning Sleep Questionnaire self-assessment |
| Digit Symbol Substitution Test | 9 hours after tablet ingestion | Assessment of next-day residual cognitive effects. The Digit Symbol Substitution Test (DSST) explores attention and psychomotor speed. Given a code table displaying the correspondence between pairs of digits (from 1 to 9) and symbols, the patient filled in blank squares with the symbol that was paired with the digit displayed above the square. The patient was required to fill in as many squares as possible in 180 seconds. |
| Digit Span Test | 9 hours post-dose | Assessment of next day residual cognitive effects via testing immediate recall of numbers. The patient was given a string of digits and asked to repeat them forward, and then a second string of digits to repeat backward. The score was the number of correct responses, where the digits were repeated correctly. One point was given for each correctly repeated string of digits. The maximum subscore in the Digits Forward was 16, and the maximum subscore in the Digits Backward was 14, for a total score of 30. |
| Visual Analog Scale (Sedation) | 9 hours after tablet ingestion | Self-assessment of next morning sedation. Patients answered the question How alert do you feel? via a 100mm scale on which 0mm indicated very sleepy and 100mm indicated wide awake and alert.The VAS measures a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. Operationally, a VAS is usually a horizontal line, 100 mm in length, anchored by word descriptors at each end (in this case, sleepiness and alertness). Patients were asked to mark the point on the line that they felt represented their current state. The VAS score was determined by measuring in millimeters from the left-hand end of the line to the point that the patient marked. |
| WASO 1-8 | Constantly throughout the 8 hour sleep period | Wake Time After Sleep Onset, measured in minutes over the full 8 hour polysomnographic recording period, is summarized by treatment group for each night during the Screening and Treatment Periods. |
| Cmax/Dose(Dose-Normalized Cmax)Pharmacokinetic (PK) Profile Characterization | Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7) | A detailed characterization of Cmax/Dose (ng/mL/mg) (maximum plasma zaleplon concentration normalized per dose) PK profile of SKP-1041 zaleplon for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics, geometric means and 90% confidence intervals were calculated for dose-normalized values of Cmax. Analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis). |
| Tmax Pharmacokinetic (PK) Profile Characterization | Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7) | A detailed characterization of Tmax (hour) (timepoint post-dose of maximum plasma zaleplon concentration) PK profile of SKP-1041 zaleplon for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis). |
| AUC Pharmacokinetic (PK) Profile Characterization | Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7) | A detailed characterization of the AUC (area under the concentration-time curve of SKP-1041 zaleplon) for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics were calculated for AUC. Analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis). |
| AUC/Dose (ng*h/mL/mg) Pharmacokinetic (PK) Profile Characterization | Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7) | A detailed characterization of the AUC/Dose (ng\*h/mL/mg) \[Area under the concentration-time curve per Dose of SKP-1041 zaleplon\] for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis). |
| Half-Life (t1/2 Hour) Pharmacokinetic (PK) Profile Characterization | Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7) | A detailed characterization of the plasma Half-Life (t1/2 in hours) of SKP-1041 zaleplon the each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA)for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis). |
| Cmax Pharmacokinetic (PK) Profile Characterization | Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7) | A detailed characterization of the Cmax (maximum plasma concentration of SKP-1041 zaleplon in ng/mL) for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis). |
Participant flow
Recruitment details
A total of 394 potential patients were screened by 8 U.S. investigative sites for enrollment into this study. Of these potential patients, 327 failed to complete the screening process.
Pre-assignment details
5 of the 67 patients who were enrolled and randomized into this crossover sleep study did not complete it. The reasons for discontinuation were withdrawal of consent (2 patients), automobile accident(1), family emergency (1) and lost to follow up(1). One additional patient withdrew after completing the sleep study but prior to the PK substudy.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 10mg SKP-1041, 15mg SKP-1041, Placebo, 20mg SKP-1041 | 16 |
| Sequence 2 Placebo, 10mg SKP-1041, 20mg SKP-1041, 15mg SKP-1041 | 17 |
| Sequence 3 20mg SKP-1041, Placebo, 15mg SKP-1041, 10mg SKP-1041 | 17 |
| Sequence 4 15mg SKP-1041, 10mg SKP-1041, 20mg SKP-1041, Placebo | 17 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| PK Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
| Sleep Study | car accident | 1 | 0 | 0 | 0 | 0 |
| Sleep Study | family emergency | 1 | 0 | 0 | 0 | 0 |
| Sleep Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Sleep Study | Withdrawal by Subject | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Sequence 2 | Sequence 3 | Sequence 1 | Sequence 4 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 17 Participants | 16 Participants | 17 Participants | 67 Participants |
| Age Continuous | 47.1 years STANDARD_DEVIATION 9.23 | 42.5 years STANDARD_DEVIATION 11.95 | 47.3 years STANDARD_DEVIATION 9.94 | 47.5 years STANDARD_DEVIATION 9.47 | 46.1 years STANDARD_DEVIATION 10.2 |
| Region of Enrollment United States | 17 participants | 17 participants | 16 participants | 17 participants | 67 participants |
| Sex: Female, Male Female | 14 Participants | 8 Participants | 11 Participants | 8 Participants | 41 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 5 Participants | 9 Participants | 26 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 | 6 / 67 | 7 / 67 | 9 / 67 | 7 / 67 |
| serious Total, serious adverse events | 0 / 67 | 0 / 67 | 0 / 67 | 0 / 67 |
Outcome results
Primary
Wake After Sleep Onset During Hours 3 to 7 Post-dose (WASO 3-7)
Wake time After Sleep Onset hours 3-7 Pairwise comparisons of treatment group vs. placebo mean change from baseline in minutes per polysomnographic recording. Each patient receives baseline placebo and then each treatment dose at bedtime for two nights of sleep laboratory PSG measurements. The WASO3-7 mean of each two night visit is then used to compare placebo vs. treatment change from baseline minutes awake during hours 3 through 7 post-dose.
Time frame: Hours 3-7 (inclusive) after tablet ingestion
Population: Efficacy analyses were performed on the Intention to Treat Population(all randomized patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Wake After Sleep Onset During Hours 3 to 7 Post-dose (WASO 3-7) | -40.19 minutes | Standard Error 2.385 |
| 10 mg SKP-1041 | Wake After Sleep Onset During Hours 3 to 7 Post-dose (WASO 3-7) | -48.79 minutes | Standard Error 2.42 |
| 15 mg SKP-1041 | Wake After Sleep Onset During Hours 3 to 7 Post-dose (WASO 3-7) | -50.17 minutes | Standard Error 2.421 |
| 20 mg SKP-1041 | Wake After Sleep Onset During Hours 3 to 7 Post-dose (WASO 3-7) | -49.34 minutes | Standard Error 2.422 |
Comparison: Literature-based estimates of WASO (Wake After Sleep Onset) SD (Standard Deviation) range from 39 to 45 minutes. Null hypothesis: difference between mean WASO3-7 values for placebo and the 15-mg SKP-1041 dose level equals 0. By using a 2-sided, 1-sample t test at the 5% level of significance of this null hypothesis and an assumed SD of 45 minutes, a sample size of 54 completed patients was calculated to provide 90% power to detect a mean treatment difference of 20 minutesp-value: 0.011895% CI: [-15.284, -1.927]Mixed Models Analysis
Comparison: Literature-based estimates of WASO SD range from 39 to 45 minutes. Null hypothesis: difference between mean WASO3-7 values for placebo and the 15-mg SKP-1041 dose level equals 0. By using a 2-sided, 1-sample t test at the 5% level of significance of this null hypothesis and an assumed SD of 45 minutes, a sample size of 54 completed patients was calculated to provide 90% power to detect a mean treatment difference of 20 minutesp-value: 0.003795% CI: [-16.685, -3.275]Mixed Models Analysis
Comparison: Literature-based estimates of WASO SD range from 39 to 45 minutes. Null hypothesis: difference between mean WASO3-7 values for placebo and the 20-mg SKP-1041 dose level equals 0. By using a 2-sided, 1-sample t test at the 5% level of significance of this null hypothesis and an assumed SD of 45 minutes, a sample size of 54 completed patients was calculated to provide 90% power to detect a mean treatment difference of 20 minutes.p-value: 0.007795% CI: [-15.857, -2.448]Mixed Models Analysis
Secondary
AUC/Dose (ng*h/mL/mg) Pharmacokinetic (PK) Profile Characterization
A detailed characterization of the AUC/Dose (ng\*h/mL/mg) \[Area under the concentration-time curve per Dose of SKP-1041 zaleplon\] for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis).
Time frame: Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7)
Population: Pharmacokinetic Population--Patients who completed night 3 of Visit 6 (the PK substudy). Note that these patients had participated in a crossover design across all doses for the sleep study but had PK assessments only for one dose (parallel group design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | AUC/Dose (ng*h/mL/mg) Pharmacokinetic (PK) Profile Characterization | 5.36 ng*h/mL/mg | Standard Error 0.4 |
| 10 mg SKP-1041 | AUC/Dose (ng*h/mL/mg) Pharmacokinetic (PK) Profile Characterization | 5.20 ng*h/mL/mg | Standard Error 0.4 |
| 15 mg SKP-1041 | AUC/Dose (ng*h/mL/mg) Pharmacokinetic (PK) Profile Characterization | 6.76 ng*h/mL/mg | Standard Error 1.1 |
Comparison: AUC/Dose (ng\*h/mL/mg)p-value: 0.2281ANOVA
Secondary
AUC Pharmacokinetic (PK) Profile Characterization
A detailed characterization of the AUC (area under the concentration-time curve of SKP-1041 zaleplon) for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics were calculated for AUC. Analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis).
Time frame: Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7)
Population: Pharmacokinetic Population--Patients who completed night 3 of Visit 6 (the PK substudy). Note that these patients had participated in a crossover design across all doses for the sleep study but had PK assessments only for one dose (parallel group design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | AUC Pharmacokinetic (PK) Profile Characterization | 56.5 ng x h/mL | Standard Error 3.9 |
| 10 mg SKP-1041 | AUC Pharmacokinetic (PK) Profile Characterization | 77.4 ng x h/mL | Standard Error 5.6 |
| 15 mg SKP-1041 | AUC Pharmacokinetic (PK) Profile Characterization | 135.3 ng x h/mL | Standard Error 22 |
Comparison: AUC ng\*h/mL)p-value: 0.0003ANOVA
Secondary
Cmax/Dose(Dose-Normalized Cmax)Pharmacokinetic (PK) Profile Characterization
A detailed characterization of Cmax/Dose (ng/mL/mg) (maximum plasma zaleplon concentration normalized per dose) PK profile of SKP-1041 zaleplon for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics, geometric means and 90% confidence intervals were calculated for dose-normalized values of Cmax. Analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis).
Time frame: Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7)
Population: Pharmacokinetic Population--Patients who completed night 3 of Visit 6 (the PK substudy). Note that these patients had participated in a crossover design across all doses for the sleep study but had PK assessments only for one dose (parallel group design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Cmax/Dose(Dose-Normalized Cmax)Pharmacokinetic (PK) Profile Characterization | 1.8 ng/mL/mg zaleplon | Standard Error 0.1 |
| 10 mg SKP-1041 | Cmax/Dose(Dose-Normalized Cmax)Pharmacokinetic (PK) Profile Characterization | 1.7 ng/mL/mg zaleplon | Standard Error 0.2 |
| 15 mg SKP-1041 | Cmax/Dose(Dose-Normalized Cmax)Pharmacokinetic (PK) Profile Characterization | 1.7 ng/mL/mg zaleplon | Standard Error 0.2 |
Comparison: Cmax normalized per dosep-value: 0.9142ANOVA
Secondary
Cmax Pharmacokinetic (PK) Profile Characterization
A detailed characterization of the Cmax (maximum plasma concentration of SKP-1041 zaleplon in ng/mL) for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis).
Time frame: Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7)
Population: Pharmacokinetic Population--Patients who completed night 3 of Visit 6 (the PK substudy). Note that these patients had participated in a crossover design across all doses for the sleep study but had PK assessments only for one dose (parallel group design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Cmax Pharmacokinetic (PK) Profile Characterization | 17.9 ng/mL | Standard Error 1.3 |
| 10 mg SKP-1041 | Cmax Pharmacokinetic (PK) Profile Characterization | 25.3 ng/mL | Standard Error 2.9 |
| 15 mg SKP-1041 | Cmax Pharmacokinetic (PK) Profile Characterization | 34.4 ng/mL | Standard Error 4.2 |
Comparison: Cmax(ng/mL) \[Maximum plasma zaleplon concentration\]p-value: 0.0009ANOVA
Secondary
Digit Span Test
Assessment of next day residual cognitive effects via testing immediate recall of numbers. The patient was given a string of digits and asked to repeat them forward, and then a second string of digits to repeat backward. The score was the number of correct responses, where the digits were repeated correctly. One point was given for each correctly repeated string of digits. The maximum subscore in the Digits Forward was 16, and the maximum subscore in the Digits Backward was 14, for a total score of 30.
Time frame: 9 hours post-dose
Population: Intention to Treat population (all randomized patients)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Digit Span Test | 0.23 units on a scale change from baseline | Standard Error 0.268 |
| 10 mg SKP-1041 | Digit Span Test | 0.71 units on a scale change from baseline | Standard Error 0.256 |
| 15 mg SKP-1041 | Digit Span Test | 0.40 units on a scale change from baseline | Standard Error 0.259 |
| 20 mg SKP-1041 | Digit Span Test | -0.02 units on a scale change from baseline | Standard Error 0.237 |
Comparison: The adjusted mean differences were analyzed with a general linear model that used change from baseline as the response variable and included effects for patient, period, sequence and treatment.p-value: 0.091495% CI: [-0.073, 0.972]Mixed Models Analysis
Comparison: The adjusted mean differences were analyzed with a general linear model that used change from baseline as the response variable and included effects for patient, period, sequence and treatment.p-value: 0.53695% CI: [-0.36, 0.69]Mixed Models Analysis
Comparison: The adjusted mean differences were analyzed with a general linear model that used change from baseline as the response variable and included effects for patient, period, sequence and treatment.p-value: 0.325495% CI: [-0.787, 0.263]Mixed Models Analysis
Secondary
Digit Symbol Substitution Test
Assessment of next-day residual cognitive effects. The Digit Symbol Substitution Test (DSST) explores attention and psychomotor speed. Given a code table displaying the correspondence between pairs of digits (from 1 to 9) and symbols, the patient filled in blank squares with the symbol that was paired with the digit displayed above the square. The patient was required to fill in as many squares as possible in 180 seconds.
Time frame: 9 hours after tablet ingestion
Population: Intention to Treat population (all randomized patients)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Digit Symbol Substitution Test | 8.56 percentage change from mean baseline | Standard Error 1.434 |
| 10 mg SKP-1041 | Digit Symbol Substitution Test | 9.26 percentage change from mean baseline | Standard Error 1.469 |
| 15 mg SKP-1041 | Digit Symbol Substitution Test | 6.59 percentage change from mean baseline | Standard Error 1.523 |
| 20 mg SKP-1041 | Digit Symbol Substitution Test | 9.95 percentage change from mean baseline | Standard Error 1.626 |
Comparison: Adjusted mean differences were analyzed by using a general linear model that used change from baseline as the response variable.p-value: 0.643395% CI: [-1.823, 2.943]Mixed Models Analysis
Comparison: Adjusted mean differences were analyzed by using a general linear model that used change from baseline as the response variable.p-value: 0.116795% CI: [-4.304, 0.481]Mixed Models Analysis
Comparison: Adjusted mean differences were analyzed by using a general linear model that used change from baseline as the response variable.p-value: 0.238595% CI: [-0.958, 3.826]Mixed Models Analysis
Secondary
Half-Life (t1/2 Hour) Pharmacokinetic (PK) Profile Characterization
A detailed characterization of the plasma Half-Life (t1/2 in hours) of SKP-1041 zaleplon the each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA)for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis).
Time frame: Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7)
Population: Pharmacokinetic Population--Patients who completed night 3 of Visit 6 (the PK substudy). Note that these patients had participated in a crossover design across all doses for the sleep study but had PK assessments only for one dose (parallel group design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Half-Life (t1/2 Hour) Pharmacokinetic (PK) Profile Characterization | 1.52 hour | Standard Error 0.05 |
| 10 mg SKP-1041 | Half-Life (t1/2 Hour) Pharmacokinetic (PK) Profile Characterization | 1.65 hour | Standard Error 0.17 |
| 15 mg SKP-1041 | Half-Life (t1/2 Hour) Pharmacokinetic (PK) Profile Characterization | 1.47 hour | Standard Error 0.09 |
Comparison: Half-Life (t1/2 in hours) of plasma zaleplon from each of 3 doses of SKP-1041p-value: 0.4835ANOVA
Secondary
Number of Awakenings After Sleep Onset During Hours 3 to 7 Post-dose (NAASO 3-7)
Number of Awakenings After Sleep Onset during hours 3-7 post-dose (inclusive) as measured with PSG (polysomnography)
Time frame: hours 3-7 (inclusive) post-dose
Population: Intention to Treat dataset (all randomized patients)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Number of Awakenings After Sleep Onset During Hours 3 to 7 Post-dose (NAASO 3-7) | -1.40 Number of awakenings | Standard Error 0.24 |
| 10 mg SKP-1041 | Number of Awakenings After Sleep Onset During Hours 3 to 7 Post-dose (NAASO 3-7) | -1.96 Number of awakenings | Standard Error 0.244 |
| 15 mg SKP-1041 | Number of Awakenings After Sleep Onset During Hours 3 to 7 Post-dose (NAASO 3-7) | -2.43 Number of awakenings | Standard Error 0.244 |
| 20 mg SKP-1041 | Number of Awakenings After Sleep Onset During Hours 3 to 7 Post-dose (NAASO 3-7) | -2.19 Number of awakenings | Standard Error 0.244 |
Comparison: This endpoint summarizes the number of times during Hours 3 7, after onset of persistent sleep, that there was a wake entry of at least 2 epochs duration. To be counted, each entry must have been separated by a sleep stage of 2, 3 4, or rapid eye movement.p-value: 0.100595% CI: [-1.235, 0.11]Mixed Models Analysis
Comparison: This endpoint summarizes the number of times during Hours 3 7, after onset of persistent sleep, that there was a wake entry of at least 2 epochs duration. To be counted, each entry must have been separated by a sleep stage of 2, 3 4, or rapid eye movement.p-value: 0.002895% CI: [-1.712, -0.362]Mixed Models Analysis
Comparison: This endpoint summarizes the number of times during Hours 3 7, after onset of persistent sleep, that there was a wake entry of at least 2 epochs duration. To be counted, each entry must have been separated by a sleep stage of 2, 3 4, or rapid eye movement.p-value: 0.021695% CI: [-1.467, -0.118]Mixed Models Analysis
Secondary
Subjective Wake Time After Sleep Onset (sWASO)
Subjective wake time after sleep onset sourced from the Morning Sleep Questionnaire self-assessment
Time frame: 9 hours after tablet ingestion
Population: All Efficacy Analyses were performed on the Intention to Treat (ITT) population (all randomized patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Subjective Wake Time After Sleep Onset (sWASO) | -14.05 minutes | Standard Error 4.873 |
| 10 mg SKP-1041 | Subjective Wake Time After Sleep Onset (sWASO) | -22.50 minutes | Standard Error 4.869 |
| 15 mg SKP-1041 | Subjective Wake Time After Sleep Onset (sWASO) | -12.68 minutes | Standard Error 4.937 |
| 20 mg SKP-1041 | Subjective Wake Time After Sleep Onset (sWASO) | -25.89 minutes | Standard Error 4.936 |
Comparison: Study was powered on the primary endpoint. Data for sWASO were sourced from Question 5 of the Morning Sleep Questionnaire. Its analysis follows a general linear model change from baseline as response variable including effects for patient, period, sequence, and treatment.p-value: 0.21995% CI: [-21.98, 5.077]Mixed Models Analysis
Comparison: Study was powered on the primary endpoint. Data for sWASO were sourced from Question 5 of the Morning Sleep Questionnaire. Its analysis follows a general linear model change from baseline as response variable including effects for patient, period, sequence, and treatment.p-value: 0.844195% CI: [-12.327, 15.056]Mixed Models Analysis
Comparison: Study was powered on the primary endpoint. Data for sWASO were sourced from Question 5 of the Morning Sleep Questionnaire. Its analysis follows a general linear model change from baseline as response variable including effects for patient, period, sequence, and treatment.p-value: 0.089495% CI: [-25.522, 1.842]Mixed Models Analysis
Secondary
Tmax Pharmacokinetic (PK) Profile Characterization
A detailed characterization of Tmax (hour) (timepoint post-dose of maximum plasma zaleplon concentration) PK profile of SKP-1041 zaleplon for each of the 3 study doses within the Pharmacokinetic Population (patients who completed the PK substudy--night 3 of Visit 6)with subsequent descriptive statistics comparing key PK characteristics across the 3 doses. Descriptive statistics and analysis of variance (ANOVA) for independent groups compared the three dosage groups using the untransformed values, as well as following rank transformation(nonparametric analysis).
Time frame: Blood samples drawn hourly from -1 to 10 hours post-dose (except hour 7)
Population: Pharmacokinetic Population--Patients who completed night 3 of Visit 6 (the PK substudy). Note that these patients had participated in a crossover design across all doses for the sleep study but had PK assessments only for one dose (parallel group design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Tmax Pharmacokinetic (PK) Profile Characterization | 4 Hours post-dose | Standard Error 2.5 |
| 10 mg SKP-1041 | Tmax Pharmacokinetic (PK) Profile Characterization | 4 Hours post-dose | Standard Error 2.5 |
| 15 mg SKP-1041 | Tmax Pharmacokinetic (PK) Profile Characterization | 4 Hours post-dose | Standard Error 3.6 |
Comparison: Time (hour)post-dose of maximum plasma zaleplon concentrationp-value: 0.1193ANOVA
Secondary
Total Sleep Time 3-7 Hours Post-dose
Total Sleep Time during hours 3-7 (inclusive) post-dose
Time frame: hours 3-7 (inclusive) post-dose
Population: Intention to Treat population (all randomized patients)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Total Sleep Time 3-7 Hours Post-dose | 39.03 Minutes | Standard Error 2.365 |
| 10 mg SKP-1041 | Total Sleep Time 3-7 Hours Post-dose | 47.86 Minutes | Standard Error 2.4 |
| 15 mg SKP-1041 | Total Sleep Time 3-7 Hours Post-dose | 49.46 Minutes | Standard Error 2.401 |
| 20 mg SKP-1041 | Total Sleep Time 3-7 Hours Post-dose | 49.18 Minutes | Standard Error 2.402 |
Comparison: The adjusted mean differences were analyzed by using a general linear model that used change from baseline as the response variable and included effects for patient, period, sequence, and treatment.p-value: 0.009295% CI: [2.208, 15.454]Mixed Models Analysis
Comparison: The adjusted mean differences were analyzed by using a general linear model that used change from baseline as the response variable and included effects for patient, period, sequence, and treatment.p-value: 0.002395% CI: [3.775, 17.075]Mixed Models Analysis
Comparison: The adjusted mean differences were analyzed by using a general linear model that used change from baseline as the response variable and included effects for patient, period, sequence, and treatment.p-value: 0.00395% CI: [3.498, 16.796]Mixed Models Analysis
Secondary
Visual Analog Scale (Sedation)
Self-assessment of next morning sedation. Patients answered the question How alert do you feel? via a 100mm scale on which 0mm indicated very sleepy and 100mm indicated wide awake and alert.The VAS measures a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. Operationally, a VAS is usually a horizontal line, 100 mm in length, anchored by word descriptors at each end (in this case, sleepiness and alertness). Patients were asked to mark the point on the line that they felt represented their current state. The VAS score was determined by measuring in millimeters from the left-hand end of the line to the point that the patient marked.
Time frame: 9 hours after tablet ingestion
Population: Safety population (patients exposed to that given treatment)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | Visual Analog Scale (Sedation) | 3.48 mm change from baseline | Standard Error 2.195 |
| 10 mg SKP-1041 | Visual Analog Scale (Sedation) | 3.83 mm change from baseline | Standard Error 1.818 |
| 15 mg SKP-1041 | Visual Analog Scale (Sedation) | 3.55 mm change from baseline | Standard Error 2.422 |
| 20 mg SKP-1041 | Visual Analog Scale (Sedation) | 4.96 mm change from baseline | Standard Error 2.058 |
p-value: 0.71995% CI: [-3.175, 4.595]Mixed Models Analysis
p-value: 0.678495% CI: [-3.08, 4.722]Mixed Models Analysis
p-value: 0.243395% CI: [-1.586, 6.214]Mixed Models Analysis
Secondary
WASO 1-8
Wake Time After Sleep Onset, measured in minutes over the full 8 hour polysomnographic recording period, is summarized by treatment group for each night during the Screening and Treatment Periods.
Time frame: Constantly throughout the 8 hour sleep period
Population: Intention to Treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar Pill) | WASO 1-8 | -44.65 Minutes | Standard Error 2.715 |
| 10 mg SKP-1041 | WASO 1-8 | -50.25 Minutes | Standard Error 2.755 |
| 15 mg SKP-1041 | WASO 1-8 | -51.56 Minutes | Standard Error 2.757 |
| 20 mg SKP-1041 | WASO 1-8 | -50.17 Minutes | Standard Error 2.757 |
Comparison: Literature-based estimates of WASO (Wake After Sleep Onset) SD (Standard Deviation) range from 39 to 45 minutes. Null hypothesis: difference between mean WASO3-7 values for placebo and the 15-mg SKP-1041 dose level equals 0. By using a 2-sided, 1-sample t test at the 5% level of significance of this null hypothesis and an assumed SD of 45 minutes, a sample size of 54 completed patients was calculated to provide 90% power to detect a mean treatment difference of 20 minutes.p-value: 0.147695% CI: [-13.208, 2]Mixed Models Analysis
Comparison: Literature-based estimates of WASO (Wake After Sleep Onset) SD (Standard Deviation) range from 39 to 45 minutes. Null hypothesis: difference between mean WASO3-7 values for placebo and the 15-mg SKP-1041 dose level equals 0. By using a 2-sided, 1-sample t test at the 5% level of significance of this null hypothesis and an assumed SD of 45 minutes, a sample size of 54 completed patients was calculated to provide 90% power to detect a mean treatment difference of 20 minutes.p-value: 0.075795% CI: [-14.546, 0.722]Mixed Models Analysis
Comparison: Literature-based estimates of WASO (Wake After Sleep Onset) SD (Standard Deviation) range from 39 to 45 minutes. Null hypothesis: difference between mean WASO3-7 values for placebo and the 15-mg SKP-1041 dose level equals 0. By using a 2-sided, 1-sample t test at the 5% level of significance of this null hypothesis and an assumed SD of 45 minutes, a sample size of 54 completed patients was calculated to provide 90% power to detect a mean treatment difference of 20 minutes.p-value: 0.155395% CI: [-13.154, 2.113]Mixed Models Analysis