Alzheimer's Disease
Conditions
Keywords
Cognition, mild Alzheimer's disease, Sleep
Brief summary
This study is a Phase 2, randomized, placebo-controlled, dose-ranging study of piromelatine (5, 20, and 50 mg daily for 6 months) versus placebo to determine an effective dose based on efficacy (cognitive performance), safety, and tolerability in patients with mild dementia due to Alzheimer's Disease (AD).
Detailed description
Patients with a documented history of mild dementia due to AD for at least 6 months, having a Mini-Mental State Examination (MMSE) score of 20 to 27 (inclusive) at Screening. A score of 27 is allowed only if accompanied by a score of ≥ 12 in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog) ADAS-cog11 portion of the ADAS-cog14 at screening, and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5 or 1 will be recruited and further screened for eligibility. Caregiver commitment to the study is also necessary. At Screening (Visit 1), patients will undergo neuropsychiatric assessments, psychometric testing, and general medical assessments (including medical history, pre-existing conditions, physical examination, vital signs, and ECG). If patients have not had brain imaging with findings consistent with the diagnosis of dementia due to AD in the last 12 months, a computed tomography (CT) or magnetic resonance imaging (MRI) scan will be obtained to rule out clinically significant comorbid pathologies. Eligible patients will start a 2-week run-in period of placebo (single-blind), followed by 26 weeks of double-blind treatment comprising administration of piromelatine or placebo, for a total treatment duration of 28 weeks. During the double-blind period, patients will be enrolled in a 1.2:1:1:1 randomization ratio to the 4 trial arms (placebo \[1.2\], and the equal piromelatine treatment arms 5, 20, and 50 mg \[1:1:1\]). Intermediate visits will be carried out at 4 weeks (Visit 3) and 13 weeks (Visit 4) after randomization. A follow-up phone call to elicit any safety concerns will be completed 2 weeks after the last dose of study medication. Patients who discontinue before Visit 5 (Week 26) will be brought back for a termination visit. Assuming an effect size between the treatment dose and placebo of 0.35 over 26 weeks, a significant level (α) of 0.05, and power of 88%, a sample size of 143 patients for the placebo arm and 119 patients for each of the 3 piromelatine arms is calculated. Assuming a 50% screen failure rate and allowing for 15% patient withdrawal, 1150 patients should be screened to randomly assign 575 patients, of whom it is expected that 500 will complete the study. Piromelatine (5, 20, and 50 mg tablets) and placebo will be administered orally, once daily after a meal, before habitual bedtime, preferably between 2100h and 2300h. Patients will be required to spend at least 2 hours a day exposed to daylight.
Interventions
DRUGPiromelatine
DRUGPlacebo
Sponsors
Neurim Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patient and caregiver are willing to take part in the entire study * Signed informed consent from the patient and the caregiver * Patient has a documented history either in medical records or from an informant of cognitive decline over at least 6 months * Patient has mild probable AD as consistent with criteria established by the National Institute on Aging and Alzheimer's Association (NIA-AA). * CT/MRI scan with finding consisting of probable AD obtained during the last 12 months before Screening * Patient has an MMSE score of 21-26 (inclusive) at Screening * Patient has a Clinical Dementia Rating Global Score (CDR-GS) of 0.5-1 (mild dementia) at Screening * Patients receiving prescribed drugs for treatment of AD including acetyl cholinesterase inhibitors \[eg, donepezil, galantamine, rivastigmine\] should be on a stable dose for at least 3 months before Screening * Patient has a negative drug screen (benzodiazepines or opiates) at Screening * Female patients must have had last natural menstruation ≥ 24 months before Screening, OR being surgically sterile * Male patients must agree to the use of effective contraception if the female partner is of childbearing potential, OR be surgically sterile
Exclusion criteria
* Patient has an alternative cause for dementia other than AD as determined by CT or MRI scan * Patient has evidence of any clinically significant neurodegenerative disease * Patient has been diagnosed with the following Axis I disorders (DSM V criteria) * Patient has a history of uncontrolled or untreated cardiovascular, endocrine, gastrointestinal, respiratory, or rheumatologic disorders within the past 5 years * Patient has severe pain that is likely to interfere with sleep * Continuous use of benzodiazepines or other sedative-hypnotics during the 2 weeks before Screening * Use of any kind of melatonin/melatonin agonist during the 2 weeks before Screening * Patient has known or suspected hypersensitivity to exogenous melatonin or melatonin receptor agonists * Patients with an irregular lifestyle or life pattern (eg, shift workers, patients likely to be jet lagged).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline | 26 weeks | The global composite score of the cNTB combines the International Shopping List Test (ISLT), One Card Learning (OCL), Identification (IDN), Detection (DET), One Back Card (OBK), Controlled Oral Word Association Test (COWAT), and the Categorical Fluency Test (CFT). For each test, a z-score relative to the study baseline is calculated. The cNTB global composite score is the mean of all z-scores from the tests listed above. The scale range is from -3 to 3. Zero Z-score means no cognitive change. A negative value means decline, while a positive value means improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Global Impression of Change (CGIC) | 13 weeks, and 26 weeks | The Change From Baseline in Global Impression of Change (CGIC) rating is made on a 7-point Likert-type scale where the change from baseline is rated as marked improvement (1), moderate improvement (2), minimal improvement (3), no change (4), minimal worsening (5), moderate worsening (6), marked worsening (7). Mean values at 13 and 26 weeks are relative to baseline. |
| Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | Baseline, 13 weeks, and 26 weeks | ADCS-MCI-ADL is an evaluation scale with information provided by an informant/caregiver to describe the functional impairment of patients with mild cognitive impairment (MCI). The ADCS-ADL is a 23-item scale that includes 6 basic ADLs (BADLs) and 17 Instrumental Activities of Daily Living (IADLs) that provide a total score of 0-78, with a lower score indicating greater severity, meaning a worse outcome. |
| Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | Baseline, 13 weeks, and 26 weeks | The ADAS was designed to measure the severity of the most important symptoms of AD. Its subscale, ADAS-cog, is the most popular cognitive testing instrument used in clinical trials, measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities that are often referred to as the core symptoms of AD. ADAS-cog14 comprises 14 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. |
| Safety and Tolerability - Blood Pressure (mmHg) | Baseline, and 26 weeks | Systolic and Diastolic Blood Pressure is followed during the study, as safety and tolerability measures. Changes in BP following treatment, leading to values out of the normal limits mean a worse outcome. |
| Safety and Tolerability - Hematology | Baseline, and 26 weeks | Hematology (GI/L). 1 gill (GI) = 0.118294118 liter (L). No major changes or shifts from baseline mean good safety and tolerability. |
| Safety and Tolerability - Blood Chemistry (mmol/L) | Baseline, and 26 weeks | Blood Chemistry follow-up during the experiment. No major changes or shifts from baseline mean good safety and tolerability. |
| Safety and Tolerability - Heart Rate (Bpm) | Baseline, and 26 weeks | Heart Rate within normal limits = 60-100 beats per minute (bpm) during the study means a good outcome in terms of safety. |
| Safety and Tolerability - ECG Interval Results - QTcF (Msec) | Baseline, and 26 weeks | QT interval corrected for heart rate by Fridericia's cube root formula (QTcF). The QTc is considered normal at \< 450 msec in males, and \< 470 msec in females. |
Other
| Measure | Time frame | Description |
|---|---|---|
| NeuroPsychiatric Inventory (NPI) Total Score | Baseline, and 26 weeks | The NPI scale consists of 12 domains that are rated for both frequency (range 1 to 4) and severity (range 1 to 3). A composite score for each domain is calculated (frequency × severity), and it ranges from 1 to 12. For each item, there is a leading question. If the symptom is absent, then the frequency, severity, and distress scores are not completed. In this case, the score is 0 for the item. The sum of the composite scores yields the NPI total score (1-12). A negative change in the score indicates an improvement from baseline (symptom reduction). |
| Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | Baseline, 4 weeks, 13 weeks, 26 weeks | PSQI is an effective instrument used to measure the quality and patterns of sleep in older adults. It differentiates poor from good sleep by measuring 7 areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction over the last month. PSQI includes seven components, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality. |
Countries
United States
Participant flow
Pre-assignment details
The first period of the study consisted of a run-in phase where all participants received Placebo, followed by a second period where participants were randomized to Piromelatine 5mg, Piromelatine 20mg, Piromelatine 50mg, or Placebo Arm/Groups for the dose escalation phase.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Piromelatine 5 mg Piromelatine 5 mg tablet once daily | 83 |
| Experimental: Piromelatine 20 mg Piromelatine 20 mg tablet once daily | 87 |
| Experimental: Piromelatine 50 mg Piromelatine 50 mg tablet once daily | 80 |
| Placebo Comparator: Placebo Placebo tablet given once daily | 102 |
| Total | 352 |
Baseline characteristics
| Characteristic | Experimental: Piromelatine 5 mg | Experimental: Piromelatine 20 mg | Experimental: Piromelatine 50 mg | Placebo Comparator: Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 83 Participants | 87 Participants | 80 Participants | 102 Participants | 352 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 73.1 years STANDARD_DEVIATION 6.65 | 72.7 years STANDARD_DEVIATION 7.97 | 73.3 years STANDARD_DEVIATION 6.62 | 73.3 years STANDARD_DEVIATION 7.11 | 73.1 years STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 21 Participants | 24 Participants | 20 Participants | 83 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 66 Participants | 56 Participants | 82 Participants | 269 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 9 Participants | 6 Participants | 8 Participants | 34 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 70 Participants | 78 Participants | 72 Participants | 92 Participants | 312 Participants |
| Region of Enrollment United States | 83 participants | 87 participants | 80 participants | 102 participants | 352 participants |
| Sex: Female, Male Female | 44 Participants | 49 Participants | 49 Participants | 58 Participants | 200 Participants |
| Sex: Female, Male Male | 39 Participants | 38 Participants | 31 Participants | 44 Participants | 152 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 88 | 0 / 88 | 0 / 87 | 0 / 105 | 0 / 368 |
| other Total, other adverse events | 12 / 88 | 14 / 88 | 14 / 87 | 29 / 105 | 0 / 368 |
| serious Total, serious adverse events | 2 / 88 | 6 / 88 | 4 / 87 | 6 / 105 | 0 / 368 |
Outcome results
Primary
Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline
The global composite score of the cNTB combines the International Shopping List Test (ISLT), One Card Learning (OCL), Identification (IDN), Detection (DET), One Back Card (OBK), Controlled Oral Word Association Test (COWAT), and the Categorical Fluency Test (CFT). For each test, a z-score relative to the study baseline is calculated. The cNTB global composite score is the mean of all z-scores from the tests listed above. The scale range is from -3 to 3. Zero Z-score means no cognitive change. A negative value means decline, while a positive value means improvement.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Piromelatine 5 mg | Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline | 0.0434 z-score |
| Piromelatine 20 mg | Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline | 0.1175 z-score |
| Piromelatine 50 mg | Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline | 0.0297 z-score |
| Placebo Comparator | Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline | 0.0591 z-score |
Secondary
Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14)
The ADAS was designed to measure the severity of the most important symptoms of AD. Its subscale, ADAS-cog, is the most popular cognitive testing instrument used in clinical trials, measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities that are often referred to as the core symptoms of AD. ADAS-cog14 comprises 14 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment.
Time frame: Baseline, 13 weeks, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | Baseline | 26.1 score on a scale | Standard Deviation 7.72 |
| Piromelatine 5 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 26 weeks | 25.3 score on a scale | Standard Deviation 8.93 |
| Piromelatine 5 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 13 weeks | 25.1 score on a scale | Standard Deviation 8.39 |
| Piromelatine 20 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | Baseline | 26.3 score on a scale | Standard Deviation 9.16 |
| Piromelatine 20 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 26 weeks | 26.0 score on a scale | Standard Deviation 10.12 |
| Piromelatine 20 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 13 weeks | 26.7 score on a scale | Standard Deviation 9.37 |
| Piromelatine 50 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 13 weeks | 25.5 score on a scale | Standard Deviation 10.01 |
| Piromelatine 50 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | Baseline | 26.4 score on a scale | Standard Deviation 7.91 |
| Piromelatine 50 mg | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 26 weeks | 24.9 score on a scale | Standard Deviation 9.35 |
| Placebo Comparator | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | Baseline | 26.6 score on a scale | Standard Deviation 8.62 |
| Placebo Comparator | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 26 weeks | 25.2 score on a scale | Standard Deviation 9.97 |
| Placebo Comparator | Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) | 13 weeks | 26.6 score on a scale | Standard Deviation 9.87 |
Secondary
Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL)
ADCS-MCI-ADL is an evaluation scale with information provided by an informant/caregiver to describe the functional impairment of patients with mild cognitive impairment (MCI). The ADCS-ADL is a 23-item scale that includes 6 basic ADLs (BADLs) and 17 Instrumental Activities of Daily Living (IADLs) that provide a total score of 0-78, with a lower score indicating greater severity, meaning a worse outcome.
Time frame: Baseline, 13 weeks, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | Baseline | 40.7 score on a scale | Standard Deviation 6.73 |
| Piromelatine 5 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 26 weeks | 40.6 score on a scale | Standard Deviation 6.59 |
| Piromelatine 5 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 13 weeks | 40.4 score on a scale | Standard Deviation 6.72 |
| Piromelatine 20 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | Baseline | 38.4 score on a scale | Standard Deviation 8.98 |
| Piromelatine 20 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 26 weeks | 39.3 score on a scale | Standard Deviation 9.11 |
| Piromelatine 20 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 13 weeks | 39.6 score on a scale | Standard Deviation 8.89 |
| Piromelatine 50 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 13 weeks | 39.1 score on a scale | Standard Deviation 8.81 |
| Piromelatine 50 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | Baseline | 39.2 score on a scale | Standard Deviation 7.6 |
| Piromelatine 50 mg | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 26 weeks | 39.8 score on a scale | Standard Deviation 7.94 |
| Placebo Comparator | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | Baseline | 39.4 score on a scale | Standard Deviation 8.6 |
| Placebo Comparator | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 26 weeks | 40.4 score on a scale | Standard Deviation 8.07 |
| Placebo Comparator | Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) | 13 weeks | 39.5 score on a scale | Standard Deviation 8.06 |
Secondary
Change From Baseline in Global Impression of Change (CGIC)
The Change From Baseline in Global Impression of Change (CGIC) rating is made on a 7-point Likert-type scale where the change from baseline is rated as marked improvement (1), moderate improvement (2), minimal improvement (3), no change (4), minimal worsening (5), moderate worsening (6), marked worsening (7). Mean values at 13 and 26 weeks are relative to baseline.
Time frame: 13 weeks, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Change From Baseline in Global Impression of Change (CGIC) | 13 weeks | 3.93 score on a scale | Standard Deviation 0.88 |
| Piromelatine 5 mg | Change From Baseline in Global Impression of Change (CGIC) | 26 weeks | 4.13 score on a scale | Standard Deviation 1.07 |
| Piromelatine 20 mg | Change From Baseline in Global Impression of Change (CGIC) | 26 weeks | 3.94 score on a scale | Standard Deviation 1.02 |
| Piromelatine 20 mg | Change From Baseline in Global Impression of Change (CGIC) | 13 weeks | 3.95 score on a scale | Standard Deviation 0.78 |
| Piromelatine 50 mg | Change From Baseline in Global Impression of Change (CGIC) | 13 weeks | 3.87 score on a scale | Standard Deviation 0.92 |
| Piromelatine 50 mg | Change From Baseline in Global Impression of Change (CGIC) | 26 weeks | 3.87 score on a scale | Standard Deviation 0.98 |
| Placebo Comparator | Change From Baseline in Global Impression of Change (CGIC) | 13 weeks | 3.89 score on a scale | Standard Deviation 0.8 |
| Placebo Comparator | Change From Baseline in Global Impression of Change (CGIC) | 26 weeks | 3.99 score on a scale | Standard Deviation 1.01 |
Secondary
Safety and Tolerability - Blood Chemistry (mmol/L)
Blood Chemistry follow-up during the experiment. No major changes or shifts from baseline mean good safety and tolerability.
Time frame: Baseline, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - baseline | 5.89 mmol/L | Standard Deviation 1.883 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - 26 weeks | 5.86 mmol/L | Standard Deviation 1.77 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - baseline | 2.385 mmol/L | Standard Deviation 0.1626 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - 26 weeks | 2.270 mmol/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium - baseline | 140.5 mmol/L | Standard Deviation 2.12 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium -26 weeks | 135.0 mmol/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - baseline | 7.35 mmol/L | Standard Deviation 0.778 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - 26 weeks | 8.20 mmol/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - 26 weeks | 6.25 mmol/L | Standard Deviation 2.121 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - baseline | 7.70 mmol/L | Standard Deviation 3.818 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium - baseline | 141.5 mmol/L | Standard Deviation 0.71 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium -26 weeks | 141.0 mmol/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - 26 weeks | 5.70 mmol/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - 26 weeks | 2.370 mmol/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - baseline | 2.470 mmol/L | Standard Deviation 0.0707 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - baseline | 5.97 mmol/L | Standard Deviation 2.045 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium - baseline | 139.3 mmol/L | Standard Deviation 2.31 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - baseline | 2.307 mmol/L | Standard Deviation 0.1007 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - 26 weeks | 2.300 mmol/L | Standard Deviation 0 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - 26 weeks | 5.35 mmol/L | Standard Deviation 0.495 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium -26 weeks | 143.0 mmol/L | Standard Deviation 2.83 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - baseline | 5.00 mmol/L | Standard Deviation 0.4 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - baseline | 5.51 mmol/L | Standard Deviation 1.322 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - 26 weeks | 5.99 mmol/L | Standard Deviation 2.351 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - baseline | 2.363 mmol/L | Standard Deviation 0.129 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Calcium - 26 weeks | 2.335 mmol/L | Standard Deviation 0.0495 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - 26 weeks | 5.80 mmol/L | Standard Deviation 1.461 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Glucose - baseline | 5.78 mmol/L | Standard Deviation 1.598 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - baseline | 5.00 mmol/L | Standard Deviation 1.212 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium -26 weeks | 140.0 mmol/L | Standard Deviation 1.41 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Urea Nitrogen - 26 weeks | 4.50 mmol/L | Standard Deviation 1.273 |
| Placebo Comparator | Safety and Tolerability - Blood Chemistry (mmol/L) | Sodium - baseline | 139.0 mmol/L | Standard Deviation 1.73 |
Secondary
Safety and Tolerability - Blood Pressure (mmHg)
Systolic and Diastolic Blood Pressure is followed during the study, as safety and tolerability measures. Changes in BP following treatment, leading to values out of the normal limits mean a worse outcome.
Time frame: Baseline, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - Baseline | 128.7 mmHg | Standard Deviation 14.51 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - 26 weeks | 131.9 mmHg | Standard Deviation 13.61 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - Baseline | 75.3 mmHg | Standard Deviation 9.15 |
| Piromelatine 5 mg | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - 26 weeeks | 76.3 mmHg | Standard Deviation 8.48 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - 26 weeks | 132.4 mmHg | Standard Deviation 12.31 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - Baseline | 76.5 mmHg | Standard Deviation 8.37 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - 26 weeeks | 76.2 mmHg | Standard Deviation 8.47 |
| Piromelatine 20 mg | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - Baseline | 130.8 mmHg | Standard Deviation 13.19 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - Baseline | 76.3 mmHg | Standard Deviation 7.57 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - 26 weeks | 129.9 mmHg | Standard Deviation 10.01 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - 26 weeeks | 77.3 mmHg | Standard Deviation 8.78 |
| Piromelatine 50 mg | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - Baseline | 128.5 mmHg | Standard Deviation 11.35 |
| Placebo Comparator | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - 26 weeeks | 76.3 mmHg | Standard Deviation 8.52 |
| Placebo Comparator | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - 26 weeks | 131.5 mmHg | Standard Deviation 12.93 |
| Placebo Comparator | Safety and Tolerability - Blood Pressure (mmHg) | Systolic BP - Baseline | 132.3 mmHg | Standard Deviation 15.13 |
| Placebo Comparator | Safety and Tolerability - Blood Pressure (mmHg) | Diastolic BP - Baseline | 76.3 mmHg | Standard Deviation 8.26 |
Secondary
Safety and Tolerability - ECG Interval Results - QTcF (Msec)
QT interval corrected for heart rate by Fridericia's cube root formula (QTcF). The QTc is considered normal at \< 450 msec in males, and \< 470 msec in females.
Time frame: Baseline, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | Baseline | 417.1 msec | Standard Deviation 24.16 |
| Piromelatine 5 mg | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | 26 weeks | 414.3 msec | Standard Deviation 27.29 |
| Piromelatine 20 mg | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | 26 weeks | 421.2 msec | Standard Deviation 24.86 |
| Piromelatine 20 mg | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | Baseline | 416.4 msec | Standard Deviation 34.97 |
| Piromelatine 50 mg | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | Baseline | 413.9 msec | Standard Deviation 50.48 |
| Piromelatine 50 mg | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | 26 weeks | 416.6 msec | Standard Deviation 24.87 |
| Placebo Comparator | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | Baseline | 416.5 msec | Standard Deviation 20.57 |
| Placebo Comparator | Safety and Tolerability - ECG Interval Results - QTcF (Msec) | 26 weeks | 408.9 msec | Standard Deviation 54.47 |
Secondary
Safety and Tolerability - Heart Rate (Bpm)
Heart Rate within normal limits = 60-100 beats per minute (bpm) during the study means a good outcome in terms of safety.
Time frame: Baseline, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - baseline | 68.1 bpm | Standard Deviation 10.67 |
| Piromelatine 5 mg | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - 26 weeks | 65.9 bpm | Standard Deviation 9.89 |
| Piromelatine 20 mg | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - 26 weeks | 67.0 bpm | Standard Deviation 9.95 |
| Piromelatine 20 mg | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - baseline | 68.7 bpm | Standard Deviation 9.44 |
| Piromelatine 50 mg | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - baseline | 69.6 bpm | Standard Deviation 9.55 |
| Piromelatine 50 mg | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - 26 weeks | 66.9 bpm | Standard Deviation 9.28 |
| Placebo Comparator | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - baseline | 67.2 bpm | Standard Deviation 9.68 |
| Placebo Comparator | Safety and Tolerability - Heart Rate (Bpm) | Heart rate - 26 weeks | 67.9 bpm | Standard Deviation 10.13 |
Secondary
Safety and Tolerability - Hematology
Hematology (GI/L). 1 gill (GI) = 0.118294118 liter (L). No major changes or shifts from baseline mean good safety and tolerability.
Time frame: Baseline, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Monocytes - baseline | 0.510 GI/L | Standard Deviation 0.2828 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Lymphocytes - baseline (GI/L) | 1.605 GI/L | Standard Deviation 0.7425 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Leukocytes - 26 weeks | 5.210 GI/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Leukocytes - baseline | 6.455 GI/L | Standard Deviation 1.5768 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Lymphocytes - 26 weeks | 0.920 GI/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Platelets - baseline | 238.5 GI/L | Standard Deviation 84.15 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Neutrophils - 26 weeks | 3.600 GI/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Basophils - 26 weeks | 0.080 GI/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Platelets - 26 weeks | 144.0 GI/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Neutrophils - baseline | 3.990 GI/L | Standard Deviation 0.4525 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Monocytes - 26 weeks | 0.450 GI/L | Standard Deviation 0 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Eosinophils - baseline | 0.290 GI/L | Standard Deviation 0.099 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Basophils - baseline | 0.050 GI/L | Standard Deviation 0.0141 |
| Piromelatine 5 mg | Safety and Tolerability - Hematology | Eosinophils - 26 weeks | 0.170 GI/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Eosinophils - 26 weeks | 0.180 GI/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Basophils - baseline | 0.070 GI/L | Standard Deviation 0.0141 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Basophils - 26 weeks | 0.050 GI/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Eosinophils - baseline | 0.215 GI/L | Standard Deviation 0.0354 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Leukocytes - baseline | 8.715 GI/L | Standard Deviation 2.7224 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Leukocytes - 26 weeks | 10.050 GI/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Lymphocytes - baseline (GI/L) | 2.535 GI/L | Standard Deviation 0.0071 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Lymphocytes - 26 weeks | 2.370 GI/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Monocytes - baseline | 0.405 GI/L | Standard Deviation 0.0919 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Monocytes - 26 weeks | 0.700 GI/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Neutrophils - baseline | 5.495 GI/L | Standard Deviation 2.6658 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Neutrophils - 26 weeks | 6.750 GI/L | Standard Deviation 0 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Platelets - baseline | 299.0 GI/L | Standard Deviation 2.83 |
| Piromelatine 20 mg | Safety and Tolerability - Hematology | Platelets - 26 weeks | 301.0 GI/L | Standard Deviation 0 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Lymphocytes - baseline (GI/L) | 1.943 GI/L | Standard Deviation 0.2397 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Platelets - 26 weeks | 223.0 GI/L | Standard Deviation 48.08 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Lymphocytes - 26 weeks | 1.805 GI/L | Standard Deviation 0.3182 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Platelets - baseline | 241.0 GI/L | Standard Deviation 46.13 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Monocytes - baseline | 0.357 GI/L | Standard Deviation 0.1102 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Monocytes - 26 weeks | 0.370 GI/L | Standard Deviation 0.0141 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Basophils - 26 weeks | 0.050 GI/L | Standard Deviation 0.0141 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Eosinophils - baseline | 0.110 GI/L | Standard Deviation 0.0693 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Neutrophils - baseline | 3.660 GI/L | Standard Deviation 0.2905 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Neutrophils - 26 weeks | 3.525 GI/L | Standard Deviation 0.0071 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Leukocytes - baseline | 6.140 GI/L | Standard Deviation 0.694 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Leukocytes - 26 weeks | 5.885 GI/L | Standard Deviation 0.3465 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Eosinophils - 26 weeks | 0.130 GI/L | Standard Deviation 0.0283 |
| Piromelatine 50 mg | Safety and Tolerability - Hematology | Basophils - baseline | 0.067 GI/L | Standard Deviation 0.0153 |
| Placebo Comparator | Safety and Tolerability - Hematology | Neutrophils - 26 weeks | 4.205 GI/L | Standard Deviation 0.3041 |
| Placebo Comparator | Safety and Tolerability - Hematology | Neutrophils - baseline | 3.483 GI/L | Standard Deviation 1.1801 |
| Placebo Comparator | Safety and Tolerability - Hematology | Basophils - baseline | 0.063 GI/L | Standard Deviation 0.0153 |
| Placebo Comparator | Safety and Tolerability - Hematology | Lymphocytes - 26 weeks | 2.085 GI/L | Standard Deviation 1.3223 |
| Placebo Comparator | Safety and Tolerability - Hematology | Eosinophils - baseline | 0.153 GI/L | Standard Deviation 0.0208 |
| Placebo Comparator | Safety and Tolerability - Hematology | Platelets - 26 weeks | 283.0 GI/L | Standard Deviation 111.72 |
| Placebo Comparator | Safety and Tolerability - Hematology | Lymphocytes - baseline (GI/L) | 1.363 GI/L | Standard Deviation 0.332 |
| Placebo Comparator | Safety and Tolerability - Hematology | Monocytes - baseline | 0.347 GI/L | Standard Deviation 0.0611 |
| Placebo Comparator | Safety and Tolerability - Hematology | Basophils - 26 weeks | 0.080 GI/L | Standard Deviation 0.0283 |
| Placebo Comparator | Safety and Tolerability - Hematology | Platelets - baseline | 167.3 GI/L | Standard Deviation 26.95 |
| Placebo Comparator | Safety and Tolerability - Hematology | Leukocytes - 26 weeks | 6.970 GI/L | Standard Deviation 0.9617 |
| Placebo Comparator | Safety and Tolerability - Hematology | Monocytes - 26 weeks | 0.345 GI/L | Standard Deviation 0.0495 |
| Placebo Comparator | Safety and Tolerability - Hematology | Leukocytes - baseline | 5.407 GI/L | Standard Deviation 0.8755 |
| Placebo Comparator | Safety and Tolerability - Hematology | Eosinophils - 26 weeks | 0.250 GI/L | Standard Deviation 0.0283 |
Other Pre-specified
NeuroPsychiatric Inventory (NPI) Total Score
The NPI scale consists of 12 domains that are rated for both frequency (range 1 to 4) and severity (range 1 to 3). A composite score for each domain is calculated (frequency × severity), and it ranges from 1 to 12. For each item, there is a leading question. If the symptom is absent, then the frequency, severity, and distress scores are not completed. In this case, the score is 0 for the item. The sum of the composite scores yields the NPI total score (1-12). A negative change in the score indicates an improvement from baseline (symptom reduction).
Time frame: Baseline, and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | NeuroPsychiatric Inventory (NPI) Total Score | Baseline | 11.2 NPI total score | Standard Deviation 10.3 |
| Piromelatine 5 mg | NeuroPsychiatric Inventory (NPI) Total Score | 26 weeks | 11.4 NPI total score | Standard Deviation 11.6 |
| Piromelatine 20 mg | NeuroPsychiatric Inventory (NPI) Total Score | 26 weeks | 9.0 NPI total score | Standard Deviation 7.85 |
| Piromelatine 20 mg | NeuroPsychiatric Inventory (NPI) Total Score | Baseline | 10.3 NPI total score | Standard Deviation 8.39 |
| Piromelatine 50 mg | NeuroPsychiatric Inventory (NPI) Total Score | Baseline | 12.0 NPI total score | Standard Deviation 8.75 |
| Piromelatine 50 mg | NeuroPsychiatric Inventory (NPI) Total Score | 26 weeks | 11.9 NPI total score | Standard Deviation 10.66 |
| Placebo Comparator | NeuroPsychiatric Inventory (NPI) Total Score | Baseline | 10.8 NPI total score | Standard Deviation 10.13 |
| Placebo Comparator | NeuroPsychiatric Inventory (NPI) Total Score | 26 weeks | 9.8 NPI total score | Standard Deviation 10.34 |
Other Pre-specified
Pittsburgh Sleep Quality Index (PSQI) - Global Component Score
PSQI is an effective instrument used to measure the quality and patterns of sleep in older adults. It differentiates poor from good sleep by measuring 7 areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction over the last month. PSQI includes seven components, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality.
Time frame: Baseline, 4 weeks, 13 weeks, 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Piromelatine 5 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | Baseline | 6.8 PSQI global score | Standard Deviation 4.39 |
| Piromelatine 5 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 4 weeks | 5.8 PSQI global score | Standard Deviation 3.97 |
| Piromelatine 5 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 13 weeks | 6.2 PSQI global score | Standard Deviation 3.85 |
| Piromelatine 5 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 26 weeks | 5.7 PSQI global score | Standard Deviation 3.62 |
| Piromelatine 20 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 4 weeks | 5.4 PSQI global score | Standard Deviation 3.36 |
| Piromelatine 20 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 13 weeks | 5.2 PSQI global score | Standard Deviation 3.04 |
| Piromelatine 20 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 26 weeks | 4.7 PSQI global score | Standard Deviation 3.26 |
| Piromelatine 20 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | Baseline | 5.9 PSQI global score | Standard Deviation 3.99 |
| Piromelatine 50 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 13 weeks | 5.5 PSQI global score | Standard Deviation 3.2 |
| Piromelatine 50 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 4 weeks | 5.4 PSQI global score | Standard Deviation 3.56 |
| Piromelatine 50 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 26 weeks | 5.2 PSQI global score | Standard Deviation 3.21 |
| Piromelatine 50 mg | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | Baseline | 6.0 PSQI global score | Standard Deviation 4.14 |
| Placebo Comparator | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 26 weeks | 5.1 PSQI global score | Standard Deviation 3.68 |
| Placebo Comparator | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 4 weeks | 5.6 PSQI global score | Standard Deviation 3.39 |
| Placebo Comparator | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | Baseline | 5.6 PSQI global score | Standard Deviation 3.66 |
| Placebo Comparator | Pittsburgh Sleep Quality Index (PSQI) - Global Component Score | 13 weeks | 5.1 PSQI global score | Standard Deviation 3.11 |