| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Insomnia disorder |
| Bezsenność |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10022437 |
| E.1.2 | Term | Insomnia |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of two doses of Lorediplon (5 and 10 mg), during two consecutive nights compared to placebo on Wake after Sleep Onset (WASO) measured by polysomnography (PSG) in adult patients with insomnia disorder. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate dose-response relationship of two doses of Lorediplon and placebo assessed by Wake after Sleep Onset (WASO) measured by polysomnography (PSG).
To evaluate the efficacy of two doses of Lorediplon, during two consecutive nights compared to Zolpidem on Wake after Sleep Onset (WASO) measured by polysomnography (PSG).
To evaluate the efficacy of Zolpidem during two consecutive nights compared to placebo on Wake after Sleep Onset (WASO) measured by polysomnography (PSG) in adult patients with insomnia disorder.
To compare the effect of two doses of Lorediplon versus placebo and versus Zolpidem on:
• PSG measurements
• Patient reported measurements (recorded by patient questionnaire or VAS
• Next-day residual effects
• Safety and tolerability
• Pharmacokinetics
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be randomly assigned to treatment in the study, patients must:
• Sign an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study and comply with the study procedures and restrictions
• Males and females aged 18 to 64 years old.
• Patients with insomnia disorder defined by the DSM -5 (Diagnostic and Statistical Manual of Mental Disorders).
• Patients who reported at least 1 hour (60 minutes) of wakefulness after sleep onset and at least 30 minutes to fall asleep at least three (3) nights a week over at least 4 weeks before the study starts confirmed by a 7 day sleep diary.
• BMI ≥ 18 kg/m2 and ≤ 32 kg/m2
• Be in good health as determined by their medical and sleep history, and results of physical examination, electrocardiogram (ECG), vital sign measurements, serum biochemistry, hematology, and urinalysis. A patient with a clinical abnormality may be included only if the investigator considers that the abnormality will not introduce additional health risk for the patient or interfere with study objectives
• Be at least 1 year postmenopausal for women older than 50 or be at least 2 years postmenopausal for women 50 or younger, or surgically sterile, or practicing an effective method of birth control (e.g. intrauterine device, or diaphragm with spermicide; or double barrier method) during the study and one month thereafter, if female. Contraceptives that induce CYP450 are not allowed.
• Be able to abstain from xanthine-containing beverages (e.g., coffee, tea, coca-cola) after 12.00 (noon) on study visit days and refrain from intensive physical activities on study visit days
• Meet the following criteria as determined by the 7-day Screening Sleep Diary:
-Provide data for at least 5 of the 7 days in the diary period
-Have an SOL of 30 minutes or more at bedtime on at least 3 nights
-Have a total WASO of at least 60 minutes on at least 3 nights
-Have a stable bedtime pattern as defined by a usual bedtime between 21.00 and 01.00 (inclusive) and a usual rise time between 05.00 and 09.00. On nights followed by nonworking days, variations in sleep schedule are allowed if, in the opinion of the investigator, they do not impact the patient’s eligibility for randomization
• Meet the following criteria during Visit 2, the 2-night, single-blind placebo PSG:
-Total sleep time (TST) on second night is < 6.5 hours
-Latency to persistent sleep (LPS) on second night is at least 20 minutes
-Wake after sleep onset (WASO) on second night is ≥ 45 minutes |
|
| E.4 | Principal exclusion criteria |
To be randomly assigned to treatment in the study, patients must NOT:
• Patients with any DSM-5 psychiatric disorder (especially anxiety and post-traumatic stress disorders) or any other sleep disorder including primary hypersomnia, narcolepsy, breathing-related sleep disorder, circadian rhythm disorder or parasomnia within 6 months before or during this study
• Patients who have any undelaying disease for which it is known it interferes with sleep (painful syndromes etc.)
• Patient with sleep abnormalities like sleep apnea –AHI more than 10 episodes/hour and/or periodic leg movement syndrome with arousal/restless syndrome- PLMAI more than 10 episodes/hour.
• Any over the counter or prescription sleep medication, medication with central effects, known properties which affect sleep/wake function or known to induce or inhibit the CYP3A4s, administered in a period equal to 5 half-lives prior to the screening or required to be administered during the period of the trial.
• Patients with a known hypersensitivity to Lorediplon, Zolpidem or other drugs of the same class or other of any of the inactive ingredients.
• Evidence of any known clinically significant disease, including known or suspected human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
• Any medical condition that in the investigators opinion may interfere with the study procedures and/or evaluations
• Lab. values, such as hemoglobin ≤12 g/dL (120 g/L) for male subjects or ≤10 g/dL (100 g/L) for female subjects. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 x ULN and any other abnormal value considered clinically significant by the investigator.
• Patients with a history of substance abuse, substance dependence or lifestyle that precludes the diagnosis of insomnia disorder
• Patients who smoke during the night.
• Shift workers or persons who have crossed more than 3 time zones by aircraft (within 1 month of the trial) or plan to do so during the trial.
• Pregnant, lactating, breastfeeding, or intends to become pregnant during the course of the study and one month thereafter (females only). All women must have a negative pregnancy test at the Screening Visit,or be surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or have a postmenopausal status (no menses) for at least one year for women older than 50 year or have postmenopausal status (no menses) for at least two years for women 50 year or younger.
• Patients taking any experimental drug or participating in other clinical trials within 30 days before or during this study.
• Have a usual alcohol consumption of more than 3 drinks per day on 3 or more days per week
• Consume more than 4 espresso, or 4 instant coffees or other xanthine-containing beverage – (tea or coca-cola) with a similar caffeine content
• Have a history or presence of gastrointestinal, hepatic, or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs
• Consume grapefruit or grapefruit juice within 1 week before Visit 1
• Have a positive result on the drugs of abuse screening test (for benzodiazepines, barbiturates, cannabinoids, opiates, amphetamines, or cocaine) or alcohol breathalyzer test on either evening of Visit 2
• Have donated 1 or more units of blood within 90 days of Visit 1 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| WASO change from baseline (minutes) measured by polysomnograpy (PSG) comparing Lorediplon (mean of two nights for each dose) with placebo (mean of two nights). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Dose-response relationship of two doses of Lorediplon versus placebo assessed by WASO.
WASO change from baseline (minutes) measured by polysomnograpy (PSG) comparing Lorediplon (mean of two nights for each dose) with Zolpidem (mean of two nights). Comparison of Lorediplon versus placebo and versus Zolpidem on the following parameters (change from baseline):
• PSG measurements:
-Total Sleep Time (TST),
-Latency to Persistent Sleep (LPS),
-Sleep Efficiency Index (SEI),
-Sleep Onset Latency (SOL),
-Number of awakenings (NAW),
-Total time awake (TTA),
-Sleep Efficiency Index by quarter of the night,
-Sleep Efficiency Index by hour of the night.
-Sleep stage effects.
-WASO by ¼ of the night.
• Patient reported measurements (recorded by patient questionnaire or VAS):
-Subjective total sleep time (sTST),
-Subjective Wake after Sleep Onset (sWASO),)
-Subjective Sleep Latency,
-Subjective number of awakenings (sNAW),
-Subjective Sleep quality (sSQ),
-Subjective Sleep onset (sSO),
-Sleepiness scale.
A PSQ (post sleep questionnaire) will be administered to measure sWASO, sTST, sSleep Latency, sSleep Quality & sNAW, each morning in the sleep lab, within the 30 min of awakening, for two days.
Sleep scoring (S-VAS) will be used for subjective Sleep Onset, subjective sleep quality and for subjective Sleepiness.
• Next-day residual effects.
Next-day residual effects evaluated by:
-Neurocognitive assessment:
Digit symbol substitution test (DSST).
-Psychomotor assessment:
Psychomotor Vigilance Test (PVT).
-Sleepiness:
Sleepiness-Alertness Visual Analogue Scale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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