A Study to Assess the Wakefulness Promoting Effect, Safety, Tolerability, and Pharmacokinetics (PK) of LML134 in Shift Work Disorder

Study Overview
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Brief Summary
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The main purpose of this study was to demonstrate that LML134 can increase wakefulness compared to placebo in patients with shift work disorder (SWD) measured by objective and subjective endpoints of wakefulness, i.e. the sleep latency in the multiple sleep latency test (MSLT) and the Karolinska Sleepiness Scale (KSS), respectively. Safety and PK of LML134 were also evaluated. In addition, novel methodologies to measure wakefulness and sleep were also to be tested and compared to gold standard methods like the MSLT and polysomnography (PSG) (at sites where staff have appropriate equipment and training). The aim of such comparisons was to evaluate the usefulness of the new technologies in clinical studies and provide preliminary validation data. This was a randomized, subject and investigator-blinded, placebo controlled, crossover, multi-center Proof of Concept (PoC) study with in-house simulated laboratory night shifts in patients with SWD. This non-confirmatory study included two treatment arms: LML134 and placebo. After a screening period, the treatment phase of the study consisted of two overnight stays in a sleep lab in each of two treatment periods, with a minimum one week wash-out in between.

Official Title
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A Randomized, Subject and Investigator-blinded, Placebo Controlled, Cross-over, Multi-center Proof of Concept (PoC) Study to Assess the Wakefulness Promoting Effect, Safety, Tolerability, and PK of LML134 in Shift Work Disorder (SWD) Patients

Conditions
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Circadian Rhythm Disorders

Intervention / Treatment
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* Drug: LML134
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects 18 to 65 years of age included. Confirmed diagnosis of SWD according to ICSD-3 criteria at Screening. Subjects who are at least moderately ill with respect to sleepiness on work nights, including commute to and from work, as assessed by the Clinical Global Impression-Severity scale (CGI-S, score ≥4) at Screening. Subjects must work 5 or more night shifts per month, and 2 or more shifts must occur on consecutive nights, with 6 or more hours worked between 10 pm and 8 am, as confirmed by subject at Screening. Subjects must have mean sleep latency ≤8 minutes on nighttime MSLT at Screening. Subjects must weigh at least 50 kg at Screening to participate in the study, and must have a body mass index (BMI) within the range of 18 - 35 kg/m2. BMI = Body weight (kg) / [Height (m)]2 Exclusion Criteria: Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) unless they are using highly effective methods of contraception from start of taking the study medication in the first period until stopping the medication in the second treatment period and for 3 additional days after AND an additional barrier method of contraception will be used while taking the study medication and for 3 additional days in both treatment periods. Sexually active males unwilling to use a condom during intercourse while taking investigational drug and for 3 days after stopping investigational drug. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of the investigational drug via seminal fluid to their partner. Heavy smokers who smoke more than 10 cigarettes a day and occasional or light smokers (not more than 10 cigarettes per day) who are not willing to, or in their own or the investigators opinion are not able to refrain from tobacco/nicotine use for at least 12 hours without nicotine craving or other withdrawal symptoms Subjects for whom it is not safe to discontinue or who are unwilling to discontinue use of modafinil, hypnotics, and antihistamines for the periods specified in the prohibited medication section. Heavy caffeine consumers, i.e. subjects who consume greater than 850 mg of caffeine per day (approximate equivalent of three tall cups of Starbucks coffee) in coffee, tea, or other caffeine-containing drinks. Subjects who have high risk of obstructive sleep apnea, indicated by score of 5 or more on the STOP-BANG questionnaire. Presence of any sleep disorder other than SWD, as confirmed by PSG at screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>LML134, then placebo | Drug: LML134<br>* LML134<br>Drug: Placebo<br>* placebo<br>|
| Experimental: Group 2<br>Placebo, then LML134 | Drug: LML134<br>* LML134<br>Drug: Placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Sleep Latency Over Two Consecutive Test Nights as Measured by the the Multiple Sleep Latency Test (MSLT) | The Multiple Sleep Latency Test (MSLT) is an objective assessment of sleepiness that measures the ability of a subject to remain awake. Long latencies to sleep are indicative of a patient's ability to remain awake. Mean sleep latency from MSLT was measured for four MSLT naps performed at scheduled timepoints (01:30, 03:30, 05:30, and 07:30). The primary efficacy variable was the mean MSLT sleep latency assessed at Day 1 and Day 2 of each treatment period. | Day 1 and Day 2 of each treatment period (midnight until 8:00) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep Latency at Separate Naps Over Two Consecutive Test Nights as Measured by the the Multiple Sleep Latency Test (MSLT) | The Multiple Sleep Latency Test (MSLT) is an objective assessment of sleepiness that measures the ability of a subject to remain awake. Long latencies to sleep are indicative of a patient's ability to remain awake. Mean sleep latency from MSLT was measured for four MSLT naps performed at scheduled timepoints (01:30, 03:30, 05:30, and 07:30). The outcome measure is the mean value of Day 1 and Day 2 assessments for each timepoint. | Day 1 and Day 2 of each treatment period (midnight until 8:00) | 
| Plasma PK Concentration | Plasma PK concentration. Due to sparse sampling, only plasma concentrations were calculated and no PK parameter was evaluated by non-compartmental analysis. | 0 to 34.5 hours post first treatment. | 
| Total Time in Bed Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Total time in bed is the time spent in bed during recording. | Day 2 (10:00 until 18:00) of each treatment period | 
| Sleep Time Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Total sleep time is the overall duration of sleep during the entire PSG recording. | Day 2 (10:00 until 18:00) of each treatment period | 
| Sleep Efficiency Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Sleep efficiency is the percentage of time spent asleep during the entire PSG recording. | Day 2 (10:00 until 18:00) of each treatment period | 
| Wake Time After Persistent Sleep Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Wake time after persistent sleep is a measure of time spent awake after a defined onset of sleep. | Day 2 (10:00 until 18:00) of each treatment period | 
| Latency to Onset of Persistent Sleep Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Latency to onset of persistent sleep is defined as latency from Lights-Off to the first epoch (30 seconds) of 20 consecutive epochs of non-Wake. | Day 2 (10:00 until 18:00) of each treatment period | 
| Number of Awakenings Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Number of awakenings is defined as the number of times of entering wake stage after onset of sleep during the PSG recording. | Day 2 (10:00 until 18:00) of each treatment period | 
| Latency to Rapid Eye Movement (REM) Sleep Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Sleep latency to REM Sleep is defined as the time from Lights-Off to reaching the first epoch (i.e. 30 seconds) of REM sleep. | Day 2 (10:00 until 18:00) of each treatment period | 
| Number of Sleep Cycles Measured by Polysomnography (PSG) | PSG encompasses the monitoring of subjects in a sleep facility using an array of medical equipment with simultaneously recording on a multi-channel analog or digital system. PSG was performed in the study to record and evaluate various aspects of sleep. Number of sleep cycles measured by Polysomnography (PSG). | Day 2 (10:00 until 18:00) of each treatment period | 
| Time Spent in Each Sleep Stage Measured by Polysomnography (PSG) | N1: is defined by a relatively low amplitude, mixed frequency EEG. N2: is defined by the presence of sleep spindles and/or K complexes and the absence of sufficient high-amplitude, slow activity to define the presence of stage N3 sleep. N3: is defined as an EEG with at least 20% of an epoch consisting of slow, high amplitude waveforms of .5 - 2 Hz and peak-to-peak amplitude of greater than 75mV. REM: is defined by the concomitant appearance of relatively low amplitude, mixed frequency EEG activity and episodes of rapid eye movement. Sawtooth waves may be present. Chin EMG activity is typically low. | Day 2 (10:00 until 18:00) of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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shift work disorder