Sleep
Conditions
Brief summary
This is a clinical study aimed at evaluating the efficacy and safety of Eschscholzia tablets in adults with insomnia disorder symptoms. The study will be conducted at one center, participants will randomly be assigned to either the treatment or placebo. Neither the participants, nor the researchers will know who is receiving the treatment (double-blind). The study is also placebo-controlled, meaning some participants receive a dummy pill instead of the actual treatment, and it involves a parallel-group design, where the treatment and placebo groups are studied at the same time. The study is exploratory, meaning it is investigating new possibilities and is not yet fully conclusive. The purpose of this study is to determine main efficacy and safety of the newly developed herbal medicinal product Eschscholzia tablets. A total of 100 subjects will be enrolled in the study and assigned to either Eschscholzia tablets or placebo. The Local Ethics Committee at the clinical site has given their approval for the study to be run. Male or female participats aged between 18 and 75 years (inclusive), generally healthy and with a self reported history of disturbed sleep on at least 3 nights per week for at least the prior 1 month with a self-reported impact on daytime functioning are allowed to take part in the study. Overall, the study has the following visits in the clinic, planned for each patient: Screening visit, Study centre Visit 2, Final study centre Visit 3. Between these visits participants will go through a "run-in" period (1 week between Visit 1 and 2) and treatment period (1 month between visit 1 and 3), both at home. Upon visit 2 participants will obtain the study product. They will be asked to administer a daily dose of 2 tablets (either Eschscholzia tablets or Placebo) over a 4-week period, starting from Visit 2 and continuing until Visit 3. Every intake of study product should be noted on the sleep diary pages that the participants obtain.
Interventions
DRUGEschscholzia tablets
The intervention will be provided as swallowable "Eschscholzia tablets" (1.0 g) containing 0.503g Eschscholzia californica Herba rec. tinct. conc. as the active pharmaceutical ingredient (API) corresponding 600 mg powdered herbal material.
DRUGPlacebo Tablets
A placebo tablet will be provided that matches the verum in its optical and sensorial properties and posology. Contains: microcrystalline cellulose, Colloidal anhydrous silica, glycerol distearate, caramel couleur and colorants.
Sponsors
A. Vogel AG
DCC Convex Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Voluntary, written, informed consent to participate in the study * Self reported difficulty or maintaining sleep or waking too early, or daytime impairement or distress based on subject's information related to sleep pattern during at least the preceding month before screening. * Self reported history of disturbed sleep on at least 3 nights per week for at least the last 1 month before screening. * ≥30 min to fall asleep * ≥30 min awake during sleep time * Self-reported total sleep time of ≤ 6.5 h * ISI total score ≥ 10 * Confirmation of presence of insomnia diagnosis according to the ICD-10 F51.0/ICD-11 7A00 criteria by the physician upon anamnesis. * Reported Impact on daytime functioning associated with sleep maintenance as measured with question 7 of the ISI, Score \>= 2 * Freezing capacities available for storage of saliva samples. * Willingness and infrastructure available to run aktigraphic device (bed sensor) properly
Exclusion criteria
* Body mass index (BMI) \<18.0 or \>30.0 kg/m2. * Individual is pregnant, planning to be pregnant during the study period, lactating, or women of childbearing potential who are unwilling to commit to the use of a medically approved form of contraception throughout the study period. * Any known acute organic disorder affecting sleep quality, such as narcolepsy, obstructive sleep apnea (OSA), restless leg syndrome (RLS), periodic limb movement syndrome (PLMS), circadian rhythm disorder, rapid-eye-movement behavior disorder, benign prostatic hyperplasia (BPH), urinary tract infections, irritated bladder, acute and/or chronic pain. * Any known acute or chronic psychiatric condition (e.g., severe mono- or bipolar depression, history of suicidal ideation or attempt, severe anxiety disorders, severe personality disorders, borderline personality disorder, psychoses). * Have a significant acute or chronic coexisting illness or any condition which contraindicates entry to the study in the opinion of the Investigator (e.g. migraines, active infections, renal insufficiency, hepatopathy, and dementia). * History of alcohol or drug misuse * Regular alcohol consumption exceeding 140g/week, heavy smoking (\>10 cigarettes/day), high caffeine intake (\>10 glasses/day). * Current intake of drugs that could influence sleep (e.g., psychotropic, sedatives, hypnotics, nicotine-replacement therapies, over-the-counter sleep aids, hormone therapy, health products and oriental herbs (such as valerian, hops, passionflower, hypericum). * Have a clinically significant high/low blood pressure (systolic over 159 mmHg, resp. lower than 80 mmHg or diastolic over 99 mmHg, resp. lower than 60 mmHg). * History or planned travel to a different time zone within 1 month of the first visit or/and during the study participation. * Shift-worker. * Not fluent in local language. * Have (known) hypersensitivity to plants from the poppy family (Papaveraceae) or known hypersensitivity to the active substance/s (Eschscholzia californica, microcrystalline cellulose, Colloidal anhydrous silica, sodium croscarmellose, glycerol distearate, caramel couleur and Ferrous(III) oxide). * Participation in another study with any investigational product within 30 days of screening and during the intervention period. * Investigator believes that the subject may be uncooperative and/or noncompliant and should therefore not participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline over the 4-week treatment phase in perceived sleep quality, as measured by the summed area under the curve (summed up ISI AUC) of the Insomnia Severity Index (ISI) Total Score. | Change between baseline and over 4-week treatment phase | Min: 0 score points, Max: 28 score points Lower scores mean better outcomes The global effect of the investigational medicinal product (IMP) on sleep will be evaluated using the area under the curve (AUC) of repeatedly measured subjective insomnia severity, assessed by the ISI Total Score. |
| Change in perceived sleep quality over time during the treatment period, as assessed by the longitudinal profile of the change from baseline in ISI total score values at each post-baseline assessment time point | From baseline over the phase of the 4 weeks treatment | Endpoint evaluates changes in perceived sleep quality over time during treatment based on Insomnia Severity Index (ISI) change from baseline at each scheduled post-baseline assessment time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to reach a clinically relevant insomnia symptom severity reduction of -9 units on the ISI total score scale | From baseline over the phase of the 4 weeks treatment | Endpoint evaluates the time to response (TTR), defined as the first study day on which a subject achieves a clinically relevant reduction in insomnia severity, corresponding to a change from baseline of Δ ISI ≤ -9 points. |
| Change in perceived sleep quality over time during the treatment and post-treatment period, as assessed by ISI AUC values at each intervention time point. | From baseline over the phase of the 4 weeks treatment | The secondary efficacy parameter ISI AUC over time is defined as the baseline-adjusted ISI AUC values calculated between consecutive assessment time points. ISI AUC values are available for the post-baseline intervention and follow-up visits on Days 9, 11, 15, 22, 29, and 36. Baseline adjustment is performed. A decrease (negative value) in ISI AUC is associated with a positive treatment effect, whereas an increase (positive value) indicates a negative treatment effect |
| Change in perceived overall sleep quality over time during the treatment, as assessed by the sleep diary composite score TSQ1 | From baseline over the phase of the 4 weeks treatment | The Total Sleep Quality Index 1 (TSQ1) is a composite parameter derived from daily sleep diary entries and is intended to quantify overall perceived sleep quality over time. TSQ1 is calculated at each diary time point as the arithmetic mean of four sleep quality subscores: Sleep Enjoyment, Well Rested, Physical Tension, and Psychological Tension. Each subscore is normalized to a common scale ranging from 0 to 100, with higher values indicating better sleep quality. For subscores reflecting negative aspects of sleep (physical and psychological tension), reverse coding is applied prior to normalization to ensure consistent score directionality. The resulting TSQ1 score ranges from 0 to 100, where higher values indicate better perceived sleep quality |
| Change in perceived overall sleep quality over time during the treatment, as assessed by the sleep diary subscores | From baseline over the phase of the 4 weeks treatment | Patients will complete the daily diary from study day 2 throughout the whole study duration until the morning of study day 36. Sleep quality is assessed with four NRS (scale from 0 (very low) to 10 (very high)) with the parameters: physical tension (QPHY\_D), psychological tension (QPSY\_D), sleep enjoyment (QEnj\_D) and restedness (QRest\_D) and sleep quality (SQ\_D). Further, the number of awakenings (NWAK\_D), duration of awakenings (DWAK\_D), sleep onset latency (SOL\_D) is assessed. |
| ISI Responder criteria assessed at the end of intervention on visit 3 | From baseline to the end of treatment after 4 weeks treatment | ISI Responder criteria assessed at the end of intervention on visit 3 (day 36): 1. Ratio of subjects with a ISI score reduction of ≥ -5 points from baseline, 2. ratio of subjects achieving a ISI score reduction of at least 50% from baseline, 3. Proportion of subjects reaching an ISI total score of ≤ 7, indicating no clinically significant insomnia symptoms, 4. Proportion of subjects achieving the ISI composite score. ISI composite score criteria: the ISI composite score will be considered achieved if a subject meet at least two of the responder criteria a)-c); |
| Change between baseline and over 4-week treatment phase in daytime sleepiness symptoms severity as measured with the Epworth Sleepiness Scale (ESS) | From baseline to the end of the treatment after 4 weeks | Min: 0 score points, Max: 24 score points Lower scores mean better outcomes |
| Change between baseline and over 4-week treatment phase in Profile of Mood states as measured with the POMS-2 questionnaire (POMS-2). | Change between baseline and over 4-week treatment phase | The POMS-2 includes the following primary scales: Tension-Anxiety Depression-Dejection Anger-Hostility Fatigue-Inertia Confusion-Bewilderment Vigor-Activity (positive scale) Higher raw scores on negative scales indicate greater mood disturbance. Higher raw scores on the Vigor-Activity scale indicate positive mood states. |
| Change between baseline and over 4-week treatment phase in state anxiety as measured with the State-Trait-Anxiety-Inventory (STAI-Y1 & Y2). | Change between baseline and over 4-week treatment phase | STAI-Y1: Measures state anxiety (temporary and situational anxiety). STAI-Y2: Measures trait anxiety (general and long-standing anxiety tendencies). Both STAI-Y1 \& STAI-Y2 are individually assessed as follows Minimum Score: 20 (low anxiety) Maximum Score: 80 (high anxiety) Lower scores mean better outcomes |
| Change between baseline and over 4-week treatment phase in anxiety disorders as per the assessment of the clinician on the HAM-A scale (HAM-A). | Change between baseline and over 4-week treatment phase | Minimum Score: 0 (no anxiety) Maximum Score: 56 (severe anxiety) Lower scores mean better outcomes |
| Change between baseline and over 4-week treatment phase in psychological well-being as measured with the Depression, Anxiety, and Stress Scale (DASS-21). | Change between baseline and over 4-week treatment phase | has 21 items, diivided into three subscales: Depression (7 items) Anxiety (7 items) Stress (7 items) Minimum Score per Subscale: 0 Maximum Score per Subscale (adjusted): 42 lower scores mean better outcomes |
| Subjective efficacy | Day 36 | Patient's perceived efficacy will be assessed upon final visit 3 by asking the question how the subjects would rate the effectiveness of the study product to treat insomnia, sleeping problems and/or accompanying symptoms on a scale: "bad" = 0, "average" = 1, "good" = 2, "very good" = 3. |
| Acceptance of the treatment | On day 36 | Patient's perceived acceptance is assessed upon final visit V3 by asking "would you take the test medication again to treat insomnia, sleeping problems and/or accompanying symptoms? Answers possible: "yes" or "no". |
| Subjective tolerability | On Day 36 | Patient's perceived tolerability will be assessed upon final visit 3 by asking the question how they rate their self-perceived tolerability of the IP on a scale: "bad" = 0, "average" = 1, "good" = 2, "very good" = 3. |
| Change between baseline and over 4-week treatment phase in physiological sleep quantity and quality and physiological measures via actigraphy (wearable). | Change between baseline and over 4-week treatment phase | In this study, actigraphy sleep data will be delivered using the multi-sensory Fitbit tracker "Fitbit Charge 6" Actigraphic parameters, which are recorded on a daily basis, will be handled and analysed in general consistency with the sleep diary data • Data log data are averaged daily for all parameters applicable Parameters: * Minutes to Sleep onset (SOL\_A) * Minute Time in bed (TIB\_A) * Minutes Total sleep time (TST\_A) * Minutes spent in deep sleep phase (DEEP\_A) from "sleep stages Day merged" * Minutes spent in deep sleep phase (DEEP\_A\_30s) from "30 seconds Sleep Stages merged" * Minutes spent in rapid-eye-movement sleep phase (REM\_A) from "sleep stages Day merged" * Minutes spent in rapid-eye-movement sleep phase (REM\_A\_30s) from "30 seconds Sleep Stages merged" * Minutes spent in light sleep phases (LIGHT\_A) from "sleep stages Day merged" * Minutes spent in light sleep phases (LIGHT\_A\_30s) from "30 seconds Sleep Stages merged" * Count awakenings (NWAK\_A) from "sleep stages |
| Rate/kind of adverse events | on day 36 | — |
| Blood pressure | Change between baseline and day 36 | Blood pressure (BP): Systolic and diastolic BP will be assessed by using an automated BP measurement device. |
| Blood pulse | Change between baseline and day 36 | Blood pulse will be assessed by using an automated measurement device |
| Change in Blood safety parameters | Change between baseline and day 36 | The following factors will be analysed as per standard normal ranges for adults (f/m) by an external independent and certified medical diagnostic laboratory: * Red blood cell counts * Leukocytes counts /White blood cell count * Lymphocyte count * Thrombocyte count /Platelet counts * Monocyte count * Granulocyte count * Hemoglobin levels * Hematocrit levels * Mean corpuscular volume * Mean corpuscular hemoglobin * Mean corpuscular hemoglobin concentration * Glutamat-pyruvat-transaminase (GPT) * Glutamat-oxaloacetate-transaminase (GOT) * Gamma-glutamyltransferase (GGT) * Total bilirubin * Creatinine * Blood Glucose * Total Cholesterol * Erythrocyte sedimentation rate (ESR) * C-reactive protein (CRP) |
| Rate/kind of comedication | Change between baseline and day 36 | — |
| Treatment compliance | on day 36 | Upon Visit 3, product intake compliance will be verified by counting the remaining tablets of the study product returned by subjects. Limits for subjects to be compliant is an intake of study product within 80% - 120% of the intended study product intake schedule. |
| Change in biomarker for stress between baseline and over 4-week treatment phase via the salivary evening cortisol levels (8 p.m.) | Change from baseline days 6/7 to chronic treatment after days 34/35 | Assessed at 8 p.m. ±20 minutes and delivered by the analytical laboratory Parameters: • Evening cortisol level |
| Change in biomarker for sleep readiness between baseline and over 4-week treatment phase via the salivary evening melatonin level (8 p.m.) | Change from baseline days 6/7 to chronic treatment by days 34/35 | Assessed at 8 p.m. ±20 minutes and delivered by the analytical laboratory Parameters: • Evening melatonin level |
| Change between baseline and over 4-week treatment phase in ratio of biomarker evening melatonin level/ evening cortisol level (8 p.m.) | Change from baseline days 6/7 to chronic treatment by days 34/35 | Assessed at 8 p.m. ±20 minutes and delivered by the analytical laboratory. Ratio = Evening melatonin level/Evening Cortisol level |
| Change between baseline and over 4-week treatment phase in biomarker for chronic stress via the CAR determined | Change from baseline days 6/7 to chronic treatment by days 34/35 | Assessed at 8 p.m. ±20 minutes and delivered by the analytical laboratory. The saliva samples in the morning are collected three times in the first hour after waking (at awakening as well as 30 and 45 min after awakening) to assess the CAR as a physiological reaction to awakening. The area under the curve (1) with respect to ground (AUCG), and (2) with respect to increase (AUCI) is calculated using the following formulae (Pruessner and colleagues, 2003): |
Countries
Bulgaria
Outcome results
None listed