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ईसाईA Study to Evaluate the Efficacy and Safety of E2086 in Adults With Narcolepsy चरण II 64
A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of E2086 in Adults With Narcolepsy
- E2086-G000-202
- 2025-523503-30 (अन्य पहचानकर्ता) (EU CTIS Number)
Narcolepsy type 2 (NT2)
E2086
| प्रतिभागी समूह/शाखा | हस्तक्षेप/उपचार |
|---|---|
प्लेसबो तुलना समूहNT1 Participants: Placebo Participants with NT1 will be randomly assigned to receive one E2086 matched placebo tablet, orally, once daily for 4 weeks during each of the E2086 low-, middle-, and high-dose-matched treatment periods. A washout period of at least 7 days will be included between dose levels, for a total of approximately 14 weeks of treatment. | प्लेसबो E2086 matching placebo tablet. |
प्रयोगात्मकNT1 Participants: E2086 Participants with NT1 will be randomly assigned to receive one E2086 tablet, orally, once daily for 4 weeks during each of the E2086 low-, middle-, and high-dose-matched treatment periods. A washout period of at least 7 days will be included between dose levels, for a total of approximately 14 weeks of treatment. | E2086 E2086 oral tablets. |
प्लेसबो तुलना समूहNT2 Participants: Placebo Participants with NT2 will be randomly assigned to receive one E2086 matched placebo tablet, orally, once daily for 4 weeks during each of the E2086 low-, middle-, and high-dose-matched treatment periods. A washout period of at least 7 days will be included between dose levels, for a total of approximately 14 weeks of treatment. | प्लेसबो E2086 matching placebo tablet. |
प्रयोगात्मकNT2 Participants: E2086 Participants with NT2 will be randomly assigned to receive one E2086 tablet, orally, once daily for 4 weeks during each of the E2086 low-, middle-, and high-dose-matched treatment periods. A washout period of at least 7 days will be included between dose levels, for a total of approximately 14 weeks of treatment. | E2086 E2086 oral tablets. |
| परिणाम माप | माप विवरण | समय सीमा |
|---|---|---|
Change from Baseline to Week 4 in MSL for E2086 Compared With Placebo Across Four MWTs in Participants With NT1 and NT2 | Sleep latency is defined as the amount of time a person takes to fall asleep. The MWT is an objective measure of the ability to stay awake. An increased ability to stay awake in the context of trying to remain awake is reflected in a prolonged sleep latency. The first 4 measurements of sleep latency at regular intervals across the day are averaged to calculate the MSL. The MWT is used to evaluate response to treatment for conditions associated with EDS and to assess alertness in individuals who must remain awake for safety reasons. The 40-minute MWT will be performed as per the 2021 guidance of the American Academy of Sleep Medicine (AASM). | Baseline and Week 4 |
| परिणाम माप | माप विवरण | समय सीमा |
|---|---|---|
Weekly Cataplexy Rate (WCR) of E2086 Compared With Placebo at Week 4 in Participants With NT1 | WCR assess through participant-reported daily diaries, is a standard measure of cataplexy burden in clinical development programs for narcolepsy treatments, similar in importance to the MWT used for evaluating EDS. | At Week 4 |
Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 4 for E2086 Compared With Placebo in Participants With NT1 and NT2 | The ESS is a subjective measure of daytime sleepiness. The participant rates on a 4-point Likert scale how likely it is that he/she would doze in 8 different situations. Scoring of the answers is 0 to 3, with 0 being "would never doze" and 3 being "high chance of dozing". The total ESS score ranges from 0 to 24, with higher scores indicating greater daytime sleepiness. Scores above 10 are considered indicative of EDS. A decrease from baseline in ESS score represents improvement. | Baseline and Week 4 |
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in Participants With NT1 and NT2 | From first dose of study drug up to Day 113 | |
Number of Participants With Markedly Abnormal Laboratory Values in Participants With NT1 and NT2 | Laboratory parameters will include hematology, chemistry and urinalysis. | Up to Day 113 |
Number of Participants With Clinically Significant Changes in Vital Sign Values in Participants With NT1 and NT2 | Vital signs will include measurement of systolic and diastolic blood pressure (BP), heart rate, respiratory rate and body temperature. Any clinically significant change in vital signs will be determined at the investigator's discretion. | Up to Day 113 |
Number of Participants With Clinically Significant Changes in 12-Lead Electrocardiogram (ECG) Parameters in Participants With NT1 and NT2 | The 12-lead ECG will be evaluated. Any clinically significant change in ECG assessment will be determined at the investigator's discretion. | Up to Day 113 |
Number of Participants With Suicidality as Assessed by Columbia - Suicide Severity Rating Scale (C-SSRS) in Participants With NT1 and NT2 | Suicidality will be assessed using the C-SSRS. The C-SSRS assesses an individual's degree of suicidality, including suicidal ideation and suicidal behavior. The C-SSRS is an interview-based rating scale to systematically assess any suicidality, suicidal behaviour, or suicidal ideation. Any suicidality is emergence of any suicidal ideation or suicidal behaviour. Any suicidal behaviour is indicated when response is "yes" for any these questions- actual attempt to suicide, engaged in non-suicidal self-injurious behaviour, interrupted attempt, aborted attempt, preparatory acts. Any suicidal ideation is indicated when response is "yes" for any of these questions- wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent to suicide. | Up to Day 113 |
Mean Change From Baseline in 24-hours Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) up to Week 4 of each dose level in Participants With NT1 and NT2 | The BP will be evaluated by Ambulatory Blood Pressure Monitoring (ABPM) for all participants based on the measurement of BP recordings after every 24 hours. | Baseline and Week 4 |
Mean Change From Baseline in Day-time and Night-time BP Measured by ABPM in Participants With NT1 and NT2 | The BP will be evaluated by ABPM for all participants based on the measurement of BP recordings after every 24 hours. | Baseline and Week 4 |
Cmax: Maximum Observed Plasma Concentration of E2086 and its Metabolite M1 | Days 28, 63 and 98: 0-24 hours post-dose | |
Tmax: Time to Reach Cmax of E2086 and its Metabolite M1 | Days 28, 63 and 98: 0-24 hours post-dose | |
AUC(0-24h): Area Under the Plasma Concentration-time Curve From Zero Time to 24 Hours of E2086 and its Metabolite M1 | Days 28, 63 and 98: 0-24 hours post-dose | |
t½: Terminal Phase Half-life of E2086 and its Metabolite M1 | Days 28, 63 and 98: 0-24 hours post-dose | |
MRp: Metabolite Ratio of AUC(0-t) | MRp calculated as ratio of plasma AUC(0-t) of metabolite to parent following molar correction where appropriate. AUC(0-t) is area under the plasma concentration-time curve from zero time to time of last quantifiable concentration of E2086 and its Metabolite M1. | Days 28, 63 and 98: 0-24 hours post-dose |
Participants must meet all of the following criteria to be included in this study:
Male or female, age greater than or equal to (>=) 18 years (or as regionally appropriate) at the time of informed consent
NT1 Cohort: Must fulfill Inclusion Criteria 2a and 2b
Diagnosis of NT1 within the last 10 years of screening, as confirmed by at least one of the following:
- Polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) results, and clinical history, consistent with the 2023 International Classification of Sleep Disorders, 3rd edition, text revision (ICSD-3-TR) criteria for NT1
- Cerebrospinal fluid orexin-A/hypocretin-1 concentration less than or equal to (<=) 110 picograms per milliliter (pg/mL)
At least 4 or more episodes of cataplexy/week as averaged over 2 weeks minimum and confirmed by the cataplexy portion of the Diary If PSG or MSLT results are not available within the last 10 years of screening to fulfill Criterion 2a then screening assessment results for PSG or MSLT can be used instead
NT2 Cohort: Diagnosis of NT2 within the last 10 years of screening, as confirmed by PSG and MSLT results, and clinical history, consistent with the 2023 ICSD-3-TR criteria for NT2 If PSG or MSLT results are not available within the last 10 years of screening to fulfill Criterion 3 then screening assessment results for PSG or MSLT can be used instead
ESS score >=10
Reports regular bedtime, defined as the time that the participant attempts to sleep, between 22:00 and 01:00 (based on data from the screening Diary)
Reports regular waketime, defined at the time the participant gets out of bed for the day, between 05:00 and 10:00 (based on data from the screening Diary)
Reports being in bed between 7 and 9 hours per night (based on data from the sleep portion of the Diary)
Compliance rate >=80 percentage (%) for completion of the Diary during screening
Body mass index (BMI) >=18 to less than (<) 35 kilograms per square meter (kg/m^2) at Screening
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin \[ß-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a minimum sensitivity of 25 international units per liter (IU/L) or equivalent units of ß-hCG \[or hCG\]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug
Females of childbearing potential who:
Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following:
- total abstinence (if it is their preferred and usual lifestyle)
- an intrauterine device or intrauterine hormone-releasing system (IUS)
- a contraceptive implant
- Combined estrogen and progestogen-containing hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception associated with inhibition of ovulation, such as desogestrel (oral, injectable). Participants using hormonal contraceptives must be on a stable dose of the same contraceptive product for at least 28 days before dosing, throughout the study and for at least 28 days following study drug discontinuation
- have a vasectomized partner with confirmed azoospermia
Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation.
Participants on an oral contraceptive must use an additional study method throughout the study and for 28 days after study drug discontinuation. For sites outside of Europe, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, that is, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide.
NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (that is, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
Clinically significant illness that requires medical treatment within 8 weeks of dosing or a clinically significant infection that requires medical treatment within 4 weeks of dosing
Evidence of disease that may influence the outcome of the study within 4 weeks before dosing (for example, psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system)
Any history of surgery that may affect PK profiles of E2086 (for example, hepatectomy, nephrectomy, digestive organ resection) or who have a congenital abnormality in metabolism at Screening
Any clinically abnormal symptom or organ impairment found by medical history at Screening, including severe renal impairment (estimated glomerular filtration rate \[eGFR\] <30 milliliters per minute (mL/min), and physical examinations, vital signs, ECG findings, or laboratory test results that require medical treatment at Screening or Baseline
A prolonged QTc interval calculated using Fridericia's formula (QTcF) greater than 450 milliseconds (ms) according to central reading at Screening or Baseline. If the QTcF machine read is greater than 450 ms on the first single 12-lead ECG, 2 additional 12-lead ECGs will be performed 1 minute apart and the mean of the 3 QTcF values will be calculated
Persistent systolic BP greater than (>) 130 or <100 millimeters of mercury (mmHg) or diastolic BP >85 or <50 mmHg at Screening (based on BP measured on at least 3 occasions over 2 weeks), or at Baseline. If outside of these limits at Screening or Baseline, BP should be repeated twice with at least 5 minutes between measurements
Persistent HR less than 50 beats/min or more than 100 beats/min at Screening (based on HR measured on at least 3 occasions over 2 weeks), or at Baseline. If outside of these limits at Screening or Baseline, HR should be repeated twice with at least 5 minutes between measurements
Any lifetime history of suicidal behavior as indicated by the C-SSRS
Current unstable psychiatric disorder, current active major depressive episode or an active major depressive episode in the past 6 months
Any suicidal ideation with intent with or without a plan at Screening or within 6 months of Screening (that is, answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS)
Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics within 2 years before Screening
Hypersensitivity to the study drug or any of the excipients
Intake of herbal preparations containing St. John's Wort within 5x the half-life before dosing
Any history of or concomitant medical condition that in the opinion of the investigator(s) would compromise the participant's ability to safely complete the study
Planned surgery that requires general, spinal, or epidural anesthesia that would take place during the study. Planned surgery which requires only local anesthesia and that can be undertaken as a day case without inpatient stay postoperatively need not result in exclusion if in the opinion of the investigator this operation does not interfere with study procedures and participant safety
Known to be human immunodeficiency virus (HIV) positive
Acute Epstein Barr virus (EBV) infection with a positive EBV Viral Capsid Antigen Antibody (VCA) IgM at Baseline
Known to be hepatitis B virus (HBV)-positive with a detectable HBV (for example, hepatitis B surface antigen \[HBsAg\] reactive) within 6 months before the 1st dose of study drug, or hepatitis C virus (HCV) positive with a detectable (for example, HCV ribonucleic acid (RNA) \[qualitative\]) viral load. Note: Participants who are HCV positive due to prior resolved disease can be enrolled, only if a confirmatory negative HCV RNA test is obtained and the participant has completed active treatment
Initiation of statin therapy, or a change to a different statin, or an increase in the dose of a statin within the 6 months before the planned start of study drug
History of formally diagnosed moderate to severe obstructive sleep apnea (OSA)
Current use of continuous positive airway pressure (CPAP), hypoglossal nerve stimulator, oral device, or other therapy for the treatment of OSA
Symptomatic restless legs syndrome
Apnea-hypopnea index >=15 on Screening PSG
Use of anticataplectic medications (including but not limited to antidepressants) within 5× the half-life before Screening
Use of psychostimulant medications, prescription and over-the-counter (OTC), within 5× the half-life before Screening until after the Follow-Up Visit. Examples of prohibited medications include OTC stimulants (for example, pseudoephedrine), methylphenidate, amphetamines, modafinil, armodafinil, sodium oxybate, pitolisant, solriamfetol, and pemoline
Use of sleep promoting or sedating medications, prescription and OTC, within 5x the half-life before Screening until after the Follow-Up Visit. Examples of prohibited medication include OTC sleep aids, trazodone, hypnotics, benzodiazepines, barbiturates,cannabinoids, melatonin, melatonin receptor agonists, dual orexin receptor antagonists, and opioids
Inability to discontinue use of strong (such as antifungal itraconazole and antibiotic clarithromycin) and moderate (such as antifungal fluconazole) Cytochrome P450 3A (CYP) 3A inhibitors within 5x the half-life before dosing until after the Follow-Up Visit
Inability to discontinue use of CYP3A inducers (such as antibiotic rifampicin and anti-convulsant phenytoin) within 5x the half-life before dosing until after the Follow-Up Visit
History of drug or alcohol dependency or abuse within 2 years before Screening, or those who have a positive urine drug test or breath (or urine) alcohol test at Screening or Baseline
Does not agree to abstain from use of recreational drugs during the study
Currently enrolled in another clinical study or used any investigational drug or device within 28 days or 5x the half-life, whichever is longer, preceding informed consent
Receipt of blood products within 4 weeks of dosing, donation of blood within 8 weeks of dosing, or donation of plasma within 1 week of dosing
Past participation in a study of an orexin agonist if discontinuation of orexin agonist use was related to an adverse drug reaction or inefficacy
ईसाई