An Open-label Long-term Extension Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,148
- 主要终点
- Change From Study Baseline in Computerized Cognitive Battery Domain Score: Identification Test (IDN) Score
研究概览
简要总结
The purpose of this study is to assess the safety and tolerability of esketamine nasal spray in participants with treatment-resistant depression (TRD).
详细描述
This is an open-label (the researchers and participants know the treatment the participant is receiving) long-term extension study. The study will consist of 2 open-label Phases: 4-week Induction phase (if applicable) and Open-Label Optimization/Maintenance phase (variable). Participants will enter the study Induction Phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3005 (NCT02422186) and ESKETINTRD3006 (US sites only). Participants will enter the study Open-Label Optimization/Maintenance phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868) (if appropriate at week 16) or ESKETINTRD3006 (US sites only). In the Open-Label Induction Phase, participants will self-administer flexibly-dosed esketamine nasal spray. During first 4 weeks in Optimization/Maintenance Phase responder participants from the induction phase of study 54135419TRD3008, will continue on the same dose of esketamine nasal spray from the induction phase and have a weekly intranasal treatment session frequency. Participants entering the optimization/maintenance phase from study ESKETINTRD3005 will also have a weekly intranasal treatment session frequency. However, as the ESKETINTRD3005 intranasal study medication is blinded at the time of entry into the current study, the dose of esketamine nasal spray will be administered as outlined in protocol. Participants entering the optimization/maintenance phase from study ESKETINTRD3003 (Direct Entry) or ESKETINTRD3004 who were ongoing in the Optimization, Maintenance, or Optimization/Maintenance phase, respectively, will have the option to have their current intranasal dosing frequency adjusted at the time of entry into 54135419TRD3008 study and should remain on the selected frequency from week 1 to week 4. A one-time dose change will be permitted at study entry. After 4 weeks, esketamine nasal spray treatment sessions will be individualized to either once weekly or once every other week at the fixed 2-week interval (based on clinical global impression - severity [CGI-S] performed at that visit), and every 4 weeks for participants dosed at the 4 week interval. Participants safety will be monitored throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Based on the prior study the participant is entering 54135419TRD3008 from: a) From ESKETINTRD3001 (NCT02417064) or ESKETINTRD3002 (NCT02418585) study: Participant has completed the induction phase and the 2-weeks follow up phase visit; or Participants completed the induction phase and was a responder and study ESKETINTRD3003 is terminated.; b) From ESKETINTRD3003 (NCT02493868) study: (1) Participant relapsed during the maintenance phase; or (2) Participant was in the induction phase of the ESKETINTRD3003 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or (3) Participant was in the optimization or maintenance phases at the time the study was terminated; or (4) or (5) Participants was in the induction phase and after completion of induction phase was determined to not meet response criteria (1) Participant completed ESKETINTRD3004 study (optimization/maintenance phase); or (2) Participant was in the induction phase of the ESKETINTRD3004 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or (3) Participant was in the optimization/maintenance phase at the time the study was terminated; (4) Participant was in the induction phase and did not meet criteria for response may be eligible for to be rolled over into 54135419TRD
- •d) From ESKETINTRD3005 (NCT02422186) study: Participant was in the induction phase of the ESKETINTRD3005 study at the time enrollment into the ESKETINTRD3004 study was closed and, after completion of the induction phase, was determined to be a responder or did not meet the criteria for response. e) From ESKETINTRD3006 study (US Study sites only) (1) Participant completed the induction phase and was a responder.
- •Participant must be medically stable on the basis of physical examination, vital signs, pulse oximetry, and 12-lead Electrocardiogram (ECG) performed predose on the day of the first intranasal treatment session. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined by the investigator and recorded in the participant's source documents and initialed by the investigator
- •Participant must be medically stable according to the investigator's judgment and knowledge of the subject's medical stability in the parent study. This determination must be documented.
- •A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [b-hCG]) predose on the day of the first intranasal treatment session
- •During the study (that is, from the first intranasal treatment session) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of intranasal study medication, a man who is sexually active with a woman of childbearing potential must be practicing a highly effective method of contraception with his female partner c) must agree not to donate sperm.
排除标准
- •The evaluation of the benefit versus risk of continued esketamine nasal spray treatment is not favorable for the participant in the opinion of the investigator
- •Since the last study visit in the participant's prior study, participant has suicidal ideation with intent to act per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS) [corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) in the suicidal ideation module of the C-SSRS] or suicidal behavior per the investigator's clinical judgment or based on the C-SSRS (corresponding to any score higher than 0 in the suicidal behavior module of the C-SSRS)
- •Participant has positive test result(s) for drugs of abuse (including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) predose on the day of the first intranasal treatment session
- •Participant has any anatomical or medical condition that, per the investigator's clinical judgment based on assessment, may impede delivery or absorption of intranasal study drug
- •Participant has taken any prohibited therapies that would not permit administration of the first intranasal treatment session
研究组 & 干预措施
Esketamine Nasal Spray
Open-Label Induction Phase: Participants will self-administer with esketamine nasal spray twice per week for 4 weeks as a flexible dose regimen (56 milligram [mg] or 84 mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years). Participants >= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants entering from studies ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3004 (NCT02497287), or ESKETINTRD3006 (US sites only) will self-administer esketamine nasal spray (same dose) once weekly. Participants entering from study ESKETINTRD3005 (NCT02422186) will self-administer esketamine nasal spray (28 mg in week 1; 28 or 56 mg in week 2; and 28, 56 or 84 mg in week 3 and 4) once weekly. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants can be adjusted based upon efficacy and tolerability.
干预措施: Esketamine Nasal Spray (Drug)
结局指标
主要结局
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Identification Test (IDN) Score
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranged from 2 to 3.3 log 10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Card Learning Test (OCL) Score
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicated better performance. Higher change from baseline indicated better performance.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Back Test (ONB) Score
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Total score ranged from 2 to 3.54 log10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.
Change From Baseline in Systolic and Diastolic Blood Pressure
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change from baseline in systolic and diastolic blood pressure were reported.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Detection Test (DET) Score
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of subjects (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranged from 2 to 3.3 log 10 milliseconds (msec). Lower score indicated better performance. Higher change from baseline indicated better performance.
Change From Baseline in Respiratory Rate
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change from baseline in respiratory rate were reported.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Groton Maze Learning Test (GMLT) Score
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranged from 0 to 999 number of errors. Lower score indicated better performance. Higher change from baseline indicated better performance.
Change From Study Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
The HVLT-R measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0-12); the total number of true-positive errors (0-12); and the range of recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher total recall score indicated higher cognition. The range of the recognition discrimination index is -12 to 12. Higher score indicated better performance and higher change from baseline indicated better performance.
Change From Baseline in Heart Rate
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change from baseline (predose) in heart rate were reported.
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
C-SSRS: interview-based instrument to systematically assess suicidal ideation (SI) and behavior, to assess whether participant experienced any of following: completed suicide, suicide attempt (response of "yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active SI with methods without intent to act or some intent to act, without or with specific plan and intent), any self-injurious behavior with no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). Here, percentage of participants with \>=1 positive behavior, participants with \>=1 positive ideations; no event were reported.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: IND Phase: up to 4 weeks; OP/MA Phase: up to 78 months
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Any AE occurring at or after the initial administration of study intervention up to end of study was considered as treatment-emergent.
Change From Baseline in Blood Oxygen Saturation
时间窗: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change from baseline in blood oxygen saturation (predose) were reported.
次要结局
- Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score(IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months)
- Change From Baseline in Participant-Reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score(IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months)
- Change From Baseline in Clinical Global Impression-severity (CGI-S) Score(IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months)
- Change From Baseline as Assessed by EQ 5D-5L: Sum Score(IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months)
- Change From Baseline in Sheehan Disability Scale (SDS) Total Score(IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months)
- Change From Baseline in Participant-Reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Valuation Index Score (VAS)(IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months)
- Change From Baseline in Participant- Reported Health Related Quality of Life Using the Quality of Life in Depression Scale (QLDS)(IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months)