An Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression
概览
- 阶段
- 2 期
- 干预措施
- (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg)
- 疾病 / 适应症
- Suicide
- 发起方
- National Institute of Mental Health (NIMH)
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Change from baseline on Montgomery-Asberg Depression Rating Scale total scores
- 状态
- 招募中
- 最后更新
- 16天前
概览
简要总结
Background:
Major depressive disorder (MDD) is a serious mental illness that can put people at risk of self-harm and death. Many drugs are used to treat MDD, but it can take a long time for them to be effective. Researchers want to know if a faster-acting drug, (2R,6R)-hydroxynorketamine (HNK), can better treat the symptoms of MDD.
Objective:
To test a study drug (HNK) in people with MDD.
Eligibility:
People aged 18 to 70 years with MDD. They must have had a screening assessment under protocol 01-M-0254.
Design:
Participants will be tapered off their current MDD drugs over 2 to 5 weeks. They will stay off of the drugs for up to 2 weeks prior to starting the study medication and procedures. They will have a physical exam with blood tests. They will have tests of their heart function, mood, and thinking. They will answer questions about their symptoms. They may choose to have imaging scans and scans of their brain activity.
HNK is given through a tube attached to a needle inserted into a vein. Participants will receive infusions on this schedule:
They will receive 4 infusions over 2 weeks. They will stay in the clinical center overnight after each infusion or for the duration of the study.
They will receive no drugs for 2 to 3 weeks.
They will have 4 more infusions over 2 weeks, with overnight stays after each or for the duration of the study.
One set of 4 infusions will be the HNK. The other set of 4 infusions will be a placebo. A placebo looks just like the real drug but contains no medicine. Participants will not know when they are getting the HNK or placebo.
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详细描述
Study Description This is a randomized, double-blind, placebo-controlled, crossover, single-site study. This experimental study will assess the efficacy and safety of two weeks of 0.25 to 2.0 mg/kg (2R,6R)-hydroxynorketamine (HNK), an enhancer of synaptic glutamate release. The study may be conducted on an inpatient or outpatient basis. Objectives Primary Objective The primary objective is to evaluate the ability of (2R,6R)-HNK, an enhancer of synaptic glutamate release, to improve overall depressive symptomatology in participants with major depressive disorder (MDD). The efficacy of a two-week course of (2R,6R)-HNK will be compared to two weeks of saline placebo in a crossover study. Montgomery-Asberg Depression Rating Scale (MADRS) score will serve as the main outcome measure. Secondary Objectives 1. To evaluate the antidepressant efficacy of (2R,6R)-HNK at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12 compared to placebo in a crossover study, as assessed by change from baseline on MADRS total scores. 2. To determine whether (2R,6R)-HNK demonstrates superior antidepressant efficacy compared to placebo in a crossover study, as assessed by the proportion of participants in remission (defined as MADRS total score \<=10). 3. To determine whether antidepressant response to (2R,6R)-HNK is superior to response to placebo in a crossover study, as assessed by the proportion of participants achieving response (defined as a \>=50% reduction from baseline in MADRS total score). 4. To evaluate the antisuicidal ideation effects of (2R,6R)-HNK at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12 compared to placebo in a crossover study, as assessed by change from baseline on item 10 (suicidality) of the MADRS, the Columbia Suicide Severity Rating Scale (C-SSRS), and the Scale for Suicide Ideation (SSI). 5. To investigate the effects of (2R,6R)-HNK on mood, anxiety, and anhedonia symptoms at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12 compared to placebo in a crossover study, as assessed by change from baseline on the Beck Depression Inventory Second Edition (BDI-II), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HAM-A), Positive and Negative Affect Schedule (PANAS), Snaith-Hamilton Pleasure Scale (SHAPS), and the Temporal Experience of Pleasure Scale (TEPS), as well as change from baseline on various cognitive tasks (Auditory, Somatosensory, and Visual Evoked Fields Task, Monetary Incentive Delay (MID) task, Hariri Hamer task, and Probabilistic Reward Task (PRT)). 6. To assess the safety and tolerability of a two-week course of (2R,6R)-HNK compared to placebo in a crossover study by incidence of adverse events (AEs) and total scores on the Clinician Administered Dissociative States Scale (CADSS), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), vital signs, changes in clinical laboratory evaluations, and electrocardiograms (ECGs). 7. To assess the analgesic efficacy of (2R,6R)-HNK compared to placebo on days -1, 1, 4, 8, and 11, as assessed by pain measures during quantitative sensory testing and brain-based biomarkers for pain measured with fMRI on day 4 and day 11. Endpoints Endpoints Primary Endpoint Effect of drug on the MADRS total score at day 12. Secondary Endpoints * Proportion of subjects in remission (defined as MADRS total score \<=10) at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12. * Proportion of subjects with response (defined as \>=50% reduction from baseline in MADRS total score) at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12. * Effect of drug on MADRS total scores at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12. * Effect of drug on HDRS, BDI-II, BPRS, CADSS, C-SSRS, HAM-A, PANAS, SHAPS, SSI, TEPS, and YMRS total scores, and the MADRS item 10 (suicidality) at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11 and 12. * Effect of drug on the Auditory, Somatosensory, and Visual Evoked Fields Task, MID task, Hariri Hamer task, and PRT. * Incidence and nature of adverse events; vital signs; weight and body mass index (BMI) changes; physical examination changes; clinical laboratory evaluations; ECG. * Effect of drug on acute pain measures derived from Quantitative Sensory Testing (QST) at days -1, 1, 4, 8, and 11. Surrogate Markers of Drug Effect, Target Engagement, and Antidepressant Response * Change in magnetoencephalography (MEG) spectral power (gamma power). * Change in brain glutamate levels using magnetic resonance spectroscopy (MRS). * Change in resting and task-based functional connectivity in functional magnetic resonance imaging (fMRI). * Change in peripheral biomarkers. * Change in brain-based biomarkers for pain.
研究者
入排标准
入选标准
- •INCLUSION CRITERIA:
- •In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- •Ability of participant to understand and willingness to sign a written informed consent document. To verify this, participants must score \>= 80% on the consent quiz.
- •Stated willingness to comply with all study procedures and availability for the duration of the study.
- •18 to 70 years of age.
- •All participants must have undergone a screening assessment under protocol 01-M-
- •Participants must fulfill DSM-IV or DSM-5 criteria for MDD, single episode or recurrent without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). Participants must be experiencing a current major depressive episode lasting at least two weeks.
- •Participants must have an initial score of \>= 20 on the MADRS and a YMRS score of \<12 within one week of study entry and upon entry into Phase II.
- •Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen.
- •Participants must have a current or past history of lack of response to at least one adequate antidepressant trial (may be from the same chemical class), with at least one in the current major depressive episode, operationally defined using the modified Antidepressant Treatment History Form (ATHF); non-response to an adequate trial of ECT or TMS would count as an adequate antidepressant trial.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Current use of disallowed concomitant medications or transcranial magnetic stimulation (TMS) two weeks prior to the start of Phase II.
- •Treatment with a reversible monoamine oxidase inhibitor (MAOI) four weeks prior to the start of Phase II.
- •Treatment with fluoxetine, aripiprazole, or brexpiprazole five weeks prior to the start of Phase II.
- •Treatment with clozapine or electroconvulsive therapy (ECT) four weeks prior to the start of Phase II.
- •Ongoing treatment with moderate or strong CYP3A4/5 inhibitors or inducers
- •Lifetime history of deep brain stimulation.
- •Previous antidepressant non-response to ketamine or esketamine (full course).
- •No structured psychotherapy will be permitted during the total duration of the study. Participants unable or unwilling to stop psychotherapy will be unable to participate in the study.
- •Pregnancy or lactation.
研究组 & 干预措施
1
Individuals in Arm 1 will receive double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1 and daily double-blinded placebo infusions four times over two weeks during Test Session 2. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise.
干预措施: (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg)
1
Individuals in Arm 1 will receive double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1 and daily double-blinded placebo infusions four times over two weeks during Test Session 2. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise.
干预措施: Placebo
2
Individuals in Arm 2 will receive double-blinded placebo infusions four times over two weeks during Test Session 2 and double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise.
干预措施: (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg)
2
Individuals in Arm 2 will receive double-blinded placebo infusions four times over two weeks during Test Session 2 and double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise.
干预措施: Placebo
结局指标
主要结局
Change from baseline on Montgomery-Asberg Depression Rating Scale total scores
时间窗: Baseline, Day 12
Clinical rating scale of depression
次要结局
- Change from baseline on the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Positive and Negative Affect Schedule, Snaith-Hamilton Pleasure Scale, Temporal Experience of Pleasure Scale, and cognitive tasks.(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Incidence of AEs and total scores using the Clinician Administered Dissociative States Scale, Young Mania Rating Scale, Brief Psychiatric Rating Scale, vital signs, changes in clinical laboratory evaluations, and electrocardiograms.(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Change from baseline on Montgomery-Asberg Depression Rating Scale total scores(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Proportion of participants in remission (defined as Montgomery-Asberg Depression Rating Scale total score =10)(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Proportion of participants achieving response (defined as a >/=50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score)(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Change from baseline on item 10 (suicidality) of the Montgomery-Asberg Depression Rating Scale and total score on the Columbia Suicide Severity Rating Scale and the Scale for Suicide Ideation.(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Incidence of AEs and total scores using the Clinician Administered Dissociative States Scale, Young Mania Rating Scale, Brief Psychiatric Rating Scale, vital signs, changes in clinical laboratory evaluations, and electrocardiograms.(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Change from baseline on the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Positive and Negative Affect Schedule, Snaith-Hamilton Pleasure Scale, Temporal Experience of Pleasure Scale, and cognitive tasks.(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Change from baseline on item 10 (suicidality) of the Montgomery-Asberg Depression Rating Scale and total score on the Columbia Suicide Severity Rating Scale and the Scale for Suicide Ideation.(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Proportion of participants achieving response (defined as a >/=50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score)(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Proportion of participants in remission (defined as Montgomery-Asberg Depression Rating Scale total score =10)(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Change from baseline on Montgomery-Asberg Depression Rating Scale total scores(Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session.)
- Pain thresholds and tolerance during quantitative sensory testing.(Baseline and Days 1, 4, 8, and 11, per Test Session.)
- Pain thresholds and tolerance during quantitative sensory testing while undergoing fMRI.(Days 4 and 11, per Test Session)