Double-blind Randomized Placebo Controlled Study on the Effect of Enoxolone ( 11-beta Hydroxysteroid-dehydrogenase Type 2 Inhibitor) on the RAAS, Autonomic and Imaging Biomarkers and the Outcome of Depression
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Plasma and urine aldosterone/cortisol ratio
研究概览
简要总结
Many different forms of depression exist. It is difficult to predict to what treatment a given patient with depression responds. Studies demonstrate that biomarkers can help to distinguish different forms of depression. Simple markers, like aldosterone/cortisol in body fluids, blood pressure and inflammation markers , have been identified as predictors of therapy resistance in depression. Enoxolone is a molecule derived from the licorice plant and has demonstrated an effect on these biomarkers, which may imply an improved response. The current randomized placebo controlled study is assessing whether the presence of markers of therapy resistance can predict a preferential effect of enoxolone vs. placebo on clinical outcome. Secondarily, it is tested whether these markers change differentially in the treatment groups. Finally, the relationship between the change of the markers and clinical change will be assessed.
详细描述
The objective of the study is 1. to confirm patient characteristics, which are related to lesser responsivity to antidepressant treatment and 2. to explore the utility of the 11-beta hydroxysteroid-dehydrogenase type 2 (11betaHSD2) and toll-like receptor (TLR)-4 inhibitor enoxolone to reverse these markers of refractoriness and, potentially, improve clinical outcome. A broad spectrum of patients is recruited in order to provide the opportunity to compare those with relevant markers of refractoriness vs. those without.
The identified markers are related to the activity of aldosterone, which appears to affect specific CNS areas, which are involved in mood and autonomic regulation. One area of particular relevance is the pontine nucleus of the solitary tract (NTS). Potential primary triggers for an increased aldosterone release under stressful conditions are related to low blood pressure, electrolyte alterations and a dysfunction of the peripheral mineralocorticoid receptor (MR). The resultant aldosterone release evokes activity at the NTS, which may lead to depression and anxiety.
Enoxolone leads to an activation primarily of the peripheral MR by reducing the activity of the 11betaHSD2, therefore allowing cortisol access to the MR and, as a consequence, suppress the release of renin, angiotensin and aldosterone. In addition, it can increase blood pressure slightly.
- A set of potentially predictive markers for therapy response of enoxolone vs. placebo will be studied, based on this mechanistic pathway, in detail:
For the primary analysis subjects are grouped into those with higher vs. lower systolic blood pressure values, as determined by the median systolic blood pressure value at baseline.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Active and Placebo Capsules of the same shape and size are utilized
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
- •Unipolar Depression
- •in women: Contraceptive means
排除标准
- •Schizophrenic and delusional disorders
- •Neurological diseases in which central nervous system involvement is known, such as epilepsies, storage diseases; severe mental retardation
- •Internistic diseases of moderate or higher severity, which may make participation in the study risky from a clinical point of view. In particular, multiple systolic blood pressure (measured after at least 5 min supine position) of > 145 mm Hg as well as hypokalemia (< 3.5 mmol/l) and clinically relevant ECG changes
- •Poorly controlled diabetes mellitus (HbA1c > 10)
- •Pregnancy or active desire for pregnancy for the duration of the study
- •Non-consent or inability to consent to the study
- •Treatment with the following substances: spironolactone or eplerenone; systemic glucocorticoids
- •Treatment with ketamine or electroconvulsive therapy in the last 3 months before randomization
- •Acute suicidality
- •Intolerance to licorice preparations or licorice contents.
研究组 & 干预措施
enoxolone
100 mg enoxolone in a capsule
干预措施: Enoxolone (Drug)
placebo
Placebo in a capsule
干预措施: Enoxolone (Drug)
结局指标
主要结局
Plasma and urine aldosterone/cortisol ratio
时间窗: Baseline, as predictor for differentiation of treatment groups clinical response
ratio of plasma aldosterone/cortisol at awakening; ratio of nocturnal urine aldosterone concentration/urine cortisol concentration
C-reactive protein
时间窗: Baseline, as predictor for differentiation of treatment groups clinical response and change from baseline (4 weeks)
C-reactive protein in plasma
Systolic blood pressure
时间窗: Baseline, as predictor for differentiation of treatment groups clinical response
Systolic blood pressure at rest at baseline as a predictor for treatment differentiation
Depression rating
时间窗: change from baseline to week 4, with systolic blood pressure as covariate
Hamilton depression rating scale (HAMD) - 17 items; higher is worse
次要结局
- Urine aldosterone/cortisol ratio(change from baseline to week 4)
- Plasma ratio of sodium/potassium(change from baseline to week 4)
- Nocturnal heart rate variability(change from baseline to week 4)
- Nocturnal blood pressure dip (difference between pre-sleep and minimal nocturnal blood pressure(change from baseline to week 4)
- Depression self rating(change from baseline to week 4)
- Total sleep duration(change from baseline to week 4)
- Salt taste preference and sensitivity(change from baseline to week 4)
- Rating for symptoms of normal pressure hydrocephalus(change from baseline to week 4)
研究者
Harald Murck
Apl. Professor
Philipps University Marburg