Effect of Pulsatile GnRH Therapy on Cognition in Down Syndrome: Randomized Placebo Control Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Cognition
研究概览
简要总结
Down syndrome (DS) is the most common chromosomal disorder; with the increasing life expectancy, about 80% of DS adults reach age 65 years old. Early Alzheimer's disease (AD) is the most common cause of death within this population. DS individuals already show AD neuropathology by the age of 30, while it becomes clinically recognized in their late forties. DS subjects also exhibit olfaction defects in adulthood.
To date, there is no treatment available for the cognitive or olfactory defects in DS. The development of an effective treatment targeting cognitive dysfunction in DS adolescents/adults would be warranted.
GnRH, a decapeptide secreted by hypothalamic neurons is the pilot light of reproduction in all mammals. Pulsatile GnRH acts on the gonadotrophs via the GnRH receptor (GNRHR) in the pituitary gland to stimulate LH and FSH, which themselves will act on the gonads to produce gametes and steroids. However, GNRHR are also expressed in cerebral cortex, hippocampus, amygdala, habenula, olfactory structures, and adrenal gland, suggesting that GnRH may have a role beyond reproduction.
Recently, GnRH has been shown to be involved in the process of ageing and lifespan control. Notably, in murine models, GnRH acts as an anti-ageing factor, independent of sex hormones. While ageing is characterized by hypothalamic inflammation and diminished neurogenesis, particularly in the hypothalamus and the hippocampus, GnRH was able to promote adult neurogenesis.
The regulation of GnRH secretion is complex and involves hormonal, neuronal input, and environmental factors.
Prévot et al. recently explored cognition within the Ts65Dn model and showed an age-dependent loss of the ability to recognize new objects. Also, these mice exhibit defects in olfaction. Given the role of GnRH in anti-aging mice model, pulsatile GnRH or continuous GnRH infusion (leading to desensitization of the GNRHR) were given to the Ts65Dn mice for two weeks. Amazingly, pulsatile but not continuous GnRH therapy was able to recover cognitive and olfaction defects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 16 Years 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of trisomy 21
- •Verbal expression (ability to follow the procedures of the study)
- •Consent to a non-hormonal contraception during the whole duration of the study For women: intra-uterine device with copper, a prior tubal ligation or condoms for the partner For men: condoms or vasectomy
排除标准
- •Acute illness (clinical or biochemical findings suggesting acute illness/hospitalization)
- •Chronic alcohol abuse, illicit drug use, anabolic steroid abuse, psychotropic drugs reported by caregivers
- •Taking medication that modifies hormones: spironolactone, ketoconazole, anticoagulants, corticosteroids, ACTH hormone, psychotropics, including antidepressants, antipsychotics and anticonvulsants.
- •Known pituitary adenoma and other hormone-dependent tumours
- •Participation in another clinical study
- •Intention to become a parent during the course of the study
- •Females: ovarian cysts, non-hypothalamic anovulation (i.e. polycystic ovary syndrome), pregnancy or lactation
- •Males: hematocrit > 54%
- •Contraindications for MRI (e.g. pacemaker, metal clips,etc)
- •Participant or his/her legal representative do not want to be informed in case of incidental findings
研究组 & 干预措施
Pulsatile placebo pump treatment
干预措施: 0.9% NaCl (Drug)
Pulsatile GnRH pump treatment
干预措施: GnRH, gonadorelin acetate (Drug)
结局指标
主要结局
Cognition
时间窗: Baseline to end of treatment (Week 24)
Montreal Cognitive Assessment (MoCA) total score ranges between 0 and 30 (cut-off set at 26 for the healthy population) Higher scores reflect better performance.
次要结局
- Health-related quality of life SF-12(baseline to end of treatment (Week 24))
- Triglycerides(baseline to end of treatment (Week 24))
- Corsi block tapping task(baseline to end of treatment (Week 24))
- Dimensional change card sorting task (DCCS)(baseline to end of treatment (Week 24))
- Adaptive behavior (Vineland II) - caregiver questionnaire(baseline to end of treatment (Week 24))
- Insulinemia(baseline to end of treatment (Week 24))
- Low density lipoprotein (LDL)-cholesterol(baseline to end of treatment (Week 24))
- Token test(baseline to end of treatment (Week 24))
- Paired Associated Learning (PAL, part of the CANTAB battery)(baseline to end of treatment (Week 24))
- Litmus non-word-repetition test(baseline to end of treatment (Week 24))
- Total cholesterol(baseline to end of treatment (Week 24))
- Glycemia(baseline to end of treatment (Week 24))
- High density lipoprotein (HDL)-cholesterol(baseline to end of treatment (Week 24))
研究者
Nelly Pitteloud
Professor, Head of the Dpt of Endocrinology, Diabetology and Metabolism
Centre Hospitalier Universitaire Vaudois