GnRH Therapy on Cognition in Down Syndrome

Study Overview
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Brief Summary
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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.

Official Title
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Effect of Pulsatile GnRH Therapy on Cognition in Down Syndrome: Randomized Placebo Control Study

Conditions
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Down Syndrome, Cognitive Decline, Alzheimer Disease, Early Onset, Olfaction Disorders

Intervention / Treatment
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* Drug: GnRH, gonadorelin acetate
* Drug: 0.9% NaCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentric randomized double-blind clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pulsatile GnRH pump treatment<br> | Drug: GnRH, gonadorelin acetate<br>* Drug administered by a subcutaneous pump<br>* Other names: Lutrelef;|
| Placebo Comparator: Pulsatile placebo pump treatment<br> | Drug: 0.9% NaCl<br>* Drug administered by a subcutaneous pump<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition | 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. | Baseline to end of treatment (Week 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dimensional change card sorting task (DCCS) | change in score of DCCS to assess executive functions | baseline to end of treatment (Week 24) | 
| Paired Associated Learning (PAL, part of the CANTAB battery) | change in score of PAL to assess learning | baseline to end of treatment (Week 24) | 
| Token test | change in score of Token test to assess verbal comprehension | baseline to end of treatment (Week 24) | 
| Corsi block tapping task | change in score to assess visuospatial memory | baseline to end of treatment (Week 24) | 
| Litmus non-word-repetition test | change in score of Litmus test to assess phonological abilities | baseline to end of treatment (Week 24) | 
| Health-related quality of life SF-12 | The health-related quality of life (HRQoL) can be used to measure the effects of healthcare interventions and provide quality-improvement outcomes. The Short Form-12 (SF-12) Health Survey is widely used in measuring HRQoL. SF-12 is a reliable, valid measure in a variety of population groups; it is an equivalent substitute for the SF-36v2 for the summary scales. The response to each of the 12 items is weighted separately by the physical and mental component summary (PCS and MCS) regression coefficients and then calculated to give the SF-12 PCS and MCS scores. | baseline to end of treatment (Week 24) | 
| Adaptive behavior (Vineland II) - caregiver questionnaire | change in score of Vineland II (normed assessment tool that assesses adaptive behavior across the areas of communication, activities of daily living, and socialization). | baseline to end of treatment (Week 24) | 
| Glycemia | Glucose concentration (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) | 
| Insulinemia | Insulin concentration (nmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) | 
| Total cholesterol | Total cholesterol (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) | 
| High density lipoprotein (HDL)-cholesterol | HDL-cholesterol (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) | 
| Low density lipoprotein (LDL)-cholesterol | LDL-cholesterol (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) | 
| Triglycerides | Triglycerides (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GnRH