Skip to main content
OpenTrials
Recruiting

NCT Number: NCT04390646

GnRH Therapy on Cognition in Down Syndrome

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.

Recruiting

Interested in participating?

Request Info

Key information

Conditions

Down Syndrome Abnormalities, Multiple Alzheimer Disease Alzheimer Disease, Early Onset Brain Diseases Central Nervous System Diseases Chromosome Disorders Cognition Disorders Cognitive Decline Cognitive Dysfunction Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Dementia Genetic Diseases, Inborn Intellectual Disability Mental Disorders Nervous System Diseases Neurobehavioral Manifestations Neurocognitive Disorders Neurodegenerative Diseases Neurologic Manifestations Olfaction Disorders Pathological Conditions, Signs and Symptoms Sensation Disorders Signs and Symptoms Tauopathies

Age range

16 year–50 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

GnRH, gonadorelin acetate

Drug

Drug administered by a subcutaneous pump

Other names: Lutrelef

0.9% NaCl

Drug

Drug administered by a subcutaneous pump

Primary outcomes

  1. Cognition

    Time frame: 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.

Secondary outcomes

  1. Dimensional change card sorting task (DCCS)

    Time frame: baseline to end of treatment (Week 24)

    change in score of DCCS to assess executive functions

  2. Paired Associated Learning (PAL, part of the CANTAB battery)

    Time frame: baseline to end of treatment (Week 24)

    change in score of PAL to assess learning

  3. Token test

    Time frame: baseline to end of treatment (Week 24)

    change in score of Token test to assess verbal comprehension

  4. Corsi block tapping task

    Time frame: baseline to end of treatment (Week 24)

    change in score to assess visuospatial memory

  5. Litmus non-word-repetition test

    Time frame: baseline to end of treatment (Week 24)

    change in score of Litmus test to assess phonological abilities

  6. Health-related quality of life SF-12

    Time frame: baseline to end of treatment (Week 24)

    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.

  7. Adaptive behavior (Vineland II) - caregiver questionnaire

    Time frame: baseline to end of treatment (Week 24)

    change in score of Vineland II (normed assessment tool that assesses adaptive behavior across the areas of communication, activities of daily living, and socialization).

  8. Glycemia

    Time frame: baseline to end of treatment (Week 24)

    Glucose concentration (mmol/L) is a metabolic parameter.

  9. Insulinemia

    Time frame: baseline to end of treatment (Week 24)

    Insulin concentration (nmol/L) is a metabolic parameter.

  10. Total cholesterol

    Time frame: baseline to end of treatment (Week 24)

    Total cholesterol (mmol/L) is a metabolic parameter.

  11. High density lipoprotein (HDL)-cholesterol

    Time frame: baseline to end of treatment (Week 24)

    HDL-cholesterol (mmol/L) is a metabolic parameter.

  12. Low density lipoprotein (LDL)-cholesterol

    Time frame: baseline to end of treatment (Week 24)

    LDL-cholesterol (mmol/L) is a metabolic parameter.

  13. Triglycerides

    Time frame: baseline to end of treatment (Week 24)

    Triglycerides (mmol/L) is a metabolic parameter.

Study contacts

Contact information is provided by the study sponsor or research team.

Pulse-UP study

CONTACT

[email protected]

+41 21 314 06 25

Tommaso Todisco, MD

CONTACT

[email protected]

+41 79 556 8513

Sponsors and collaborators

Lead sponsor

Nelly Pitteloud

Other

Registry information

Official study title

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

Important dates

Study start
2020
Primary completion
2028
Study completion
2028
First posted
May 15, 2020
Registry last updated
Feb 12, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.