GnRH Therapy on Cognition in Down Syndrome

NCTNCT04390646Other idPulse-UPOther id700779Other id2020-00270

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Overview

Status: Recruiting
Phase: Phase 2/3
Enrollment: 56 participants (estimated)
Sponsor: Nelly Pitteloud · Other
Design: Randomized · Triple masking
Countries: 1 country
Switzerland
Start: 27 Aug 2020
Primary completion: Dec 2028 (estimated)
Completion: Dec 2028 (estimated)
First posted: 15 May 2020
Last update posted: 12 Feb 2024
Conditions: Down Syndrome · Cognitive Decline · Alzheimer Disease, Early Onset · Olfaction Disorders

Timeline

1 trial · 1 ongoing

Completed
Ongoing
Not yet recruiting
Stopped
Estimated dates (est.)
Results posted

20202022202420262028

Ph 2/3
GnRH Therapy on Cognition in Down Syndrome
NCT04390646
27 Aug 2020 to est. Dec 2028

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

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.

Interventions

GnRH, gonadorelin acetateDrug
0.9% NaClDrug

Arms2

Active comparator
Pulsatile GnRH pump treatment
Placebo comparator
Pulsatile placebo pump treatment

Primary outcomes1

Outcomes the sponsor listed as primary.

Cognition
Time frame · Baseline to end of treatment (Week 24)
Registry description
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(13)

Dimensional change card sorting task (DCCS)
Time frame · baseline to end of treatment (Week 24)
Registry description
change in score of DCCS to assess executive functions
Paired Associated Learning (PAL, part of the CANTAB battery)
Time frame · baseline to end of treatment (Week 24)
Registry description
change in score of PAL to assess learning
Token test
Time frame · baseline to end of treatment (Week 24)
Registry description
change in score of Token test to assess verbal comprehension
Corsi block tapping task
Time frame · baseline to end of treatment (Week 24)
Registry description
change in score to assess visuospatial memory
Litmus non-word-repetition test
Time frame · baseline to end of treatment (Week 24)
Registry description
change in score of Litmus test to assess phonological abilities
Health-related quality of life SF-12
Time frame · baseline to end of treatment (Week 24)
Registry description
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.
Adaptive behavior (Vineland II) - caregiver questionnaire
Time frame · baseline to end of treatment (Week 24)
Registry description
change in score of Vineland II (normed assessment tool that assesses adaptive behavior across the areas of communication, activities of daily living, and socialization).
Glycemia
Time frame · baseline to end of treatment (Week 24)
Registry description
Glucose concentration (mmol/L) is a metabolic parameter.
Insulinemia
Time frame · baseline to end of treatment (Week 24)
Registry description
Insulin concentration (nmol/L) is a metabolic parameter.
Total cholesterol
Time frame · baseline to end of treatment (Week 24)
Registry description
Total cholesterol (mmol/L) is a metabolic parameter.
High density lipoprotein (HDL)-cholesterol
Time frame · baseline to end of treatment (Week 24)
Registry description
HDL-cholesterol (mmol/L) is a metabolic parameter.
Low density lipoprotein (LDL)-cholesterol
Time frame · baseline to end of treatment (Week 24)
Registry description
LDL-cholesterol (mmol/L) is a metabolic parameter.
Triglycerides
Time frame · baseline to end of treatment (Week 24)
Registry description
Triglycerides (mmol/L) is a metabolic parameter.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

No results are posted for this trial.

A trial that is still running, or that stopped early, may post results later.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies0

Studies that cite this trial.

No study cites this trial.

Other registry references

References listed at the registry that are not in PepBank. They link to PubMed.

ResultManfredi-Lozano M, Leysen V, Adamo M, Paiva I, Rovera R, Pignat JM, Timzoura FE, Candlish M, Eddarkaoui S, Malone SA, Silva MSB, Trova S, Imbernon M, Decoster L, Cotellessa L, Tena-Sempere M, Claret M, Paoloni-Giacobino A, Plassard D, Paccou E, Vionnet N, Acierno J, Maceski AM, Lutti A, Pfrieger F, Rasika S, Santoni F, Boehm U, Ciofi P, Buee L, Haddjeri N, Boutillier AL, Kuhle J, Messina A, Draganski B, Giacobini P, Pitteloud N, Prevot V. GnRH replacement rescues cognition in Down syndrome. Science. 2022 Sep 2;377(6610):eabq4515. doi: 10.1126/science.abq4515. Epub 2022 Sep 2. PMID 36048943

Eligibility

Who could join, as posted.

Sex: All
Age: from 16 Years up to 50 Years
Healthy volunteers: Not accepted

Inclusion and exclusion criteria, as posted

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

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