GnRH Therapy on Cognition in Down Syndrome

NCT ID: NCT04390646

Last Updated: 2024-02-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-27
• Study Completion Date: 2028-12-31

Brief Summary

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Pulsatile GnRH pump treatment

Group Type: ACTIVE_COMPARATOR

GnRH, gonadorelin acetate

Intervention Type: DRUG

Drug administered by a subcutaneous pump

Pulsatile placebo pump treatment

Group Type: PLACEBO_COMPARATOR

0.9% NaCl

Intervention Type: DRUG

Drug administered by a subcutaneous pump

Interventions

GnRH, gonadorelin acetate

Drug administered by a subcutaneous pump

Intervention Type: DRUG

0.9% NaCl

Drug administered by a subcutaneous pump

Intervention Type: DRUG

Other Intervention Names

Lutrelef

Eligibility Criteria

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

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Nelly Pitteloud

OTHER

Sponsor Role: lead

Responsible Party

Nelly Pitteloud

Professor, Head of the Dpt of Endocrinology, Diabetology and Metabolism

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Nelly Pitteloud, MD

Role: PRINCIPAL_INVESTIGATOR

Endocrinology, Metabolism, Diabetology (CHUV)

Locations

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Canton of Vaud, Switzerland

Site Status: RECRUITING

Countries

Switzerland

Central Contacts

Pulse-UP study

Role: CONTACT

pulseup@chuv.ch

+41 21 314 06 25

Tommaso Todisco, MD

Role: CONTACT

tommaso.todisco@chuv.ch

+41 79 556 8513

Facility Contacts

Pulse-UP Study

Role: primary

pulseup@chuv.ch

+41 21 314 06 25

Tommaso Todisco, MD

Role: backup

tommaso.todisco@chuv.ch

+41 79 556 85 13

References

Manfredi-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.

Reference Type: RESULT

PMID: 36048943 (View on PubMed)

Related Links

https://www.chuv.ch/fr/edm/edm-home/recherche/etude-pulse-up-trisomie-21

CHUV - Etude Pulse-UP

Other Identifiers

700779

Identifier Type: OTHER

Identifier Source: secondary_id

2020-00270

Identifier Type: OTHER

Identifier Source: secondary_id

Pulse-UP

Identifier Type: -

Identifier Source: org_study_id