GnRH Therapy on Cognition in Down Syndrome

NCT04390646 | Recruiting Phase 2 DMC

• 3 other identifiers: Pulse-UP7007792020-00270
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

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

Keywords

GnRH

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Dimensional change card sorting task (DCCS)

  baseline to end of treatment (Week 24)

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

  baseline to end of treatment (Week 24)

• Token test

  baseline to end of treatment (Week 24)

• Corsi block tapping task

  baseline to end of treatment (Week 24)

• Litmus non-word-repetition test

  baseline to end of treatment (Week 24)

Study Arms (2)

Pulsatile GnRH pump treatment

ACTIVE COMPARATOR

Drug: GnRH, gonadorelin acetate

Pulsatile placebo pump treatment

PLACEBO COMPARATOR

Drug: 0.9% NaCl

Interventions

GnRH, gonadorelin acetate DRUG

Drug administered by a subcutaneous pump

Also known as: Lutrelef

Pulsatile GnRH pump treatment

0.9% NaCl DRUG

Drug administered by a subcutaneous pump

Pulsatile placebo pump treatment

Eligibility Criteria

• Age: 16 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Nelly Pitteloud: lead

Study Sites (1)

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Canton of Vaud, 1011, Switzerland

RECRUITING

Related Publications (1)

• 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.

  PMID: 36048943 RESULT

Related Links

• CHUV - Etude Pulse-UP

MeSH Terms

Conditions

Down Syndrome; Cognitive Dysfunction; Alzheimer Disease; Olfaction Disorders

Interventions

Gonadotropin-Releasing Hormone; Saline Solution

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Dementia; Brain Diseases; Central Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Sensation Disorders; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Nelly Pitteloud, MD

  Endocrinology, Metabolism, Diabetology (CHUV)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Pulse-UP study

CONTACT

+41 21 314 06 25; pulseup@chuv.ch

Tommaso Todisco, MD

CONTACT

+41 79 556 8513; tommaso.todisco@chuv.ch

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Head of the Dpt of Endocrinology, Diabetology and Metabolism

Model Details: Multicentric randomized double-blind clinical trial

Study Record Dates

• First Submitted: May 5, 2020
• First Posted: May 15, 2020
• Study Start: August 27, 2020
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: February 12, 2024

Record last verified: 2024-02

Locations

CH (1)