GnRH Therapy on Cognition in Down Syndrome

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

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.

Study Overview

• Status: Recruiting
• Conditions: Down Syndrome; Cognitive Decline; Alzheimer Disease, Early Onset; Olfaction Disorders
• Intervention / Treatment: Drug: GnRH, gonadorelin acetate; Drug: 0.9% NaCl

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Pulse-UP Study; Phone Number: +41 21 314 06 25; Email: pulseup@chuv.ch
• Study Contact Backup: Name: Tommaso Todisco, MD; Phone Number: +41 79 556 8513; Email: tommaso.todisco@chuv.ch

Study Locations

• Switzerland
  • Vaud
    • Lausanne, Vaud, Switzerland, 1011
      • Recruiting
      • Centre Hospitalier Universitaire Vaudois (CHUV)
      • Contact: Pulse-UP Study; Phone Number: +41 21 314 06 25; Email: pulseup@chuv.ch
      • Contact: Tommaso Todisco, MD; Phone Number: +41 79 556 85 13; Email: tommaso.todisco@chuv.ch
      • Principal Investigator: Nelly Pitteloud, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 48 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pulsatile GnRH pump treatment	Drug: GnRH, gonadorelin acetate; Drug administered by a subcutaneous pump; Other Names: Lutrelef
Placebo Comparator: Pulsatile placebo pump treatment	Drug: 0.9% NaCl; Drug administered by a subcutaneous pump

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycemia	Glucose concentration (mmol/L) is a metabolic parameter.	baseline to Week 12, and to the end of treatment (Week 24)
Insulinemia	Insulin concentration (nmol/L) is a metabolic parameter.	baseline to Week12, and to the end of treatment (Week 24)
Leptinemia	Leptin concentration (µg/L) is a metabolic parameter.	baseline to Week 12, and to the end of treatment (Week 24)
Glycated hemoglobin (HbA1c)	Glycated hemoglobin (mmol/mol and %) is a metabolic parameter.	baseline to Week 24
Interleukin-6 (IL-6)	IL-6 (pg/mL) is an inflammatory mediator.	baseline to Week 24
Interferon-alfa (IFN-a)	IFN-a (pg/mL) is an inflammatory mediator.	baseline to Week 24
Tumor necrosis factor- alfa (TNF-a)	TNF-a (pg/mL) is an inflammatory mediator.	baseline to Week 24
Total cholesterol	Total cholesterol (mmol/L) is a metabolic parameter.	baseline to Week 24
High density lipoprotein (HDL)-cholesterol	HDL-cholesterol (mmol/L) is a metabolic parameter.	baseline to Week 24
Low density lipoprotein (LDL)-cholesterol	LDL-cholesterol (mmol/L) is a metabolic parameter.	baseline to Week 24
Triglycerides	Triglycerides (mmol/L) is a metabolic parameter.	baseline to Week 24

Collaborators and Investigators

• Sponsor: Nelly Pitteloud
• Investigators: Principal Investigator: Nelly Pitteloud, MD, Endocrinology, Metabolism, Diabetology (CHUV)

Publications and helpful links

General Publications

• 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.

Helpful Links

• CHUV - Etude Pulse-UP
• Kofam - Etude Pulse-UP

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2020
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: May 5, 2020
• First Submitted That Met QC Criteria: May 13, 2020
• First Posted (Actual): May 15, 2020

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: GnRH
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Intellectual Disability; Dementia; Tauopathies; Cognition Disorders; Sensation Disorders; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Alzheimer Disease; Cognitive Dysfunction; Down Syndrome; Olfaction Disorders; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Prolactin Release-Inhibiting Factors
• Other Study ID Numbers: Pulse-UP; 2020-00270 (Other Identifier: Swissethics); 700779 (Other Identifier: Swissmedic)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No