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GnRH Therapy on Cognition in Down Syndrome (Lutre-UP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04390646
Recruitment Status : Not yet recruiting
First Posted : May 15, 2020
Last Update Posted : May 15, 2020
Sponsor:
Information provided by (Responsible Party):
Nelly Pitteloud, Centre Hospitalier Universitaire Vaudois

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.


Condition or disease Intervention/treatment Phase
Down Syndrome Cognitive Decline Alzheimer Disease, Early Onset Olfaction Disorders Drug: GnRH, gonadorelin acetate Drug: 0.9% NaCl Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A pilot study (n=12) will be conducted to verify the feasibility and the efficacy of the therapy on cognition and olfaction in this population. A randomized clinical trial will follow the pilot study if at least one among the cognitive or olfactory scores will significantly improve (>=10%).
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Effect of Pulsatile GnRH Therapy on Cognition in Down Syndrome: Randomized Placebo Control Study
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : March 2024


Arm Intervention/treatment
Active Comparator: Pulsatile GnRH pump treatment Drug: GnRH, gonadorelin acetate
Drug administered by a subcutaneous pump during 24 weeks, at a dosage of 75 ng/kg/pulse giving a pulse every 90 minutes in women and every 120 minutes in men.
Other Name: Lutrelef

Placebo Comparator: Pulsatile placebo pump treatment Drug: 0.9% NaCl
Drug administered by a subcutaneous pump during 24 weeks, at a dosage of 75 ng/kg/pulse giving a pulse every 90 minutes in women and every 120 minutes in men.




Primary Outcome Measures :
  1. Cognition [ Time Frame: Baseline to end of treatment (Week 24) ]

    The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) includes 12 subtests that measure 5 indices:

    • Immediate Memory: List Learning (score 0-40), Story Memory (score 0-24)
    • Visuospatial/Construction Index: Figure Copy (score 0-20), Line Orientation (score 0-20)
    • Language: Picture Naming (score 0-10), Semantic Fluency (score in 60 sec)
    • Attention: Digit Span (score 0-16), Coding (score in 90 sec)
    • Delayed Memory: List Recall (score 0-10), Story Recall (score 0-12), List Recognition (score 0-20), Figure Recall (score 0-20)

    The sum of these 5 Index scores is converted to a Total Scale value via a mapping table. The Total Scale is a norm-based t score based on a distribution with a mean of 100 and standard deviation of 15.

    Higher scores reflect better performance.



Secondary Outcome Measures :
  1. Olfaction [ Time Frame: baseline to Week 12, and to the end of treatment (Week 24) ]

    The "Sniffin' Sticks" test is a widely used tool for assessment of olfactory performance consisting of three subtests: olfactory threshold (T), odor discrimination (D) and odor identification (I).

    Each subtest may be scored 1-16. The sum of the three score, the TDI, gives a score 3-48.

    Higher scores reflect better performance.

    Most recent normative data is on an sample of more than 9000 subjects. European Archives of Oto-Rhino-Laryngology (2019) 276:719-728 doi.org/10.1007/s00405-018-5248-1


  2. Amyloidosis [ Time Frame: baseline to Week 12, and to the end of treatment (Week 24) ]
    change in amyloidosis biomarkers (Aβ1-40, Aβ1-42, and truncated forms)

  3. Brain MRI [ Time Frame: baseline to the end of treatment (Week 24) ]
    change in brain MRI signals

  4. Health-related quality of life (HRQoL) [ Time Frame: baseline to Week 4, 12, and to the 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.

    A booklet "SF-12: How to score the SF-12 Physicial and Mental Health Summary Scales" by Ware, Kosinski and Keller contains the algorithm to be used for the scoring of the PCS and MCS components.



Other Outcome Measures:
  1. Glycemia [ Time Frame: baseline to Week 12, and to the end of treatment (Week 24) ]
    Glucose concentration (mmol/L) is a metabolic parameter.

  2. Insulinemia [ Time Frame: baseline to Week12, and to the end of treatment (Week 24) ]
    Insulin concentration (nmol/L) is a metabolic parameter.

  3. Leptinemia [ Time Frame: baseline to Week 12, and to the end of treatment (Week 24) ]
    Leptin concentration (µg/L) is a metabolic parameter.

  4. Glycated hemoglobin (HbA1c) [ Time Frame: baseline to Week 24 ]
    Glycated hemoglobin (mmol/mol and %) is a metabolic parameter.

  5. Interleukin-6 (IL-6) [ Time Frame: baseline to Week 24 ]
    IL-6 (pg/mL) is an inflammatory mediator.

  6. Interferon-alfa (IFN-a) [ Time Frame: baseline to Week 24 ]
    IFN-a (pg/mL) is an inflammatory mediator.

  7. Tumor necrosis factor- alfa (TNF-a) [ Time Frame: baseline to Week 24 ]
    TNF-a (pg/mL) is an inflammatory mediator.

  8. Total cholesterol [ Time Frame: baseline to Week 24 ]
    Total cholesterol (mmol/L) is a metabolic parameter.

  9. High density lipoprotein (HDL)-cholesterol [ Time Frame: baseline to Week 24 ]
    HDL-cholesterol (mmol/L) is a metabolic parameter.

  10. Low density lipoprotein (LDL)-cholesterol [ Time Frame: baseline to Week 24 ]
    LDL-cholesterol (mmol/L) is a metabolic parameter.

  11. Triglycerides [ Time Frame: baseline to Week 24 ]
    Triglycerides (mmol/L) is a metabolic parameter.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Participant eligibility is based on self-representation of gender identity.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of trisomy 21
  • Ability to follow the procedures of the study
  • Olfactory impairment (Sniffin' Sticks, identification score: for men ≤11, for women ≤12)
  • Consent to a non-hormonal contraception during the whole duration of the study

Exclusion Criteria:

  • Clinical or biochemical findings suggesting acute illness/hospitalization
  • Chronic alcohol abuse, illicit drug use, or anabolic steroid abuse
  • Pituitary adenoma and other hormone-dependent tumours
  • Participation in another clinical study
  • Intention to become a parent during the course of the study
  • Pregnant or breastfeeding women
  • Participant or his/her legal representative do not want to be informed in case of incidental findings

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04390646


Contacts
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Contact: Michela Adamo, MD +41 79 556 85 14 michela.adamo@chuv.ch
Contact: Emmanuelle Paccou +41 79 556 60 13 emmanuelle.paccou@chuv.ch

Locations
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Switzerland
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Vaud, Switzerland, 1011
Contact: Michela Adamo, MD    +41 79 556 85 14    michela.adamo@chuv.ch   
Contact: Emmanuelle Paccou, RN    +41 79 556 60 13    emmanuelle.paccou@chuv.ch   
Principal Investigator: Nelly Pitteloud, M.D.         
Sponsors and Collaborators
Nelly Pitteloud
Investigators
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Principal Investigator: Nelly Pitteloud, MD Endocrinology, Metabolism, Diabetology (CHUV)
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Responsible Party: Nelly Pitteloud, Professor, Head of the Dpt of Endocrinology, Diabetology and Metabolism, Centre Hospitalier Universitaire Vaudois
ClinicalTrials.gov Identifier: NCT04390646    
Other Study ID Numbers: 2020-00270
First Posted: May 15, 2020    Key Record Dates
Last Update Posted: May 15, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nelly Pitteloud, Centre Hospitalier Universitaire Vaudois:
GnRH
Additional relevant MeSH terms:
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Alzheimer Disease
Down Syndrome
Olfaction Disorders
Syndrome
Cognitive Dysfunction
Disease
Pathologic Processes
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Sensation Disorders
Signs and Symptoms
Prolactin Release-Inhibiting Factors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs