Down SyndromePhase 2/3NCT04390646
GnRH Therapy on Cognition in Down Syndrome
A Phase 2/3 study testing GnRH, gonadorelin acetate and 0.9% NaCl in people with Down Syndrome and Cognitive Decline, run by Nelly Pitteloud at 1 site in Switzerland.
Trial 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. Read more about this study
- Who is it for?
- Ages 16 to 50 years
- Conditions the study is for
- Down Syndrome, Cognitive Decline, Alzheimer Disease, Early Onset
- What is being tested?
- GnRH, gonadorelin acetate and 0.9% NaCl
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 56 participants
- Where
- 1 siteSwitzerland
- Study dates
- 27 Aug 2020to Dec 2028
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 50 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Switzerland1 site, 1 recruiting
- Recruiting
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Canton of Vaud, 1011
Pulse-UP Study, +41 21 314 06 25, pulseup@chuv.ch
Tommaso Todisco, MD, +41 79 556 85 13, tommaso.todisco@chuv.ch
About this study
Official title: 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.
Read more
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.
- Being tested
- GnRH, gonadorelin acetate, 0.9% NaCl
- Keywords
- GnRH
- Medical subject headings
- Down Syndrome, Cognitive Dysfunction, Alzheimer Disease, Olfaction Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GnRH, gonadorelin acetateDrug
Also called Lutrelef
Drug administered by a subcutaneous pump
0.9% NaClDrug
Drug administered by a subcutaneous pump
| Study group | Role | What they receive |
|---|---|---|
| Pulsatile GnRH pump treatment | Active comparator | Not described Receives: Drug: GnRH, gonadorelin acetate |
| Pulsatile placebo pump treatment | Placebo comparator | Not described Receives: Drug: 0.9% NaCl |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to end of treatment (Week 24)
Secondary outcomes (13)
Dimensional change card sorting task (DCCS)
change in score of DCCS to assess executive functions
Measured: baseline to end of treatment (Week 24)
Paired Associated Learning (PAL, part of the CANTAB battery)
change in score of PAL to assess learning
Measured: baseline to end of treatment (Week 24)
Token test
change in score of Token test to assess verbal comprehension
Measured: baseline to end of treatment (Week 24)
Corsi block tapping task
change in score to assess visuospatial memory
Measured: baseline to end of treatment (Week 24)
Litmus non-word-repetition test
change in score of Litmus test to assess phonological abilities
Measured: 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.
Measured: 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).
Measured: baseline to end of treatment (Week 24)
Glycemia
Glucose concentration (mmol/L) is a metabolic parameter.
Measured: baseline to end of treatment (Week 24)
Insulinemia
Insulin concentration (nmol/L) is a metabolic parameter.
Measured: baseline to end of treatment (Week 24)
Total cholesterol
Total cholesterol (mmol/L) is a metabolic parameter.
Measured: baseline to end of treatment (Week 24)
High density lipoprotein (HDL)-cholesterol
HDL-cholesterol (mmol/L) is a metabolic parameter.
Measured: baseline to end of treatment (Week 24)
Low density lipoprotein (LDL)-cholesterol
LDL-cholesterol (mmol/L) is a metabolic parameter.
Measured: baseline to end of treatment (Week 24)
Triglycerides
Triglycerides (mmol/L) is a metabolic parameter.
Measured: baseline to end of treatment (Week 24)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 May 2020
- Study start27 Aug 2020
- Primary completionDec 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Down SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Multicentric randomized double-blind clinical trial
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 56 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Nelly Pitteloud
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Nelly Pitteloud, Centre Hospitalier Universitaire Vaudois
- Investigators
- Nelly Pitteloud, MD, Principal investigator, Endocrinology, Metabolism, Diabetology (CHUV)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04390646
- Sponsor's protocol ID
- Pulse-UP
- Other IDs
- 700779, 2020-00270
- Status last verified
- Feb 2024
- First submitted
- 5 May 2020
- Last updated
- 12 Feb 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
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.
PubMed 36048943
Study at a glance
From the registry record, last updated by the sponsor on 12 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Pulsatile GnRH Therapy on Cognition in Down Syndrome: Randomized Placebo Control Study
- ClinicalTrials.gov ID
- NCT04390646
- Acronym / sponsor ID
- Pulse-UP
- Keywords
- GnRH
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 56 participants (estimated)
- Lead sponsor
- Nelly PitteloudUniversity, hospital or other
- Study start
- 27 Aug 2020 (actual)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 15 May 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Multicentric randomized double-blind clinical trial
| Arm | Type | Receives |
|---|---|---|
| Pulsatile GnRH pump treatment | Active comparator | Drug: GnRH, gonadorelin acetate |
| Pulsatile placebo pump treatment | Placebo comparator | Drug: 0.9% NaCl |
Who may qualify
- Ages
- 16 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GnRH, gonadorelin acetateAlso: LutrelefDrug administered by a subcutaneous pump | Drug | Pulsatile GnRH pump treatment |
| 0.9% NaClDrug administered by a subcutaneous pump | Drug | Pulsatile placebo pump treatment |
Primary outcome
Cognition
Time frame: Baseline to end of treatment (Week 24)
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.
13 secondary outcomes
Dimensional change card sorting task (DCCS)
Time frame: baseline to end of treatment (Week 24)
Paired Associated Learning (PAL, part of the CANTAB battery)
Time frame: baseline to end of treatment (Week 24)
Token test
Time frame: baseline to end of treatment (Week 24)
Corsi block tapping task
Time frame: baseline to end of treatment (Week 24)
Litmus non-word-repetition test
Time frame: baseline to end of treatment (Week 24)
Health-related quality of life SF-12
Time frame: baseline to end of treatment (Week 24)
Adaptive behavior (Vineland II) - caregiver questionnaire
Time frame: baseline to end of treatment (Week 24)
Glycemia
Time frame: baseline to end of treatment (Week 24)
Insulinemia
Time frame: baseline to end of treatment (Week 24)
Total cholesterol
Time frame: baseline to end of treatment (Week 24)
High density lipoprotein (HDL)-cholesterol
Time frame: baseline to end of treatment (Week 24)
Low density lipoprotein (LDL)-cholesterol
Time frame: baseline to end of treatment (Week 24)
Triglycerides
Time frame: baseline to end of treatment (Week 24)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Feb 2024.
- Results publication: PubMed 36048943Manfredi-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.
- CHUV - Etude Pulse-UPLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Nelly Pitteloud, MD principal investigator
Endocrinology, Metabolism, Diabetology (CHUV)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing GnRH, gonadorelin acetate and 0.9% NaCl in people with Down Syndrome and Cognitive Decline, run by Nelly Pitteloud at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 12 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Pulse-UP study (+41 21 314 06 25, pulseup@chuv.ch), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cognition (time frame: Baseline to end of treatment (Week 24)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04390646, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Feb 2024.