GnRH Therapy for Cognition in Down Syndrome (NCT04390646)

Overview

The GnRH Therapy on Cognition in Down Syndrome study (ClinicalTrials.gov identifier: NCT04390646) is an ongoing Phase 2/3 randomized, double-blind, placebo-controlled clinical trial investigating the effects of pulsatile [gonadotropin-releasing hormone](/entities/gnrh) (GnRH) therapy on cognitive function in adults with [Down Syndrome](/diseases/down-syndrome)[@clinicaltrialsgov]. The study is conducted at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland, under the leadership of Professor Nelly Pitteloud.

Overview

The GnRH Therapy on Cognition in Down Syndrome study (ClinicalTrials.gov identifier: NCT04390646) is an ongoing Phase 2/3 randomized, double-blind, placebo-controlled clinical trial investigating the effects of pulsatile [gonadotropin-releasing hormone](/entities/gnrh) (GnRH) therapy on cognitive function in adults with [Down Syndrome](/diseases/down-syndrome)[@clinicaltrialsgov]. The study is conducted at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland, under the leadership of Professor Nelly Pitteloud.

Down Syndrome is the most common chromosomal disorder, affecting approximately 1 in 700 births. With increasing life expectancy, approximately 80% of individuals with Down Syndrome now reach age 65 years["@clinicaltrialsgov"]. This population faces a dramatically elevated risk of early-onset [Alzheimer's disease](/diseases/alzheimers-disease), with neuropathology typically appearing by age 30 and clinical symptoms emerging in the late forties["@clinicaltrialsgov"]. Currently, no effective treatments exist for the cognitive or olfactory deficits in Down Syndrome.

Scientific Rationale

GnRH is a decapeptide hormone secreted by hypothalamic neurons that serves as the primary regulator of the reproductive axis. However, GnRH receptors ([GNRHR](/proteins/gnrhr)) are also expressed in brain regions beyond the pituitary, including the cerebral cortex, hippocampus, amygdala, habenula, olfactory structures, and adrenal gland[@clinicaltrialsgov]. This widespread expression suggests that GnRH may have functions extending beyond reproduction.

Recent research has demonstrated that GnRH plays a role in ageing and lifespan control. In murine models, GnRH has been shown to function as an anti-ageing factor independent of sex hormones. Ageing is characterized by hypothalamic inflammation and diminished neurogenesis, particularly in the hypothalamus and hippocampus. Notably, GnRH treatment was able to promote adult neurogenesis in these models[@clinicaltrialsgov].

Research by Prévot et al. explored cognition in the Ts65Dn mouse model of Down Syndrome, demonstrating an age-dependent loss of object recognition ability along with olfactory defects. When pulsatile GnRH therapy (but not continuous GnRH infusion) was administered for two weeks, both cognitive and olfactory defects were recovered[@prevot2020]. This preclinical evidence provided the foundation for the current clinical trial.

Study Design

Methodology

The study employs a multicentric randomized double-blind design with triple masking (participant, care provider, and investigator are all blinded)[@clinicaltrialsgov].

Key design parameters:

• Study Type: Interventional
• Phases: Phase 2 / Phase 3
• Allocation: Randomized
• Intervention Model: Parallel
• Masking: Triple-blind

Participants

The trial aims to enroll approximately 56 participants with the following conditions:

• Down Syndrome
• Cognitive Decline
• Early-onset Alzheimer's Disease
• Olfaction Disorders[@clinicaltrialsgov]

Interventions

| Arm | Type | Intervention |
|-----|------|---------------|
| Pulsatile GnRH pump treatment | Active Comparator | GnRH (gonadorelin acetate) administered via subcutaneous pump |
| Pulsatile placebo pump treatment | Placebo Comparator | 0.9% NaCl (saline) administered via subcutaneous pump |

The drug (Lutrelef, gonadorelin acetate) is delivered using a pulsatile pump system to mimic the natural physiological secretion pattern of GnRH[@clinicaltrialsgov].

Outcomes

Primary Outcome

| Measure | Time Frame |
|---------|------------|
| Cognition | Baseline to end of treatment (Week 24) |

Secondary Outcomes

Cognitive Assessments:

• Dimensional change card sorting task (DCCS): baseline to Week 24
• Paired Associated Learning (PAL, CANTAB battery): baseline to Week 24
• Token test: baseline to Week 24
• Corsi block tapping task: baseline to Week 24
• Litmus non-word-repetition test: baseline to Week 24

• Health-related quality of life SF-12: baseline to Week 24
• Adaptive behavior (Vineland II) caregiver questionnaire: baseline to Week 24

• Glycemia: baseline to Week 24
• Insulinemia: baseline to Week 24
• Total cholesterol: baseline to Week 24
• HDL-cholesterol: baseline to Week 24
• LDL-cholesterol: baseline to Week 24
• Triglycerides: baseline to Week 24[@clinicaltrialsgov]

Trial Status

| Parameter | Value |
|-----------|-------|
| Status | Recruiting |
| Start Date | August 27, 2020 |
| Primary Completion Date | December 2028 (estimated) |
| Completion Date | December 2028 (estimated) |
| Last Updated | February 9, 2024 |

Research Team and Location

Lead Sponsor/Principal Investigator:

• Nelly Pitteloud, Professor
• Head, Department of Endocrinology, Diabetology and Metabolism
• Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

• Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland[@clinicaltrialsgov]

Significance

This trial represents a novel therapeutic approach targeting a population with extremely high unmet medical needs. Individuals with Down Syndrome face near-universal development of Alzheimer's disease neuropathology by age 30, yet no approved treatments exist for their cognitive decline. The repurposing of GnRH—already approved for reproductive disorders—for cognitive enhancement in Down Syndrome could provide a transformative therapy if efficacy is demonstrated.

The trial also explores the relationship between GnRH and olfactory function, as smell deficits often precede cognitive decline in both Down Syndrome and Alzheimer's disease. If successful, this approach could potentially be extended to sporadic AD and other forms of cognitive decline associated with ageing.

References