Piromelatine 20 mg for Mild Dementia Due to Alzheimer's Disease (NCT05267535)

Overview

Overview

Study Title: Piromelatine 20 mg in Participants With Mild Dementia Due to Alzheimer's Disease NCT Identifier: [NCT05267535](https://clinicaltrials.gov/study/NCT05267535) Phase: Phase 2/3 Status: Active, not recruiting Sponsor: Neurim Pharmaceuticals Ltd. Org Study ID: NEUP11-7 Study Type: Interventional Allocation: Randomized Enrollment: 225 participants Study Start: May 12, 2022 Estimated Completion: June 2025

Mechanism of Action

Multimodal Receptor Pharmacology

Piromelatine is a novel sleep-promoting agent with a unique polypharmacology profile targeting three receptor systems:

Melatonin MT1/MT2 Receptor Agonism:

• Melatonin receptors regulate circadian rhythm and sleep-wake transitions
• MT1 activation promotes sleep onset; MT2 activation phase-shifts the circadian clock
• Piromelatine's melatonin agonism is the primary driver of its sleep-promoting effects
• Unlike pure melatonin supplements, piromelatine has higher receptor affinity and longer duration

• 5-HT1A somatodendritic autoreceptor activation reduces serotonergic tone, promoting sleep
• 5-HT1D receptors are expressed in the dorsal raphe nucleus and modulate sleep architecture
• This dual serotonergic activity may contribute to both sleep maintenance and mood benefits

The bidirectional relationship between sleep disruption and AD pathology makes sleep-targeted therapy promising:

• Sleep fragmentation is among the earliest symptoms in AD, often appearing years before cognitive decline
• Poor sleep quality correlates with greater amyloid burden and faster cognitive decline
• The glymphatic system — critical for amyloid and tau clearance — operates primarily during slow-wave sleep
• Orexin/hypocretin neurons in the lateral hypothalamus are particularly vulnerable to AD pathology, leading to wake-promoting system dysfunction
• Circadian rhythm disturbances in AD patients are associated with melatonin dysregulation and suprachiasmatic nucleus dysfunction

Study Design

Design Architecture

Double-Blind Phase (26 weeks):

• Randomized, placebo-controlled, parallel group
• 1:1 allocation ratio (piromelatine 20 mg vs placebo)
• Quadruple masking: participants, care providers, investigators, outcomes assessors
• Single oral dose daily, 1-2 hours before bedtime (preferably 21:00-22:00), after food

• Placebo participants cross over to piromelatine 20 mg
• Piromelatine participants continue treatment
• Total treatment duration: 18 months
• Exploratory phase aimed at differentiating symptomatic from disease-modifying effects

• Participants must be non-carriers of the 2:107,510,000-107,540,000 polymorphism
• This genetic exclusion suggests the trial targets a specific responder population

Intervention

| Arm | Intervention | Dose | Route | Frequency |
|-----|-------------|------|-------|-----------|
| Experimental | Piromelatine 20 mg tablet | 20 mg | Oral | Once daily at bedtime |
| Placebo Comparator | Placebo tablet | N/A | Oral | Once daily at bedtime |

Eligibility Criteria

Inclusion Criteria

• Age 60-85 years (inclusive), outpatient living at home or assisted living
• Has a consistent study partner (not expected to change) who can accompany clinic visits and monitor medication compliance
• Meets NIA-AA research criteria for probable AD (McKhann et al. 2011) with clearly documented cognitive decline over at least 12 months
• MRI/CT within 12 months before screening consistent with AD diagnosis (no significant comorbid pathologies)
• MMSE score 20-26 at screening, with stability (no more than 3-point change between successive visits)
• Clinical Dementia Rating Global Score (CDR GS) 0.5-1 (mild dementia) at screening
• Current AD medication: stable on acetylcholinesterase inhibitors and/or memantine for at least 6 months (dose stable for last 4 months)
• Non-AD medication users: stable off acetylcholinesterase inhibitors for at least 3 months before baseline
• Negative drug screen (benzodiazepines, opiates); intermittent BZD use allowed if 4+ days before visit
• Female: natural menopause ≥24 months before screening OR surgically sterile
• Male/female of childbearing potential: must use two forms of contraception (including one barrier) from screening through 90 days post-last dose
• Stable doses of non-excluded concurrent medications for at least 4 weeks before screening
• Allowed antidepressants on stable dose for ≥3 months
• Commitment to at least 2 hours per day of daylight exposure (preferably outdoor, or next to window)
• Fully vaccinated for COVID-19 including booster doses
• Ability to read/write in English or Spanish; adequate hearing, vision, and physical abilities for assessments
• Signed informed consent from both patient (capacity-confirmed) and study partner

Exclusion Criteria

• Carrier of 2:107,510,000-107,540,000 polymorphism
• Alternative cause for dementia other than AD
• MRI/CT findings: cortical infarct >1.5 cm³; >2 lacunar infarcts ≤1.5 cm³; Fazekas score >1; significant white matter disease
• Clinically significant neurodegenerative disease other than AD; serious neurological disorders (neurosyphilis, meningitis, encephalitis)
• Concurrent psychiatric disorder preventing participation: schizophrenia, bipolar disorder, substance use disorder within 2 years, major depression
• Uncontrolled/untreated cardiovascular, endocrine, GI, respiratory, or rheumatologic disorders (within 5 years)
• History of severe agitation (medically treated)
• History of serious infectious disease
• Primary or recurrent malignancy not in remission for >5 years (exceptions: excised squamous/basal cell carcinoma, resected in situ cancers)
• Severe pain likely to interfere with sleep
• Concurrent progressive disease: liver disease (AST/ALT/GGT >3× ULN), total bilirubin >3× ULN, macrocytosis >95 fL from chronic alcoholism, renal failure (creatinine clearance <30 mL/min)
• Prohibited medications (benzodiazepines, other sedative hypnotics, melatonin/melatonin agonists)
• Known hypersensitivity to melatonin or melatonin receptor agonists
• Clinically significant abnormal laboratory findings (not approved by safety officer)
• Persistent bradycardia (<50 bpm) or tachycardia (>100 bpm)
• Cardiac conduction abnormalities: AV block type II/Mobitz II, type III, congenital long QT syndrome, sinus node dysfunction, QTc >450 msec (male) or >470 msec (female)
• Untreated B12 and/or folic acid deficiency
• Participation in any investigational trial within 3 months; monoclonal antibody AD trial participants excluded until 6 months after last visit; prior AD active vaccine recipients excluded
• BMI >35 or <18
• Lifestyle exclusions: alcohol >30 g/day, inability to abstain after 20:00, unwilling to spend 2 hours/day in daylight, irregular lifestyle/shift work/jet lag, caffeine >7 cups/day (650 mg), medication compliance divergence outside 70-130%
• Suicidal ideation (active with intent, items 4-5 on C-SSRS in past 6 months) or suicidal behavior (past 2 years)

Outcome Measures

Primary Endpoint (Week 26)

Alzheimer's Disease Assessment Scale — Cognitive Subscale 14 (ADAS-Cog 14):

• 11 tasks measuring memory, language, praxis, attention, and cognitive abilities
• Total score range: 0-70 (lower = less severe impairment)
• Negative change from baseline indicates improvement
• ADAS-Cog 14 includes delayed recall, number cancellation, and maze tasks for enhanced sensitivity in early-stage AD

Secondary Endpoints (Week 26)

Efficacy:

• ADCS-Instrumental Activities of Daily Living (ADCS-iADL): Items 7-23 analyzed (range 0-56, lower = greater severity)
• ADCS-Clinical Global Impression of Change (ADCS-CGIC): Independent clinician assessment of cognitive, functional, and behavioral change from baseline (blinded assessor)
• MMSE: Brief cognitive screen (range 0-30, positive change = improvement)

• Adverse Events: Treatment-emergent AEs coded via MedDRA; TEAEs defined as AEs first occurring or worsening after first dose; descriptive statistics at 26 weeks and 78 weeks

Exploratory Endpoint

Delayed-Start Analysis:

• Comparison of early-start (piromelatine 18 months) vs delayed-start (piromelatine 12 months) groups
• Aims to distinguish symptomatic treatment effects (would converge) from disease-modifying effects (would diverge)

Study Locations

All sites are in the United States:

• ATP Clinical Research
• Collaborative Neuroscience Research, LLC
• Alliance Research (Asclepes Research Centers, P.C.)
• Pacific Research Network, LLC
• Syrentis Clinical Research (RAA Apex Acquisition LLC)
• The Mile High Research Center
• Linfritz Research Institute Inc.
• Finlay Medical Research Corp.
• Velocity Clinical Research, Inc. (multiple sites)
• K2 Medical Research (The Villages, Winter Garden)
• Verus Clinical Research Corp.
• BioMed Research Institute, Inc.
• CCM Clinical Research Group, LLC
• Advance Medical Research Center
• Allied Biomedical Research Institute (Clinical Trials)
• Vitae Research Center LLC
• Stein Gerontological Institute, Inc.
• Miami Dade Medical Research Institute
• Interspond, LLC
• University of South Florida Board of Trustees
• Alzheimer's Research and Treatment Center
• Ocean Medical Research
• Advanced Memory Research Institute of New Jersey
• Integrative Clinical Trials LLC
• New York University School of Medicine
• AMC Research, LLC
• Rhode Island Mood and Memory Research Institute
• Neurology Clinic, P.C.
• Northwest Clinical Research Center
• Froedtert & Medical College of Wisconsin
• Centricity Research Halifax Multispecialty
• Bluewater Clinical Research Group Inc
• LMC Clinical Research Inc. d.b.a. Centricity Research
• OCT Research ULC (dba Okanagan Clinical Trials)
• Medical Arts Health Research Group

Rationale

Sleep as a Therapeutic Target in AD

Sleep disturbances in AD are bidirectional — they are both a consequence of amyloid pathology in sleep-regulating circuits and a contributor to disease progression. The glymphatic system, which clears amyloid and tau during slow-wave sleep, operates at ~40-60% reduced efficiency during sleep deprivation.

Piromelatine's multimodal mechanism (melatonin + serotonergic) addresses multiple pathways:

• Circadian rhythm restoration via MT1/MT2 agonism
• Sleep architecture improvement (increased SWS, reduced wake after sleep onset)
• Potential neuroprotective effects through 5-HT1A modulation

Why a Delayed-Start Design?

The delayed-start (placebo-cross-over) design is the gold standard for detecting disease-modifying effects in AD trials. If piromelatine is merely symptomatic:

• Early-start and delayed-start groups would converge on similar outcomes after the delayed group catches up
• Both would benefit equally from the drug

• The early-start group would maintain greater benefit over the delayed-start group
• The difference at the end of the extension period would reflect cumulative disease modification

Previous Phase 2 Results

A Phase 2 trial (2013) in 120 adults with insomnia showed that piromelatine 20 mg and 50 mg improved sleep over 4 weeks vs placebo. Phase 1A/1B studies (2011) demonstrated safe, dose-dependent sleep improvements with antihypertensive, antinociceptive, and cognitive benefits in preclinical models. Antidepressant and anti-anxiety effects have been shown in animal models.

Safety Profile

Known adverse effects from earlier studies:

• Generally well-tolerated at 20 mg dose
• Lower daytime somnolence risk than benzodiazepine-based hypnotics
• No significant next-day residual effects at studied doses

• Interaction with acetylcholinesterase inhibitors and memantine (monitored in this trial)
• Cardiovascular monitoring (QTc, bradycardia exclusions in protocol)
• Fall risk in elderly with balance issues
• Melatonin-related: headache, GI effects (mild)

Current Status

The study completed its double-blind phase in June 2025 with 225 enrolled participants. Results are pending publication. Given the active-not-recruiting status as of the database update, primary endpoint analysis at 26 weeks has likely been completed.

References

[^1]: [NCT05267535 — Piromelatine 20 mg in Participants With Mild Dementia Due to Alzheimer's Disease](https://clinicaltrials.gov/study/NCT05267535)
[^2]: [Piromelatine — Wikipedia](https://en.wikipedia.org/wiki/Piromelatine)
[^3]: [McKhann GM et al., The diagnosis of dementia due to Alzheimer's disease (2011)](https://pubmed.ncbi.nlm.nih.gov/21526208/)
[^4]: [Neurim Pharmaceuticals Ltd.](https://www.neurim.com)

Related Pages

• [Sleep Disorders in Alzheimer's Disease](/diseases/sleep-disorders-in-alzheimers)
• [Glymphatic System in Neurodegeneration](/mechanisms/glymphatic-system-neurodegeneration)
• [Circadian Rhythm Dysfunction in Neurodegeneration](/mechanisms/circadian-rhythm-neurodegeneration)
• [Melatonin in Neuroprotection](/therapeutics/melatonin-therapy-neurodegeneration)
• [Alzheimer's Disease Assessment Scale (ADAS-Cog)](/diagnostics/adas-cog)
• [Lemborexant for AD Biomarkers (NCT06274528)](/clinical-trials/lemborexant-ad-nct06274528) — similar sleep-AD trial with dual orexin receptor antagonist

Pathway Diagram

The following diagram shows the key molecular relationships involving Piromelatine 20 mg for Mild Dementia Due to Alzheimer's Disease (NCT05267535) discovered through SciDEX knowledge graph analysis: