Study Title: Piromelatine 20 mg in Participants With Mild Dementia Due to Alzheimer's Disease
NCT Identifier: 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
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
Serotonin 5-HT1A/5-HT1D Receptor Agonism:
- 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
Why Sleep Promotion in Alzheimer's Disease?
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
By improving sleep architecture through melatonin and serotonin receptor activation, piromelatine may:
- Enhance glymphatic clearance of amyloid-beta
- Reduce tau propagation (which accelerates during sleep deprivation)
- Support hippocampal memory consolidation during NREM sleep
- Potentially slow cognitive decline through improved sleep quality
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
Delayed-Start Open-Label Extension (12 months):
- 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
Key Enrollment Restriction:
- 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
| 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 |
- 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
- 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)
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
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)
Safety:
- 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
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)
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
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
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
If piromelatine modifies disease progression:
- 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
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.
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
Specific considerations for AD population:
- 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)
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.