CompletedNCT00940589Updated Jun 1, 2018Results posted

Efficacy of Circadin® 2 mg in Patients With Mild to Moderate Alzheimer Disease Treated With AChE Inhibitor

A Phase 2 interventional study of Circadin and Placebo in Alzheimer's Disease and Sleep Disorder, sponsored by Neurim Pharmaceuticals Ltd.. Completed at 6 sites in 3 countries. Open to participants aged 50 Years to 85 Years. Per ClinicalTrials.gov, last updated 2018-06-01.

Sponsored by Neurim Pharmaceuticals Ltd. · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 73
Allocation: Randomized
Ages: 50 Years to 85 Years
Sex: All

Study summary

The aim of this exploratory randomized, placebo controlled study is to evaluate the efficacy of Circadin® 2mg in patients with mild to moderate Alzheimer Disease (AD) treated with the acetylcholinesterase (AChE) inhibitor. The effects of add-on Circadin® 2mg vs. placebo on the decline in cognitive skills and global functioning, as well as on daytime somnolence and will be assessed.

Conditions studied

Alzheimer's Disease
Sleep Disorder

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Keywords

Alzheimer's Disease
Acetylcholinesterase inhibitor
cognitive function
Circadin
Sleep disturbances

In context

Alzheimer Disease

3,678 studies on the registry are indexed under Alzheimer Disease; 872 are open to participants now.

This study's enrollment of 73 is close to the median of 70 across 2,808 interventional studies indexed under Alzheimer Disease.

Browse Alzheimer Disease studies →

Lead sponsor

Neurim Pharmaceuticals Ltd. is the lead sponsor of 14 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 50 Years to 85 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Written informed consent as dictated by local legal circumstances.
Age range: adult patients between 50-85 years of age.
Gender: men and women. Women of child bearing potential or within two years of the menopause must have a negative urine pregnancy test at the Screening Visit.
A documented history of confirmed Alzheimer's disease
Dementia severity: MMSE score > 15,
Stable AChE inhibitor dose for 2 months prior to Screening visit.
Stable medications for non-excluded concurrent medical conditions for four weeks prior to the screening visit.
Stable doses of B12 and/or Folic acid supplements for at least 3 months prior to enrollment and throughout the study.
Cranial image: no evidence of focal disease to account for dementia (established by CT, PET or MRI). If there is no such available scan (CT, PET or MRI), one must be performed prior to enrollment.
Health: Physically acceptable for the study with no pathology likely to occur during or immediately after the study, as confirmed by medical history and exam and ECG.
Clinical laboratory values must be within normal limits, or judged not clinically significant by the investigator.
Residence: Stable home situation with no planned move during the 28-week investigational period.
A family member or a regular caregiver that will be available for visits and will ensure compliance. The caregiver must speak fluent Hebrew, Russian or English.
Ability to ingest oral medication and participate in all scheduled evaluations.
Ability to spend 2 daily hours outdoors exposed to sunlight.

Exclusion criteria

Exclusion Criteria:

Severe agitation.
Unstable medical condition, mental retardation.
moderate to severe depression as defined by DSM-IV
Use of benzodiazepines or other hypnotics during the study and the preceding four weeks.
Use of Circadin® during the two weeks prior to study enrollment.
Pharmacological immunosuppression.
Participation in a clinical trial with any investigational agent within two months prior to study enrollment.
Alcoholism.
Known or suspected hypersensitivity to exogenous melatonin or melatonin receptor agonists.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactose deficiency or glucose mal absorption.
Renal Failure with creatinine >150 micromol/l.
Hepatic Failure with ASAT; ALAT; GGT levels above three times the upper normal limit.
Clinically significant abnormal laboratory findings which have not been approved by the Safety Officer (sponsor)
Other serious diseases that could interfere with patient assessment.
Caregivers who are unwilling or unable to give informed consent or otherwise fulfill requirements of the study.
Untreated B12 and/or Folic acid deficiency.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 73 participants (actual)

Study arms

Experimental
Circadin
Drug
Drug: Circadin
Placebo comparator
Placebo
drug
Drug: Placebo

Interventions

DrugCircadin
Prolonged Release melatonin (Circadin) 2mg tablets
DrugPlacebo
Matched placebo tablets, with identical features to the Circadin tablets

What researchers measure

Primary outcomes

Change From Baseline to 24 Weeks in ADAS-cog
ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) is a cognitive testing instrument used in clinical trials. It consists of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities that are often referred to as the core symptoms of AD. The test comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. ADAS-cog was measured at base line and at end of treatment after 24 weeks.
Time frame: 24 weeks

Secondary outcomes

Change From Baseline to 24 Weeks in iADL
Instrumental Activities of Daily Living (iADL). The scale rates activities that represent key life tasks that people need to manage. These tasks are valuable for evaluating persons with early-stage disease, both to assess the level of disease and to determine the person's ability to care for himself or herself. Scores of 0 or 1 are given to every task (Bathing, Dressing, Tolieting, transferring, Continence and Feeding) to a total score of 6. , while 0 represents a patient who is very dependent and 6 represents patient who is independent. iADL was measured at base line and at end of treatment after 24 weeks.
Time frame: 24 weeks
Change From Baseline to 24 Weeks in MMSE
The Mini Mental State Examination (MMSE) is a brief assessment instrument used to assess cognitive function in elderly patients. The MMSE can be used to screen for cognitive impairment and as a measurement of cognition over time and with pharmacologic treatment. The instrument is divided into 2 sections. The first section measures orientation, memory, and attention: the maximum score is 21. The second section tests the ability of the patient to name objects, follow verbal and written commands, write a sentence, and copy figures: the maximum score is 9. The scoring range for the MMSE is 0-30. Higher score represents better performance. MMSE was measured at base line and at end of treatment after 24 weeks.
Time frame: 24 weeks

Results

Posted Jun 1, 2018

Participant flow

Participant flow — Overall Study
Milestone	Circadin	Placebo
Started	39	34
Completed	31	29
Not completed	8	5

Outcome measures

PrimaryChange From Baseline to 24 Weeks in ADAS-cog

ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) is a cognitive testing instrument used in clinical trials. It consists of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities that are often referred to as the core symptoms of AD. The test comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. ADAS-cog was measured at base line and at end of treatment after 24 weeks.

Time frame:: 24 weeks
Reported as:: Mean · Scores on a scale

Change From Baseline to 24 Weeks in ADAS-cog
Scores on a scale	Circadin	Placebo
Change From Baseline to 24 Weeks in ADAS-cog	0.45 ± 5	0.19 ± 6.28

SecondaryChange From Baseline to 24 Weeks in iADL

Instrumental Activities of Daily Living (iADL). The scale rates activities that represent key life tasks that people need to manage. These tasks are valuable for evaluating persons with early-stage disease, both to assess the level of disease and to determine the person's ability to care for himself or herself. Scores of 0 or 1 are given to every task (Bathing, Dressing, Tolieting, transferring, Continence and Feeding) to a total score of 6. , while 0 represents a patient who is very dependent and 6 represents patient who is independent. iADL was measured at base line and at end of treatment after 24 weeks.

Time frame:: 24 weeks
Reported as:: Mean · Scores on a scale

Change From Baseline to 24 Weeks in iADL
Scores on a scale	Circadin	Placebo
Change From Baseline to 24 Weeks in iADL	0.77 ± 1.41	1.62 ± 1.57

Statistical analysis

Circadin vs Placebo · ANCOVA · p = <0.045

SecondaryChange From Baseline to 24 Weeks in MMSE

The Mini Mental State Examination (MMSE) is a brief assessment instrument used to assess cognitive function in elderly patients. The MMSE can be used to screen for cognitive impairment and as a measurement of cognition over time and with pharmacologic treatment. The instrument is divided into 2 sections. The first section measures orientation, memory, and attention: the maximum score is 21. The second section tests the ability of the patient to name objects, follow verbal and written commands, write a sentence, and copy figures: the maximum score is 9. The scoring range for the MMSE is 0-30. Higher score represents better performance. MMSE was measured at base line and at end of treatment after 24 weeks.

Time frame:: 24 weeks
Reported as:: Mean · Scores on a scale

Change From Baseline to 24 Weeks in MMSE
Scores on a scale	Circadin	Placebo
Change From Baseline to 24 Weeks in MMSE	-0.3 ± 2.8	-1.9 ± 3.5

Statistical analysis

Circadin vs Placebo · ANCOVA · p = <0.044

Adverse events

Collected over 26 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Circadin	—	2/39 (5.1%)	32/39 (82.1%)
Placebo	—	5/34 (14.7%)	23/34 (67.6%)

Most frequent serious events

Showing 10 of 12

Most frequent serious events
Event	Circadin	Placebo
esophageal stenosisRespiratory, thoracic and mediastinal disorders	0/39	1/34
Severe miocardial infractionCardiac disorders	0/39	1/34
SomnolenceNervous system disorders	0/39	1/34
RhinorrhoeaRespiratory, thoracic and mediastinal disorders	0/39	1/34
GastritisGastrointestinal disorders	0/39	1/34
HyperglycaemiaEndocrine disorders	0/39	1/34
Oesophageal stenosisGastrointestinal disorders	0/39	1/34
Pneumonia aspirationRespiratory, thoracic and mediastinal disorders	0/39	1/34
DehydrationMetabolism and nutrition disorders	0/39	1/34
Urinary tract infectionRenal and urinary disorders	0/39	1/34

Most frequent other events

Showing 10 of 20

Most frequent other events
Event	Circadin	Placebo
Urinary tract infectionRenal and urinary disorders	1/39	5/34
Abdominal discomfortGastrointestinal disorders	4/39	0/34
DiarrhoeaGastrointestinal disorders	4/39	2/34
Upper respiratory tract infectionRespiratory, thoracic and mediastinal disorders	2/39	3/34
Angina pectorisCardiac disorders	3/39	0/34
VomitingGastrointestinal disorders	3/39	1/34
FallInjury, poisoning and procedural complications	3/39	0/34
NauseaGastrointestinal disorders	0/39	2/34
Blood creatinine increasedBlood and lymphatic system disorders	0/39	2/34
AgitationPsychiatric disorders	2/39	2/34

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Circadin	Placebo	Total
Mean	73.5 ± 8.6	77.3 ± 6.6	75.4 ± 7.6

Sex: Female, Male
Sex: Female, Male(Participants)	Circadin	Placebo	Total
Female	16	20	36
Male	23	14	37

Study locations

6 sites

Meridien Research
Brooksville, Florida 34601, United States
Meridien Research
Saint Petersburg, Florida 33709, United States
Exodon LLC
Mount Arlington, New Jersey 07856, United States
Scranton Medical Institute
Scranton, Pennsylvania 18503, United States
Merchav clinics
Tel-Aviv, Israel
CPS Research
Glasgow, G20 0XA, United Kingdom

References and documents

Publications

Wade AG, Farmer M, Harari G, Fund N, Laudon M, Nir T, Frydman-Marom A, Zisapel N. Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 2014 Jun 18;9:947-61. doi: 10.2147/CIA.S65625. eCollection 2014. PubMed 24971004 ↗
McCleery J, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev. 2020 Nov 15;11(11):CD009178. doi: 10.1002/14651858.CD009178.pub4. PubMed 33189083 ↗

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jun 1, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT00940589
Lead sponsor: Neurim Pharmaceuticals Ltd.
Responsible party: Sponsor
First posted: Jul 16, 2009
Start date: Sep 2009
Primary completion: Feb 2013
Completion: May 2013
Results posted: Jun 1, 2018
Last update: Jun 1, 2018

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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