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

A Double-blind, Parallel Group, Randomized, Placebo Controlled Study of the Efficacy of Circadin® 2mg in Patients With Mild to Moderate Alzheimer Disease (AD) Treated With Acetylcholinesterase (AChE) Inhibitor

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.

Study Overview

• Status: Completed
• Conditions: Sleep Disorder; Alzheimer's Disease
• Intervention / Treatment: Drug: Circadin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent as dictated by local legal circumstances.
2. Age range: adult patients between 50-85 years of age.
3. 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.
4. A documented history of confirmed Alzheimer's disease
5. Dementia severity: MMSE score > 15,
6. Stable AChE inhibitor dose for 2 months prior to Screening visit.
7. Stable medications for non-excluded concurrent medical conditions for four weeks prior to the screening visit.
8. Stable doses of B12 and/or Folic acid supplements for at least 3 months prior to enrollment and throughout the study.
9. 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.
10. 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.
11. Clinical laboratory values must be within normal limits, or judged not clinically significant by the investigator.
12. Residence: Stable home situation with no planned move during the 28-week investigational period.
13. 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.
14. Ability to ingest oral medication and participate in all scheduled evaluations.
15. Ability to spend 2 daily hours outdoors exposed to sunlight.

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Circadin; Drug	Drug: Circadin; Prolonged Release melatonin (Circadin) 2mg tablets
Placebo Comparator: Placebo; drug	Drug: Placebo; Matched placebo tablets, with identical features to the Circadin tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	24 weeks

Collaborators and Investigators

• Sponsor: Neurim Pharmaceuticals Ltd.

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: July 15, 2009
• First Submitted That Met QC Criteria: July 15, 2009
• First Posted (Estimate): July 16, 2009

Study Record Updates

• Last Update Posted (Actual): June 1, 2018
• Last Update Submitted That Met QC Criteria: May 29, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; cognitive function; Sleep disturbances; Acetylcholinesterase inhibitor; Circadin
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Sleep Wake Disorders; Alzheimer Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: NEU AZ1