Clinical trial NCT02615002: Safety and Efficacy of Piromelatine in Mild Alzheimer's Disease Patients (ReCOGNITION)
Official title: Randomized, Double-blind, Parallel-group, Placebo-controlled, Dose Ranging Study of Piromelatine in Patients With Mild Dementia Due to Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: Cognition
mild Alzheimer's disease
Sleep
Lead sponsor: Neurim Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2015-11-25
Enrollment: 371
Sex: ALL
Minimum age (years): 60
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a Phase 2, randomized, placebo-controlled, dose-ranging study of piromelatine (5, 20, and 50 mg daily for 6 months) versus placebo to determine an effective dose based on efficacy (cognitive performance), safety, and tolerability in patients with mild dementia due to Alzheimer's Disease (AD).

Detailed description: Patients with a documented history of mild dementia due to AD for at least 6 months, having a Mini-Mental State Examination (MMSE) score of 20 to 27 (inclusive) at Screening.

A score of 27 is allowed only if accompanied by a score of ≥ 12 in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog) ADAS-cog11 portion of the ADAS-cog14 at screening, and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5 or 1 will be recruited and further screened for eligibility. Caregiver commitment to the study is also necessary.

At Screening (Visit 1), patients will undergo neuropsychiatric assessments, psychometric testing, and general medical assessments (including medical history, pre-existing conditions, physical examination, vital signs, and ECG). If patients have not had brain imaging with findings consistent with the diagnosis of dementia due to AD in the last 12 months, a computed tomography (CT) or magnetic resonance imaging (MRI) scan will be obtained to rule out clinically significant comorbid pathologies.

Eligible patients will start a 2-week run-in period of placebo (single-blind), followed by 26 weeks of double-blind treatment comprising administration of piromelatine or placebo, for a total treatment duration of 28 weeks. During the double-blind period, patients will be enrolled in a 1.2:1:1:1 randomization ratio to the 4 trial arms (placebo \[1.2\], and the equal piromelatine treatment arms 5, 20, and 50 mg \[1:1:1\]).

Intermediate visits will be carried out at 4 weeks (Visit 3) and 13 weeks (Visit 4) after randomization. A follow-up phone call to elicit any safety concerns will be completed 2 weeks after the last dose of study medication. Patients who discontinue before Visit 5 (Week 26) will be brought back for a termination visit.

Assuming an effect size between the treatment dose and placebo of 0.35 over 26 weeks, a significant level (α) of 0.05, and power of 88%, a sample size of 143 patients for the placebo arm and 119 patients for each of the 3 piromelatine arms is calculated. Assuming a 50% screen failure rate and allowing for 15% patient withdrawal, 1150 patients should be screened to randomly assign 575 patients, of whom it is expected that 500 will complete the study.

Piromelatine (5, 20, and 50 mg tablets) and placebo will be administered orally, once daily after a meal, before habitual bedtime, preferably between 2100h and 2300h. Patients will be required to spend at least 2 hours a day exposed to daylight.

Eligibility criteria: Inclusion Criteria:

* Patient and caregiver are willing to take part in the entire study
* Signed informed consent from the patient and the caregiver
* Patient has a documented history either in medical records or from an informant of cognitive decline over at least 6 months
* Patient has mild probable AD as consistent with criteria established by the National Institute on Aging and Alzheimer's Association (NIA-AA).
* CT/MRI scan with finding consisting of probable AD obtained during the last 12 months before Screening
* Patient has an MMSE score of 21-26 (inclusive) at Screening
* Patient has a Clinical Dementia Rating Global Score (CDR-GS) of 0.5-1 (mild dementia) at Screening
* Patients receiving prescribed drugs for treatment of AD including acetyl cholinesterase inhibitors \[eg, donepezil, galantamine, rivastigmine\] should be on a stable dose for at least 3 months before Screening
* Patient has a negative drug screen (benzodiazepines or opiates) at Screening
* Female patients must have had last natural menstruation ≥ 24 months before Screening, OR being surgically sterile
* Male patients must agree to the use of effective contraception if the female partner is of childbearing potential, OR be surgically sterile

Exclusion Criteria:

* Patient has an alternative cause for dementia other than AD as determined by CT or MRI scan
* Patient has evidence of any clinically significant neurodegenerative disease
* Patient has been diagnosed with the following Axis I disorders (DSM V criteria)
* Patient has a history of uncontrolled or untreated cardiovascular, endocrine, gastrointestinal, respiratory, or rheumatologic disorders within the past 5 years
* Patient has severe pain that is likely to interfere with sleep
* Continuous use of benzodiazepines or other sedative-hypnotics during the 2 weeks before Screening
* Use of any kind of melatonin/melatonin agonist during the 2 weeks before Screening
* Patient has known or suspected hypersensitivity to exogenous melatonin or melatonin receptor agonists
* Patients with an irregular lifestyle or life pattern (eg, shift workers, patients likely to be jet lagged).

Primary outcomes:
measure: Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline
timeFrame: 26 weeks
Secondary outcomes:
measure: Change From Baseline in Global Impression of Change (CGIC)
timeFrame: 13 weeks, and 26 weeks
measure: Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL)
timeFrame: Baseline, 13 weeks, and 26 weeks
measure: Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14)
timeFrame: Baseline, 13 weeks, and 26 weeks
measure: Safety and Tolerability - Blood Pressure (mmHg)
timeFrame: Baseline, and 26 weeks
measure: Safety and Tolerability - Heart Rate (Bpm)
timeFrame: Baseline, and 26 weeks
measure: Safety and Tolerability - ECG Interval Results - QTcF (Msec)
timeFrame: Baseline, and 26 weeks
measure: Safety and Tolerability - Hematology
timeFrame: Baseline, and 26 weeks
measure: Safety and Tolerability - Blood Chemistry (mmol/L)
timeFrame: Baseline, and 26 weeks
Other outcomes:
measure: NeuroPsychiatric Inventory (NPI) Total Score
timeFrame: Baseline, and 26 weeks
measure: Pittsburgh Sleep Quality Index (PSQI) - Global Component Score
timeFrame: Baseline, 4 weeks, 13 weeks, 26 weeks
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tucson
country: United States
facility: Territory Neurology & Research Institute
state: Arizona
city: Bellflower
country: United States
facility: Citrials Inc
state: California
city: Long Beach
country: United States
facility: Alliance for Research
state: California
city: Long Beach
country: United States
facility: Renew Behavioral Health, Inc
state: California
city: Pomona
country: United States
facility: ABS Health LLC
state: California
city: Redlands
country: United States
facility: Anderson Clinical Research
state: California
city: San Diego
country: United States
facility: Pacific Research Network, Inc
state: California
city: San Diego
country: United States
facility: Sharp Mesa Vista Clinical research
state: California
city: Santa Ana
country: United States
facility: Syrentis Clinical Research
state: California
city: Norwalk
country: United States
facility: Research Center For Clinical Studies, Inc
state: Connecticut
city: Coconut Creek
country: United States
facility: Pioneer Clinical research
state: Florida
city: Coral Gables
country: United States
facility: University of Miami
state: Florida
city: Hallandale Beach
country: United States
facility: MD Clinical
state: Florida
city: Hialeah
country: United States
facility: New Life Medical Research Center
state: Florida
city: Hialeah
country: United States
facility: Galiz reserach
state: Florida
city: Miami
country: United States
facility: Biomed Research Institute
state: Florida
city: Miami
country: United States
facility: Miami Jewish Health Systems
state: Florida
city: Miami
country: United States
facility: Advanced Clinical research Network
state: Florida
city: Orange City
country: United States
facility: Medical Research Group of central Florida Inc.
state: Florida
city: Sarasota
country: United States
facility: The Roskamp Institute, Inc
state: Florida
city: Sunrise
country: United States
facility: Infinity Clinical Research, LLC.
state: Florida
city: Tampa
country: United States
facility: Olympian Clinical Research
state: Florida
city: Lenexa
country: United States
facility: Rowe Neurology
state: Kansas
city: Wichita
country: United States
facility: KU School of Medicine-Wichita
state: Kansas
city: Lake Charles
country: United States
facility: Lake Charles Clinical Trials, LLC
state: Louisiana
city: Baltimore
country: United States
facility: Pharmasite Research INC
state: Maryland
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: Flowood
country: United States
facility: Precise Research Centers
state: Mississippi
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic, P.A.
state: Mississippi
city: Chesterfield
country: United States
facility: Galen Research
state: Missouri
city: Manchester
country: United States
facility: Alzheimer's Research Corporation
state: New Jersey
city: Mount Arlington
country: United States
facility: The Neurocognitive Institute, LLC
state: New Jersey
city: Princeton
country: United States
facility: Global Medical Institutes
state: New Jersey
city: West Long Branch
country: United States
facility: Neurology Specialists of Monmouth County
state: New Jersey
city: Amherst
country: United States
facility: Dent Neurosciences Research Center, Inc
state: New York
city: Brooklyn
country: United States
facility: Integrative Clinical Trials, LLC
state: New York
city: Brooklyn
country: United States
facility: SPRI Clinical Trials, LLC
state: New York
city: New York
country: United States
facility: Manhattan Behavioral Medicine, PLLC
state: New York
city: Staten Island
country: United States
facility: Richmond Behavioral Associates
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: New Hope Clinical research
state: North Carolina
city: Raleigh
country: United States
facility: Richard H. Weisler, M.D., P.A. & Associates
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Red river medical research Center
state: Oklahoma
city: Tulsa
country: United States
facility: Tulsa Clinical Research, LLC.
state: Oklahoma
city: Jenkintown
country: United States
facility: The Clinical research Center LLC
state: Pennsylvania
city: Media
country: United States
facility: Suburban Research Associates
state: Pennsylvania
city: Charleston
country: United States
facility: Roper St. Francis Healthcare
state: South Carolina
city: Lewisville
country: United States
facility: Shepherd Clinical Research LLC
state: Texas
city: San Antonio
country: United States
facility: Radiant Research
state: Texas
city: Wichita Falls
country: United States
facility: Grayline Research Center
state: Texas
city: Orem
country: United States
facility: Aspen Clinical research
state: Utah
city: Salt Lake City
country: United States
facility: Wasatch Clinical Research LLC
state: Utah
city: Richland
country: United States
facility: Zain Research, Llc
state: Washington
city: Madison
country: United States
facility: SSM Health/Dean Medical Group
state: Wisconsin
Study officials:
affiliation: Keck School of Medicine of USC, Los Angeles, CA
name: Lon Schneider, MD
role: STUDY_CHAIR
References:
citation: Schneider LS, Laudon M, Nir T, Caceres J, Ianniciello G, Capulli M, Zisapel N. A Polymorphism Cluster at the 2q12 locus May Predict Response to Piromelatine in Patients with Mild Alzheimer's Disease. J Prev Alzheimers Dis. 2022;9(2):247-254. doi: 10.14283/jpad.2021.61.