Safety and Efficacy of Piromelatine in Mild Alzheimer's Disease Patients (ReCOGNITION)
- Registration Number
- NCT02615002
- Lead Sponsor
- Neurim Pharmaceuticals Ltd.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 371
- 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
- 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Piromelatine 5 mg Piromelatine 2 weeks of Placebo (run-in), followed by 26 weeks of 5 mg tablets once daily. Placebo Placebo 2 weeks of Placebo (run-in), followed by 26 weeks of Placebo tablets once daily. Piromelatine 20 mg Piromelatine 2 weeks of Placebo (run-in), followed by 26 weeks of 20 mg tablets once daily. Piromelatine 50 mg Piromelatine 2 weeks of Placebo (run-in), followed by 26 weeks of 50 mg tablets once daily.
- Primary Outcome Measures
Name Time Method Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline 26 weeks The global composite score of the cNTB combines the International Shopping List Test (ISLT), One Card Learning (OCL), Identification (IDN), Detection (DET), One Back Card (OBK), Controlled Oral Word Association Test (COWAT), and the Categorical Fluency Test (CFT). For each test, a z-score relative to the study baseline is calculated.
The cNTB global composite score is the mean of all z-scores from the tests listed above.
The scale range is from -3 to 3. Zero Z-score means no cognitive change. A negative value means decline, while a positive value means improvement.
- Secondary Outcome Measures
Name Time Method Safety and Tolerability - Blood Chemistry (mmol/L) Baseline, and 26 weeks Blood Chemistry follow-up during the experiment. No major changes or shifts from baseline mean good safety and tolerability.
Change From Baseline in Global Impression of Change (CGIC) 13 weeks, and 26 weeks The Change From Baseline in Global Impression of Change (CGIC) rating is made on a 7-point Likert-type scale where the change from baseline is rated as marked improvement (1), moderate improvement (2), minimal improvement (3), no change (4), minimal worsening (5), moderate worsening (6), marked worsening (7).
Mean values at 13 and 26 weeks are relative to baseline.Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL) Baseline, 13 weeks, and 26 weeks ADCS-MCI-ADL is an evaluation scale with information provided by an informant/caregiver to describe the functional impairment of patients with mild cognitive impairment (MCI).
The ADCS-ADL is a 23-item scale that includes 6 basic ADLs (BADLs) and 17 Instrumental Activities of Daily Living (IADLs) that provide a total score of 0-78, with a lower score indicating greater severity, meaning a worse outcome.Safety and Tolerability - Blood Pressure (mmHg) Baseline, and 26 weeks Systolic and Diastolic Blood Pressure is followed during the study, as safety and tolerability measures.
Changes in BP following treatment, leading to values out of the normal limits mean a worse outcome.Safety and Tolerability - Heart Rate (Bpm) Baseline, and 26 weeks Heart Rate within normal limits = 60-100 beats per minute (bpm) during the study means a good outcome in terms of safety.
Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14) Baseline, 13 weeks, and 26 weeks The ADAS was designed to measure the severity of the most important symptoms of AD. Its subscale, ADAS-cog, is the most popular cognitive testing instrument used in clinical trials, measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities that are often referred to as the core symptoms of AD.
ADAS-cog14 comprises 14 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment.Safety and Tolerability - ECG Interval Results - QTcF (Msec) Baseline, and 26 weeks QT interval corrected for heart rate by Fridericia's cube root formula (QTcF). The QTc is considered normal at \< 450 msec in males, and \< 470 msec in females.
Safety and Tolerability - Hematology Baseline, and 26 weeks Hematology (GI/L).
1 gill (GI) = 0.118294118 liter (L). No major changes or shifts from baseline mean good safety and tolerability.
Trial Locations
- Locations (56)
Biomed Research Institute
🇺🇸Miami, Florida, United States
Advanced Clinical research Network
🇺🇸Miami, Florida, United States
Alliance for Research
🇺🇸Long Beach, California, United States
Renew Behavioral Health, Inc
🇺🇸Long Beach, California, United States
ABS Health LLC
🇺🇸Pomona, California, United States
Anderson Clinical Research
🇺🇸Redlands, California, United States
Pacific Research Network, Inc
🇺🇸San Diego, California, United States
Sharp Mesa Vista Clinical research
🇺🇸San Diego, California, United States
Pioneer Clinical research
🇺🇸Coconut Creek, Florida, United States
University of Miami
🇺🇸Coral Gables, Florida, United States
Galiz reserach
🇺🇸Hialeah, Florida, United States
Rowe Neurology
🇺🇸Lenexa, Kansas, United States
KU School of Medicine-Wichita
🇺🇸Wichita, Kansas, United States
Pharmasite Research INC
🇺🇸Baltimore, Maryland, United States
Quest Research Institute
🇺🇸Farmington Hills, Michigan, United States
Precise Research Centers
🇺🇸Flowood, Mississippi, United States
The Neurocognitive Institute, LLC
🇺🇸Mount Arlington, New Jersey, United States
Global Medical Institutes
🇺🇸Princeton, New Jersey, United States
Integrative Clinical Trials, LLC
🇺🇸Brooklyn, New York, United States
Dent Neurosciences Research Center, Inc
🇺🇸Amherst, New York, United States
Manhattan Behavioral Medicine, PLLC
🇺🇸New York, New York, United States
Richmond Behavioral Associates
🇺🇸Staten Island, New York, United States
SPRI Clinical Trials, LLC
🇺🇸Brooklyn, New York, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
New Hope Clinical research
🇺🇸Charlotte, North Carolina, United States
Tulsa Clinical Research, LLC.
🇺🇸Tulsa, Oklahoma, United States
The Clinical research Center LLC
🇺🇸Jenkintown, Pennsylvania, United States
Suburban Research Associates
🇺🇸Media, Pennsylvania, United States
Shepherd Clinical Research LLC
🇺🇸Lewisville, Texas, United States
Grayline Research Center
🇺🇸Wichita Falls, Texas, United States
Aspen Clinical research
🇺🇸Orem, Utah, United States
Zain Research, Llc
🇺🇸Richland, Washington, United States
Galen Research
🇺🇸Chesterfield, Missouri, United States
Syrentis Clinical Research
🇺🇸Santa Ana, California, United States
Richard H. Weisler, M.D., P.A. & Associates
🇺🇸Raleigh, North Carolina, United States
Citrials Inc
🇺🇸Bellflower, California, United States
The Ohio State University
🇺🇸Columbus, Ohio, United States
Wasatch Clinical Research LLC
🇺🇸Salt Lake City, Utah, United States
The Roskamp Institute, Inc
🇺🇸Sarasota, Florida, United States
Miami Jewish Health Systems
🇺🇸Miami, Florida, United States
Territory Neurology & Research Institute
🇺🇸Tucson, Arizona, United States
MD Clinical
🇺🇸Hallandale Beach, Florida, United States
Research Center For Clinical Studies, Inc
🇺🇸Norwalk, Connecticut, United States
Medical Research Group of central Florida Inc.
🇺🇸Orange City, Florida, United States
New Life Medical Research Center
🇺🇸Hialeah, Florida, United States
Lake Charles Clinical Trials, LLC
🇺🇸Lake Charles, Louisiana, United States
Neurology Specialists of Monmouth County
🇺🇸West Long Branch, New Jersey, United States
Alzheimer's Research Corporation
🇺🇸Manchester, New Jersey, United States
Hattiesburg Clinic, P.A.
🇺🇸Hattiesburg, Mississippi, United States
Infinity Clinical Research, LLC.
🇺🇸Sunrise, Florida, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Red river medical research Center
🇺🇸Oklahoma City, Oklahoma, United States
Olympian Clinical Research
🇺🇸Tampa, Florida, United States
Roper St. Francis Healthcare
🇺🇸Charleston, South Carolina, United States
SSM Health/Dean Medical Group
🇺🇸Madison, Wisconsin, United States
Radiant Research
🇺🇸San Antonio, Texas, United States