Safety and Efficacy of Piromelatine in Mild Alzheimer's Disease Patients (ReCOGNITION)

Randomized, Double-blind, Parallel-group, Placebo-controlled, Dose Ranging Study of Piromelatine in Patients With Mild Dementia Due to Alzheimer's Disease

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).

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Placebo; Drug: Piromelatine

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.

• Study Type: Interventional
• Enrollment (Actual): 371
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Territory Neurology & Research Institute
  • California
    • Bellflower, California, United States, 90706
      • Citrials Inc
    • Long Beach, California, United States, 90807
      • Alliance for Research
    • Long Beach, California, United States, 90807
      • Renew Behavioral Health, Inc
    • Pomona, California, United States, 91767
      • ABS Health LLC
    • Redlands, California, United States, 92374
      • Anderson Clinical Research
    • San Diego, California, United States, 92103
      • Pacific Research Network, Inc
    • San Diego, California, United States, 92123
      • Sharp Mesa Vista Clinical research
    • Santa Ana, California, United States, 92705
      • Syrentis Clinical Research
  • Connecticut
    • Norwalk, Connecticut, United States, 06851
      • Research Center for Clinical Studies, Inc
  • Florida
    • Coconut Creek, Florida, United States, 33066
      • Pioneer Clinical Research
    • Coral Gables, Florida, United States, 33146
      • University of Miami
    • Hallandale Beach, Florida, United States, 33009
      • MD Clinical
    • Hialeah, Florida, United States, 33012
      • New Life Medical Research Center
    • Hialeah, Florida, United States, 33016
      • Galiz reserach
    • Miami, Florida, United States, 33126
      • BioMed Research Institute
    • Miami, Florida, United States, 33137
      • Miami Jewish Health Systems
    • Miami, Florida, United States, 33176
      • Advanced Clinical Research Network
    • Orange City, Florida, United States, 32763
      • Medical Research Group of central Florida Inc.
    • Sarasota, Florida, United States, 34243
      • The Roskamp Institute, Inc
    • Sunrise, Florida, United States, 33351
      • Infinity Clinical Research, LLC.
    • Tampa, Florida, United States, 33609
      • Olympian Clinical Research
  • Kansas
    • Lenexa, Kansas, United States, 66214
      • Rowe Neurology
    • Wichita, Kansas, United States, 67214
      • KU School of Medicine-Wichita
  • Louisiana
    • Lake Charles, Louisiana, United States, 27604
      • Lake Charles Clinical Trials, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21208
      • Pharmasite Research Inc
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Quest Research Institute
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Precise Research Centers
    • Hattiesburg, Mississippi, United States, 39401
      • Hattiesburg Clinic, P.A.
  • Missouri
    • Chesterfield, Missouri, United States, 63005
      • Galen Research
  • New Jersey
    • Manchester, New Jersey, United States, 08759
      • Alzheimer's Research Corporation
    • Mount Arlington, New Jersey, United States, 07856
      • The Neurocognitive Institute, LLC
    • Princeton, New Jersey, United States, 08540
      • Global Medical Institutes
    • West Long Branch, New Jersey, United States, 07764
      • Neurology Specialists of Monmouth County
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurosciences Research Center, Inc
    • Brooklyn, New York, United States, 11229
      • Integrative Clinical Trials, Llc
    • Brooklyn, New York, United States, 11235
      • SPRI Clinical Trials, LLC
    • New York, New York, United States, 10022
      • Manhattan Behavioral Medicine, PLLC
    • Staten Island, New York, United States, 10312
      • Richmond Behavioral Associates
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Charlotte, North Carolina, United States, 28211
      • New Hope Clinical Research
    • Raleigh, North Carolina, United States, 27609
      • Richard H. Weisler, M.D., P.A. & Associates
  • Ohio
    • Columbus, Ohio, United States, 43221
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Red river medical research Center
    • Tulsa, Oklahoma, United States, 74104
      • Tulsa Clinical Research, LLC.
  • Pennsylvania
    • Jenkintown, Pennsylvania, United States, 19046
      • The Clinical Research Center LLC
    • Media, Pennsylvania, United States, 19063
      • Suburban Research Associates
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Roper St. Francis Healthcare
  • Texas
    • Lewisville, Texas, United States, 75067
      • Shepherd Clinical Research LLC
    • San Antonio, Texas, United States, 78229
      • Radiant Research
    • Wichita Falls, Texas, United States, 76309
      • Grayline Research Center
  • Utah
    • Orem, Utah, United States, 84058
      • Aspen Clinical Research
    • Salt Lake City, Utah, United States, 84107
      • Wasatch Clinical Research LLC
  • Washington
    • Richland, Washington, United States, 99352
      • Zain Research, Llc
  • Wisconsin
    • Madison, Wisconsin, United States, 53715
      • SSM Health/Dean Medical Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Piromelatine 5 mg; 2 weeks of Placebo (run-in), followed by 26 weeks of 5 mg tablets once daily.	Drug: Piromelatine; Other Names: Neu-P11
Experimental: Piromelatine 20 mg; 2 weeks of Placebo (run-in), followed by 26 weeks of 20 mg tablets once daily.	Drug: Piromelatine; Other Names: Neu-P11
Experimental: Piromelatine 50 mg; 2 weeks of Placebo (run-in), followed by 26 weeks of 50 mg tablets once daily.	Drug: Piromelatine; Other Names: Neu-P11
Placebo Comparator: Placebo; 2 weeks of Placebo (run-in), followed by 26 weeks of Placebo tablets once daily.	Drug: Placebo; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Computerized Neuropsychological Test Battery (cNTB) Z-Scores - Change From Baseline	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.	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Global Impression of Change (CGIC)	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.	13 weeks, and 26 weeks
Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI (Mild Cognitive Impairment) Patients (ADCS-MCI-ADL)	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.	Baseline, 13 weeks, and 26 weeks
Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog14)	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.	Baseline, 13 weeks, and 26 weeks
Safety and Tolerability - Blood Pressure (mmHg)	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.	Baseline, and 26 weeks
Safety and Tolerability - Heart Rate (Bpm)	Heart Rate within normal limits = 60-100 beats per minute (bpm) during the study means a good outcome in terms of safety.	Baseline, and 26 weeks
Safety and Tolerability - ECG Interval Results - QTcF (Msec)	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.	Baseline, and 26 weeks
Safety and Tolerability - Hematology	Hematology (GI/L). 1 gill (GI) = 0.118294118 liter (L). No major changes or shifts from baseline mean good safety and tolerability.	Baseline, and 26 weeks
Safety and Tolerability - Blood Chemistry (mmol/L)	Blood Chemistry follow-up during the experiment. No major changes or shifts from baseline mean good safety and tolerability.	Baseline, and 26 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
NeuroPsychiatric Inventory (NPI) Total Score	The NPI scale consists of 12 domains that are rated for both frequency (range 1 to 4) and severity (range 1 to 3). A composite score for each domain is calculated (frequency × severity), and it ranges from 1 to 12. For each item, there is a leading question. If the symptom is absent, then the frequency, severity, and distress scores are not completed. In this case, the score is 0 for the item. The sum of the composite scores yields the NPI total score (1-12). A negative change in the score indicates an improvement from baseline (symptom reduction).	Baseline, and 26 weeks
Pittsburgh Sleep Quality Index (PSQI) - Global Component Score	PSQI is an effective instrument used to measure the quality and patterns of sleep in older adults. It differentiates "poor" from "good" sleep by measuring 7 areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction over the last month. PSQI includes seven components, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality.	Baseline, 4 weeks, 13 weeks, 26 weeks

Collaborators and Investigators

• Sponsor: Neurim Pharmaceuticals Ltd.
• Investigators: Study Chair: Lon Schneider, MD, Keck School of Medicine of USC, Los Angeles, CA

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): November 19, 2019

Study Registration Dates

• First Submitted: November 18, 2015
• First Submitted That Met QC Criteria: November 22, 2015
• First Posted (Estimated): November 25, 2015

Study Record Updates

• Last Update Posted (Actual): July 5, 2024
• Last Update Submitted That Met QC Criteria: July 2, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Sleep; Cognition; mild Alzheimer's disease
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: NeuP11-AD2

Plan for Individual participant data (IPD)

Study Data/Documents

1. Study website