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

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.

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).