Piromelatine 20 mg in Participants With Mild Dementia Due to Alzheimer's Disease

Inclusion Criteria:

• Male or female aged 60 85 years (inclusive).

• Participant is an outpatient living at home or in an assisted living facility and iswilling to attend all planned visits during the study.

• The participant has a study partner (who is not expected to change during the study)who will accompany the patient to the clinic, and/or be available by telephone atdesignated times, monitor administration of prescribed medications, control theminimum 2 hour daily light exposure requirement. The study partner must, in theopinion of the investigator, have enough contact with the participant to be able toperform the duties described above.

• Signed informed consent from the patient who has the capacity to provide informedconsent as judged by the study investigator

• Signed informed consent from the study partner.

• Meets NIA AA research criteria for probable AD (McKhann, Knopman et al. 2011).

• Patient has a clearly documented history of cognitive decline over at least 12months.

• Patient has MRI/CT scan, performed within 12 months before Screening, with findingsconsistent with the diagnosis of AD without any other clinically significantcomorbid pathologies as detailed in Appendix 3. If MRI/CT was not performed within 12 months before Screening, it can be done during the screening period

• MMSE score of 20 26 (inclusive) at Screening and stability of MMSE - no more thanthree-point change on successive screening and baseline visits before randomization.

• Patient has a CDR GS of 0.5 1 (mild dementia) at Screening.

• Patients taking acetylcholinesterase inhibitors and or memantine for the treatmentof AD may be enrolled if the patient has been taking such medication for at least 6months before Visit 2 (Baseline) and is stable on any dose for the last 4 monthsprior to Baseline, and if the dose is not expected to change during studyparticipation.

• Patients not receiving acetylcholinesterase inhibitors may be enrolled but must bestable off acetylcholinesterase inhibitors for at least 3 months before Baseline,and agreeable to not starting throughout the first 26 weeks of the trial.

• Patient has a negative drug screen (benzodiazepines or opiates) at Screening.Positive drug screen of BZDs, is allowed only if the use is intermittent and drugintake was 4 days or more before the visit

• Female patients must have had last natural menstruation ≥ 24 months before ScreeningOR be surgically sterile.

• Male patients and their female spouse/partners who are of childbearing potentialmust agree to use highly effective methods of contraception, consisting of 2 formsof birth control (at least one of which must be a barrier method) starting atScreening, throughout the study and for 90 days post last dose, OR be surgicallysterile.

• Patients who are taking medications for non excluded concurrent medical conditionsshould be on a stable dose for at least 4 weeks before Screening. Patients takingallowed antidepressants (see Section 12.9) should be on a stable dose for at least 3months before Screening and throughout the study

• Patient has ability and commitment to spend at least 2 hours per day exposed todaylight (preferably outside but can be next to a window if weather or personalsituation does not permit).

• Participant and study partner have the ability to read and write in English orSpanish and have hearing, vision, and physical abilities adequate to performassessments (corrective aids allowed).

• Participant and study partner are fully vaccinated for COVID 19 including boosterdoses as indicated (6 months post second dose). Having been diagnosed with COVID 19after completing the initial full Covid vaccine would meet the requirements for abooster shot

Exclusion Criteria:

• Declines whole genome screening for 2:107,510,000-107,540,000 polymorphism and APOE4genotyping.

• Patient is 2:107,510,000-107,540,000 polymorphism carrier.

• Patient has an alternative cause for dementia other than AD.

• A past or recent CT or MRI scan or report indicating any cortical infarct defined as > 1.5 cm3; more than 2 lacunar infracts defined as ≤ 1.5 cm3; or diffuse whitematter disease), Fazekas score of more than 1 on MRI or CT scan (more detailsAppendix 3).

• Patient has evidence of any clinically significant neurodegenerative disease, orother serious neurological disorders other than AD as detailed in Appendix 3,

• Patient has a concurrent psychiatric disorder that prevents his/her participation inthe trial including but not limited to Schizophrenia, Bipolar and related disorders,Substance use disorders within the past 2 years, major depression, etc.

• Patient has a history of uncontrolled or untreated cardiovascular, endocrine,gastrointestinal, respiratory, or rheumatologic disorders within the past 5 years.

• Patient has a history of severe agitation and medically treated agitation.

• Patient has a history of serious infectious disease including:

• Neurosyphilis

• Meningitis

• Encephalitis

• Patient has a history of a primary or recurrent malignant disease that has not beenin remission for > 5 years prior to the Screening visit, with the exceptions ofexcised cutaneous squamous cell carcinoma in situ, basal cell carcinoma withoutrecurrences; and history of intraductal breast cancer, cervical carcinoma in situ,or in situ prostate cancer resected over 5 years previously. (For resected in situprostate cancer, i.e., high grade intraepithelial neoplasia, the patient must have anormal prostate specific antigen [PSA] prior to Screening and no increase in PSAsince his resection surgery).

• Patient has severe pain that is likely to interfere with sleep (in the opinion ofthe investigator).

• Patient has any concomitant documented progressive disease likely to interfere withthe conduct of the study, particularly:

• Liver disease with aspartate aminotransferase (AST), alanine aminotransferase (ALT) or gamma glutamyltransferase (GGT) > 3 times the upper limits of normal (ULN)

• Total bilirubin > 3 times the ULN

• Mean corpuscular volume > 95 µ3 if due to chronic alcoholism

• Renal failure with creatinine < 30 ml / min

• Patients that are taking prohibited medications according to Appendix 2 See alsosection 12.9.

• Continuous use of benzodiazepines or other sedative hypnotics during the 2 weeksbefore Screening (see Section 12.9).

• Patient has a history of chronic use (more than 3 months of continuous use) andabuse of benzodiazepines or other sedative hypnotics.

• Use of any kind of melatonin/melatonin agonist during the 2 weeks before Screening (see Section 12.9).

• Patient has known or suspected hypersensitivity to exogenous melatonin or melatoninreceptor agonists.

• Patient has clinically significant abnormal laboratory findings that have not beenapproved by the study safety officer.

• Patient has persistent bradycardia (heart beat < 50 bpm) or tachycardia (heart beat > 100 bpm).

• Patient has atrioventricular block (type II/Mobitz II and type III), congenital longQT syndrome, sinus node dysfunction or a marked prolongation of QTc interval (repeated demonstration in ECGs of QTc interval > 450 msec for males and > 470 msecfor females using Fridericia's formula: QTc = QT/cube root of RR).

• Patient has other serious diseases that could interfere with patient assessment, inthe opinion of the investigator.

• Patient has untreated B12 and/or folic acid deficiency.

• Patient has participated in a clinical trial with any investigational agent within 3months before Screening. Participants in any former monoclonal antibody clinicaltrial for AD are not eligible until 6 months after the last visit of the previousstudy. Patients who have received active vaccine for AD in the past will beexcluded.

• Patient with a body mass index (BMI) above 35 or below 18.

• Lifestyle exclusions:

• Patients unwilling to limit alcohol intake to less than 30 g of pure alcohol per day (see Appendix 1) and to abstain after 2000h throughout the study

• Patients unwilling to be exposed to at least 2 hours of daylight each day

• Divergence from the accepted level of study medication compliance (70% 130% ofexpected consumption) as verified at Visit 2 (see Section 12.10)

• Patients consuming more than 7 cups of tea or coffee (or equivalent amount ofcaffeine [650 mg] in other caffeinated beverages) per day

• Patients with an irregular lifestyle or life pattern (e.g., shift workers, patientslikely to be jet lagged)

• Patients with evidence of serious risk of suicide based on the Columbia-SuicideSeverity Rating Scale, i.e., active suicidal ideation with some intent to act, withor without a specific plan (a positive response to Suicidal Ideation Items 4 or 5)in the 6 months prior to Screening, OR with evidence of suicidal behavior in the 2years prior to Screening (a positive response to any of the 5 Suicidal BehaviorItems {actual attempt, interrupted attempt, aborted attempt, preparatory acts, orbehavior}), OR who, in the opinion of the investigator, present a serious risk ofsuicide.