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

• Status: Not yet recruiting
• Trial end date: 2025-06-01
• Target enrollment: 0
• Participant gender: All

Summary

Randomized efficacy and safety study of piromelatine 20 mg versus placebo in participants with mild dementia due to Alzheimer's disease (AD) who are 2:107,510,000-107,540,000 polymorphism non-carriers with the primary objective to compare the effect of piromelatine to that of placebo on the AD Assessment Scale cognitive subscale (ADAS-cog14) at Week 26 of double-blind treatment.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Neurim Pharmaceuticals Ltd.
• Collaborator: Syneos Health

Criteria

Inclusion Criteria:

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

• Participant is an outpatient living at home or in an assisted living facility and is willing 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 at designated times, monitor administration of prescribed medications, control the minimum 2 hour daily light exposure requirement. The study partner must, in the opinion of the investigator, have enough contact with the participant to be able to perform the duties described above.

• Signed informed consent from the patient who has the capacity to provide informed consent 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 12 months.

• Patient has MRI/CT scan, performed within 12 months before Screening, with findings consistent with the diagnosis of AD without any other clinically significant comorbid pathologies as detailed in Appendix 3.

• MMSE score of 20 26 (inclusive) at Screening and stability of MMSE - no more than three-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 treatment of AD may be enrolled if the patient has been taking such medication for at least 6 months before Visit 2 (Baseline) and is stable on any dose for the last 4 months prior to Baseline, and if the dose is not expected to change during study participation.

• Patients not receiving acetylcholinesterase inhibitors may be enrolled but must be stable 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.

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

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

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

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

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

• Participant and study partner are fully vaccinated for COVID 19 including booster doses as indicated (6 months post second dose).

Exclusion Criteria:

• Declines whole genome screening for 2:107,510,000-107,540,000 polymorphism and APOE4 genotyping.

• 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 white matter disease), Fazekas score of more than 1 on MRI and number of micro hemorrhages (MCH) to be > 4 (more details Appendix 3).

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

• Patient has a concurrent psychiatric disorder that prevents his/her participation in the 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 been in remission for > 5 years prior to the Screening visit, with the exceptions of excised cutaneous squamous cell carcinoma in situ, basal cell carcinoma without recurrences; and history of intraductal breast cancer, cervical carcinoma in situ, or in situ prostate cancer resected over 5 years previously. (For resected in situ prostate cancer, i.e., high grade intraepithelial neoplasia, the patient must have a normal prostate specific antigen [PSA] prior to Screening and no increase in PSA since his resection surgery).

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

• Patient has any concomitant documented progressive disease likely to interfere with the 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 also section 12.9.

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

• Patient has a history of chronic use (more than 3 months of continuous use) and abuse 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 melatonin receptor agonists.

• Patient has clinically significant abnormal laboratory findings that have not been approved 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 long QT syndrome, sinus node dysfunction or a marked prolongation of QTc interval (repeated demonstration in ECGs of QTc interval > 450 msec for males and > 470 msec for females using Fridericia's formula: QTc = QT/cube root of RR).

• Patient has other serious diseases that could interfere with patient assessment, in the 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 3 months before Screening. Participants in any former monoclonal antibody clinical trial for AD are not eligible until 6 months after the last visit of the previous study. Patients who have received active vaccine for AD in the past will be excluded.

• 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% of expected consumption) as verified at Visit 2 (see Section 12.10)

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

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

• Patients with evidence of serious risk of suicide based on the Columbia-Suicide Severity Rating Scale, i.e., active suicidal ideation with some intent to act, with or 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 2 years prior to Screening (a positive response to any of the 5 Suicidal Behavior Items {actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior}), OR who, in the opinion of the investigator, present a serious risk of suicide.