Repurposing Bromocriptine for Abeta Metabolism in Alzheimer's Disease

To investigate the safety and efficacy of an orally administered dose of TW-012R in patients with Alzheimer's disease bearing PSEN1 (presenilin 1) mutations (PSEN1-AD), using a placebo group as a control. In addition, long-term safety will be examined in an open-label extension trial.

Inclusion criteria

• Alzheimer's disease patients with PSEN1 mutations
• Patients diagnosed with "probable AD" according to the diagnostic guideline of NIA-AA or "probable Alzheimer-type dementia" according to the diagnostic criteria for Alzheimer's disease specified in DSM-5
• An MMSE-J score of <= 25
• Patients whose cognitive function and everyday function are obviously impaired based on their medical record or information provided by a person who knows the patient well
• Patients for whom intellectual disability and mental disorders other than dementia can be ruled out based on their academic background, work history, and life history.
• Patients with a reliable and close relationship with a partner/caregiver
• Age>=20 years at the time of giving informed consent
• Written informed consent has been obtained from the patient or his/her legally acceptable representative to participate in this trial

Exclusion criteria

• Difficulty with the oral intake of tablets
• Patients receiving anti-dementia drugs who have changed the dosing regimen during the 2 months prior to giving informed consent
• Patients with dementia due to pathology other than Alzheimer's disease (e.g., vascular dementia, frontotemporal dementia, Lewy body dementia, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, and prion disease)
• Presence of clinically relevant or unstable mental disorders. Patients with major depression in remission can be enrolled.
• Imminent risk of self-harm or harm to others
• Body mass index (BMI) of <= 17 or >= 35
• Patients with a history of alcohol dependence, drug dependence, or drug abuse within the 5 years before providing informed consent
• HBs antigen positive
• Anti-HIV antibody positive
• Anti-HTLV-1 antibody positive
• Patients with an active infection, such as hepatitis C and syphilis (STS/TPHA)
• Patients with the following liver function values on the test before enrollment
• AST(GOT) > 4.0 x Upper limit of the institutional reference range or
• ALT (GPT) > 4.0 x Upper limit of the institutional reference range
• Patients who have uncontrolled, clinically significant medical conditions (e.g., diabetes melitus, hypertension, thyroid/endocrine disease, congestive cardiac failure, angina pectoris, cardiac/gastrointestinal disease, dialysis, and abnormal renal function with an estimated CLcr < 30 mL/min)within 3 months prior to giving informed consent in addition to the underlying disease to be investigated in the trial and for whom the investigator or sub-investigator considers that there is a significant medical risk in the patient's participation in the trial
• Patients with long QT syndrome or tendency toward prolonged QTc interval (male: >=470 msec, female: >= 480 msec), or patients with a history/complication of torsades de pointes
• Patients with a history of malignancies within 5 years prior to providing informed consent. However, patients with the following diseases can be enrolled if they are treated appropriately:
• Skin cancer (basal cell, squamous cell)
• Cervical carcinoma in situ
• Localized prostate cancer
• Malignancies that have not recurred for at least 3 years since surgery and the patient's physician has determined that the risk of recurrence is low
• Patients with clinically significant vitamin B1/B12 deficiency or folic acid deficiency within 6 months prior to giving informed consent
• Patients who have participated in other clinical research/trials involving interventions within the 3 months prior to providing informed consent
• Patients who have previously received bromocriptine or TW-012R
• Patients with a history of hypersensitivity to bromocriptine or ergot alkaloids
• Patients with current or a history of thickened heart valve cusps, restricted heart valve motion, and the associated heart valve lesions, such as stenosis, confirmed by echocardiography
• Pregnant females, lactating females, females who may be pregnant, and females who wish to become pregnant
• Other patients who are considered inappropriate to participate in this trial at the discretion of the investigator or sub-investigator