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.

• Bromocriptine Mesilate (Drug), also known as TW-012R: Each tablet contains 2.87 mg of bromocriptine mesilate (JP) (2.5 mg of bromocriptine)
• Placebos (Drug), also known as Placebo: Identical tablets which contain no active ingredient

Primary outcomes

• Safety (Incidence and severity of adverse events and adverse reactions) [Until Week 50 (end of trial)]: to assess safety
• Severe impairment battery-Japanese version (SIB-J) [Until Week 20 and 36]: to assess cognitive function
• Neuropsychiatric Inventory (NPI) [Until Week 20 and 36]: to assess behavioral and psychiatric symptoms of dementia

Secondary outcomes

• Mental Function Impairment Scale (MENFIS) [Until Week 20 and 36]: to assess cognitive function
• Mini-Mental State Examination-Japanese (MMSE-J) [Until Week 20 and 36]: to assess cognitive function
• Disability Assessment for Dementia (DAD) [Until Week 20 and 36]: to assess activities of daily living
• Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III [Until Week 20 and 36]: to assess motor symptoms and signs
• Apathy Scale [Until Week 20 and 36]: to assess apathy
• Plasma Aβ protein concentration [Until Week 20 and 36]: to assess Aβ protein metabolism
• Plasma NfL protein concentration [Until Week 20 and 36]: to assess neurodegeneration
• Plasma Total Tau, Plasma p-Tau concentration [Until Week 20 and 36]: to assess tau protein metabolism
• Cerebrospinal fluid (CSF) Aβ concentration [Until Week 36]: to assess Aβ protein metabolism
• CSF Total Tau, CSF p-Tau concentration [Until Week 36]: to assess tau protein metabolism
• Blood bromocriptine concentration [Until Week 20 and 36]: to assess safety

Other outcomes

• Wearable physical activity meter [Until Week 20 and 36]: to assess activities of daily living
• Finger tapping sensor readout [Until Week 20 and 36]: to assess finger tapping
• Brain amyloid PET image [Until Week 36]: to assess Aβ protein metabolism
• Brain tau PET image [Until Week 36]: to assess tau protein metabolism
• Upper motor neuron burden score [Until Week 20 and 36]: to assess spasticity
• Plasma Aβ-related peptides concentration [Until Week 20 and 36]: to assess Aβ protein metabolism

Sex: All, ages: 20 Years to any

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

• Results publication: Kondo T, Banno H, Okunomiya T, Amino Y, Endo K, Nakakura A, Uozumi R, Kinoshita A, Tada H, Morita S, Ishikawa H, Shindo A, Yasuda K, Taruno Y, Maki T, Suehiro T, Mori K, Ikeda M, Fujita K, Izumi Y, Kanemaru K, Ishii K, Shigenobu K, Kutoku Y, Sunada Y, Kawakatsu S, Shiota S, Watanabe T, Uchikawa O, Takahashi R, Tomimoto H, Inoue H. Repurposing bromocriptine for Abeta metabolism in Alzheimer's disease (REBRAnD) study: randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer's disease with presenilin 1 (PSEN1) mutations. BMJ Open. 2021 Jun 30;11(6):e051343. doi: 10.1136/bmjopen-2021-051343. PMID 34193504

• Haruhisa Inoue, MD, PhD, Principal investigator, Kyoto University
• Hidekazu Tomimoto, MD, PhD, Study director, Mie University Hospital
• Haruhiko Banno, MD, PhD, Study director, Kyoto University Hospital