Repurposing Bromocriptine for Abeta Metabolism in Alzheimer's Disease (REBRAnD)

Double-Blind Comparative Trial and Open-Label Extension Trial to Investigate the Safety and Efficacy of TW-012R in Alzheimer's Disease With Presenilin 1 (PSEN1) Mutations

The goal of this clinical trial is to learn about safety and efficacy of bromocriptine in familial Alzheimer's disease with presenilin 1 mutations.

The main questions it aims to answer are: •safety of bromocriptine •efficacy of bromocriptine

Participants will answer questions, have blood exams, lumbar punctures and MRI/PET scans. Researchers will compare a participants group taking bromocriptine with a participants group taking placebo to see if there is any changes in cognitive function, and behavioral and psychiatric symptoms with dementia.

Study Overview

• Status: Completed
• Conditions: Familial Alzheimer Disease (FAD); PSEN1 Mutation
• Intervention / Treatment: Drug: Bromocriptine Mesilate; Drug: Placebos

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Japan
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan, 467-8602
      • Nagoya City University Hospital
  • Kyoto
    • Kyoto, Kyoto, Japan, 606-8507
      • Kyoto University Hospital
  • Mie-ken
    • Tsu, Mie-ken, Japan, 514-8507
      • Mie University Hospital
  • Okayama-ken
    • Kurashiki, Okayama-ken, Japan, 701-0192
      • Kawasaki Medical School Hospital
  • Osaka
    • Sakai, Osaka, Japan, 590-0018
      • Asakayama Hospital
    • Suita, Osaka, Japan, 565-0871
      • Osaka University
  • Tokushima
    • Tokushima, Tokushima, Japan, 770-8503
      • Tokushima University Hospital
  • Tokyo
    • Tokyo, Tokyo, Japan, 173-0015
      • Tokyo Metropolitan Institute for Geriatrics and Gerontology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active; Bromocriptine mesilate, 2.5 to 22.5 mg per day, divided three times a day, for 50 weeks.	Drug: Bromocriptine Mesilate; Each tablet contains 2.87 mg of bromocriptine mesilate (JP) (2.5 mg of bromocriptine); Other Names: TW-012R
Placebo Comparator: Placebo; Placebo, divided three times a day, for 50 weeks.	Drug: Placebos; Identical tablets which contain no active ingredient; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Kyoto University
• Collaborators: Osaka University; Mie University; Tokushima University; Asakayama Hospital; Kawasaki Medical School Hospital; Nagoya City University Hospital; Time Therapeutics, Inc.; Towa Pharmaceutical Co.,Ltd.; Tokyo Metropolitan Institute for Geriatrics and Gerontology
• Investigators: Principal Investigator: Haruhisa Inoue, MD, PhD, Kyoto University; Study Director: Hidekazu Tomimoto, MD, PhD, Mie University Hospital; Study Director: Haruhiko Banno, MD, PhD, Kyoto University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2020
• Primary Completion (Actual): November 24, 2021
• Study Completion (Actual): November 24, 2021

Study Registration Dates

• First Submitted: May 28, 2020
• First Submitted That Met QC Criteria: May 28, 2020
• First Posted (Actual): June 2, 2020

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 25, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Substandard Drugs; Pharmaceutical Preparations; Therapeutics; Alkaloids; Heterocyclic Compounds, 4 or More Rings; Ergotamines; Ergot Alkaloids; Ergolines; Bromocriptine; Counterfeit Drugs; Placebos
• Other Study ID Numbers: IACT19029

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual data from all the participants are illustrated in the figures and in appendix of journal article. Any data shown will be available from the corresponding author on reasonable request.
• IPD Sharing Time Frame: After publication
• IPD Sharing Access Criteria: Reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No