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

Primary Purpose

Familial Alzheimer Disease (FAD), PSEN1 Mutation

Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
Bromocriptine
Placebos
Sponsored by
Kyoto University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Alzheimer Disease (FAD)

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Nagoya City University Hospital
  • Mie University Hospital
  • Kawasaki Medical School Hospital
  • Asakayama Hospital
  • Osaka University
  • Kyoto University Hospital
  • Tokushima University Hospital
  • Tokyo Metropolitan Geriatric Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Safety (Incidence and severity of adverse events and adverse reactions)
Severe impairment battery-Japanese version (SIB-J)
Neuropsychiatric Inventory (NPI)

Secondary Outcome Measures

Mental Function Impairment Scale (MENFIS)
Mini-Mental State Examination-Japanese (MMSE-J)
Disability Assessment for Dementia (DAD)
Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
Apathy Scale
Plasma Aβ protein concentration
Plasma NfL protein concentration
Plasma Total Tau, Plasma p-Tau concentration
Cerebrospinal fluid (CSF) Aβ concentration
CSF Total Tau, CSF p-Tau concentration
Blood bromocriptine concentration

Full Information

First Posted
May 28, 2020
Last Updated
March 29, 2022
Sponsor
Kyoto University
Collaborators
Mie University, Osaka University, Tokushima University, Tokyo Metropolitan Geriatric Medical Center, Asakayama Hospital, Kawasaki Medical School Hospital, Nagoya City University Hospital, Time Therapeutics, Inc., Towa Pharmaceutical Co.,Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04413344
Brief Title
Repurposing Bromocriptine for Abeta Metabolism in Alzheimer's Disease
Acronym
REBRAnD
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
June 5, 2020 (Actual)
Primary Completion Date
November 15, 2021 (Actual)
Study Completion Date
November 15, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Kyoto University
Collaborators
Mie University, Osaka University, Tokushima University, Tokyo Metropolitan Geriatric Medical Center, Asakayama Hospital, Kawasaki Medical School Hospital, Nagoya City University Hospital, Time Therapeutics, Inc., Towa Pharmaceutical Co.,Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Alzheimer Disease (FAD), PSEN1 Mutation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
[Double-blind phase] Multicenter, randomized, placebo-controlled, double-blind, parallel-group comparison clinical trial [Extension phase] Multicenter, open-label, extension trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Bromocriptine
Intervention Description
TW-012R: Each tablet contains 2.87 mg of bromocriptine mesilate (JP) (2.5 mg of bromocriptine)
Intervention Type
Drug
Intervention Name(s)
Placebos
Intervention Description
Placebo: Identical tablets which contain no active ingredient
Primary Outcome Measure Information:
Title
Safety (Incidence and severity of adverse events and adverse reactions)
Time Frame
Until Week 50 (end of trial)
Title
Severe impairment battery-Japanese version (SIB-J)
Time Frame
Until Week 20 and 36
Title
Neuropsychiatric Inventory (NPI)
Time Frame
Until Week 20 and 36
Secondary Outcome Measure Information:
Title
Mental Function Impairment Scale (MENFIS)
Time Frame
Until Week 20 and 36
Title
Mini-Mental State Examination-Japanese (MMSE-J)
Time Frame
Until Week 20 and 36
Title
Disability Assessment for Dementia (DAD)
Time Frame
Until Week 20 and 36
Title
Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
Time Frame
Until Week 20 and 36
Title
Apathy Scale
Time Frame
Until Week 20 and 36
Title
Plasma Aβ protein concentration
Time Frame
Until Week 20 and 36
Title
Plasma NfL protein concentration
Time Frame
Until Week 20 and 36
Title
Plasma Total Tau, Plasma p-Tau concentration
Time Frame
Until Week 20 and 36
Title
Cerebrospinal fluid (CSF) Aβ concentration
Time Frame
Until Week 36
Title
CSF Total Tau, CSF p-Tau concentration
Time Frame
Until Week 36
Title
Blood bromocriptine concentration
Time Frame
Until Week 20 and 36
Other Pre-specified Outcome Measures:
Title
Wearable physical activity meter
Time Frame
Until Week 20 and 36
Title
Finger tapping sensor readout
Time Frame
Until Week 20 and 36
Title
Brain amyloid PET image
Time Frame
Until Week 36
Title
Brain tau PET image
Time Frame
Until Week 36
Title
Upper motor neuron burden score
Time Frame
Until Week 20 and 36
Title
Plasma Aβ-related peptides concentration
Time Frame
Until Week 20 and 36

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Haruhisa Inoue, MD, PhD
Organizational Affiliation
Kyoto University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hidekazu Tomimoto, MD, PhD
Organizational Affiliation
Mie University Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Haruhiko Banno, MD, PhD
Organizational Affiliation
Kyoto University
Official's Role
Study Director
Facility Information:
Facility Name
Nagoya City University Hospital
City
Nagoya
State/Province
Aichi
ZIP/Postal Code
467-8602
Country
Japan
Facility Name
Mie University Hospital
City
Tsu
State/Province
Mie
ZIP/Postal Code
514-8507
Country
Japan
Facility Name
Kawasaki Medical School Hospital
City
Kurashiki
State/Province
Okayama
ZIP/Postal Code
701-0192
Country
Japan
Facility Name
Asakayama Hospital
City
Sakai
State/Province
Osaka
ZIP/Postal Code
590-0018
Country
Japan
Facility Name
Osaka University
City
Suita
State/Province
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
Kyoto University Hospital
City
Kyoto
ZIP/Postal Code
606-8507
Country
Japan
Facility Name
Tokushima University Hospital
City
Tokushima
ZIP/Postal Code
770-8503
Country
Japan
Facility Name
Tokyo Metropolitan Geriatric Hospital
City
Tokyo
ZIP/Postal Code
173-0015
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34193504
Citation
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.
Results Reference
derived

Learn more about this trial

Repurposing Bromocriptine for Abeta Metabolism in Alzheimer's Disease

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