Repurposing Bromocriptine for Abeta Metabolism in Alzheimer's Disease

Familial Alzheimer Disease (FAD) Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04413344
• Other study ID #: IACT19029
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 5, 2020
• Est. completion date: November 15, 2021

Study information

• Verified date: March 2022
• Source: Kyoto University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: November 15, 2021
• Est. primary completion date: November 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Familial Alzheimer Disease (FAD)
• PSEN1 Mutation

Intervention

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

Locations

Country	Name	City	State
Japan	Kawasaki Medical School Hospital	Kurashiki	Okayama
Japan	Kyoto University Hospital	Kyoto
Japan	Nagoya City University Hospital	Nagoya	Aichi
Japan	Asakayama Hospital	Sakai	Osaka
Japan	Osaka University	Suita	Osaka
Japan	Tokushima University Hospital	Tokushima
Japan	Tokyo Metropolitan Geriatric Hospital	Tokyo
Japan	Mie University Hospital	Tsu	Mie

Sponsors (10)

Lead Sponsor	Collaborator
Kyoto University	Asakayama Hospital, Kawasaki Medical School Hospital, Mie University, Nagoya City University Hospital, Osaka University, Time Therapeutics, Inc., Tokushima University, Tokyo Metropolitan Geriatric Medical Center, Towa Pharmaceutical Co.,Ltd.

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Wearable physical activity meter		Until Week 20 and 36
Other	Finger tapping sensor readout		Until Week 20 and 36
Other	Brain amyloid PET image		Until Week 36
Other	Brain tau PET image		Until Week 36
Other	Upper motor neuron burden score		Until Week 20 and 36
Other	Plasma Aß-related peptides concentration		Until Week 20 and 36
Primary	Safety (Incidence and severity of adverse events and adverse reactions)		Until Week 50 (end of trial)
Primary	Severe impairment battery-Japanese version (SIB-J)		Until Week 20 and 36
Primary	Neuropsychiatric Inventory (NPI)		Until Week 20 and 36
Secondary	Mental Function Impairment Scale (MENFIS)		Until Week 20 and 36
Secondary	Mini-Mental State Examination-Japanese (MMSE-J)		Until Week 20 and 36
Secondary	Disability Assessment for Dementia (DAD)		Until Week 20 and 36
Secondary	Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III		Until Week 20 and 36
Secondary	Apathy Scale		Until Week 20 and 36
Secondary	Plasma Aß protein concentration		Until Week 20 and 36
Secondary	Plasma NfL protein concentration		Until Week 20 and 36
Secondary	Plasma Total Tau, Plasma p-Tau concentration		Until Week 20 and 36
Secondary	Cerebrospinal fluid (CSF) Aß concentration		Until Week 36
Secondary	CSF Total Tau, CSF p-Tau concentration		Until Week 36
Secondary	Blood bromocriptine concentration		Until Week 20 and 36