Japanease

April. 30, 2020

July. 17, 2020

jRCT2041200008

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 mutations (REBRAnD)

Repurposing bromocriptine for Abeta metabolism in Alzheimer's disease (REBRAnD)

Tomimoto Hidekazu

Mie University Hospital

2-174 Edobashi, Tsu-city

+81-59-231-5107

tomimoto@clin.medic.mie-u.ac.jp

Banno Haruhiko

Kyoto University Hospital

54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-city

+81-75-751-4748

rebrand_office@kuhp.kyoto-u.ac.jp

June. 09, 2020

10

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

none

1. Alzheimer's disease patients with PSEN1 mutations
2. 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
3. An MMSE-J score of <= 25
4. 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
5. 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.
6. Patients with a reliable and close relationship with a partner/caregiver
7. Age>=20 years at the time of giving informed consent
8. Written informed consent has been obtained from the patient or his/her legally acceptable representative to participate in this trial

1. Difficulty with the oral intake of tablets
2. Patients receiving anti-dementia drugs who have changed the dosing regimen during the 2 months prior to giving informed consent
3. 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)
4. Presence of clinically relevant or unstable mental disorders. Patients with major depression in remission can be enrolled.
5. Imminent risk of self-harm or harm to others
6. Body mass index (BMI) of <= 17 or >= 35
7. Patients with a history of alcohol dependence, drug dependence, or drug abuse within the 5 years before providing informed consent
8. HBs antigen positive
9. Anti-HIV antibody positive
10. Anti-HTLV-1 antibody positive
11. Patients with an active infection, such as hepatitis C and syphilis (STS/TPHA)
12. 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
13. 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
14. 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
15. 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
16. Patients with clinically significant vitamin B1/B12 deficiency or folic acid deficiency within 6 months prior to giving informed consent
17. Patients who have participated in other clinical research/trials involving interventions within the 3 months prior to providing informed consent
18. Patients who have previously received bromocriptine or TW-012R
19. Patients with a history of hypersensitivity to bromocriptine or ergot alkaloids
20. 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
21. Pregnant females, lactating females, females who may be pregnant (pregnancy test will be done to see if she is pregnant), or females who wish to become pregnant
22. Other patients who are considered inappropriate to participate in this trial at the discretion of the investigator or sub-investigator

20age old over
No limit

Both

Alzheimer's disease patients with PSEN1 mutations

D001971

Bromocriptine, Dopamine-agonist

[Double -blind phase]
1) Low-dose maintenance period (start of trial treatment--Week20)
Oral administration of the trial drug (TW-012R or placebo) will be started at 1 tablet once a day immediately after breakfast. The daily dose will be increased by 1 tablet per week up to 4 tablets daily as the maintenance dose. When the daily dose is 2 tablets, the drug will be administered immediately after breakfast and dinner. When the daily dose is 3 tablets or more, the drug will be administered in divided doses immediately after each meal.
2) High-dose maintenance period (Weeks 20--36)
Treatment with the trial drug (TW-012R or placebo) will be started at 5 tablets daily (the daily dose will be further increased by 1 tablet from the maintenance dose for the low-dose maintenance period).The daily dose will be increased by 1 tablet per week up to 9 tablets daily as the maintenance dose. The drug will be orally administered in divided doses immediately after each meal.
3) Tapering period of the trial drug (Weeks 36--37)
The dose will be tapered to 1 tablet over 1 week from the last dose in the high-dose maintenance period.

[Extended treatment period] (Weeks 37--50)
From Week 37, the oral administration of TW-012R will be started at 1 tablet (2.5mg) once a day, and the daily dose will be increased by 1 tablet per week. The drug will be orally administered in divided doses immediately after each meal at a standard maintenance dose of 4 tablets (10mg) daily, up to a maximum of 9 tablets (22.5 mg) daily. The drug will be administered until Week 48, and then tapered over about 1 to 2 weeks to complete the treatment.
The dose may be increased or decreased as appropriate at the discretion of the investigator or sub-investigator from the viewpoint of the safety of trial subjects.

D000544

Dementia, Alzheimer's disease, familial, genetic, presenilin 1

1) Safety (incidence and severity of adverse events and adverse reactions)
2) Efficacy: SIB-J
3) Efficacy: NPI

<Secondary endpoints>
Efficacy
1) MENFIS
2) MMSE-J
3) DAD
4) UPDRS part III
5) Apathy Scale
6) Plasma Abeta protein
7) Plasma NfL protein
8) Plasma Total Tau, Plasma p-Tau
9) CSF Abeta
10) CSF Total Tau, CSF p-Tau
11) Blood bromocriptine concentration
<Reference endpoints>
1) Wearable physical activity meter
2) Finger tapping
3) Brain amyloid PET
4) Brain tau PET
5) Upper motor neuron burden
6) Plasma Abeta related peptides

Recruiting

Time Therapeutics, Inc.
Not applicable
Towa Pharmaceutical Co.,Ltd.
Not applicable
Mie University Hospital, Institutional Review Board
2-174 Edobashi, Tsu-city, Mie

+81-59-231-5246

chiken-jim@clin.medic.mie-u.ac.jp
Approval

Mar. 18, 2020