CLINICAL TRIAL PROTOCOL OF BROMOCRIPTINE IN ALZHEIMER'S DISEASE WITH PRESENILIN 1 (PSEN1) MUTATIONST

BACKGROUND: Pathogenic variants in the PSEN1 gene are the most frequent cause of early-onset Alzheimer's disease (AD). Most of the AD patients with mutations in the PSEN1 gene (PSEN1-AD) experience onset in their 20s to 50s, and their cognitive function deteriorates rapidly, leading to death within several years. Medications for PSEN1-AD are limited to symptomatic therapies and no established radical treatments are available. To develop therapeutic compounds for PSEN1-AD, we previously established induced pluripotent stem cells (iPSCs) from patients with PSEN1-AD. iPSCs were established by introducing a small number of genes into patients' cells. Established iPSCs can differentiate into any type of cell in the body and proliferate indefinitely. We established an iPSC-based screening system by modelling Aβ phenotypes of PSEN-1AD. We utilized an existing drug library the safety and pharmacokinetic profile of which had already been confirmed clinically and approved for use in human. After the screening, we found bromocriptine to be the most potent modifier of Aβ production for PSEN1-AD neurons among existing drugs. Bromocriptine is an already approved drug with few safety concerns and a long history of usage in clinical settings. Bromocriptine was approved for the treatment of Parkinson's disease (approved dosage 22.5mg/day), pituitary tumor, and hyperprolactinaemia, and was proven to penetrate the blood-brain barrier. Based on iPSC studies, as we hypothesized that bromocriptine might attenuate the clinical symptoms of PSEN1-AD patients, we decided to conduct a clinical trial to evaluate the safety and efficacy of the first-time administration to PSEN1-AD patients as an investigator-initiated clinical trial (exploratory study). OBJECTIVES: In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. METHODS: This is a multi-center, randomized, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese (MMSE-J) score of ≤ 25 will be randomly assigned, at a 2 : 1 ratio, to the trial drug or placebo group (≥ 4 patients in TW-012R and ≥ 2 patients in placebo). Owing to the ethical issue for patients assigned to the placebo group, unequal randomization will be employed. This clinical trial consists of a screening period, double-blind phase (9 months), and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day), and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. For cognitive function, Severe Impairment Battery-Japanese (SIB-J) will be evaluated. For psychological function to evaluate behavioral and psychological symptoms of dementia (BPSD), Neuropsychiatric Inventory (NPI) will be assessed. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. Secondary endpoints include Mental Function Impairment Scale (MENFIS), MMSE-J, Disability Assessment for Dementia (DAD), Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, Apathy Evaluation Scale Informant Version, plasma Aβ protein, plasma neurofilament light chain protein (NfL), plasma total tau and plasma phosphorylated tau protein, cerebrospinal fluid Aβ (CSF Aβ), cerebrospinal fluid total tau and phosphorylated tau protein (CSF total/p-tau), and blood bromocriptine concentration. In addition, wearable physical activity meter, measurement with finger tapping device, brain amyloid PET, brain tau PET, Upper Motor Neuron Burden Score (UMNB), and plasma Aβ-related peptides will be assessed as reference endpoints. Due to the COVID-19 pandemic in 2020, we amended our protocol to make it possible to deliver study drugs if a participant cannot visit a medical facility. For participant retention and safety reasons, a participant will have 10 phone-call-visits in addition to monthly onsite-visits. This trial registration numbers are jRCT2041200008 (Japan Registry of Clinical Trials), and NCT 04413344 (ClinicalTrials.gov). RESULTS: This ongoing clinical trial started to enroll participants in June 2020 and will end in March 2022. This study will be conducted at 6 academic hospitals and 1 community hospital in Japan. CONCLUSION: This study is the first to use bromocriptine for PSEN1-AD patients, and it presents both a low- and a high-dose safety verification as well as cognitive, neuropsychiatric and biomarker-based efficacy detections. The trial design includes enrichment of the patient population by iPSC technology. Digital biomarkers will potentially reduce participants' and caregivers' burden in future trials. This is an investigator-initiated clinical trial for the safety and early efficacy evaluation with a small number of participants. Therefore, a large-scale study will be needed in the following phases.