A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Kazuo Washida; Satoshi Saito; Tomotaka Tanaka; Yuriko Nakaoku; Hiroyuki Ishiyama; Soichiro Abe; Takehito Kuroda; Shinsaku Nakazawa; Chikage Kakuta; Katsuhiro Omae; Kenta Tanaka; Manabu Minami; Yoshiaki Morita; Tetsuya Fukuda; Akihiro Shindo; Takakuni Maki; Kazuo Kitamura; Hidekazu Tomimoto; Toshihiko Aso; Masafumi Ihara

doi:10.1016/j.cccb.2024.100211

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cereb Circ Cogn Behav. 2024 Feb 6:6:100211. doi: 10.1016/j.cccb.2024.100211. eCollection 2024.

Authors

Kazuo Washida¹, Satoshi Saito¹, Tomotaka Tanaka¹, Yuriko Nakaoku², Hiroyuki Ishiyama¹, Soichiro Abe¹, Takehito Kuroda¹, Shinsaku Nakazawa¹, Chikage Kakuta¹, Katsuhiro Omae³, Kenta Tanaka³, Manabu Minami³, Yoshiaki Morita⁴, Tetsuya Fukuda⁴, Akihiro Shindo⁵, Takakuni Maki⁶, Kazuo Kitamura⁷, Hidekazu Tomimoto⁵, Toshihiko Aso⁸, Masafumi Ihara¹

Affiliations

¹ Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.
² Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Suita, Japan.
³ Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan.
⁴ Department of Radiology, National Cerebral and Cardiovascular Center, Suita, Japan.
⁵ Department of Neurology, Mie University Graduate school of Medicine, Tsu, Japan.
⁶ Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁷ Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
⁸ Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit.

Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL.

Sample size: Overall, 60 patients will be recruited.

Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180.

Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis.

Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition.

Clinical trial registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Keywords: Adrenomedullin; Arterial spin labeling; Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; Cerebral blood flow; Clinical trial.