Efficacy of a digital therapeutics system in the management of essential hypertension: the HERB-DH1 pivotal trial Kazuomi Kario 1*, Akihiro Nomura 2,3,4, Noriko Harada 1, Ayako Okura 1, Kiyose Nakagawa 5, Tomoyuki Tanigawa 5, and Eisuke Hida 6 1 Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498, Japan 2 Innovative Clinical Research Center, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan 3 Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan 4 Department of Biomedical Informatics, CureApp Institute, 4136-1 Azayakozawa, Nagakutra, Kitasaku-Gun, Karuizawa, Nagano 389-0111, Japan 5 CureApp, Inc., . Kodenma-Cho YS building 4th floor, 12-5 Nihonbashi kodenma-Cho, Chuo-ku, Tokyo 103-0001, Japan 6 Department of Biostatistics and Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita-Shi, Osaka 565-0871, Japan * Corresponding author. Tel: +81 285 58 7538, Fax: +81 285 44 4311, Email: [email protected] Aims Digital therapeutics is a new approach to facilitate the non-pharmacological treatment of hypertension using software programmes such as smartphone applications and/or device algorithms. Based on promising findings from a small pilot trial, the HERB Digital Hypertension 1 (HERB-DH1) pivotal trial investigated the efficacy of digital therapeutics in patients with hypertension not receiving antihypertensive medication. Methods and results This prospective, open-label, randomized controlled study was performed at 12 sites in Japan. Patients with hypertension [office systolic blood pressure (SBP) 140 to <180 mmHg and 24 h SBP ≥130 mmHg] were randomly assigned 1:1 to the digital therapeutics group (HERB system + standard lifestyle modification) or control group (standard lifestyle modification alone). The primary efficacy endpoint was the mean change in 24 h ambulatory SBP from baseline to 12 weeks; key secondary efficacy endpoints were mean changes in office and home blood pressure (BP) from baseline to 12 weeks. All analyses were conducted in the full analysis set population. Between December 2019 and June 2020, 390 patients were randomly assigned to the digital therapeutics group (n = 199) or control (n = 191) group. Between-group differences in 24-h ambulatory, home, and office SBPs at 12 weeks were −2.4 (95% confidence interval −4.5 to −0.3), −4.3 (−6.7 to −1.9), and −3.6 (−6.2 to −1.0) mmHg, respectively. No major programme-related safety events occurred up to 24 weeks. Conclusion The HERB-DH1 pivotal study showed the superiority of digital therapeutics compared with standard lifestyle modification alone to reduce 24-h ambulatory, home, and office BPs in the absence of antihypertensive medications. Keywords Hypertension • Digital therapeutics • Lifestyle modification • Ambulatory blood pressure • Home blood pressure