This research paper presents a study protocol for an exploratory clinical trial evaluating the safety and potential efficacy of autologous peripheral blood mononuclear cell (PBMNC)-loaded injectable cell scaffold (ICS-001) for angiogenic therapy in chronic limb-threatening ischaemia (CLTI). CLTI, the advanced stage of peripheral artery disease, presents significant therapeutic challenges.

Angiogenic therapy using ICS-001 with PBMNCs—a novel approach designed to enhance local cell retention and promote neovascularisation—will be explored. The study will address the pathophysiology of CLTI, the limitations of current treatments and the rationale for cell-based therapies, alongside the clinical trial design for evaluating the safety and efficacy of ICS-001. We hypothesise that ICS-001 will improve ulcer healing and reduce ischaemic rest pain in patients with CLTI. This paper outlines the methodology, including patient selection, CD34⁺ cell mobilisation, scaffold preparation, injection protocols, clinical assessments, data collection and safety monitoring. The anticipated results, discussion and conclusion will offer insight into the clinical significance and potential impact of ICS-001 as a pioneering angiogenic therapy for CLTI.

The institutional review boards of all participating hospitals approved this study protocol (latest version V.6.0, 5 June 2025). Final data will be made publicly available. A report detailing the study results will be submitted for publication in an appropriate peer-reviewed journal.

Data are available on reasonable request. Technical appendix, statistical code is available by contacting the corresponding author. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) licence, which permits others to distribute, remix, adapt, build on this work non-commercially, and licence their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

jRCT2052230115, Japan Registry of Clinical Trials.

Hypertension is a major health challenge imposing substantial economic and health burdens worldwide. This study compared treatment outcomes and costs between cost-intensive and non-cost-intensive pharmacotherapies, defined by prescribing intervals and the type of drugs, using electronic health record (EHR) data from multiple healthcare facilities, focusing on the type of antihypertensive drug and prescribing patterns.

A retrospective cohort study. A mixed-effects Cox proportional hazards model was used to investigate the association between cardiovascular events and healthcare resource use.

EHRs from 34 primary care facilities in Japan.

Patients prescribed either angiotensin receptor blockers (ARBs) alone or calcium channel blockers (CCBs) alone were included.

During 6629 person-years of follow-up, 71 events were observed. Model diagnostics confirmed the proportional hazards assumption and substantial inter-clinic heterogeneity. The type of drug (ARBs or CCBs) had no statistically significant impact on the incidence of cardiovascular events (HR 0.999, 95% CI 0.603 to 1.655). Similarly, shorter prescribing intervals (less than 36 days) were not significantly associated with the outcome (HR 1.724, 95% CI 0.906 to 3.279). The mean annual medical cost per patient for the cost-intensive (ARB with short prescribing intervals) and non-cost-intensive (CCB with long prescribing intervals) groups was Japanese yen (JPY) 137 023 and JPY 85 911, respectively. Sensitivity analysis using different time windows yielded similar results, confirming the robustness of the findings.

No apparent reduction in cardiovascular events associated with the use of ARBs or shorter prescribing intervals was observed despite the elevated cost caused by intensive pharmacotherapy and frequent clinic visits.