Examining the usefulness of the brain network marker program using fMRI for the diagnosis and stratification of major depressive disorder: a non-randomized study protocol.

BACKGROUND: Although many studies have reported the biological basis of major depressive disorder (MDD), none have been put into practical use. Recently, we developed a generalizable brain network marker for MDD diagnoses (diagnostic marker) across multiple imaging sites using resting-state functional magnetic resonance imaging (rs-fMRI). We have planned this clinical trial to establish evidence for the practical applicability of this diagnostic marker as a medical device. In addition, we have developed generalizable brain network markers for MDD stratification (stratification markers), and the verification of these brain network markers is a secondary endpoint of this study. METHODS: This is a non-randomized, open-label study involving patients with MDD and healthy controls (HCs). We will prospectively acquire rs-fMRI data from 50 patients with MDD and 50 HCs and anterogradely verify whether our diagnostic marker can distinguish between patients with MDD and HCs. Furthermore, we will longitudinally obtain rs-fMRI and clinical data at baseline and 6 weeks later in 80 patients with MDD treated with escitalopram and verify whether it is possible to prospectively distinguish MDD subtypes that are expected to be effectively responsive to escitalopram using our stratification markers. DISCUSSION: In this study, we will confirm that sufficient accuracy of the diagnostic marker could be reproduced for data from a prospective clinical study. Using longitudinally obtained data, we will also examine whether the "brain network marker for MDD diagnosis" reflects treatment effects in patients with MDD and whether treatment effects can be predicted by "brain network markers for MDD stratification". Data collected in this study will be extremely important for the clinical application of the brain network markers for MDD diagnosis and stratification. TRIAL REGISTRATION: Japan Registry of Clinical Trials ( jRCTs062220063 ). Registered 12/10/2022.

Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/ß-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial.

BACKGROUND: There is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis. METHODS: In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160mg/m2/day for six cycles of 1week on and 1week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440). FINDINGS: Between Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)]. After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40mg/m2/day cohort, and improved in one patient by 3 points in the 160mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10mg/m2/day cohort, and improved in one patient in the 40mg/m2/day cohort. INTERPRETATION: This study showed that administration of 10 or 40mg/m2/day intravenous PRI-724 over 12weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160mg/m2/day cohort. FUNDING SOURCE: AMED.

Long-term clinical outcome after intramuscular transplantation of granulocyte colony stimulating factor-mobilized CD34 positive cells in patients with critical limb ischemia.

BACKGROUND: Our phase I/IIa clinical trial revealed that intramuscular transplantation of autologous, GCSF-mobilized CD34+ cells was safe, feasible and potentially effective at week 4 and 12 post cellular therapy in 17 patients with chronic critical limb ischemia (CLI) (5 patients with atherosclerotic peripheral arterial disease (PAD) and 12 with Buerger's disease). However, long-term outcome of the cell therapy has yet to be reported. METHODS AND RESULTS: Incidence of major clinical events and physiological parameters of limb ischemia were evaluated at week 52, 104, 156 and 208 post CD34+ cell therapy. No patients died by week 104, whereas 3 patients with PAD died by week 156 and 1 patient with Buerger's disease died by week 208 due to cardiac complications. No patients underwent major amputation, whereas 1 patient with Buerger's disease underwent unplanned minor amputation by week 104. CLI-free ratio was 88.2% at week 52 and 104, 92.3% at week 156 and 84.6% at week 208 in all patients. Significant improvement of toe brachial pressure index versus baseline was sustained up to week 208 and that of transcutaneous partial oxygen pressure was kept up to week 156. The Wong-Baker FACES pain rating scale, ulcer size and exercise tolerance significantly improved at week 52, the final evaluation time point, compared with baseline. Subgroup analysis revealed the similar outcome in patients with Buerger's disease. CONCLUSIONS: Favorable clinical outcomes as well as physiological evidences strongly indicate the long-term benefit of GCSF-mobilized CD34+ cell transplantation for retrieval from CLI, especially in patients with Buerger's disease.