PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial.

BACKGROUND: Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization. METHODS: People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12-36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events. RESULTS: Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048). CONCLUSION: Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).

Placental expanded mesenchymal-like cells (PLX-R18) for poor graft function after hematopoietic cell transplantation: A phase I study.

Persistent cytopenia in the post-hematopoietic cell transplantation (HCT) setting can occur despite adequate engraftment of donor cells. PLX-R18, a placental-derived mesenchymal-like cell product, is expanded ex vivo in a 3-dimensional environment. PLX-R18 cells secrete a large array of hematopoietic factors, which promote regeneration, maturation, and differentiation of hematopoietic cells and stimulate their migration to peripheral blood. This phase 1, first-in-human study (NCT03002519), included 21 patients with incomplete hematopoietic recovery post-HCT. Patients were treated with escalating doses of PLX-R18: 3 patients received 1 million cells/kg, 6 received 2 million cells/kg, and 12 received 4 million cells/kg via multiple intramuscular injections. While patients received only two administrations of cells during the first week, peripheral blood counts continued to increase for months, peaking at 6 months for hemoglobin (Hb, p = 0.002), lymphocytes (p = 0.008), and neutrophils (ANC, p = 0.063), and at 9 months for platelets (p < 0.001) and was maintained until 12 months for all but ANC. The need for platelet transfusions was reduced from 5.09 units/month at baseline to 0.55 at month 12 (p = 0.05). Likewise, red blood cell transfusions decreased from 2.91 units/month at baseline to 0 at month 12 (p = 0.0005). PLX-R18 was safe and well tolerated and shows promise in improving incomplete hematopoietic recovery post-HCT.

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study.

BACKGROUND: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. METHODS: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. RESULTS: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. CONCLUSIONS: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02610283.

Safety and Tolerability Study of an Intravenously Administered Small Interfering Ribonucleic Acid (siRNA) Post On-Pump Cardiothoracic Surgery in Patients at Risk of Acute Kidney Injury.

INTRODUCTION: Patients undergoing on-pump cardiac surgery are at an increased risk of acute kidney injury. QPI-1002, a small interfering ribonucleic acid, is under clinical development for the prevention of acute kidney injury. The safety, tolerability, and pharmacokinetics of QPI-1002 was evaluated in this first-in-man, Phase 1 study of a small, interfering ribonucleic acid in patients at risk of acute kidney injury after on-pump cardiac surgery. METHODS: In this phase 1 randomized, placebo-controlled dose-escalation study, a single i.v. dose of QPI-1002 was administered in subjects undergoing on-pump cardiac surgery. Subjects received placebo (n = 4), or QPI-1002 in increasing doses of 0.5 mg/kg (n = 3), 1.5 mg/kg (n = 3), 5 mg/kg (n = 3), and 10 mg/kg (n = 3). RESULTS: A total of 16 subjects were enrolled in the study. The average maximum concentration and area under the curve from the time of dosing to the last measurable concentration of QPI-1002 were generally dose proportional, indicating that exposure increased with increasing dose. The average mean residence time (mean residence time to the last measurable concentration) was 10 to 13 minutes in all 4 drug-dosing cohorts. Adverse events occurred at a similar rate in all study groups. Of the total 109 reported adverse events, the events were distributed as 26 in the placebo group and 21, 19, 24, and 19 in the QPI-1002 0.5, 1.5, 5.0, and 10.0 mg/kg groups, respectively. Eight of the 16 subjects experienced at least 1 serious adverse event: 4 (100%) in the placebo group and 4 (33.3%) in the combined QPI-1002 cohorts. DISCUSSION: QPI-1002 was rapidly eliminated from plasma. QPI-1002 was safe and well tolerated across all dose groups. Overall, no dose-limiting toxicities or safety signals were observed in the study. Further development of QPI-1002 for prophylaxis of acute kidney injury is warranted.

Molecular analysis of transitional cell carcinoma using cDNA microarray.

The incidence of transitional cell carcinoma (TCC), the fourth most common neoplasm diagnosed in men, is rising. Despite the development of several noninvasive diagnostic tests, none have gained full recognition by the clinicians. Gene expression profiling of tumors can identify new molecular markers for early diagnosis and disease follow-up. It also allows the classification of tumors into subclasses assisting in disease diagnosis and prognosis, as well as in treatment selection. In this paper, we employed expression profiling for molecular analysis of TCC. A TCC-derived cDNA microarray was constructed and hybridized with 19 probes from normal urothelium and TCC tissues. Hierarchical clustering analysis identified all normal urothelium samples to be tightly clustered and separated from the TCC samples, with 29 of the genes significantly induced (t-test, P<10(-5)) in noninvasive TCC compared to normal urothelium. The identified genes are involved in epithelial cells' functions, tumorigenesis or apoptosis, and could become molecular tools for noninvasive TCC diagnosis. Principal components analysis of the noninvasive and invasive TCC expression profiles further revealed sets of genes that are specifically induced in different tumor subsets, thus providing molecular fingerprints that expand the information gained from classical staging and grading.