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.

CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis.

BACKGROUND: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). OBJECTIVE: Evaluate laquinimod's efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months (n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. RESULTS: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67-1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo (p < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both, p = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg. CONCLUSION: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01707992).

Perceptions of race/ethnic discrimination in relation to mortality among Black women: results from the Black Women's Health Study.

BACKGROUND: Because racial discrimination is a form of chronic psychological stress that might unfavorably affect health, we examined whether perceived experiences of racism among black women are associated with mortality. METHODS: We followed 48 924 participants in the Black Women's Health Study (mean age, 40.5 years) for 8 years to assess the risk of all-cause mortality associated with perceived experiences of racism. Subanalyses of cancer and cardiovascular mortality were also conducted. Perceived racism was evaluated by 8 questions about institutionalized racism (unfair treatment on the job, in housing, or by the police) and everyday experiences of racism (eg, others acting as if the woman was not intelligent). We estimated the relative risk of death with Cox proportional hazard models, adjusting for traditional and socioenvironmental risk factors. RESULTS: During 412 224 person years of follow-up from 1997 to 2005, there were 920 deaths, including 277 due to cancer and 195 due to cardiovascular causes. All-cause mortality was not associated with institutionalized racism (relative risk, 1.0; 95% confidence interval, 0.8-1.2) for the highest category vs the lowest or with everyday racism (relative risk, 0.9; 95% confidence interval, 0.8-1.2) for the highest quartile compared with the lowest. Risk estimates for the highest categories of perceived racism relative to the lowest were greater than 1.0 for cancer deaths and less than 1.0 for cardiovascular disease death but were not statistically significant. CONCLUSIONS: In this large prospective study of black women, reported experiences of racism were not significantly related to mortality. Longer follow-up of this relatively young cohort and further work is warranted in this complex area of research because continued race/ethnic disparities in mortality are not entirely explained by traditional risk factors.

Cardiovascular risk indicators and perceived race/ethnic discrimination in the Dallas Heart Study.

BACKGROUND: The objective of the study was to evaluate the association between race/ethnic (r/e) discrimination and subclinical cardiovascular disease (CVD). Although r/e discrimination is a chronic stressor that might have negative health effects, cardiovascular data related to experiences with discrimination among different r/e groups in the United States remain sparse. METHODS: Using data from the Dallas Heart Study, we assessed the association between perceived r/e discrimination and traditional CVD risk factors, C-reactive protein (CRP), aortic plaque area and wall thickness, and coronary calcium (CAC) score among black, white, and Hispanic participants. Prevalent CAC was defined as a CAC score > or =10 Agatston units; CRP elevation was defined as > or =3 mg/L. Participants were asked, "Have you ever been discriminated against due to your race/ethnicity? (responses: yes, no, or don't know)". RESULTS: Blacks reported r/e discrimination more frequently than whites or Hispanics (P < .0001). Blacks who reported r/e discrimination were more likely to be college graduates, to have a family history of myocardial infarction, and to be more physically active than blacks who did not report r/e discrimination (each P < .05). Hispanics who reported r/e discrimination had a higher prevalence of smoking (P < .01) and were more likely to be born in the United States. In models that adjusted for traditional CVD risk factors and medication use, we generally found no association between reports of r/e discrimination and aortic wall thickness, aortic plaque area, prevalent CAC, or elevated CRP in any of the r/e groups. Among blacks, stratification by gender and education did not change the observed relationship between perceived r/e discrimination and CAC or CRP. CONCLUSIONS: Although perceived r/e discrimination is associated with certain health characteristics that may result in negative health outcomes, in general, we found no association of r/e discrimination with either subclinical atherosclerosis as determined by CAC score, aortic wall thickness and aortic plaque area, or inflammation as assessed by elevated CRP levels.