ABSTRACT
OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. METHODS: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. RESULTS: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer ≥100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 µg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for ≥155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. CONCLUSIONS: These results support the continued investigation of VX15/2503 in neurodegenerative diseases. CLINICALTRIALSGOV IDENTIFIER: NCT01764737. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference -0.7%, 95% CI -28.0% to 32.7%).
ABSTRACT
BACKGROUND: Despite the beneficial effects of cardiac rehabilitation (CR) on morbidity and mortality after an acute coronary syndrome (ACS), CR referral rates have been lower than recommended. Using the Canadian Global Registry of Acute Coronary Events (GRACE) database, we examined the temporal trends of CR referral rates in Ontario and its associated factors. METHODS: From the main Canadian GRACE, we retrospectively analyzed data from 11 Ontario hospitals. CR referral rates were analyzed over time. Using multivariate logistic regression, we examined patient characteristics, in-hospital diagnosis, clinical events, and investigations associated with CR referral. RESULTS: From 2000 to 2007, 3338 ACS patients (median age, 64 years; 32% women) were assessed. CR referral rate increased from 2.7% in 2000 to 51.2% in 2007 (P < 0.0001 for trend). Multivariate analysis identified increasing age per decade (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.14-1.29), presentation Killip class ≥ 2 (OR, 1.42; 95% CI, 1.09-1.84), non-ST-elevation ACS (OR, 1.60; 95% CI, 1.35-1.89), no left ventricular function assessment (OR, 1.33; 95% CI, 1.11-1.59), heart failure during hospital admission (OR, 1.48; 95% CI, 1.10-2.00), and in-patient cardiac revascularization (OR, 1.70; 95% CI, 1.38-2.09) as independently associated with lack of CR referral. CONCLUSIONS: CR referral rate after ACS in Ontario continues to be lower than recommended, although there has been a steady increase over time. Factors independently associated with lack of CR referral include advanced age, higher Killip class, non-ST-elevation ACS, lack of left ventricular function assessment, in-hospital heart failure, and revascularization. Targeting nonreferred populations might improve quality of care and close care gaps in secondary prevention.
