Novel non-linear models for clinical trial analysis with longitudinal data: A tutorial using SAS for both frequentist and Bayesian methods.

Longitudinal data from clinical trials are commonly analyzed using mixed models for repeated measures (MMRM) when the time variable is categorical or linear mixed-effects models (ie, random effects model) when the time variable is continuous. In these models, statistical inference is typically based on the absolute difference in the adjusted mean change (for categorical time) or the rate of change (for continuous time). Previously, we proposed a novel approach: modeling the percentage reduction in disease progression associated with the treatment relative to the placebo decline using proportional models. This concept of proportionality provides an innovative and flexible method for simultaneously modeling different cohorts, multivariate endpoints, and jointly modeling continuous and survival endpoints. Through simulated data, we demonstrate the implementation of these models using SAS procedures in both frequentist and Bayesian approaches. Additionally, we introduce a novel method for implementing MMRM models (ie, analysis of response profile) using the nlmixed procedure.

Safety and efficacy of vernakalant for the conversion of atrial fibrillation to sinus rhythm; a phase 3b randomized controlled trial.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with significant health risks. One strategy to mitigate the risks associated with long-term AF is to convert AF to sinus rhythm (SR). This study assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to SR. METHODS: Patients with recent-onset (duration >3 h- ≤ 7 days) symptomatic AF and no evidence or history of congestive heart failure were randomized in a 2:1 ratio to receive vernakalant or placebo. Patients received an infusion of vernakalant (3 mg/kg) or placebo over 10 min, followed by a second infusion of vernakalant (2 mg/kg) or placebo 15 min later if AF had not been terminated. The primary efficacy endpoint was conversion of AF to SR for at least 1 min within 90 min of the start of drug infusion. The primary safety endpoint was a composite of: occurrence of clinically significant hypotension, clinically significant ventricular arrhythmia (including torsades de pointes, ventricular tachycardia or ventricular fibrillation) or death within 2 h of starting the drug infusion. RESULTS: A total of 217 patients were randomized to receive vernakalant (n = 145) or placebo (n = 72). Of the 129 individuals who received vernakalant, 59 (45.7 %) converted to SR compared with one of the 68 patients (1.5 %) who received placebo (p < 0.0001). Conversion to SR was significantly faster with vernakalant than with placebo (p < 0.0001), and a greater proportion of patients who received vernakalant than those who received placebo reported no AF-related symptoms at 90 min (p = 0.0264). The primary composite safety endpoint was observed in one patient receiving vernakalant and in no patients receiving placebo. In the vernakalant arm, dysgeusia, paraesthesia and sneezing were the most common treatment-emergent adverse events, and three serious adverse events occurred that were considered to be related to study drug. CONCLUSIONS: Vernakalant resulted in rapid cardioversion of recent-onset AF in almost half of the study population and was generally well tolerated. The safety outcomes affirmed the need for careful selection and management of haemodynamically stable candidates for cardioversion. TRIAL REGISTRATION: NCT00989001 .

Persistence of Antibody to Influenza A/H5N1 Vaccine Virus: Impact of AS03 Adjuvant.

The adjuvant AS03 is stockpiled for future formulations with new and existing vaccines for the control of pandemic influenza virus. We previously reported the immunogenicity of an A/H5N1 vaccine extemporaneously mixed with the AS03 adjuvant for 42 days following vaccination. This report extends those findings to 1 year after vaccination.

Safety, Reactogenicity, and Immunogenicity of Inactivated Monovalent Influenza A(H5N1) Virus Vaccine Administered With or Without AS03 Adjuvant.

BACKGROUND: The national stockpile for influenza pandemic preparedness includes vaccines against an array of strains and adjuvants that could be utilized to induce immunologic priming as a pandemic wave emerges. We assessed the feasibility of a strategy that allows the flexibility of postmanufacture mixture of vaccine and adjuvant at the point of care. METHODS: We conducted a randomized, double-blind, multicenter trial among healthy adults aged 18-49 years who received 2 doses of inactivated influenza A/Indonesia/05/2005 (H5N1 clade 2.2.3) virus vaccine containing either 3.75, 7.5, or 15 µg of hemagglutinin (HA) with or without AS03 adjuvant, administered 21 days apart. Subjects were observed for local (injection site) and systemic reactogenicity and adverse events. Sera were tested for hemagglutination inhibition (HAI) and microneutralization (MN) antibody levels against the homologous strain and 4 heterologous avian strains. RESULTS: Vaccine containing ASO3 adjuvant was associated with significantly more local reactions compared with nonadjuvanted vaccine, but these were short-lived and resolved spontaneously. Although the immune response to nonadjuvanted vaccine was poor, 2 doses of AS03-adjuvanted vaccine containing as little as 3.75 µg of HA elicited robust immune responses resulting in seroprotective titers (≥1:40) to the homologous strain in ≥86% of subjects by HAI and in 95% of subjects by MN. Cross-clade antibody responses were also observed with AS03-adjuvanted vaccine, but not nonadjuvanted vaccine. CONCLUSIONS: AS03 adjuvant formulated with inactivated vaccine at the administration site significantly enhanced the immune responses to H5N1 vaccine and has the potential to markedly improve vaccine responses and accelerate delivery during an influenza pandemic. CLINICAL TRIALS REGISTRATION: NCT01317758.

Point-of-Use Mixing of Influenza H5N1 Vaccine and MF59 Adjuvant for Pandemic Vaccination Preparedness: Antibody Responses and Safety. A Phase 1 Clinical Trial.

BACKGROUND: Avian influenza A/H5N1 has threatened human health for nearly 2 decades. Avian influenza A vaccine without adjuvant is poorly immunogenic. A flexible rapid tactic for mass vaccination will be needed if a pandemic occurs. METHODS: A multicenter, randomized, blinded phase 1 clinical trial evaluated safety and antibody responses after point-of-use mixing of influenza A/Indonesia/05/2005 (H5N1) vaccine with MF59 adjuvant. Field-site pharmacies mixed 3.75, 7.5, or 15 mcg of antigen with or without MF59 adjuvant just prior to intramuscular administration on days 0 and 21 of healthy adults aged 18-49 years. RESULTS: Two hundred and seventy subjects were enrolled. After vaccination, titers of hemagglutination inhibition antibody ≥1:40 were achieved in 80% of subjects receiving 3.75 mcg + MF59 vs only 14% receiving 15 mcg without adjuvant (P < .0001). Peak hemagglutination inhibition antibody geometric mean titers for vaccine + MF59 were ∼65 regardless of antigen dose, and neutralizing titers were 2- to 3-fold higher. Vaccine + MF59 produced cross-reactive antibody responses against 4 heterologous H5N1 viruses. Excellent safety and tolerability were demonstrated. CONCLUSIONS: Point-of-use mixing of H5N1 antigen and MF59 adjuvant achieved target antibody titers in a high percentage of subjects and was safe. The feasibility of the point-of-use mixing should be studied further.

A randomized, placebo-controlled study of vernakalant (oral) for the prevention of atrial fibrillation recurrence after cardioversion.

BACKGROUND: Vernakalant, a relatively atrial-selective antiarrhythmic drug, has previously demonstrated efficacy for the acute conversion of atrial fibrillation (AF) to sinus rhythm. This study was designed to determine the most appropriate oral dose of vernakalant for the prevention of AF recurrence postcardioversion. METHODS AND RESULTS: Patients with nonpermanent AF were randomized to 150, 300, or 500 mg vernakalant or placebo twice daily for up to 90 days. The efficacy analysis was conducted on 605 of 735 patients who entered the maintenance phase on day 3 after cardioversion. The time to the first recurrence of symptomatic sustained AF was significantly longer in the 500 mg vernakalant group, with a median of >90 days versus 29 days in the placebo group (hazard ratio, 0.735; P=0.0275). No significant effect was seen at the lower doses. The percent of patients in sinus rhythm at day 90 was 41%, 39%, and 49% in the 150-mg (n=147), 300-mg (n=148), and 500-mg (n=150) vernakalant groups, respectively, compared with 36% in the placebo group (n=160). There were no vernakalant-related proarrhythmic events. Related serious adverse events occurred in 2 patients in the 150-mg vernakalant group and in 1 patient in each of the other groups. CONCLUSIONS: Vernakalant, 500 mg twice daily, appears to be effective and safe for the prevention of AF recurrence after cardioversion. The absence of proarrhythmia and favorable safety profile is an important finding for the drug. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526136.

A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation.

OBJECTIVES: This randomized double-blind study compared the efficacy and safety of intravenous vernakalant and amiodarone for the acute conversion of recent-onset atrial fibrillation (AF). BACKGROUND: Intravenous vernakalant has effectively converted recent-onset AF and was well tolerated in placebo-controlled studies. METHODS: A total of 254 adult patients with AF (3 to 48 h duration) eligible for cardioversion were enrolled in the study. Patients received either a 10-min infusion of vernakalant (3 mg/kg) followed by a 15-min observation period and a second 10-min infusion (2 mg/kg) if still in AF, plus a sham amiodarone infusion, or a 60-min infusion of amiodarone (5 mg/kg) followed by a maintenance infusion (50 mg) over an additional 60 min, plus a sham vernakalant infusion. RESULTS: Conversion from AF to sinus rhythm within the first 90 min (primary end point) was achieved in 60 of 116 (51.7%) vernakalant patients compared with 6 of 116 (5.2%) amiodarone patients (p < 0.0001). Vernakalant resulted in rapid conversion (median time of 11 min in responders) and was associated with a higher rate of symptom relief compared with amiodarone (53.4% of vernakalant patients reported no AF symptoms at 90 min compared with 32.8% of amiodarone patients; p = 0.0012). Serious adverse events or events leading to discontinuation of study drug were uncommon. There were no cases of torsades de pointes, ventricular fibrillation, or polymorphic or sustained ventricular tachycardia. CONCLUSIONS: Vernakalant demonstrated efficacy superior to amiodarone for acute conversion of recent-onset AF. Both vernakalant and amiodarone were safe and well tolerated in this study. (A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation [AVRO]; NCT00668759).

Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study.

OBJECTIVES: This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy. BACKGROUND: Increased XO activity may contribute to heart failure pathophysiology. METHODS: Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life. RESULTS: The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by approximately 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (-2.3 +/- 2.1 mg/dl vs. -1.0 +/- 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome. CONCLUSIONS: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687).

The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study.

BACKGROUND: Reactive oxygen species (ROS) have been linked to hypertrophy, remodeling and abnormal excitation-contraction coupling. Previous data demonstrated that an increase in oxidative stress is associated to the pathogenesis of congestive heart failure (CHF). We examined whether inhibition of the superoxide anion (*O2(-))-generating enzyme xanthine oxidase (XO) with oxypurinol may improve cardiac function in patients with CHF. METHODS AND RESULTS: A randomized, placebo-controlled, double-blind study on 60 patients (30/group) with New York Heart Association class II-III CHF, comparing 600-mg/day oxypurinol during 1 month with placebo, added to standard therapy. Effects on left ventricular ejection fraction (LVEF), serum uric acid (SUA) level, and 6-minute walking test were analyzed. SUA decreased by 16.0 +/- 2.8 mg/L from baseline to Week 4 in the oxypurinol group relative to placebo (P < .01, n = 30 per group). LVEF showed an increase of 4.7 +/- 2.6% from baseline to Week 4 in the oxypurinol group relative to placebo that did not reach statistical significance (P < .08). When patients with LVEF > 40% at baseline were excluded, a statistically significant increase of 6.8 +/- 2.8% from baseline to Week 4 was seen in the oxypurinol group relative to placebo (P < .02, n = 26 placebo, n = 21 oxypurinol). No treatment-related adverse effects or increase in walking capacity were detected. CONCLUSION: Inhibition of XO by oxypurinol in patients with CHF decreases SUA and improves LVEF in patients with LVEF < or = 40% after 1 month of treatment.