Attenuating the atopic march: Meta-analysis of the dupilumab atopic dermatitis database for incident allergic events.

BACKGROUND: Atopic march refers to the sequential development of allergic diseases from infancy through adolescence, typically beginning with atopic dermatitis (AD), followed by food allergy and then airway diseases, later evolving to broader or worsened spectrum of allergic diatheses. No intervention has shown to alter its course. OBJECTIVE: We sought to determine the rate of acquisition of new or worsened allergic events for dupilumab versus placebo in patients with AD. METHODS: Allergy-associated events from 12 clinical trials were grouped into 17 allergy categories, and IgE changes from baseline were defined. A new/worsened event was considered one step of atopic march. Treatment effect was assessed by incidence rate ratios (IRRs), dupilumab versus placebo, by meta-analysis. RESULTS: The duration of pooled AD studies was 4 to 52 weeks (1359 patient-years; n = 2296 dupilumab, n = 1229 placebo, median age 35 years). The median age at AD onset was 2 years. Baseline allergic disease burden was comparable between groups. Dupilumab reduced the risk of new/worsening allergies by 34% (IRR 0.66; 95% confidence interval [CI], 0.52-0.84) and new allergies by 37% (IRR 0.63; 95% CI, 0.48-0.83) versus placebo. Including IgE category shift, the IRR for combined new/worsening allergies was reduced by 54% (IRR 0.46; 95% CI, 0.36-0.57). These treatment benefits did not reverse on treatment discontinuation in off-treatment follow-up. CONCLUSIONS: The acquisition/worsening of allergic conditions suggestive of atopic march was observed in a pooled adult/adolescent AD study population with inadequately controlled AD. Treatment with dupilumab reduced new/worsened allergy events versus placebo; inclusion of IgE category change increased the apparent benefit.

Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI). METHODS: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI). RESULTS: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups. CONCLUSIONS: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts. CLINICAL TRIALS REGISTRATION: NCT02325791.

Treatment of chronic low back pain with etoricoxib, a new cyclo-oxygenase-2 selective inhibitor: improvement in pain and disability--a randomized, placebo-controlled, 3-month trial.

We evaluated etoricoxib, a novel COX-2-specific inhibitor, in 319 patients with chronic low back pain (LBP) in this double-blind, placebo-controlled trial. Patients were randomized to a 60 mg dose (n = 103) or 90 mg dose (n = 107) of etoricoxib, or placebo (n = 109), daily for 12 weeks. The primary endpoint was low back pain intensity scale (Visual Analog Scale of 0- to 100-mm) time-weighted average change from baseline over 4 weeks. Other endpoints included evaluation over 3 months of low back pain intensity scale, Roland-Morris Disability Questionnaire (RMDQ), low back pain bothersomeness scale, patient- and investigator-global assessments, Patient Health Survey (MOS SF-12), rescue acetaminophen use, and discontinuation due to lack of efficacy. Etoricoxib provided significant improvement from baseline versus placebo in pain intensity (4 weeks: 12.9 mm and 10.3 mm for 60-mg and 90-mg doses, P <.001 for each; 12 weeks: 10.5 mm and 7.5 mm for 60-mg and 90-mg doses, P =.001 and.018, respectively). Etoricoxib at either dose led to significant improvement in other endpoints, including RMDQ scores, bothersomeness scores and global assessments. Etoricoxib given once daily provided significant relief of symptoms, and disability associated with chronic LBP that was observed 1 week after initiating therapy, was maximal at 4 weeks, and was maintained over 3 months.

Pain management in osteoarthritis: a focus on onset of efficacy--a comparison of rofecoxib, celecoxib, acetaminophen, and nabumetone across four clinical trials.

UNLABELLED: We compared onset of efficacy (during days 1 to 6) of 2 coxibs (rofecoxib, celecoxib) with acetaminophen and nabumetone by using a prespecified approach to data from 4 similarly designed 6-week randomized osteoarthritis trials. In 2 trials, rofecoxib (12.5 mg and 25 mg once daily) was compared with celecoxib (200 mg once daily) and acetaminophen (4000 mg daily). In the other 2 trials, rofecoxib (12.5 mg) was compared with nabumetone (1000 mg once daily) and placebo. Efficacy end points included Patient Global Response to Therapy and Western Ontario and McMaster Osteoarthritis Index scores. Rofecoxib (12.5- and 25-mg doses) consistently demonstrated a faster onset of osteoarthritis (OA) efficacy than the comparator drugs during the first 6 days of therapy of OA patients experiencing "flare." Acetaminophen resulted in the slowest onset of efficacy. There was a strong correlation (0.7) between efficacy response during days 1 to 6 and that averaged over 6 weeks. Rates of discontinuation as a result of lack of efficacy were significantly lower (P < .02) for each of the coxib-treated groups compared with acetaminophen and for rofecoxib 12.5 mg (P = .01) compared with nabumetone. Rofecoxib treatment, with its faster onset of OA efficacy and lower rates of related discontinuations, might provide efficacy advantages in the treatment of OA pain. PERSPECTIVE: The efficacy of rofecoxib, celecoxib, nabumetone, and acetaminophen is established for the majority of OA patients within the first 6 days of therapy, and this predicts efficacy during the longer term. Rofecoxib provides significantly faster time to onset of efficacy and better improvement on multiple measures versus the comparators.