Placebo-controlled Non-inferiority Trial Research Articles

One-Day Compared With 7-Day Nitrofurantoin for Asymptomatic Bacteriuria in Pregnancy

To evaluate whether a 1-day nitrofurantoin regimen is as effective as a 7-day regimen in eradicating asymptomatic bacteriuria during pregnancy. A multicenter, double-blind, randomized, placebo controlled noninferiority trial was conducted in antenatal clinics in Thailand, the Philippines, Vietnam, and Argentina. Pregnant women seeking antenatal care between March 2004 and March 2007 who met the inclusion and exclusion criteria were invited to participate in the study. Those who consented were randomly allocated to receive either a 1-day or a 7-day course of 100 mg capsules of nitrofurantoin, which was taken twice daily. The primary outcome was bacteriologic cure on day 14 of treatment. : A total of 1,248 of 24,430 eligible women had asymptomatic bacteriuria, making the overall prevalence of 5.1%. Of these 1,248 women, 778 women were successfully recruited, and 386 and 392 women were randomly allocated to 1-day and 7-day regimens, respectively. Escherichia coli was the most common potentially pathogenic bacteria detected, its prevalence approaching 50%. Bacteriologic cure rates at treatment day 14 were 75.7% and 86.2% for 1-day and 7-day regimens, respectively. The cure rate difference was -10.5% (95% confidence interval -16.1% to -4.9%). Mean birth weight and mean gestational age at delivery were significantly lower in the 1-day regimen group. There were fewer adverse effects in the 1-day regimen group, but the differences were not statistically significant. A 1-day regimen of nitrofurantoin is significantly less effective than a 7-day regimen. Women with asymptomatic bacteriuria in pregnancy should receive the standard 7-day regimen. ISRCTN, isrctn.org, ISRCTN11966080 I.

The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE). To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE. Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002. 16 university-affiliated rheumatology clinics or practices in 11 U.S. states. 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE. 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group. The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite. Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis. Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis. Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo.

A randomized, double-blind, placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age

Debate continues with respect to a "watch and wait" approach versus immediate antibiotic treatment for the initial treatment of acute otitis media. In this double-blind noninferiority trial, we compared clinical improvement rates at 14 days for children (6 months to 5 years of age) with acute otitis media who were randomly assigned to receive amoxicillin or placebo. We enrolled healthy children who presented to clinics or the emergency department with a new episode of acute otitis media during the fall and winter months in Ottawa (from December 1999 to the end of March 2002). The children were randomly assigned to receive amoxicillin (60 mg/kg daily) or placebo for 10 days. Telephone follow-up was performed on each of days 1, 2 and 3 and once between day 10 and day 14. The primary outcome was clinical resolution of symptoms, defined as absence of receipt of an antimicrobial (other than the amoxicillin in the treatment group) at any time during the 14-day period. Secondary outcomes were the presence of pain and fever and the activity level in the first 3 days, recurrence rates, and the presence of middle ear effusion at 1 and 3 months. According to clinical scoring, 415 of the 512 children who could be evaluated had moderate disease. At 14 days 84.2% of the children receiving placebo and 92.8% of those receiving amoxicillin had clinical resolution of symptoms (absolute difference -8.6%, 95% confidence interval -14.4% to -3.0%). Children who received placebo had more pain and fever in the first 2 days. There were no statistical differences in adverse events between the 2 groups, nor were there any significant differences in recurrence rates or middle ear effusion at 1 and 3 months. Our results did not support the hypothesis that placebo was noninferior to amoxicillin (i.e., that the 14-day cure rates among children with clinically diagnosed acute otitis media would not be substantially worse in the placebo group than the treatment group). Nevertheless, delaying treatment was associated with resolution of clinical signs and symptoms in most of the children.