2 Minute Medicine Rewind May 7, 2018

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

Verubecestat is an oral agent that inhibits the β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) and has been shown to reduce the level of amyloid-beta in cerebrospinal fluid (CSF) in patients with Alzheimer’s disease (AD). This randomized controlled trial investigated verubecestat for its efficacy in treating mild-to-moderate AD at two daily doses, 12 mg and 40 mg, as compared to placebo. Efficacy was determined by the change in score on the cognitive subscale of the AD Assessment Scale (ADAS-cog) and the change in score on the AD Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL), both measured at 78 weeks. Results for the 1958 patients enrolled showed no significant difference in mean changes in ADAS-cog for  the 12 mg and 40 mg groups, which yielded mean changes of 7.9 and 8.0, respectively, as compared to placebo, which yielded a mean change of 7.7 (p=0.63 for 12 mg vs. placebo, p=0.46 for 40 mg vs. placebo). The mean change from baseline in the ADCS-ADL was also not significantly different from placebo for  either the 12 mg (p=0.49)  or 40 mg (p=0.32) groups, resulting in mean changes of -8.4 and -8.2, respectively, when analyzed with respect to placebo. Additionally, adverse effects were more common in the groups treated with verubecestat. As such, this trial was stopped early for futility. Investigators therefore concluded that verubecestat does not reduce cognitive decline or improve functional status in patients with mild-to-moderate AD compared to placebo.

Emollient Bath Additives for the Treatment of Childhood Eczema (BATHE): Multicentre Pragmatic Parallel Group Randomised Controlled Trial of Clinical and Cost Effectiveness

Emollient therapy is frequently recommended in the management of childhood eczema, a common pediatric skin condition. However, the efficacy of bath emollients is unknown. In this randomized controlled trial, 482 children age 1 to 11 years with atopic dermatitis were randomized to receive emollient bath additives in addition to standard care or standard care only to investigate the effectiveness of bath emollients in the management of childhood eczema. The primary outcome, the patient oriented eczema measure (POEM), was measured weekly for 16 weeks. After adjusting for the baseline severity and confounding variables, researchers found that POEM scores were not significantly different between groups, where there was an average point increase of 0.41 for the emollient group (95% CI -0.27 to 1.10). This was significantly lower than the minimal clinically important difference of a 3 point difference on the POEM. Other measures, such as eczema severity at one year and disease-specific quality of life, did not differ between the two groups. Investigators therefore concluded that there is no evidence of clinical benefit for the use of bath emollients in the standard management of eczema in children.

Effect of Glyburide vs Subcutaneous Insulin on Perinatal Complications Among Women with Gestational Diabetes: A Randomized Clinical Trial

The effective management of gestational diabetes is essential in reducing the risk of both fetal and maternal morbidity. Insulin continues to be the first-line and only pharmacologic treatment approved by the US Food and Drug Administration (FDA), Glyburide represents a potential alternative treatment. This noninferiority randomized controlled trial aimed to compare oral glyburide to subcutaneous insulin for its effects on the composite primary outcome of fetal macrosomia, neonatal hypoglycemia, and hyperbilirubinemia. Investigators randomized 914 women with gestational diabetes requiring pharmacologic treatment after 10 days of dietary intervention.  Patients received either a starting dose of 2.5 mg daily of oral glyburide or a dose of 4 to 20 international units of insulin, given between 1 and 4 times per day. Doses of both insulin and glyburide could be adjusted as necessary, using self-measured blood glucose concentrations. Researchers found  that there was no significant difference between groups with respect to the percentage of patients that met the composite outcome (difference: 4.4%, 1-sided 97.5% CI -∞ to 10.5%, p=0.209), although the upper confidence limit exceeded the non-inferiority margin of 7%. The higher rate of the primary outcome was mainly due to an increased rate of neonatal hypoglycemia. Investigators therefore concluded that this study failed to show that glyburide use in women with gestational diabetes does not result in a greater frequency of perinatal complications, as compared to subcutaneous insulin. The results of this study do not justify the use of glyburide as a first-line treatment in the management of gestational diabetes.

Child Mortality in England Compared with Sweden: a Birth Cohort Study

The United Kingdom has a relatively high child mortality rate within Western Europe. In 2013, the mortality rate in children less than 5 years was 4.9 per 1000 births, significantly higher than rates seen in Sweden, France, Germany, and other Western European countries. This study aimed to evaluate adverse birth characteristics and socioeconomic factors as contributors to the high child mortality rate seen in England, as compared to Sweden. Using nationally-representative cohorts from both countries and using mortality as the outcome, models were constructed adjusting for birth characteristics and socioeconomic factors. Birth characteristics included gestational age, birth weight, and the presence of congenital anomalies. The presence of relevant International Classification of Diseases (ICD-10) diagnoses recorded at birth, during any admission before age 2 years, or death was also taken into account. In the unadjusted analysis, England had a significantly higher rate of mortality at each of the following ages: 2 to 27 days (HR 1.66, 95% CI 1.53 to 1.81), 28 to 364 days (HR 1.59, 95% CI 1.47 to 1.71), and 1 to 4 years (HR 1.27, 95% CI 1.15 to 1.40). However, adjusting for birth characteristics explained 77% of the excess risk of death in England between 2 and 27 days. Adjusting for socioeconomic factors further accounted for an additional 3% of the increased risk of mortality. Between age 28 and 364 days, 68% of the increased risk in England was explained by adverse characteristics at birth and 11% was explained by socioeconomic factors. There was no significant difference between England and Sweden child mortality rates after adjusting for both factors in the age 1 to 4 years group (HR 1.06, 95% CI 0.96 to 1.18). Researchers therefore concluded that adverse birth characteristics and socioeconomics explain a large part of the relatively high child mortality in England.

Effect of Atropine with Propofol vs Atropine with Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Non-emergency Intubation: A Randomized Clinical Trial

All neonates requiring non-emergent intubation should receive pre-medication. In this randomized controlled trial, 173 neonates requiring nasotracheal intubation were randomized to receive premedication with atropine and propofol or atropine, atracurium, and sufentanil to compare prolonged desaturation during neonatal nasotracheal intubation. Prolonged desaturation was defined as an oxygen saturation of less than 80% for longer than 60 seconds. Researchers found that there was no significant difference in the percentage of patients meeting the primary outcome (adjusted risk difference -6.7, 95% CI -21 to 8.1, p=0.38). The atropine-propofol group, however, had a longer mean procedure duration than did the atropine-atracurium-sufentanil (p =0.04) as well as a less frequent excellent quality of sedation rate (51.7% vs. 92.6%,p <0.001). Nevertheless, in the 60 minutes after inclusion, oxygen saturation was preserved significantly better in the atropine-propofol group (p =0.02). Investigators therefore concluded that there were no significant differences in the frequency of prolonged desaturation between the two premedication regimens. However, researchers maintain that the study may have been underpowered to detect clinically important differences. Adverse event rates were similar between the two groups.

Image: PD

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