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Concept: Dose

271

Background Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. Methods In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. Results A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. Conclusions Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).

Concepts: Clinical trial, Blood, Stroke, Thrombosis, Warfarin, Dose, Aspirin, Bayer

191

Background Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. Methods In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed. Results Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group. Conclusions Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).

Concepts: Immune system, Clinical trial, Asthma, Respiratory physiology, Effectiveness, Dose, Glucocorticoid, Spirometry

169

After sixty years of continuous use, primaquine remains the only therapy licensed for arresting transmission and relapse of malaria. The US Army developed primaquine for soldiers in a wartime crisis setting. Dosing strategies suited to that narrow population were adopted without modification or validation for the broader population of humans exposed to risk of malaria. The poor suitability of these strategies in populations exhibiting greater vulnerability to hemolytic toxicity among glucose-6-phosphate dehydrogenase deficient patients has not been addressed. Primaquine requires chemotherapeutic reinvention delivering less threatening doses by leveraging unexplored co-drug synergies.

Concepts: Malaria, Population, Glucose-6-phosphate dehydrogenase deficiency, Dose, World population, United States Army, Military, Primaquine

168

BACKGROUND: The management of pregnancy in patients with narcolepsy poses many questions regarding therapy, including the risk to the mother and fetus related to the disease, potential risks at the time of conception, the risk to both the mother and the fetus of the medications used to treat narcolepsy, and the risk to the infant from medications that might be secreted in breast milk. There are no detailed practice parameters on the treatment of narcolepsy patients during pregnancy. We surveyed narcolepsy specialists from around the world to determine their clinical approach to the management of patients with narcolepsy at the time of conception, during pregnancy and while breastfeeding. METHODS: Survey invitations were sent via e-mail to 75 clinicians worldwide between 2/2011 and 3/2011 with 34 responses (USA, n=10; Brazil, n=3; Czech Republic, n=2; France, n=2; Italy; n=2; Netherlands, n=2; Canada, n=1; Denmark, n=1; Finland, n=1; Germany, n=1; Japan, n=1; Spain, n=1; unknown n=7). Responders who completed the survey had 20years (median range, 5-35) of experience in sleep medicine practice with a median number of five narcolepsy patients seen per week. The number of pregnant narcoleptic patients followed per physician was five (median range 1-40). RESULTS: The survey results indicated that the management of patients with narcolepsy varies greatly from clinician to clinician and from country to country. The majority of the clinicians stopped the narcolepsy medications at the time of conception, during pregnancy, and during breastfeeding some reduced the dose and others did not change the dosage, depending on the particular medication. CONCLUSIONS: The findings from our survey and literature review suggest that the perceived risks of narcolepsy medication during pregnancy to the mother and the fetus usually are overestimated, as the risk for teratogenic effects from narcolepsy medications in therapeutic doses is essentially nonexistent. However, the potential for rare complications during pregnancy and congenital abnormalities cannot be excluded. Most narcolepsy patients have vaginal delivery without complications. In rare cases patients had cataplexy that interfered with delivery, but if caesarian is required there appears to be no increased anaesthetic or surgical risks. Further prospective information for the appropriate treatment of narcolepsy patients during pregnancy is needed.

Concepts: Pregnancy, Childbirth, Infant, Hospital, Median, Breastfeeding, Dose, Narcolepsy

167

The acetylcholinesterase inhibitor (AChEI), huperzine A has been used in the treatment of the cognitive deterioration associated with Alzheimer’s disease (AD). However, the side-effects of huperzine A associated with increased cholinergic activity, particularly in the gastrointestinal system, are evident. It is not yet known how quickly these side-effects become tolerated; this information would provide guidance to doctors on how to use huperzine A so as to attenuate the adverse events. The present study aimed to observe the effects of huperzine A on gastrointestinal motility and acetylcholinesterase (AChE) activity in mice. After oral administration of huperzine A with single and multiple dosing, the gastrointestinal motility and AChE activity of the mice were examined. The results revealed that, following a single dose of huperzine A, the AChE activity in the stomach and duodenum were significantly inhibited and the gastrointestinal motility was significantly increased. However, following multiple doses (7 or 28 doses, one dose per day), no significant changes in the AChE activity and gastrointestinal motility were identified. These findings indicate that the gastrointestinal adverse effects of huperzine A may be well-tolerated relatively quickly and do not recur. Additionally, it suggests that patients with AD are likely to have minimal gastrointestinal side-effects after taking multiple doses of huperzine A.

Concepts: Alzheimer's disease, Dose, Acetylcholine, Digestion, Acetylcholinesterase, Acetylcholinesterase inhibitor, Acetylcholinesterase inhibitors, Huperzine A

164

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had three treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared rFVIII and rFVIIIFc pharmacokinetics. Endpoints included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 h) was extended 1.5-fold versus rFVIII (12.4 h; P<.001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with one injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1-2 times per week. This study is registered at www.clinicaltrials.gov, ID: NCT01181128.

Concepts: Pharmacology, Dose, The Terminal, Inhibitor, Factor VIII

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Background The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. Methods We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. Results At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. Conclusions Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657 .).

Concepts: Pharmacology, Clinical trial, Blood, ClinicalTrials.gov, Warfarin, Dose, Anticoagulant, Prothrombin time

83

Birds that travel long distances between their wintering and breeding grounds may be particularly susceptible to neurotoxic insecticides, but the influence of insecticides on migration ability is poorly understood. Following acute exposure to two widely used agricultural insecticides, imidacloprid (neonicotinoid) and chlorpyrifos (organophosphate), we compared effects on body mass, migratory activity and orientation in a seed-eating bird, the white-crowned sparrow (Zonotrichia leucophrys). During spring migration, sparrows were captured, held and dosed by gavage daily for 3 days with either the vehicle control, low (10% LD50) or high (25% LD50) doses of imidacloprid or chlorpyrifos and tested in migratory orientation trials pre-exposure, post-exposure and during recovery. Control birds maintained body mass and a seasonally appropriate northward orientation throughout the experiment. Imidacloprid dosed birds exhibited significant declines in fat stores and body mass (mean loss: -17% low, -25% high dose) and failed to orient correctly. Chlorpyrifos had no overt effects on mass but significantly impaired orientation. These results suggest that wild songbirds consuming the equivalent of just four imidacloprid-treated canola seeds or eight chlorpyrifos granules per day over 3 days could suffer impaired condition, migration delays and improper migratory direction, which could lead to increased risk of mortality or lost breeding opportunity.

Concepts: Bird, Dose, Toxicology, Insecticide, Sparrow, American sparrow, White-crowned Sparrow, Zonotrichia

69

Here we present results of a three-year study to determine the fate of imidacloprid residues in hive matrices and to assess chronic sublethal effects on whole honey bee colonies fed supplemental pollen diet containing imidacloprid at 5, 20 and 100 μg/kg over multiple brood cycles. Various endpoints of colony performance and foraging behavior were measured during and after exposure, including winter survival. Imidacloprid residues became diluted or non-detectable within colonies due to the processing of beebread and honey and the rapid metabolism of the chemical. Imidacloprid exposure doses up to 100 μg/kg had no significant effects on foraging activity or other colony performance indicators during and shortly after exposure. Diseases and pest species did not affect colony health but infestations of Varroa mites were significantly higher in exposed colonies. Honey stores indicated that exposed colonies may have avoided the contaminated food. Imidacloprid dose effects was delayed later in the summer, when colonies exposed to 20 and 100 μg/kg experienced higher rates of queen failure and broodless periods, which led to weaker colonies going into the winter. Pooled over two years, winter survival of colonies averaged 85.7, 72.4, 61.2 and 59.2% in the control, 5, 20 and 100 μg/kg treatment groups, respectively. Analysis of colony survival data showed a significant dose effect, and all contrast tests comparing survival between control and treatment groups were significant, except for colonies exposed to 5 μg/kg. Given the weight of evidence, chronic exposure to imidacloprid at the higher range of field doses (20 to 100 μg/kg) in pollen of certain treated crops could cause negative impacts on honey bee colony health and reduced overwintering success, but the most likely encountered high range of field doses relevant for seed-treated crops (5 μg/kg) had negligible effects on colony health and are unlikely a sole cause of colony declines.

Concepts: Insect, Dose, Honey bee, Beekeeping, Flower, Varroa destructor, Colony, Colony collapse disorder

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Background The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. Methods In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. Results The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). Conclusions The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319 .).

Concepts: Immune system, Antibody, Clinical trial, Cancer, Apoptosis, Chemotherapy, Dose, Programmed cell death