Centanafadine in Adults with Attention Deficit Hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) likely results from dysregulation of the complex interplay of adrenergic and dopaminergic neurotransmission, resulting in deficits in executive function, reward processing, and attention. Centanafadine, a stimulant with nonstimulant characteristics that acts by inhibiting reuptake of norepinephrine, dopamine, and serotonin, is being investigated for use in adults with ADHD.
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A report in the Journal of Clinical Psychopharmacology describes the first large-scale studies to demonstrate the safety and efficacy of centanafadine in adults with ADHD. The two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies were conducted from January 2019 through early 2020 in 45 clinical sites in the United States. To limit placebo effect, both studies were designed with a single-blind placebo run-in period, in which subjects who experienced an improvement in symptoms didn’t move on to randomization. The studies then randomized subjects to receive 200 mg/day of centanafadine sustained-release tablets (n = 149 study 1, 145 study 2); 400 mg/day of centanafadine sustained-release tablets (n = 149 study 1, 143 study 2); or placebo (n = 148 study 1, 142 study 2). Patients in both studies had moderate to severe ADHD at baseline (mean Adult ADHD Investigator Symptom Rating Scale [AISRS] total score, 38.7).
Investigators determined change from baseline at day 42 in AISRS total score and in the Clinical Global Impression-Severity of Illness Scale (CGI-S). At day 42, statistically significant improvement in AISRS total score was achieved for both dosages compared with placebo in both studies. The AISRS total scores at day 42 were reduced by 25.5% in study 1 and 32.2% in study 2 for the 200-mg dose, by 24.6% in study 1 and 32.2% in study 2 for the 400-mg dose, compared to 17.7% in study 1 and 21.4% in study 2 for placebo. The differences in AISRS for centanafadine vs. placebo were as follows:
• Study 1: -3.16 for 200 mg, -2.74 for 400 mg
• Study 2: -4.01 for 200 mg, -4.42 for 400 mg
These differences were seen as early as day 28 and persisted throughout the study. Both dosages also produced statistically significant improvements in CGI-S score vs. placebo at day 42, as follows:
• Study 1: -0.27 for 200 mg, -0.28 for 400 mg
• Study 2: -0.33 for 200 mg, -0.28 for 400 mg
The overall rate of treatment-emergent adverse events was low, but there was a small increase noted with increases in centanafadine dose. The most common were headache and decreased appetite, which were considered mild or moderate.
These trials were affected by the COVID-19 pandemic; study protocols had to be altered in late March 2020. As of March 23, study 1 had met its targets, so subjects still in treatment were withdrawn and continued to the safety follow-up phase, but study 2 had not yet met its completed-subject targets. All subjects who had not been randomized yet had treatment discontinued, and those who had been randomized continued to study completion, unless they tested positive for COVID. As a result, 348 subjects completed study 1 and 336 completed study 2. The most reported reason for discontinuation in study 1 was protocol deviation (5.6%), followed by adverse effects (4.1%) and withdrawal by subject (3.2%); in study 2 it was “other, not COVID-related” (6.6%), followed by withdrawal by subject (4.5%) and adverse effects (3.0%). Nine subjects in each study withdrew for reasons related to COVID-19.
But despite these restrictions, the results still reached statistical significance. Future studies should determine long-term safety and should compare centanafadine to other available therapies for adults with ADHS. (Lenard, A., et al. (2022). Efficacy, safety, and tolerability of centanafadine sustained-release tablets in adults with attention-deficit/hyperactivity disorder: Results of 2 phase 3, randomized, double-blind, multicenter, placebo-controlled trials. J Clin Psychopharmacol. 42(5), 429–439. Retrieved October 2022 from https://journals.lww.com/psychopharmacology/Fulltext/2022/09000/Efficacy,_Safety,_and_Tolerability_of.2.aspx)
Released: October 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
Mepolizumab Significantly Reduced Asthma Exacerbations in Children at High Risk
Research has shown that therapies directed at the eosinophilic phenotype reduced asthma exacerbations in adults, but the effect on children was not as clear. Economically disadvantaged Black American and Hispanic American children are among those with the highest risk of morbidity and mortality associated with asthma, but there is scant data available on effective strategies in this vulnerable population. A new study demonstrates that adjunctive treatment with the humanized monoclonal antibody mepolizumab significantly reduced the number of asthma exacerbations in urban Black American and Hispanic American children. The study, MUPPITS-2 (Mechanisms Underlying Asthma Exacerbations Prevented and Persistent with Immune-based Therapy), was published in The Lancet.
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Between November 2017 and mid-March 2020, 290 children and adolescents were enrolled in the double-blind, placebo-controlled study, which was conducted at nine urban medical centers in the United States. The researchers enrolled children and adolescents ages 6 to 17 years who lived in socioeconomically disadvantaged neighborhoods and had exacerbation-prone asthma (that is, at least two exacerbations in the prior year) and blood eosinophil count of at least 150 cells/microliter. Median age of participants was 10 years; 55% were boys; approximately 70% were Black American and approximately 25% were Hispanic American. Median household income was $1,250 or less/month in 37% to 40% of participants, and between $1,251 and $2,500/month in 32% to 37% of participants. The children were randomly assigned to mepolizumab (n = 146) or to placebo (n = 144) injections once every 4 weeks for 52 weeks. The dosage of mepolizumab varied by age: 40 mg was given to those ages 6 to 11 years, and 100 mg was given to those ages 12 to 17 years. All participants also continued to receive guideline-based care for their asthma. The researchers aimed to determine whether adding mepolizumab to guideline-based care reduced the number of asthma exacerbations treated with systemic steroids during the 52 weeks of therapy.
The average number of asthma exacerbations requiring treatment with systemic steroids fell significantly during the 52 weeks of the study. Among children and adolescents treated with mepolizumab, the number of exacerbations was 0.96; with placebo, it was 1.30. Relative decrease in these patients was 27%. Blood eosinophil levels were markedly reduced in patients who received mepolizumab, from a mean of more than 400 cells/microliter at baseline to less than 200 cells/microliter by week 8. These levels remained over 400 cells/microliter in placebo-treated children. Time to first asthma exacerbation wasn’t significantly different between the two groups, and no differences were shown in other asthma outcomes (lung function, change in disease severity). On patient global assessment, 84% of participants treated with mepolizumab and 89% of those treated with placebo self-reported clinically moderate or significant disease improvements. Study clinicians completed that same assessment and found improvement among 66% treated with mepolizumab and 71% treated with placebo.
Researchers concluded that these findings highlighted the importance of evaluating treatment response in urban Black American and Hispanic American children, populations that are typically underrepresented in clinical trials. (Jackson, D. J., et al. (2022). Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): A randomised, double-blind, placebo-controlled, parallel-group trial. JAMA, 400(10351), P502–P511. Retrieved October 2022 from
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01198-9/fulltext; Slomski, A. (2022). Mepolizumab cuts asthma exacerbations among high-risk kids
JAMA, 328(12), 1171–1172. Retrieved October 2022 from https://jamanetwork.com/journals/jama/fullarticle/2796694)
Released: October 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
Obesity May Potentiate Risk of Thrombotic Events in Users of Oral Contraceptives
Despite the understanding that obesity and estrogen-containing contraceptives are independent risk factors for cardiovascular (CV) complications, a significant number of women with obesity continue to be prescribed these products for contraception. A review of current literature published in ESC Heart Failure, a journal from the European Society of Cardiology, provides evidence that obesity can potentiate CV risks—especially of venous thromboembolism (VTE)—in women of reproductive age taking combination oral contraceptives (COCs).
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The review examined the latest evidence and ongoing research on the CV impact of both obesity and contraceptive use, with a specific focus on clinical implications. An Italian review article cited a large population-based study showing that a body mass index (BMI) greater than 25 but less than 30 was associated with a 1.7-fold increased risk of VTE and a BMI above 30 was associated with a 2.4-fold increased risk. The study showed that when these subjects took COCs, risks increased to 12-fold in the group with BMI between 25 and 30 and to 24-fold in the group with BMI over 30 when compared to women who are nonobese not taking COCs. Another study was a meta-analysis that determined odds ratios (ORs) of VTE in women using COCs and showed that OR increased with BMI. When compared with COC users with BMI between 20 and 24.9, the odds of VTE in women using COC with BMI between 30 and 34.9 was 1.8 and in those with BMI of 35 or greater was 3.1. Another study showed that obesity has a greater impact on CV risk in women younger than age 40, the population that uses contraception; the risk of thrombosis in these individuals is 6.1 times higher than the risk in women who are nonobese. In addition, risk of drug-induced thrombosis can be dependent on the duration of drug therapy, a relevant issue with COCs, since users typically take them long-term.
These findings should spur conversations between clinicians and young women early in their reproductive years to enable them to understand the risks and to make lifestyle and contraceptive choices that can minimize these risks. Women with a BMI over 30 taking COCs should be viewed as an at-risk population and should be advised to avoid other CV risk factors as primary prevention. In addition, clinicians should prioritize long-acting reversible methods of contraceptives such as intrauterine devices and subdermal implants, both for safety and effectiveness, in these patients. (McKeown, L. A. (2022). Obesity may boost thrombotic events in contraceptive users, review suggests. TCTMD. Retrieved October 2022 from https://www.tctmd.com/news/obesity-may-boost-thrombotic-events-contraceptive-users-review-suggests; Rosano, G. M. C., et al. (2022). Obesity and contraceptive use: Impact on CV risk. ESC Heart Failure. Advance online publication. Retrieved October 2022 from https://onlinelibrary.wiley.com/doi/full/10.1002/ehf2.14104)
Released: October 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
CDC Analysis Indicates Need for Improvements in Management of Children with Sickle Cell Anemia
Analysis of Medicaid data on more than 3,300 children with sickle cell anemia demonstrated that many of these at-risk children are not receiving potentially lifesaving screening and treatment related to their disease. Sickle cell anemia is the most severe form of sickle cell disease, a disorder that results in misshapen, sticky red blood cells that break down easily, blocking blood flow and therefore resulting in impaired oxygenation of body tissues. The Centers for Disease Control and Prevention (CDC), which published this report, notes two health care measures are important in preventing complications in children with sickle cell anemia:
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- Transcranial Doppler (TCD) ultrasound screening, which identifies children at risk for stroke
- Hydroxyurea, a myelosuppressive agent, which reduces the occurrence of several complications of sickle cell anemia, including severe acute pain episodes and acute chest syndrome, which can result in lung injury and trouble breathing
Sickle cell anemia is a leading cause of stroke, but data showed that fewer than half of children with the disorder received the recommended stroke screening in 2019. The CDC’s analysis of 2019 Medicaid data showed that only 38% of children with sickle cell anemia ages 10 to 16 and 47% of those ages 2 to 9 had undergone TCD ultrasound screening. In addition, only 2 in 5 children ages 2 to 9 received hydroxyurea, the recommended treatment. The CDC study showed that in 2019, 53% of those ages 10 to 16 and 38% of those ages 2 to 9 were prescribed hydroxyurea. Stroke screening and hydroxyurea use were highest among children with high levels of health care use and those with prior complications.
These results reflect the barriers to care of sickle cell patients, including structural racism. Patients lack access to providers with expertise in treating the disease and report having their symptoms dismissed or being stigmatized when they do engage with the health care system. In addition, both family members and providers hesitate to make use of hydroxyurea due to fear of potential side effects and uncertainty about its effectiveness.
The CDC recommends that clinicians take steps to ensure that children with sickle cell anemia receive this important screening and this potentially lifesaving treatment. Among their recommendations:
- Increase TCD stroke screening by educating patients and families about the risk of stroke and the screening, identifying barriers to access (transportation, finances) and taking steps to alleviate them.
- Make stroke screening part of a single comprehensive visit when possible, and track TCD ultrasound screenings and follow-up in electronic health records.
- Encourage the patient and family to discuss with a health care provider the results of the TCD ultrasound screening and the next steps to take if the results indicate a greater risk of stroke.
- Become familiar with the guidelines on prescribing hydroxyurea and with studies showing the safety of the drug in these patients.
- To encourage adherence and follow-up, address barriers to patient access and incorporate reminders into the electronic health record.
- Educate the patient and family about hydroxyurea and the pros and cons of adherence to treatment protocol, and develop tools to help patients take hydroxyurea as directed.
(CDC. Media Statements. (2022). Many children with sickle cell anemia not receiving lifesaving screening and treatment. Retrieved October 2022 from https://www.cdc.gov/media/releases/2022/s0920-vs-sickle-cell-anemia.html; CDC. Vital Signs. (2022). Preventing sickle cell complications in children. Retrieved October 2022 from https://www.cdc.gov/vitalsigns/sickle-cell-anemia/)
Released: October 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer