COVID Boosters Supported by CDC, Fauci
In a White House press briefing, U.S. health officials laid out the case for a scientific rationale for administering a third dose of the COVID-19 mRNA vaccines for all U.S. adults. CDC Director Rochelle Walensky presented evidence that showed that vaccine effectiveness has been decreasing over time against both symptomatic and asymptomatic infections, although protection against severe disease, hospitalizations, and death remains relatively high. Dr. Walensky presented evidence from several studies published in MMWR and by the Mayo Clinic (posted on medRxiv).
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MMWR data from New York showed a decline in vaccine effectiveness against infection from May 3 to July 25, from 91.7% to 79.8%. Overall age-adjusted vaccine effectiveness against hospitalization was relatively stable: from 91.9% to 95.3%. The total of new cases was 9,675 among fully vaccinated adults, compared with 38,505 among unvaccinated persons (rate of 1.31 per 1,000 person-days vs.10.69 per 1,000 person-days).
Data from the Mayo Clinic found a similar decrease in vaccine effectiveness in Minnesota. Moderna vaccine effectiveness fell from 86% earlier in the year to 76% during July, and Pfizer vaccine effectiveness fell from 76% to 42% over the same time. The analysis also found that both mRNA vaccines were effective at protecting against COVID-associated hospitalizations (91.6% for Moderna, 85% for Pfizer) and ICU admissions (93.3% for Moderna, 87% for Pfizer), with no deaths in either cohort.
New nursing home data reported in MMWR also showed a reduction in protection against infection, from 78% in March to 53% by August 1. These results may reflect the effect of the greater transmissibility of the Delta variant along with demonstrating waning immunity: adjusted effectiveness against infection in the pre-Delta period (March 1 to May 9) was 74.7%, fell to 67.5% in the intermediate period (May 10 to June 20), and to 53.1% during the Delta-dominant period (June 21 to August 1).
At the briefing, Anthony Fauci provided the immunologic evidence supporting booster shots. A paper published in Science showed that antibody levels peaked 43 days after the second dose of Moderna, but fell by 209 days after vaccination. Additional research demonstrated that a serum neutralizing titer of 1:100 is needed to produce a vaccine efficacy rate of 91%. Dr. Fauci believes that the booster shot should increase antibody titers by tenfold and that such higher antibody levels are likely to be necessary to protect against the Delta variant. (Fiore, K. (2021). The science supporting the U.S. case for COVID boosters. MedPage Today. Retrieved August 2021 from https://www.medpagetoday.com/infectiousdisease/covid19vaccine)
Released: September 2021
Nursing Drug Handbook
© 2021 Wolters Kluwer
Triple-Drug Therapy Effective for Cystic Fibrosis
Use of a three-drug combination improved lung functionand sweatchloride concentration relative to an active control in a subclass of patients with cystic fibrosis.In a phase 3, double-blind, randomized, active-control trial, the three-drug combination ivacaftor–tezacaftor–elexacaftor was tested as treatment for cystic fibrosis in patients who had Phe508del-gating or Phe508del-residual function genotypes. In cystic fibrosis, deficiencies in the cystic fibrosis transmembrane conductance regulator (CFTR) proteins manifests in progressive respiratory impairment, exocrine pancreatic insufficiency, hepatobiliary disease, and abnormal sweat composition. Cystic fibrosis results from biallelic mutations in the CFTR gene, among them processing mutations, which reduce the quantity of CFTR protein on the cell surface; channel-gating defects, which limit anion transport; and residual function mutations, which result in lesser impairment of CFTR protein activity. Ivacaftor is a CFTR potentiator that augments gating of mutant CFTR proteins, tezacaftor is a CFTR corrector that acts to ease the defects of CFTR processing and cell-surface trafficking intrinsic to Phe508del, andelexacaftor is a CFTR corrector with a mechanism of action complementary to tezacaftor.
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The trial aimed to determine whether additional clinical benefit could be derived from that complementarity. The trial enrolled 258 patients and randomized them to receive the three-drug combination at 200 mg/day (n = 132) or to one of two active control regimens (n = 126): ivacaftor 150 mg b.i.d. or ivacaftor 150 mg b.i.d. and tezacaftor 100 mg/day, based on the patients’ specific genotype and approvals in their country. At baseline, the mean sweat chloride concentration was 58 mmol/L; the mean forced expiratory volume in 1 second (FEV1) was 67% to 68%, with about half in the 40% to 70% range and the rest at 70% to 90%; and the mean score on the Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain was 77.
The mean absolute change in percentage of predicted FEV1 from baseline through week 8 was 3.7 percentage points (range, 2.8 to 4.6) in patients receiving the three-drug combination and 0.2 percentage points (range, –0.7 to 1.1) in patients on active control, reflecting a between-group difference of 3.5 percentage points. The mean absolute change in sweat chloride concentration from baseline through week 8 with the three-drug combination was –22.3 mmol/L (range, –24.5 to –20.2 mmol/L) and with active controls was 0.7 mmol/L (range, –1.4 to –2.8 mmol/L), a between-group difference of –23.1 mmol/L. Change from baseline in scores on the CFQ-R respiratory domain was 10.3 points (range, 8.0 to 12.7) on the three-drug combination and 1.6 points (range, –0.8 to 4.1 points) on active control, reflecting a between-group difference of 8.7 points.
Two-thirds of patients experienced an adverse event, but most were mild or moderate in severity and resolved during the trial. Serious events were reported in 5 patients (3.8%) in the treatment group and 11 patients (8.7%) in the control group. (Gever, J. (2021). Three drugs better than two (or one) in cystic fibrosis. MedPage Today. Retrieved August 2021 from https://www.medpagetoday.com/pulmonology/cysticfibrosis; Barry, P. J., et al. (2021). Triple therapy for cystic fibrosis Phe508del–gating and –residual function genotypes. New Engl J Med 385, 815–825.)
Released: September 2021
Nursing Drug Handbook
© 2021 Wolters Kluwer
Atopegant: An Effective Oral Migraine Preventive
Once-daily oral treatment with atopegant, a small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist, was effective in reducing the number of migraine days and headache days over 12 weeks in patients with episodic migraine. These are the findings of ADVANCE, a phase 3multinational, randomized, double-blind, parallel-group, placebo-controlled trial that examined three dosage strengths of atopegant for prevention of migraine.
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In the trial, adults with 4 to 14 migraine days/month were randomly assigned to receive once-daily doses of 10 mg, 30 mg, or 60 mg of atopegant or to placebo for 12 weeks. Patient characteristics were similar across all groups: mean age, 41.6 years; 88% female and 83.4% white; with a mean BMI of 30.6. Overall, patients reported an average of 7.4 migraine days/month over the previous 3 months; at screening, 99.3% reported current use of medications to treat migraine attacks, and 70.3% reported having previously used a preventive medication for migraine.
After screening and randomization, patients returned to the clinic five times during the double-blind 12-week period, with another visit at 16 weeks. The protocol was amended due to the COVID-19 pandemic to allow remote visits, with the final visit being conducted remotely for all participants. In an electronic diary, patients recorded headache duration, the clinical features of the headache (pain severity, location, and the effect of routine physical activity on migraine), nonheadache-associated symptoms (nausea/vomiting, photophobia, phonophobia, aura), and any medications used to treat the migraine attacks.
Analysis included 873 patients: 214 in the 10-mg group, 223 in the 30-mg group, 222 in the 60-mg group, and 214 in the placebo group. Oral atopegant at any of the doses resulted in significantly greater reductions in the number of migraine days per month versus placebo. The change from baseline was –3.7 days for the 10-mg dose, –3.9 days for the 30-mg dose, and –4.2 days for the 60-mg dose, compared to –2.5 days with placebo. The differences with placebo in secondary outcomes were also significant: The change from baseline in mean number of headache days/month was –3.9 days for the 10-mg dose, –4.0 days for the 30-mg dose, and –4.2 days for the 60-mg dose, compared to –2.5 days with placebo. The change in the mean number of days of medication use to treat migraine was –3.7 days for the 10-mg dose, –3.9 days for the 30-mg dose, and –3.9 days for the 60-mg dose, compared to –2.4 days with placebo. The percentage of participants with a reduction of at least 50% in the 3-month average of migraine days/month has been recommended as a particularly relevant endpoint in controlled trials of preventive treatments for migraine; in this trial, this goal was reached at all three dosage levels: 55.6% of those receiving the 10-mg dose, 58.7% of those receiving the 30-mg dose, and 60.8% of those receiving the 60-mg dose, compared to 29.0% of those receiving placebo.
Adverse events were reported in 486/902 participants (53.9%) with similar frequency across all groups. The most common adverse events were constipation, nausea, and upper respiratory infections. Serious adverse events were reported in 4 participants, 2 on the 10-mg dose and 2 on placebo. Because of potential hepatotoxicity, elevated ALT or AST levels at least three times the upper level of normal were evaluated throughout the trial. These elevated levels were found in 2 participants in the 10-mg group, 2 in the 30-mg group, 1 in the 60-mg group, and 4 in the placebo group.
Previous studies have shown an association between CGRP blockade and decreased GI motility, so continued monitoring for constipation, as well as measuring for hepatotoxicity, is appropriate going forward. In addition, longer, larger trials are necessary to examine the long-term safety of once-daily atopegant as a migraine preventative; a 52-week trial is currently underway. (Ailani, J., et al. (2021). Atogepant for the preventive treatment of migraine. New Engl J Med; 385: 695–706.)
Released: September 2021
Nursing Drug Handbook
© 2021 Wolters Kluwer