COVID-19 Antivirals
The FDA granted an emergency use authorization (EUA) for the combination of nirmatrelvir and ritonavir (Paxlovid, Pfizer), on 12/22/21, for the treatment of mild-to-moderate COVID-19 in patients 12 years of age and older weighing at least 88 pounds who are at high risk for progression to severe COVID-19. The treatment is dosed as two tablets of nirmatrelvir and one tablet of ritonavir taken together orally twice daily for five days. Please see the Fact Sheet for Healthcare Providers and Fact Sheet for Patients and Caregivers for additional information. Pfizer will begin shipping nirmatrelvir and ritonavir to the U.S. government immediately and expects to complete delivery of 10 million courses of treatment in 2022. The FDA granted an emergency use authorization (EUA) for molnupiravir (Lagevrio, Merck), on 12/23/21, for the treatment of mild-to-moderate COVID-19 in patients 18 years of age and older who are at high risk for progression to severe COVID-19 and alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. The treatment is dosed as four tablets twice daily for five days. Molnupiravir is not recommended for use during pregnancy. Please see the Fact Sheet for Healthcare Providers and Fact Sheet for Patients and Caregivers for additional information. Merck will begin shipping 3.1 million doses of molnupiravir to the U.S. government as soon as a final label is approved by the FDA. In the 29-day, 1,443 patient, Phase II/III, MOVe-OUT trial (NCT04575597), 6.8% of patients treated with a five-day course of molnupiravir were hospitalized or died compared to 9.7% with placebo in unvaccinated outpatients with mild-to-moderate COVID-19 with at least one risk factor to progress to severe disease. An interim analysis from 775 patients had suggested that 7.3% of patients treated with molnupiravir were hospitalized or died compared to 14.1% with placebo. In the 28-day, 562 patient, Phase III, PINETREE trial (NCT04501952), 0.7% of patients treated with a 3-day course of remdesivir were hospitalized or died compared to 5.3% with placebo in nonhospitalized patients with at least one risk factor to progress to severe disease. COVID-19 Vaccines The CDC’s ACIP recommended that COVID-19 vaccines from Pfizer and Moderna should be preferred over the J&J vaccine due to the risk for a rare but potentially fatal thrombosis with thrombocytopenia syndrome with the J&J vaccine. Moderna announced that preliminary lab results found that antibody levels after a booster (third) dose of their COVID-19 vaccine increased antibody levels that are thought to be high enough to neutralize the Omicron variant. A pre-print draft described how antibody levels were not high enough after two doses of the vaccine to neutralize the Omicron variant. In a review of 4, 155, 361 patients that received an mRNA vaccine the rate of myocarditis was estimated to be 1.4 per 100 ,000 patients with the Pfizer-BioNTech COVDI-19 vaccine and 4.2 per 100 ,000 patients with the Moderna vaccine. Sanofi and GSK announced that in a 521 patient, Phase I/II trial (NCT04537208), using their COVID-19 vaccine as a booster dose for vaccines from Pfizer/BioNTech, Moderna, Johnson & Johnson, and AstraZeneca resulted in an increase in neutralizing antibodies of 9- to 43-fold. In the 29,582 patient, Phase III, PREVENT-19 trial (NCT04611802), two immunizations of NVX-CoV2373 (Novavax)ngiven 21-days apart resulted in 90.4% efficacy for developing a COVID-19 infection and 100% efficacy in preventing severe COVID-19. Pfizer and BioNTech announced that in 4,500 patient, Phase I/II/III trial (NCT04816643), two 3 mcg doses of their COVID-19 vaccine given to patients 6 to 24 months old demonstrated immunogenicity similar to that seen with the adult dose in patients 16 to 25 years old. An inadequate response was elicited in patients 2 to under 5 years old with the 3 mcg dose, so a third dose will be evaluated in patients 6 months to under 5 years. COVID-19 Antibodies In a pre-print draft of a 28-day, 1,181 patient, Phase II trial (NCT04373460), 2.9% of patients treated with high titer convalescent plasma were hospitalized for COVID-19 compared to 6.3% with placebo in outpatients with recent onset of COVID-19. COVID-19 Antivirals
Pfizer announced that in the 28-day, 2,246 patient, Phase II/III, EPIC-HR trial (NCT04960202), where 0.7% of patients treated with the combination of nirmatrelvir and ritonavir were hospitalized with no deaths compared to 6.5% who were hospitalized or died with placebo in unvaccinated patients with mild-to-moderate COVID-19 at risk to progress to severe illness. After an interim analysis found an 89% reduction in COVID-19 related hospitalization or death, the FDA agreed with the Data Monitoring Committee, that the trial could be stopped in November 2021. COVID-19 Vaccines Pfizer and BioNTech announced that preliminary lab results found that antibody levels after a booster (third) dose of their COVID-19 vaccine neutralized the Omicron variant. There was a 25-fold reduction in neutralization in patients that received just two vaccine doses. This may not be enough to prevent infection but may protect against severe disease. South African scientists tested antibody neutralization with serum from 12 patient that had received the Pfizer-BioNTech COVID-19 vaccine. Half of the patients had recovered from COVID-19. There was a 41-fold decrease in neutralization, but previously infected patients have high neutralization. Therefore, patients that have received a booster (third) dose may maintain neutralization against Omicron. The FDA and CDC authorized a booster dose given six-months after their second dose of the Pfizer-BioNTech COVID-19 vaccine for 16 and 17 year-olds, on 12/9/2021. COVID-19 Antibodies The FDA approved an Emergency Use Authorization (EUA) for the combination of tixagevimab and cilgavimab (Evusheld, AstraZeneca) on 12/8/2021, for pre-exposure prophylaxis (prevention) of COVID-19 in patients 12 and older and weighting at least 40 kg with moderate to severe immune compromise due to a medical condition or immunosuppressive medications and who may not mount an adequate immune response to COVID-19 vaccination, currently have COVID-19 or if COVID-19 vaccination is not recommended. Tixagevimab and cilgavimab are administered as a one-time intramuscular dose. The FDA advised against using the drug in hospitalized patients, because a benefit has not been demonstrated. Healthcare providers should review the Fact Sheet for information on the authorized use of casirivimab and imdevimab and mandatory requirements of the EUA. Please see the FDA Letter of Authorization, Fact Sheet for Healthcare Providers, and Fact Sheet for Patients, Parents, and Caregivers. The U.S. government has purchased 700,000 doses that will be distributed at no charge. In a 14-day, 941 patient, Phase III, CONTAIN COVID-19 trial (NCT04364737), treatment with convalescent plasma did not increase the number of patients that achieved clinical improvement compared to placebo in hospitalized COVID-19 patients. COVID-19 Vaccines
ISMP issued a warning regarding use of an incorrect dose of the Pfizer-BioNTech COVID-19 vaccine. The pediatric vaccine (10 mcg/0.2 ml) has been used in patients 12 and older and the adult dosage (30 mcg/0.3 ml) has been used in patients under 12. ISMP further warns against diluting the adult vaccine to make a pediatric vaccine. Due to the vaccine being a suspension and the small volume, it would not be possible to create an accurate dose. To avoid errors, ISMP recommends
Medicago and GSK announced that in a 24,000 patient, Phase II/III trial (NCT04636697), where use of their COVID-19 vaccine had an overall vaccine efficacy 71% and 75.3% against the Delta variant. A retrospective study of patients 21 years or younger who experienced myocarditis within 30 days of COVID-19 vaccination found most cases had a mild clinical course with rapid resolution of symptoms. The 2,878 patient, Phase II, British COV-BOOST trial found that any COVID-19 vaccine can be used as a booster, regardless of the initial vaccine given. Patients received the Pfizer-BioNTech or AstraZeneca COVID-19 vaccines. After the Pfizer-BioNTech vaccine a good immunity boost was achieved with vaccines from Pfizer-BioNTech, Moderna, Johnson & Johnson, Novavax, AstraZeneca and CureVac. There was also a good boost in immunity after the AstraZeneca vaccine with the same set of vaccines, plus an investigational vaccine from Valneva In the 1,072 patient, Phase III, Com-COV2 trial, patients received their first COVID-19 immunization with either the AstraZeneca or Pfizer-BioNTech vaccines. The second dose was given with the same vaccine, a vaccine from Moderna or Novovax. Both the Moderna and Novovax vaccines elicited higher antibody titers following the AZ vaccine than AZ’s own vaccine. Compared to a second dose of the Pfizer-BioNTech vaccine, Moderna elicited higher antibody titers, but Novovax did not. COVID-19 Anti-Inflammatory In the 28-day, 479 patient, Phase III, LIVE-AIR trial (NCT04351152), 84% of patients treated with lenzilumab were alive and did not require invasive mechanical ventilation compared to 78% with placebo in hospitalized patients with COVID-19, not requiring ventilation. 94% of patients received a corticosteroid, 72% received remdesivir and 69% received both. COVID-19 Vaccines
A new variant of concern, designated Omicron, has been identified. The variant has several mutations that have been associated with increased transmissibility and higher immune evasion in other variants. Omicron also has new mutations in the spike protein that vaccine antibodies target. Right now, the threat is theoretical. But the vaccine manufacturers are already working on a vaccine to combat omicron, if tests show that current vaccine antibodies do not provide protection. A review of French National Health Data from 3.9 million patients 75 years or older who had received at least 1 dose of Pfizer-BioNTech COVID-19 vaccine and 3.2 million who had received 2 doses found no increase in the incidence of acute myocardial infarction, stroke, or pulmonary embolism within 14 days of vaccine administration. COVID-19 Antivirals Merck announced that in the 29-day, 1,443 patient, Phase II/III, MOVe-OUT trial (NCT04575597), 6.8% of patients treated with a five-day course of molnupiravir were hospitalized or died compared to 9.7% with placebo in outpatients with mild-to-moderate COVID-19 with at least one risk factor to progress to severe disease. An interim analysis from 775 patients had suggested that 7.3% of patients treated with molnupiravir were hospitalized or died compared to 14.1% with placebo. The FDA’s Antimicrobial Drugs Advisory Committee voted 13 to 10 to recommend an emergency use authorization for molnupiravir. COVID-19 Vaccines
The FDA approved a booster dose of the Moderna and Pfizer-BioNTech COVID-19 vaccines for all patients 18 and older on 11/18/2021. On 11/19/2021, the CDC recommended booster doses of both vaccines for the same group of patients. All patients have already been approved to receive a booster of the J&J vaccine. Pfizer and BioNTech announced that follow-up data from their COVID-19 vaccine teen study (NCT04368728) demonstrated 100% efficacy from seven days after the second dose through four months. COVID-19 Vaccines
A Norwegian case–control study examined first-trimester pregnancies in 13,956 women from registry data and found no evidence of an increased risk for early pregnancy loss after Covid-19 vaccination. COVID-19 Anti-inflammatories In the 28-day, 2,052 patient, Phase III, PREPARE-IT 2 trial (NCT04460651), treatment with icosapent ethyl did not reduce hospitalization or death compared to placebo (13.69% vs 11.16%) in nonhospitalized Argentinian COVID-19 patients. COVID-19 Antibodies AZ announced that after six months 4,991 patients enrolled in the PROVENT trial, no cases of severe COVID-19 or COVID-19-related death occurred in patients that received AZD7442 compared to five cases of severe COVID-19 and two COVID-related deaths with placebo. In the 15-day, 511 patient, Phase III, C3PO trial (NCT04355767 treatment with convalescent plasma did not reduce emergency treatment, hospitalization or death in high-risk outpatients with COVID-19. In the 29-day, 583 patient, Phase III, COMET-ICE trial (NCT04545060), 1% of patients treated with sotrovimab were hospitalized or died compared to placebo in outpatients with COVID-19 who were at high risk of progression to severe disease. COVID-19 Vaccines
In a final analysis of the 30,451 patient, Phase III COVE trial (NCT04470427), vaccine efficacy was 93.2% to prevent COVID-19 and 98.2% to prevent severe disease with the Moderna COVID-19 vaccine. In a 2,268 patient, Phase II/III trial (NCT04816643), two 10 mcg doses of the Pfizer-BioNTech COVID-19 vaccine given 21 days apart, to children 5 to 11 years, produced antibody titers comparable to the levels seen with two 30 mcg adult doses in adolescents and young adults age 16 to 25 years. Vaccine effectiveness was 90.7% one month after the second injection. COVID-19 Antivirals Pfizer announced interim data from 1,219 patients enrolled in the 28-day, 3,000 patient, Phase III, EPIC-HR trial (NCT04960202), where 0.8% of patients treated with the combination of PF-07321332 and ritonavir were hospitalized or died compared to 7% with placebo in unvaccinated patients with mild-to-moderate COVID-19 at risk to progress to severe illness. Due to the 89% reduction in COVID-19-related hospitalization or death, the FDA agreed with Data Monitoring Committee, the trial could be stopped. Pfizer plans to submit the data as part of a rolling NDA. The United Kingdom Medicines and Healthcare products Regulatory Agency approved molnupiravir for the treatment of mild-to-moderate COVID-19 in adults at risk to develop severe illness. COVID-19 Anti-inflammatories In the seven-day, 203 patient, Phase II, CONTAIN trial (NCT04435795), treatment with inhaled and intranasal ciclesonide did not improve symptom resolution compared to placebo in low-risk, Canadian outpatients with COVID-19. COVID-19 Antibodies In a long term extension of the Phase III, PREVENTION trial, patients that received REGEN-COV had an 81.6% reduction in developing symptomatic COVID-19 compared to placebo after eight months. COVID-19 Vaccines
Pfizer and BioNTech COVID-19 vaccine approved for use in children 5 to 11 years of age.
Researchers analyzed historical and current data from Olmsted County, Minnesota and found the incidence of cerebral venous sinus thrombosis (CVST) had increased in females who received the J&J COVID-19 vaccine. The highest incidence of CVST was in women 40-49, followed by women aged 30 to 39 years. CDC analysts compared the outcomes of 20,101 fully vaccinated immunocompromised adults to 69,116 fully vaccinated immunocompetent adults and found vaccine effectiveness to prevent COVID-19 related hospitalizations to be 77% for immunocompromised adults compared to 90% for immunocompetent adults. This decrease in effectiveness was present regardless of the type of vaccine used, patient’s geographic location, prevalence of the Delta variant or underlying cause for the immunocompromised state. COVID-19 Booster Vaccines
Pfizer and BioNTech announced that in a Phase 3 trial (NCT04955626) of over 10,000 patients, a booster dose of their COVID-19 vaccine demonstrated 95.6% effectiveness in preventing COVID-19. In an update to its COVID-19 vaccine guidance, the CDC is recommending that moderately and severely immunocompromised people aged 18 years or older, who completed an mRNA COVID-19 vaccine primary series, may receive a single COVID-19 booster dose (Pfizer-BioNTech, Moderna, or Janssen) at least 6 months after completing their third mRNA vaccine dose for a total of four COVID-19 vaccine doses. COVID-19 Vaccines An FDA review of data for the Pfizer-BioNTech COVID-19 vaccine in children ages 5-11 years, found benefits to outweigh the risks for this age group. In the study, children were given two 10 mcg doses of the vaccine, 21 days apart and found comparative antibody titers to levels seen in ages 16-25 with a 30 mcg dose. Adverse events were also similar. Based on limited follow-up, vaccine effectiveness was estimated to be 90.7% with no cases of severe COVID-19. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 17-0 with one member abstaining to recommend the Pfizer-BioNTech COVID-19 vaccine in children 5-11 years of age. A CDC analysis of data from 464 adolescents, hospitalized for COVID-19, found the Pfizer-BioNTech COVID-19 vaccine to be 93% effective in preventing hospitalizations from 6/1/2021 to 9/30/2021, a period when the predominant variant was the Delta variant. Moderna announced interim data from a cohort of 4,753 children, age 6 to under 12 years of age, enrolled in the Phase II/III KidCOVE trial(NCT04796896), where two 50 mcg doses of Moderna’s COVID-19 vaccine, given 28-days apart, elicited a strong immune response and was well tolerated. A retrospective analysis of 2.5 million patients, in an Israeli HMO database, who received the Pfizer-BioNTech COVID-19 vaccine found the estimated incidence of myocarditis to be 2.13 cases per 100,000 persons with the highest incidence in male patients between the ages of 16 and 29 years (10.69 cases per 100,000). In a similar study from a national database of 5.1 million Israelis that received the Pfizer-BioNTech COVID-19 vaccine, the estimated incidence of myocarditis was 1.76 cases per 100,000 persons with the highest incidence in male patients ages 16 to 19 years (13.73 cases per 100,000). An analysis of the response to vaccination with mRNA vaccines found that pregnant and lactating women develop lower antibody titers after the first vaccine dose. Antibody levels rise to match the immunological response seen in non-pregnant and non-lactating women after the second dose. COVID-19 Antivirals Roche and Atea Pharmaceuticals announced that in the seven-day, 100 patient, Phase II, MOONSONG Trial (NCT04709835), treatment with AT-527 did not reduce viral load compared to placebo in non-hospitalized patients with mild to moderate COVID-19. MOONSONG included vaccinated patients, which could have affected the outcome. The Oregon Poison Center reported an increase in calls for toxic effects of ivermectin. The drug was being taken to treat or prevent COVID-19. Most of the patients were treating themselves using a veterinary formulation. Some of the patients were taking a dose much higher than the 21 mg used in humans. Six of the patients were hospitalized and four admitted to the ICU. In the 28-day, 1,497 patient, Brazilian Phase III, TOGETHER trial (NCT04727424), 11% of patients treated with fluvoxamine required prolonged emergency treatment or were admitted to a hospital for worsening COVID-19 compared to 16% with placebo in outpatients with COVID-19 at high risk to progress to severe disease. COVID-19 Anti-Inflammatories In the 28-day, 982 patient, Phase III, COVID STEROID trial (NCT04509973), treatment with IV dexamethasone 12 mg did not increase days alive without life support compared to a 6 mg dose (22 vs 20.5 days) in patients with COVID-19 and severe hypoxemia. COVID-19 Antibodies Interim data from the 29-day, 583 patient, Phase III, COMET-ICE trial (NCT04545060), found that 1% of patients treated with VIR-7831 were hospitalization or death compared to 7% with placebo in patients with mild to moderate COVID-19 who are at high risk of progression to severe disease.
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