Favipiravir in Patients With Early Mild-to-moderate Coronavirus Disease 2019 (COVID-19): A Randomized Controlled Trial.

BACKGROUND: Despite vaccination, many remain vulnerable to coronavirus disease 2019 (COVID-19) and its complications. Oral antivirals to prevent COVID-19 progression are vital. Based on perceived potency and clinical efficacy, favipiravir is widely used to treat COVID-19. Evidence from large randomized controlled trials (RCT) is lacking. METHODS: In this multicenter double-blinded placebo-controlled RCT, adults with early mild-to-moderate COVID-19 were 1:1 randomized to favipiravir or placebo. The study evaluated time to sustained clinical recovery (TT-SCR), COVID-19 progression, and cessation of viral shedding. RESULTS: Of 1187 analyzed patients across 40 centers, 83.3% were Hispanic, 89.0% unvaccinated, 70.3% severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seronegative, and 77.8% had risk factors for COVID-19 progression. The median time from symptom presentation and from positive test to randomization was 3 and 2 days, respectively. There was no difference in TT-SCR (median of 7 days for both groups; P = .80), COVID-19 progression [11 patients each (1.9% vs 1.8%); P = .96], time to undetectable virus (median = 6 days, 95% confidence interval [CI] [6-8] vs 7 days, 95% CI [6-9]), or in undetectable virus by end of therapy (73.4% vs 72.3%; P = .94). Outcomes were consistent across the analyzed sub-groups. Adverse events were observed in 13.8% and 14.8% of favipiravir-treated and placebo-treated subjects, respectively. Uric acid elevation was more frequent among favipiravir-treated subjects (19.9% vs 2.8%). CONCLUSIONS: Favipiravir was well tolerated but lacked efficacy in TT-SCR, progression to severe COVID-19, or cessation of viral shedding and should not be used to treat patients with COVID-19. (Supported by Appili Therapeutics). CLINICAL TRIALS REGISTRATION: NCT04600895.

Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab-cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab-cilgavimab in preventing progression to severe COVID-19 or death. METHODS: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab-cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394. FINDINGS: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab-cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab-cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6-71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1-8·0; p<0·0001). Adverse events occurred in 132 (29%) of 452 participants in the tixagevimab-cilgavimab group and 163 (36%) of 451 participants in the placebo group, and were mostly of mild or moderate severity. There were three COVID-19-reported deaths in the tixagevimab-cilgavimab group and six in the placebo group. INTERPRETATION: A single intramuscular tixagevimab-cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab-cilgavimab might lead to more favourable outcomes. FUNDING: AstraZeneca.

REGEN-COV Antibody Cocktail Clinical Outcomes Study in Covid-19 Outpatients

BackgroundREGEN-COV antibody cocktail (casirivimab with imdevimab) rapidly reduced viral load and decreased medically-attended visits in the phase 1/2 portion of this trial; REGEN-COV, retains activity in vitro against emerging SARS-CoV-2 variants of concern. MethodsThe phase 3 portion of this adaptive, randomized, master protocol, included 4,057 Covid-19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV, and followed for 28 days. The prespecified hierarchical analysis first compared REGEN-COV 2400mg dose vs concurrent placebo, then compared the 1200mg dose vs concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients. ResultsBoth REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; p<0.0001] and 70.4% reduction [1.0% vs 3.2%; p=0.0024], respectively). The median time to resolution of Covid-19 symptoms was 4 days shorter in both dose arms vs placebo (10 vs 14 days; p<0.0001). Efficacy of REGEN-COV was consistent across subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. REGEN-COV more rapidly reduced viral load than placebo. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200mg (1.1%) and 2400mg (1.3%) groups and grade [≥]2 infusion-related reactions were infrequent (<0.3% in all groups). ConclusionsTreatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

Menor incidencia de daño grave en órganos diana en pacientes mexicanos con esclerosis sistémica con afección cutánea difusa / Lower incidence of severe damage to target organs in mexican patients with systemic sclerosis and diffuse skin affection

Objetivo: Determinar la incidencia acumulada de daño grave en órganos diana en la esclerosis sistémica con afección cutánea difusa (ESD), en una cohorte de pacientes mexicanos a los 3 años desde el inicio de los síntomas de la enfermedad, y compararla con lo observado en una cohorte de pacientes blancos. Pacientes y método: Se incluyó a los pacientes evaluados por primera vez en los primeros 2 años desde el inicio de los síntomas de la ESD. Se determinó la incidencia acumulada de daño grave en los siguientes órganos: piel, riñones, sistemas cardiovascular, pulmonar y gastrointestinal, y se comparó con lo observado en una cohorte donde el 94% de los pacientes son blancos, mediante la prueba de una muestra para una proporción binomial. Resultados: Se encontró que 63 pacientes cumplían los criterios del estudio. La incidencia acumulada de daño grave en la piel fue del 3,17% (2/63) (intervalo de confianza [IC] del 95%, 0,04-11); daño renal del 4,17% (3/63) (IC del 95%, 0,99-13,29); daño cardiovascular del 1,6% (1/63) (IC del 95%, 0,04-8,5); daño pulmonar grave del 11,11% (7/63) (IC del 95%, 4,5-21,5), y daño gastrointestinal del 4,7% (3/63) (IC del 95%, 0,99-13,3). Al comparar los datos con los observados en pacientes blancos en el mismo período de evolución de la ESD, se encontró una menor incidencia de daño grave en la piel (p = 0,0001), y daño renal (p = 0,03) y cardiovascular (p = 0,03). Conclusiones: Se determinó la incidencia de daño grave en órganos diana en pacientes mexicanos con ESD a los 3 años desde el inicio de los síntomas. La incidencia de daño de piel, y daño renal y cardiovascular es menor que lo observado en pacientes de raza blanca (AU)

Objective: To determine the cumulative incidence of severe organ involvement in Mexican patients with systemic sclerosis (SS) and diffuse scleroderma at 3 years from the onset of SS symptoms, and to compare it with the cumulative incidence observed in a cohort of white patients with SS. Patients and method: Patients with SS and diffuse scleroderma were evaluated within the first 2 years from the onset of SS symptoms and were included. An estimation of the cumulative incidence of severe involvement to the skin, kidney, heart, lungs, and gastrointestinal track at 3 years from the onset of SS symptoms was carried out. This cumulative incidence was compared with that of white SS patients with diffuse scleroderma, using the one sample test for a binomial proportion. Results: Sixty-three patients were included. The cumulative incidence of severe involvement to the skin was 3.17% (2/63) (95% CI, 0.04%-11); kidney involvement in 4.17% (3/63) (95% CI, 0.99%-13.29%); heart involvement in 1.6% (1/63) (95% CI, 0.04%-8.5%); lung involvement in 11.11% (7/63) (95% IC, 4.5%- 21.5%); and gastrointestinal involvement in 4.7% (3/63) (95% IC, 0.99%-13.3%). Mexican patients had a lower incidence of severe skin involvement (P=.0001), kidney involvement (P=.03) and heart involvement (P=.03) compared to white SS patients with diffuse scleroderma. Conclusions: The cumulative incidence of severe organ involvement in SS Mexican patients with diffuse scleroderma was determined. The incidence of severe skin, kidney and heart involvement is lower than in white SS patients with diffuse scleroderma (AU)

[Lower incidence of severe damage to target organs in mexican patients with systemic sclerosis and diffuse skin affection]. / Menor incidencia de daño grave en órganos diana en pacientes mexicanos con esclerosis sistémica con afección cutánea difusa.

OBJECTIVE: To determine the cumulative incidence of severe organ involvement in Mexican patients with systemic sclerosis (SS) and diffuse scleroderma at 3 years from the onset of SS symptoms, and to compare itwith the cumulative incidence observed in a cohort of white patients with SS. PATIENTS AND METHOD: Patients with SS and diffuse scleroderma were evaluated within the first 2 years from the onset of SS symptoms and were included. An estimation of the cumulative incidence of severe involvement to the skin, kidney, heart, lungs, and gastrointestinal track at 3 years from the onset of SS symptoms was carried out. This cumulative incidence was compared with that of white SS patients with diffuse scleroderma, using the one sample test for a binomial proportion. RESULTS: Sixty-three patients were included. The cumulative incidence of severe involvement to the skin was 3.17% (2/63) (95% CI, 0.04%-11); kidney involvement in 4.17% (3/63) (95% CI, 0.99%-13.29%); heart involvement in 1.6% (1/63) (95% CI, 0.04%-8.5%); lung involvement in 11.11% (7/63) (95% IC, 4.5%-21.5%); and gastrointestinal involvement in 4.7% (3/63) (95% IC, 0.99%-13.3%). Mexican patients had a lower Reumatol Clin. 2008;4(1):3-7 3 02 ORIG 2582 (3-7).qxp 23/1/08 11:09 Página 4 Rojas-Serrano J et al. Incidencia de daño grave en pacientes mexicanos con esclerosis sistémica incidence of severe skin involvement (P=.0001), kidney involvement (P=.03) and heart involvement (P=.03) compared to white SS patients with diffuse scleroderma. CONCLUSIONS: The cumulative incidence of severe organ involvement in SS Mexican patients with diffuse scleroderma was determined. The incidence of severe skin, kidney and heart involvement is lower than in white SS patients with diffuse scleroderma.

Antinucleosome antibodies may help predict development of systemic lupus erythematosus in patients with primary antiphospholipid syndrome.

Patients with primary antiphospholipid syndrome (PAPS) may evolve to systemic lupus erythematosus (SLE), even many years later. This makes differentiation between primary and secondary antiphospholipid syndrome a difficult task. Studies in murine models of lupus have shown that the development of antinucleosome (anti-NCS) antibodies may occur from the early stages of life. We therefore hypothesize that anti-NCS antibodies could help predict development of SLE in patients with PAPS. We studied anti-NCS antibodies in 18 PAPS patients (15 female, three male), followed for a mean of 11 years to evaluate the potential development of SLE. When PAPS was diagnosed, nine patients were positive for anti-NCS antibodies. Six of them developed clinical manifestations of SLE. In contrast, none of the patients who were negative to anti-NCS antibodies developed it. These findings suggest that anti-NCS antibodies could help predict which patients with PAPS may eventually develop SLE.

[Survival, clinical and laboratory characteristics of de novo and secondary megakaryoblastic leukemia]. / Supervivencia, características clínicas y de laboratorio en leucemias megacarioblásticas de novo y secundaria.

OBJECTIVE: To describe the frequency and compare the clinical characteristics, treatment response, survival and hematologic, immunophenotypic, cytogenetic, and histologic findings in adult patients with acute megakaryoblastic leukemia (AMegL) and megakaryocytic blast crisis of chronic myeloid leukemia (MegBC-CML). MATERIAL AND METHODS: The records of patients with AMegL and MegBC-CML attended in our institution between July 1993 and December 2000 were revised. Megakaryocytic lineage was established by the presence of one or more megakaryocyte/platelet associated antigens (CD41, CD42b, and CD61) in > 20% blast cells. RESULTS: In 90 months, 277 patients with acute leukemia were admitted and 25 with chronic myeloid leukemia (CML) in blast crisis (BC) were identified. Twelve of 125 patients (9.6%) with acute myeloid leukemia were AMegL and 32% of cases with CML-BC were MegBC-CML. Leukemic cells of patients with AMegL expressed more frequently CD15 antigen than blast cells of those with MegBC-CML (83% and 37.5%; p < 0.05). In contrast, blast cells expressing myeloperoxidase were present in 50% and 10% of cases with MegBC-CML and AMegL, respectively (p < 0.05). Only one patient in each group obtained remission. Although median survival in patients with AMegL was lower (70 days) than in those with MegBC-CML (175 days) the difference did not reach statistical significance. CONCLUSION: AMegL and MegBC-CML differ in some clinical and laboratory characteristics and are diseases with poor treatment response and short survival.

[Biological therapy in rheumatoid arthritis]. / Terapia biológica en artritis reumatoide.

Rheumatoid arthritis is an autoimmune disease of unknown etiology. It represents a public health problem since it affects 2% of economically active population. Treatment with cytotoxic drugs has improved quality of life in these patients. However, a significant amount of patients do not respond or do not tolerate this treatment modality. Biotechnology advances have given rise to a new treatment approach known as biological therapy. This new approach has opened a new therapeutical perspective in these patients. The objective of this publication is to review the different aspects of biological therapy, as well as to inform the initial results of clinical trials in patients with rheumatoid arthritis.