Publications by authors named "Arzhang C Javan"
The United States Government (USG) public-private partnership "Accelerating COVID-19 Treatment Interventions and Vaccines" (ACTIV) was launched to identify safe, effective therapeutics to treat patients with Coronavirus Disease 2019 (COVID-19) and prevent hospitalization, progression of disease, and death. Eleven original master protocols were developed by ACTIV, and thirty-seven therapeutic agents entered evaluation for treatment benefit. Challenges encountered during trial implementation led to innovations enabling initiation and enrollment of over 26,000 participants in the trials.
View Article and Find Full Text PDFWe explored viral and symptom rebound after COVID-19 amubarvimab/romlusevimab monoclonal antibody therapy vs placebo in the randomized ACTIV-2/A5401 trial. Participants underwent nasal SARS-CoV-2 PCR at study days 3, 7, 14, and 28. Viral rebound was defined as RNA ≥3 and ≥0.
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- A study investigated whether the monoclonal antibodies amubarvimab/romlusevimab could lower the risk of Long COVID in non-hospitalized high-risk adults treated soon after COVID-19 symptoms began.
- Results showed that while this treatment significantly reduced hospitalizations and deaths (4% vs. 13% in the placebo group), it did not decrease the incidence of Long COVID symptoms, with 16% of treated participants reporting Long COVID compared to 14% in the placebo group.
- The conclusion is that although amubarvimab/romlusevimab is effective for immediate COVID-19 outcomes, additional strategies are necessary to prevent Long COVID.
Background: We evaluated the fully human polyclonal antibody product SAB-185 in a phase 3 trial for COVID-19.
Methods: Nonhospitalized high-risk adults within 7 days of symptom onset were randomized 1:1 to open-label SAB-185 3840 units/kg or casirivimab/imdevimab 1200 mg. Noninferiority comparison was undertaken for pre-Omicron population (casirivimab/imdevimab expected to be fully active) and superiority comparison for the Omicron population (casirivimab/imdevimab not expected to be active).
Article Synopsis
- Outpatient treatment of COVID-19 using subcutaneous monoclonal antibodies (mAbs) could simplify logistics compared to intravenous delivery.
- In a clinical trial with 211 participants, the BMS mAbs did not show significant benefits in symptom improvement or viral load reduction compared to placebo, despite being safe with fewer severe adverse events reported.
- The results suggest that subcutaneous administration of BMS mAbs may not be effective for low-risk COVID-19 patients, potentially due to how the body absorbs mAbs through this method.
Background: With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need.
Methods: Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.govNCT04518410).
Article Synopsis
- The study analyzed the effectiveness of time to symptom resolution (TSR) as a measure in outpatient COVID-19 treatment trials, using data from the ACTIV-2/A5401 trial involving high-risk and standard-risk participants.
- Participants tracked 13 symptoms and overall health for 29 days to assess the correlation between the sustained resolution of targeted symptoms and broader health outcomes.
- Results showed a strong correlation between TSR and overall symptom improvement, supporting TSR as a viable endpoint for clinical trials, while emphasizing the need for a careful definition of symptom resolution duration to reduce the chance of symptom recurrence.
Background: Prospective evaluations of long COVID in outpatients with coronavirus disease 2019 (COVID-19) are lacking. We aimed to determine the frequency and predictors of long COVID after treatment with the monoclonal antibody bamlanivimab in ACTIV-2/A5401.
Methods: Data were analyzed from participants who received bamlanivimab 700 mg in ACTIV-2 from October 2020 to February 2021.
Article Synopsis
- Clinical trials for COVID-19 therapeutics often measure antiviral activity by assessing changes in nasal SARS-CoV-2 RNA levels, typically using statistical methods like ANCOVA or MMRM.
- Using single imputation for results below the assay’s lower limits of quantification (LLoQ) can introduce bias in estimating treatment effects.
- The article underscores best practices for analyzing quantitative viral RNA data, emphasizing the importance of detailing assay specifics, completeness summaries, and considering values below LLoQ as censored measurements.
Article Synopsis
- Adaptive platform trials were used during the COVID-19 pandemic to quickly test new treatments, such as the ACTIV-2 trial that looked at seven different investigational therapies.
- The trial used a pooled placebo control group, which included participants receiving either a placebo for the specific agent being tested or for other agents being evaluated at the same time.
- This approach reduced the overall sample size by 6% compared to separate placebo groups and achieved a larger 26% reduction during overlapping evaluations, highlighting the complexities of using pooled versus separate controls in clinical trial designs.
Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410.
View Article and Find Full Text PDFBackground: There is little information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA as a predictor for clinical outcomes in outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19).
Methods: Anterior nasal (AN) and plasma SARS-CoV-2 RNA data from 2115 nonhospitalized adults who received monoclonal antibodies (mAbs) or placebo in the ACTIV-2/A5401 trial were analyzed for associations with hospitalization or death.
Results: One hundred two participants were hospitalized or died through 28 days of follow-up.
Background: Camostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults.
Methods: We conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm.
Importance: Development of effective, scalable therapeutics for SARS-CoV-2 is a priority.
Objective: To test the efficacy of combined tixagevimab and cilgavimab monoclonal antibodies for early COVID-19 treatment.
Design, Setting, And Participants: Two phase 2 randomized blinded placebo-controlled clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-2/A5401 platform were performed at US ambulatory sites.
Article Synopsis
- A phase 2 and 3 clinical trial was conducted to evaluate the safety and effectiveness of two monoclonal antibodies, amubarvimab and romlusevimab, in treating patients with SARS-CoV-2 who are at high risk for severe illness.
- *The trial involved 807 participants across multiple countries, showing that the antibody combination significantly reduced hospitalizations and deaths by 79% compared to a placebo group, with fewer severe adverse events reported.
- *However, a limitation of the study is that the majority of participants were unvaccinated against COVID-19, which may impact the generalizability of the results.
Article Synopsis
- Many clinical trials for COVID-19 treatments assess antiviral effectiveness by monitoring changes in nasal SARS-CoV-2 RNA levels.
- Using methods like ANCOVA or MMRM and filling in missing data (imputation) can distort treatment effect estimates.
- The paper emphasizes best practices for data analysis, recommending the careful treatment of measurements below the lower limits of quantification (LLoQ) and full transparency regarding assay details and participant outcomes.
Background: SAB-185, a novel fully human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for nonhospitalized adults with mild-moderate coronavirus disease 2019 (COVID-19).
Methods: Participants received intravenous SAB-185 3840 units/kg (low-dose) or placebo, or 10 240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA < lower limit of quantification (LLOQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28.
Article Synopsis
- Identifying characteristics associated with SARS-CoV-2 RNA shedding can help in understanding how the virus behaves, how it causes disease, and the risk of its spread.
- A study evaluated SARS-CoV-2 RNA levels in different body fluids from participants, finding strong correlations between nasopharyngeal and nasal RNA levels, as well as factors affecting these levels like age and race.
- Results showed that older age increases RNA levels, and women clear the virus more quickly than men, potentially explaining differences in COVID-19 severity.
Article Synopsis
- SARS-CoV-2 mutations that confer resistance to monoclonal antibody therapy, specifically bamlanivimab, have been observed, particularly after the lower 700 mg dosage is administered.
- In a clinical trial involving symptomatic non-hospitalized participants, 7% of those receiving the 700 mg dose developed treatment-emergent resistance mutations compared to none in the placebo group, while a higher 7,000 mg dose showed no such mutations.
- The study indicated that patients with these mutations had higher initial viral loads and experienced significant viral rebound, emphasizing the need for monitoring viral resistance when developing COVID-19 treatments.
Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement. Clinical Trials Registration.
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- - Anti-SARS-CoV-2 monoclonal antibodies, like bamlanivimab, are important treatments for COVID-19, and their safety and effectiveness were tested in a study called ACTIV-2/A5401.
- - In this randomized trial, non-hospitalized adults with early COVID-19 symptoms were given either bamlanivimab or a placebo, but the primary results showed no significant differences in undetectable viruses or symptom improvement between the two groups.
- - Although bamlanivimab didn’t reduce symptom duration, it was linked to lower viral levels in the nose after three days and quicker drops in inflammation and viral levels, suggesting it may help control the virus's spread early on. *
Article Synopsis
- AZD7442 (Evusheld) is a treatment for COVID-19 that uses two monoclonal antibodies, tixagevimab and cilgavimab, administered either intramuscularly (i.m.) or intravenously (i.v.).
- A study compared the pharmacokinetics (PKs) of a 600 mg i.m. dose in the thigh to a 300 mg i.v. dose in patients with symptomatic COVID-19, finding similar serum concentrations after 3 days from both routes.
- The results indicated that i.m. administration provides almost equivalent exposure to the i.v. method, suggesting it could enhance treatment access and maintain consistent antibody levels.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) are among the treatments recommended for high-risk ambulatory persons with coronavirus 2019 (COVID-19). Here, we study viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial (ClinicalTrials.gov: NCT04518410).
View Article and Find Full Text PDFMonoclonal antibodies (mAbs) are the treatment of choice for high-risk ambulatory persons with mild to moderate COVID-19. We studied viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial. Viral load by qPCR and viral culture were performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7.
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