The Dutch Cohort Study for the Evaluation of the Use of Neutralizing Monoclonal Antibodies and Other Antiviral Agents Against SARS-CoV-2
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 1,178
- 试验地点
- 4
- 主要终点
- Incidence of Treatment-Emergent Adverse Events of treatment with monoclonal antibodies and antiviral agents
研究概览
简要总结
Novel antiviral drugs can mark a turning point in the prevention and treatment of patients with Covid-19. Recently, several independent large phase-III RCTs have shown that the intravenous administration of one gift of neutralizing SARS-CoV-2 monoclonal antibodies can reduce the relative risk of hospital admission and/or death with 70-85% in seronegative patients with SARS-CoV-2 infection when given within 3 to 7 days after state of symptoms. Moreover, novel oral anti-viral compunds such as molnupiravir and nirmatrelvir/ritonavir could reduce the risk of hospitalisation or death by 30% to89% in at-risk adults with Covid-19. These are potential breakthroughs in the treatment of SARS-CoV-2 infection and can be of special importantance for immunocompromised patients who have a diminished or complete lack of an effective humoral response towards Covid-19 vaccination. Monoclonal SARS-CoV-2 antibodies and antivirals have been given an emergency use authorization by regulatory authorities and are or will become available in the Netherlands to treat SARS-CoV-2 infected patients who are at high risk of developing severe disease. Now, urgent key questions need to be addressed: Which patient categories will benefit most from these new drugs? What are the SARS-CoV-2 viral load as well as inflammatory response kinetics during and after treatment with the new SARS-CoV-2 therapies? What is the safety profile in () patients; do new SARS-CoV-2 variants occur during treatment? This study aims to establish a prospective cohort together with a biobank of patients treated with new SARS-CoV-2 therapies to evaluate its real world effect and safety.
Primary Objectives:
- A. What are the SARS-CoV-2 viral load kinetics during and after treatment withneutralizing monoclonal antibodies and other antiviral agents against SARS-CoV-2?
- B. Do viralvariants, spike mutations and immune escape occur during treatment with neutralizing monoclonal antibodies and other antiviral agents against SARS-CoV-2?new SARS-CoV-2 therapies?
- C. What are the viral antibody and inflammatory response kinetics during and after treatment with neutralizing monoclonal antibodies and other antiviral agents against SARS-CoV-2?
- D. To create a biobank to address future questions regarding the current use of neutralizing monoclonal antibodies and other antiviral agents against SARS-CoV-2compared to novel COVID-19 treatments which are in development.
Study design:
Establishment of an observational cohort study including a biobank of patients who receive neutralizing monoclonal antibodies and other novel antiviral agents against SARS-CoV-2.
Study population: All patients above 18 years of age treated with neutralizing monoclonal antibodies and other novel antiviral agents against SARS-CoV-2.
Intervention (if applicable): None Main study parameters/endpoints: Viral load kinetics during treatment. Viral mutations during and after treatment. Presence of monoclonal antibody during treatment and host antibody production and inflammatory responses during treatment.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participating in this observational study will not directly benefit the participants and healthy volunteers. The study will provide information about the effect, host response and safety of thse new anti-SARS-CoV-2 therapies during Covid-19. Clinical data will be obtained through the electronic patient dossier. The knowledge obtained can potentially benefit Covid-19 patients in the future by optimizing treatment strategies. The burden and risks for patients participating in the TURN-COVID biobank study is minimal.
Patients will be visited by a research physician or research nurse during or within three days after receiving neutralizing monoclonal antibodies and other antiviral agents against SARS-CoV-2. Baseline data regarding medical history, admission and vital parameters will be collected through the electronic patient dossier. At the follow-up visits we will draw a total of (3x 43 ML and 1x16 ml = 145 ml of venous blood) and obtain 4 oro-/nasopharyngeal swabs divided over four time-points (day of treatment and day 7, 28 and 90 post treatment).
详细描述
2. INTRODUCTION AND RATIONALE New SARS-CoV-2 specific monoclonal antibodiestherapies From the beginning of the worldwide pandemic till now no effective specific anti- SARS-CoV-2 treatment was available1,2. In June 2021 the use of SARS-CoV-2 monoclonal antibodies as early treatment for SARS-CoV-2 infected individuals became available in the Netherlands after an emergency use authorisation of the FDA and EMA. First large phase-III randomised controlled clinical trials have showed that SARS-CoV-2 monoclonal antibodies, when given early after the onset of symptoms, bind the SARS-CoV-2 spike protein effectively and prevent hospital admission and death3-7. Additionally, promising SARS-CoV-2 compounds ,such as the oral antivirals molnupiravir8 and nirmatrelvir/ritonavir paxlovid9received recently received an emergency use authorization of the FDA in patients with Covid-19 at high risk of hospitalization and death. EMA's human medicines committee (CHMP) has also started a rolling review of the oral antiviral medicine molnupiravir.
Pathophysiology SARS-CoV-2 monoclonal antibodies
SARS-CoV-2 monoclonal antibodies recognize a single and unique epitope on the SARS-CoV-2 spike proteins and are derived from donor B lymphocytes. The donor B-lymphocytes can be derived either from patients who had Covid-19 or humanized mice who were exposed to SARS-CoV-23,10. The SARS-CoV-2 monoclonal antibodies inhibit the entry of the virus into the host cells (neutralization). Furthermore, antibody binding results in opsonization and is the first step of phagocytosis, eventually resulting in apoptosis and necrosis of the infected cells3. Monoclonal antibodies can be altered artificially in the laboratory to combat emerging variants of SARS-CoV-23. Threewo frequently investigated combinations are casirivimab with imdevimab, sotrovimabsotrovimab and and balanivimab with etesevimab4-7,11.
Small-molecules for Covid-19 At present, many candidate small-molecule therapeutics have been developed that can inhibit both the infection and replication of SARS-CoV-2 and even potentially relieve cytokine storms and other related complications. As SARS-CoV-2 infects cells, reproduces itself, and spreads, the coronavirus relies on dozens of viral and host proteins to complete its life cycle. The new oral pill paxlovid (Phizer) inhibits the main viral protease used to create other proteins for the virus9 (REF. The oral pill molnupiravir (Merck) inserts a defective RNA building block when the virus uses an enzyme known as a polymerase to copy its genome. (REF Molnupiravir)8
The role of SARS-CoV-2new monoclonal antibodies in treatment of SARS-CoV-2 therapies There are a number of factors that most probably will lead to seasonally peaks of infection and hospital admissions for SARS-CoV-2 infections12-14. First, there will remain a group within our population that remains willingly unvaccinated. Second, it is shown that numerous immunocompromised patients have inadequate antibody response to vaccinations and do not produce long-term protection15,16. At last, with new emerging viral variants arising with expected higher viral spread, it is assumed that outbreaks of SARS-CoV-2 infections will remain prevalent in the coming years12-14,17.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All patients that are treated with neutralizing monoclonal SARS-CoV-2 antibodies or with small-molecules for Covid-19 as standard of care.
- •Patients have to be aged ≥ 18 y.
排除标准
- •No informed consent is provided by the patient or by his/her legal representative
- •Patients not suitable to fulfil study procedures
研究组 & 干预措施
COVID-19
Patients diagnosed with COVID-19
干预措施: molnupiravir (Drug)
COVID-19
Patients diagnosed with COVID-19
干预措施: casirivimab with imdevimab (Drug)
COVID-19
Patients diagnosed with COVID-19
干预措施: sotrovimab (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events of treatment with monoclonal antibodies and antiviral agents
时间窗: At day 90
Therapeutic effect of treatment with monoclonal antibodies and antiviral agents
时间窗: At day 90
Cost-effectiveness of treatment with monoclonal antibodies and antiviral agents
时间窗: At day 90
次要结局
- Change of serologic response during treatment with monoclonal antibodies and antiviral agents(At baseline, day 7, day 28 and day 90)
研究者
W. J. Wiersinga, MD
Clinical Professor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)