Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial,The Lancet Respiratory Medicine

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Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial
The Lancet Respiratory Medicine ( IF 76.2 ) Pub Date : 2021-10-18 , DOI: 10.1016/s2213-2600(21)00384-2
Andre C Kalil ₁ , Aneesh K Mehta ₂ , Thomas F Patterson ₃ , Nathaniel Erdmann ₄ , Carlos A Gomez ₅ , Mamta K Jain ₆ , Cameron R Wolfe ₇ , Guillermo M Ruiz-Palacios ₈ , Susan Kline ₉ , Justino Regalado Pineda ₁₀ , Anne F Luetkemeyer ₁₁ , Michelle S Harkins ₁₂ , Patrick E H Jackson ₁₃ , Nicole M Iovine ₁₄ , Victor F Tapson ₁₅ , Myoung-Don Oh ₁₆ , Jennifer A Whitaker ₁₇ , Richard A Mularski ₁₈ , Catharine I Paules ₁₉ , Dilek Ince ₂₀ , Jin Takasaki ₂₁ , Daniel A Sweeney ₂₂ , Uriel Sandkovsky ₂₃ , David L Wyles ₂₄ , Elizabeth Hohmann ₂₅ , Kevin A Grimes ₂₆ , Robert Grossberg ₂₇ , Maryrose Laguio-Vila ₂₈ , Allison A Lambert ₂₉ , Diego Lopez de Castilla ₃₀ , EuSuk Kim ₃₁ , LuAnn Larson ₁ , Claire R Wan ₂ , Jessica J Traenkner ₂ , Philip O Ponce ₃ , Jan E Patterson ₃ , Paul A Goepfert ₄ , Theresa A Sofarelli ₅ , Satish Mocherla ₆ , Emily R Ko ₇ , Alfredo Ponce de Leon ₈ , Sarah B Doernberg ₁₁ , Robert L Atmar ₁₇ , Ryan C Maves ₃₂ , Fernando Dangond ₃₃ , Jennifer Ferreira ₃₄ , Michelle Green ₃₄ , Mat Makowski ₃₄ , Tyler Bonnett ₃₅ , Tatiana Beresnev ₃₆ , Varduhi Ghazaryan ₃₆ , Walla Dempsey ₃₆ , Seema U Nayak ₃₆ , Lori Dodd ₃₆ , Kay M Tomashek ₃₆ , John H Beigel ₃₆ ,

Affiliation

University of Nebraska Medical Center, Omaha, NE, USA.
Emory University, Atlanta, GA, USA.
University of Texas Health San Antonio, University Health System, and the South Texas Veterans Health Care System, San Antonio, TX, USA.
University of Alabama at Birmingham, Birmingham, AL, USA.
University of Utah, Salt Lake City, UT, USA.
University of Texas Southwestern Medical Center, Parkland Health & Hospital System, Dallas, TX, USA; UT Southwestern Medical Center, Parkland Health and Hospital System, Dallas, TX, USA.
Duke University, Durham, NC.
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
University of Minnesota Medical School, Minneapolis, MN, USA.
Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
University of California San Francisco, San Francisco, CA, USA.
University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
University of Virginia, Charlottesville, VA, USA.
University of Florida, Gainesville, FL, USA.
Cedars Sinai Medical Center, Los Angeles, CA, USA.
Seoul National University Hospital, Seoul, Korea.
Baylor College of Medicine, Houston, TX, USA.
Kaiser Permanente Northwest, Portland, OR, USA.
Pennsylvania State Health Milton S Hershey Medical Center, Hershey, PA, USA.
Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
National Center for Global Health and Medicine, Tokyo, Japan.
University of California San Diego, La Jolla, CA, USA.
Baylor Scott & White Health, Dallas, TX, USA.
Denver Health and Hospital Authority, Denver, CO, USA.
Massachusetts General Hospital, Boston, MA, USA.
Houston Methodist, Houston, TX, USA.
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
University of Rochester and Rochester Regional Health, Rochester, NY, USA.
Providence Sacred Heart Medical Center, Spokane, WA, USA.
Evergreen Health Medical Center, Kirkland, WA, USA.
Seoul National University Bundang Hospital, Seongnam, Korea.
Naval Medical Center, San Diego, CA, USA; Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
EMD Serono Research & Development Institute, Billerica, MA, USA.
The Emmes Company, Rockville, MD, USA.
Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Background

Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.

Methods

We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.

Findings

Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.

Interpretation

Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.

Funding

The National Institute of Allergy and Infectious Diseases (USA).

中文翻译：

干扰素 β-1a 加瑞德西韦与单用瑞德西韦治疗住院成人 COVID-19 的疗效：一项双结合、随机、安慰剂对照 3 期试验

背景

干扰素是免疫系统的天然抗病毒成分，其功能受损与 COVID-19 的发病机制和严重程度有关。我们的目的是比较干扰素 β-1a 联合瑞德西韦与单独使用瑞德西韦对住院 COVID-19 患者的疗效。

方法

我们在五个国家（日本、墨西哥、新加坡、韩国和美国）的 63 家医院进行了一项双盲、随机、安慰剂对照试验。符合条件的患者是经 RT-PCR 检测阳性证实患有 SARS-CoV-2 感染的住院成人（年龄≥18 岁），并且符合以下提示下呼吸道感染的标准之一：成像、室内空气中的外周血氧饱和度为 94% 或更低，或需要补充氧气。如果患者的丙氨酸转氨酶或天冬氨酸转氨酶浓度超过正常上限的五倍，则被排除；肾功能受损；对研究产品过敏；怀孕或哺乳；已经接受机械通气；或预计在入组后 72 小时内出院或转至另一家医院。患者被随机分配（1:1），在第一天接受静脉注射瑞德西韦 200 mg 负荷剂量，随后每天服用 100 mg 维持剂量，持续长达 9 天，以及最多四剂 44 μg 干扰素 beta-1a（干扰素β-1a组加瑞德西韦组）或安慰剂（安慰剂加瑞德西韦组）每隔一天皮下注射一次。随机分组根据研究地点和入组时的疾病严重程度进行分层。患者、研究人员和现场工作人员不接受干扰素 β-1a 和安慰剂治疗；所有患者均在不掩蔽的情况下接受瑞德西韦治疗。主要结果是恢复时间，定义为患者在 28 天内在八类序数量表上获得 1、2 或 3 类评分的第一天，在修改后的意向治疗人群中进行评估，定义为根据实际临床严重程度进行分类的所有随机患者。在接受治疗的人群中评估安全性，接受治疗的人群定义为接受至少一剂指定治疗的所有患者。该试验已在 ClinicalTrials.gov 注册，NCT04492475。

发现

2020年8月5日至2020年11月11日期间，共招募了969名患者，并随机分配至干扰素β-1a加瑞德西韦组（n=487）或安慰剂加瑞德西韦组（n=482）。干扰素β-1a加瑞德西韦组入组前的平均症状持续时间为8·7天(SD 4·4)，安慰剂加瑞德西韦组为8·5天(SD 4·3)。两组患者的恢复时间均为 5 天（95% CI 不可估计）（干扰素 β-1a 加瑞德西韦组与安慰剂加瑞德西韦组的比率为 0·99 [ 95% CI 0·87–1·13]； p=0·88）。Kaplan-Meier 估计的 28 天死亡率在干扰素 β-1a 加瑞德西韦组中为 5% (95% CI 3–7%)，在安慰剂加瑞德西韦组中为 3% (2–6%)（风险比 1） ·33 [95% CI 0·69–2·55]；p=0·39）。与安慰剂加瑞德西韦组（15 名患者中的 15 名患者相比，干扰素 β-1a 联合瑞德西韦组中的 33 名患者（442 名患者中的 7%））在基线时不需要高流量吸氧的患者更有可能发生至少一种相关不良事件。 [435 的 3%]）。在基线时需要高流量吸氧的患者中，干扰素 β-1a 加瑞德西韦组的 35 例患者中，有 24 例 (69%) 发生不良事件，其中 21 例 (60%) 发生严重不良事件，而干扰素 β-1a 加瑞德西韦组中有 13 例 (39%) 发生严重不良事件。在安慰剂加瑞德西韦组中，有 33 名患者出现不良事件，8 名患者 (24%) 出现严重不良事件。