The Efficacy and Safety of Thalidomide in the Adjuvant Treatment of Moderate New Coronavirus (COVID-19) Pneumonia

• ClinicalTrials.gov Identifier: NCT04273529
• Recruitment Status: Unknown
• First Posted: February 18, 2020
• Last Update Posted: February 21, 2020
• Sponsor: First Affiliated Hospital of Wenzhou Medical University
• Collaborators: Second Affiliated Hospital of Wenzhou Medical University; Wenzhou Central Hospital
• Information provided by (Responsible Party): First Affiliated Hospital of Wenzhou Medical University

Study Description

Brief Summary:

In December 2019, Wuhan, in Hubei province, China, became the center of an outbreak of pneumonia of unknown cause. In a short time, Chinese scientists had shared the genome information of a novel coronavirus (2019-nCoV) from these pneumonia patients and developed a real-time reverse transcription PCR (real time RT-PCR) diagnostic assay.

In view of the fact that there is currently no effective antiviral therapy, the prevention or treatment of lung injury caused by COVID-19 can be an alternative target for current treatment. Thalidomide has anti-inflammatory, anti-fibrotic, anti-angiogenesis, and immune regulation effects. This study is the first Prospective, Multicenter, Randomized, Double-blind, Placebo, Parallel Controlled Clinical Study at home and abroad to use immunomodulators to treat patients with COVID-19 infection.

Condition or disease	Intervention/treatment	Phase
COVID-19 Thalidomide	Drug: thalidomide; Drug: placebo	Phase 2

Detailed Description:

The new coronavirus (COVID-19) [1] belongs to the new beta coronavirus. Current research shows that it has 85% homology with bat SARS-like coronavirus (bat-SL-CoVZC45), but its genetic characteristics are similar to SARSr-CoV. There is a clear difference from MERSr-COV. Since December 2019, Wuhan City, Hubei Province has successively found multiple cases of patients with pneumonia infected by a new type of coronavirus. With the spread of the epidemic, as of 12:00 on February 12, 2020, a total of 44726 confirmed cases nationwide (Hubei Province) 33,366 cases, accounting for 74.6%), with 1,114 deaths (1068 cases in Hubei Province), and a mortality rate of 2.49% (3.20% in Hubei Province).

In view of the fact that there is currently no effective antiviral therapy, the prevention or treatment of lung injury caused by COVID-19 can be an alternative target for current treatment. Thalidomide has anti-inflammatory, anti-fibrotic, anti-angiogenesis, and immune regulation effects. In the early clinical practice of treating severe A H1N1, it was clinically concerned, and combined with hormones and conventional treatment, and achieved good results.

Although the death rate of COVID-19 infected persons is not high, their rapid infectiousness and the lack of effective antiviral treatment currently have become the focus of the national and international epidemic. Thalidomide has been available for more than sixty years, and has been widely used in clinical applications. It has been proved to be safe and effective in IPF, severe H1N1 influenza lung injury and paraquat poisoning lung injury, and the mechanism of anti-inflammatory and anti-fibrosis is relatively clear. As the current research on COVID-19 at home and abroad mainly focuses on the exploration of antiviral efficacy, this study intends to find another way to start with host treatment in the case that antiviral is difficult to overcome in the short term, in order to control or relieve lung inflammation caused by the virus To improve lung function. This study is the first study at home and abroad to use immunomodulators to treat patients with COVID-19 infection. It is hoped that the patients can get out of the bitter sea as soon as possible and provide effective solutions for the country and society.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Efficacy and Safety of Thalidomide in the Adjuvant Treatment of Moderate New Coronavirus (COVID-19) Pneumonia: a Prospective, Multicenter, Randomized, Double-blind, Placebo, Parallel Controlled Clinical Study
• Estimated Study Start Date: February 20, 2020
• Estimated Primary Completion Date: May 30, 2020
• Estimated Study Completion Date: June 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Control group; placebo	Drug: placebo; 100mg，po，qn，for 14 days.
Experimental: Thalidomide group; thalidomide	Drug: thalidomide; 100mg，po，qn，for 14 days.; Other Name: fanyingting

Outcome Measures

Primary Outcome Measures :

1. Time to Clinical recoveryTime to Clinical Recovery (TTCR) [ Time Frame: up to 28 days ]

   TTCR is defined as the time (in hours) from initiation of study treatment (active or placebo) until normalisation of fever, respiratory rate, and oxygen saturation, and alleviation of cough, sustained for at least 72 hours. Normalisation and alleviation criteria:

   Fever - ≤36.6°C or -axilla, ≤37.2 °C oral or ≤37.8°C rectal or tympanic, Respiratory rate - ≤24/minute on room air, Oxygen saturation - >94% on room air, Cough - mild or absent on a patient reported scale of severe, moderate, mild, absent.

Secondary Outcome Measures :

1. All cause mortality [ Time Frame: up to 28 days ]
   baseline SpO2 during screening, PaO2/FiO2 <300mmHg or a respiratory rate ≥ 24 breaths per min without supplemental oxygen
2. Frequency of respiratory progression [ Time Frame: up to 28 days ]
   Defined as SPO2≤ 94% on room air or PaO2/FiO2 <300mmHg and requirement for supplemental oxygen or more advanced ventilator support.
3. Time to defervescence [ Time Frame: up to 28 days ]
   in those with fever at enrolment

Other Outcome Measures:

1. Time to cough reported as mild or absent [ Time Frame: up to 28 days ]
   in those with cough at enrolment rated severe or moderate
2. Respiratory improvement time [ Time Frame: up to 28 days ]
   patients with moderate / severe dyspnea when enrolled
3. Frequency of requirement for supplemental oxygen or non-invasive ventilation [ Time Frame: up to 28 days ]
4. Time to 2019-nCoV RT-PCR negative in upper respiratory tract specimen [ Time Frame: up to 28 days ]
5. Change (reduction) in 2019-nCoV viral load in upper respiratory tract specimen as assessed by area under viral load curve [ Time Frame: up to 28 days ]
6. Frequency of requirement for mechanical ventilation [ Time Frame: up to 28 days ]
7. Frequency of serious adverse events [ Time Frame: up to 28 days ]
8. Serum TNF-α, IL-1β, IL-2, IL-6, IL-7, IL-10, GSCF, IP10，MCP1, MIP1α and other cytokine expression levels before and after treatment [ Time Frame: up to 28 days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥18 years;
2. Laboratory (RT-PCR) diagnosis of common patients infected with COVID-19 (refer to the fifth edition of the Chinese Guidelines for Diagnosis and Treatment);
3. chest imaging confirmed lung damage;
4. The diagnosis is less than or equal to 8 days;

Exclusion Criteria:

1. Severe liver disease (such as Child Pugh score ≥ C, AST> 5 times the upper limit); severe renal dysfunction (the glomerulus is 30ml / min / 1.73m2 or less)
2. Positive pregnancy or breastfeeding or pregnancy test;
3. In the 30 days before the screening assessment, have taken any experimental treatment drugs for COVID-19 (including off-label, informed consent use or trial-related);
4. Those with a history of thromboembolism, except for those caused by PICC.

Contacts and Locations

Contacts

Contact: Jinglin Xia, MD; 0577-55578166; xiajinglin@fudan.edu.cn

Sponsors and Collaborators

First Affiliated Hospital of Wenzhou Medical University

Second Affiliated Hospital of Wenzhou Medical University

Wenzhou Central Hospital

Investigators

• Principal Investigator: Jinglin Xia, MD; First Affiliated Hospital of Wenzhou Medical University

More Information

Publications of Results:

Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004 Apr;4(4):314-22. doi: 10.1038/nrc1323. No abstract available.

Other Publications:

Zhao L, Xiao K, Wang H, Wang Z, Sun L, Zhang F, Zhang X, Tang F, He W. Thalidomide has a therapeutic effect on interstitial lung fibrosis: evidence from in vitro and in vivo studies. Clin Exp Immunol. 2009 Aug;157(2):310-5. doi: 10.1111/j.1365-2249.2009.03962.x.

Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020 Feb 15;395(10223):473-475. doi: 10.1016/S0140-6736(20)30317-2. Epub 2020 Feb 7. No abstract available.

Jin YH, Cai L, Cheng ZS, Cheng H, Deng T, Fan YP, Fang C, Huang D, Huang LQ, Huang Q, Han Y, Hu B, Hu F, Li BH, Li YR, Liang K, Lin LK, Luo LS, Ma J, Ma LL, Peng ZY, Pan YB, Pan ZY, Ren XQ, Sun HM, Wang Y, Wang YY, Weng H, Wei CJ, Wu DF, Xia J, Xiong Y, Xu HB, Yao XM, Yuan YF, Ye TS, Zhang XC, Zhang YW, Zhang YG, Zhang HM, Zhao Y, Zhao MJ, Zi H, Zeng XT, Wang YY, Wang XH; , for the Zhongnan Hospital of Wuhan University Novel Coronavirus Management and Research Team, Evidence-Based Medicine Chapter of China International Exchange and Promotive Association for Medical and Health Care (CPAM). A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020 Feb 6;7(1):4. doi: 10.1186/s40779-020-0233-6.

Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585. Erratum In: JAMA. 2021 Mar 16;325(11):1113.

Wen H, Ma H, Cai Q, Lin S, Lei X, He B, Wu S, Wang Z, Gao Y, Liu W, Liu W, Tao Q, Long Z, Yan M, Li D, Kelley KW, Yang Y, Huang H, Liu Q. Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma. Nat Med. 2018 Feb;24(2):154-164. doi: 10.1038/nm.4456. Epub 2018 Jan 1.

Kwon HY, Han YJ, Im JH, Baek JH, Lee JS. Two cases of immune reconstitution inflammatory syndrome in HIV patients treated with thalidomide. Int J STD AIDS. 2019 Oct;30(11):1131-1135. doi: 10.1177/0956462419847297. Epub 2019 Sep 19. No abstract available.

Zhu H, Shi X, Ju D, Huang H, Wei W, Dong X. Anti-inflammatory effect of thalidomide on H1N1 influenza virus-induced pulmonary injury in mice. Inflammation. 2014 Dec;37(6):2091-8. doi: 10.1007/s10753-014-9943-9.

• Responsible Party: First Affiliated Hospital of Wenzhou Medical University
• ClinicalTrials.gov Identifier: NCT04273529
• Other Study ID Numbers: 20200214-COVID-19-M-T
• First Posted: February 18, 2020
• Last Update Posted: February 21, 2020
• Last Verified: February 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

COVID-19; Pneumonia; Pneumonia, Viral; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Thalidomide; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Leprostatic Agents; Anti-Bacterial Agents; Anti-Infective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antineoplastic Agents