Camostat and Artemisia Annua vs Placebo in COVID-19 Outpatients

Obesity Clinical Trial

Official title:

Randomized, Double-blind, Placebo-controlled, Multicenter, Multi-arm, Phase II Trial of Novel Agents for the Treatment of Mild to Moderate COVID-19 Positive Outpatients

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04530617
• Other study ID #: 3421
• Status: Terminated
• Phase: Phase 2
• Start date: October 5, 2020
• Est. completion date: June 10, 2021

Study information

• Verified date: August 2020
• Source: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, double-blind, placebo-controlled, multi-arm, multicenter, phase II trial design to allow a rapid efficacy and toxicity assessment of potential therapies (camostat mesilate and artemisia annua) immediately after COVID-19 positive testing in mild to moderate disease and high-risk factors such as diabetes, hypertension, and obesity among others.

Description:

Coronavirus Disease 2019 (COVID-19) is a highly contagious disease, caused by a novel enveloped RNA beta-coronavirus, also known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This disease has caused a global health crisis. While the majority of patients with COVID-19 develop a mild or uncomplicated illness, approximately 20-30% of hospitalized patients have required intensive care support and 5% of those have multi-organ failure or shock. The case fatality rate ranges from 1 to 4% and it is higher among those with pre-existing comorbid conditions (high-risk) such as cardiovascular disease, diabetes mellitus, obesity, chronic respiratory disease, hypertension, and cancer. To date, treatments for COVID-19 in high-risk individuals remain experimental and therapeutic strategies to deal with the infection are at best supportive, with prevention aimed at reducing transmission in the community as the best weapon. No proven therapies have been demonstrated to prevent progression of COVID-19 to severe illness in confirmed outpatients with COVID-19 and this is a critical unmet need for high-risk individuals and warrants study. Furthermore, there are no effective medications for the use in outpatients with confirmed mild to moderate COVID-19 disease. This is a randomized, double-blind, placebo-controlled, multi-arm, multicenter, phase II trial design to allow a rapid efficacy and toxicity assessment of potential therapies, camostat mesilate (serine protease inhibitor) and Artemisia annua (unknown mechanism) immediately after COVID-19 positive testing in mild to moderate disease and high-risk factors such as diabetes, hypertension, and obesity among others. The hypothesis of this study is that the addition of agents that inhibit viral entry or replication of SARS-CoV-2 virus, such as Artemisia annua and camostat, will reduce the rate of a composite outcome of hospitalization due to COVID-19 pneumonia or the use of oxygen therapy; will be devoid of additional moderate to severe toxicities; and will improve viral clearance at Day 14 in high-risk individuals. The main hypothesis is that the clinical outcomes in COVID-19 infected patients at higher risk of poor outcomes following infection will be improved compared to the standard of care when introduced as an early intervention after diagnosis.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 246
• Est. completion date: June 10, 2021
• Est. primary completion date: June 10, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age =18 years
• Laboratory-confirmed SARS-CoV-2 infection within 3 days (of proposed consent) or the presence of symptoms or signs providing a high probability of COVID-19 disease who have symptoms within 7 days prior to diagnosis as determined by Infectious Disease specialist or treating physicians.
• Outpatients. No previous hospitalization within the past 3 months.
• Subjects must have at least one of the following high-risk features for clinical

deterioration:

• Hypertension
• Diabetes mellitus
• Moderate to severe Chronic Obstructive Pulmonary Disease or asthma
• Cancer patients who have received any immunosuppressive drugs within a year from enrollment.
• Obesity as defined by a body mass index > 30 kg/m2.
• Living in a nursing home or long-term facility
• Underlying serious heart condition as determined by the treating physician
• Immunocompromised subject as defined by the treating physician or by the Infectious Disease specialist
• Ability to provide informed consent by the patient or healthcare proxy.
• Ability to return for repeated testing and observation to the hospital.
• Patients must have adequate organ and marrow function measured within the last 30

days as defined below:

• platelets =100,000
• aspartate transaminase or alanine transaminase =3 times institutional upper limit of normal
• creatinine = 1.5 times institutional upper limit of normal OR
• glomerular filtration rate =45 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2

Exclusion Criteria:

• Severe COVID-19 is defined by one or more of the following:
• blood oxygen saturation = 90%
• partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300
• lung infiltrates = 50% within 24 to 48 hours
• Life-threatening COVID-19 is defined as one or more of the following:
• respiratory failure
• septic shock
• multiple organ dysfunction or failure
• Weight less than 45 kg.
• Pregnant or breast-feeding females
• Subjects on dialysis or with creatinine clearance < 45 ml/min
• Subjects who need antiviral administration due to severe viral diseases other than COVID-19, such as HIV, hepatitis B, and hepatitis C
• Existing Division of Microbiology and Infectious Disease Toxicity Scale for determining the severity of adverse events grade 3 or greater.
• Uncontrolled seizure disorder
• Subjects with reflux esophagitis after chronic pancreatitis and gastrectomy surgery.
• Patients with reflux esophagitis after surgery.
• Known allergy to Artemisia annua or camostat mesilate.
• Currently receiving any study medications for other indications.
• Concurrent use of medication that would cause moderate or severe due to drug-drug interactions with study medication.

Specifically:

• Patients receiving Artemisia annua tea may not be currently taking strong inducers of CYP2A6, including phenobarbital and rifampin.
• Receipt in the 12 hours prior to enrollment, or planned administration during the 14-day study period that treating clinicians feel cannot be substituted for another medication, of any of the following: amiodarone; cimetidine; dofetilide; phenobarbital; phenytoin; or sotalol.
• Cancer patients receiving active immunosuppressive treatment cannot be enrolled unless they are on a treatment holiday with no antineoplastic treatment with 3 weeks of enrollment.
• Patients with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
• Subjects who have a history of drug and/or alcohol abuse within 52 weeks before screening
• Enrollment on other experimental therapies for COVID-19.
• Inability to receive enteral medications
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• Subjects who have a history of drug and/or alcohol abuse within 52 weeks before screening
• Any other condition that in the opinion of the treating physician justifies exclusion from the study.

Related Conditions & MeSH terms

• Covid19
• Diabetes
• Hypertension
• Obesity

Intervention

Drug:
• Camostat Mesilate
Tablets
• Artemisia Annua Leaf
Tea bags

Locations

Country	Name	City	State
Mexico	Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán	Mexico City	None - Non-US/Canada

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Country where clinical trial is conducted

Mexico, 

References & Publications (29)

Becker RC. COVID-19 update: Covid-19-associated coagulopathy. J Thromb Thrombolysis. 2020 Jul;50(1):54-67. doi: 10.1007/s11239-020-02134-3. Review. — View Citation

Berry SM, Alarid ET, Beebe DJ. One-step purification of nucleic acid for gene expression analysis via Immiscible Filtration Assisted by Surface Tension (IFAST). Lab Chip. 2011 May 21;11(10):1747-53. doi: 10.1039/c1lc00004g. Epub 2011 Mar 21. — View Citation

Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, Edwards KM, Gandhi R, Muller WJ, O'Horo JC, Shoham S, Murad MH, Mustafa RA, Sultan S, Falck-Ytter Y. Infectious Diseases Society of America Guidelines on the Treatment and Management of Pat — View Citation

Coote K, Atherton-Watson HC, Sugar R, Young A, MacKenzie-Beevor A, Gosling M, Bhalay G, Bloomfield G, Dunstan A, Bridges RJ, Sabater JR, Abraham WM, Tully D, Pacoma R, Schumacher A, Harris J, Danahay H. Camostat attenuates airway epithelial sodium channel — View Citation

Del Rio C, Malani PN. COVID-19-New Insights on a Rapidly Changing Epidemic. JAMA. 2020 Apr 14;323(14):1339-1340. doi: 10.1001/jama.2020.3072. — View Citation

Garg S, Kim L, Whitaker M, O'Halloran A, Cummings C, Holstein R, Prill M, Chai SJ, Kirley PD, Alden NB, Kawasaki B, Yousey-Hindes K, Niccolai L, Anderson EJ, Openo KP, Weigel A, Monroe ML, Ryan P, Henderson J, Kim S, Como-Sabetti K, Lynfield R, Sosin D, T — View Citation

Gee JR, Saltzstein DR, Kim K, Kolesar J, Huang W, Havighurst TC, Wollmer BW, Stublaski J, Downs T, Mukhtar H, House MG, Parnes HL, Bailey HH. A Phase II Randomized, Double-blind, Presurgical Trial of Polyphenon E in Bladder Cancer Patients to Evaluate Pha — View Citation

Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, Rusconi S, Gervasoni C, Ridolfo AL, Rizzardini G, Antinori S, Galli M. Self-reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross — View Citation

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ — View Citation

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibi — View Citation

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 20 — View Citation

Kawase M, Shirato K, van der Hoek L, Taguchi F, Matsuyama S. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J Virol. 2012 Jun;86(12):653 — View Citation

Krishna S, Bustamante L, Haynes RK, Staines HM. Artemisinins: their growing importance in medicine. Trends Pharmacol Sci. 2008 Oct;29(10):520-7. doi: 10.1016/j.tips.2008.07.004. Epub 2008 Aug 25. Review. — View Citation

Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, Zhang X, Hua SN, Yu J, Xiao PG, Li RS, Tan X. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 2005 Jul;67(1):18-23. — View Citation

Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018 Apr;104:8-13. doi: 10.1016/j.cyto.2018.01.025. Epub 2018 Feb 2. — View Citation

Munyangi J, Cornet-Vernet L, Idumbo M, Lu C, Lutgen P, Perronne C, Ngombe N, Bianga J, Mupenda B, Lalukala P, Mergeai G, Mumba D, Towler M, Weathers P. Artemisia annua and Artemisia afra tea infusions vs. artesunate-amodiaquine (ASAQ) in treating Plasmodi — View Citation

Naesens L, Bonnafous P, Agut H, De Clercq E. Antiviral activity of diverse classes of broad-acting agents and natural compounds in HHV-6-infected lymphoblasts. J Clin Virol. 2006 Dec;37 Suppl 1:S69-75. — View Citation

Ortiz-Brizuela E, Villanueva-Reza M, González-Lara MF, Tamez-Torres KM, Román-Montes CM, Díaz-Mejía BA, Pérez-García E, Olivas-Martínez A, Rajme-López S, Martinez-Guerra BA, de-León-Cividanes NA, Fernández-García OA, Guerrero-Torres L, Torres-González L, — View Citation

Rosenthal PJ. Artesunate for the treatment of severe falciparum malaria. N Engl J Med. 2008 Apr 24;358(17):1829-36. doi: 10.1056/NEJMct0709050. Review. — View Citation

Rowe SM, Reeves G, Hathorne H, Solomon GM, Abbi S, Renard D, Lock R, Zhou P, Danahay H, Clancy JP, Waltz DA. Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis. Chest. 2013 Jul;144(1):20 — View Citation

Sohrabi C, Alsafi Z, O'Neill N, Khan M, Kerwan A, Al-Jabir A, Iosifidis C, Agha R. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg. 2020 Apr;76:71-76. doi: 10.1016/j.ijsu.2020.02.034. Epub — View Citation

Wang C, Xuan X, Yao W, Huang G, Jin J. Anti-profibrotic effects of artesunate on bleomycin-induced pulmonary fibrosis in Sprague Dawley rats. Mol Med Rep. 2015 Jul;12(1):1291-7. doi: 10.3892/mmr.2015.3500. Epub 2015 Mar 17. — View Citation

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):106 — View Citation

Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004 Apr;136(1):95-103. — View Citation

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndro — View Citation

Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, Li SB, Wang HY, Zhang S, Gao HN, Sheng JF, Cai HL, Qiu YQ, Li LJ. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case ser — View Citation

Yamaya M, Shimotai Y, Hatachi Y, Lusamba Kalonji N, Tando Y, Kitajima Y, Matsuo K, Kubo H, Nagatomi R, Hongo S, Homma M, Nishimura H. The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures o — View Citation

Zhang X, Zhao Y, Guo L, Qiu Z, Huang L, Qu X. Differences in chemical constituents of Artemisia annua L from different geographical regions in China. PLoS One. 2017 Sep 7;12(9):e0183047. doi: 10.1371/journal.pone.0183047. eCollection 2017. — View Citation

Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R Jr, Nunneley JW, Barnard D, Pöhlmann S, McKerrow JH, Renslo AR, Simmons G. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015 Apr;116:76-84. doi: 10.1016/j.antiviral.2015.01.0 — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of hospitalizations and oxygen use	Decrease in a composite outcome of hospitalization and supplemental oxygen use at day 14 between treatment pairs.	14 days

External Links

•   14. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
•   ohns Hopkins University of Medicine Coronavirus Resource Center Map
•   WHO supports scientifically-proven traditional medicine.