Ivermectin and Nitazoxanide Combination Therapy for COVID-19
Primary Purpose
COVID-19
Status
Unknown status
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Ivermectin plus Nitazoxanide
Standard Care
Sponsored by
About this trial
This is an interventional treatment trial for COVID-19 focused on measuring Ivermectin, Nitazoxanide, COVID-19
Eligibility Criteria
Inclusion Criteria:
- Adult symptomatic patients (18-65 years old), both sexes, and PCR positive in nasopharyngeal sample at admission.
Exclusion Criteria:
- Abnormal liver function (ALT, AST), chronic kidney disease or dialysis (CrCl< 30 ml/min), immunocompromised patients taking medication upon screening, subjects on warfarin or dicumarol therapy and those with comorbid condition like hypertension, hypotension, cardiovascular disease, diabetes mellitus, asthma, COPD, seizures, coagulation disorder and malignancy.
- Patients will be also excluded if they had a known allergy to Ivermectin and/or Nitazoxanide, and those with contraindication towards the study medication.
- Pregnant women or women who are breastfeeding will be also excluded.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Ivermectin plus Nitazoxanide
Standard care
Arm Description
Ivermectin 200 mcg/kg once orally on empty stomach plus Nitazoxanide 500 mg twice daily orally with meal for 6 days
Oxygen via ventilators
Outcomes
Primary Outcome Measures
Number of Patients with COVID-19-negative PCR
COVID-19 PCR analysis
Secondary Outcome Measures
Number of patients with improved respiratory rate
improved breaths per minute for the patients
Number of patients with improved PaO2
Change in PaO2 in mmHg of the patients
Number of patients with normalized Serum IL6
Serum IL6 in pg/mL of the patients
Number of patients with normalized Serum TNFα
Serum TNFα in pg/mL of the patients
Number of patients with normalized Serum iron
Serum iron in microgram/dL of the patients
Number of patients with normalized Serum ferritin
Serum ferritinin microgram/L of the patients
Number of patients with normalized International normalized ratio "INR" for prothrombin time
International normalized ratio "INR" for prothrombin time of 2
Number of patients with normalized complete blood count "CBC"
CBC for lymphocyte count in cells/microliter
The Mortality rate among treated patients
Mortality rate [number of dead patients/total number of treated patients]
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04360356
Brief Title
Ivermectin and Nitazoxanide Combination Therapy for COVID-19
Official Title
Clinical Trial Evaluating Safety and Efficacy of Ivermectin and Nitazoxanide Combination as Adjuvant Therapy in COVID-19 Newly Diagnosed Egyptian Patients: A Tanta University Hope
Study Type
Interventional
2. Study Status
Record Verification Date
April 2020
Overall Recruitment Status
Unknown status
Study Start Date
May 2020 (Anticipated)
Primary Completion Date
October 2020 (Anticipated)
Study Completion Date
December 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tanta University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Research Background and Rationale
In December 2019, a new infectious respiratory disease emerged in Wuhan, Hubei province, China. An initial cluster of infections was linked to Huanan seafood market, potentially due to animal contact. Subsequently, human-to-human transmission occurred and the disease, now termed coronavirus disease 19 (COVID-19) rapidly spread within China and all over the world. A novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), which is closely related to SARS-CoV, was detected in patients and is believed to be the etiologic agent of the new lung disease. The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV).
Detailed Description
Selected Drugs
Ivermectin has anti-parasitic effect along with anti-viral activity against a broad range of viruses in vitro. Ivermectin was identified as an inhibitor of interaction between the human immunodeficiency virus-1 (HIV-1) integrase protein (IN) and the importin (IMP) α/β1 heterodimer responsible for IN nuclear import. Ivermectin has since been confirmed to inhibit HIV-1 replication. Importantly, Ivermectin has been demonstrated to limit infection by RNA viruses such as West Nile Virus and influenza. This broad-spectrum activity is believed to be due to the reliance by many different RNA viruses on IMPα/β1 during infection. Ivermectin has similarly been shown to be effective against the DNA virus pseudorabies virus (PRV) both in vitro and in vivo. Finally, Ivermectin was the focus of a phase III clinical trial in Thailand against DENV infection, in which a single daily oral dose was observed to be safe and resulted in a significant reduction in serum levels of viral NS1 protein, but no change in viremia or clinical benefit was observed.
The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV). Studies on SARS-CoV proteins have revealed a potential role for IMPα/β1 during infection in signal-dependent nucleocytoplasmic shutting of the SARS-CoV nucleocapsid protein that may impact host cell division. In addition, the SARS-CoV accessory protein ORF6 has been shown to antagonize the antiviral activity of the STAT1 transcription factor by sequestering IMPα/β1 on the rough ER/Golgi membrane.
Taken together, these reports suggested that Ivermectin's nuclear transport inhibitory activity may be effective against SARS-CoV-2. Interestingly, it has been postulated that the FDA-approved drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro whereas a single treatment was able to provoke approximately 5000-fold reduction in viral load within 48h. Ivermectin has an established safety profile for human use. Recent reviews and meta-analysis indicate that high dose Ivermectin has comparable safety as the standard low-dose treatment, although there is not enough evidence to make conclusion about the safety profile in pregnancy. In clinical setting, Ivermectin was the focus of a phase III clinical trial on patients with dengue viral infection in Thailand, in which a single daily dose (200 - 400 µg/kg once daily for 2 days in one arm and 200-400 µg/kg once daily for 3 days in the other arm) was found to be safe but did not produce any clinical benefit. In previous clinical study, one dose of Ivermectin 200 μg/kg or four doses of Ivermectin 200 μg/kg (given on days 1, 2, 15, and 16) for the treatment of non-disseminated strongyloidiasis were implicated. The author proposed that, multiple doses of Ivermectin did not show higher efficacy and was tolerated less than a single dose. A single dose should, therefore, be preferred for the treatment of non-disseminated strongyloidiasis.
Nitazoxanide is originally developed as an antiprotozoal agent and has a broad-spectrum antiviral activity undergoing development for the treatment of influenza and other viral respiratory infections. In addition to its antiviral activity, Nitazoxanide inhibits the production of pro-inflammatory cytokines TNFα, IL-2, IL-4, IL-5, IL-6, IL-8 and IL-10 in peripheral blood mononuclear cells. Nitazoxanide could improve outcomes in patients infected with MERS-CoV by suppressing overproduction of pro-inflammatory cytokines, including IL-6. Nitazoxanide has been tested in clinical setting for the treatment of acute uncomplicated influenza, where the subjects received either 600 or 300 mg of Nitazoxanide or placebo orally twice daily for five days and were followed for 28 days. Subjects who received Nitazoxanide 600 mg twice daily experienced shorter times to alleviation of symptoms compared with subjects who received 300 mg Nitazoxanide twice daily, which in turn, was shorter than placebo.
According to the National Health Commission of the People's Republic of China, there is lack of effective antiviral therapy against COVID-19. Nearly all patients who suffered from COVID-19-associated pneumonia accepted oxygen therapy and WHO recommended extracorporeal membrane oxygenation (ECMO) to patients with refractory hypoxemia. Rescue treatment with convalescent plasma and immunoglobulin G are delivered to some critical cases according to their condition.
The rationale of the use of Ivermectin and Nitazoxanide combination for treatment of COVID-19 infected patients is based on the antiviral and anti-inflammatory activity of the selected drugs. Since the two drugs exhibit different modes of action, it would be of value in containing the viral infection through targeting different sites in the pathophysiology of the disease.
Diagnostic criteria
The viral research institution in China has conducted preliminary identification of the SARS-CoV-2 through the classical Koch's postulates and observing its morphology through electron microscopy. So far, the golden clinical diagnosis method of COVID-19 is nucleic acid detection in the nasal and throat swab sampling or other respiratory tract samplings by real-time PCR and further confirmation by next-generation sequencing.
Common Side Effects of Ivermectin
Itching and rash
Swelling
Headache
Joint pain
Pink eye, inflammation of the eyes or discomfort
Dizziness and drop in blood pressure upon standing
Racing heart beat
Changes in liver function tests
Serious Side Effects of Ivermectin (Generally with Ivermectin tablets)
Severe skin reactions
Seizures
Asthma flare-up
Changes in vision
Sudden drop in blood pressure
Dizziness upon standing
Liver dysfunction
Bleeding
Drug interactions of Ivermectin
Warfarin and Coumarin Ivermectin may decrease the anticoagulant activities of warfarin and 4-hydroxycoumarin
Albendazole The metabolism of Albendazole can be increased when combined with Ivermectin
Doxycyline
Additive pharmacodynamic effect
Contraindication of Ivermectin
Abnormal liver function tests
Allergies towards Ivermectin
Side effects of Nitazoxanide
The most common adverse effects are GIT as nausea and occasional stomach cramps with mild diarrhea, reduced appetite and vomiting. Nervous system side effects as headache, dizziness, somnolence, insomnia, tremor, and hypesthesia have been reported in less than 1% of the patients.
Contraindications of Nitazoxanide
There are no data on the excretion of Nitazoxanide into human milk. The manufacturer recommends that caution should be used when administering Nitazoxanide to nursing women.
Interactions of Nitazoxanide
Tizoxanide (the active metabolite of Nitazoxanide) is highly bound to plasma protein (> 99.9%). Therefore, it is necessary to monitor for adverse reactions when administering Nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin).
Warning
Nitazoxanide should be used with caution in patients with significant renal and hepatic impairment.
Research Objectives
The pandemic disease COVID-19 is particularly of major importance in Egypt where a heavy population lives. There is an acute need for comprehensive, continuous, and cost-effective health care delivery for infected people. Early detection and strategies for prevention of progression of COVID-19 would make a major difference for these patients and would also be economically beneficial for a resource-constrained country.
This research proposal was employed as a practical strategy for providing a suitable drug combination for possible treatment of COVID-19 infected patients. This drug combination may help to prevent the progression of respiratory complications. This can be achieved through different goals as follows:
Screening of different drugs related to different pharmacological classes depending on its possible activity against COVID-19 virus.
Providing cost-effective and easy-to-implement treatment strategy for infected patients and/or patients with high risk of developing respiratory failure.
Finally, this clinical strategy remains an important goal in improving Egyptian health state which can save people life and save a lot of money.
Scope of Work
The scope of work will be conducted through
Use of new drug combination of Ivermectin and Nitazoxanide for treatment of COVID-19 infected people. Since the two drugs exhibit different modes of action, it would be of value in containing the viral infection through targeting different sites in the pathophysiology of the disease.
Evaluation of the effect of new drug combination on the symptomatic treatment of COVID-19 patients according to WHO (Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected) interim guidance published at 13 March 2020.
Investigating the impact of new drug combination on the prevention of severe compilations such as acute respiratory distress syndrome (ARDS).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19
Keywords
Ivermectin, Nitazoxanide, COVID-19
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
This study will be a double blind randomized controlled parallel study
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
100 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Ivermectin plus Nitazoxanide
Arm Type
Experimental
Arm Description
Ivermectin 200 mcg/kg once orally on empty stomach plus Nitazoxanide 500 mg twice daily orally with meal for 6 days
Arm Title
Standard care
Arm Type
Active Comparator
Arm Description
Oxygen via ventilators
Intervention Type
Combination Product
Intervention Name(s)
Ivermectin plus Nitazoxanide
Intervention Description
Ivermectin 200 mcg/kg once orally on empty stomach plus Nitazoxanide 500 mg twice daily orally with meal for 6 days
Intervention Type
Other
Intervention Name(s)
Standard Care
Intervention Description
Oxygen via Ventilators
Primary Outcome Measure Information:
Title
Number of Patients with COVID-19-negative PCR
Description
COVID-19 PCR analysis
Time Frame
within 10 days
Secondary Outcome Measure Information:
Title
Number of patients with improved respiratory rate
Description
improved breaths per minute for the patients
Time Frame
within 30 days
Title
Number of patients with improved PaO2
Description
Change in PaO2 in mmHg of the patients
Time Frame
within 30 days
Title
Number of patients with normalized Serum IL6
Description
Serum IL6 in pg/mL of the patients
Time Frame
within 30 days
Title
Number of patients with normalized Serum TNFα
Description
Serum TNFα in pg/mL of the patients
Time Frame
within 30 days
Title
Number of patients with normalized Serum iron
Description
Serum iron in microgram/dL of the patients
Time Frame
within 30 days
Title
Number of patients with normalized Serum ferritin
Description
Serum ferritinin microgram/L of the patients
Time Frame
within 30 days
Title
Number of patients with normalized International normalized ratio "INR" for prothrombin time
Description
International normalized ratio "INR" for prothrombin time of 2
Time Frame
within 30 days
Title
Number of patients with normalized complete blood count "CBC"
Description
CBC for lymphocyte count in cells/microliter
Time Frame
within 30 days
Title
The Mortality rate among treated patients
Description
Mortality rate [number of dead patients/total number of treated patients]
Time Frame
within 30 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adult symptomatic patients (18-65 years old), both sexes, and PCR positive in nasopharyngeal sample at admission.
Exclusion Criteria:
Abnormal liver function (ALT, AST), chronic kidney disease or dialysis (CrCl< 30 ml/min), immunocompromised patients taking medication upon screening, subjects on warfarin or dicumarol therapy and those with comorbid condition like hypertension, hypotension, cardiovascular disease, diabetes mellitus, asthma, COPD, seizures, coagulation disorder and malignancy.
Patients will be also excluded if they had a known allergy to Ivermectin and/or Nitazoxanide, and those with contraindication towards the study medication.
Pregnant women or women who are breastfeeding will be also excluded.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kamal Okasha, Md, PhD
Phone
+201004706770
Email
vp_research@unv.tanta.edu.eg
First Name & Middle Initial & Last Name or Official Title & Degree
Nahla Elashmawy, Md, PhD
Phone
+2010111672982
Email
nahla.elashmawi@pharm.tanta.edu.eg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kamal Okasha, Md, PhD
Organizational Affiliation
Tanta University
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
31986264
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 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
Results Reference
background
PubMed Identifier
31986257
Citation
Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020 Feb 15;395(10223):470-473. doi: 10.1016/S0140-6736(20)30185-9. Epub 2020 Jan 24. No abstract available. Erratum In: Lancet. 2020 Jan 29;:
Results Reference
background
PubMed Identifier
31978945
Citation
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.
Results Reference
background
PubMed Identifier
32251768
Citation
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.
Results Reference
background
PubMed Identifier
21297106
Citation
Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA. An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import. J Biomol Screen. 2011 Feb;16(2):192-200. doi: 10.1177/1087057110390360.
Results Reference
background
PubMed Identifier
26988202
Citation
Gotz V, Magar L, Dornfeld D, Giese S, Pohlmann A, Hoper D, Kong BW, Jans DA, Beer M, Haller O, Schwemmle M. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016 Mar 18;6:23138. doi: 10.1038/srep23138. Erratum In: Sci Rep. 2016 May 09;6:25428.
Results Reference
background
PubMed Identifier
30826604
Citation
Jans DA, Martin AJ, Wagstaff KM. Inhibitors of nuclear transport. Curr Opin Cell Biol. 2019 Jun;58:50-60. doi: 10.1016/j.ceb.2019.01.001. Epub 2019 Feb 28.
Results Reference
background
PubMed Identifier
30266338
Citation
Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, Yan C, Yang Z, Wang X. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. 2018 Nov;159:55-62. doi: 10.1016/j.antiviral.2018.09.010. Epub 2018 Sep 26.
Results Reference
background
PubMed Identifier
26082769
Citation
Wulan WN, Heydet D, Walker EJ, Gahan ME, Ghildyal R. Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses. Front Microbiol. 2015 Jun 2;6:553. doi: 10.3389/fmicb.2015.00553. eCollection 2015.
Results Reference
background
PubMed Identifier
11533198
Citation
Wurm T, Chen H, Hodgson T, Britton P, Brooks G, Hiscox JA. Localization to the nucleolus is a common feature of coronavirus nucleoproteins, and the protein may disrupt host cell division. J Virol. 2001 Oct;75(19):9345-56. doi: 10.1128/JVI.75.19.9345-9356.2001.
Results Reference
background
PubMed Identifier
17596301
Citation
Frieman M, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol. 2007 Sep;81(18):9812-24. doi: 10.1128/JVI.01012-07. Epub 2007 Jun 27.
Results Reference
background
PubMed Identifier
31960060
Citation
Navarro M, Camprubi D, Requena-Mendez A, Buonfrate D, Giorli G, Kamgno J, Gardon J, Boussinesq M, Munoz J, Krolewiecki A. Safety of high-dose ivermectin: a systematic review and meta-analysis. J Antimicrob Chemother. 2020 Apr 1;75(4):827-834. doi: 10.1093/jac/dkz524.
Results Reference
background
PubMed Identifier
25108173
Citation
Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014 Oct;110:94-103. doi: 10.1016/j.antiviral.2014.07.014. Epub 2014 Aug 7.
Results Reference
background
PubMed Identifier
22430099
Citation
Hong SK, Kim HJ, Song CS, Choi IS, Lee JB, Park SY. Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. Int Immunopharmacol. 2012 May;13(1):23-7. doi: 10.1016/j.intimp.2012.03.002. Epub 2012 Mar 17.
Results Reference
background
PubMed Identifier
32113510
Citation
Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020 Apr;20(4):398-400. doi: 10.1016/S1473-3099(20)30141-9. Epub 2020 Feb 27. No abstract available.
Results Reference
background
PubMed Identifier
31950516
Citation
Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. J Med Virol. 2020 Apr;92(4):401-402. doi: 10.1002/jmv.25678. Epub 2020 Feb 12. No abstract available.
Results Reference
background
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Ivermectin and Nitazoxanide Combination Therapy for COVID-19
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