Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are rapidlyspreading worldwide and continue to be a global public health crisis. The use ofrepurposed drugs with the potential to inhibit SARS-CoV-2 could be a vital alternativeapproach when the novel therapeutic has not yet available. The guidelines for emergencytreatment of COVID-19 vary across different countries and largely rely on the off-labelprescription of repurposed drugs. As a result, clinical studies to generate robustefficacy data for these repurposed drugs are warranted to effectively fight against theongoing COVID-19 pandemic.The broad spectrum antiparasitic drug ivermectin has previously been shown to exhibitbroad antiviral activities against many RNA and DNA viruses. It has a reliable safetyprofile with comprehensive data for decades especially in mass drug administrationprograms for river blindness prophylaxis in several countries in Africa. Owing to itsstrong inhibitory activity against the replication of SARS-CoV-2 in vitro and itsputative role in reducing cytokine storm, the drug has been repurposed to treat COVID-19patients and has shown promising results in several clinical studies. Ivermectin has thusgained a considerable attention as a potential treatment for COVID-19. However, theNational Institute of Health (NIH) and World Health Organization (WHO) currently statethat studies on using ivermectin to treat COVID-19 patients remain inconclusive due toinsufficient data. Therefore, a large well designed randomized, double blinded,placebo-controlled trial to assess the efficacy of ivermectin is urgently needed.Another important treatment option for COVID-19 is favipiravir, an antiviral drug forinfluenza treatment. Although the drug has not been approved for a COVID-19 treatment bythe US-FDA, it has been included in Guidelines on clinical practice, diagnosis,treatment, and prevention of healthcare-associated infection for COVID-19 in Thailand.Favipiravir, a known inhibitor of RNA-dependent RNA polymerase, was shown to have an invitro activity against SARS-CoV-2. The meta-analysis showed a significant improvement inclinical outcome at day 14 along with chest imaging in the favipiravir group compared tostandard care. However, there are no significant differences in terms of clinicaldeterioration rates, viral clearance, oxygen support requirement and side effectprofiles. There are still ongoing clinical trials assessing the effectiveness offavipiravir in the treatment of COVID-19.Antivirals can be generally divided into direct-acting antivirals (DAA) andhost-targeting drugs. For example, the widely used drug remdesivir repurposed to treatCOVID-19 is a DAA, and chloroquine is considered a host-targeting drug. Because theserepurposed drugs were not specifically designed and developed for COVID-19, they arelikely to be less efficacious, and partner drugs need to be further explored. Finding aright combination for DAA is a common practice for developing virus treatment regimens.Relying on different modes of action and absence of unfavorable drug interaction, thecombinations are usually additive or synergistic. It is important to note that our invitro data demonstrated the synergistic profile for the combination of favipiravir andivermectin against SARS-CoV-2. It resulted in 4-fold reduction in the half maximalinhibitory concentration (IC50) as compared to individual drugs, from 1.2 µM to 0.3 µMwith a peak Loewe synergy score of over 33.2 and a mean score of 18.8 (noted that Loewesynergy score > 10 indicates synergistic effect).In response to this COVID-19 pandemic crisis, especially in a resource limited settinglike Thailand, clinical studies to evaluate affordable and implementable interventionsare a priority and are urgently needed. Ivermectin, a cheap and safe drug, has beenwidely used in humans for decades, and it has also demonstrated an inhibitory effectagainst SARS-CoV-2 in vitro. Here, we aim to conduct a multi-center, double-blind,randomized controlled trial in Thailand to reveal the effectiveness of ivermectin as acombination therapy with favipiravir (standard treatment) for COVID-19. The results ofthis study will provide much needed information for pursuing larger efficacy clinicaltrials to confirm whether the combination could be effectively used to treat COVID-19.Also, they could provide information on the rate of viral clearance, the primary endpointof this study, which was proposed to be a predictive surrogate of clinical benefits andused as a proper endpoint in the phase II trials for candidate drug screening forCOVID-19.
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Drug: Ivermectin Tablets
6 mg/tablet
Other: Placebo
The placebo has same form as Ivermectin.
Inclusion Criteria:
- Adult patient age between 18-65 years old
- Has confirmed SARS-CoV-2 infection by RT-PCR method using sample collected from
nasopharyngeal swab (NP) and oropharyngeal swab (OP) with Ct value in either one of
the following cases
1. Ct ≤ 26 if the subject has RT-PCR performed as part of screening procedures
2. Ct ≤ 24 if the subject has had RT-PCR performed before admission and the time
between the sample collection for RT-PCR and randomization is ≤ 24 hours
- Has been admitted for medical care at the investigational sites
- In case of symptomatic patient, date of symptoms onset is ≤ 7 days prior to
randomization. In case of asymptomatic patient, the first date of positive result
from RT-PCR or antigen test kit for SARS-CoV-2 is ≤ 7 days prior to randomization.
- Qualified for the criteria to receive favipiravir for COVID-19 treatment according
to Guidelines on clinical practice, diagnosis, treatment, and prevention of
healthcare-associated infection for COVID-19 in Thailand in either one of the
following cases
1. Will start receiving favipiravir during the study period or
2. Has received favipiravir no more than 24 hours before receiving the
investigational drug
- Asymptomatic or has mild to moderate COVID-19 as defined in section 7.2.2.
- Willing to participate in the study and able to provide written informed consent
- Women of childbearing potential must agree to either abstinence or use at least one
primary form of contraception from the time of screening through D28.
Exclusion Criteria:
- Has severe or critical COVID-19 as defined in section 7.2.2.
- Bedridden (totally confined to bed)
- Has elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) over
3 times the upper range of normal limits, or history of liver cirrhosis
- Females only: Currently pregnant, as determined by positive β-human
choriogonadotropin (HCG) test in urine, or breast-feeding
- Receiving other potential drugs for COVID-19 treatment prior to randomization
including Remdesivir, Nitazoxanide, Chloroquine, Hydroxychloroquine, Azithromycin,
Lopinavir-ritonavir, Famotidine, Tocilizumab, Baricitinib (except favipiravir)
- Received ivermectin within 1 month prior to the randomization
- Receiving other immunosuppressive or immunomodulatory drugs for the treatment of
other conditions (not including topical steroids)
- History of hypersensitivity to ivermectin or favipiravir or any components of the
drugs
- Receiving medications that increase gamma-aminobutyric acid (GABA) potentiating
activity such as barbiturates, benzodiazepines, sodium oxybate, valproic acid, or
receiving medications that prevent or inhibit the p-glycoprotein transport system
such as amiodarone, carvedilol, clarithromycin, cyclosporine, erythromycin,
itraconazole, ketoconazole, quinidine, ritonavir, tamoxifen, verapamil, amprenavir,
clotrimazole, phenothiazines, rifampin, St. John's Wort etc.
- Has history of hereditary xanthinuria
- Has hypouricemia (serum uric acid ≤ 1 mg/dL), uncontrolled gout or history of
xanthine urolithiasis
- Participating in other clinical trials or participated in other clinical trials in a
period of one month or less than 5 half-lives of the study drug before screening
JC Kevin Sathorn Bangkok Hotel
Bangkok, Thailand
Songklanagarind Hospital
Bangkok, Thailand
Not Provided