Covid19Phase 2/3NCT04712279
The (HD)IVACOV Trial (The High-Dose IVermectin Against COVID-19 Trial)
A Phase 2/3 study testing Ivermectin 0.6mg/kg/day, Ivermectin 1.0mg/kg/day and Hydroxychloroquine in people with Covid19, run by Corpometria Institute.
Trial summary
Ivermectin, a classical antiparasitic and anti-scabies agent, has demonstrated antiviral activity for a variety of viruses including chikungunya virus, zyka virus and dengue virus and was tested as a potentially effective for COVID-19. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Covid19
- What is being tested?
- Ivermectin 0.6mg/kg/day, Ivermectin 1.0mg/kg/day and Hydroxychloroquine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 294 participants
- Where
- No sites listed yet
- Study dates
- 25 Jan 2021to 20 Apr 2021
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Laboratory or clinically confirmed positive SARS-CoV-2 rtPCR test (AndroCoV Clinical Scoring for COVID-19 Diagnosis1) within 7 days prior to randomization
- ≥18 years old
- Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to randomization
- Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 1 to 3
- Subject (or legally authorized representative) gives written informed consent prior to performing any study procedures
- Subject (or legally authorized representative) agree that subject will not participate in another COVID-19 trial while participating in this study
Who cannot join
- Subject enrolled in a study to investigate a treatment for COVID-19
- Require oxygen use, hospitalization or mechanical ventilation
- Tachycardia (HR > 150 bpm) or hypotension (BP < 90/60 mmHg)
- Patients who are allergic to the investigational product or similar drugs (or any excipients);
- Subjects with QTcF > 450 ms
- Subjects with uncontrolled medical conditions that could compromise participation in the study - uncontrolled hypertension (BP > 220/120 mmHg), uncontrolled hypothyroidism (TSH > 10 iU/L), uncontrolled diabetes mellitus (HbA1c > 12%)
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- Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit of normal.
- Estimated glomerular filtration rate (eGFR) < 30 ml/min or requiring dialysis
- Subject (or legally authorized representative) not willing or unable to provide informed consent
Trial locations and contacts
No sites are listed yet.
About this study
Official title: High-Dose Ivermectin for Mild-to-Moderate COVID-19 - The (HD)IVACOV Trial
Ivermectin, a classical antiparasitic and anti-scabies agent, has demonstrated antiviral activity for a variety of viruses including chikungunya virus, zyka virus and dengue virus and was tested as a potentially effective for COVID-19.
Although ivermectin demonstrated potent in vitro action by reducing viral load by 5000x after 48 hours of incubation, simultaneous pharmacokinetics simulations suggested that the minimum effective concentrations would be unfeasible to be reached within safety range (EC-50 = 2 Micromol).
Read more
However, despite the theoretical unfeasible concentrations to be achieved, preliminary observational yet well-structured studies followed by randomized clinical trials (RCTs) demonstrated ivermectin efficacy when combined with hydroxychloroquine, doxycycline or azithromycin, which was corroborated by a recent systematic review and metanalysis. In common, a dose-response effect for effectiveness was observed, and no adverse effects was reported at any dose between 0.2mg/kg/day and 1.0mg/kg/day.
Based on the scientific rationale combined with the preliminary evidence, ivermectin has sufficient evidence to be tested in higher doses in a RCT for COVID-19. The investigators propose to test ivermectin at high doses as a treatment for patients recently diagnosed with COVID-19, aiming to explore the possible protective role of high-dose ivermectin in SARS-CoV-2 infection in terms of reduction of clinic and virologic disease duration, and prevention of oxygen use, hospitalization, mechanical ventilation, death, and post-COVID persisting symptoms.
Read the detailed description
Overall
COVID-19 is a multisystemic disease caused by SARS-CoV-2 that has become a pandemic largely due to a combination of favorable transmission and infection characteristics for its spread, including prolonged preclinical or also asymptomatic yet transmitting period, relatively highly resistant to mechanical and physical barriers and prolonged survival in the air, and transmission patterns not yet fully elucidated.
While vaccines are not widely available, the number of new cases should not decrease dramatically, unfortunately, since a large percentage of the population has not been infected by the SARS-CoV-2 yet, reinfection becomes increasingly plausible with mutations in the virus, and virus contention policies failed to be 100% effective.
Considering potential antiviral approaches for COVID-19, their effectiveness only make sense if tested and given early in the disease, during viral dissemination. The learning that oseltamivir is only effective for Influenza A in the first three days of disease finds strong plausibility, and reinforces the expected lack of effectiveness of any drug with in vitro or preliminary antiviral activity reported when tested in hospitalized or non-mild patients, once COVID-19 presents tend to present mild symptoms during the viral dissemination stage.
An actual early detection of COVID-19, i.e., before its progression to further inflammatory stages, is challenging, once the earliest symptoms tend to be unspecific, mild, and hardly attributable to COVID-19. By suspecting of COVID-19 in the presence of any symptom, specific to COVID-19 or not, sensitivity was met to be above 90% while specificity was also relatively high (above 50%). In addition, time-to-treat, rather than which drug to choose, could better determine the effectiveness of a specific approach.
Ivermectin: potential antiviral activity for COVID-19
Among drugs potentially effective for COVID-19, despite the classical antiparasitic and anti-scabies use, ivermectin has demonstrated antiviral activity for a variety of viruses by inhibiting and reducing the viral shedding duration, including chikungunya and other alphaviruses, zyka virus, dengue virus and other simple-strain RNA viruses.
In the search for drugs with anti-SARS-CoV-2 activity, considering its effects on other viruses, ivermectin was tested in a Vero-hSLAM cell model and demonstrated potent in vitro action, by reducing viral load by 5000x after 48 hours of incubation. However, after initial promising results, simultaneous pharmacokinetics simulations suggested that the minimum effective concentrations would be unfeasible to be reached within safety range (EC-50 = 2 Micromol).
Although the theoretical minimum concentration required for antiviral action was apparently at least 17 times higher than the lethal dose and up to 10,000 times the usually prescribed doses for humans ( IC50 of 2.2 - 2.8 µM for monkeys), which would reduce the chances of ivermectin efficacy for COVID-19, preliminary observational yet well-structured studies demonstrated substantial synergistic action of ivermectin when added to "standard of care", usually hydroxychloroquine with or without macrolides. In a specific study, the use of ivermectin, even in low doses, reduced by 40% the absolute risk of death among patients more severely affected by COVID-19.
Some randomized clinical trials (RCTs) demonstrated efficacy of ivermectin when combined with hydroxychloroquine, doxycycline or azithromycin, in both mildly (and presumedly early) and more severely affected subjects with COVID-19. Demonstrated benefits included lower disease progression and reduced COVID-related mortality.
In comparative analyses, combinations between ivermectin and azithromycin, doxycycline or hydroxychloroquine demonstrated superiority compared to combinations between hydroxychloroquine and azithromycin or hydroxychloroquine alone.
The exact mechanisms of action remain nuclear. At least one study employing higher doses (0.6mg/kg/day) demonstrated in vivo antiviral activity, but only when maximum concentration reached serum levels above 160 ng/ml, which only occurred in 45% of subjects, even at higher doses. The antiviral mechanisms include modification in the ACE-2 glycation patterns, inhibition of the viral Helicase (NSP13) and disruption of the alpha-importin heterodimer.
In a recent systematic review and metanalysis, a dose-response correlation has also been observed in terms of endpoints, reinforcing the role of ivermectin as actins as an anti-SARS-CoV-2 action drug. However, even in lower doses ivermectin was able to demonstrate clinical benefits, allowing the hypothesis that ivermectin also exerts anti-inflammatory effects, which could include the blockage of STAT-1 migration to the nucleus, and could justify its use even at later stages of the disease.
Collectively, higher yet safe ivermectin doses find stronger plausibility and preliminary evidence to be tested in RCTs. In addition, approaches to increase ivermectin absorption and bioavailability should be encouraged.
Based on the scientific rationale combined with preliminary evidence, ivermectin has sufficient evidence to be tested at higher doses in a RCT for COVID-19. The investigators propose to test ivermectin at high doses as a treatment for patients recently diagnosed with COVID-19. This study is intended to explore the possible protective role of high-dose ivermectin in SARS-CoV-2 infection in terms of reduction of clinic and virologic disease duration, and prevention of oxygen use, hospitalization, mechanical ventilation, death, and post-COVID persisting symptoms.
- Conditions
- Covid19
- Being tested
- Ivermectin 0.6mg/kg/day, Ivermectin 1.0mg/kg/day, Placebo, Hydroxychloroquine
- Keywords
- COVID-19, SARS-CoV-2, Covid19, Ivermectin
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ivermectin 0.6mg/kg/dayDrug
Use of ivermectin 0.6m/kg/day q.d.for 05 days
Ivermectin 1.0mg/kg/dayDrug
Ivermectin 1.0mg/kg/day q.d. for 05 days
PlaceboDrug
Placebo q.d.for 05 days
Hydroxychloroquine 200mg/day q.d. for 05 days
| Study group | Role | What they receive |
|---|---|---|
| Ivermectin 0.6mg/kg/day | Active comparator | Not described Receives: Drug: Ivermectin 0.6mg/kg/day; Drug: Hydroxychloroquine |
| Ivermectin 1.0mg/kg/day | Active comparator | Not described Receives: Drug: Ivermectin 1.0mg/kg/day; Drug: Hydroxychloroquine |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo; Drug: Hydroxychloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death]
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death]
Measured: Day 14
Secondary outcomes (38)
World Health Organization (WHO) COVID=19 Ordinal Scale for Clinical Improvement [1 to 8; 1 = not hospitalized, no limitation on activities; 8 = death] [Time Frame: Day 7]
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by World Health Organization (WHO) COVID=19 Ordinal Scale for Clinical Improvement [1 to 8; 1 = not hospitalized, no limitation on activities; 8 = death]
Measured: Day 7
Time-to-recovery
Recovery is defined as the first day on which the subject satisfies category one from the COVID ordinal scale (defined in Section 5.1): (1) Not hospitalized, no limitations on activities. [Parameter: Number of days until achieve Category 1 of the World Health Organization (WHO) COVID=19 Ordinal Scale for Clinical Improvement [1 to 8; 1 = not hospitalized, no limitation on activities; 8 = death]
Measured: Day 28
Viral load
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by viral load measured by rtPCR-SARS-CoV-2 (CTs)
Measured: Day 5
Positivity rate of rtPCR-SARS-CoV-2 (qualitative analysis)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by viral load measured by positivity rate (% of positive, detected rtSARS-CoV-2)
Measured: Day 5
Duration of fatigue
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by duration of fatigue (days)
Measured: Day 14
Duration of anosmia
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by duration of anosmia (days)
Measured: Day 14
Overall duration of clinical manifestations
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by duration of overall symptoms (days)
Measured: Day 14
Proportion of subjects needing additional drugs or interventions
Defined as the number of subjects who have required additional drugs (glucocorticoids, anticoagulants, etc) or interventions allocated to each arm divided by the number of subjects randomized to that specific arm (%). Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the proportion of subjects needing additional drugs or interventions in each arm.
Measured: Day 28
Proportion of subjects needing oxygen use
Defined as the number of subjects who have required oxygen use allocated to each arm divided by the number of subjects randomized to that specific arm (%). Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the proportion of subjects needing oxygen use in each arm.
Measured: Day 28
Proportion of subjects needing high-flow oxygen therapy or non-invasive ventilation
Defined as the number of subjects who have required high-flow oxygen use or non-invasive mechanical ventilation allocated to each arm divided by the number of subjects randomized to that specific arm (%). Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the proportion of subjects needing high-flow oxygen use or non-invasive mechanical ventilation in each arm.
Measured: Day 28
Proportion of hospitalizations
Defined as the number of hospitalizations in each arm divided by the number of subjects randomized to that specific arm (%). Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the proportion of hospitalizations in each arm.
Measured: Day 28
Proportion of mechanical ventilation use
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of mechanical ventilation use in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 28
Proportion of pressors use
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects needing use of pressors in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 28
Proportion of deaths
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects who have died in each arm divided by the numbers of subjects randomized to the treatment arm (%).
Measured: Day 28
Proportion of post-COVID mental symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with mental symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 30
Proportion of post-COVID mental symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with mental symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 60
Proportion of post-COVID mental symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with mental symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 90
Proportion of post-COVID physical symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with physical symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 30
Proportion of post-COVID physical symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with physical symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 60
Proportion of post-COVID physical symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with physical symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 90
Proportion of post-COVID overall symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with any symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 30
Proportion of post-COVID overall symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with any symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 60
Proportion of post-COVID overall symptoms
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects persisting with any symptoms after COVID-19 resolution in each arm divided by the number of subjects randomized to that specific arm (%).
Measured: Day 90
Duration of new oxygen use
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the duration of new oxygen use measured in days among subjects that did not require oxygen upon randomization and required oxygen use after the beginning of treatment, in each arm (days)
Measured: Day 28
Duration of hospitalization
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the duration of hospitalization measured in days among subjects that required hospitalization, in each arm (days)
Measured: Day 28
Duration of mechanical ventilation
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the duration of mechanical ventilation measured in days among subjects that required mechanical ventilation, in each arm (days)
Measured: Day 28
Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting increased ultrasensitive C-reactive protein (usCRP) at Days 1, 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 1
Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting increased ultrasensitive C-reactive protein (usCRP) at Days 1, 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 3
Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting increased ultrasensitive C-reactive protein (usCRP) at Days 1, 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 7
Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting ESR decrease > 50% at Days 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 1
Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting ESR decrease > 50% at Days 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 3
Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting ESR decrease > 50% at Days 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 7
Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting eosinophils increase > 50% at Days 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 1
Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting eosinophils increase > 50% at Days 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 3
Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting eosinophils increase > 50% at Days 2, 3 and 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 7
Proportion of increased d-dimer (defined as d-dimer > 500 mg/dL)
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by the number of subjects presenting increased d-dimer protein (usCRP) at Day 7, divided by the number of subjects randomized to that specific arm (%).
Measured: Day 7
Disease duration
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by duration of symptoms, complications, or any other COVID-related clinical or biochemical sign of disease
Measured: Day 14
Change in viral load from baseline to Day 5
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by change in viral load from baseline to Day 5 measured by rtPCR-SARS-CoV-2 (CTs)
Measured: Day 30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jan 2021
- Study start25 Jan 2021 (estimated)
- Primary completion21 Mar 2021 (estimated)
- Study completion20 Apr 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Covid19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 294 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Corpometria Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ricardo A Zimerman, MD, Study director, Corpometria InstituteFlavio A Cadegiani, MD, PhD, Principal investigator, Corpometria Institute; Applied Biology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04712279
- Sponsor's protocol ID
- CORPO-DRUG-SARSCoV2-001
- Status last verified
- Jan 2021
- First submitted
- 13 Jan 2021
- Last updated
- 15 Jan 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
PubMed 32109013Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.
PubMed 32171076Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020 May 5;172(9):577-582. doi: 10.7326/M20-0504. Epub 2020 Mar 10.
PubMed 32150748Li L, Liu J, Qin K. Comparison of double-dose vs standard-dose oseltamivir in the treatment of influenza: A systematic review and meta-analysis. J Clin Pharm Ther. 2020 Oct;45(5):918-926. doi: 10.1111/jcpt.13203. Epub 2020 Jun 4.
PubMed 32497319Varghese FS, Kaukinen P, Glasker S, Bespalov M, Hanski L, Wennerberg K, Kummerer BM, Ahola T. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Res. 2016 Feb;126:117-24. doi: 10.1016/j.antiviral.2015.12.012. Epub 2016 Jan 2.
PubMed 26752081Padhy BM, Mohanty RR, Das S, Meher BR. Therapeutic potential of ivermectin as add on treatment in COVID 19: A systematic review and meta-analysis. J Pharm Pharm Sci. 2020;23:462-469. doi: 10.18433/jpps31457.
PubMed 33227231Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study. Chest. 2021 Jan;159(1):85-92. doi: 10.1016/j.chest.2020.10.009. Epub 2020 Oct 13.
PubMed 33065103Elgazzar, A et al. Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic. Research Square doi.org/10.21203, 2020
Chowdhury, ATMM et al. A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients. Research Square: https://doi.org/10.21203/rs.3.rs-38896/v1, 2020.
Niaee, MS et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial. Research Square: https://doi.org/10.21203/rs.3.rs-109670/v1, 2020.
Francés-Monerris, A et al. Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent. ChemRxiv, 2020.
Study at a glance
From the registry record, last updated by the sponsor on 15 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- High-Dose Ivermectin for Mild-to-Moderate COVID-19 - The (HD)IVACOV Trial
- ClinicalTrials.gov ID
- NCT04712279
- Acronym / sponsor ID
- CORPO-DRUG-SARSCoV2-001
- Conditions
- Covid19
- Keywords
- COVID-19, SARS-CoV-2, Covid19, Ivermectin
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 294 participants (estimated)
- Lead sponsor
- Corpometria InstituteUniversity, hospital or other
- Study start
- 25 Jan 2021 (estimated)
- Primary completion
- 21 Mar 2021 (estimated)
- Study completion
- 20 Apr 2021 (estimated)
- First posted
- 15 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Ivermectin, a classical antiparasitic and anti-scabies agent, has demonstrated antiviral activity for a variety of viruses including chikungunya virus, zyka virus and dengue virus and was tested as a potentially effective for COVID-19.
Although ivermectin demonstrated potent in vitro action by reducing viral load by 5000x after 48 hours of incubation, simultaneous pharmacokinetics simulations suggested that the minimum effective concentrations would be unfeasible to be reached within safety range (EC-50 = 2 Micromol).
However, despite the theoretical unfeasible concentrations to be achieved, preliminary observational yet well-structured studies followed by randomized clinical trials (RCTs) demonstrated ivermectin efficacy when combined with hydroxychloroquine, doxycycline or azithromycin, which was corroborated by a recent systematic review and metanalysis. In common, a dose-response effect for effectiveness was observed, and no adverse effects was reported at any dose between 0.2mg/kg/day and 1.0mg/kg/day.
Based on the scientific rationale combined with the preliminary evidence, ivermectin has sufficient evidence to be tested in higher doses in a RCT for COVID-19. The investigators propose to test ivermectin at high doses as a treatment for patients recently diagnosed with COVID-19, aiming to explore the possible protective role of high-dose ivermectin in SARS-CoV-2 infection in terms of reduction of clinic and virologic disease duration, and prevention of oxygen use, hospitalization, mechanical ventilation, death, and post-COVID persisting symptoms.
Detailed description
Overall
COVID-19 is a multisystemic disease caused by SARS-CoV-2 that has become a pandemic largely due to a combination of favorable transmission and infection characteristics for its spread, including prolonged preclinical or also asymptomatic yet transmitting period, relatively highly resistant to mechanical and physical barriers and prolonged survival in the air, and transmission patterns not yet fully elucidated.
While vaccines are not widely available, the number of new cases should not decrease dramatically, unfortunately, since a large percentage of the population has not been infected by the SARS-CoV-2 yet, reinfection becomes increasingly plausible with mutations in the virus, and virus contention policies failed to be 100% effective.
Considering potential antiviral approaches for COVID-19, their effectiveness only make sense if tested and given early in the disease, during viral dissemination. The learning that oseltamivir is only effective for Influenza A in the first three days of disease finds strong plausibility, and reinforces the expected lack of effectiveness of any drug with in vitro or preliminary antiviral activity reported when tested in hospitalized or non-mild patients, once COVID-19 presents tend to present mild symptoms during the viral dissemination stage.
An actual early detection of COVID-19, i.e., before its progression to further inflammatory stages, is challenging, once the earliest symptoms tend to be unspecific, mild, and hardly attributable to COVID-19. By suspecting of COVID-19 in the presence of any symptom, specific to COVID-19 or not, sensitivity was met to be above 90% while specificity was also relatively high (above 50%). In addition, time-to-treat, rather than which drug to choose, could better determine the effectiveness of a specific approach.
Ivermectin: potential antiviral activity for COVID-19
Among drugs potentially effective for COVID-19, despite the classical antiparasitic and anti-scabies use, ivermectin has demonstrated antiviral activity for a variety of viruses by inhibiting and reducing the viral shedding duration, including chikungunya and other alphaviruses, zyka virus, dengue virus and other simple-strain RNA viruses.
In the search for drugs with anti-SARS-CoV-2 activity, considering its effects on other viruses, ivermectin was tested in a Vero-hSLAM cell model and demonstrated potent in vitro action, by reducing viral load by 5000x after 48 hours of incubation. However, after initial promising results, simultaneous pharmacokinetics simulations suggested that the minimum effective concentrations would be unfeasible to be reached within safety range (EC-50 = 2 Micromol).
Although the theoretical minimum concentration required for antiviral action was apparently at least 17 times higher than the lethal dose and up to 10,000 times the usually prescribed doses for humans ( IC50 of 2.2 - 2.8 µM for monkeys), which would reduce the chances of ivermectin efficacy for COVID-19, preliminary observational yet well-structured studies demonstrated substantial synergistic action of ivermectin when added to "standard of care", usually hydroxychloroquine with or without macrolides. In a specific study, the use of ivermectin, even in low doses, reduced by 40% the absolute risk of death among patients more severely affected by COVID-19.
Some randomized clinical trials (RCTs) demonstrated efficacy of ivermectin when combined with hydroxychloroquine, doxycycline or azithromycin, in both mildly (and presumedly early) and more severely affected subjects with COVID-19. Demonstrated benefits included lower disease progression and reduced COVID-related mortality.
In comparative analyses, combinations between ivermectin and azithromycin, doxycycline or hydroxychloroquine demonstrated superiority compared to combinations between hydroxychloroquine and azithromycin or hydroxychloroquine alone.
The exact mechanisms of action remain nuclear. At least one study employing higher doses (0.6mg/kg/day) demonstrated in vivo antiviral activity, but only when maximum concentration reached serum levels above 160 ng/ml, which only occurred in 45% of subjects, even at higher doses. The antiviral mechanisms include modification in the ACE-2 glycation patterns, inhibition of the viral Helicase (NSP13) and disruption of the alpha-importin heterodimer.
In a recent systematic review and metanalysis, a dose-response correlation has also been observed in terms of endpoints, reinforcing the role of ivermectin as actins as an anti-SARS-CoV-2 action drug. However, even in lower doses ivermectin was able to demonstrate clinical benefits, allowing the hypothesis that ivermectin also exerts anti-inflammatory effects, which could include the blockage of STAT-1 migration to the nucleus, and could justify its use even at later stages of the disease.
Collectively, higher yet safe ivermectin doses find stronger plausibility and preliminary evidence to be tested in RCTs. In addition, approaches to increase ivermectin absorption and bioavailability should be encouraged.
Based on the scientific rationale combined with preliminary evidence, ivermectin has sufficient evidence to be tested at higher doses in a RCT for COVID-19. The investigators propose to test ivermectin at high doses as a treatment for patients recently diagnosed with COVID-19. This study is intended to explore the possible protective role of high-dose ivermectin in SARS-CoV-2 infection in terms of reduction of clinic and virologic disease duration, and prevention of oxygen use, hospitalization, mechanical ventilation, death, and post-COVID persisting symptoms.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Ivermectin 0.6mg/kg/day | Active comparator | Drug: Ivermectin 0.6mg/kg/day, Drug: Hydroxychloroquine |
| Ivermectin 1.0mg/kg/day | Active comparator | Drug: Ivermectin 1.0mg/kg/day, Drug: Hydroxychloroquine |
| Placebo | Placebo comparator | Drug: Placebo, Drug: Hydroxychloroquine |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Laboratory or clinically confirmed positive SARS-CoV-2 rtPCR test (AndroCoV Clinical Scoring for COVID-19 Diagnosis1) within 7 days prior to randomization
- ≥18 years old
- Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to randomization
- Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 1 to 3
- Subject (or legally authorized representative) gives written informed consent prior to performing any study procedures
Key exclusion criteria (9 listed)
- Subject enrolled in a study to investigate a treatment for COVID-19
- Require oxygen use, hospitalization or mechanical ventilation
- Tachycardia (HR > 150 bpm) or hypotension (BP < 90/60 mmHg)
- Patients who are allergic to the investigational product or similar drugs (or any excipients);
- Subjects with QTcF > 450 ms
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ivermectin 0.6mg/kg/dayUse of ivermectin 0.6m/kg/day q.d.for 05 days | Drug | Ivermectin 0.6mg/kg/day |
| Ivermectin 1.0mg/kg/dayIvermectin 1.0mg/kg/day q.d. for 05 days | Drug | Ivermectin 1.0mg/kg/day |
| PlaceboPlacebo q.d.for 05 days | Drug | Placebo |
| HydroxychloroquineHydroxychloroquine 200mg/day q.d. for 05 days | Drug | Ivermectin 0.6mg/kg/day, Ivermectin 1.0mg/kg/day, Placebo |
Primary outcome
World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death]
Time frame: Day 14
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death]
38 secondary outcomes
World Health Organization (WHO) COVID=19 Ordinal Scale for Clinical Improvement [1 to 8; 1 = not hospitalized, no limitation on activities; 8 = death] [Time Frame: Day 7]
Time frame: Day 7
Time-to-recovery
Time frame: Day 28
Viral load
Time frame: Day 5
Positivity rate of rtPCR-SARS-CoV-2 (qualitative analysis)
Time frame: Day 5
Duration of fatigue
Time frame: Day 14
Duration of anosmia
Time frame: Day 14
Overall duration of clinical manifestations
Time frame: Day 14
Proportion of subjects needing additional drugs or interventions
Time frame: Day 28
Proportion of subjects needing oxygen use
Time frame: Day 28
Proportion of subjects needing high-flow oxygen therapy or non-invasive ventilation
Time frame: Day 28
Proportion of hospitalizations
Time frame: Day 28
Proportion of mechanical ventilation use
Time frame: Day 28
Proportion of pressors use
Time frame: Day 28
Proportion of deaths
Time frame: Day 28
Proportion of post-COVID mental symptoms
Time frame: Day 30
Proportion of post-COVID mental symptoms
Time frame: Day 60
Proportion of post-COVID mental symptoms
Time frame: Day 90
Proportion of post-COVID physical symptoms
Time frame: Day 30
Proportion of post-COVID physical symptoms
Time frame: Day 60
Proportion of post-COVID physical symptoms
Time frame: Day 90
Proportion of post-COVID overall symptoms
Time frame: Day 30
Proportion of post-COVID overall symptoms
Time frame: Day 60
Proportion of post-COVID overall symptoms
Time frame: Day 90
Duration of new oxygen use
Time frame: Day 28
Duration of hospitalization
Time frame: Day 28
Duration of mechanical ventilation
Time frame: Day 28
Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
Time frame: Day 1
Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
Time frame: Day 3
Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
Time frame: Day 7
Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1)
Time frame: Day 1
Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1)
Time frame: Day 3
Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1)
Time frame: Day 7
Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1)
Time frame: Day 1
Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1)
Time frame: Day 3
Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1)
Time frame: Day 7
Proportion of increased d-dimer (defined as d-dimer > 500 mg/dL)
Time frame: Day 7
Disease duration
Time frame: Day 14
Change in viral load from baseline to Day 5
Time frame: Day 30
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jan 2021.
- Results publication: PubMed 32109013Guan 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, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
- Results publication: PubMed 32171076Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.
- Results publication: PubMed 32150748Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020 May 5;172(9):577-582. doi: 10.7326/M20-0504. Epub 2020 Mar 10.
- Results publication: PubMed 32497319Li L, Liu J, Qin K. Comparison of double-dose vs standard-dose oseltamivir in the treatment of influenza: A systematic review and meta-analysis. J Clin Pharm Ther. 2020 Oct;45(5):918-926. doi: 10.1111/jcpt.13203. Epub 2020 Jun 4.
- Results publication: PubMed 26752081Varghese FS, Kaukinen P, Glasker S, Bespalov M, Hanski L, Wennerberg K, Kummerer BM, Ahola T. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Res. 2016 Feb;126:117-24. doi: 10.1016/j.antiviral.2015.12.012. Epub 2016 Jan 2.
- Results publication: PubMed 33227231Padhy BM, Mohanty RR, Das S, Meher BR. Therapeutic potential of ivermectin as add on treatment in COVID 19: A systematic review and meta-analysis. J Pharm Pharm Sci. 2020;23:462-469. doi: 10.18433/jpps31457.
- Results publication: PubMed 33065103Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study. Chest. 2021 Jan;159(1):85-92. doi: 10.1016/j.chest.2020.10.009. Epub 2020 Oct 13.
- Results publicationElgazzar, A et al. Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic. Research Square doi.org/10.21203, 2020
- Results publicationChowdhury, ATMM et al. A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients. Research Square: https://doi.org/10.21203/rs.3.rs-38896/v1, 2020.
- Results publicationNiaee, MS et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial. Research Square: https://doi.org/10.21203/rs.3.rs-109670/v1, 2020.
- Results publicationFrancés-Monerris, A et al. Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent. ChemRxiv, 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ricardo A Zimerman, MD study director
Corpometria Institute
Flavio A Cadegiani, MD, PhD principal investigator
Corpometria Institute; Applied Biology
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Ivermectin 0.6mg/kg/day, Ivermectin 1.0mg/kg/day and Hydroxychloroquine in people with Covid19, run by Corpometria Institute.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 15 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Flavio A Cadegiani, MD, PhD (+55 61 99650.6111, flavio.cadegiani@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death] (time frame: Day 14). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04712279, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jan 2021.