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The (HD)IVACOV Trial (The High-Dose IVermectin Against COVID-19 Trial)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04712279
Recruitment Status : Not yet recruiting
First Posted : January 15, 2021
Last Update Posted : January 15, 2021
Sponsor:
Information provided by (Responsible Party):
Corpometria Institute

Brief 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.

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.


Condition or disease Intervention/treatment Phase
Covid19 Drug: Ivermectin 0.6mg/kg/day Drug: Ivermectin 1.0mg/kg/day Drug: Placebo Drug: Hydroxychloroquine Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 294 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: High-Dose Ivermectin for Mild-to-Moderate COVID-19 - The (HD)IVACOV Trial
Estimated Study Start Date : January 25, 2021
Estimated Primary Completion Date : March 21, 2021
Estimated Study Completion Date : April 20, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ivermectin

Arm Intervention/treatment
Active Comparator: Ivermectin 0.6mg/kg/day Drug: Ivermectin 0.6mg/kg/day
Use of ivermectin 0.6m/kg/day q.d.for 05 days

Drug: Hydroxychloroquine
Hydroxychloroquine 200mg/day q.d. for 05 days

Active Comparator: Ivermectin 1.0mg/kg/day Drug: Ivermectin 1.0mg/kg/day
Ivermectin 1.0mg/kg/day q.d. for 05 days

Drug: Hydroxychloroquine
Hydroxychloroquine 200mg/day q.d. for 05 days

Placebo Comparator: Placebo Drug: Placebo
Placebo q.d.for 05 days

Drug: Hydroxychloroquine
Hydroxychloroquine 200mg/day q.d. for 05 days




Primary Outcome Measures :
  1. 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]


Secondary Outcome Measures :
  1. 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 ]
    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]

  2. Time-to-recovery [ Time Frame: Day 28 ]
    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]

  3. Viral load [ Time Frame: Day 5 ]
    Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by viral load measured by rtPCR-SARS-CoV-2 (CTs)

  4. Positivity rate of rtPCR-SARS-CoV-2 (qualitative analysis) [ Time Frame: Day 5 ]
    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)

  5. Duration of fatigue [ Time Frame: Day 14 ]
    Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by duration of fatigue (days)

  6. Duration of anosmia [ Time Frame: Day 14 ]
    Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by duration of anosmia (days)

  7. Overall duration of clinical manifestations [ Time Frame: Day 14 ]
    Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by duration of overall symptoms (days)

  8. Proportion of subjects needing additional drugs or interventions [ Time Frame: Day 28 ]
    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.

  9. Proportion of subjects needing oxygen use [ Time Frame: Day 28 ]
    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.

  10. Proportion of subjects needing high-flow oxygen therapy or non-invasive ventilation [ Time Frame: Day 28 ]
    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.

  11. Proportion of hospitalizations [ Time Frame: Day 28 ]
    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.

  12. Proportion of mechanical ventilation use [ Time Frame: Day 28 ]
    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 (%).

  13. Proportion of pressors use [ Time Frame: Day 28 ]
    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 (%).

  14. Proportion of deaths [ Time Frame: Day 28 ]
    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 (%).

  15. Proportion of post-COVID mental symptoms [ Time Frame: Day 30 ]
    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 (%).

  16. Proportion of post-COVID mental symptoms [ Time Frame: Day 60 ]
    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 (%).

  17. Proportion of post-COVID mental symptoms [ Time Frame: Day 90 ]
    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 (%).

  18. Proportion of post-COVID physical symptoms [ Time Frame: Day 30 ]
    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 (%).

  19. Proportion of post-COVID physical symptoms [ Time Frame: Day 60 ]
    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 (%).

  20. Proportion of post-COVID physical symptoms [ Time Frame: Day 90 ]
    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 (%).

  21. Proportion of post-COVID overall symptoms [ Time Frame: Day 30 ]
    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 (%).

  22. Proportion of post-COVID overall symptoms [ Time Frame: Day 60 ]
    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 (%).

  23. Proportion of post-COVID overall symptoms [ Time Frame: Day 90 ]
    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 (%).

  24. Duration of new oxygen use [ Time Frame: Day 28 ]
    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)

  25. Duration of hospitalization [ Time Frame: Day 28 ]
    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)

  26. Duration of mechanical ventilation [ Time Frame: Day 28 ]
    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)

  27. Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L) [ Time Frame: Day 1 ]
    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 (%).

  28. Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L) [ Time Frame: Day 3 ]
    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 (%).

  29. Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L) [ Time Frame: Day 7 ]
    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 (%).

  30. Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1) [ Time Frame: 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 (%).

  31. Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1) [ Time Frame: Day 3 ]
    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 (%).

  32. Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1) [ Time Frame: Day 7 ]
    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 (%).

  33. Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1) [ Time Frame: 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 (%).

  34. Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1) [ Time Frame: Day 3 ]
    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 (%).

  35. Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1) [ Time Frame: Day 7 ]
    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 (%).

  36. Proportion of increased d-dimer (defined as d-dimer > 500 mg/dL) [ Time Frame: Day 7 ]
    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 (%).

  37. Disease duration [ Time Frame: Day 14 ]
    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

  38. Change in viral load from baseline to Day 5 [ Time Frame: Day 30 ]
    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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Laboratory or clinically confirmed positive SARS-CoV-2 rtPCR test (AndroCoV Clinical Scoring for COVID-19 Diagnosis1) within 7 days prior to randomization
  2. ≥18 years old
  3. Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to randomization
  4. Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 1 to 3
  5. Subject (or legally authorized representative) gives written informed consent prior to performing any study procedures
  6. Subject (or legally authorized representative) agree that subject will not participate in another COVID-19 trial while participating in this study

Exclusion Criteria:

  1. Subject enrolled in a study to investigate a treatment for COVID-19
  2. Require oxygen use, hospitalization or mechanical ventilation
  3. Tachycardia (HR > 150 bpm) or hypotension (BP < 90/60 mmHg)
  4. Patients who are allergic to the investigational product or similar drugs (or any excipients);
  5. Subjects with QTcF > 450 ms
  6. 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%)
  7. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit of normal.
  8. Estimated glomerular filtration rate (eGFR) < 30 ml/min or requiring dialysis
  9. Subject (or legally authorized representative) not willing or unable to provide informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04712279


Contacts
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Contact: Flavio A Cadegiani, MD, PhD +55 61 99650.6111 flavio.cadegiani@gmail.com

Sponsors and Collaborators
Corpometria Institute
Investigators
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Study Director: Ricardo A Zimerman, MD Corpometria Institute
Principal Investigator: Flavio A Cadegiani, MD, PhD Corpometria Institute; Applied Biology
Publications of Results:
Elgazzar, 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.

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Responsible Party: Corpometria Institute
ClinicalTrials.gov Identifier: NCT04712279    
Other Study ID Numbers: CORPO-DRUG-SARSCoV2-001
First Posted: January 15, 2021    Key Record Dates
Last Update Posted: January 15, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Corpometria Institute:
COVID-19
SARS-CoV-2
Covid19
Ivermectin
Additional relevant MeSH terms:
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Hydroxychloroquine
Ivermectin
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents