SILVERBULLET: Efficacy, Safety and Tolerability of Ivermectin in Subjects Infected With SARS-CoV-2 With or Without Symptoms

• Sponsor: Investigacion Biomedica para el Desarrollo de Farmacos S.A. de C.V. (Other)
• Overall Status: Completed
• CT.gov ID: NCT04407507
• Collaborator: (none)
• Enrollment: 66
• Location: 1
• Arms: 2
• Actual Duration (Months): 7
• Patients Per Site Per Month: 9.5

Study Details

Study Description

Brief Summary

This study aims to evaluate the efficacy, safety and tolerability of Ivermectin in patients with mild SARS-CoV-2 infection, in the rate of progression to severe 2019 novel coronavirus disease (COVID-19).

The primary efficacy endpoint is the proportion of participants with a disease control status defined as no progression of severe disease Hypothesis (H0): There is no difference between group A (ivermectin + paracetamol) and group B (ivermectin + paracetamol) in terms of the primary endpoint on day 14.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Ivermectin; Drug: Placebo	Phase 2

Detailed Description

In late 2019, an unidentified viral pneumonia was detected in Wuhan, China. Later, it was declared that it was pneumonia due to a new coronavirus. The World Health Organization (WHO) officially called it COVID-19 disease (Xie and Chen 2020).

Ivermectin is a broad-spectrum antiparasitic agent, developed to combat parasitic worms in veterinary use and in human medicine. This compound has been used orally in humans to treat filariasis, but is also effective against other worm-associated infections, as well as parasitic skin diseases and insect infections. It is approved for human use in several countries, to treat onchocerciasis, lymphatic filariasis, strongyloidiasis, and scabies, and recently in capillary pediculosis. When avermectins were discovered, they represented a new class of compounds that kill various ranges of disease-causing organisms, as well as pathogen vectors, inside and outside the body. Ivermectin is a semi-synthetic mixture of two chemically modified avermectins, comprising 80% 22,23-dihydroavermectin B1 and 20% 22,23-dihydroavermectin-B1b.

Other diseases that have been treated with ivermectin are: trichinosis, vector insects, malaria, trypanosomiasis, allergic asthma, rosacea, bedbugs, schistosomiasis, chagas disease, epilepsy, neurological diseases. Furthermore, it has been observed to have effects as an antibiotic and anticancer (Crump 2017).

In turn, Ivermectin has been described as a broad-spectrum antiviral, inhibiting nuclear import by its ability to inactivate host nuclear transport proteins, such as integrase and nonstructural protein 5 (NS5), limiting the ability to infect the western virus of the Nile in low concentrations (Yang et al. 2020), as well as inhibiting the replication of the yellow fever virus and other flaviviruses, such as dengue, and encephalitis, probably attacking the activity of nonstructural helicase 3 (Crump 2017).

Ivermectin, at a dose of 150-200 mcg / kg, is the first line of treatment for river blind disease (onchocerca volvulus), lymphatic filariasis, and strongyloidiasis(Crump 2017)..

French authorities approved ivermectin for humans in 1987. Shortly thereafter, Merck & Co Inc donated ivermectin for onchocerciasis control. Since then, more than two billion treatments have been distributed in Africa and Latin America for onchocerciasis and lymphatic filariasis (Chaccour et al. 2013; Smit et al. 2016).

In this context, ivermectin adverse events have been mild, transient and associated with the intensity of the infection. No significant association was found between ivermectin plasma levels and adverse events(Merck & Co 2009).

Wagstaff et al. published preliminary studies in in vitro cultures, where they observed that a 5000-fold reduction in the viral RNA content of cells infected with the SARS-CoV-2 virus, treated with a single dose of ivermectin (Caly et al. 2020).

Ivermectin therapy has not been tested in COVID-19 subjects and is therefore intended to be used as an adjuvant treatment; therefore, all study subjects will receive ivermectin or placebo in addition to therapy that their treating physician deems appropriate. Since ivermectin is in an early phase of clinical development, the use of base therapy will ensure that all subjects, including subjects who are randomized to receive placebo, have the benefit of receiving treatment with the base therapy that is available.

Research Objectives The main objective of this study is to evaluate the efficacy, safety and tolerability of ivermectin in patients with mild SARS-CoV-2 infection, in the rate of progression to severe COVID-19.

Secondary objectives

• Quantify the replication rate of the SARS-CoV-2 virus at days 5 and 14 after diagnosis quantitatively by real-time reverse transcription polymerase chain reaction (RT-PCR).

• Evaluate the presence and frequency of symptoms associated with COVID-19 disease (fever, cough, myalgia, fatigue, shortness of breath, headache, diarrhea, and expectoration) daily for 14 days.

• Investigate the presence of adverse events associated or not with the study drug for 14 days.

• Search for associations between the morbidities of the evaluated subjects and the intensity of the disease.

• Search for a relationship between medical history of bacille Calmette Guerin (BCG) vaccines and the intensity of the disease.

• Evaluate the frequency of death in the subjects, associated with COVID-19.

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Care Provider)
• Primary Purpose: Treatment
• Official Title: Multicenter, Double-blind, Randomized, Placebo-controlled Study to Assess the Efficacy, Safety and Tolerability of Ivermectin in Mild Virus-positive Subjects (SARS-CoV)-2 With or Without Symptoms
• Actual Study Start Date: Jul 1, 2020
• Actual Primary Completion Date: Jan 29, 2021
• Actual Study Completion Date: Jan 29, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ivermectin Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days	Drug: Ivermectin; ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days
Placebo Comparator: Placebo Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days	Drug: Placebo; Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days

Outcome Measures

Primary Outcome Measures

1. Participants With a Disease Control Status Defined as no Disease Progression to Severe. [14 days]

   The subject is considered to have progressed to severe illness when one or more of the following criteria are present: Breathing difficulty (≥30 breaths per minute); Resting oxygen saturation ≤93%; Severe complications such as: respiratory failure, need for mechanical ventilation, septic shock, non-respiratory organic failure.

Secondary Outcome Measures

1. SARS-CoV-2 Viral Load, at 5 and 14 Days [days 1, 5 and 14]

   To determine viral load indirectly, the Ct value of the SARS-COV-2 gene N was used on days 1, 5 and 14 of treatment, considering values greater than 37.5 as negative.

2. Presence and Frequency of Symptoms Associated With the COVID-19 Disease [14 days]

   Subjects were asked to answer a symptoms dairy during 14 days, where they recorded the presence of the following symptoms; fever, cough, muscular pain, fatigue, breath difficulty, headache, diarrhea, palpitations, expectoration and "Other", in the other question several subjects answer hypogeusia/ageusia, hyposmia/anosmia and backpain. The total of days anaylized were considered as 100%; 364 days for placebo patients(26 subjects x 14 days), and 420 for ivermectin subjects (30 subjects x 14 days), then the number of days reported correspond to de % of days when symptom was present.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of acute severe respiratory syndrome due to SARS-CoV-12 coronavirus infection defined by RT-PCR.

• Asymptomatic, or with mild symptoms who are taking outpatient treatment of the disease.

• Signed Informed Consent.

Exclusion Criteria:

1. Patients with severe disease COVID-19.

2. Positive to proof of infection by some other virus such as influenza H1N1, SARS, etc.

3. Recurrent urinary tract infections.

4. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)> 5 times above its normal limits.

5. Pregnant or lactating patients

6. Patients receiving antihypertensive medication verapamil, the immunosuppressant cyclosporin A and / or the antipsychotic trifluoperazine.

7. Patients with a known allergy or hypersensitivity to dewormers.

8. Patients who are using an antioxidant supplement.

9. Patients with a history of filariasis, strongyloidiasis, scabies, river blindness, or any parasitic disease in the last twelve months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigacion Biomédica para el Desarrollo de Fármacos S.A. de C.V.	Zapopan	Jalisco	Mexico

Sponsors and Collaborators

• Investigacion Biomedica para el Desarrollo de Farmacos S.A. de C.V.

Investigators

• Principal Investigator: Alma M Perez, MD, Centro de Investigación Farmacéutica Especializada de Occidente S.C.

Study Documents (Full-Text)

• Study Protocol - Aug 5, 2020
• Statistical Analysis Plan - Aug 5, 2020

More Information

Additional Information:

• Stromectol. FDA Approved Package Insert 2009

Publications

None provided.

• Responsible Party: Investigacion Biomedica para el Desarrollo de Farmacos S.A. de C.V.
• ClinicalTrials.gov Identifier: NCT04407507
• Other Study ID Numbers: SARS-COV-IverMX-01
• First Posted: May 29, 2020
• Last Update Posted: May 21, 2021
• Last Verified: May 1, 2021

• 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 Investigacion Biomedica para el Desarrollo de Farmacos S.A. de C.V.: Ivermectin
• Additional relevant MeSH terms: Ivermectin

Study Results

Participant Flow

Arm/Group Title	Ivermectin	Placebo
Arm/Group Description	Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Ivermectin: ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days	Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Placebo: Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days
Period Title: Overall Study
STARTED	33	33
COMPLETED	33	32
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Ivermectin	Placebo	Total
Arm/Group Description	Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Ivermectin: ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days	Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Placebo: Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days	Total of all reporting groups
Overall Participants	33	33	66
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	30 90.9%	31 93.9%	61 92.4%
>=65 years	3 9.1%	2 6.1%	5 7.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.24 (14.48)	36.82 (13.90)	38.53 (14.19)
Sex: Female, Male (Count of Participants)
Female	26 78.8%	22 66.7%	48 72.7%
Male	7 21.2%	11 33.3%	18 27.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	11 33.3%	11 33.3%	22 33.3%
More than one race	19 57.6%	19 57.6%	38 57.6%
Unknown or Not Reported	3 9.1%	3 9.1%	6 9.1%
Region of Enrollment (participants) [Number]
Mexico	33 100%	33 100%	66 100%

Outcome Measures

1. Primary Outcome

Title	Participants With a Disease Control Status Defined as no Disease Progression to Severe.
Description	The subject is considered to have progressed to severe illness when one or more of the following criteria are present: Breathing difficulty (≥30 breaths per minute); Resting oxygen saturation ≤93%; Severe complications such as: respiratory failure, need for mechanical ventilation, septic shock, non-respiratory organic failure.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

Participants With a Disease Control Status Defined as no Disease Progression to Severe, 3 subjects of the Ivermectin arm group and 7 of the placebo were excluded of the efficacy analysis due to wrong criteria of inclusion (3 of ivermectin and 6 from placebo) and withdrawal of consent (1 in placebo).

Arm/Group Title	Ivermectin	Placebo
Arm/Group Description	Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Ivermectin: ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days	Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Placebo: Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days
Measure Participants	30	26
Count of Participants [Participants]	30 90.9%	26 78.8%

2. Secondary Outcome

Title	SARS-CoV-2 Viral Load, at 5 and 14 Days
Description	To determine viral load indirectly, the Ct value of the SARS-COV-2 gene N was used on days 1, 5 and 14 of treatment, considering values greater than 37.5 as negative.
Time Frame	days 1, 5 and 14

Outcome Measure Data

Analysis Population Description

Only positive subjects are reported, since Ct is not reported in negative subjects, therefore there is no data available to analyze this criterion, as negative subjects are reported, the values for analysis decrease.

Arm/Group Title	Ivermectin	Placebo
Arm/Group Description	Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Ivermectin: ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days	Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Placebo: Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days
Measure Participants	30	26
Day 1	26.17 (6.36)	23.3 (5.15)
Day 5	30.52 (4.21)	28.5 (3.73)
Day 14	33.74 (4.77)	32.94 (4.74)

3. Secondary Outcome

Title	Presence and Frequency of Symptoms Associated With the COVID-19 Disease
Description	Subjects were asked to answer a symptoms dairy during 14 days, where they recorded the presence of the following symptoms; fever, cough, muscular pain, fatigue, breath difficulty, headache, diarrhea, palpitations, expectoration and "Other", in the other question several subjects answer hypogeusia/ageusia, hyposmia/anosmia and backpain. The total of days anaylized were considered as 100%; 364 days for placebo patients(26 subjects x 14 days), and 420 for ivermectin subjects (30 subjects x 14 days), then the number of days reported correspond to de % of days when symptom was present.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

Subjects were asked to answer a symptoms dairy during 14 days, where they recorded the presence of the following symptoms; fever, cough, muscular pain, fatigue, breath difficulty, headache, diarrhea, palpitations, expectoration and "Other", in the other question several subjects answer hypogeusia/ageusia, hyposmia/anosmia and backpain.

Arm/Group Title	Ivermectin	Placebo
Arm/Group Description	Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Ivermectin: ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days	Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Placebo: Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days
Measure Participants	30	26
Fever	7.67	5.44
Cough	51.7	34.1
Muscular pain	29.5	24.6
Fatigue	45.4	38.1
Breath difficulty	16.7	14.9
Headache	32.3	26.9
Palpitations	13	9.74
Expectoration	25.7	17.5
Diarrhea	13	7.16
Hypogeusia/ageusia	18.9	8.31
Hyposmia/anosmia	19.4	10.9
Backpain	1.79	0.57
Other	28.6	14.3

Adverse Events

Time Frame	21 days
Arm/Group Title	Ivermectin		Placebo
Arm/Group Description	Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Ivermectin: ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days		Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days Placebo: Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days
All Cause Mortality
	Ivermectin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/33 (0%)
Serious Adverse Events
	Ivermectin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/33 (3%)		0/33 (0%)
Nervous system disorders
HT Central nervous system and spinal cord infections	1/33 (3%)	1	0/33 (0%)	0
Other (Not Including Serious) Adverse Events
	Ivermectin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/33 (18.2%)		9/33 (27.3%)
Blood and lymphatic system disorders
SOC Blood and lymphatic system disorders	0/33 (0%)	0	1/33 (3%)	1
Ear and labyrinth disorders
LLT Otitis	1/33 (3%)	1	0/33 (0%)	0
Endocrine disorders
LLT elevated Lipase	0/33 (0%)	0	1/33 (3%)	1
Gastrointestinal disorders
HLGT Inflammatory gastrointestinal diseases	1/33 (3%)	1	0/33 (0%)	0
LLT acidity	0/33 (0%)	0	1/33 (3%)	1
LLT Nausea	0/33 (0%)	0	2/33 (6.1%)	2
PT Acid Peptic Disease	0/33 (0%)	0	1/33 (3%)	1
General disorders
PF Vertigo	1/33 (3%)	1	0/33 (0%)	0
LLT Dizziness	0/33 (0%)	0	1/33 (3%)	1
Metabolism and nutrition disorders
HLGT Glucose metabolism disorders (including diabetes mellitus)	0/33 (0%)	0	1/33 (3%)	1
Musculoskeletal and connective tissue disorders
HLT Musculoskeletal pain and discomfort	0/33 (0%)	0	2/33 (6.1%)	2
LLT Back pain	0/33 (0%)	0	1/33 (3%)	1
Psychiatric disorders
HLGT anxiety disorders and symptoms	1/33 (3%)	1	0/33 (0%)	0
Renal and urinary disorders
LLT Cystitis	1/33 (3%)	1	0/33 (0%)	0
HLT Urinary tract infections	2/33 (6.1%)	2	0/33 (0%)	0
Respiratory, thoracic and mediastinal disorders
LLT pharyngitis	1/33 (3%)	1	0/33 (0%)	0
HLT Nasal congestion and inflammation	1/33 (3%)	1	1/33 (3%)	1
LLT Pneumonia	0/33 (0%)	0	1/33 (3%)	1
Skin and subcutaneous tissue disorders
HLT RASH	1/33 (3%)	1	1/33 (3%)	1
HLGT Epidermal and dermal diseases	1/33 (3%)	1	0/33 (0%)	0
SOC Skin and subcutaneous tissue disorders	0/33 (0%)	0	1/33 (3%)	1
Vascular disorders
LLT Hypertension	1/33 (3%)	1	1/33 (3%)	1
LLT Tachycardia	0/33 (0%)	0	1/33 (3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.