COVID-19
Conditions
Keywords
SARS-CoV-2, Coronavirus, Treatment, Pill, Telehealth, Viral shedding
Brief summary
This study will evaluate the antihelmintic drug, Niclosamide, as a potential treatment for mild to moderate coronavirus disease 2019 (COVID-19).
Detailed description
Niclosamide, which has potent antiviral activity against single-stranded RNA viruses including coronaviruses, was proposed as an antiviral during the Severe Acute Respiratory Syndrome (SARS) outbreak in 2002 and has activity including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) where it was found to inhibit SARS coronavirus, SARS-CoV, in in vitro studies and similarly structured RNA viruses (both in vitro and in vivo). The investigators hypothesize that the antiviral activity of Niclosamide may be extended to COVID-19.
Interventions
DRUGNiclosamide
Participants in the treatment arm will receive Niclosamide 2 grams orally once daily for 7 days in addition to current standard of care treatment. Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 3, 7, 10, 14. Fecal samples will be collected for viral shedding as measured by PCR on days 3, 7, 10, 14, 21. A baseline fecal and oropharyngeal sample will be obtained on Day 1 prior to starting dosing of Niclosamide/ placebo.
DRUGPlacebo
The collection of oropharyngeal samples will be observed by a Study Team member via the telehealth platform.
In addition to Niclosamide or placebo treatments, all enrolled patients will be provided a home thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. The collection of oropharyngeal samples will be directly observed by a Study Team member via the telehealth platform.
Sponsors
Tufts Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
As all members of the Study Team will be blinded, Tufts Investigational Drug Services (IDS) will be unblinded and will dispense both the Niclosamide and placebo. The study intervention (Niclosamide) and placebo will be packaged and as indistinguishable as possible.
Intervention model description
Double-blinded randomized controlled trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Positive SARS-CoV-2 test by PCR * No requirement of oxygen supplementation * Ability to take oral medication
Exclusion criteria
* Known allergic reactions to any components of Niclosamide medication * Participation in another trial or use of any experimental treatment for COVID-19, including chloroquine, hydroxychloroquine, remdesivir, and lopinavir/ritonavir * Hospitalization or requirement of hospitalization at the time of enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Respiratory Viral Clearance | Reduction in viral shedding as measured by oropharyngeal swab on days, 3, 7, 10, 14. | Respiratory viral clearance is defined as the first day a participant's oropharyngeal (oral) sample result is negative, provided that none of the subsequent oral sample results are positive. We will calculate the time to clearance since Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Fecal Viral Clearance | Reduction in fecal viral shedding as measured by fecal PCR on days, 3, 7, 10, 14 and 21. | Reduction in fecal viral shedding as measured by fecal PCR on days, 3, 7, 10, 14 and 21. Fecal viral clearance is defined as the first day a participant's fecal sample result is negative, provided that none of the subsequent fecal sample results are positive; calculated as the time to clearance since Day 1. |
| Number of Participants With Progression to Severe COVID-19 Disease | Day 1- 30 | Defined as 1) O2 saturation \<92% on room air (in two consecutive measurements at least 2 hours apart) OR 2) requirement of hospitalization OR 3) need for artificial ventilation OR 4) death. 1) We will compare the proportion of participants who progressed to severe COVID disease between groups. |
| Number of Days to Resolution of a Fever | Day 1-30 | Mean time to fever resolution (symptom no longer reported). |
Countries
United States
Participant flow
Recruitment details
Enrollment was among individuals reporting at Tufts Medical Center and Wellforce Network in Massachusetts for outpatient COVID-19 testing. The trial opened to accrual on October 1, 2020; the last participant enrolled on April 20, 2021.
Pre-assignment details
Of 139 participants were assessed for eligibility, 73 met inclusion criteria and were randomized to treatment (66 participants were excluded: 23 did not meet inclusion criteria, 42 declined participation, 1 co-habited with a previously enrolled participant).
Participants by arm
| Arm | Count |
|---|---|
| Niclosamide Participants in the treatment arm will receive Niclosamide 2 grams orally on day 1 and daily for 6 more days (total 7 days of treatment)
Niclosamide: Participants in the treatment arm will receive Niclosamide 2 grams orally once daily for 7 days in addition to current standard of care treatment. Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 3, 7, 10, 14. Fecal samples will be collected for viral shedding as measured by PCR on days 3, 7, 10, 14, 21. A baseline fecal and oropharyngeal sample will be obtained on Day 1 prior to starting dosing of Niclosamide/ placebo.
Telehealth monitoring: In addition to Niclosamide or placebo treatments, all enrolled patients will be provided a home thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. The collection of oropharyngeal samples will be directly observed by a Study Team member via the telehealth platform. | 33 |
| Control Participants in the control group will receive identical-appearing placebo by mouth in the same numbers of pills on day 1 and daily for 6 more days (total 7 days of treatment)
Placebo: The collection of oropharyngeal samples will be observed by a Study Team member via the telehealth platform.
Telehealth monitoring: In addition to Niclosamide or placebo treatments, all enrolled patients will be provided a home thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. The collection of oropharyngeal samples will be directly observed by a Study Team member via the telehealth platform. | 34 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discontinued Niclosamide/ Placebo | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Niclosamide | Total | Control |
|---|---|---|---|
| Age, Continuous | 36.82 years STANDARD_DEVIATION 12.92 | 36.39 years STANDARD_DEVIATION 13.01 | 35.97 years STANDARD_DEVIATION 13.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 7 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 56 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 26 Participants | 53 Participants | 27 Participants |
| Region of Enrollment United States | 33 participants | 67 participants | 34 participants |
| Sex: Female, Male Female | 13 Participants | 26 Participants | 13 Participants |
| Sex: Female, Male Male | 20 Participants | 41 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 34 |
| other Total, other adverse events | 5 / 33 | 12 / 34 |
| serious Total, serious adverse events | 0 / 33 | 0 / 34 |
Outcome results
Primary
Time to Respiratory Viral Clearance
Respiratory viral clearance is defined as the first day a participant's oropharyngeal (oral) sample result is negative, provided that none of the subsequent oral sample results are positive. We will calculate the time to clearance since Day 1.
Time frame: Reduction in viral shedding as measured by oropharyngeal swab on days, 3, 7, 10, 14.
Population: We evaluated efficacy of niclosamide in shortening contagious period as determined by time to oropharyngeal viral clearance. Primary analysis was based on ITT population (all randomized participants). The cumulative probability of being in clearance in each randomization group was calculated using the Kaplan-Meier estimator. The cumulative probability of clearance at day 3 between the groups was calculated using a chi-square test based on a log(- log(·)) transformation for the survival function.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Niclosamide- Experimental Group | Time to Respiratory Viral Clearance | 3.39 Days |
| Control Group | Time to Respiratory Viral Clearance | 3.44 Days |
Secondary
Number of Days to Resolution of a Fever
Mean time to fever resolution (symptom no longer reported).
Time frame: Day 1-30
Population: The mean time to resolution of fever \*symptom no longer reported)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Niclosamide- Experimental Group | Number of Days to Resolution of a Fever | 10.2 Days |
| Control Group | Number of Days to Resolution of a Fever | 3.6 Days |
Secondary
Number of Participants With Progression to Severe COVID-19 Disease
Defined as 1) O2 saturation \<92% on room air (in two consecutive measurements at least 2 hours apart) OR 2) requirement of hospitalization OR 3) need for artificial ventilation OR 4) death. 1) We will compare the proportion of participants who progressed to severe COVID disease between groups.
Time frame: Day 1- 30
Population: Progression to Severe COVID
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niclosamide- Experimental Group | Number of Participants With Progression to Severe COVID-19 Disease | 0 Participants |
| Control Group | Number of Participants With Progression to Severe COVID-19 Disease | 1 Participants |
Secondary
Time to Fecal Viral Clearance
Reduction in fecal viral shedding as measured by fecal PCR on days, 3, 7, 10, 14 and 21. Fecal viral clearance is defined as the first day a participant's fecal sample result is negative, provided that none of the subsequent fecal sample results are positive; calculated as the time to clearance since Day 1.
Time frame: Reduction in fecal viral shedding as measured by fecal PCR on days, 3, 7, 10, 14 and 21.
Population: We evaluated efficacy of niclosamide in shortening contagious period as determined by time to fecal viral clearance. Primary analysis was based on ITT population (all randomized participants). The cumulative probability of being in clearance in each randomization group was calculated using the Kaplan-Meier estimator. The cumulative probability of clearance at day 14 between the groups was calculated using a chi-square test based on a log(- log(·)) transformation for the survival function.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Niclosamide- Experimental Group | Time to Fecal Viral Clearance | 6.12 Days |
| Control Group | Time to Fecal Viral Clearance | 5.77 Days |