COVID-19
Conditions
Brief summary
Trial to Evaluate Efficacy and Safety of Nitazoxanide in the Treatment of Mild or Moderate COVID-19
Detailed description
Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety of Nitazoxanide in the Treatment of Mild or Moderate COVID-19
Interventions
DRUGNitazoxanide
Two nitazoxanide 300 mg tablets administered orally twice daily with food for 5 days
DRUGPlacebo
Two placebo tablets administered orally twice daily with food for 5 days
DIETARY_SUPPLEMENTVitamin Super B-Complex
Vitamin Super B-Complex administered orally twice daily to maintain the blind
Sponsors
Romark Laboratories L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Male or female outpatients at least 12 years of age * Presence of clinical signs and/or symptoms consistent with worsening or stable mild or moderate COVID-19 (one of the following is required): 1. Presence of at least two respiratory symptom domains (head, throat, nose, chest, cough) with a score of ≥2 as determined by Screening FLU-PRO OR 2. Presence of at least one respiratory symptom domain (head, throat, nose, chest, cough) with a score of ≥2 as determined by Screening FLU-PRO with pulse rate ≥90 OR 3. Presence of at least one respiratory symptom domain (head, throat, nose, chest, cough) with a score of ≥2 as determined by Screening FLU-PRO with respiratory rate ≥16 AND patient reported assessment that symptoms are present, the symptoms are not consistent with the subject's usual health, the symptoms interfere with daily activities, and the symptoms have worsened or remained the same relative to the previous day, as confirmed by responses to questions in the Screening FLU-PRO. * Onset of symptoms no more than 72 hours before enrollment in the trial. Onset of symptoms is defined as the earlier of the first time at which the subject experienced subjective fever or any respiratory symptom (head, throat, nose, chest, or cough symptoms). * Willing and able to provide written informed consent (including assent by legal guardian if under 18 years of age) and comply with the requirements of the protocol, including completion of the subject diary and all protocol procedures.
Exclusion criteria
* Persons with any clinical sign or symptoms suggestive of severe systemic illness with COVID-19, including the following: 1. shortness of breath at rest, 2. resting pulse ≥125 beats per minute, 3. resting respiratory rate ≥30 breaths per minute, or 4. SpO2 ≤ 93% on room air at sea level. * Subjects who experienced a previous episode of acute upper respiratory tract infection, otitis, bronchitis or sinusitis or received antibiotics for these conditions within two weeks prior to and including study day 1. * Severely immunodeficient persons including: 1. Subjects with immunologic disorders or receiving immunosuppressive therapy (e.g., for organ or bone marrow transplants, immunomodulatory therapies for certain autoimmune diseases) 2. Subjects with untreated human immunodeficiency virus (HIV) infection or treated human immunodeficiency virus (HIV) infection with a CD4 count below 350 cells/mm3 in the last six months 3. Subjects actively undergoing systemic chemotherapy or radiotherapy treatment for malignancy 4. Subjects using steroids as maintenance therapy for chronic conditions * Subjects with active respiratory allergies or subjects expected to require anti- allergy medications during the study period for respiratory allergies. * Females of childbearing potential who are either pregnant or sexually active without the use of birth control. Female subjects of child-bearing potential that are sexually active must have a negative baseline pregnancy test and must agree to continue an acceptable method of birth control for the duration of the study and for 1 month post-treatment. A double barrier method, oral birth control pills administered for at least 2 monthly cycles prior to study drug administration, an intrauterine device (IUD), or medroxyprogesterone acetate administered intramuscularly for a minimum of one month prior to study drug administration are acceptable methods of birth control for inclusion into the study. Female subjects are considered of childbearing potential unless they are postmenopausal (absence of menstrual bleeding for 1 year - or 6 months if laboratory confirmation of hormonal status), or have had a hysterectomy, bilateral tubular ligation or bilateral oophorectomy. * Subjects with a history of COVID-19 or known to have developed anti-SARS- CoV-2 antibodies. * Subjects residing in the same household with another subject participating in the study. * Treatment with any investigational drug or vaccine therapy within 30 days prior to screening and willing to avoid them during the course of the study. * Receipt of any dose of nitazoxanide within seven days prior to screening. * Known sensitivity to nitazoxanide or any of the excipients comprising the study medication. * Subjects unable to swallow oral tablets or capsules. * Subjects with known severe heart, lung, neurological or other systemic disease that the Investigator believes could preclude safe participation. * Subjects likely or expected to require hospitalization unrelated to COVID-19 during the study period. * Subjects taking medications considered to be major CYP2C8 substrates. * Subjects who, in the judgment of the Investigator, will be unlikely to comply with the requirements of this protocol including completion of the subject diary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Sustained Clinical Recovery | Up to 21 days | Time to Sustained Clinical Recovery is the time in days from the first dose of study medication to the first time at which the subject reports a decrease in total FLU-PRO score from the previous diary with assessment that symptoms are at least somewhat better than yesterday, no oral temperature ≥100.4 F in the prior 24 hours, and no future increase in any of the FLU-PRO domains except within validated background levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Progressing to Severe COVID-19 | Up to 21 days | Analysis of proportions of subjects with progression to severe COVID-19 illness defined as subject-reported shortness of breath at rest and blood oxygen saturation ≤93% on room air |
Other
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at Each of Days 4 and 10 | Day 4 and Day 10 | — |
| Change From Baseline in Quantitative SARS-CoV-2 RNA Measured by RT-PCR at Each of Days 4 and 10 | Day 4 and Day 10 | — |
| Proportion of Subjects Requiring Hospitalization | 28 days | Analysis of proportions of subjects requiring hospitalization for any reason during the study period |
| All-Cause Mortality | 28 days | Analysis of proportions experiencing mortality from any cause during the study period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nitazoxanide Two nitazoxanide 300 mg tablets orally twice daily for 5 days | 472 |
| Placebo Two placebo tablets orally twice daily for 5 days | 463 |
| Total | 935 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Lost to Follow-up | 7 | 9 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 6 |
Baseline characteristics
| Characteristic | Nitazoxanide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 40.2 years STANDARD_DEVIATION 14.83 | 40.7 years STANDARD_DEVIATION 14.68 | 40.5 years STANDARD_DEVIATION 14.75 |
| BMI | 30.7 kilograms per meters squared STANDARD_DEVIATION 7.72 | 31.1 kilograms per meters squared STANDARD_DEVIATION 7.51 | 30.9 kilograms per meters squared STANDARD_DEVIATION 7.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 117 Participants | 112 Participants | 229 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 349 Participants | 343 Participants | 692 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 8 Participants | 14 Participants |
| Height | 169.1 centimeters STANDARD_DEVIATION 10.84 | 168.4 centimeters STANDARD_DEVIATION 9.96 | 168.7 centimeters STANDARD_DEVIATION 10.41 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants | 43 Participants | 84 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 6 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 19 Participants | 33 Participants |
| Race (NIH/OMB) White | 404 Participants | 388 Participants | 792 Participants |
| Risk of Severe Illness At Increased Risk of Severe Illness | 330 Participants | 338 Participants | 668 Participants |
| Risk of Severe Illness Not At Increased Risk of Severe Illness | 142 Participants | 125 Participants | 267 Participants |
| Severity of Disease Mild Illness | 301 Participants | 305 Participants | 606 Participants |
| Severity of Disease Moderate Illness | 170 Participants | 158 Participants | 328 Participants |
| Severity of Disease Unknown | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 282 Participants | 284 Participants | 566 Participants |
| Sex: Female, Male Male | 190 Participants | 179 Participants | 369 Participants |
| Time from Onset of Symptoms to Randomization | 41.5 hours STANDARD_DEVIATION 15.73 | 41.9 hours STANDARD_DEVIATION 16.71 | 41.7 hours STANDARD_DEVIATION 16.21 |
| Tobacco Use Current Tobacco User | 115 Participants | 106 Participants | 221 Participants |
| Tobacco Use Never Used Tobacco | 295 Participants | 288 Participants | 583 Participants |
| Tobacco Use Past Tobacco User | 62 Participants | 69 Participants | 131 Participants |
| Weight | 88.0 kilograms STANDARD_DEVIATION 24.44 | 88.5 kilograms STANDARD_DEVIATION 23.36 | 88.3 kilograms STANDARD_DEVIATION 23.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 472 | 0 / 463 |
| other Total, other adverse events | 16 / 472 | 10 / 463 |
| serious Total, serious adverse events | 2 / 472 | 7 / 463 |
Outcome results
Primary
Time to Sustained Clinical Recovery
Time to Sustained Clinical Recovery is the time in days from the first dose of study medication to the first time at which the subject reports a decrease in total FLU-PRO score from the previous diary with assessment that symptoms are at least somewhat better than yesterday, no oral temperature ≥100.4 F in the prior 24 hours, and no future increase in any of the FLU-PRO domains except within validated background levels.
Time frame: Up to 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Sustained Clinical Recovery | 13.3 days |
| Placebo | Time to Sustained Clinical Recovery | 12.4 days |
p-value: 0.8786Gehan-Wilcoxon Test
Secondary
Proportion of Subjects Progressing to Severe COVID-19
Analysis of proportions of subjects with progression to severe COVID-19 illness defined as subject-reported shortness of breath at rest and blood oxygen saturation ≤93% on room air
Time frame: Up to 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | Proportion of Subjects Progressing to Severe COVID-19 | 0.005 proportion of subjects |
| Placebo | Proportion of Subjects Progressing to Severe COVID-19 | 0.036 proportion of subjects |
p-value: 0.074Cochran-Mantel-Haenszel
Other Pre-specified
All-Cause Mortality
Analysis of proportions experiencing mortality from any cause during the study period
Time frame: 28 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | All-Cause Mortality | 0.005 proportion of subjects |
| Placebo | All-Cause Mortality | 0.000 proportion of subjects |
p-value: 0.2399Cochran-Mantel-Haenszel
Other Pre-specified
Change From Baseline in Quantitative SARS-CoV-2 RNA Measured by RT-PCR at Each of Days 4 and 10
Time frame: Day 4 and Day 10
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nitazoxanide | Change From Baseline in Quantitative SARS-CoV-2 RNA Measured by RT-PCR at Each of Days 4 and 10 | Day 4 | -0.70 log10 RNA copies/milliliter | Standard Error 0.118 |
| Nitazoxanide | Change From Baseline in Quantitative SARS-CoV-2 RNA Measured by RT-PCR at Each of Days 4 and 10 | Day 10 | -2.49 log10 RNA copies/milliliter | Standard Error 0.119 |
| Placebo | Change From Baseline in Quantitative SARS-CoV-2 RNA Measured by RT-PCR at Each of Days 4 and 10 | Day 4 | -1.02 log10 RNA copies/milliliter | Standard Error 0.126 |
| Placebo | Change From Baseline in Quantitative SARS-CoV-2 RNA Measured by RT-PCR at Each of Days 4 and 10 | Day 10 | -2.61 log10 RNA copies/milliliter | Standard Error 0.12 |
Comparison: Comparison of change from Baseline to Day 4p-value: 0.0665t-test, 2 sided
Comparison: Comparison of change from Baseline to Day 10p-value: 0.4974t-test, 2 sided
Post Hoc
Progression to Severe COVID-19 for Subjects At Increased Risk Per CDC Guidelines
Analysis of proportions of subjects with progression to severe COVID-19 illness defined as subject-reported shortness of breath at rest and blood oxygen saturation ≤93% on room air for the subgroup of subjects considered high risk per CDC guidelines
Time frame: 28 days
Population: Subjects positive for SARS-CoV-2 by RT-PCR with one of the following risk factors: COPD, Type 2 diabetes mellitus, obesity (BMI≥30), chronic kidney disease, sickle cell disease, serious heart conditions, ≥65 years of age.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | Progression to Severe COVID-19 for Subjects At Increased Risk Per CDC Guidelines | 0.009 proportion of subjects |
| Placebo | Progression to Severe COVID-19 for Subjects At Increased Risk Per CDC Guidelines | 0.057 proportion of subjects |
p-value: 0.05Cochran-Mantel-Haenszel
Post Hoc
Progression to Severe COVID-19 for Subjects At Least Possibly At Increased Risk Per CDC Guidelines
Analysis of proportions of subjects with progression to severe COVID-19 illness defined as subject-reported shortness of breath at rest and blood oxygen saturation ≤93% on room air for the subgroup of subjects considered possibly at high risk per CDC guidelines
Time frame: 28 days
Population: Subjects positive for SARS-CoV-2 by RT-PCR with one of the following risk factors: COPD, Type 2 diabetes mellitus, obesity (BMI≥30), chronic kidney disease, sickle cell disease, serious heart conditions, ≥65 years of age, asthma (moderate or severe), cerebrovascular disease, cystic fibrosis, hypertension or high blood pressure, immunocompromised state, neurologic conditions, liver disease, pulmonary fibrosis, past or present history of smoking, thalassemia, Type 1 diabetes mellitus
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | Progression to Severe COVID-19 for Subjects At Least Possibly At Increased Risk Per CDC Guidelines | 0.009 proportion of subjects |
| Placebo | Progression to Severe COVID-19 for Subjects At Least Possibly At Increased Risk Per CDC Guidelines | 0.056 proportion of subjects |
p-value: 0.05Cochran-Mantel-Haenszel
Post Hoc
Progression to Severe COVID-19 in Subjects at High Risk by FDA Guidelines
Analysis of proportions of subjects with progression to severe COVID-19 illness defined as subject-reported shortness of breath at rest and blood oxygen saturation ≤93% on room air for the subgroup of subjects considered at high risk per FDA guidelines
Time frame: 28 days
Population: Subjects positive for SARS-CoV-2 with at least one of the following risk factors: ≥ 65 years of age, BMI ≥35 kg/m2, chronic kidney disease, diabetes, immunosuppressive disease, current receipt of immunosuppressive treatment, or ≥55 years of age with at least one of cardiovascular disease, hypertension, or chronic obstructive pulmonary disease or another chronic respiratory disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | Progression to Severe COVID-19 in Subjects at High Risk by FDA Guidelines | 0.016 proportion of subjects |
| Placebo | Progression to Severe COVID-19 in Subjects at High Risk by FDA Guidelines | 0.086 proportion of subjects |
p-value: 0.08Cochran-Mantel-Haenszel
Other Pre-specified
Proportion of Subjects Positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at Each of Days 4 and 10
Time frame: Day 4 and Day 10
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nitazoxanide | Proportion of Subjects Positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at Each of Days 4 and 10 | Day 4 | 0.908 proportion of subjects |
| Nitazoxanide | Proportion of Subjects Positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at Each of Days 4 and 10 | Day 10 | 0.707 proportion of subjects |
| Placebo | Proportion of Subjects Positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at Each of Days 4 and 10 | Day 4 | 0.862 proportion of subjects |
| Placebo | Proportion of Subjects Positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at Each of Days 4 and 10 | Day 10 | 0.662 proportion of subjects |
Comparison: Comparison of proportion positive for SARS-CoV-2 at Day 4p-value: 0.4479Cochran-Mantel-Haenszel
Comparison: Comparison of proportion positive for SARS-CoV-2 at Day 10p-value: 0.2814Cochran-Mantel-Haenszel
Other Pre-specified
Proportion of Subjects Requiring Hospitalization
Analysis of proportions of subjects requiring hospitalization for any reason during the study period
Time frame: 28 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | Proportion of Subjects Requiring Hospitalization | 0.005 proportion of subjects |
| Placebo | Proportion of Subjects Requiring Hospitalization | 0.026 proportion of subjects |
p-value: 0.1771Cochran-Mantel-Haenszel
Post Hoc
Time to Return to Usual Health for Subjects With Mild Illness
Subjects completed a diary daily in the evening. The time from first dose to ability to return to usual health is the time in days from the first dose of study medication to the first time when the subject answered Have you returned to your usual health? with yes for two consecutive daily diary periods.
Time frame: 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR. Mild illness is defined as subjects with pulse \<90 beats per minute and respiratory rate \<20 breaths per minute at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Return to Usual Health for Subjects With Mild Illness | 13.2 days |
| Placebo | Time to Return to Usual Health for Subjects With Mild Illness | 18.4 days |
p-value: 0.0077Gehan-Wilcoxon Test
Post Hoc
Time to Sustained Recovery for Subjects With Mild Illness
Time to Sustained Clinical Recovery is the time in days from the first dose of study medication to the first time at which the subject reports a decrease in total FLU-PRO score from the previous diary with assessment that symptoms are at least somewhat better than yesterday, no oral temperature ≥100.4 F in the prior 24 hours, and no future increase in any of the FLU-PRO domains except within validated background levels.
Time frame: 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for SARS-CoV-2 by RT-PCR. Mild illness is defined as subjects with pulse \<90 beats per minute and respiratory rate \<20 breaths per minute at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Sustained Recovery for Subjects With Mild Illness | 10.3 days |
| Placebo | Time to Sustained Recovery for Subjects With Mild Illness | 13.4 days |
p-value: 0.09Gehan-Wilcoxon Test