Covid-19
Conditions
Keywords
covid19, covid 19, covid-19, coronavirus, SARS-CoV, SARS-CoV-2, novel coronavirus, adult, JWT629, acute respiratory syndrome coronavirus
Brief summary
Two recent studies have suggested that in patients with Covid19, treatment with hydroxychloroquine may shorten the duration of symptoms and improve viral clearance, an effect that appears most pronounced when combined with azithromycin. Hydroxychloroquine treatment may inhibit viral nucleic acid-mediated activation of various innate immune pathways, as well as blockade of lysosomal functions in cell types relevant for viral entry and antigen presentation. The purpose of the study was to determine if oral hydroxychloroquine monotherapy, or in combination with azithromycin results in clinical benefit in patients hospitalized with COVID19 pneumonia.
Interventions
DRUGHCQ
Hydroxychloroquine Monotherapy
DRUGHCQ+AZT
Hydroxychloroquine with azithromycin
DRUGPlacebo
Placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Informed consent must be obtained prior to participation in the study 2. Adult patient ≥ 18 years old 3. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test from respiratory tract specimen (e.g nasopharyngeal swab) 4. Onset of signs and symptoms of COVID19 illness ≤ 7 days prior to randomization (including but not limited to fever, cough, myalgias, fatigue, abnormal chest imaging) 5. Currently hospitalized or requiring hospitalization due to COVID-19 disease
Exclusion criteria
1. Use of other investigational drugs or newly approved COVID-19 treatments within 5-half lives or 30 days of enrolment 2. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes 3. Participation in any other clinical trial of an experimental treatment for COVID-19 4. Expectation of concurrent treatment with any other agents or potential direct acting antiviral activity against SARS-Co V-2 during study drug dosing 5. Requires, in the judgement of the investigator, admission to the intensive care unit (ICU) or mechanical ventilatory support (invasive or non-invasive) prior to first dose of study drug (There might be a patient who cannot be admitted to the ICU, even if the patient's condition is severe enough, due to administrative reasons under the current circumstances. This case is also considered under admission to the ICU judged by the investigator) 6. Evidence of cytokine storm syndrome or multi-organ system failure 7. Confirmed co-infection with influenza 8. Creatinine clearance \< 45 mL/min or requiring acute renal replacement therapy 9. History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study 10. Any other condition which in the opinion of the investigator, would put the safety of the participant at risk, impede compliance or hinder completion of the study 11. Pregnant or nursing (lactating) women 12. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to use basic methods of contraception during dosing of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Clinical Response by Day 15 | 15 days | Clinical response was defined as a) discharged alive; or b) No need for mechanical ventilation in any participants and no need for supplemental oxygen requirement (SpO2) in participants without pre-morbid O2 requirement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Viral Clearance | 6 days and 10 Days | Number and percentage of participants with negative or below LLOQ SARS-COV-2 based on polymerase chain reaction (PCR) test |
| Number of Participants Discharged or Ready for Discharge | 15 days | Number of participants who received hydrochloroquine plus azithromycin relative to placebo who were discharged from hospital |
| Time to Return to Pre-morbid Supplemental Oxygen Requirement in Participants Receiving Hydrochloroquine or Hydrochloroquine Plus Azithromycin Relative to Placebo | 15 days | Number of participants requiring supplemental oxygen at the time of randomization who returned to pre-morbid supplemental oxygen |
Countries
United States
Participant flow
Recruitment details
Study was conducted in 9 centers in the United States. A total of 20 participants were randomized, of whom 19 were treated.
Pre-assignment details
One patient was mis-randomized and never received any treatment. This patient has creatine clearance level \<45 mL/min or required acute renal replacement therapy and therefore was not eligible for inclusion in the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Hydroxychloroquine + Aithromycin Placebo Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin placebo o.d. | 7 |
| Arm 2: Hydroxychloroquine + Azithromycin Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5 | 7 |
| Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d. | 5 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Study Completion Phase | Death | 0 | 0 | 1 |
| Study Completion Phase | Lost to Follow-up | 1 | 0 | 1 |
| Treatment Phase of Study | Adverse Event | 1 | 0 | 1 |
| Treatment Phase of Study | Physician Decision | 2 | 0 | 1 |
| Treatment Phase of Study | Protocol Violation | 1 | 0 | 0 |
| Treatment Phase of Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm 2: Hydroxychloroquine + Azithromycin | Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo | Arm 1: Hydroxychloroquine + Aithromycin Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 5 Participants | 7 Participants | 16 Participants |
| Age, Continuous | 60.9 years STANDARD_DEVIATION 12.5 | 55.2 years STANDARD_DEVIATION 11.1 | 45.9 years STANDARD_DEVIATION 10.6 | 53.8 years STANDARD_DEVIATION 12.7 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 3 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 | 1 / 5 | 1 / 19 |
| other Total, other adverse events | 4 / 7 | 5 / 7 | 2 / 5 | 11 / 19 |
| serious Total, serious adverse events | 1 / 7 | 0 / 7 | 2 / 5 | 3 / 19 |
Outcome results
Primary
Number of Participants Who Achieved Clinical Response by Day 15
Clinical response was defined as a) discharged alive; or b) No need for mechanical ventilation in any participants and no need for supplemental oxygen requirement (SpO2) in participants without pre-morbid O2 requirement.
Time frame: 15 days
Population: Full Analysis Set (FAS) was comprised of all participants to whom study treatment had been assigned by randomization excluding one mis-randomized participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Hydroxychloroquine + Aithromycin Placebo | Number of Participants Who Achieved Clinical Response by Day 15 | 7 Participants |
| Arm 2: Hydroxychloroquine + Azithromycin | Number of Participants Who Achieved Clinical Response by Day 15 | 7 Participants |
| Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo | Number of Participants Who Achieved Clinical Response by Day 15 | 4 Participants |
Secondary
Number of Participants Discharged or Ready for Discharge
Number of participants who received hydrochloroquine plus azithromycin relative to placebo who were discharged from hospital
Time frame: 15 days
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Hydroxychloroquine + Aithromycin Placebo | Number of Participants Discharged or Ready for Discharge | 7 participants |
| Arm 2: Hydroxychloroquine + Azithromycin | Number of Participants Discharged or Ready for Discharge | 7 participants |
| Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo | Number of Participants Discharged or Ready for Discharge | 4 participants |
Secondary
Number of Participants Who Achieved Viral Clearance
Number and percentage of participants with negative or below LLOQ SARS-COV-2 based on polymerase chain reaction (PCR) test
Time frame: 6 days and 10 Days
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: Hydroxychloroquine + Aithromycin Placebo | Number of Participants Who Achieved Viral Clearance | by 6 days | 2 Participants |
| Arm 1: Hydroxychloroquine + Aithromycin Placebo | Number of Participants Who Achieved Viral Clearance | by 10 days | 2 Participants |
| Arm 2: Hydroxychloroquine + Azithromycin | Number of Participants Who Achieved Viral Clearance | by 6 days | 3 Participants |
| Arm 2: Hydroxychloroquine + Azithromycin | Number of Participants Who Achieved Viral Clearance | by 10 days | 3 Participants |
| Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo | Number of Participants Who Achieved Viral Clearance | by 6 days | 3 Participants |
| Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo | Number of Participants Who Achieved Viral Clearance | by 10 days | 3 Participants |
Secondary
Time to Return to Pre-morbid Supplemental Oxygen Requirement in Participants Receiving Hydrochloroquine or Hydrochloroquine Plus Azithromycin Relative to Placebo
Number of participants requiring supplemental oxygen at the time of randomization who returned to pre-morbid supplemental oxygen
Time frame: 15 days
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Hydroxychloroquine + Aithromycin Placebo | Time to Return to Pre-morbid Supplemental Oxygen Requirement in Participants Receiving Hydrochloroquine or Hydrochloroquine Plus Azithromycin Relative to Placebo | 7 participants |
| Arm 2: Hydroxychloroquine + Azithromycin | Time to Return to Pre-morbid Supplemental Oxygen Requirement in Participants Receiving Hydrochloroquine or Hydrochloroquine Plus Azithromycin Relative to Placebo | 6 participants |
| Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo | Time to Return to Pre-morbid Supplemental Oxygen Requirement in Participants Receiving Hydrochloroquine or Hydrochloroquine Plus Azithromycin Relative to Placebo | 4 participants |