COVID-19
Conditions
Brief summary
The primary objective of this study is to evaluate the efficacy of 2 remdesivir (RDV) regimens with respect to clinical status assessed by a 7-point ordinal scale on Day 14.
Interventions
DRUGRemdesivir
Administered as an intravenous infusion
DRUGStandard of Care
Standard of Care Treatment for COVID-19 Infection
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Willing and able to provide written informed consent, or with a legal representative who can provide informed consent, or enrolled under International Conference on Harmonization (ICH) E6(R2) 4.8.15 emergency use provisions as deemed necessary by the investigator (age ≥ 18), or willing and able to provide assent (age ≥ 12 to \< 18, where locally and nationally approved) prior to performing study procedures * Aged ≥ 18 years (at all sites), or aged ≥ 12 and \< 18 years of age weighing ≥ 40 kg (where permitted according to local law and approved nationally and by the relevant institutional review board (IRB) or independent ethics committee (IEC)) * Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test ≤ 4 days before randomization * Currently hospitalized * Peripheral capillary oxygen saturation (SpO2) ≤ 94% or requiring supplemental oxygen at screening Key
Exclusion criteria
* Participation in any other clinical trial of an experimental treatment for COVID-19 * Concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 is prohibited \< 24 hours prior to study drug dosing * Evidence of multiorgan failure * Mechanically ventilated \[including veno-venous (V-V) extracorporeal membrane oxygenation (ECMO)\] ≥ 5 days, or any duration of veno-arterial (V-A) ECMO. * Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) \> 5 X upper limit of normal (ULN) * Creatinine clearance \< 50 mL/min using the Cockcroft-Gault formula for participants ≥ 18 years of age {Cockcroft 1976} and Schwartz Formula for participants \< 18 years of age Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Day 14 | Clinical status was derived from death, hospital discharge, and the ordinal scale as follows: score of 1 was used for all days on or after the date of death; score of 7 was used for all days on or after discharged alive date; last assessment carried forward for any missing values.The scale is as follows: 1. Death; 2. Hospitalized, on invasive mechanical ventilation or ECMO; 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring low flow supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer required ongoing medical care (other than per protocol remdesivir administration); 7. Not hospitalized. The odds ratio represents the odds of improvement in the ordinal scale for the Remdesivir for 10 days group vs the Remdesivir for 5 days group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | First dose date up to last dose date (maximum: 10 days) plus 30 days | Treatment-emergent Adverse Events (TEAE) were defined as AEs with onset dates on or after the study treatment start date and no later than 30 days after the permanent discontinuation of the study treatment and/or the AEs that led to premature discontinuation of study treatment. |
Countries
China, France, Germany, Hong Kong, Italy, Japan, Netherlands, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, Europe, and Asia. The first participant was screened on 06 March 2020. The last study visit occurred on 30 June 2020.
Pre-assignment details
4958 participants were screened. 4891 participants were enrolled. 4 participants in Part A and 49 participants in Part B did not receive treatment and are not included in the analyses.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Remdesivir (RDV) for 5 Days Participants received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-5. | 200 |
| Part A: Remdesivir for 10 Days Participants received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10. | 197 |
| Part B: Remdesivir for 10 Days (Mechanically Ventilated Group) Participants on mechanical ventilation received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10. | 844 |
| Part B: Remdesivir for 10 Days (Extension Group) Participants who were not mechanically ventilated received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10. | 3,597 |
| Total | 4,838 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 2 | 2 |
| Overall Study | Death | 21 | 28 | 188 | 371 |
| Overall Study | Investigator's Discretion | 0 | 0 | 0 | 3 |
| Overall Study | Lost to Follow-up | 8 | 4 | 22 | 235 |
| Overall Study | Non-compliance With Study Drug | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 |
| Overall Study | Withdrew consent | 1 | 0 | 11 | 32 |
Baseline characteristics
| Characteristic | Part B: Remdesivir for 10 Days (Mechanically Ventilated Group) | Part A: Remdesivir for 10 Days | Part A: Remdesivir (RDV) for 5 Days | Part B: Remdesivir for 10 Days (Extension Group) | Total |
|---|---|---|---|---|---|
| Age, Customized Age Categories < 65 | 581 Participants | 113 Participants | 116 Participants | 2399 Participants | 3209 Participants |
| Age, Customized Age Categories ≥ 65 | 263 Participants | 84 Participants | 84 Participants | 1198 Participants | 1629 Participants |
| Clinical Status (7-point ordinal scale) Score: 1 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Clinical Status (7-point ordinal scale) Score: 2 | 844 Participants | 9 Participants | 4 Participants | 0 Participants | 857 Participants |
| Clinical Status (7-point ordinal scale) Score: 3 | 0 Participants | 59 Participants | 49 Participants | 1069 Participants | 1177 Participants |
| Clinical Status (7-point ordinal scale) Score: 4 | 0 Participants | 108 Participants | 113 Participants | 2214 Participants | 2435 Participants |
| Clinical Status (7-point ordinal scale) Score: 5 | 0 Participants | 21 Participants | 34 Participants | 314 Participants | 369 Participants |
| Clinical Status (7-point ordinal scale) Score: 6 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Clinical Status (7-point ordinal scale) Score: 7 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 328 Participants | 38 Participants | 47 Participants | 1341 Participants | 1754 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 1 Participants | 0 Participants | 0 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 478 Participants | 150 Participants | 152 Participants | 2123 Participants | 2903 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 37 Participants | 9 Participants | 1 Participants | 129 Participants | 176 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 5 Participants | 0 Participants | 2 Participants | 40 Participants | 47 Participants |
| Race/Ethnicity, Customized Race Asian | 88 Participants | 25 Participants | 20 Participants | 313 Participants | 446 Participants |
| Race/Ethnicity, Customized Race Black | 149 Participants | 23 Participants | 21 Participants | 611 Participants | 804 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 11 Participants | 0 Participants | 1 Participants | 29 Participants | 41 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 56 Participants | 5 Participants | 0 Participants | 179 Participants | 240 Participants |
| Race/Ethnicity, Customized Race Other | 159 Participants | 10 Participants | 14 Participants | 510 Participants | 693 Participants |
| Race/Ethnicity, Customized Race White | 376 Participants | 134 Participants | 142 Participants | 1915 Participants | 2567 Participants |
| Region of Enrollment France | 2 Participants | 0 Participants | 0 Participants | 25 Participants | 27 Participants |
| Region of Enrollment Germany | 12 Participants | 1 Participants | 3 Participants | 27 Participants | 43 Participants |
| Region of Enrollment Hong Kong | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 6 Participants |
| Region of Enrollment Italy | 16 Participants | 38 Participants | 39 Participants | 108 Participants | 201 Participants |
| Region of Enrollment Japan | 1 Participants | 0 Participants | 0 Participants | 4 Participants | 5 Participants |
| Region of Enrollment Netherlands | 2 Participants | 0 Participants | 0 Participants | 45 Participants | 47 Participants |
| Region of Enrollment Singapore | 7 Participants | 8 Participants | 1 Participants | 44 Participants | 60 Participants |
| Region of Enrollment South Korea | 0 Participants | 6 Participants | 6 Participants | 10 Participants | 22 Participants |
| Region of Enrollment Spain | 27 Participants | 30 Participants | 31 Participants | 134 Participants | 222 Participants |
| Region of Enrollment Sweden | 5 Participants | 0 Participants | 0 Participants | 83 Participants | 88 Participants |
| Region of Enrollment Switzerland | 13 Participants | 0 Participants | 0 Participants | 44 Participants | 57 Participants |
| Region of Enrollment Taiwan | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Region of Enrollment United Kingdom | 33 Participants | 0 Participants | 0 Participants | 144 Participants | 177 Participants |
| Region of Enrollment United States | 722 Participants | 111 Participants | 118 Participants | 2927 Participants | 3878 Participants |
| Sex: Female, Male Female | 312 Participants | 64 Participants | 80 Participants | 1351 Participants | 1807 Participants |
| Sex: Female, Male Male | 532 Participants | 133 Participants | 120 Participants | 2246 Participants | 3031 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 | 25 / 200 | 28 / 197 | 213 / 844 | 422 / 3,597 |
| other Total, other adverse events | 79 / 200 | 92 / 197 | 508 / 844 | 1,258 / 3,597 |
| serious Total, serious adverse events | 43 / 200 | 68 / 197 | 362 / 844 | 851 / 3,597 |
Outcome results
Primary
Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14
Clinical status was derived from death, hospital discharge, and the ordinal scale as follows: score of 1 was used for all days on or after the date of death; score of 7 was used for all days on or after discharged alive date; last assessment carried forward for any missing values.The scale is as follows: 1. Death; 2. Hospitalized, on invasive mechanical ventilation or ECMO; 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring low flow supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer required ongoing medical care (other than per protocol remdesivir administration); 7. Not hospitalized. The odds ratio represents the odds of improvement in the ordinal scale for the Remdesivir for 10 days group vs the Remdesivir for 5 days group.
Time frame: Day 14
Population: Full Analysis Set included participants who were randomized into part A of the study and received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 3 | 4.0 percentage of participants |
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 6 | 4.0 percentage of participants |
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 7 | 60.0 percentage of participants |
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 2 | 8.5 percentage of participants |
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 4 | 9.5 percentage of participants |
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 5 | 6.0 percentage of participants |
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 1 | 8.0 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 7 | 52.3 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 1 | 10.7 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 2 | 16.8 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 3 | 5.1 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 4 | 7.6 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 5 | 6.1 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 | Score: 6 | 1.5 percentage of participants |
p-value: 0.156395% CI: [0.507, 1.115]Proportional odds model
p-value: 0.036895% CI: [0.458, 0.976]Proportional odds model
Secondary
Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)
Treatment-emergent Adverse Events (TEAE) were defined as AEs with onset dates on or after the study treatment start date and no later than 30 days after the permanent discontinuation of the study treatment and/or the AEs that led to premature discontinuation of study treatment.
Time frame: First dose date up to last dose date (maximum: 10 days) plus 30 days
Population: Part A: Safety Analysis Set included participants who were randomized into part A of the study and received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Remdesivir (RDV) for 5 Days | Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 71.5 percentage of participants |
| Part A: Remdesivir for 10 Days | Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 75.1 percentage of participants |
p-value: 0.767895% CI: [-7.4, 10]Cochran-Mantel-Haenszel