COVID-19
Conditions
Keywords
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronavirus disease 2019 (COVID-19), COVID-19 rebound, Paxlovid, Nirmatrelvir
Brief summary
The purpose of this study is to learn about the safety and effects of nirmatrelvir/ritonavir for the potential treatment of COVID-19 rebound. The study is seeking participants who: * Have completed treatment with nirmatrelvir/ritonavir * Have a rebound in COVID-19 symptoms * Are SARS-CoV-2 (COVID-19) positive All study medications will be taken 2 times a day by mouth for 5 days. The first dose of study medication is taken at the study clinic and the rest at home. We will examine the experiences of people receiving the study medicines to those who do not. This will help us determine if the study medicines are safe and effective. People taking part will be in this study for about 24 weeks. Enrolled participants will need to visit the study clinic at least 8 times during the study.
Interventions
DRUGnirmatrelvir
Participants will receive 2 tablets of nirmatrelvir every 12 hours
DRUGritonavir
Participants will receive 1 capsule of ritonavir every 12 hours
Participants will receive 2 tablets of placebo for nirmatrelvir every 12 hours. A placebo does not have any medicine in it but looks just like the medicine being studied.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documentation of nirmatrelvir/ritonavir treatment with patient-reported 100% compliance. Symptom alleviation or resolution in COVID-19 signs/symptoms followed by a worsening (rebound) of signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir * Onset of rebound in COVID-19 symptoms within 2 weeks (14 days) after the completion of the initial 5-day course of nirmatrelvir/ritonavir. * Onset of rebound in signs/symptoms attributable to COVID-19 within 48 hours prior to randomization and ≥1 sign/symptom attributable to COVID-19 present on the day of randomization. * SARS-CoV-2 infection as determined by rapid antigen testing within 24 hours prior to randomization * At least 1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19.
Exclusion criteria
* Current need for hospitalization, hospitalized for the COVID-19 infection or anticipated need for hospitalization within 24 hours after randomization * History of severe chronic liver disease * Receiving dialysis or have known age-specific estimated glomerular filtration rate (eGFR) or estimated creatinine clearance (eCrCl) \<30 mL/min/1.73 m2 at screening as measured by a serum creatinine point of care device * Oxygen saturation of \<92% on room air obtained at rest within 24 hours prior to randomization * Immunocompromised. * Current use of any prohibited concomitant medication(s) * Females who are pregnant and \<14 weeks gestation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Ribonucleic Acid (RNA) Level in Nasopharyngeal (NP) Swabs: mITT Population | Baseline, Day 5 | Baseline was defined as the latest measurement between Day -1 and Day 1, but post-dose samples that were collected within 1 hour post start of dosing were also treated as baseline. Samples with result \< lower limit of quantification (LLOQ) were imputed as 1.7 log10 copies/milliliter (mL), and samples with result Not Detected were imputed as 0.0 log10 copies/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours Apart Through Day 28: mITT Population | Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first | The event of 2 consecutive negative RAT results obtained at least 24 (-2) hours apart through Day 28 was defined as achieving 2 consecutive non-missing RATs with negative results through Day 28, where the 2 tests were at least 22 hours and at most 7 days apart. For the event of 2 consecutive negative RAT results obtained at least 24 hours apart through Day 28, the date of the first negative RAT result was considered the first event date. Time to 2 consecutive negative RAT results obtained at least 24 hours apart defined as: for participant achieving event, time to event = (first event date) -(first dose date) + 1. For participant not achieving event (censored), censoring date was at last date of RAT measurement, time = (censoring date) - (first dose date) + 1 or Day 27 whichever occurred first (Day 27 was last possible day to achieve 2 consecutive negative RAT results obtained at least 24 hours apart through Day 28). |
| Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28: mITT Population | Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first | Sustained alleviation of all targeted COVID-19 signs/symptoms was defined as the event occurring on the first of 2 consecutive days when all symptoms scored as moderate or severe at study entry are scored as mild or absent and all symptoms scored mild or absent at study entry are scored as absent. The first day of the 2 consecutive-day period was considered the first event date. The time to sustained symptom alleviation was defined as for a participant with sustained symptom alleviation, time to event was calculated as (First Event Date) - (First Dose Date) +1. For a participant that either completed Day 28 of the study or discontinued from the study before Day 28 without sustained symptom alleviation (censored), censoring date was at the last date on which symptom alleviation was assessed, and time was calculated as (Censoring Date) - (First Dose Date) +1 or Day 27 whichever occurred first. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study | Day 1 of dosing up to maximum Week 24 follow-up | An AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect, was a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. TEAEs were defined as AE that started on or after study medication on Day 1 up to Week 24 follow-up. AEs included both SAEs and all non-SAEs. |
Countries
Canada, Greece, Italy, Taiwan, United States
Participant flow
Pre-assignment details
A total of 436 participants were randomized and treated in this study with a repeat 5-day treatment course of nirmatrelvir/ritonavir or placebo/ritonavir for mild-to moderate coronavirus disease 2019 (COVID-19).
Participants by arm
| Arm | Count |
|---|---|
| Nirmatrelvir 300 mg + Ritonavir 100 mg Participants received nirmatrelvir 300 milligrams (mg) (participants with estimated glomerular filtration rate \[eGFR\] greater than or equal to \[\>=\] 30 to less than \[\<\] 60 milliliter per minute \[mL/min\]/1.73 meters squared \[m\^2\] or estimated creatinine clearance \[CrCl\] \>=30 to \<60 mL/min received 150 mg every 12 hours \[q12h\] for 5 days) and ritonavir 100 mg, orally for 5 days q12h from Day 1 to Day 5. | 292 |
| Placebo + Ritonavir 100 mg Participants received placebo matched to nirmatrelvir followed by ritonavir 100 mg orally, for 5 days q12h from Day 1 to Day 5. | 144 |
| Total | 436 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Other | 3 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 3 |
Baseline characteristics
| Characteristic | Nirmatrelvir 300 mg + Ritonavir 100 mg | Placebo + Ritonavir 100 mg | Total |
|---|---|---|---|
| Age, Continuous | 53.5 Years STANDARD_DEVIATION 16.52 | 53.5 Years STANDARD_DEVIATION 16.43 | 53.5 Years STANDARD_DEVIATION 16.47 |
| Age, Customized 12 to less than 18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized 18 to 44 years | 88 Participants | 40 Participants | 128 Participants |
| Age, Customized 45 to 64 years | 121 Participants | 64 Participants | 185 Participants |
| Age, Customized >= 65 years | 82 Participants | 40 Participants | 122 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 159 Participants | 72 Participants | 231 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 131 Participants | 72 Participants | 203 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 2 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 8 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 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 | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 264 Participants | 132 Participants | 396 Participants |
| Sex: Female, Male Female | 167 Participants | 80 Participants | 247 Participants |
| Sex: Female, Male Male | 125 Participants | 64 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 289 | 0 / 144 |
| other Total, other adverse events | 29 / 289 | 2 / 144 |
| serious Total, serious adverse events | 3 / 289 | 1 / 144 |
Outcome results
Primary
Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Ribonucleic Acid (RNA) Level in Nasopharyngeal (NP) Swabs: mITT Population
Baseline was defined as the latest measurement between Day -1 and Day 1, but post-dose samples that were collected within 1 hour post start of dosing were also treated as baseline. Samples with result \< lower limit of quantification (LLOQ) were imputed as 1.7 log10 copies/milliliter (mL), and samples with result Not Detected were imputed as 0.0 log10 copies/mL.
Time frame: Baseline, Day 5
Population: Modified intent-to-treat (mITT) analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention and who had a positive viral RNA NP swab test result (\>= 2.0 log10 copies per mL) at baseline. Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nirmatrelvir 300 mg + Ritonavir 100 mg | Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Ribonucleic Acid (RNA) Level in Nasopharyngeal (NP) Swabs: mITT Population | -3.871 Log10 copies/mL | Standard Error 0.129 |
| Placebo + Ritonavir 100 mg | Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Ribonucleic Acid (RNA) Level in Nasopharyngeal (NP) Swabs: mITT Population | -3.166 Log10 copies/mL | Standard Error 0.171 |
Comparison: Mixed model for repeated measures (MMRM) included fixed effects of treatment, geographic region, baseline SARS-CoV-2 RNA level, visit, and treatment-by-visit interaction; an unstructured (co) variance structure was used.p-value: =0.000495% CI: [-1.093, -0.316]MMRM
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study
An AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect, was a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. TEAEs were defined as AE that started on or after study medication on Day 1 up to Week 24 follow-up. AEs included both SAEs and all non-SAEs.
Time frame: Day 1 of dosing up to maximum Week 24 follow-up
Population: Safety population included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nirmatrelvir 300 mg + Ritonavir 100 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study | AEs | 148 Participants |
| Nirmatrelvir 300 mg + Ritonavir 100 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study | SAEs | 3 Participants |
| Nirmatrelvir 300 mg + Ritonavir 100 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study | AEs leading to discontinuation from study | 0 Participants |
| Placebo + Ritonavir 100 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study | AEs | 55 Participants |
| Placebo + Ritonavir 100 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study | SAEs | 1 Participants |
| Placebo + Ritonavir 100 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study | AEs leading to discontinuation from study | 0 Participants |
Secondary
Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28: mITT Population
Sustained alleviation of all targeted COVID-19 signs/symptoms was defined as the event occurring on the first of 2 consecutive days when all symptoms scored as moderate or severe at study entry are scored as mild or absent and all symptoms scored mild or absent at study entry are scored as absent. The first day of the 2 consecutive-day period was considered the first event date. The time to sustained symptom alleviation was defined as for a participant with sustained symptom alleviation, time to event was calculated as (First Event Date) - (First Dose Date) +1. For a participant that either completed Day 28 of the study or discontinued from the study before Day 28 without sustained symptom alleviation (censored), censoring date was at the last date on which symptom alleviation was assessed, and time was calculated as (Censoring Date) - (First Dose Date) +1 or Day 27 whichever occurred first.
Time frame: Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first
Population: mITT analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention and who had a positive viral RNA NP swab test result (\>= 2.0 log10 copies per mL) at baseline. Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Nirmatrelvir 300 mg + Ritonavir 100 mg | Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28: mITT Population | 8.000 Days | 95% Confidence Interval 7 |
| Placebo + Ritonavir 100 mg | Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28: mITT Population | 9.000 Days | 95% Confidence Interval 8 |
Comparison: Analysis was based on Cox proportional hazard (PH) model which included treatment, geographic region, baseline SARS-CoV-2 RNA level (\< 4 log10 copies/mL or \>= 4 log10 copies/mL) and time since the last vaccination (\<=6 months, \> 6 months or unvaccinated) as appropriate.p-value: =0.520295% CI: [0.848, 1.385]COX proportional hazard ratio
Secondary
Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours Apart Through Day 28: mITT Population
The event of 2 consecutive negative RAT results obtained at least 24 (-2) hours apart through Day 28 was defined as achieving 2 consecutive non-missing RATs with negative results through Day 28, where the 2 tests were at least 22 hours and at most 7 days apart. For the event of 2 consecutive negative RAT results obtained at least 24 hours apart through Day 28, the date of the first negative RAT result was considered the first event date. Time to 2 consecutive negative RAT results obtained at least 24 hours apart defined as: for participant achieving event, time to event = (first event date) -(first dose date) + 1. For participant not achieving event (censored), censoring date was at last date of RAT measurement, time = (censoring date) - (first dose date) + 1 or Day 27 whichever occurred first (Day 27 was last possible day to achieve 2 consecutive negative RAT results obtained at least 24 hours apart through Day 28).
Time frame: Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first
Population: mITT analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention and who had a positive viral RNA NP swab test result (\>= 2.0 log10 copies per mL) at baseline. Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nirmatrelvir 300 mg + Ritonavir 100 mg | Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours Apart Through Day 28: mITT Population | 4.000 Days |
| Placebo + Ritonavir 100 mg | Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours Apart Through Day 28: mITT Population | 5.000 Days |
Comparison: Analysis was based on Cox proportional hazard (PH) model which included treatment, geographic region, baseline SARS-CoV-2 RNA level (\< 4 log10 copies/mL or \>= 4 log10 copies/mL) and time since the last vaccination (less than or equal to \[\<=6\] months, \> 6 months or unvaccinated) as appropriate.p-value: =0.069795% CI: [0.983, 1.551]COX proportional hazard ratio