COVID-19
Conditions
Keywords
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), kidney disease, kidney failure, renal disease, renal failure, dialysis, renal dialysis, hemodialysis, coronavirus disease 2019 (COVID-19), COVID, Paxlovid, antiviral, nirmatrelvir, mild to moderate COVID-19, high risk
Brief summary
The purpose of this study is to learn about the side effects (safety) of the study medicine PF-07321332 (nirmatrelvir)/ritonavir for the treatment of mild to moderate COVID-19 infection in adults with severe renal impairment. The study will also look at the amounts of study drug in your blood. There will be 24 participants in this study; 12 of them will have severe renal impairment and not be on hemodialysis and 12 of them will be on hemodialysis. All participants in this study will take PF-07321332 (nirmatrelvir)/ritonavir by mouth for 5 days. During this time, they will have to collect blood samples to measure the study drug levels in their blood. After taking the study drug for 5 days, the participants will have follow-up visits for about another 28 days for a total of about 34 days in the study. The study team will check how each participant is doing during regular visits at the study clinic.
Interventions
DRUGPF-07321332 (nirmatrelvir)/ritonavir
Patients with Covid-19 infection and severe renal impairment. Capsule and tablet once a day by mouth.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Covid-19 infection * Severe kidney disease (on hemodialysis or not on hemodialysis)
Exclusion criteria
* Hospitalized * Take medications that are not allowed * Renal transplant patients * HIV infection This is not a complete list. Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Concentration (Ctrough) of Nirmatrelvir | 24 Hours after each dose on Treatment Day 1 to Day 5 | Ctrough was measured at 24 hours post-dose (pre the next dose). It was analyzed using nonlinear mixed effect models. |
| Area Under the Curve Over a Dosing Interval (AUC0-tau) of Nirmatrelvir | 24 Hours after each dose on Treatment Day 1 to Day 5 | AUC0-tau was measured at 24 hours post-dose. |
| Terminal Half-Life (T1/2) of Nirmatrelvir | Treatment Day 1 to Day 5 | T1/2 was observed directly from data. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs (SAEs) | From start of treatment on Day 1 to Day 34 | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose, meets one or more of the following criteria: 1. results in death. 2. is life-threatening. 3. Requires inpatient hospitalization or prolongation of existing hospitalization. 4. Results in persistent or significant disability/incapacity. 5. Is a congenital anomaly/birth defect. 6. Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. 7. other important medical events. Any events occurring following start of treatment were considered treatment emergent. |
| Number of Participants With Permanent Discontinuation From Study or Study Intervention Due to Adverse Events and Serious Adverse Events | From start of treatment on Day 1 to Day 34 | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose, meets one or more of the following criteria: 1. results in death. 2. is life-threatening. 3. Requires inpatient hospitalization or prolongation of existing hospitalization. 4. Results in persistent or significant disability/incapacity. 5. Is a congenital anomaly/birth defect. 6. Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. 7. other important medical events. Any events occurring following start of treatment were considered treatment emergent. |
| Maximum Plasma Concentration (Cmax) of PF-07321332 (Nirmatrelvir) | Treatment Day 1 to Day 5, see description for details | Nirmatrelvir plasma concentration data were analyzed using nonlinear mixed effects models. Time frame was: For Cohort 1: Day 1 (anytime between 1-3 hours post-dose), Day 2 (anytime between 4-8 hours post-dose), Day 3 (anytime between 9-15 hours post-dose), Day 4 (pre-dose, anytime between 1-4 hours post-dose), Day 5 (pre-dose, anytime between 0.5-6 hours post-dose, anytime between 9-15 hours post-dose). For Cohort 2: Day 1 (anytime between 1-3 hours post-dose), Day 3 (pre-HD), Day 4 (pre-HD, pre-dose, anytime between 0.5-3 hours post-dose, anytime between 4-8 hours post-dose, anytime between 9-15 hours post-dose). |
| Apparent Volume of Distribution (Vz/F) of Nirmatrelvir | Treatment Day 1 to Day 5 | Vz/F was estimated at steady state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fraction of Drug Removed During Dialysis (Fd) of Nirmatrelvir | Pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose on Day 3 and Day 4 | Fd of nirmatrelvir was calculated for Cohort 2 using non-compartmental analysis of arterial and venous port plasma concentration-time data. Only participants in Cohort 2 were on hemodialysis. |
| Hemodialysis Clearance (CLd) of Nirmatrelvir | Pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose on Day 3 and Day 4 | CLd of nirmatrelvir was calculated for Cohort 2 using non-compartmental analysis of arterial and venous port plasma concentration-time data. Only participants in Cohort 2 were on hemodialysis. |
Countries
United States
Participant flow
Recruitment details
The study was terminated early following completion of Cohort 2. The decision to terminate was not due to safety, but was based on an assessment that available pharmacokinetic (PK) and safety data are sufficient to inform dosing recommendations for participants with severe renal impairment (SRI).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (No HD) Participants in Cohort 1 had SRI (defined as estimated glomerular filtration \[eGFR\] rate \< 30 milliliter per minute per 1.73 square meter \[mL/min/1.73m\^2\]) not on hemodialysis (HD) and mild to moderate COVID-19 disease with confirmed SARS-CoV-2 infection and initial onset of signs/symptoms attributable to COVID-19 within 5 days prior to the day of treatment assignment. All eligible participants were assigned to receive a single dose of PF-07321332 (nirmatrelvir)/ritonavir 300 mg/100 mg orally on Day 1 followed by PF-07321332 (nirmatrelvir)/ritonavir 150 mg/100 mg once daily (QD) from Day 2 to Day 5. | 3 |
| Cohort 2 (Intermittent HD) Participants in Cohort 2 had SRI on HD and mild-to-moderate COVID-19 disease with confirmed SARS-CoV-2 infection and initial onset of signs/symptoms attributable to COVID-19 within 5 days prior to the day of treatment assignment. All eligible participants were assigned to receive a single dose of PF-07321332 (nirmatrelvir)/ritonavir 300 mg/100 mg orally on Day 1 followed by PF-07321332 (nirmatrelvir)/ritonavir 150 mg/100 mg QD from Day 2 to Day 5. | 12 |
| Total | 15 |
Baseline characteristics
| Characteristic | Cohort 2 (Intermittent HD) | Total | Cohort 1 (No HD) |
|---|---|---|---|
| Age, Continuous | 52.8 Years STANDARD_DEVIATION 13.24 | 54.7 Years STANDARD_DEVIATION 16.53 | 62.0 Years STANDARD_DEVIATION 29.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 9 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 11 Participants | 3 Participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 12 |
| other Total, other adverse events | 1 / 3 | 2 / 12 |
| serious Total, serious adverse events | 0 / 3 | 1 / 12 |
Outcome results
Primary
Apparent Volume of Distribution (Vz/F) of Nirmatrelvir
Vz/F was estimated at steady state.
Time frame: Treatment Day 1 to Day 5
Population: All participants assigned to study intervention and treated who had at least 1 PK parameter measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (No HD) | Apparent Volume of Distribution (Vz/F) of Nirmatrelvir | NA Liter (L) | — |
| Cohort 2 (Intermittent HD) | Apparent Volume of Distribution (Vz/F) of Nirmatrelvir | 99.8 Liter (L) | Geometric Coefficient of Variation 49 |
Primary
Area Under the Curve Over a Dosing Interval (AUC0-tau) of Nirmatrelvir
AUC0-tau was measured at 24 hours post-dose.
Time frame: 24 Hours after each dose on Treatment Day 1 to Day 5
Population: All participants assigned to investigational product and treated who had at least 1 PK parameter measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (No HD) | Area Under the Curve Over a Dosing Interval (AUC0-tau) of Nirmatrelvir | NA nanogram*hour per milliliter (ng*hr/mL) | — |
| Cohort 2 (Intermittent HD) | Area Under the Curve Over a Dosing Interval (AUC0-tau) of Nirmatrelvir | 65740 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 59 |
Primary
Maximum Plasma Concentration (Cmax) of PF-07321332 (Nirmatrelvir)
Nirmatrelvir plasma concentration data were analyzed using nonlinear mixed effects models. Time frame was: For Cohort 1: Day 1 (anytime between 1-3 hours post-dose), Day 2 (anytime between 4-8 hours post-dose), Day 3 (anytime between 9-15 hours post-dose), Day 4 (pre-dose, anytime between 1-4 hours post-dose), Day 5 (pre-dose, anytime between 0.5-6 hours post-dose, anytime between 9-15 hours post-dose). For Cohort 2: Day 1 (anytime between 1-3 hours post-dose), Day 3 (pre-HD), Day 4 (pre-HD, pre-dose, anytime between 0.5-3 hours post-dose, anytime between 4-8 hours post-dose, anytime between 9-15 hours post-dose).
Time frame: Treatment Day 1 to Day 5, see description for details
Population: All participants assigned to study intervention and treated who had at least 1 PK parameter measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (No HD) | Maximum Plasma Concentration (Cmax) of PF-07321332 (Nirmatrelvir) | NA nanogram per milliliter (ng/mL) | — |
| Cohort 2 (Intermittent HD) | Maximum Plasma Concentration (Cmax) of PF-07321332 (Nirmatrelvir) | 3280 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 48 |
Primary
Number of Participants With Permanent Discontinuation From Study or Study Intervention Due to Adverse Events and Serious Adverse Events
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose, meets one or more of the following criteria: 1. results in death. 2. is life-threatening. 3. Requires inpatient hospitalization or prolongation of existing hospitalization. 4. Results in persistent or significant disability/incapacity. 5. Is a congenital anomaly/birth defect. 6. Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. 7. other important medical events. Any events occurring following start of treatment were considered treatment emergent.
Time frame: From start of treatment on Day 1 to Day 34
Population: The analysis population was the SAS which was all participants assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (No HD) | Number of Participants With Permanent Discontinuation From Study or Study Intervention Due to Adverse Events and Serious Adverse Events | Permanent Discontinuation From Study | 0 Participants |
| Cohort 1 (No HD) | Number of Participants With Permanent Discontinuation From Study or Study Intervention Due to Adverse Events and Serious Adverse Events | Permanent Discontinuation From Study Intervention | 0 Participants |
| Cohort 2 (Intermittent HD) | Number of Participants With Permanent Discontinuation From Study or Study Intervention Due to Adverse Events and Serious Adverse Events | Permanent Discontinuation From Study | 0 Participants |
| Cohort 2 (Intermittent HD) | Number of Participants With Permanent Discontinuation From Study or Study Intervention Due to Adverse Events and Serious Adverse Events | Permanent Discontinuation From Study Intervention | 1 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs (SAEs)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose, meets one or more of the following criteria: 1. results in death. 2. is life-threatening. 3. Requires inpatient hospitalization or prolongation of existing hospitalization. 4. Results in persistent or significant disability/incapacity. 5. Is a congenital anomaly/birth defect. 6. Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. 7. other important medical events. Any events occurring following start of treatment were considered treatment emergent.
Time frame: From start of treatment on Day 1 to Day 34
Population: The analysis population was the SAS which was all participants assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (No HD) | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Participants with treatment emergent AEs | 1 Participants |
| Cohort 1 (No HD) | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Participants with treatment emergent SAEs | 0 Participants |
| Cohort 2 (Intermittent HD) | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Participants with treatment emergent AEs | 2 Participants |
| Cohort 2 (Intermittent HD) | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Participants with treatment emergent SAEs | 1 Participants |
Primary
Terminal Half-Life (T1/2) of Nirmatrelvir
T1/2 was observed directly from data.
Time frame: Treatment Day 1 to Day 5
Population: All participants assigned to study intervention and treated who had at least 1 of PK parameter measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (No HD) | Terminal Half-Life (T1/2) of Nirmatrelvir | NA Hour (hr) | — |
| Cohort 2 (Intermittent HD) | Terminal Half-Life (T1/2) of Nirmatrelvir | 78.93 Hour (hr) | Standard Deviation 49.761 |
Primary
Trough Concentration (Ctrough) of Nirmatrelvir
Ctrough was measured at 24 hours post-dose (pre the next dose). It was analyzed using nonlinear mixed effect models.
Time frame: 24 Hours after each dose on Treatment Day 1 to Day 5
Population: All participants assigned to study intervention and treated who had at least 1 PK parameter measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (No HD) | Trough Concentration (Ctrough) of Nirmatrelvir | NA ng/mL | — |
| Cohort 2 (Intermittent HD) | Trough Concentration (Ctrough) of Nirmatrelvir | 2188 ng/mL | Geometric Coefficient of Variation 81 |
Secondary
Fraction of Drug Removed During Dialysis (Fd) of Nirmatrelvir
Fd of nirmatrelvir was calculated for Cohort 2 using non-compartmental analysis of arterial and venous port plasma concentration-time data. Only participants in Cohort 2 were on hemodialysis.
Time frame: Pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose on Day 3 and Day 4
Population: All participants assigned to study intervention and treated who had at least 1 of the PK parameters of interest measured. Here, overall number of participants analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (No HD) | Fraction of Drug Removed During Dialysis (Fd) of Nirmatrelvir | 6.937 Percentage of drug removed | Geometric Coefficient of Variation 138 |
Secondary
Hemodialysis Clearance (CLd) of Nirmatrelvir
CLd of nirmatrelvir was calculated for Cohort 2 using non-compartmental analysis of arterial and venous port plasma concentration-time data. Only participants in Cohort 2 were on hemodialysis.
Time frame: Pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose on Day 3 and Day 4
Population: All participants assigned to study intervention and treated who had at least 1 of the PK parameters of interest measured. Here, overall number of participants analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (No HD) | Hemodialysis Clearance (CLd) of Nirmatrelvir | 30.53 milliliter per minute (mL/min) | Geometric Coefficient of Variation 35 |