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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-003590-62 | EudraCT Number |
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The purpose of this study is to estimate the effect PF-07321332/Ritonavir and Ritonavir on Midazolam (a cytochrome P450 [CYP]3A4 substrate) in Healthy Adult Participants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment A | Active Comparator | Midazolam orally |
|
| Treatment B | Experimental | PF-07321332/ritonavir orally + Midazolam orally |
|
| Treatment C | Active Comparator | Ritonavir orally + Midazolam orally |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midazolam | Drug | Midazolam administered as a single dose on Day 1 |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | Cmax for midazolam following single dose administration with and without PF-07321332/ritonavir was observed directly from data. Natural log-transformed Cmax for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinity Time (AUCinf) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | AUCinf for midazolam following single dose administration with and without PF-07321332/ritonavir was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. Natural log-transformed AUCinf for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (Clast) (AUClast) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | AUClast for midazolam following single dose administration with and without PF-07321332/ritonavir was calculated by Linear/Log trapezoidal method. Natural log-transformed AUClast for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event was considered a TEAE if the event started during the effective duration of treatment. All events that start on or after the first dosing day and time/ start time, if collected, but before the last dose plus the lag time (28 days) were flagged as TEAEs. The algorithm did consider any events that started prior to the first dose date. Any events occurring following start of treatment or increasing in severity were counted as treatment emergent. Events that occur in a non-treatment period (for example, Washout or Follow-up) were counted as treatment emergent and attributed to the previous treatment taken. |
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Inclusion Criteria:
Female participants of childbearing potential must have a negative (urine or serum) pregnancy test.
Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
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Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pfizer CT.gov Call Center | Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brussels Clinical Research Unit | Brussels | Bruxelles-capitale, Région de | B-1070 | Belgium |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37354048 | Derived | Cox DS, Rehman M, Khan T, Ginman K, Salageanu J, LaBadie RR, Wan K, Damle B. Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants. Br J Clin Pharmacol. 2023 Nov;89(11):3352-3363. doi: 10.1111/bcp.15835. Epub 2023 Jul 12. | |
| 37231296 | Derived | Sagawa K, Lin J, Jaini R, Di L. Physiologically-Based Pharmacokinetic Modeling of PAXLOVID with First-Order Absorption Kinetics. Pharm Res. 2023 Aug;40(8):1927-1938. doi: 10.1007/s11095-023-03538-5. Epub 2023 May 25. |
| Label | URL |
|---|---|
| To obtain contact information for a study center near you, click here. | View source |
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Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.
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A total of 12 healthy participants were randomized to receive midazolam, PF-07321332/ritonavir + midazolam, and ritonavir + midazolam in a total of 6 sequences.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment Sequence 1 | Period 1: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3). Period 2: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 3: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). |
| FG001 | Treatment Sequence 2 | Period 1: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 2: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3). Period 3: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). |
| FG002 | Treatment Sequence 3 | Period 1: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 2: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 3: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3). |
| FG003 | Treatment Sequence 4 | Period 1: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 2: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 3: Treatment A: Midazolam Single dose of 2 mg midazolam administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3). |
| FG004 | Treatment Sequence 5 | Period 1: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 2: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3). Period 3: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). |
| FG005 | Treatment Sequence 6 | Period 1: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3). Period 2: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). Period 3: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | All participants enrolled in this study |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Plasma Concentration (Cmax) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | Cmax for midazolam following single dose administration with and without PF-07321332/ritonavir was observed directly from data. Natural log-transformed Cmax for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
|
Baseline up to Day 28
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Midazolam 2 mg | Midazolam administered as a single dose on Day 1 | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nodal rhythm | Cardiac disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pfizer ClinicalTrials.gov Call Center | Pfizer Inc. | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 23, 2021 | Nov 30, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 30, 2021 | Nov 30, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D045169 | Severe Acute Respiratory Syndrome |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| C000718217 | nirmatrelvir |
| D019438 | Ritonavir |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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This is a Phase I, crossover, 3-treatment, 6-sequence study to evaluate the effect of PF-07321332/ritonavir and ritonavir on the PK of midazolam in healthy participants. Midazolam is a substrate for CYP3A4. A total of approximately 12 healthy male and/or female participants will be enrolled into the study.
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| PF-07321332/ritonavir + Midazolam |
| Drug |
PF-07321332/ritonavir: Administered orally every 12 hours for a total of 9 doses on Days 1-5 Midazolam: Administered orally as a single dose on Day 5 |
|
| Ritonavir + Midazolam | Drug | Ritonavir: Administered orally every 12 hours for a total of 9 doses on Day1-5. Midazolam: Administered orally as a single dose on Day 5 |
|
| Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| Baseline up to Day 28 |
| Number of Participants With Laboratory Abnormalities | The haematological, clinical chemistry (serum) and urinalysis safety tests were assessed against the criteria specified in the sponsor reporting standards to determine if there were any clinically significant laboratory abnormalities. The assessment took into account whether each participant's baseline test result was within or outside the laboratory reference range for the particular laboratory parameter. Baseline was defined as the last planned predose measurement taken in each study period. | Baseline up to Day 28 |
| Number of Participants With Vital Signs Abnormalities | Baseline was the last predose recording in each study period. Only post baseline values are included in this analysis | Baseline up to Day 28 |
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline and changes from baseline in PR, QT, QRS, heart rate and QTcF were summarized by treatment and time postdose. Baseline was defined as the average of the triplicate predose recordings in each study period. ECG endpoints and changes from baseline (QTcF, PR, QRS), over all measurements taken postdose, were also summarized descriptively by treatment using categories as defined in the Criteria for Safety Values of Potential Clinical Concern appendix of the protocol and for QTc values corresponding to ICH E14 thresholds, which are: QTcF (msec): 450<value≤480; 480<value≤500; >500; QTcF (msec) increase from baseline: 30<change≤60; change>60 | Baseline up to Day 28 |
| Cmax of Midazolam When Administered Alone and With Ritonavir | Cmax for midazolam following single dose administration with and without ritonavir was observed directly form data. Natural log-transformed Cmax for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| AUCinf of Midazolam When Administered Alone and With Ritonavir | AUCinf for midazolam following single dose administration with and without ritonavir was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. Natural log-transformed AUCinf for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| AUClast of Midazolam When Administered Alone and With Ritonavir | AUClast for midazolam following single dose administration with and without ritonavir was calculated by Linear/Log trapezoidal method. Natural log-transformed AUClast for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose |
| Apparent Clearance (CL/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | CL/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/AUCinf. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| Apparent Volume of Distribution (Vz/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | Vz/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/(AUCinf • kel). | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | Tmax for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by observed directly from data as time of first occurrence. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | t½ for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear. | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
| Years |
|
| Age, Customized | Number | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
|
| Midazolam 2 mg |
Midazolam administered as a single dose on Day 1 |
| OG001 | PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | PF-07321332/ritonavir: Administered orally every 12 hours for a total of 9 doses on Days 1-5 Midazolam: Administered orally as a single dose on Day 5 |
|
|
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| Primary | Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinity Time (AUCinf) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | AUCinf for midazolam following single dose administration with and without PF-07321332/ritonavir was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. Natural log-transformed AUCinf for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
|
|
|
|
| Primary | Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (Clast) (AUClast) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | AUClast for midazolam following single dose administration with and without PF-07321332/ritonavir was calculated by Linear/Log trapezoidal method. Natural log-transformed AUClast for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
|
|
|
|
| Secondary | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event was considered a TEAE if the event started during the effective duration of treatment. All events that start on or after the first dosing day and time/ start time, if collected, but before the last dose plus the lag time (28 days) were flagged as TEAEs. The algorithm did consider any events that started prior to the first dose date. Any events occurring following start of treatment or increasing in severity were counted as treatment emergent. Events that occur in a non-treatment period (for example, Washout or Follow-up) were counted as treatment emergent and attributed to the previous treatment taken. | All participants randomly assigned to study intervention and who take at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received. | Posted | Count of Participants | Participants | Baseline up to Day 28 |
|
|
|
| Secondary | Number of Participants With Laboratory Abnormalities | The haematological, clinical chemistry (serum) and urinalysis safety tests were assessed against the criteria specified in the sponsor reporting standards to determine if there were any clinically significant laboratory abnormalities. The assessment took into account whether each participant's baseline test result was within or outside the laboratory reference range for the particular laboratory parameter. Baseline was defined as the last planned predose measurement taken in each study period. | All participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received. | Posted | Count of Participants | Participants | Baseline up to Day 28 |
|
|
|
| Secondary | Number of Participants With Vital Signs Abnormalities | Baseline was the last predose recording in each study period. Only post baseline values are included in this analysis | All participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received. | Posted | Count of Participants | Participants | Baseline up to Day 28 |
|
|
|
| Secondary | Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline and changes from baseline in PR, QT, QRS, heart rate and QTcF were summarized by treatment and time postdose. Baseline was defined as the average of the triplicate predose recordings in each study period. ECG endpoints and changes from baseline (QTcF, PR, QRS), over all measurements taken postdose, were also summarized descriptively by treatment using categories as defined in the Criteria for Safety Values of Potential Clinical Concern appendix of the protocol and for QTc values corresponding to ICH E14 thresholds, which are: QTcF (msec): 450<value≤480; 480<value≤500; >500; QTcF (msec) increase from baseline: 30<change≤60; change>60 | All participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received. | Posted | Count of Participants | Participants | Baseline up to Day 28 |
|
|
|
| Secondary | Cmax of Midazolam When Administered Alone and With Ritonavir | Cmax for midazolam following single dose administration with and without ritonavir was observed directly form data. Natural log-transformed Cmax for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
|
|
|
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| Secondary | AUCinf of Midazolam When Administered Alone and With Ritonavir | AUCinf for midazolam following single dose administration with and without ritonavir was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. Natural log-transformed AUCinf for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
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| Secondary | AUClast of Midazolam When Administered Alone and With Ritonavir | AUClast for midazolam following single dose administration with and without ritonavir was calculated by Linear/Log trapezoidal method. Natural log-transformed AUClast for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose |
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| Secondary | Apparent Clearance (CL/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | CL/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/AUCinf. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | Litre/hour | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
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| Secondary | Apparent Volume of Distribution (Vz/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | Vz/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/(AUCinf • kel). | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | Litre | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
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| Secondary | Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | Tmax for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by observed directly from data as time of first occurrence. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Median | Full Range | Hour | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
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| Secondary | Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | t½ for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear. | The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. | Posted | Mean | Standard Deviation | Hour | Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose |
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| 10 |
| 0 |
| 10 |
| 4 |
| 10 |
| EG001 | PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | PF-07321332/ritonavir: Administered orally every 12 hours for a total of 9 doses on Days 1-5 Midazolam: Administered orally as a single dose on Day 5 | 0 | 11 | 0 | 11 | 9 | 11 |
| EG002 | Ritonavir 100 mg + Midazolam 2 mg | Ritonavir: Administered orally every 12 hours for a total of 9 doses on Days 1-5 Midazolam: Administered orally as a single dose on Day 5 | 0 | 11 | 0 | 11 | 7 | 11 |
| Abdominal discomfort | Gastrointestinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Dry mouth | Gastrointestinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Haematochezia | Gastrointestinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Chest discomfort | General disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Vessel puncture site pain | General disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Vessel puncture site reaction | General disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Folliculitis | Infections and infestations | MedDRA version 24.1 | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Nightmare | Psychiatric disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Heavy menstrual bleeding | Reproductive system and breast disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Vaginal haemorrhage | Reproductive system and breast disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Dry throat | Respiratory, thoracic and mediastinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA version 24.1 | Non-systematic Assessment |
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| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA version 24.1 | Non-systematic Assessment |
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Not provided
Not provided
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006571 | Heterocyclic Compounds |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
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| Participants with serious adverse events |
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| Participants with severe adverse events |
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| HEMATOLOGY - Neutrophils/Leukocytes (%) <0.8x LLN |
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| HEMATOLOGY - Eosinophils/Leukocytes (%) >1.2x ULN |
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| HEMATOLOGY - Monocytes/Leukocytes (%) >1.2x ULN |
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| HEMATOLOGY - Prothrombin Time (sec) >1.1x ULN |
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| CLINICAL CHEMISTRY - Thyrotropin (uIU/mL) <0.8x LLN |
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| CLINICAL CHEMISTRY - Fibrinogen (mg/dL) >1.25x Baseline |
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| URINALYSIS - URINE Hemoglobin (Scalar) ≥1 |
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| QRS DURATION, AGGREGATE (MSEC) - Value≥140 |
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| QRS DURATION, AGGREGATE (MSEC) - %Change≥50% |
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| QTCF INTERVAL, AGGREGATE (MSEC) - 450<Value≤480 |
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| QTCF INTERVAL, AGGREGATE (MSEC) - 480<Value≤500 |
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| QTCF INTERVAL, AGGREGATE (MSEC) - Value>500 |
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| QTCF INTERVAL, AGGREGATE (MSEC) - 30<Change≤60 |
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| QTCF INTERVAL, AGGREGATE (MSEC) - Change>60 |
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