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    Clinical Trial Results:
    An Interventional Efficacy And Safety, Phase 2/3, Double-Blind, 2-Arm Study To Investigate Orally Administered PF-07321332/Ritonavir Compared With Placebo In Nonhospitalised Symptomatic Adult Subjects With Covid-19 Who Are At Low Risk Of Progressing To Severe Illness

    Summary
    EudraCT number
    		 2021-002857-28
    Trial protocol
    		 ES   HU   BG   CZ   SK  
    Global end of trial date
    25 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2023
    First version publication date
    11 Aug 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C4671002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05011513
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    An Interventional Efficacy And Safety, Phase 2/3, Double-Blind, 2-Arm Study To Investigate Orally Administered Pf-07321332/Ritonavir Compared With Placebo In Nonhospitalised Symptomatic Adult Subjects With Covid-19 Who Are At Low Risk Of Progressing To Severe Illness
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Aug 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 47
    Country: Number of subjects enrolled
    Brazil: 32
    Country: Number of subjects enrolled
    Bulgaria: 260
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 5
    Country: Number of subjects enrolled
    Malaysia: 19
    Country: Number of subjects enrolled
    Mexico: 113
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Puerto Rico: 6
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Slovakia: 25
    Country: Number of subjects enrolled
    South Africa: 24
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Thailand: 94
    Country: Number of subjects enrolled
    Turkey: 75
    Country: Number of subjects enrolled
    Ukraine: 88
    Country: Number of subjects enrolled
    United States: 413
    Worldwide total number of subjects
    1288
    EEA total number of subjects
    346
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1223
    From 65 to 84 years
    65
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects who had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as determined by reverse transcription polymerase chain reaction (RT-PCR) within 5 days prior to randomization were included in the study.

    Pre-assignment
    Screening details
    		 A total of 1440 subjects signed informed consent form and were randomised. Out of which, 1288 subjects received study drug.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg
    Arm description
    		 Subjects were randomised to receive nirmatrelvir 300 mg and ritonavir 100 mg orally every 12 hours from Day 1 to 5
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ritonavir 100 mg every 12 hours

    Investigational medicinal product name
    Nirmatrelvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nirmatrelvir 300 mg every 12 hours

    Arm title
    		 Placebo
    Arm description
    		 Subjects were randomised to receive placebo matched to nirmatrelvir/ritonavir every 12 hours for 10 doses from Day 1 through Day 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo every 12 hours

    Number of subjects in period 1
    		Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Started
    654
    634
    Completed
    519
    507
    Not completed
    135
    127
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    17
    18
         Study terminated by sponsor
    108
    105
         Unspecified
    1
    -
         Lost to follow-up
    9
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg
    Reporting group description
    		 Subjects were randomised to receive nirmatrelvir 300 mg and ritonavir 100 mg orally every 12 hours from Day 1 to 5

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to receive placebo matched to nirmatrelvir/ritonavir every 12 hours for 10 doses from Day 1 through Day 5.

    Reporting group values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo Total
    Number of subjects
    		 654 634 1288
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 618 605 1223
        From 65-84 years
    		 36 29 65
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 41.76 ( 13.47 ) 42.63 ( 13.13 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 344 352 696
        Male
    		 310 282 592
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 39 32 71
        Asian
    		 69 72 141
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 28 23 51
        White
    		 512 498 1010
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 6 9 15
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 272 261 533
        Not Hispanic or Latino
    		 378 367 745
        Unknown or Not Reported
    		 4 6 10

    End points

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    End points reporting groups
    Reporting group title
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg
    Reporting group description
    		 Subjects were randomised to receive nirmatrelvir 300 mg and ritonavir 100 mg orally every 12 hours from Day 1 to 5

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to receive placebo matched to nirmatrelvir/ritonavir every 12 hours for 10 doses from Day 1 through Day 5.

    Primary: Time to Sustained Alleviation of Overall COVID-19 Signs and Symptoms Through Day 28

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    End point title
    		 Time to Sustained Alleviation of Overall COVID-19 Signs and Symptoms Through Day 28
    End point description
    Sustained alleviation of targeted COVID-19 signs/symptoms was defined as the event occurring on the first 4 consecutive days when all symptoms scored as moderate or severe at the time of enrollment were scored as mild or absent and those scored mild or absent at the time of enrollment were scored as absent. Missing severity at baseline was considered as mild. Time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28, was calculated as time (days) from start of study intervention or placebo (Day 1) until sustained alleviation of all targeted COVID-19 associated signs and symptoms. In this end point, time to sustained alleviation is reported consolidated for overall COVID-19 signs and symptoms. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Days
        median (confidence interval 95%)
    12.000 (11.000 to 13.000)
    13.000 (12.000 to 14.000)
    Statistical analysis title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg, Placebo
    Comparison groups
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg v Placebo
    Number of subjects included in analysis
    1288
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6027
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious AEs and AEs Leading to Study and Study Drug Discontinuation

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious AEs and AEs Leading to Study and Study Drug Discontinuation
    End point description
    AE=any untoward medical occurrence in a subject or clinical study subject temporally associated with use of study intervention, whether or not considered related to study intervention.SAE=any untoward medical occurrence at any dose that resulted in any of following outcomes: death; life-threatening; required inpatient hospitalisation or prolongation of existing hospitalisation; persistent or significant disability/incapacity; congenital anomaly/birth defect; or that was considered as an important medical event. TEAEs=events started on or after study medication start date and time. AEs included serious and non-serious adverse events. AEs that led to study discontinuation and AEs that led to discontinuation of study intervention and then continued study were also reported. Safety analysis set=subjects who received at least 1 dose of study intervention; analyzed according to intervention they actually received. A randomised but not treated subjects was excluded from safety analyses.
    End point type
    Secondary
    End point timeframe
    From start of study intervention (Day 1) up to Day 34
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Subjects
        TEAEs
    169
    153
        SAEs
    8
    13
        AEs led to discontinuation of study
    0
    1
        AEs led to discontinue study drug;continued study
    16
    5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With COVID-19 Related Hospitalization or Death From any Cause Through Day 28

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    End point title
    		 Percentage of Subjects With COVID-19 Related Hospitalization or Death From any Cause Through Day 28
    End point description
    Percentage of subjects with COVID-19 related hospitalisation or death from any cause during the first 28 days of the study was estimated using the Kaplan-Meier (KM) method. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Percentage of subjects
    number (not applicable)
        COVID-19 hospitalization
    0.765
    1.577
        Death
    0
    0.158
    Statistical analysis title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg, Placebo
    Comparison groups
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg v Placebo
    Number of subjects included in analysis
    1288
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1796 [1]
    Method
    		 Normal approximation
    Confidence interval
    Notes
    [1] - P-value reported for COVID-19 hospitalization and death due to any cause.

    Secondary: Percentage of Subjects With Death Through Week 24

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    End point title
    		 Percentage of Subjects With Death Through Week 24
    End point description
    Percentage of subjects with death (all-cause) event were reported in this end point. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Week 24
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Percentage of subjects
        number (not applicable)
    0
    0.2
    No statistical analyses for this end point

    Secondary: Number of COVID-19 Related Medical Visits per Day Through Day 28

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    End point title
    		 Number of COVID-19 Related Medical Visits per Day Through Day 28
    End point description
    Number of COVID-19 related medical visits per day were reported in this endpoint. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Medical visits per day
        least squares mean (confidence interval 95%)
    0.0010 (0.0005 to 0.0019)
    0.0020 (0.0010 to 0.0038)
    Statistical analysis title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg, Placebo
    Comparison groups
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg v Placebo
    Number of subjects included in analysis
    1288
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0971
    Method
    		 Negative binomial
    Confidence interval

    Secondary: Duration of Hospitalisation and Intensive Care Unit (ICU) Stay Through Day 28

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    End point title
    		 Duration of Hospitalisation and Intensive Care Unit (ICU) Stay Through Day 28
    End point description
    mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Days
    arithmetic mean (standard deviation)
        Hospitalization
    0.049 ( 0.591 )
    0.181 ( 1.787 )
        ICU
    0.000 ( 0.000 )
    0.065 ( 1.004 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Severe Signs and Symptoms of COVID-19 Through Day 28

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    End point title
    		 Percentage of Subjects With Severe Signs and Symptoms of COVID-19 Through Day 28
    End point description
    Subjects recorded a daily severity rating of their symptom severity over past 24 hours based on a 4-point scale in which 0 was reported if no symptoms were present; 1 if mild; 2 if moderate; and 3 if severe. A subject with severe score for any targeted symptoms post-baseline was counted as severe. Vomiting and diarrhea each was rated on a 4-point frequency scale where 0 was reported for no occurrence, 1 for 1 to 2 times, 2 for 3 to 4 times, and 3 for 5 or greater. Sense of smell and sense of taste each be rated on a 3-point Likert scale where 0 was reported if the sense of smell/taste was the same as usual, 1 if the sense of smell/taste was less than usual, and 2 for no sense of smell/taste. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised. Here, ‘Number of Subjects Analysed’ signifies subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    648
    633
    Units: Percentage of subjects
        number (not applicable)
    19.136
    21.643
    Statistical analysis title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg, Placebo
    Statistical analysis description
    Main effects of treatment, geographic region, baseline SARS-CoV-2 serology status and baseline viral load (< 4 log10 copies/mL, >= 4 log10 copies/mL).
    Comparison groups
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg v Placebo
    Number of subjects included in analysis
    1281
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1622
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.819
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.618
         upper limit
    		 1.084

    Secondary: Time to Sustained Resolution of Each COVID-19 Signs and Symptoms Through Day 28

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    End point title
    		 Time to Sustained Resolution of Each COVID-19 Signs and Symptoms Through Day 28
    End point description
    Sustained resolution was defined as when targeted symptoms are scored as absent for 4 consecutive days. The first day of the 4 consecutive-day period was considered the first event date. In this endpoint time to sustained alleviation is reported for each COVID-19 signs and symptoms. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised. Here ''Number of Subjects Analysed''=subjects evaluable for this end point and ''number analysed''= subjects evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Days
    median (confidence interval 95%)
        Muscle or body aches (n=466,449)
    8.000 (7.000 to 9.000)
    9.000 (7.000 to 10.000)
        Short of breath or difficult breathing(n=222,205)
    7.000 (5.000 to 7.000)
    8.000 (7.000 to 11.000)
        Chills or shivering(n=318,319)
    4.000 (3.000 to 5.000)
    5.000 (4.000 to 6.000)
        Cough(n=512,502)
    11.000 (10.000 to 12.000)
    12.000 (11.000 to 13.000)
        Diarrhea(n=143,117)
    6.000 (6.000 to 8.000)
    5.000 (4.000 to 6.000)
        Feeling hot or feverish(n=356,350)
    4.000 (3.000 to 5.000)
    5.000 (5.000 to 6.000)
        Headache(n=429,424)
    7.000 (7.000 to 9.000)
    9.000 (8.000 to 10.000)
        Nausea(n=180,165)
    6.000 (4.000 to 7.000)
    5.000 (4.000 to 7.000)
        Stuffy or runny nose(n=491,484)
    9.000 (7.000 to 10.000)
    10.000 (9.000 to 11.000)
        Sore throat(n=371,381)
    6.000 (6.000 to 7.000)
    8.000 (7.000 to 8.000)
        Vomit(n=52,43)
    3.000 (2.000 to 4.000)
    3.000 (2.000 to 7.000)
    No statistical analyses for this end point

    Secondary: Time to Sustained Resolution of Overall COVID-19 Signs and Symptoms Through Day 28

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    End point title
    		 Time to Sustained Resolution of Overall COVID-19 Signs and Symptoms Through Day 28
    End point description
    Sustained resolution was defined as when targeted symptoms are scored as absent for 4 consecutive days. The first day of the 4 consecutive-day period was considered the first event date. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised. Here, ''Number of Subjects Analysed'' signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    428
    425
    Units: Days
        median (confidence interval 95%)
    15.000 (14.000 to 16.000)
    16.000 (15.000 to 17.000)
    Statistical analysis title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg, Placebo
    Comparison groups
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg v Placebo
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4298
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to Sustained Alleviation of Each COVID-19 Signs and Symptoms Through Day 28

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    End point title
    		 Time to Sustained Alleviation of Each COVID-19 Signs and Symptoms Through Day 28
    End point description
    Sustained alleviation of targeted COVID-19 signs/symptoms = event occurring on first 4 consecutive days when all symptoms scored as moderate or severe at time of enrollment were scored as mild or absent and those scored mild or absent at time of enrollment were scored absent. Missing severity at baseline was treated as mild.Time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28, was calculated as time (days) from start of study intervention or placebo(Day 1)until sustained alleviation of all targeted COVID-19 associated signs and symptoms. In this endpoint time to sustained resolution is reported consolidated for each COVID-19 signs and symptoms. mITT1 population analysed. 99999=due to variability of data, number of subjects with events available was not sufficient for calculation of limits using Kaplan-Meier method. Subjects analysed according to study intervention they were randomised.''Number of Subjects Analysed''=subjects evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    654
    634
    Units: Days
    median (confidence interval 95%)
        Muscle or body aches(n=466, 449)
    5.000 (4.000 to 6.000)
    5.000 (4.000 to 6.000)
        Short of breath or difficulty breathing(n=222,205)
    5.000 (4.000 to 6.000)
    6.000 (5.000 to 7.000)
        Chills or shivering(n=318,319)
    3.000 (3.000 to 4.000)
    3.000 (3.000 to 4.000)
        Cough(n=512,502)
    7.000 (6.000 to 8.000)
    8.000 (7.000 to 9.000)
        Diarrhea(n=143,117)
    6.000 (5.000 to 9.000)
    4.000 (3.000 to 6.000)
        Feeling hot or feverish(n=356,350)
    3.000 (-99999 to 99999)
    4.000 (3.000 to 4.000)
        Headache(n=429,424)
    5.000 (4.000 to 5.000)
    5.000 (5.000 to 6.000)
        Nausea(n=180,165)
    4.000 (3.000 to 5.000)
    4.000 (3.000 to 5.000)
        Stuffy or runny nose(n=491,484)
    5.000 (4.000 to 6.000)
    7.000 (6.000 to 7.000)
        Sore throat(n=371,381)
    4.000 (4.000 to 5.000)
    5.000 (4.000 to 6.000)
        Vomit(n=52,43)
    3.000 (2.000 to 4.000)
    3.000 (2.000 to 7.000)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Progression to Worsening Status of COVID-19 Signs and Symptoms

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    End point title
    		 Percentage of Subjects With Progression to Worsening Status of COVID-19 Signs and Symptoms
    End point description
    Subjects recorded a daily severity rating of their symptom severity over the past 24 hours based on a 4-point scale in which 0 was reported if no symptoms were present; 1 if mild; 2 if moderate; and 3 if severe. Vomiting and diarrhea was rated on a 4-point frequency scale where 0 is reported for no occurrence, 1 (mild) for 1 to 2 times, 2 (moderate) for 3 to 4 times, and 3 (severe) for 5 or greater. Progression to a worsening status for any targeted symptom was based up on increasing severity (i.e. the first time any targeted symptoms worsened after treatment relative to baseline). mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 28
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    648
    633
    Units: Percentage of subjects
        number (not applicable)
    75.463
    78.515
    Statistical analysis title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg, Placebo
    Statistical analysis description
    Main effects of treatment, geographic region, symptom onset duration (<=3, >3), baseline SARS-CoV-2 serology status (positive/negative), vaccination status (complete/not vaccinated) and baseline viral load (<4 log10 copies/mL, >=4 log10 copies/mL).
    Comparison groups
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg v Placebo
    Number of subjects included in analysis
    1281
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1086
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.802
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.613
         upper limit
    		 1.05

    Secondary: Plasma Concentration Versus Time Summary of PF-07321332

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    End point title
    		 Plasma Concentration Versus Time Summary of PF-07321332 [2]
    End point description
    Safety analysis set included all subjects who received at least 1 dose of study intervention. Subjects were analyzed according to the intervention they actually received. A randomised but not treated subjects was excluded from the safety analyses. Here ' Number of Subjects Analysed'=subjects evaluable for this end point and 'number analysed'= subjects evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Day 1: 1 hour post dose; Day 5: 0 minutes pre-dose
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg
    Number of subjects analysed
    287
    Units: Nanograms per milliliter
    arithmetic mean (standard deviation)
        Day 1 (1 hour post-dose) (n=104)
    2437 ( 1791.3 )
        Day 5 (0 minutes pre-dose) (n=287)
    3468 ( 2454.7 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Resting Peripheral Oxygen Saturation Greater Than or Equal to (>=) 95% at Day 1 and Day 5

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    End point title
    		 Percentage of Subjects With Resting Peripheral Oxygen Saturation Greater Than or Equal to (>=) 95% at Day 1 and Day 5
    End point description
    Percentage of subjects with a resting peripheral oxygen saturation >=95% were reported in this endpoint.mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 5
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    638
    604
    Units: Percentage of subjects
    number (not applicable)
        Day 1(n=16,28)
    62.500
    67.857
        Day 5(n=638,604)
    94.671
    93.212
    Statistical analysis title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg, Placebo
    Comparison groups
    Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg v Placebo
    Number of subjects included in analysis
    1242
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3262
    Method
    		 Breslow-Day Test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    50.333
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.163
         upper limit
    		 192.472

    Secondary: Change From Baseline in Logarithm to Base10 (Log10) Transformed Viral Load at Days 3, 5, 10 and 14

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    End point title
    		 Change From Baseline in Logarithm to Base10 (Log10) Transformed Viral Load at Days 3, 5, 10 and 14
    End point description
    Nasal samples were collected to estimate the viral load in subjects in terms of logarithm to base 10 (log10) copies per milliliter. mITT1 population included all subjects randomly assigned to study intervention, who received at least 1 dose of study intervention. Subjects were analysed according to the study intervention they were randomised. Here, ''Number of Subjects Analysed'' signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 3, 5, 10 and 14
    End point values
    		 Nirmatrelvir 300 milligram (mg) + Ritonavir 100 mg Placebo
    Number of subjects analysed
    515
    493
    Units: Log 10 copies per milliliter
    least squares mean (standard error)
        Day 3 (n=515, 493)
    -2.302 ( 0.096 )
    -1.565 ( 0.098 )
        Day 5 (n=505, 480)
    -3.669 ( 0.090 )
    -2.835 ( 0.093 )
        Day 10 (n=489, 478)
    -4.873 ( 0.081 )
    -4.642 ( 0.082 )
        Day 14 (n=508, 484)
    -5.464 ( 0.072 )
    -5.249 ( 0.075 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and Non-SAEs: From Day 1 to Week 24; All-cause mortality: till Week 24
    Adverse event reporting additional description
    Same event may appear as both SAE and non-SAE but are distinct events. An event may be categorised as serious in 1 subject and non-serious in another, or a subject may have experienced both SAE and non-SAE. Safety population comprised of all subjects who received at least 1 dose of study intervention during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to receive placebo matched to nirmatrelvir/ritonavir every 12 hours for 10 doses from Day 1 through Day 5.

    Reporting group title
    Nirmatrelvir 300 mg + Ritonavir 100 mg
    Reporting group description
    		 Subjects were randomised to receive nirmatrelvir 300 mg and ritonavir 100 mg orally every 12 hours from Day 1 to 5.

    Serious adverse events
    		 Placebo Nirmatrelvir 300 mg + Ritonavir 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 634 (2.05%)
    8 / 654 (1.22%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 634 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 634 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer metastatic
         subjects affected / exposed
    0 / 634 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 634 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    0 / 634 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    0 / 634 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    8 / 634 (1.26%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 634 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 634 (0.32%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 634 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 634 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    0 / 634 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Placebo Nirmatrelvir 300 mg + Ritonavir 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 634 (11.20%)
    120 / 654 (18.35%)
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    12 / 634 (1.89%)
    7 / 654 (1.07%)
         occurrences all number
    12
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 634 (0.63%)
    9 / 654 (1.38%)
         occurrences all number
    4
    11
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    7 / 634 (1.10%)
    4 / 654 (0.61%)
         occurrences all number
    7
    4
    Fibrin D dimer increased
         subjects affected / exposed
    9 / 634 (1.42%)
    8 / 654 (1.22%)
         occurrences all number
    10
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 634 (1.26%)
    14 / 654 (2.14%)
         occurrences all number
    10
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 634 (1.42%)
    6 / 654 (0.92%)
         occurrences all number
    9
    6
    Dysgeusia
         subjects affected / exposed
    3 / 634 (0.47%)
    44 / 654 (6.73%)
         occurrences all number
    3
    44
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 634 (3.00%)
    26 / 654 (3.98%)
         occurrences all number
    20
    30
    Dyspepsia
         subjects affected / exposed
    2 / 634 (0.32%)
    8 / 654 (1.22%)
         occurrences all number
    2
    8
    Nausea
         subjects affected / exposed
    17 / 634 (2.68%)
    21 / 654 (3.21%)
         occurrences all number
    18
    24
    Vomiting
         subjects affected / exposed
    11 / 634 (1.74%)
    11 / 654 (1.68%)
         occurrences all number
    14
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jul 2021
    Amendment 1: Changed endpoint to include, instead of exclude hospitalisation: Number of COVID-19 related medical visits including hospitalisation through Day 28. Confirmed SARS-CoV-2 infection requirement updated from 72 hours to 5 days.
    19 Jul 2021
    Amendment 2: Vaccination criteria was updated from partially to fully vaccinated and the risk factor of =60 years of age was added.
    03 Aug 2021
    Amendment 3: Vaccination criteria was updated to clarify that subjects without underlying medical conditions associated with an increased risk of developing severe illness from COVID-19 are not eligible if they have been vaccinated. It is only fully vaccinated subjects with underlying medical conditions that are eligible. Primary estimand changed to specify inclusion of participants who were randomised <=3 days after symptom onset.
    23 Nov 2021
    Amendment 4: Secondary endpoints and estimands updated to reflect new hypothesis testing hierarchy. Language was added to provide additional information about the study unblinding plan.
    21 Jan 2022
    Amendment 5: The secondary endpoint of incidence of COVID-19-associated hospitalisations or death from any cause will be analyzed to provide a point estimate and 95% CI to measure associated variability. Other clinically relevant secondary endpoints (COVID-19 related medical visits) will also be analysed. Extend study enrollment to assess potential benefit to subjects at low risk of progression to severe COVID-19 in the clinically relevant endpoint of hospitalisation or death.
    09 Jun 2022
    Amendment 6: Added hypertension as a potential risk and removed hemodynamic and inflammatory effects, and TSH and T4 (free) elevations as potential risks.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In subject disposition, there was discontinuations due to AE, which was captured under "Death" as reason for discontinuation. Adverse event was COVID-19 pneumonia and the subject died due to that event and discontinued study.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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