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    Clinical Trial Results:
    An Interventional, Efficacy and Safety, Phase 2, Randomized, Double-Blind, 2-arm Study to Investigate a Repeat 5-day Course of Nirmatrelvir/Ritonavir Compared to Placebo/Ritonavir in Participants at Least 12 Years of age with Rebound of COVID-19 Symptoms and Rapid Antigen Test Positivity

    Summary
    EudraCT number
    		 2022-002827-36
    Trial protocol
    		 DE   GR   IT  
    Global end of trial date
    09 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Aug 2024
    First version publication date
    02 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C4671042
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05567952
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    66 Hudson Boulevard Est, New York, United States, NY 10001
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on viral ribonucleic acid (RNA) level in nasopharyngeal (NP) swabs in participants with mild-to-moderate coronavirus disease 2019 (COVID-19).
    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 Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Oct 2022
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    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
    Canada: 2
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 426
    Worldwide total number of subjects
    436
    EEA total number of subjects
    1
    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)
    1
    Adults (18-64 years)
    313
    From 65 to 84 years
    116
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 436 participants were randomized and treated in this study to evaluate the efficacy and safety of a repeat 5-day treatment course of nirmatrelvir/ritonavir or placebo/ritonavir for the treatment of mild-to moderate COVID-19.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg
    Arm description
    		 Participants received nirmatrelvir 300 milligrams (mg) (participants with estimated glomerular filtration rate [eGFR] greater than or equal to [>=] 30 to less than [<] 60 millilitre per minute [mL/min]/1.73 meters squared [m^2] [or estimated creatinine clearance [CrCl] >=30 to <60 mL/min] received 150 mg every 12 hours [q12h] for 5 days at screening) and ritonavir 100 mg, orally for 5 days q12h from Day 1 to Day 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nirmatrelvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Nirmatrelvir 300 mg q12h for 5 days, as oral dose.

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Ritonavir 100 mg q12h for 5 days, as oral dose.

    Arm title
    		 Placebo + Ritonavir 100 mg
    Arm description
    		 Participants received placebo matched to nirmatrelvir followed by ritonavir 100 mg orally, for 5 days q12h from Day 1 to Day 5.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Ritonavir 100 mg q12h for 5 days, as oral dose.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo q12h for 5 days, as oral dose.

    Number of subjects in period 1
    		Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg
    Started
    292
    144
    Completed
    280
    138
    Not completed
    12
    6
         Consent withdrawn by subject
    6
    3
         Unspecified
    3
    1
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nirmatrelvir 300 mg + Ritonavir 100 mg
    Reporting group description
    		 Participants received nirmatrelvir 300 milligrams (mg) (participants with estimated glomerular filtration rate [eGFR] greater than or equal to [>=] 30 to less than [<] 60 millilitre per minute [mL/min]/1.73 meters squared [m^2] [or estimated creatinine clearance [CrCl] >=30 to <60 mL/min] received 150 mg every 12 hours [q12h] for 5 days at screening) and ritonavir 100 mg, orally for 5 days q12h from Day 1 to Day 5.

    Reporting group title
    Placebo + Ritonavir 100 mg
    Reporting group description
    		 Participants received placebo matched to nirmatrelvir followed by ritonavir 100 mg orally, for 5 days q12h from Day 1 to Day 5.

    Reporting group values
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg Total
    Number of subjects
    		 292 144 436
    Age Categorical
    Units: Participants
        Adolescents (12-17 years)
    		 1 0 1
        Adults (18-64 years)
    		 209 104 313
        From 65-84 years
    		 77 39 116
        85 years and over
    		 5 1 6
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.5 ( 16.52 ) 53.5 ( 16.43 ) -
    Gender Categorical
    Units: Participants
        Female
    		 167 80 247
        Male
    		 125 64 189
    Race
    Units: Subjects
        White
    		 264 132 396
        Black or African American
    		 12 8 20
        Asian
    		 13 2 15
        American Indian or Alaska Native
    		 0 1 1
        Multiracial
    		 1 0 1
        Not reported
    		 2 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 159 72 231
        Not Hispanic or Latino
    		 131 72 203
        Not reported
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Nirmatrelvir 300 mg + Ritonavir 100 mg
    Reporting group description
    		 Participants received nirmatrelvir 300 milligrams (mg) (participants with estimated glomerular filtration rate [eGFR] greater than or equal to [>=] 30 to less than [<] 60 millilitre per minute [mL/min]/1.73 meters squared [m^2] [or estimated creatinine clearance [CrCl] >=30 to <60 mL/min] received 150 mg every 12 hours [q12h] for 5 days at screening) and ritonavir 100 mg, orally for 5 days q12h from Day 1 to Day 5.

    Reporting group title
    Placebo + Ritonavir 100 mg
    Reporting group description
    		 Participants received placebo matched to nirmatrelvir followed by ritonavir 100 mg orally, for 5 days q12h from Day 1 to Day 5.

    Primary: Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA Level in NP Swabs - mITT Population

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    End point title
    		 Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA Level in NP Swabs - mITT Population
    End point description
    Baseline was defined as the latest measurement between Day -1 and Day 1, but post-dose samples that are collected within 1 hour post start of dosing were treated as baseline. Samples with result "less than (<) lower limit of quantification (LLOQ)" are imputed as 1.7 log10 copies/milliliter (mL), and samples with result "Not Detected" are imputed as 0.0 log10 copies/mL. Modified intent-to-treat (mITT) analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention and who had a positive viral RNA NP swab test result (>= 2.0 log10 copies per mL) at baseline. Here, 'Number of Subjects Analysed (N)' signifies participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 5
    End point values
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg
    Number of subjects analysed
    218
    113
    Units: Log10 copies/mL
        least squares mean (standard error)
    -3.871 ( 0.129 )
    -3.166 ( 0.171 )
    Statistical analysis title
    		 Nirmatrelvir300+Ritonavir100/Placebo+Ritonavir100
    Statistical analysis description
    Mixed model for repeated measures (MMRM) included fixed effects of treatment, geographic region, baseline SARS-CoV-2 RNA level, visit, and treatment-by-visit interaction; an unstructured (co) variance structure was used.
    Comparison groups
    Nirmatrelvir 300 mg + Ritonavir 100 mg v Placebo + Ritonavir 100 mg
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 MMRM
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -0.705
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.093
         upper limit
    		 -0.316

    Secondary: Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours (hrs) Apart Through Day 28- mITT Population

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    End point title
    		 Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours (hrs) Apart Through Day 28- mITT Population
    End point description
    The event of 2 consecutive negative RAT results obtained at least 24 (-2) hrs apart through Day 28 was defined as achieving 2 consecutive non-missing RATs with negative results through Day 28, where the 2 tests are at least 22 hours and at most 7 days apart. For the event of 2 consecutive negative RAT results obtained at least 24 hrs apart through Day 28, the date of the first negative RAT result was considered the first event date. Time to 2 consecutives negative RAT results obtained at least 24 hrs apart defined as: for participant achieving event, time to event = (first event date) -(first dose date) + 1. For participant not achieving event (censored), censoring date was at last date of RAT measurement, time = (censoring date)-(first dose date) + 1 or Day 27 whichever occurred first (Day 27 was last possible day to achieve 2 consecutive negative RAT results obtained at least 24 hrs apart through Day 28). mITT analysis set evaluated. 'N'= participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of dosing maximum up to Day 28
    End point values
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg
    Number of subjects analysed
    223
    115
    Units: Days
        median (confidence interval 95%)
    4.000 (4.000 to 5.000)
    5.000 (5.000 to 6.000)
    Statistical analysis title
    		 Nirmatrelvir300+Ritonavir100/Placebo+Ritonavir100
    Statistical analysis description
    Analysis was based on Cox proportional hazard (PH) model which included treatment, geographic region, baseline SARS-CoV-2 RNA level (< 4 log10 copies/mL or >= 4 log10 copies/mL) and time since the last vaccination (less than or equal to [<=6] months, > 6 months or unvaccinated) as appropriate.
    Comparison groups
    Nirmatrelvir 300 mg + Ritonavir 100 mg v Placebo + Ritonavir 100 mg
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0697
    Method
    		 COX proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.235
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.983
         upper limit
    		 1.551

    Secondary: Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28- mITT Population

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    End point title
    		 Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28- mITT Population
    End point description
    Sustained alleviation of all targeted COVID-19 signs/symptoms was defined as the event occurring on the first of 2 consecutive days when all symptoms scored as moderate or severe at study entry are scored as mild or absent and all symptoms scored mild or absent at study entry are scored as absent. The first day of the 2 consecutive-day period was considered the first event date. The time to sustained symptom alleviation was defined as for a participant with sustained symptom alleviation, time to event was calculated as (First Event Date) – (First Dose Date) +1. For a participant that either completed Day 28 of the study or discontinued from the study before Day 28 without sustained symptom alleviation (censored), censoring date was at the last date on which symptom alleviation was assessed, and time was calculated as (Censoring Date) – (First Dose Date) +1 or Day 27 whichever occurred first. mITT analysis set evaluated. 'N'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of dosing maximum up to Day 28
    End point values
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg
    Number of subjects analysed
    186
    99
    Units: Days
        median (confidence interval 95%)
    8.000 (7.000 to 10.000)
    9.000 (8.000 to 11.000)
    Statistical analysis title
    		 Nirmatrelvir300+Ritonavir100/Placebo+Ritonavir100
    Statistical analysis description
    Analysis was based on Cox proportional hazard (PH) model which included treatment, geographic region, baseline SARS-CoV-2 RNA level (< 4 log10 copies/mL or >= 4 log10 copies/mL) and time since the last vaccination (<=6 months, > 6 months or unvaccinated) as appropriate.
    Comparison groups
    Nirmatrelvir 300 mg + Ritonavir 100 mg v Placebo + Ritonavir 100 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5202
    Method
    		 COX proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.084
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.848
         upper limit
    		 1.385

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

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study
    End point description
    An AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect, was a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. TEAEs were defined as AE that started on or after study medication on Day 1 up to Week 24 follow-up. AEs included both SAEs and all non-SAEs. Safety population included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Day 1 of dosing maximum up to Week 24 follow-up
    End point values
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg
    Number of subjects analysed
    289
    144
    Units: Participants
        AEs
    148
    55
        SAEs
    3
    1
        AEs leading to discontinuation from study
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 of dosing maximum up to Week 24 follow-up
    Adverse event reporting additional description
    An event may be categorized as serious in 1 participant and non-serious in other, or a participant may experience both serious and non-serious event. Safety population: all participants randomly assigned to study intervention, who took at least 1 dose of study intervention.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v26.1
    Reporting groups
    Reporting group title
    Nirmatrelvir 300 mg + Ritonavir 100 mg
    Reporting group description
    		 Enter Description here

    Reporting group title
    Placebo + Ritonavir 100 mg
    Reporting group description
    		 Enter Description here

    Serious adverse events
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 289 (1.04%)
    1 / 144 (0.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised anxiety disorder
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypovolaemia
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 144 (0.69%)
         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: 5%
    Non-serious adverse events
    		 Nirmatrelvir 300 mg + Ritonavir 100 mg Placebo + Ritonavir 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 289 (10.03%)
    2 / 144 (1.39%)
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    29 / 289 (10.03%)
    2 / 144 (1.39%)
         occurrences all number
    29
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Sep 2022
    The population in the estimands and the primary analysis population was updated with the requirement of a positive rapid antigen test at baseline to align with the inclusion/exclusion criteria. Endpoint of: ‘Proportion of participants with SARS-CoV-2 RNA in NP swabs below the LLOQ (defined as <2.0 log10 copies/mL) on both Days 5 and 10’. Removed as a secondary endpoint and added as a tertiary/exploratory endpoint. New secondary endpoint/estimand of: ‘Time to 2 consecutive negative rapid antigen test results.’ Added. The corresponding analysis for secondary endpoints were updated /added with more details. Updated sample size assumptions and the corresponding calculation to reflect the change in the primary analysis population. Amended to add self-administered daily rapid antigen tests for all study days between scheduled visits until 2 consecutive negative rapid antigen test results are obtained at which point, rapid antigen testing will be performed only at remaining scheduled visits. Text describing Tables 4 and 5 was revised to clarify DDI table content. Tables were updated with information from the Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid (August 2022).
    12 May 2023
    Primary and secondary estimands and the mITT analysis set description have been updated to include that participants must have a positive viral RNA NP swab test result at baseline. Sample size calculation updated.
    29 Jun 2023
    Additional secondary analyses for primary and secondary efficacy endpoints using the new analysis set (mITT1). Update the multiplicity adjustment accordingly.

    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.
    None reported
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    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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