A Retrospective Observational Non-Interventional Study (NIS) to Assess Patient Characteristics and Healthcare Resource Use (HCRU) Among COVID-19 Patients Receiving Treatment With Nirmatrelvir; Ritonavir (PAXLOVID TM) in the Kingdom of Saudi Arabia (KSA).
Conditions: Covid-19
Sponsor: Pfizer

Nir m atrel vir; rit o na vir ( P A X L O VI D ™) 
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N O N- I N T E R V E N TI O N A L S T U D Y ( NI S) P R O T O C O L
St u d y Inf or m ati o n
Title
A Retr os pecti ve O bser vati o nal N o n -I nter ve nti o nal
St u d y ( NI S) t o assess Patie nt C haracteristics a n d 
Healt hcare Res o urce Use ( H C R U) a m o n g C O VI D - 1 9 
Patie nts Recei vi n g Treat me nt wit h Nir matrel vi r;
Rit o na vir ( P A X L O VI D T M ) i n t he K i n g d om of S a u di 
A ra bia ( K S A).
Pr ot oc ol n u m ber
C 4 6 7 1 0 5 4
Pr ot oc ol versi o n i de ntifier
1. 0
D ate
1 7 Marc h
2 0 2 3
Acti ve s u bst a nce
P F - 0 7 3 2 1 3 3 2; n o a nat o mical t hera pe utic c he mical 
( A T C) c o de ye t
Me dici n al pr o d uct
Nir matrel vi r; rit o na vir ( P A X L O VI D ™)
Rese arc h o bjecti ves
Pri mar y  o bjecti ve:
1. T o descri be t he baseli ne de m o gra p hic a n d cli nical
c haracteristics, i ncl u di n g pre- e xisti n g 
c o m or bi dities, of a d ult C or o na Vir us Disease 2 0 1 9 
ca use d b y S A R S -C o V - 2 ( C O VI D-1 9) patie nts w h o 
ha ve b een prescri be d nir matrel vir, rit o na vir 
treat me nt.
Sec o n dar y  o bjecti ve:
1.
T o assess a d ult C O VI D -1 9 patie nts’ H C R U wit hi n
t he 3 0-d a y  peri o d f oll o wi n g nir matrel vir, rit o na vir 
prescri pti o n, i ncl u di n g:

O verall H C R U i n i n patie nt a n d o ut patie nt
setti n gs.
A ut h or
Pfizer E mer gi n g Mar ket Africa a n d Mi d dle Eas t
6 6 H u ds o n Y ar d, Ne w Y or k, N Y, 1 0 0 0 1
 
P P D
P P D

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This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................7
4. ABSTRACT...........................................................................................................................8
5. AMENDMENTS AND UPDATES.......................................................................................9
6. MILESTONES.....................................................................................................................10
7. RATIONALE AND BACKGROUND................................................................................10
8. RESEARCH QUESTION AND OBJECTIVES .................................................................13
9. RESEARCH METHODS ....................................................................................................14
9.1. Study Design ...........................................................................................................14
9.2. Setting......................................................................................................................15
9.2.1. Inclusion Criteria ........................................................................................16
9.2.2. Exclusion Criteria.......................................................................................16
9.3. Variables..................................................................................................................16
9.4. Data Sources............................................................................................................18
9.5. Patient Medical Records..........................................................................................19
9.6. Study Size................................................................................................................19
9.7. Data Management ...................................................................................................19
9.7.1. Electronic Case Report Forms (eCRFs) .....................................................20
9.8. Statistical Analysis ..................................................................................................20
9.8.1. Primary Objective:......................................................................................21
9.8.2. Secondary Objective:..................................................................................21
9.9. Quality Control........................................................................................................22
9.10. Strengths and Limitations of the Research Methods.............................................23
9.11. Other Aspects ........................................................................................................24
10. PROTECTION OF HUMAN SUBJECTS ........................................................................24
10.1. Patient Information................................................................................................24
10.2. Patient Consent......................................................................................................25
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............25

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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................25
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........27
13. REFERENCES ..................................................................................................................28
14. LIST OF TABLES.............................................................................................................33
15. LIST OF FIGURES ...........................................................................................................33
ANNEX 1. ADDITIONAL INFORMATION.........................................................................34

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
AEM
Adverse Event Monitoring
BMI
Body Mass Index
CDC
Center for disease Control and prevention
COVID-19
Corona Virus Disease 2019 caused by SARS-
CoV-2
eCRF
electronic Case Report Form
ECMO
extracorporeal mechanical oxygenation
EDC
Electronic Data Capture
EPIC-HR
Evaluation of Protease Inhibition for COVID-
19 in High-Risk Patients
ER
Emergency Room
EU
European Union
EUA
Emergency Use Authorization
FDA
Food and Drug Administration
GPP
Good Pharmacoepidemiology Practice
HCRU
Healthcare Resource Use
HFNC
High-flow nasal cannula
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IMV
Invasive Mechanical Ventilation
IRB
Institutional Review Board

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Abbreviation
Definition
ISMF
Investigator Site Master File
KSA
Kingdom of Saudi Arabia
LOS
Length of Stay
MENA
Middle East and North Africa
NIH
National Institutes of Health
NIMV
Non-invasive Mechanical Ventilation
NIS
Non-interventional Study
NIV
Non Invasive Ventilation
PCR
Polymerase Chain Reaction
RWE
Real World Evidence
SAP
Statistical Analysis Plan
SAS
Statistical Analyses System
SARS-CoV-2
Severe Acute Respiratory Syndrome 
Coronavirus 2
SOP
Standard Operating Procedure
STROBE
Strengthening the Reporting of Observational 
Studies in Epidemiology 
USA
United States of America
PHEIC
Public Health Emergency of International
Concern
PhD
Doctor of Philosopy
WHO
World Health Organization 

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3. R E S P O N SI B L E P A R TI E S
Pri nci p al I n vesti g at or (s) of t he Pr ot oc ol
N a m e, d e gree(s)
J o b title
Affili ati o n
A d dress
Ki n g Faisal S pecialist 
H os pital a n d Researc h 
Ce ntre, Je d d ah Sa u di 
Ara bia
Ki n g Faisal S pecialist 
H os pital a n d Researc h 
Ce ntre
P. O B O X 4 0 0 4 7 Je d da h 
2 1 4 9 9 M B C J 46 Je d da h-
Sa u di Ara bia
De part me nt of Me dici ne 
( M B C 4 6)
Ki n g Faisal S pecialist 
H os pital a n d Researc h 
Ce n tre - Ri ya d h
De part me nt of Me dici ne 
( M B C 4 6)
Ki n g Faisal S pecialist 
H os pital a n d Researc h 
Ce ntre
P. O. B o x 3 3 5 4, Ri ya d h 
1 1 2 1 1
K S A
Ki n g A b d ulaziz Me dical 
Cit y - Nati o nal G uar d 
Healt h Affairs -
Ri ya d h Di visi o n of 
I nfecti o us Diseases –
De par tme nt of Me dici ne
Ki n g A b d ulaziz Me dical 
Cit y - Nati o nal G uar d 
Healt h Affairs -
Ri ya d h Di visi o n of 
I nfecti o us Diseases –
De part me nt of Me dici ne
P. O. B o x 2 2 4 9 0 Ri ya d h 
1 1 4 2 6 i nter nal c o de 
1 1 4 3, Sa u di Ara bia
Pf izer E mer gi n g Mar kets
6 6 H u ds o n Yar d, Ne w  
Y or k, N Y, 1 0 0 0 1
Real -W orl d E vi de nce 
Lea d, Me dical Affairs
Pfizer E mer gi n g Mar ket 
Africa a n d Mi d dle Eas t
6 6 H u ds o n Yar d, Ne w  
Y or k, N Y, 1 0 0 0 1
Pfizer M E R A
Pfizer, Je d da h Sa u di 
Ara bia
E M E pi de mi ol o g y a n d 
Scie ntific Affairs
Pfi zer, U S A
Vacci ne a n d A nti viral
E vi de nce Ge nerati o n
Pfizer, U S A
 
P P D

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4. ABSTRACT
Not Applicable.

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5. AMENDMENTS AND UPDATES
None.

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6. MILESTONES
Milestone
Planned date
Start of data collection 
01 July 2023
Interim report 1*
01 October 2023
End of data collection
01 February 2024
Final Study Report
01 November 2024
*If the target sample size is achieved from Cohort 1 (and Cohort 2 is not initiated), then the interim analysis will 
not be required.
DISCLAIMER AND USE
This protocol template is to be used as a guide for countries to develop a real-world evidence 
(RWE) study evaluating the real-world usage of nirmatrelvir, ritonavir. The research 
objectives in this protocol are contingent on the availability of data elements and data capture 
methods per country. It should be noted that this document should only be used as a guide 
and may be adapted as necessary to accommodate for missing data. Protocols should undergo 
necessary local, global reviews and approvals.
7. RATIONALE AND BACKGROUND
Background
Coronaviruses are a group of viruses of zoonotic origin, of which seven species have been 
identified thus far as infectious to humans.1 In December, 2019, clusters of patients with 
idiopathic pneumonia were identified in Wuhan, China, with clinical presentation including 
fever, cough, dyspnea, and chest discomfort.2 A novel coronavirus sequence was isolated 
from the cluster of patients, termed severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2), with the associated respiratory disease termed COVID-19.1 By January 
30th, 2020, the World Health Organization (WHO) declared COVID-19 a Public Health 
Emergency of International Concern (PHEIC) due to rapid community transmission via 
respiratory droplets, leading to an exponential surge in the number of cases and severity, 
especially in a context where knowledge on this novel virus’ epidemiology and potentiality
was scarce.3 COVID-19 was declared as a pandemic on 11 March 2020,4 and as of February
2023, more than 679 million cases and 6.8 million deaths have been confirmed globally in 
228 countries and territories.5
COVID-19 clinical presentation and severity is vastly heterogenous, whereby patients may 
experience asymptomatic infection, mild illness, moderate illness, severe illness, or critical 
illness requiring hospitalization. Common symptoms include cough, fever, dyspnea, fatigue, 
sore throat, anosmia, and nausea.6 Critical illness is characterized by severe respiratory

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failure, systemic inflammatory response, septic shock, and multi-system dysfunction and 
failure, including the cardiovascular system, central nervous system, gastrointestinal system, 
renal system, and skin.7,8 Recent data related to COVID-19 symptom severity have revealed 
that approximately 80% of cases are mild-to-moderate, 15% are severe, and 5% are critical.9
Whilst the majority of cases are indeed asymptomatic or mild,10 COVID-19 patients who are 
hospitalized due to infection are at great risk of prolonged disease, complications, increased
hospital length of stay (LOS), high morbidity and mortality.11-15
Based on the most recent treatment guidelines put forth by the National Institutes of Health 
(NIH), management of non-hospitalized adults with acute COVID-19 infection includes 
supportive care (eg, adequate hydration, rest, monitoring body temperature, and taking 
antipyretics and analgesics to reduce symptom severity), advice on reducing viral 
transmission, and advice on when to seek healthcare provision or in-person evaluation.16
Adults that do not require hospitalization or supplemental oxygen yet are at high-risk of 
disease progression to severe/critical illness (eg, patients with malignancies, neurological 
diseases, hypertension, diabetes mellitus, obesity, and immunocompromised conditions),
may additionally receive antiviral therapy to reduce risk of progression, hospitalization, or 
death.16 Current COVID-19 antiviral therapeutic options, in order of preference, include 
ritonavir-boosted nirmatrelvir (PaxlovidTM) or remdesivir. Molnupiravir may additionally be 
considered as an alternative therapeutic option only when the aforementioned are 
unavailable, infeasible, or clinically inappropriate to use.17
The Saudi MoH Protocol for Patients Suspected of/Confirmed with COVID-19 Supportive 
care and antiviral treatment of suspected or confirmed COVID-19 infection (Version 3.7) 
September 29th, 2022 follows the same guidance described above.18
Nirmatrelvir, ritonavir is an antiviral therapy consisting of two active substances that reduce 
the ability of SARS-CoV-2 to multiply in the body, and thus prevent disease progression.19
The first active substance, nirmatrelvir (PF-07321332), works by blocking viral enzyme 
activity and subsequent multiplication.19 The second active substance, ritonavir, delays 
breakdown of nirmatrelvir; thus, maintains sufficient levels of nirmatrelvir in the body to
allow it to continue its effect on reducing viral multiplication.19 Nirmatrelvir, ritonavir should 
be initiated after confirmed COVID-19 diagnosis and within 5 days of symptom onset; 
administered as 300 mg of nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 
100 mg tablet) together, every 12 hours, for 5 days.20 Based on the guidelines put forth by the 
Center for Disease Control and Prevention (CDC), COVID-19 patients who are at high-risk 
of disease progression to severe COVID-19 include patients aged >50 years, those who are
unvaccinated or incompletely vaccinated, in addition to specific underlying medical 
conditions including asthma, cancer, chronic lung diseases, chronic liver diseases, Diabetes 
mellitus, and Down’s syndrome.21
Nirmatrelvir, ritonavir EUA was based on data from an interim analysis of a Phase II-III 
randomized, double-blind, placebo-controlled clinical trial in non-hospitalized adult patients 
with a confirmed COVID-19 diagnosis, who were symptomatic, and had at least 1 risk factor 
for progression to severe disease.22,23 Interim analysis results from this trial, titled 

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“Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR)” 
(NCT04960202), revealed 89% reduced risk of COVID-19-related hospitalization and 
28-day mortality among the Paxlovid group compared to the placebo group.23,24 A 
meta-analysis on the efficacy and safety of nirmatrelvir, ritonavir for COVID-19 treatment 
has additionally shown an overall 78% reduction in COVID-19-related mortality and 
hospitalization.24 Whilst the trial was conducted prior to the emergence of the SARS-CoV-2 
omicron variants, recent studies in real-world settings have shown that nirmatrelvir, ritonavir 
is also effective against these variants.25-27 Other COVID-19 antiviral therapies with reported 
risk reduction of hospitalization or death include remdesivir (87% reduced risk),28
sotrovimab (85% reduced risk),29 and molnupiravir (50% reduced risk).30 Sotrovimab is no 
longer authorized to treat COVID-19 in any United States of America (USA) region due to 
increases in the proportion of COVID-19 cases caused by the Omicron BA.2 sub-variant.31
Bebtelovimab has also been authorized for emergency use, and available data from the 
BLAZE-4 clinical trial have revealed reduced viral load and improvement in symptoms, 
however, no clinical efficacy data of patients at risk of progressing to severe COVID-19 is 
available yet.32 Since November 2022 bebtelovimab is not currently authorized for 
emergency use in the USA because it is not expected to neutralize Omicron subvariants BQ.1 
and BQ.1.1.33
Real-world studies assessing nirmatrelvir, ritonavir effectiveness and health impact are 
limited, and there are no studies yet that assess patients’ treatment patterns. A real-world
study conducted in Israel among high-risk patients showed nirmatrelvir, ritonavir to be 
highly effective, and was significantly associated with reducing the rate of progression to 
severe COVID-19 and COVID-19-specific mortality.26 Another study conducted in Hong 
Kong to assess the effectiveness of molnupiravir and nirmatrelvir, ritonavir during the 
Omicron BA.2 variant of COVID-19 among patients initially not requiring oxygen therapy 
revealed shorter time to achieve lower viral load, lower risk of disease progression, reduced 
hospital LOS, and lower risk of all-cause mortality.34 In Shanghai, China, results from a 
study assessing nirmatrelvir, ritonavir among immunocompromised inpatients further 
revealed treatment effectiveness in terms of faster viral load clearance, and shorter time to 
viral elimination, with patients having better prognosis when treatment was initiated ≤5 days 
following COVID-19 diagnosis.35
Several countries have incorporated nirmatrelvir, ritonavir within their national COVID-19 
treatment protocols after regulatory body approval for emergency use, including the USA,8
several countries in Europe including the United Kingdom,36 and European Union (EU) 
countries including Italy, Germany, and Belgium,19,37 and the Middle East and North Africa 
(MENA) region, including the KSA and Bahrain.18,38 Moreover, it is expected that additional 
countries will adopt the use of nirmatrelvir, ritonavir within their protocol as it becomes more 
readily available, particularly considering near-future decentralization and generic production 
of nirmatrelvir, ritonavir across a larger number of countries, including low- and middle-
income countries.39

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Rationale
The COVID-19 pandemic has exacerbated healthcare systems globally, with dire 
repercussions on patients, healthcare infrastructure, resources, and finances.40 Although 
COVID-19 patient characteristics and disease course in healthcare settings have been 
described in the literature since the beginning of the pandemic in various regions including 
the USA,41,42 EU,43-45 and the MENA region;46-48 there is limited data related to COVID-19 
patient characteristics, treatment patterns, and HCRU identified in an outpatient setting, 
particularly in the MENA region. One study reported that among other factors such as age, 
male gender, and underlying medical conditions; being of Arab ethnicity was associated with 
increased risk of severe COVID-19 and related mortality.26
In KSA, nirmatrelvir, ritonavir has been approved and conditionally registered by the Saudi
Food and Drug Authority (SFDA) for patients aged ≥12 years, weighing ≥40 kg with 
mild-to-moderate COVID-19 symptoms and at high-risk for progression to severe 
COVID-19 infection.18 The availability of antiviral therapies such as nirmatrelvir, ritonavir in 
an outpatient setting has the ability to reduce disease progression, hospitalization, and 
COVID-19-related mortality, when eligible patients are treated.39 With the current EU 
authorization and subsequent use of nirmatrelvir, ritonavir, there is a need to generate -RWE
during this early EUA utilization phase to inform decision-making on national levels.
As such, this study aims to describe the baseline demographic, clinical characteristics, and 
HCRU of adult COVID-19 patients who have been prescribed nirmatrelvir, ritonavir 
treatment in KSA.
8. RESEARCH QUESTION AND OBJECTIVES
The aim of this study is to describe the baseline demographic, clinical characteristics, and 
HCRU of adult (≥18 years) COVID-19 patients who have been prescribed nirmatrelvir, 
ritonavir treatment.
Primary objective:
1. To describe the baseline demographic and clinical characteristics, including pre-
existing comorbidities, of adult COVID-19 patients who have been prescribed 
nirmatrelvir, ritonavir treatment.
Secondary objective:
1. To assess adult COVID-19 patients’ HCRU within the 30-day period following 
nirmatrelvir, ritonavir prescription, including:

Overall HCRU in inpatient and outpatient settings.

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9. RESEARCH METHODS
9.1. Study Design
This is a multi-center, retrospective observational study that will be conducted in KSA. The 
aim of this study is to capture data on the baseline demographic, clinical characteristics, and 
HCRU of adult COVID-19 patients who have been prescribed nirmatrelvir, ritonavir 
treatment.
An overview of the study design is depicted in Figure 1. The sample size for this study 
depends on the number of COVID-19 patients visiting the selected sites, in addition to 
nirmatrelvir, ritonavir prescription practices by the treating physician in line with local 
prescription guidelines in KSA. However, based on feasibility assessments, the minimum 
target sample size for the study is approximately 500 evaluable patients across 3 sites in 
KSA. The study will aim to meet this target sample size with a single cohort of patients 
identified retrospectively prior to the date of site initiation (Cohort 1); however, if the target 
sample size is not met, then a second cohort of patients will be initiated after the site 
initiation date (Cohort 2).
Cohort 1:
The study will involve collection of pre-defined, data retrospectively from medical records
(electronic and/or paper if necessary) of patients who meet the study eligibility criteria (see
Section 9.2.1) and who have been prescribed nirmatrelvir, ritonavir treatment within a 
15-month lookback period from the date of site initiation (Cohort 1). The lookback period 
will span from 01 April 2022 to 30 June 2023. Data abstracted from patients’ medical records 
will include patient demographics and clinical characteristics at index date (defined as the
date of nirmatrelvir, ritonavir treatment prescribing), in addition to patients’ HCRU during 
the 30-day period post-index date.
Cohort 2:
If the minimum target sample size of 500 patients is not achieved from Cohort 1, then a 
second cohort of patients (Cohort 2) will be initiated and will be included in the study until 
the target sample size is met. Cohort 2 patients are those who meet the eligibility criteria (see 
Section 9.2.1), and who have been prescribed nirmatrelvir, ritonavir treatment after the date 
of site initiation. As for patients in Cohort 1, the following data will be collected for patients 
in Cohort 2: demographics and clinical characteristics at index date, and HCRU during the 
30-day period post-index date.
Patients in Cohort 1 will be enrolled in the study either in a sequential manner or selected via 
computer-generated random allocation in case the number of eligible patients is significantly 
larger than the sample size. For Cohort 2, patients will be enrolled in the study in a sequential 
manner. An electronic Case Report Form (eCRF) will be available for the selected sites to fill 
in for each patient included in Cohort 1 or Cohort 2. Patient data will be extracted from the 
medical records and entered into the eCRFs by trained site study personnel. Participation in 
this study is not intended to change the routine treatment patients receive, as determined by 

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their prescribing physicians; all treatment decisions, type and timing of the disease 
monitoring are per routine clinical care, and at the discretion of the treating physician and 
patient.
Figure 1.
Study Design
9.2. Setting
Data will be collected for all eligible adult COVID-19 patients who have been prescribed
nirmatrelvir, ritonavir across 3 selected sites in KSA. These 3 healthcare centers are the 
largest COVID-19 care providers in KSA representing the majority of COVID-19 patients 
who have been prescribed nirmatrelvir, ritonavir at the national level. In addition, these three
healthcare centers have the same guidelines for treatment and management of patients with 
COVID-19.
The selected sites with well-established clinical research infrastructures, are situated in the 
major cities of KSA, where COVID-19 patients are most prevalent. They provide medical 
attention to any COVID-19 patient and provide healthcare to complicated patients, including 
immunocompromised patients.
These facilities also maintain patient records and have access to electronic medical records 
for patient data retrieval.
The minimum target sample size is 500 patients. Patient eligibility will be assessed at patient 
index date. Patients in Cohort 1 will be identified during a 15-month lookback period prior to 
the date of site initiation, and patients in Cohort 2 will be identified following the date of site 
initiation if the minimum target sample size for the study is not achieved from Cohort 1. For 
both Cohorts, patient data will be collected at index date and during the 30-day post-index 
period. Available data from patient medical records that meet the study aims will be
abstracted and entered into the eCRFs.

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9.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Confirmed COVID-19 infection during the study observation period.
2. Age ≥18 years old.
3. Nirmatrelvir, ritonavir written prescription.
9.2.2. Exclusion Criteria
There are no exclusion criteria for this study.
9.3. Variables
Table 1 below depicts patient demographics, clinical characteristics, COVID-19 vaccination 
history, and nirmatrelvir, ritonavir prescription data. Table 2 presents COVID-19 infection 
data, and Table 3 presents HCRU variables. Detailed operational definitions of variables are 
listed below.
Table 1.
Patient Baseline Demographics and Clinical Characteristics Variables
Variable
Operational definition
Patient demographics

Age (years)

Gender (male; female)

Ethnicity (Arab; Afro-Asian; Asian/Pacific Islander; Black/African 
American, Hispanic/Latino; Native American/Alaskan Native; 
White/Caucasian, Multiracial/Biracial; Unknown; Other [specify])

Education (no formal education/primary school/secondary 
school/undergraduate university degree/master’s degree/PhD or doctorate)

Employment status (full-time employment, part-time employment, 
homemaker, student, retired, disabled/too ill to work, unemployed) 
Patient clinical 
characteristics

Height (m)

Weight (kg)

Body Mass Index (BMI) (kg/m2)

Smoking status (never smoker; former smoker; current smoker)

Pre-existing comorbidities (specify)

Concomitant medications for comorbidities at index date (no/yes 

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Variable
Operational definition
[specify])

Medications used to treat COVID-19 (antiviral (specify), antibiotic 
(specify), steroid (specify), anti-thrombotic (specify), monoclonal 
antibody, hydroxychloroquine); other medications [specify])

Previous COVID-19 infection during the last 6 months (yes/no) 
COVID-19 vaccination 
history

Patient has received COVID-19 vaccination (yes/no)

Type of vaccine, number of doses and dates (if available)
Nirmatrelvir, ritonavir 
prescription data

Index date (prescription date) (DD/MM/YYYY)

Specialty of provider at index date

Prescription data (dose, frequency and dispensed amount)

Dispensed date if available
BMI: body mass index; COVID-19: Corona Virus Disease 2019 caused by SARS-CoV-2; PhD: Doctor of 
Philosophy.
Table 2.
COVID-19 Infection Data
Variables
Operational definition
COVID-19 infection data 

Positive COVID-19 PCR/antigen test date (DD/MM/YYYY) before initiating
treatment with nirmatrelvir, ritonavir

COVID-19 symptoms onset date (DD/MM/YYYY)

COVID-19 variant (if available) (alpha [B.1.7 and Q], beta [B.1.351], gamma 
[P.1], delta [B.1.617.2; AY], epsilon [B.1.427; B.1.429], eta [B.1.525], iota 
[B.1.526], kappa [B.1.617.1], B.1.617.3, omicron [B.1.1.529; BA.1; BA.1.1; 
BA.2; BA.3; BA.4; BA.5], zeta [P.2], mu [B.1.621; B.1.621.1], XBB.1.5., 
other [specify])

COVID-19 PCR and / or antigen test result(s) following index date (positive; 
indeterminate; negative) (if available)
COVID-19: Corona Virus Disease 2019 caused by SARS-CoV-2; PCR: polymerase chain reaction.

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Table 3.
HCRU Data
Variables
Operational definition
HCRU data
At index date and during the 30-day post-index period:

Patient hospitalization (specify cause if available), LOS [days])

Intensive care unit (ICU) admission, and LOS (days)

Supplemental oxygen use (yes [type: oxygen mask, nasal prongs, NIMV, 
HFNC, IMV, ECMO]/no), vasopressor use (yes [specify]/no), patient 
intubation (yes/no))

Outpatient visits (yes/no) (reason if available)

ER visits (yes/no) (reason if available)
COVID-19: Corona Virus Disease 2019 caused by SARS-CoV-2; ECMO: extracorporeal mechanical 
oxygenation; ER: emergency room; HCRU: Healthcare Resource Use; HFNC: high-flow nasal cannula; IMV: 
invasive mechanical ventilation; LOS: length of stay; NIMV: non-invasive mechanical ventilation.
9.4. Data Sources
This is an observational, non-interventional study (NIS) involving retrospective collection of 
data throughout the observation period, obtained from the source outlined below.

Medical records of patients prescribed nirmatrelvir; ritonavir: The authorized 
physician or study investigator will record patient demographics, clinical 
characteristics, COVID-19 vaccination history, nirmatrelvir, ritonavir prescription 
data, and HCRU data from patients’ medical records into an eCRF.
All data collected in this study are intended to capture COVID-19 patient demographics, 
clinical characteristics, and patients’ HCRU in a real-world setting. An eCRF will primarily 
be used for data collection, located on a secure web-based electronic data capture (EDC) 
system. The use of a standardised eCRF will ensure data is captured consistently across all 
sites. The eCRF must be signed by the investigator, and the signature serves to attest that the 
information contained in the eCRF is true. At all times, the investigator has the final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered into 
the eCRFs.
Table 4 below depicts the data collection schedule for the study.

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Table 4.
Data Collection Schedule
Variables
Cohort 1
Cohort 2
Index datea
During the 30-day 
post-index periodb
Index datea
During the 30-day 
post-index periodc
Patient demographics
X
X
Patient clinical characteristics
X
X
COVID-19 vaccination 
history
X
X
COVID-19 infection data
X
X
X
X
Nirmatrelvir, ritonavir 
prescription data 
X
X
HCRU data
X
X
X
X
COVID-19: Corona Virus Disease 2019 caused by SARS-CoV-2; HCRU: Healthcare Resource Use.
a Cohort 1/Cohort 2: Index date is defined as the date of nirmatrelvir, ritonavir prescription.
b Cohort 1: Post-index period is defined as the 30-day period after the index date and prior to the site initiation 
date.
c Cohort 2: Post-index period is defined as the 30-day period after the index date and after the site initiation 
date.
9.5. Patient Medical Records
The investigator or authorized physician will record all data related to patient demographics, 
clinical characteristics, COVID-19 vaccination history, nirmatrelvir, ritonavir prescription 
data, and HCRU data into an eCRF per patient.
9.6. Study Size
This is an observational study without any pre-defined hypothesis to be tested; rather, it 
addresses descriptive objectives. As such, power calculations are not applicable. However, 
based on feasibility assessments, a planned minimum total sample size of 500 patients for 
this study will ensure adequate exploration of the study objectives, and sufficient 
generalizability of findings.
9.7. Data Management
This study will use anonymized secondary data, collected through medical records. A data 
management plan will be created before data collection begins and will describe all 
functions, processes, and specifications for data collection, cleaning and validation. The 
eCRFs will include programmable edits to obtain immediate feedback if data are missing, out 
of range, illogical or potentially erroneous. Concurrent manual data review will be performed 
based on parameters dictated by the plan. Ad hoc queries will be generated within the EDC 
system and followed-up for resolution.
High data quality standards will be maintained, and processes and procedures utilized to 
repeatedly ensure that the data are as clean and accurate as possible when presented for 
analysis. Data quality will be enhanced through a series of programmed data quality checks 
that automatically detect out of range or anomalous data.

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9.7.1. Electronic Case Report Forms (eCRFs)
As used in this protocol, the term CRF[/DCT] should be understood to refer to either a paper 
form or an electronic data record or both, depending on the data collection method used in 
this study.
An eCRF is required and should be completed for each patient included. The completed 
original eCRFs are the sole property of Pfizer and should not be made available in any form 
to third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
eCRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
eCRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the eCRFs are true. Any corrections to entries made in the eCRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
The source documents are the hospital/physician’s chart or medical records. In these cases, 
data collected on the eCRFs must match those charts.
In some cases, the eCRF may also serve as the source document. In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the eCRF, and for which the eCRF will stand as the source document.
9.8. Statistical Analysis
Detailed methodology for summary and statistical analyses of data collected in this study will
be documented in a statistical analysis plan (SAP), which will be dated, filed and maintained 
by the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment.
This is a descriptive study, and as such, no statistical testing will be conducted. Analyses will
be conducted using Statistical Analysis System (SAS) (version 9.3 or higher). Summary 
statistics for patient demographics, clinical characteristics, treatment patterns, and patient 
HCRU will be performed. Continuous variables will be summarized using standard summary 
statistics such as number of observations (n), mean, median, standard deviation (SD), first
and third quartile, minimum and maximum value. Categorical variables will be summarized 
in frequency tables as counts and proportions of the total study population, and by subgroups 
where appropriate. The proportion of missing data will be reported for each variable.

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Ad hoc population analyses would include stratification by demographic characteristics and 
presence of Underlying Medical Conditions Associated with Higher Risk for Severe 
COVID-19. The corresponding analysis plan will be defined.21
9.8.1. Primary Objective:
To describe the baseline demographic and clinical characteristics, including pre-existing 
comorbidities, of adult COVID-19 patients who have been prescribed nirmatrelvir, ritonavir 
treatment.
Descriptive summary statistics will be conducted for Cohort 1 and Cohort 2 patients, as well 
as the overall population:
Cohorts 1 and 2:

Patient demographics: age, gender, ethnicity, education, employment status;

Patient clinical characteristics: BMI, smoking status, pre-existing comorbidities, 
concomitant medications at index date, medications used to treat COVID-19, and 
previous COVID-19 infection during the last 6 months;

COVID-19 vaccination history: vaccinated/unvaccinated patient, number of doses 
and dates (if available);

Nirmatrelvir, ritonavir prescription data: specialty of provider at index date, 
prescription data, time from symptom onset (if available);

COVID-19 infection data: COVID-19 variant, PCR/antigen test result following 
index date (if available).
9.8.2. Secondary Objective:
To assess adult COVID-19 patients’ HCRU within the 30-day period following nirmatrelvir, 
ritonavir prescription, including:

Overall HCRU in inpatient and outpatient settings.
Descriptive Summary statistics will be conducted for the following:
Cohorts 1 and 2:

Patient HCRU (hospitalization and LOS, ICU admission and LOS, supplemental 
oxygen use and type, outpatient visits, and ER visits
Exploratory stratifications will be conducted, as appropriate and where the sample size 
permits, to explore differences by:

Age groups: 18–29, 30–49, 50–64, 65–74, ≥75 years of age;

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
Gender;

BMI categories: (<18.5 = underweight, 18–24.9 = normal, 25–29.9 = overweight,
≥30 = obese);

Smoking status;

Medications used to treat COVID-19 in addition to nirmatrelvir, ritonavir;

Previous COVID-19 infection;

COVID-19 vaccination history;

Nirmatrelvir, ritonavir treatment completion (if available);

Days from COVID-19 diagnosis to nirmatrelvir, ritonavir index date;

Days from prescription to dispensing (if available).
Should missing data occur, the data will be analyzed as they are recorded in the eCRFs, and
no imputation of missing data will be performed. The number of missing values for data
elements will be reported.
9.9. Quality Control
Investigators will be trained with an initial on-site visit to the clinic on the protocol, EDC 
system (ie, eCRF), investigator site master file (ISMF), documentation, and any applicable 
study processes. Any new information relevant to the performance of this NIS will be 
forwarded to the medical staff during the study. Remote data monitoring will be conducted 
during the life of the study to ensure timely reporting of safety data, data integrity and 
consistency. The eCRFs for all included patients will be made available to the remote data 
monitor for review. A list of critical variables will be created as required elements for review 
during the remote data monitoring process. The study sites will be queried and managed to 
request resolution to any issues that may arise during the study.
Monitoring visits may be made, if necessary, to monitor study process by Pfizer, Inc. or its
delegate. In the event of a visit, direct access to original source data will be required for
monitoring visits and/or inspections/audits, which will be carried out with due consideration
for data protection and patient confidentiality. Items routinely checked during on-site visits 
include:

Documentation of the informed consent process.

Compliance with patient eligibility criteria.

Proper maintenance of records, such as study protocol.

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
Completed eCRFs.

Documentation of adverse events (AEs), and transmission of serious adverse events 
(SAEs).

Identification of patients lost to follow-up.

Study correspondence.

Compliance with Institutional review board (IRB)/Independent ethics committee
(IEC) approval requirements.

Review of the ISMF.

Archiving of the study documents will be performed according to Pfizer standard 
operating procedures (SOPs).
9.10. Strengths and Limitations of the Research Methods
Strengths
A strength of this study includes the use of patients’ medical records for data collection, 
which allows data to be captured on a large, diverse cohort of patients with different 
characteristics in a quick and efficient manner.
To ensure the completion of the eCRF is conducted in a systematic manner, eCRF 
completion guidelines will be supplied to sites to provide consistent instructions on the 
completion of the eCRF. Metrics for data quality and completeness will be reviewed, which 
will help to proactively identify sites with potential issues in data abstraction. Training will 
also be provided to ensure that all investigators understand the minimum dataset 
requirements in this study and help prevent major differences between sites with regards to 
the data abstracted.
Another strength is the eligibility criteria, which has been selected to be as broad as possible
for the target patient population, so as to reflect the real-world clinical setting to the extent
possible, and to minimize selection bias.
Limitations
Since this study will involve collection of existing data from medical records, 
misclassification bias due to recording errors is possible. Medical records may not always be 
complete, the availability and quality/completeness of data may vary considerably between 
different sites within KSA, and there may be abstraction errors and differences in reporting 
standards between the different sites.

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Another limitation to be considered is the characteristics of the patient population to be 
included in the final analysis, which may potentially be biased based on the KSA national 
recommendations put in place for the management and treatment of COVID-19 during the 
observational period. This may affect the generalizability of findings from this study across 
different countries in the real-world setting.
At the patient-level, misclassification of drug exposure has to be considered. Medical records 
provide detailed information on patient demographics, clinical characteristics, and prescribed 
nirmatrelvir, ritonavir treatment, but may not contain information on the intended duration of 
use (days of supply) and may not contain accurate information on the actual treatment pattern 
of nirmatrelvir, ritonavir medications by the patient ie, patient adherence (if any). 
COVID-19 outcomes are dependent on individuals seeking healthcare (ie, individual may 
have symptoms for long but if there is not an interaction with the health system, it will be 
unknown.
9.11. Other Aspects
Not Applicable.
10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient Information
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. The 
personal data will be stored at the study site in eCRF (encrypted electronic and/or paper 
form) and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by a single, patient-specific code. The 
investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the CSA and applicable privacy laws.

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10.2. Patient Consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required.
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (eg, informed consent forms if applicable) from the relevant IRBs/IECs. 
All correspondence with the IRB/IEC must be retained. Copies of IRB/IEC approvals must 
be forwarded to Pfizer.Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPPs) issued by the 
Public Policy Committee, International Society for Pharmacoepidemiology (ISPE), 
Declaration of Helsinki and its amendments, and any applicable national guidelines. This 
study will follow the Strengthening the Reporting of Observational Studies in Epidemiology 
(STROBE) reporting guideline.49
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
x-rays, or narrative fields in a database. The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information
(defined per the patient population and study period specified in the protocol). Explicit
attribution is not inferred by a temporal relationship between drug administration and an AE 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the eCRF and reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form.

Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form.

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
For exposure during pregnancy in studies of pregnant women, data on the exposure to
Nirmatrelvir, ritonavir during pregnancy, are not reportable unless associated with 
serious or non-serious adverse events. 

For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer 
product, the safety information identified in the unstructured data reviewed is 
captured in the Event Narrative section of the report form, and constitutes all clinical 
information known regarding these AEs. No follow-up on related AEs will be 
conducted.
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources. While not all demographic fields will be completed, at the 
very least, at least one patient identifier (eg, gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation. All identifiers will
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...”  Other identifiers will have been removed. 
Additionally, the onset/start dates and stop dates for “Illness,” “Study Drug,” and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month/year of occurrence in the day/month/year 
(DD/MMM/YYYY) format.”
All research staff members must complete the following Pfizer training requirements:  

“Your Reporting Responsibilities (YRR) with Supplemental Topics.”
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Statement” (for signature by the 
trainee) as a record of completion of the training, which must be kept in a retrievable format. 
Copies of all signed training statements must be provided to Pfizer. 
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities (YRR) with Supplemental Topics training materials. Where Pfizer issues an 
updated safety training program, including during the course of a calendar year, vendor shall 
ensure all vendor personnel complete the updated safety training within sixty (60) calendar 
days of issuance by Pfizer.

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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
A final study report detailing the final study protocol and the analysis results will be provided 
when the study is complete. In the event of any prohibition or restriction imposed 
(eg, clinical hold) by an applicable competent authority in any area of the world, or if the 
investigator is aware of any new information which might influence the evaluation of the 
benefits and risks of a Pfizer product, Pfizer should be informed immediately.
Any publication of the results from this study must be consistent with Pfizer’s publication 
policy and guided by the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals: Writing and Editing for Biomedical Publication of the International Committee of 
Medical Journal Editors (ICMJE), updated December 2019.50 All reporting will be consistent 
with the STROBE Initiative checklist for cohort studies.49

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13. REFERENCES
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Hasöksüz M, Kiliç S, Saraç F. Coronaviruses and SARS-COV-2. Turk J Med Sci. 
2020;50(Si-1):549-56.
2.
Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat 
Rev Microbiol. 2021;19(3):141-54.
3.
World Health Organization. COVID-19 Public Health Emergency of International 
Concern (PHEIC) Global research and innovation forum. 12 February 2020. [Available 
from: https://www.who.int/publications/m/item/covid-19-public-health-emergency-of-
international-concern-(pheic)-global-research-and-innovation-forum] Accessed on 
October 11, 2022.
4.
World Health Organization. WHO Situation Report 51 Coronavirus disease 2019 
(COVID-19). 11 March 2020.  [Available from: 
https://www.who.int/publications/m/item/situation-report---51] Accessed on October 
11, 2022.
5.
Worldometers. COVID Live- Coronavirus statistics. 11 October 2022. [Available from: 
https://www.worldometers.info/coronavirus/] Accessed on October 11, 2022.
6.
Johns Hopkins Medicine. COVID Symptoms. 27 January 2022 [Available from: 
https://www.hopkinsmedicine.org/health/conditions-and-
diseases/coronavirus/coronavirus-symptoms-frequently-asked-questions] Accessed on 
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14. LIST OF TABLES
Table 1.
Patient Baseline Demographics and Clinical Characteristics Variables
Table 2.
COVID-19 Infection Data
Table 3.
HCRU Data
Table 4.
Data Collection Schedule
15. LIST OF FIGURES
Figure 1.
Study Design

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ANNEX 1. ADDITIONAL INFORMATION
Annex Table 1 WHO Clinical Progression Scale.51
Patient State
Definition
Score
Hospitalized: moderate disease
Hospitalization without oxygen therapy
4
Hospitalization with oxygen therapy by mask or 
nasal prongs
5
Hospitalized: severe disease
Hospitalized with oxygen therapy by NIV or 
HFNC
6
Intubation and mechanical ventilation or 
vasopressors
7
Mechanical ventilation or vasopressors
8
Mechanical ventilation and vasopressors, 
dialysis, or ECMO
9
Dead
Dead
10
ECMO: extracorporeal membranous oxygenation; HFNC: high-flow nasal cannula; NIV: non-invasive
ventilation.

D o c u m e nt A p pr o v al R e c or d
D o c u m e nt N a m e:
D o c u m e nt Titl e:
Si g n e d B y:
D at e( G M T)
Si g ni n g C a p a cit y
 
P P D