A Real-World Evidence Study Evaluating Quality of Life Parameters Following Use of Emergen-C
Phase: PHASE4
Conditions: Dietary Supplements
Sponsor: HALEON

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CLINICAL PROTOCOL
A Real-World Evidence study evaluating Quality of Life parameters 
following use of Emergen-C
Protocol Number: 
300217
Compound/Product Name: 
Emergen-C Core Super Orange 
Powder
Phase: 
IV
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publicly available version
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Sponsor Information
   
Sponsor Name & Legal Registered 
Address
Haleon (UK) 
Building 5, First Floor, 
The Heights, 
Weybridge, 
Surrey, 
KT13 0NY
Sponsor Contact Details
Haleon
184 Liberty Corner Road, 
Warren, NJ, 07059
USA
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Document History
Document
Version
Summary of Changes 
Original protocol
1.0
Not applicable (N/A)
Amendment 1
2.0
Section 4.2 Inclusion Criteria: Criteria #4 updated to clarify 
MFI scoring for eligibility is during pre-screening. 
Table 5-1 Schedule of Activities
•
MFI completion has been moved from Visit 1 
(Screening & Baseline) to Pre-screening.
•
To correct error in time of collection of Adverse 
Events to align with section 9.1.3. AEs are to be 
collected from date of randomization, not date of ICF 
completion.
Section 5.1 Schedule of Activities: Footnote added for MFI
Section 5.2 Pre-screening: removal of language to schedule 
a screening and baseline visit as a pre-screening activity. A 
screening and baseline visit will only be scheduled for those 
who satisfy the MFI inclusion criteria.  
Section 5.3 Pre-screening Assessments: MFI completion 
moved from Visit 1 (Screening & Baseline) to Pre-screening.
Section 5.4 Screening & Baseline: Virtual Visit 1. MFI 
completion removed from this section. 
Section 9.9 Schedule of Activities Schematic: MFI 
completion has been moved from Virtual Visit 1 to pre-
screening activities.
Section 9.10.2 Additional QoL Questions: The possible 
responses to questions have been added to the table. 
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Principal Investigator Protocol Agreement Page
●
I confirm agreement to conduct the study in compliance with the protocol and any 
amendments according to the current Good Clinical Practice guidelines (GCP).
●
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct 
or supervise the described study.
●
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure site staff 
receives all appropriate information throughout the study.
●
I agree to conduct this study in full conformance with the laws and regulations of the 
country in which the research is conducted and the Declaration of Helsinki.
Protocol Version/Date
Version 2.0 
Investigator Name:
Investigator Qualifications:
Investigator Signature:
Date of Signature/Agreement:
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Table of Contents
1 INTRODUCTION
8
Background & Study Rationale
8
2 STUDY OBJECTIVES AND ENDPOINTS
12
3 STUDY DESIGN
13
4 STUDY POPULATION
13
4.1  Type and Planned Number of Subjects
13
4.2  Inclusion Criteria
14
4.3  Exclusion Criteria
14
4.4  Lifestyle Considerations
15
5 STUDY PROCEDURES
15
5.1 Schedule of Activities
16
5.2 Pre-screening
17
5.2.1 Inclusion/Exclusion Criteria
17
5.2.2 Demographics
17
5.2.3 Informed Consent
17
5.2.4 Medical History and Prior Medication/Treatment
17
5.2.5 Enrolled Subjects and Screen Failures
18
5.3 Pre-screening Assessments
18
5.4 Screening & Baseline: Virtual Visit 1
19
5.5 Follow-up: Virtual Visits 2-4
20
5.6 On-going Daily eDiaries
20
5.7 On-going Assessments: Week 4, Week 8 & Week 12
20
6 STUDY ASSESSMENTS
20
6.1 Outcome Assessments
21
6.2 Safety and Other Assessments
22
6.2.1 Pregnancy Testing
22
7 STUDY PRODUCTS
22
7.1 Study Product Supplies
22
7.2 Product Supplies, Product Storage, Accountability, Returns and Destruction
23
7.3 Blinding and Randomization
24
7.4       Breaking the Blind
24
8 STATISTICAL CONSIDERATIONS AND DATA ANALYSES
25
8.1  Sample Size Determination
25
8.2  Populations for Analysis
25
8.2.1  Definitions of Analysis Populations
25
8.2.2  Exclusions of Data from Analysis
26
8.3  Statistical Analyses
26
8.3.1  Primary Endpoint Analysis(es)
27
8.3.2  Secondary Endpoint Analysis(es)
27
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8.3.3  Exploratory Analyses
28
8.3.4  Safety Analysis(es)
28
8.3.5  Other Analysis(es)
29
8.3.6  Demographic and Baseline Characteristics
29
8.3.7  Study Product Compliance and Use of Other Therapies
29
8.3.8  Handling of Dropouts and Missing Data
29
9 APPENDICES
30
9.1 Adverse Event (AE) and Serious AE (SAE)
30
9.1.1        Definition of an Adverse Event (AE)
30
9.1.2        Definition of a Serious Adverse Event
31
9.1.3        Time Period and Frequency for Collecting AE and SAE Information
32
9.1.4        Reporting Procedures
32
9.1.5        Reporting an AE
33
9.1.6        Reporting an SAE
33
9.1.7        Evaluating AEs
34
9.1.8        Follow-up of AEs and SAEs
35
9.1.9        Withdrawal Due to an Adverse Event
36
9.1.10    Regulatory Reporting Requirements for SAEs
36
9.2 Pregnancy
36
9.2.1 Time Period for Collecting Pregnancy Information
36
9.2.2 Action to be Taken if Pregnancy Occurs
37
9.3 Discontinuation of Study Product and Subject Discontinuation/Withdrawal
37
9.3.1 Discontinuation of Study Product
37
9.3.2 Subject Discontinuation/Withdrawal
37
9.3.3 Lost to Follow up
38
9.4 Data Management
38
9.4.1  Case Report Form
38
9.4.2  Data Handling
39
9.4.3  Data Queries
39
9.5  Processing Patient Reported Outcomes and Data Collection from Internet of Medical 
Things
39
9.6  Regulatory and Ethical Considerations
40
9.6.1  Institutional Review Board/ Ethics Committee
40
9.6.2  Ethical Conduct of the Study
40
9.6.3  Subject Information
40
9.7  Records Retention
41
9.8  Disclosure and Publication Policy
41
9.9  Schedule of Activities Schematic
42
9.10  Study Questionnaires
43
9.10.1  Multidimensional Fatigue Index (MFI-20)
43
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9.10.2  Additional QoL Questions
43
10  ABBREVIATIONS
44
11     REFERENCES
46
List of in text tables
Table 2-1 Study Objectives and Endpoints
12
Table 5-1 Schedule of Activities
17
Table 7-1 Investigational/Study Product Supplies
23
Table 10-1 Abbreviations
45
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1
INTRODUCTION
1.1 Background & Study Rationale
Adequate nutrition and appropriate nutritional interventions, like dietary supplements, can play 
an important role in maintaining a person’s immune defenses. While frank nutrient deficiencies  
are not common in the United States, sub-optimal intake of several micronutrients important 
for the immune response has been documented in the literature. The consumption of nutrient 
dense foods like fruits and vegetables help individuals meet the daily recommended intakes, as 
established by the Institute of Medicine (IOM). The Dietary Guidelines for Americans (2020-
2025) states the average intake of total vegetables, total fruits and total dairy is less than 
recommended intake ranges for ages 14 and up (1). Additional supplementation of essential 
nutrients at levels well-below upper safety levels as established by the IOM, provides an 
effective way to supplement the diet, optimize micronutrient status, and support immune 
function.
The human immune system is the body’s natural way to protect itself. It is constantly working 
to protect the body from infection, injury, and disease. Vitamins and minerals are essential for 
the integrity and optimum function of the immune system (2,3). An adequate supply of 
nutrients is required for the immune system's baseline functions as well as for ramping up its 
activity when necessary. It is well established that micronutrient status plays an important role 
in the immune response and that deficiencies in one or more essential micronutrients can 
diminish immune function (2,3).
Vitamin C is an essential nutrient that plays an important role in the immune system. In addition 
to vitamin C, Emergen-C products contain a variety of additional immune supporting nutrients 
to provide a more comprehensive immune support formula compared to products just 
containing vitamin C.
Emergen-C core powders contain a variety of nutrients (vitamin C, zinc, vitamin B6, vitamin 
B12, folate, manganese) that are critical for maintaining proper immune function. Vitamin C, 
zinc, and manganese are powerful antioxidants. The oxidant-antioxidant balance is an 
important determinant of immune cell function, including maintaining the integrity and 
functionality of membrane lipids, cellular proteins, and nucleic acids and controlling signal 
transduction and gene expression in immune cells. Optimal amounts of antioxidants are needed 
to maintain and support the immune response across all age groups. 
Vitamin B12, folate and vitamin B6 have an essential role in the production and development 
of all new cells in the body, including immune cells. This process is crucial for the immune 
system to maintain its normal functions and to ramp up production when needed to respond to 
foreign invaders.
Much of the research investigating high vitamin C supplementation has focused on its impact 
on the common cold (4-9). In 1971, Linus Pauling carried out a meta-analysis of vita-min C 
and the common cold, including the four placebo-controlled trials available at that time. He 
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found very strong evidence that vitamin C decreased morbidity caused by the common cold (P 
= 0.000022) (10,11). Subsequent larger and methodologically more robust randomized 
controlled trials (RCTs) supported Pauling’s conclusions. In a recent Cochrane review on 
vitamin C and the common cold, regular vitamin C supplementation of ≥ 0.2 g/day shortened 
the duration of colds by 9.4% (P < 0.00001) (10,11).Nevertheless, despite the strong evidence 
indicating that vitamin C has physiological effects on the common cold, there is a persistent 
wide-spread belief that vitamin C is of no benefit.
While the available evidence shows that vitamin C can affect colds, the optimal doses and the 
size of maximal benefit are not known, although two controlled trials indicated that 6–8 g/day 
of vitamin C might be twice as effective as 3–4 g/day (12-17). 
Despite the research there are no current clinical recommendations that support the possibility 
of the potential impact on the risk of infection and of significantly reducing the severity of   
respiratory infections, by using high-dose supplements of vitamin C in a well-nourished general 
population. Only in restricted subgroups (e.g., athletes or the military) and in subjects with a 
low plasma vitamin C concentration may a supplementation be justified. Furthermore, in 
categories at high risk of infection (i.e., the obese, diabetics, the elderly, etc.), vitamin C 
supplementation can modulate inflammation, with potential positive effects on immune 
response to infections. The impact of an extra oral intake of vitamin C on the duration of a cold 
and the prevention or treatment of pneumonia is still questioned.
Other research into high doses of vitamin C has investigated how supplements have impacted 
physical and emotional measures of health.  The B-vitamins are widely accepted as playing a 
role in brain function, and there is evidence to suggest that B-vitamins may have a modifying 
effect on cognitive function. Therefore, much of the research into B12 and B6 has investigated 
the impact of these vitamins on cognition as well as mood and stress. 
Vitamins and minerals and their impact on quality of life in terms of   energy and cognition is 
an area of increasing interest (18). A recent meta-analysis of vitamin C supplementation on 
mood status in adults showed that it may be beneficial in certain populations (19).  A meta-
analysis of the effects of vitamin and mineral supplementation on stress, mild psychiatric 
symptoms, and mood in nonclinical samples showed that subjects taking supplements with 
high levels of vitamin C and B-vitamins had lower levels of stress, improved mood, and better 
energy than placebo (20). 
An extensive literature review investigating the research behind immune supplements (with 
high levels of vitamin C and the B-vitamins) showed that high doses of vitamin C can lead to 
increased levels of perceived energy. Twenty-nine studies have looked at the impact of 
supplement brands on various aspects of physical health, psychological health, and emotional 
including supplements such as Berocca, Supradyn, Elevit, and Centrum. Berocca and Supradyn 
(manufactured by Bayer) contain high levels of vitamin C and the B-vitamins and make similar 
claims to Emergen-C regarding immunity support and energy. There are 6 studies (21-26) on 
Berocca and Supradyn that are particularly pertinent to our proposed research investigating 
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various parameters of perceived physical and mental energy as well as mood and stress. These 
studies have run from 28 days, 33 days, 4 weeks, 9 weeks, and 90 days. Physical and mental 
energy measured by validated tools such as the General Health Questionnaire-12 (GHQ-12) 
appear to be positively impacted more quickly than parameters like stress and emotional 
wellbeing as measured by scales such as the Profile of Mood States (POMS) as outlined in the 
table below.
Competitor supplement brands and their impact on physical and emotional measures of health.
Study 
Brand
Duration
Results
1.Vitamins and psychological 
functioning: a mobile phone 
assessment of the effects of a 
B vitamin complex, vitamin C 
and minerals on cognitive 
performance and subjective 
mood and energy.
Human Psychopharmacology, 
Haskell et al. 2010.
Berocca
28 days
Participants in the vitamin/mineral group 
rated themselves as having greater 
'physical stamina' across assessments and 
weeks. They also rated themselves as 
having had greater 'concentration' and 
'mental stamina' during the working day.
Participants in this group also reported 
greater subjective 'alertness' on Bond-
Lader mood scales during the post-work 
assessment on day 14 and both the pre-
and post-work assessments on day 28.
2.Effects of high-dose B 
vitamin complex with vitamin 
C and minerals on subjective 
mood and performance in 
healthy males. 
Psychopharmacology, Kennedy 
et al. 2010.
Berocca
33 days
Vitamin/mineral supplementation led to 
significant improvements in ratings on the 
Perceived stress scale (PSS), General Health 
Questionnaire (GHQ-12) and the 'vigor' 
subscale of the Profile of Mood States 
(POMS). The vitamin/mineral group also 
performed better on the Serial 3s 
subtractions task and rated themselves as 
less 'mentally tired' both pre-and post-
completion of the cognitive demand 
battery. 
3.Acute and chronic effects of 
multivitamin/mineral 
supplementation on objective 
and subjective energy 
measures
Nutrition and Metabolism, 
Dodd et al. 2024.
Berocca
28 days
These findings extend on existing 
knowledge, demonstrating increased 
carbohydrate oxidation and increased 
energy expenditure in males following 
supplementation for the first time. 
Importantly, they show modulation of 
energy expenditure and subjective 
tiredness following a single dose, providing 
further evidence for acute effects of 
supplementation. Differential effects in 
men and women suggest that sex may play 
an important role in the effects of 
supplementation on energy metabolism.
4.Effects of Four-Week 
Supplementation with a Multi-
Vitamin/Mineral Preparation 
on Mood and Blood 
Biomarkers in Young Adults: A 
Berocca
Performanc
e
4 weeks 
Compared to placebo, supplementation 
was associated with significantly lowered 
homocysteine and increased blood B-
vitamin levels (p < 0.01). Supplementation 
treatment was also associated with 
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Randomized, Double-Blind, 
Placebo-Controlled Trial.
Nutrients, White et al, 2015. 
significantly improved mood, as measured 
by reduced scores on the “depression-
dejection” subscale of the Profile of Mood 
States (p = 0.018). These findings suggest 
that the four weeks of supplementation 
may have beneficial effects on mood, 
underpinned by elevated B-vitamins and 
lowered homocysteine in healthy young 
adults.
5.Effects of a multi-
vitamin/mineral supplement 
on cognitive function and 
fatigue during extended multi-
tasking
Brain Performance and 
Nutrition Research, Haskell et 
al, 2015.
Supradyn
9 weeks
Those in the supplement group exhibited 
an attenuation of the negative effects of 
extended task completion on 
mood/fatigue. Multi-tasking performance 
for this group was also improved in terms 
of accuracy across all tasks, and on two of 
the individual tasks (Mathematical 
Processing and Stroop) in terms of both 
faster and more accurate responses.
6. The effect of 90-day 
administration of a high dose 
vitamin B-complex on work 
stress. 
Human Psychopharmacology 
Stough et al. 2011.
Supradyn
90 days
After individual differences in personality 
and work demands were statistically 
controlled, the vitamin B complex 
treatment groups reported significantly 
lower personal strain and a reduction in 
confusion and depressed/dejected mood 
after 12 weeks.
Consumer insights research points to the fact that consumers are interested in learning more 
about the scientific rationale behind the brand and want to understand the benefits of taking 
Emergen-C on a routine or daily basis. A study was developed to examine the effects of 
consistent daily Emergen-C use for 12 weeks during a fall/winter season. This timeframe was 
selected given the greater demand on the immune system during this time with higher incidence 
of cough, cold, and flu. The aim of this research is to determine how Emergen-C use can 
improve QoL in a real-world setting, that can be communicated to help consumers and 
healthcare professionals better understand the science behind the brand. 
The aim of this randomized double-blind placebo-controlled clinical trial is to evaluate the 
effectiveness of daily consumption (over 12 weeks) of Emergen-C core super orange powder 
Emergen-C core powders on QoL in a real-world setting. This study will enroll a healthy adult 
population (aged 18-64 yrs.) in the United States into one of two study arms (study product, or 
placebo). It is hypothesized the study group will demonstrate a significant decrease in MFI 
(Multidimensional Fatigue Inventory) domain scores (i.e. meaning an improvement of energy 
level) from baseline compared to the placebo group following 12 weeks of daily 
supplementation. 
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2
STUDY OBJECTIVES AND ENDPOINTS
Table 2-1
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the effect of daily 
supplementation with Emergen-C in 
improving QoL parameters as measured 
by the Multidimensional Fatigue 
Inventory (MFI) domains, compared to 
placebo at Week 12.
Change from Baseline at Week 12 in: 
●
General Fatigue Domain score (items 
1,5,12,16)
●
Physical Fatigue Domain score (items 
2,8,14,20)
●
Reduced Activity Domain score (items 
3,6,10,17)
●
Reduced Motivation Domain score (items 
4,9,15,18)
●
Mental Fatigue Domain score (items 
7,11,13,19)
Secondary 
To evaluate the effect of daily 
supplementation with Emergen-C in 
improving QoL parameters as measured 
by the Multidimensional Fatigue 
Inventory (MFI) domains, compared to 
placebo at Week 4 and 8.
Change from Baseline at Week 4 and 8 in: 
●
General Fatigue Domain score (items 
1,5,12,16)
●
Physical Fatigue Domain score (items 
2,8,14,20)
●
Reduced Activity Domain score (items 
3,6,10,17)
●
Reduced Motivation Domain score (items 
4,9,15,18)
●
Mental Fatigue Domain score (items 
7,11,13,19)
To evaluate the effect of daily 
supplementation with Emergen-C in 
improving QoL parameters as measured 
by the Multidimensional Fatigue 
Inventory (MFI) individual items, 
compared to placebo at Week 4, Week 8 
and Week 12.
Change from Baseline at Week 4, Week 8 and 
Week 12 for each of the individual items in the 
MFI.
To evaluate the effect of daily 
supplementation with Emergen-C in 
improving additional QoL parameters as 
measured by additional QoL Questions, 
compared to placebo at Week 4, Week 8 
and Week 12.
Change from Baseline at Week 4, Week 8 and 
Week 12 for: 
●
Family support 
●
Resilience 
●
Ability to relax and unwind 
Exploratory
To evaluate the effect of daily 
supplementation with Emergen-C in 
improving additional QoL parameters as 
measured by additional QoL Questions, 
compared to placebo at Week 4, Week 8 
and Week 12.
Number of days reported  at Week 4, Week 8 
and Week 12, for: 
●
days feeling unwell
●
days canceling plans
●
days with cough and cold symptoms
●
days sick in bed
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Subgroup analyses for primary and 
secondary endpoints.
Subgroup analyses for
●
sex (male and female)
●
age (18-34 and 35-64 years)
Safety 
To monitor the safety of the study 
treatment with daily use for 12 weeks. 
The number of Treatment-emergent adverse 
events (TEAEs)
This study will be considered successful if daily use of Emergen-C supplementation improves 
QoL (as measured by any of the individual domain scores), compared to placebo at Week 12.  
3
STUDY DESIGN 
This is a randomized, double-blinded, placebo-controlled clinical trial in healthy male and 
female subjects, aged 18-64 years, evaluating the over-time effects of 12-weeks Emergen-C 
supplementation on QoL parameters in a real-world setting. A sufficient number of adults 
(approximately 430), aged 18-64 years, will be screened for eligibility. The study expects to 
enroll about 300 eligible subjects across the United States. Subjects will be enrolled into one 
of two study groups (at a 1:1 ratio) and will take one sachet of study product (Emergen-C or 
placebo) once daily in the morning at approximately the same time each day for 12 weeks. A 
total of approximately 240 subjects are expected to complete the study, approximately 120 in 
each study group. 
Subjects will be recruited through targeted advertising on social media platforms. This study 
is entirely decentralized, and subjects will not be required to physically attend any on-site visits 
(only virtual visits). All study data will be collected remotely through a study platform using 
the subject’s personal mobile device, tablet or computer. 
Detailed study procedures can be found in Section 5 of the protocol.  
4
STUDY POPULATION
4.1 
Type and Planned Number of Subjects
This study will be conducted in healthy male and female subjects, aged 18-64 years (inclusive), 
and of any race/ethnicity. No discrimination of any kind (e.g. social class, gender, skin color, 
ethnicity) should preclude eligible participants from participating in the study.  The study will 
aim to recruit a diverse population representative of the US census.
Sufficient subjects will be screened in order to enroll about 300 eligible subjects 
(approximately 150 subjects per study group) and approximately 240 subjects are expected to 
complete the study (approximately 120 subjects per study group, allowing for up to 20% 
dropouts). Potential participants will be recruited through targeted digital advertising 
campaigns. 
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The study will be sufficiently powered to demonstrate statistically significant differences 
between Emergen-C core super orange powder compared to Placebo for QoL parameters as 
measured by the MFI at Week 12 (primary objective). A sample size of 120 evaluable subjects 
per treatment group will provide over 90% power to detect a mean difference of 0.5 standard 
deviations (27) Cohen’s d), using a 2-tailed 2-sample t-test with a 1% significance level 
(Bonferroni-adjusted p-value). This effect is in line with the estimated minimal clinically 
important difference for the MFI in patients with lupus erythematosus (28).
The sample size calculation was performed using R software version 4.4.1.
This study can fulfill its objectives only if appropriate subjects are enrolled. All relevant 
medical and non-medical conditions should be taken into consideration when deciding whether 
a subject is suitable for this protocol. Subject eligibility to participate in the clinical study 
should be reviewed and documented by a delegated member of the investigator’s study team 
before subjects are included in the study. The following eligibility criteria are designed to select 
subjects for whom participation in the study is considered appropriate.  
4.2 
Inclusion Criteria
An individual must meet all the following inclusion criteria to be eligible to be included into 
the study:
1. Individual’s provision of a signed and dated electronic informed consent document 
indicating that the subject has been informed of all pertinent aspects of the study before any 
assessment is performed.
2. Healthy Adults, 18-64 years of age at the time of electronic consent (does not exclude any 
ethnicities, races, or gender identities)
3. Individual is seeking to improve their energy/less fatigue levels
4. Individuals whose baseline score (assessed during pre-screening) is ≥10 on the dimension 
of general fatigue of the Multidimensional Fatigue Inventory (MFI) and a score ≥3 for at 
least ten of the 20 questions of the MFI
5. Individuals who are willing and able to comply with all study related activities as shown in 
the Schedule of Activities. 
6. Individuals who reside in the United States (except for Hawaii and Alaska) 
7. Individuals who own a mobile device, tablet or computer with access to stable internet 
connection and are willing to use their device to complete study surveys and assessments
4.3 
Exclusion Criteria
An individual who meets any of the following criteria will be excluded from the study:
1. Individuals who are an employee of 
, either directly involved in the conduct 
of the study or a member of their immediate family; or a Haleon employee directly involved 
in the conduct of the study or a member of their immediate family.
2. Individuals who have participated in other studies (including non-medicinal studies) 
involving investigational product(s) within 30 days prior to study entry and/or during study 
participation.
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3. Individuals who are pregnant, lactating, or plan to be pregnant or lactating during the course 
of the study (self-report). 
4. Individuals with known or suspected intolerance or hypersensitivity to any study materials 
(or closely related compounds) or any of their stated ingredients. 
5. Individuals who are hypertensive or salt-sensitive should be excluded from this study.
6. Individuals who report being a heavy drinker (defined as drinking 3 or more alcoholic 
beverages per day).
7. Individuals who are unable to read and understand English.
8. Individuals who report current and/or recent (up to 3 months ago) major illnesses and/ or 
major surgery
9. Individuals who report a planned surgery during the study duration. 
10. Individuals who report a diagnosis of heart failure, heart rhythm disturbances, severe liver 
disease, severe mental health diagnosis, or severe renal failure. 
11. Individuals who report taking medications (in the previous 21 days) that have well 
established moderate or severe interaction with any of the study product ingredients: 
Anticoagulants, 
antihypertensives, 
anxiolytics, 
antidepressants, 
chemotherapy, 
immunotherapy, sedative hypnotics, medications that warn against grapefruit consumption, 
corticosteroids at doses greater than 5 mg per day, diabetic medications, oral anti-infectives 
(antibiotics, antifungals, antivirals) to treat an acute infection, antipsychotics, Monoamine 
Oxidase Inhibitors (MAOIs), or thyroid products.
12. Individuals who are currently taking a multivitamin or have taken a multivitamin in the past 
30 days & are not willing to stop taking a multivitamin for the duration of the trial.
13. Individuals who are currently taking other Vitamin C or B supplements or have taken 
Vitamin C or B supplements in the past 30 days & are not willing to stop taking other 
Vitamin C or B supplements for the duration of the trial.
14. Individuals who are currently consuming energy drinks or energy shots or have consumed 
an energy drink or energy shot in the past 30 days & are not willing to stop consuming 
energy drinks and energy shots for the duration of the trial.
15. A subject who has previously been enrolled in this study. 
16. A subject who, in the opinion of the investigator or delegate, should not participate in the 
study.
4.4 
Lifestyle Considerations
As a real-world evidence study, there will be no lifestyle considerations. 
5
STUDY PROCEDURES
This section lists the procedures and assessments to be completed at each planned study time 
point. However, as per nature of Real World Evidence (RWE) studies, if a subject fails to 
complete their daily questionnaire at any time point post-baseline, subjects will be permitted 
to continue in the study. The timing of each procedure is listed in the Table 5-1 Schedule of 
Activities section.
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5.1
Schedule of Activities
The Schedule of Activities (Table 5-1) provides an overview of the subjects virtual visits, study 
procedures and assessments. The investigator may schedule additional (unplanned) virtual 
visits to conduct additional evaluations or assessments required to protect the well-being of the 
subject. A detailed schematic of the Schedule of Activities is located in section 9.9 Schedule 
of Activities Schematic. 
Table 5-1
Schedule of Activities
Footnotes:
aSubject-reported (self-reported) assessments.
Visit
Treatment Period
Pre-
screening
Visit 1 
Screening 
& Baseline
Treatment 
Initiation
Virtual
Visit 2
Virtual 
Visit 3
Virtual
Visit 4
Study Day
Day-7 to 
Day -2
Day -7 to 
Day -2
Day 1
Week 4
Day 28  
(+5)
Week 8
Day 56 
(+5)
Week 12
Day 84 
(+5)
Medical/Medication Historya
X
Demographicsa
X
Informed Consent
X
Subject ID Verification
X
Inclusions/Exclusion 
Criteriac
X
Eligibility Assessment 
X
MFI a
X
X
X
X
Supplementary QOL 
questionnaire a
X
X
X
X
Randomization
X
Participant Training
X
Study Product Shipped
X
Concomitant Medication 
Check
X
X
X
X
Adverse Event (AE/ Serious 
Adverse Event)
X
X
X
X
X
Study Product 
Administrationb
X (Daily through Week 12 visit)
Participant Daily eDiaryd
X (Daily through Week 12 visit)
Subject Conclusion/Subject 
Exit from Study
X
Exit Surveya
X
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bSubject will take the study product in the morning of each day
cSubject will self-report pregnancy status during Visit 1
dSubject-reported (self-reported) they took the investigational product on that day.
The virtual site may contact subjects prior to study visits, either as part of pre-screening 
activities or as a reminder of the approaching scheduled visit. Further details should be included 
in the electronic informed consent (eICF). 
5.2
Pre-screening
The study team will identify and recruit potential subjects via social media platform 
advertising. Potential subjects will be directed to the study web page where they will complete 
an online pre-screening questionnaire assessing their eligibility to participate in the study. The 
information collected from the pre-screening questionnaire serves as the preliminary screening 
tool to isolate potentially eligible participants from ineligible subjects. Subjects who 
successfully pass the pre-screening questionnaire are deemed potentially eligible for 
participation and are directed to complete an online eICF. Potentially eligible subjects who 
execute the eICF will receive a copy of the signed eICF via email. 
5.2.1
Inclusion/Exclusion Criteria
Inclusion and exclusion criteria as per Section 4.2 and 4.3 will be collected via pre-screening 
survey and confirmed during the Screening and Baseline virtual visit with a trained & delegated 
study team member. 
5.2.2
Demographics
The following demographic information will be collected:  year of birth and age, sex at birth, 
race, ethnicity, height, weight, and smoking (including vaping) status. 
5.2.3
Informed Consent
The eICF is a tool that assists in the consenting process by using multimedia components 
delivered by an electronic system. The eICF process for this study will be performed on the 
subject’s mobile device, tablet or computer following successful completion of the study pre-
screening questionnaire. Informed consent must be obtained before any study-specific activity 
is performed. Once the eICF has been signed and dated by the subject, the subject will be 
provided with a copy via email. An additional copy of the signed eICF will be saved as a 
Portable Document Format (PDF) in the virtual site file.
If, during a subject’s participation in the study, the eICF undergoes any changes, each ongoing 
subject should receive a copy of this new information and be re-consented into the study. Each 
subject should be provided with a copy of the signed and dated amended consent form. 
5.2.4
Medical History and Prior Medication/Treatment
Relevant medical and/or surgical history (in the previous 12 months) will be self-reported, 
including allergies or drug sensitivity and prior medications/treatments, including prescription 
and non-prescription drugs, dietary supplements and herbal remedies, that began before 
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obtaining informed consent will be recorded as the Medical History/Current Medical 
Conditions. 
Female subjects only: 
●
Female subjects who report being pregnant or confirm planning pregnancy during the 
study will be discontinued from participation in this study.
●
Given the potential impact of pregnancy on study outcomes, female subjects of child-
bearing potential will be reminded to inform the investigator site immediately if 
pregnancy is known or suspected.
Relevant medical and surgical history, including allergies or drug sensitivity can be 
documented by the investigator or designee in the medical history form.
Please refer to section 9 for further details on Adverse Event and Serious Adverse Event 
Monitoring and to section 8.3.6.2 for further details on concomitant medications.
The investigator and/or delegated study team member will review inclusion/exclusion criteria, 
medical history and prior medications to confirm subject eligibility to participate in the study. 
5.2.5
Enrolled Subjects and Screen Failures
An enrolled subject is one who has agreed to participate in the clinical study following 
completion of the informed consent process and who has directly and successfully met 
eligibility criteria to proceed beyond the screening visit.
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized to a study group. 
To ensure transparent reporting of screen failure subjects, a minimal set of screen failure 
information will include demography and screen failure details (e.g., withdrawal of consent, 
eligibility criteria, any protocol deviations and any adverse events).
Individuals who do not meet the criteria for participation in this study (screen failure) will not 
be re-screened. 
5.3
Pre-screening Assessments
Prior to their scheduled Screening and Baseline virtual visit, subjects will be asked to complete 
the following: 
●
Medical & concomitant medication history
●
Demographic information 
●
The MFI 
○
Following MFI completion, the participant’s MFI score will be automatically 
calculated via the Citrus platform to determine eligibility. A subject is 
considered eligible if their baseline score is ≥10 on the dimension of general 
fatigue of the MFI and a score ≥3 for at least ten of the 20 questions of the MFI. 
Note: If the participant is not eligible based on responses to the above items, a member of the 
study team will notify and screen fail the participant. 
     
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5.4
Screening & Baseline: Virtual Visit 1
During the Screening and Baseline virtual visit, a trained member of the study team will verify 
the subject's identification (i.e. driver’s license or government issued passport) on camera at 
the beginning of the visit. Should the subject elect not to show a form of identification or is 
unable to provide a valid identification at the beginning of the virtual visit, the visit may be 
rescheduled, or the subject may be considered a screen failure. 
Following subject identification verification, the following visit procedures will be performed:
●
Review self-reported medical and concomitant medication history
●
Review inclusion/exclusion criteria 
●
Complete supplemental QoL questionnaire 
●
Provide instructions for the completion of the study questionnaire, daily diaries, and 
storage, preparation and administration of the study product
●
Verify address for study product shipment
●
Answer any questions the subject may have about the study
If the responses to all screening criteria are fulfilled, the subject will be considered enrolled. 
At enrollment, the following activities will occur:
●
The subject will move forward to randomization into one of two study groups (on a 1:1 
allocation) as follows: Group 1) Emergen-C Core Super Orange Powder or Group 2) 
Placebo. 
○
Upon group allocation, subjects will be shipped the study product. Neither the 
subject or study team will be made aware which group arm the subject is 
allocated to. 
○
Once the shipment is successfully received, the subject will confirm receipt via 
an online questionnaire directly entered into the EDC platform. 
■
If unsuccessful (e.g. lost, damaged) study team will discuss with 
participant and arrange a new shipment if needed 
Following the completion of the screening visit, and prior to Virtual Visit 2, subjects will be 
reminded each morning to consume the study product with 4-6 ounces of water at 
approximately the same time each day. Each evening, subjects will be prompted to complete 
an Electronic Diary (eDiary) consisting of one question to confirm the subject has consumed 
the study product. 
5.5
Follow-up: Virtual Visits 2-4 
Randomized subjects will participate in three follow-up visits conducted virtually with a 
trained study team member to review the following:
●
Changes in concomitant medications and changes in health
●
Subjects eDiary compliance & study product use 
○
Subjects who are non-compliant with eDiary completion or study product use 
for greater than two consecutive days will receive a follow-up from a trained 
member of the study team re-educating them on study procedures.
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●
Review any adverse events or safety events and pregnancies which may have occurred 
since the last virtual visit. Participants will also be able to report any (S)AEs and 
pregnancies to the study team between virtual visits via dedicated trial phone number. 
5.6
On-going Daily eDiaries
The subject will receive links via text and email with instructions for completion of the study 
daily diaries. The subject will input their responses directly into the EDC platform. The daily 
eDiary consists of one question to confirm the subject has consumed the study product. 
If subjects fail to complete or state “no” to the study product consumption survey for greater 
than 48-hours, the study team will contact the subject to re-educate on the study procedures 
and compliance. 
5.7
On-going Assessments: Week 4, Week 8 & Week 12
On the first day of the visit window of week 4, week 8, and week 12, the subject will receive 
links via text and email with instructions for completion of the MFI and Supplementary QoL 
questionnaire. The subject will input their responses directly into the EDC platform. The 
subject will receive reminders to complete the MFI and the Supplementary QoL questionnaire. 
If the subject does not complete the MFI and the Supplementary QoL questionnaire within the 
48-hour timeframe, a trained member of the study team will contact them via text, phone, or 
email. If the subject has not completed the MFI by the time of their scheduled virtual visit, they 
will be instructed to complete the MFI during the visit. 
End of Treatment Period
Subjects will have the option to discontinue treatment at their discretion. The reasons for 
discontinuing treatment will be captured by a trained study team member and every effort will 
be made to capture reasons for discontinuation (i.e. follow up calls, letters, texts, or e-mails to 
the subjects, etc. Subjects will be informed that the study will end after week 12 and will be 
asked to fill out an exit survey. 
6
STUDY ASSESSMENTS
Every effort should be made to ensure that protocol-required assessments and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it infeasible to complete 
an assessment.  When a protocol-required assessment cannot be performed, the investigator (or 
designee) will document the reason for the missed assessment as a protocol deviation and any 
corrective and preventative actions that he or she has taken to ensure that required processes 
are adhered to as soon as possible. The Sponsor must be informed of any missed assessments.
6.1
Outcome Assessments
Assessments will be performed by delegated staff at the times, and in the order, defined in the 
Study Procedures section of this protocol. 
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The objective of the study is to evaluate the effectiveness of daily Emergen-C on QoL 
parameters. This includes self-reported outcomes from the Multidimensional Fatigue Inventory 
domains and supplemental QoL questions at baseline, week 4, week 8, and week 12. 
Multidimensional Fatigue Inventory (MFI-20): The MFI (29) is a 20-item scale designed to 
evaluate five dimensions of fatigue: general fatigue (items 1, 5, 12, 16), physical fatigue (items 
2, 8, 14, 20), reduced motivation (items 4, 9, 15, 18), reduced activity (items 3, 6, 10, 17), and 
mental fatigue (items 7, 11, 13, 19). Subjects will answer a series of questions indicating how 
they feel about each statement, lately. Items are scored 1–5,  1- indicating “yes, that is true” 
and 5- indicating “no, that is not true”, with higher total scores representing a worse outcome. 
For scoring, 10 positively phrased items reverse scored (this concerns the following items: 2, 
5, 9, 10, 13, 14, 16, 17, 18, 19) while 10 negatively phrased items are scored at face value (this 
concerns the following items: 1, 3, 4, 6, 7, 8, 11, 12, 15, 20). For each of the 5 scales (general 
fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue) a total score 
is calculated by summation of the scores of the individual items. Domain scores can range from 
the minimum of 4 to the maximum of 20, the higher the score the worse the level of fatigue 
outcome. 
Supplemental QoL questions: Six additional questions will be asked to evaluate the 
effectiveness of the intervention on target outcomes. Subjects will answer a series of questions 
indicating how they feel about each statement, lately. Questions are scored 1–5,  1- indicating 
“yes, that is true” and 5- indicating “no, that is not true”, with higher total scores representing 
a worse outcome. Additional questions include:
●
I feel more energized to look after my family and/or loved ones
●
I feel more prepared for the future
●
I feel resilient so I can be at my best each day
●
I feel ready to cope with life’s challenges
●
I feel relaxed
●
I feel able to unwind
Subjects will be asked to report their health in the previous 4 weeks using four additional 
questions:
●
In the last 4 weeks, how many days did you feel rundown, if any?
●
In the last 4 weeks, how many days did you have to cancel plans or work because you 
were not feeling 100%, if any?
●
In the last 4 weeks, how many days did you have cold and cough symptoms (for 
example: runny nose, blocked nose, sneezing, cough, sore throat), if any? 
●
In the last 4 weeks, how many days were you in bed sick, if any?
Exit survey question: Subjects will be asked to complete an exit survey following their 
completion of the study asking one question:
●
Would you use your assigned supplement again?
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6.2
Safety and Other Assessments
The following safety assessments will be performed by appropriately trained staff/clinical 
examiners, at the times and in the order defined in the Study Procedures section of this protocol.  
6.2.1
Pregnancy Testing
For Haleon studies in which no drug is utilized or studies of single use marketed products that 
are classified as a non-medicinal product in the market where the testing is occurring and there 
is no pregnancy warning on labeling, a pregnancy test will not be required.
Female subjects will provide verbal confirmation of pregnancy status at Screening (Visit 1) 
and will be asked to inform study staff immediately should this change at any point during the 
study. Female subjects who are pregnant or planning pregnancy during the study (self-reported) 
will not participate further in the study.
7
STUDY PRODUCTS
For the purposes of this study, per International Conference on Harmonization (ICH) 
guidelines, and Haleon policy, study intervention is defined as any investigational 
intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered 
to a study participant according to the study protocol. This includes a product with a marketing 
authorization when used or assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when used to gain further 
information about an approved use. 
7.1
Study Product Supplies
Each subject will receive sufficient study product to cover usage during the treatment period 
of the study. The following study products will be supplied by the Sponsor’s preferred vendor 
(Table 7-1). Study test product usage instructions are consistent with the commercially 
available pack instructions (excludes reference product). Subjects will not be required to return 
unused study products after treatment discontinuation or completion of week 12 study 
activities. However, subjects will be instructed to destroy unused study product after treatment 
discontinuation or completion of week 12 study activities. 
Table 7-1
Investigational/Study Product Supplies
Test Product
Reference Product 
Product Name
Emergen-C Core Super 
Orange Powder
Placebo
Pack Design
Large carton containing 3 
small cartons of 30 sachets 
each
Large carton containing 3 
small cartons of 30 sachets 
each
Dispensing Details
One labeled carton 
(containing 3 cartons, with 30 
sachets per carton) shipped to 
One labeled carton(containing 
3 cartons, with 30 sachets per 
carton) shipped to subject 
following baseline visit 
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subject following baseline 
visit 
Haleon formula codes:
Dose
As per label instructions: 
Subjects will consume one 
sachet stirred in 4-6 ounces of 
water once per day in the 
morning at approximately the 
same time each day
As per label instructions: 
Subjects will consume one 
sachet stirred in 4-6 ounces of 
water once per day in the 
morning at approximately the 
same time each day
Route of Administration
Oral
Oral
Usage Instructions
As per directions stated on 
the label
As per directions stated on 
the label
Return Requirements
All unused study products will 
be destroyed/disposed of.
All unused study products will 
be destroyed/disposed of.
7.2
Product Supplies, Product Storage, Accountability, Returns and 
Destruction
All study products supplied are for use only in this clinical study and should not be used for 
any other purpose. Guidance will be provided to the Sponsor’s preferred vendor for the receipt, 
storage and management of products for the duration of the trial by Haleon Clinical Supplies 
and with further instructions included with the shipping documentation.
 preferred vendor should ensure that the room or area set aside for storage is 
able to maintain the correct temperature (room temperature) to meet the product label storage 
conditions, is sufficient to store all products and is secure and access controlled.
Any temperature excursions or discrepancies whilst study products are stored at site require 
the affected products to be quarantined and this must be communicated immediately to the 
Sponsor who will provide documentation to approve further usage. Use of any of the affected 
product(s) prior to sponsor approval will be considered a protocol deviation.
Study products are to be dispensed only to subjects enrolled in the study in accordance with 
the protocol, by designated investigator staff. Enrolled/randomized subjects will be informed 
on product usage and storage and what to do in the event of product loss when the products are 
first dispensed. 
All study products will be accounted for using the investigational/study product accountability 
form/record. 
 preferred vendor is responsible for study product accountability, 
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reconciliation, and record maintenance. Unused study products will not be returned or 
destroyed. 
7.3
Blinding and Randomization
Qualifying subjects will be centrally randomized into one of two study groups using a  
randomization list provided by Haleon Clinical Supplies. Before the study is initiated, training 
and directions for the randomization will be provided to the investigator study team. Study 
products will be dispensed in sequential order as per the randomization schedule. 
will submit a list of subject ID numbers and corresponding kit codes to the Vendor each day 
for study product shipment. Only subjects who meet the study inclusion criteria will be 
randomized to a study product.
This study is described as double-blind (i.e., the clinical examiner and study participants will 
be blinded to the study product each subject receives). Additionally, investigator staff involved 
in the clinical or safety assessments, study statistician(s), data management staff, other 
employees of the sponsor (including the sponsor’s Clinical Research Scientist (CRS)) and 
vendors acting on behalf of the sponsor who may influence study outcomes, will also be 
blinded to treatment allocation. 
To maintain the blind throughout the study:
●
Subjects will see and use only one of the two study products during the study. They 
will be instructed not to discuss the appearance, usage, or perceived performance of 
their allocated study product with staff involved in clinical assessments or with other
study subjects. 
●
The study product will be provided to the 
 preferred vendor in 
unmarked cartons masking their identity and obscure any branding on the commercial 
product with a study label affixed. Both study products (treatment and placebo) are 
packaged in individual, unmarked, identical foil sachets. 
●
The study product will be supplied in individual packs (cartons); each large carton will 
contain three smaller cartons, each containing 30 sachets of study product (90 sachets 
total). Each subject will receive one large carton, marked with a kit number containing 
only their randomized study product; product codes will not be used. 
7.4 
     Breaking the Blind
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a subject’s product assignment is warranted. Subject safety must always be the 
first consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a subject’s product assignment unless this could delay emergency treatment of the 
subject.
If a subject’s study product assignment is unblinded, the sponsor must be notified within 24 
hours after breaking the blind. The date and reason that the blind was broken must be recorded 
in the source documentation and case report form, as applicable.
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8
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
8.1 
Sample Size Determination
The primary objective for this study is to evaluate the over-time effects of Emergen-C Core 
Super Orange Powder on QoL parameters, as measured by the MFI domain scores (General 
Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, Mental Fatigue), compared 
to placebo, when taken daily over 12 weeks.
A total of 300 subjects will be randomized (approximately 150 per group) to ensure sufficient 
power for the primary analysis. Assuming a maximum drop-out rate of 20%, approximately 
240 evaluable subjects in total (120 per group) complete the entire study.
The sample size calculation was performed using R software version 4.4.1.
8.2 
Populations for Analysis
8.2.1 Definitions of Analysis Populations
The following four study populations will be used for statistical analysis:
●
The modified Intention-To-Treat (mITT) population consists of all subjects who have 
been randomized, completed baseline visit (visit 1), completed at least one-post 
baseline MFI domain assessment and have taken at least one dose of their allocated 
randomized product. Group allocation will be based on the study product to which the 
subject was randomized. All subjects who receive a randomization number will be 
considered randomized. The mITT population will be used as the primary population 
for the assessment of efficacy.
●
The Per-Protocol (PP) population includes all mITT subjects who have adhered to the 
allocated treatment regime and are not considered to have been affected by protocol 
deviations.
●
The Safety population (SP) includes all randomized subjects who have taken at least 
one dose of their randomized study product. Analyses of this population will be based 
on the investigational product received. 
8.2.2 Exclusions of Data from Analysis
Exclusion of any data/subject from the analyses will be agreed during a Blinded Data Review 
(BDR) Meeting prior to database lock. The reasons for exclusion of a subject from an analysis 
population or data from an analysis will be documented and listed, if applicable.
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Any efficacy data agreed to have been potentially impacted by a protocol deviation will be 
excluded from the PP analysis. A PP analysis will be performed on the primary endpoint if 
there is greater than or equal to a 10% difference in the number of subjects between the PP and 
mITT populations. A decision on whether a protocol deviation impacts any efficacy data and 
whether a PP analysis will be performed will be made as part of the BDR Meeting prior to 
database lock.
8.3 
Statistical Analyses
Additional details of the proposed statistical analysis will be documented in the statistical 
analysis plan (SAP), which will be written following finalization of the protocol and prior to 
study unblinding/analysis (as appropriate). This section is a summary of the planned statistical 
analyses of the primary and key secondary endpoints and a brief summary of how other 
collected data will be analyzed.
The mITT population will be used for all efficacy analyses.
All p-values presented will be two-sided and assessed at the 5% significance level. A sequential 
testing strategy will be used to adjust for the comparisons between the Emergen-C and placebo 
group at each assessment time point.
Change from Baseline in each of the MFI domain scores at earlier timepoints will only be 
assessed for confirmatory evidence if the change from the later timepoint achieves a 
statistically significant difference. Each domain will only be evaluated if the change from 
Baseline to 12 weeks (primary endpoint) was significant at the Bonferroni-Holm adjusted 
significance level. A significance level of 5% applies to all subsequent analyses of timepoints.
This strategy will begin at Week 12, then move to Week 8, then to Week 4. There will be no 
further adjustments for multiplicity for other secondary endpoints.
Summary Statistics (mean, median, SE, SD, minimum, maximum) will be presented for each 
outcome variable at each assessment time point. Raw means (+/- SE) of the primary and 
secondary endpoints will be plotted by treatment group.
The results from each Mixed Model with Repeated Measures (MMRM) will be tabulated, 
presenting the least square mean change from baseline for each treatment group at each 
timepoint and the comparison between Emergen-C and Placebo, with two-sided p-values and 
95% CIs. 
8.3.1 Primary Endpoint Analysis(es) 
The primary endpoint of this study is the Change from Baseline in QoL parameters as measured 
by the MFI domains at Week 12. The primary hypothesis test will be the comparison between 
Emergen-C and Placebo in the mITT population.
Change from Baseline will be calculated at Week 12 for all MFI domain scores:
●General Fatigue Domain score (sum of items 1,5,12,16)
●Physical Fatigue Domain score (sum of items 2,8,14,20)
●Reduced Activity Domain score (sum of items 3,6,10,17)
●Reduced Motivation Domain score (sum of items 4,9,15,18)
●Mental Fatigue Domain score (sum of items 7,11,13,19)
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Change from Baseline will be calculated at the subject level first then the mean change from 
baseline will be calculated for each of the MFI domains across all subjects.
Change from Baseline for each of the MFI domains listed above will be analyzed using a 
MMRM with treatment, timepoint as a factor and [treatment x timepoint] interaction as fixed 
effects, and the respective Baseline MFI domain score as a covariate. Subject will be included 
as a repeated measure with an unstructured covariance matrix. Kenward-Rogers degrees of 
freedom will be applied (Kenward, 1997). The difference between the least square mean 
change from baseline for the treatment compared to placebo group at Week 12 from the 
MMRM will be presented along with the two-sided p-value and 95% CIs. A Bonferroni-Holm 
correction will be applied to the p-values and CIs of the least square mean change between 
groups to account for multiple testing. Adjusted and non-adjusted p-values will be reported.
The assumption of normality and homogeneity of variance in the MMRM will be investigated. 
In case of violation of these assumptions, a suitable non-parametric test will be performed to 
assess the change from baseline comparison. The results will be provided to support the 
MMRM results.
For each MFI domain listed above, the value at each timepoint (Baseline, Week 4, Week 8 and 
Week 12) and the corresponding Change from Baseline will be summarized descriptively for 
each treatment group. Raw means (+/- SE) for each MFI endpoint at each assessment timepoint 
will be plotted by treatment group.
8.3.2 Secondary Endpoint Analysis(es)
The secondary endpoints of each MFI domain at Week 4 and Week 8 will be analyzed as 
described for the primary endpoint. Non-adjusted p-values and 95%-CIs will be reported, 
which need to be interpreted in light of the results of the primary endpoint, as described in 
section 8.2.
Similarly, the secondary endpoint for each of the individual MFI questions will be analyzed as 
described for the primary endpoint, but with baseline of the MFI domain score replaced with 
the individual MFI question score at baseline for the respective MFI item for each timepoint 
(Week 4, Week 8 and Week 12).
The secondary endpoint for the each of the supplementary QoL questions will also be analyzed 
using the same MMRM model described above, but with baseline of the MFI domain score 
replaced with the Baseline of the respective QoL question for each timepoint (Week 4, Week 
8 and Week 12).
8.3.3 Exploratory Analyses
The number of days reported at each timepoint (and total) will be listed and summarized by 
treatment group in the mITT population using descriptive statistics for: 
●
days feeling unwell
●
days canceling plans
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●
days with cough and cold symptoms
●
days sick in bed
Raw means (± SE) will be plotted for each assessment timepoint by treatment group. Analysis 
will be performed comparing treatment groups at each timepoint using a student’s t-test. If data 
are found to be non-normal, a suitable non-parametric test will be used.
8.3.4 Safety Analysis(es)
The absolute and relative frequency of AEs in each group will be reported, including the total 
number of events, the total number of patients experiencing at least one event, and the 
frequency of events by severity and AE category.
Safety analyses will be performed on the Safety population, according to investigational 
product received. AEs will be regarded as ‘treatment emergent’ if they occur on or after the 
first use of investigational product at Baseline (Visit 2). In the event of a missing start date, an 
AE will be assumed to be ‘treatment emergent’ unless the end date is prior to starting treatment. 
In case of misallocation compared to the randomization schedule, TEAEs will be associated 
with the most recent investigational product received.
AE will be assessed by the investigator or medically qualified designee. AE review and coding 
will be in line with the Site and Safety Management Plan. 
A listing of all AEs will be presented for all subjects in the Safety population with the following 
AE summaries (number of distinct AEs and frequency/proportion of subjects affected) 
presented by treatment group and overall:
• TEAEs
• TEAEs by System Organ Class (SOC) and Preferred Term (PT)
• Treatment emergent treatment related AEs by SOC and PT
• Treatment emergent treatment related serious AEs by SOC and PT
Separate listings will be presented for:
• Deaths, SAEs and any AEs leading to product or study discontinuation.
• Exposure to study product
8.3.5 Other Analysis(es)
A subgroup analysis will be conducted for the primary and secondary analysis as an exploratory 
outcome for:
●
sex (male and female)
●
age ( ≥18 to < 35 and ≥35 to ≤64 years)
8.3.6 Demographic and Baseline Characteristics
Demographic and baseline characteristics for each group will be reported for the mITT and 
Safety populations (and for the PP population, if a PP analysis is performed) using descriptive 
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statistics. Categorical variables (such as sex, race, ethnicity) will be summarized by the number 
and percentage of subjects with each relevant characteristic in each treatment group. Arithmetic 
mean, standard deviation, as well as median and 25%- and 75%-iles, minimum and maximum 
will be reported for continuous variables.
Outcome data collected repeatedly will be described for each measurement point in time.
8.3.7 Study Product Compliance and Use of Other Therapies
8.3.7.1 
Study Product Compliance
Treatment compliance will be assessed daily during the 12-week treatment period.  Compliance 
will be analyzed descriptively by reporting the absolute and relative frequency of subjects with 
80% compliance to treatment per block of 4 treatment weeks and overall, for each group. A 
compliance score will be calculated for each subject by dividing the number of days the 
allocated treatment was taken by the number of days the treatment was allocated. The 
compliance score will be summarized for each group and compared between groups.
8.3.7.2 
Prior and Concomitant Medications
Prior medication use will be assessed during the Screening visit. Concomitant medication use 
will be monitored at each study visit. Subjects will be able to report concomitant medications 
between visits. Prior medications/non-drug therapies and concomitant medications/significant 
non-drug therapies used prior to treatment initiation and in the treatment phase will be listed, 
including the frequency within each group, for the Safety population.
8.3.8 Handling of Dropouts and Missing Data 
MMRM analyses account for missing data using ‘a missing at random’ assumption, i.e., there 
is a systematic relationship between the propensity for missing values and the observed data, 
but not the missing data.
Under such assumptions, MMRM is shown to provide unbiased estimates of the treatment 
effect whilst analysis of only complete cases using analysis of covariance (ANCOVA) is biased 
(Ashbeck, 2016; Baron, 2008).
Such complete case analysis requires a ‘missing completely at random’ assumption to remain 
unbiased and this is unlikely to hold, i.e., the fact that the data are missing is independent of 
the observed and unobserved data.
Using an MMRM, it will therefore be assumed that a subject with missing data at one post-
Baseline assessment visit would have obtained a similar efficacy result at that visit compared 
to a subject using the same investigational product with similar non-missing results at other 
timepoints (Baseline and the other post-Baseline assessment visits).
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9
APPENDICES
9.1      Adverse Event (AE) and Serious AE (SAE)
Adverse events can be reported / recorded by any member of the trial team. The investigator 
and their authorized safety designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to study product, a study procedure or 
study participation, or that caused the subject to discontinue use of a study product or study 
participation. 
All Adverse Events and Serious Adverse Events will be managed in line with the protocol 
and in line with the Site and Safety Management Plan. 
9.1.1        Definition of an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of a study product including an acclimatisation product whether or not considered 
related to the study product, including an acclimatisation product Note: An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a study product 
including an acclimatization product (or medical device).
Events Meeting the AE Definition: 
●
Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or 
other safety assessments (e.g., electrocardiogram, radiological scans, vital sign 
measurements), including those that worsen from Baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related to 
progression of underlying disease).
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study product administration even though 
it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
product or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
●
‘Lack of efficacy’ or ‘failure of expected pharmacological action’ per se will not be 
reported as an AE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms and/or clinical sequelae resulting from lack of efficacy 
will be reported as an AE if they fulfill the definition of an AE.
Events NOT meeting the AE definition:
●
Any clinically significant abnormal laboratory findings (if applicable) or other 
abnormal safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the subject’s condition.
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●
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
●
A medical or surgical procedure (e.g., endoscopy, appendectomy) is not an AE. The 
condition that leads to the procedure is an AE (e.g., appendicitis). Planned medical or 
surgical procedures for pre existing illnesses are not an adverse event.
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
9.1.2        Definition of a Serious Adverse Event
An SAE is a particular category of AE where the outcome is serious. If an event is not an AE 
per definition above, then it cannot be an SAE, even if serious conditions are met (e.g., 
hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease). A serious adverse event is any untoward medical occurrence at any dose that:
●
Results in death
●
Is life‑threatening
-   The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to 
an event, which hypothetically might have caused death, if it were more severe.
●
Requires inpatient hospitalization or prolongation of existing hospitalization
-   In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolonged hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
‘hospitalization’ occurred, or was necessary, the AE should be considered serious.
-   Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline more than would be expected under the normal progression 
of the disease not considered an AE.
●
Results in persistent or significant disability/incapacity
-   The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.
-   This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
●
Results in congenital anomaly/birth defect
●
Other situations:
-   Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
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may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
Note: Classification of an AE as ‘serious’ is based on the outcome of the event and is a factor 
in determining reporting requirements.
Events exempt from immediate reporting as SAEs
Hospitalization for a pre-existing condition, including elective procedures planned prior to
trial entry, which has not worsened, does not constitute an SAE.
9.1.3        Time Period and Frequency for Collecting AE and SAE Information
All AEs, and therefore all SAEs (except from those exempt from recording, as described in 
section 9.1.1 and section 9.1.2) will be collected from immediately after a subject is randomised 
within the trial and until 2 days following the last administration of study product (or the last 
study procedure).
Medical occurrences that began before randomisation will be recorded in the Medical 
History/Current Medical Conditions section of the Electronic Case Report Form (eCRF), not 
the AE section.
Details recorded by the subject that meet the definition of a serious AE must be discussed with 
the subjects and transcribed into the SAE section of the eCRF.
All SAEs will be recorded and reported to the sponsor or designee immediately, and under no 
circumstance should this exceed 24 hours. The investigator will submit updated SAE data to 
the sponsor within 24 hours of it being available.
9.1.4        Reporting Procedures
The investigator and study delegated designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE and remain responsible for following up AEs 
that are serious, considered related to study product, a study procedure or study participation, 
or that caused the subject to discontinue use of study product or study participation, until 
stabilization, resolution, trial completion or loss to follow up, whichever comes sooner.
The investigator and their authorized trial designees are to report all AEs at study visits and all 
AEs spontaneously reported by study subjects.
Study subjects will be questioned about AEs. Care will be taken not to introduce bias when 
questioning a subject about any changes in their health. Open-ended and non-leading verbal 
questioning should be used.
AEs spontaneously reported by study subjects and those elicited by asking subjects to respond 
to non-leading questions (such as ‘how do you feel?’) will be assessed, recorded in the eCRF 
and reported, as appropriate.
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Each AE is to be assessed to determine if it meets the criteria for a SAE. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
When an AE occurs, it is the responsibility of the investigator or their medically qualified 
designee to assess the severity of the event, which may require a review of additional 
documentation (e.g., hospital progress notes, laboratory and diagnostics reports) related to the 
event. The investigator or study staff will then record all relevant information relating to the 
event in the SAE section of the eCRF. In addition, all details relating to an SAE will be recorded 
electronically within Citrus using the SAE eCRF provided.
It is not acceptable for the investigator or their authorized safety designee to send photocopies 
of a subject’s medical records to the sponsor in lieu of completion of the AE section of the 
eCRF/paper SAE form. There may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In this instance, all subject identifiers, except for the subject 
number, will be redacted on the copies of the medical records prior to submission to the 
sponsor.
The investigator or their medically qualified designee will attempt to establish a diagnosis 
based on signs, symptoms and/or other available clinical information related to the event. The 
diagnosis will be documented as the AE/SAE, where known, and not the individual 
signs/symptoms (e.g., upper respiratory tract infection or seasonal allergy, not ‘runny nose’).
9.1.5        Reporting an AE
AEs will be reported by the investigator, their authorized trial designee or investigator staff in 
the AE section of the eCRF.  These are collected throughout the study at each follow-up visit. 
Additionally, the subject will have the option to report any AEs to the study staff at any point 
during the study. Where an SAE is recorded the electronic SAE form should be utilized and 
reported within 24 hours of awareness. AEs/SAEs should be reported using concise medical 
terminology. Where the same data are collected, the AE section of the eCRF and the SAE eCRF 
must be completed in a consistent manner (e.g., the same AE term should be used for both). 
9.1.6        Reporting an SAE
In addition to recording the details of each SAE in the AE section of the eCRF, an SAE form 
should be completed, as fully as possible. All SAE reporting will utilize the eCRF in Citrus
It is essential to record the following information for each SAE:
●
Protocol and subject identifiers
●
Subject demography
●
Description of event with diagnosis, if available
●
Investigator opinion of relationship to study product (or study procedure)
●
Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and sponsor 
assessment of the SAE report:
●
Date of onset of SAE
●
Date SAE stopped, if relevant
●
Study product start date
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●
Study product end date, if relevant
●
Action taken in relation to study product
●
Outcome, if known
The SAE form, completed as fully as possible, must be exported from Citrus, e-mailed to the 
sponsor’s Case Management Group mailbox 
, with the 
appropriate sponsor Study Manager in copy, with the study number and subject number in the 
subject line of the email immediately after investigator staff learn of the event, and under 
no circumstances should this exceed 24 hours. The investigator will submit any updated 
SAE data to the sponsor, immediately once it becomes available, and under no 
circumstance should this exceed 24 hours of it being available.
The initial report will be followed up with more information as relevant, or as requested by the 
sponsor’s Study Manager. The sponsor’s Study Manager will be responsible for forwarding 
the SAE form to other sponsor personnel as appropriate.
9.1.7        Evaluating AEs
Assessment of Intensity
The investigator or their medically qualified designee will make an assessment of intensity for 
each AE reported during the study and will assign it to one of the following categories:
●
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities.
●
Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities
●
Severe:  An event that prevents normal everyday activities.
Note: An AE assessed as ‘severe’ should not be confused with an SAE. ‘Severe’ is a category 
utilized for rating the intensity of an event. Both non-serious AEs and SAEs can be assessed as 
severe, e.g., a headache may be severe (significantly interferes with the subject's usual function) 
but would not be classified as serious unless it met one of the criteria for SAEs listed in Section 
9.1.2. An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes 
described in the definition of an SAE (Section 9.1.2), not when it is rated as ‘severe’.
Assessment of Causality
For each AE (non-serious and serious), the investigator or their medically qualified designee 
must provide an assessment of causality in the AE section of the eCRF and on the SAE form 
(as appropriate, subject to classification of the AE). Causality is one of the criteria used to 
determine regulatory reporting requirements.
A ‘reasonable possibility’ of a relationship conveys there are facts (evidence) and/or arguments 
to suggest a causal relationship, rather than a relationship cannot be ruled out. Generally, the 
facts (evidence) or arguments to suggest a causal relationship should be provided in the 
AE/SAE report.
The investigator or their medically qualified designee will use clinical judgment to determine 
causality and will also consult the Investigator Brochure (IB), Safety Statement and/or Product 
Information, as appropriate, when making their assessment. Alternative causes, such as 
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underlying disease(s), concomitant therapy, other risk factors and the temporal relationship of 
the event to study product use will be considered and investigated.
Documentation of the (S)AE assessment will be recorded in trial database, including 
documenting the assessment of causality.Where applicable, the investigator or their medically 
qualified designee must document in the medical notes they have reviewed the AE/SAE and 
provided an assessment of causality.
There may be situations, when an SAE has occurred, where the investigator or their medically 
qualified designee has minimal information to include in the initial SAE report. However, it is 
very important that the investigator or their medically qualified designee always makes 
an assessment of causality for every event prior to initial transmission of the SAE data to 
the sponsor. The investigator may change their opinion of causality, in light of follow-up 
information, and send an SAE follow-up report with an updated causality assessment.
9.1.8        Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator or their authorized safety designee is required 
to proactively follow up all ongoing serious and severe AE with each subject and provide 
further information on the subject’s condition, as available.
All severe AEs (non-serious and serious) should be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained or until the subject is lost to follow-
up. 
The investigator or their medically qualified designee is obligated to perform or arrange for the 
conduct of supplemental measurements and/or evaluations as may be indicated (or as requested 
by the sponsor) to elucidate as fully as possible the nature and/or causality of the AE/SAE. 
These may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other healthcare professionals.
New or updated information will be recorded in the AE section of the eCRF and on the SAE 
form (as appropriate, subject to classification of the AE). The investigator or their authorized 
safety designee will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
The investigator and their authorized safety designees are not obligated to actively seek AEs 
or SAEs after the conclusion of study participation. However, if the investigator or their 
medically qualified designee learns of an SAE, including a death, at any time after a subject 
has been discharged from the study, and they consider the event to be reasonably related to 
study product or study participation, they must promptly notify the sponsor by emailing the 
information 
to 
the 
sponsor’s 
Case 
Management 
Group 
mailbox 
, with the appropriate sponsor Study Manager in copy.
The investigator or their authorized trial designee will submit any updated SAE data to the 
sponsor within the designated reporting time frames.
9.1.9        Withdrawal Due to an Adverse Event
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Withdrawal due to AEs should be distinguished from withdrawal due to other causes, according 
to the definition of an AE provided (Section 9.1.1) and recorded in the withdrawalAE section 
of the eCRF.
When a subject withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined in this protocol.
9.1.10    Regulatory Reporting Requirements for SAEs
The sponsor has a legal responsibility to notify, as appropriate, the local regulatory authority 
and other regulatory authorities about the safety of a product under clinical investigation.  
Prompt notification of SAEs by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
The sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, the Institutional Review Board (IRB) and the investigator.
Investigator safety reports must be prepared for suspected Unexpected Serious Related Event 
(USRE) according to local regulatory requirements and sponsor policy, and forwarded to the 
investigator, as appropriate.
If the investigator receives an investigator safety report describing a SAE or other specific 
safety information (e.g., a summary or listing of SAEs) from the sponsor, they will review it, 
file it with other safety information (e.g., the IB) in the investigator site file and notify the 
REC, if appropriate, according to local requirements.
9.2     Pregnancy
9.2.1     Time Period for Collecting Pregnancy Information
Pregnancy information will be collected on all pregnancies reported while a female subject is 
participating in the study from the date/time of signing the informed consent until 5 days after 
the last administration of the study product.
9.2.2     Action to be Taken if Pregnancy Occurs
The investigator or their authorized trial designee will record pregnancy information on the 
appropriate 
eCRF 
and 
e-mail 
it 
to 
the 
Case 
Management 
Group 
mailbox 
) within 24 hours, with the appropriate sponsor Study 
Manager in copy. Original completed pregnancy information forms will be retained in the 
investigator site file.
The female subject will not be followed to determine the outcome of the pregnancy. Any female 
subject who becomes pregnant while participating will be withdrawn.  
9.3     Discontinuation of Study Product and Subject 
Discontinuation/Withdrawal
If a subject is discontinued early from the study product (Section 9.3.1) or discontinued or 
prematurely withdraws from the study (Section 9.3.2), the reason(s) for intervention 
discontinuation or withdrawal and the associated date must be documented in the relevant 
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section(s) of the eCRF. If a subject is discontinued early from the study product, the subject 
should stay in the study and complete the remaining assessments unless they need to be 
withdrawn (see Section 9.3.2).
9.3.1     Discontinuation of Study Product
A subject may be discontinued from the study product at any time whilst still in the study at 
the discretion of the investigator related to safety, subject consent or a potential worsening of 
the risk / benefit assessment from the subject of remaining on the intervention for the following 
reasons:
●
Adverse Event
●
Lack of efficacy from the intervention
●
Subject request
●
Subject to be withdrawn from the study (see Section 9.3.2) 
9.3.2     Subject Discontinuation/Withdrawal
A subject may withdraw from the study at any time at his or her own request or may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures.  
The following circumstances require discontinuation of study product and/or premature subject 
withdrawal:
●
Protocol violation that may impact the subject’s safety
●
Withdrawal of informed consent
●
Subject lost to follow-up 
●
Unblinding of the subject 
●
Pregnancy
If the subject withdraws from the study and withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
9.3.3     Lost to Follow up
If a subject fails to attend required virtual visit, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls or emails or local 
equivalent methods) and reschedule the missed visit as soon as possible and counsel the subject 
on the importance of maintaining the assigned visit schedule and ascertain whether the subject 
wishes to and/or should continue in the study.
A subject will be considered lost to follow up and withdrawn from the study if he or she 
repeatedly fails to attend scheduled virtual visits and is unable to be contacted by the study 
team. 
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If contact is made with the subject, the investigator should inquire about the reason for 
withdrawal and if appropriate request that the subject attend a final virtual visit and follow-up 
with the subject regarding any unresolved adverse events (AEs).
9.4 Data Management
As used in this protocol, the term eCRF is understood to refer to an electronic data record.
The source documents which contain the source of data recorded in the eCRF should be 
specified.  The eCRF and/or eDiary can be used as a source document at the discretion of data 
management.
Each subject will be assigned and identified by a unique Screening Subject Number. Any 
reference made to an individual subject within the study must be done using their unique 
Screening Subject Number.
9.4.1 Case Report Form
An eCRF is an electronic document designed to record the protocol required information to be 
reported to the sponsor on each trial subject.
For each subject who has given informed consent the eCRF must be completed and signed by 
the Principal Investigator (or authorized designee) to certify that the data are complete and 
correct.  The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
Management of clinical data will be performed in accordance with Third Party Biostatistics 
and Data Management (BDM) Vendor applicable standards and data cleaning procedures with 
oversight by Haleon to ensure integrity of the data, for example, to remove errors and 
inconsistencies in the data. To protect the privacy of subjects, no Personal Information (PI) 
(including the subject's name or initials or full birth date) is to be recorded in the CRF or as 
part of the query text. All CRF pages should be completed during a subject assessment when 
the CRF has been designated as the source. Data that is sourced elsewhere should be entered 
into the CRF in an agreed upon timeframe between the Investigator and Sponsor. Haleon will 
obtain and retain all CRFs and associated study data as applicable at the completion of the 
study.
9.4.2 Data Handling
Documentation of all data management activities should allow step-by-step retrospective 
assessment of data quality and study performance. 
Any changes or corrections to data will be performed in the Electronic Data Capture (EDC) 
System, and it will include rationale for changes. The EDC system has an audit trail, which 
will provide a complete record of the changes and corrections endorsed by the Investigator.
Adverse events will be coded (in line with the Site and Safety Management Plan) and 
concomitant medications terms (if applicable) using the 
 dictionary.
Programmed edit checks will be generated automatically, as the data are being entered into the 
system. Reports and listings on the CRF data will also be run, in addition to the queries already 
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programmed and generated by the system, to raise manual queries as needed for site 
clarification or correction. The 3rd Party BDM Vendor will raise queries as needed on safety 
data to code the terms (AEs and Drugs or concomitant medication) appropriately. 
The study monitor will perform ongoing review the of the CRFs in accordance with the 
monitoring plan, to confirm that data entered into the CRF by authorized site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.
9.4.3 Data Queries
Any queries will be generated in the EDC System to the Investigator or designee, enabling the 
errors to be addressed in parallel with Data Management review. The study monitor can also 
run reports and listings on the CRFs, to raise manual queries as needed for site clarification or 
correction.
Due to the low risk associated with the study intervention, there will be no data monitoring 
committee for the study. Monitoring will occur as documented on the study risk assessment 
and monitoring plan.
9.5
Processing Patient Reported Outcomes and Data Collection from 
Internet of Medical Things
Electronic Patient reported outcome (ePRO) that are measured by Internet of Medical Things 
(IoMT) devices (i.e., wearables, patches, sensors, and mobile data collection units such as 
smartphones and tablets) will be transferred in the protocol-specified aggregated and/or raw 
form electronically to Haleon or Third-party DM vendor.
All ePRO source data should be reviewed by the study staff and the study monitor to ensure 
accurate transcription of data and that any potential AEs or concomitant medications reported 
on these documents are discussed with the subject and transcribed accurately to the eCRF 
and/or DMS. ePROs that are classed as source data will be retained by the investigator and 
true/certified copies may be sent to a designated vendor or Haleon as required. Any AEs or 
concomitant medications collected as ePRO will be reviewed and transcribed to the eCRF by 
the site.
To protect the privacy of subjects, no Personal Information (PI) (including the subject's name 
or initials or birth date) is to be recorded on any PRO/ePRO/IoMT Devices Data that will be 
forwarded to Haleon or Third-Party Vendor.
9.6 
Regulatory and Ethical Considerations
9.6.1 Institutional Review Board/ Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent document, safety statement (including any updates) 
and other relevant documents, e.g. recruitment advertisements, if applicable, from the IRB/EC.  
All correspondence with the IRB/EC should be retained in the investigator file.  Copies of 
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IRB/EC approvals should be forwarded to Haleon prior to the initiation of the study, and also 
when subsequent amendments to the protocol are made.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/EC and Haleon in writing immediately after the 
implementation.
9.6.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol and legal and regulatory 
requirements, as well as the ethical principles set forth in the International Ethical Guidelines 
for Biomedical Research Involving Human Subjects (Council for International Organizations 
of Medical Sciences 2002), International Ethical Guidelines for Health-Related Research 
Involving Humans (Council for International Organizations of Medical Sciences, 2016), 
guidelines for GCP (ICH 1996 and revision 2), and the Declaration of Helsinki (World Medical 
Association 2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws.
9.6.3 Subject Information 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Haleon and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Haleon in order to de-identify study subjects.  
The study site will maintain a confidential list of subjects who participated in the study, linking 
each subject’s numerical code to his or her actual identity.  In case of data transfer, Haleon will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
9.7 
Records Retention
Following closure of the study, the investigator must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and secure location.  
The duration of archiving will be as per local regulatory requirements. 
Where permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution needs to be exercised before such action is taken. 
The investigator must notify Haleon of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in the 
event the investigator is no longer associated with the site.
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9.8 
Disclosure and Publication Policy
Study information from this protocol may be posted on publicly available clinical trial registers 
before enrollment of subjects begins in accordance with applicable Haleon policies.
Haleon intends to make anonymized subject-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 
science. This helps ensure the data provided by study participants are used to maximum effect 
in the creation of knowledge and understanding.
The procedures and timing for public disclosure of the results summary and for development 
of a manuscript for publication will be in accordance with sponsor policy and as per the country 
specific requirements for disclosure.
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9.9 
Schedule of Activities Schematic
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9.10 
Study Questionnaires
9.10.1 
Multidimensional Fatigue Index (MFI-20)
Question:
Response:
1.
I feel fit
yes, that is true
1
2 3 4 5 no, that is not true
2.
Physically I feel only able to do a little
yes, that is true
1
2 3 4 5 no, that is not true
3.
I feel very active
yes, that is true
1
2 3 4 5 no, that is not true
4.
I feel like doing all sorts of nice things
yes, that is true
1
2 3 4 5 no, that is not true
5.
I feel tired
yes, that is true
1
2 3 4 5 no, that is not true
6.
I think I do a lot in a day
yes, that is true
1
2 3 4 5 no, that is not true
7.
When I am doing something, I can keep my 
thoughts on it
yes, that is true
1
2 3 4 5 no, that is not true
8.
Physically I can take on a lot
yes, that is true
1
2 3 4 5 no, that is not true
9.
I dread having to do things
yes, that is true
1
2 3 4 5 no, that is not true
10. I think I do very little in a day
yes, that is true
1
2 3 4 5 no, that is not true
11. I can concentrate well
yes, that is true
1
2 3 4 5 no, that is not true
12. I am rested
yes, that is true
1
2 3 4 5 no, that is not true
13. It takes a lot of effort to concentrate on things
yes, that is true
1
2 3 4 5 no, that is not true
14. Physically I feel I am in a bad condition
yes, that is true
1
2 3 4 5 no, that is not true
15. I have a lot of plans
yes, that is true
1
2 3 4 5 no, that is not true
16. I tire easily
yes, that is true
1
2 3 4 5 no, that is not true
17. I get little done
yes, that is true
1
2 3 4 5 no, that is not true
18. I don't feel like doing anything
yes, that is true
1
2 3 4 5 no, that is not true
19. My thoughts easily wander
yes, that is true
1
2 3 4 5 no, that is not true
20. Physically I feel I am in an excellent condition
yes, that is true
1
2 3 4 5 no, that is not true
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9.10.2 
Additional QoL Questions
I feel more energized to look after my family and/or 
loved ones
yes, that is true
1
2
3
4
5
no, that is not 
true
I feel more prepared for the future
yes, that is true
1
2
3
4
5
no, that is not 
true
I feel resilient so I can be at my best each day
yes, that is true
1
2
3
4
5
no, that is not 
true
I feel ready to cope with life's challenges
yes, that is true
1
2
3
4
5
no, that is not 
true
I feel relaxed
yes, that is true
1
2
3
4
5
no, that is not 
true
I feel able to unwind 
yes, that is true
1
2
3
4
5
no, that is not 
true
In the last 4 weeks, how many days of work did you 
miss, if any?
yes, that is true
1
2
3
4
5
no, that is not 
true
In the last 4 weeks, how many days with cold and flu 
symptoms did you have, if any?
yes, that is true
1
2
3
4
5
no, that is not 
true
In the last 4 weeks, how many days did you feel 
rundown, if any?
yes, that is true
1
2
3
4
5
no, that is not 
true
In the last 4 weeks, how many days did you have to 
cancel plans or work because you were not feeling 
100%, if any?
yes, that is true
1
2
3
4
5
no, that is not 
true
In the last 4 weeks, how many days did you have cold 
and cough symptoms (for example: runny nose, blocked 
nose, sneezing, cough, sore throat), if any? 
yes, that is true
1
2
3
4
5
no, that is not 
true
In the last 4 weeks, how many days were you in bed 
sick, if any?
yes, that is true
1
2
3
4
5
no, that is not 
true
End of Study question:
●
Would you use your assigned supplement again?
10 
ABBREVIATIONS
The following is a list of abbreviations that may be used in the protocol.
Table 10-1
Abbreviations
Abbreviation
Term
AE
Adverse Event
BDR
Blinded Data Review
CRS
Clinical Research Scientist
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Abbreviation
Term
eCRF
Electronic Case Report Form
eDiary
Electronic Diary
eICF
Electronic Informed Consent Form
ePRO
Electronic Patient Reported Outcome
EDC
Electronic Data Capture
e.g.
exempli gratia (for example)
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
Identification
IRB
Institutional Review Board
IoMT
Internet of Medical Things
ITT
Intention-To-Treat
MAOI
Monoamine Oxidase Inhibitors 
mITT
Modified Intention-to-Treat
MCID
Minimal Clinically Important Difference 
MFI
Multidimensional Fatigue Index
mg
milligrams
MMRM
Mixed Model with Repeated Measures
N/A
Not Applicable
PDF
Portable Document Format
PP
Per Protocol
QoL
Quality of Life
RWE
Real World Evidence
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SP
Safety Population
SUSAR
Suspected Unexpected Serious Adverse Event
UK
United Kingdom
US
United States
Wi-Fi
Wireless Fidelity
Yr
Years
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