Clinical trial NCT04668352
Conditions: Respiratory Tract Infections
Sponsor: Restorbio Inc.
Start date: 2019-04-15; Completion date: 2019-12-02
Enrollment: 1024 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine if RTB101 as compared to placebo decreases the percentage of subjects with clinically symptomatic respiratory illness (with or without an associated laboratory-confirmed pathogen) through Week 16.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Dactolisib intervention 2: Placebo
Intervention descriptions: intervention 1: TORC1 inhibitor intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
A Multicenter, Randomized, Double Blind, Placebo-Controlled, Phase 3 Study 
to Determine if RTB101 Prevents Clinically Symptomatic Respiratory Illness 
in the Elderly 
 
 
Compound: 
RTB101 
Protocol Number: 
RTB-101-204 
Protocol Date: 
16 September 2019 
Version Number: 
06 (Amendment 03) 
Sponsor: 
resTORbio, Inc. 
500 Boylston Street 
13th Floor 
Boston MA 02116 USA 
Clinical Trial Phase: 
3 
 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of resTORbio Inc. 




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Investigator Agreement 
Protocol Title: 
A Multicenter, Randomized, Double Blind, Placebo-
Controlled, Phase 3 Study to Determine if RTB101 Prevents 
Clinically Symptomatic Respiratory Illness in the Elderly 
Protocol Number: 
RTB-101-204, Version 06 (Amendment 03) 
Study Phase: 
3 
Sponsor: 
resTORbio, Inc. 
I confirm that I have read and that I understand this protocol amendment, the Investigator’s Brochure, and 
other product information provided by the Sponsor. 
I agree to conduct this study in accordance with the requirements of this protocol and protect the rights, 
safety, privacy, and well-being of study subjects in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference on Harmonization Guidance for Industry, Good Clinical Practice E6 (R2). 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• 
Regulatory requirements for reporting serious adverse events defined in this protocol. 
 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 


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Protocol Synopsis 
Protocol Number 
RTB-101-204 
Title 
A Multicenter, Randomized, Double Blind, Placebo-Controlled, Phase 
3 Study to Determine if RTB101 Prevents Clinically Symptomatic 
Respiratory Illness in the Elderly 
Brief Title 
Phase 3 study to determine if RTB101 prevents respiratory illness 
associated with respiratory tract infections (RTIs) in the elderly 
Sponsor 
resTORbio, Inc. 
Clinical Phase 
3 
Investigation Type 
Drug 
Study Type 
Interventional 
Purpose and 
Rationale 
The purpose of this study is to determine if RTB101 prevents clinically 
symptomatic respiratory illness (CSRI) in subjects ≥65 years of age. 
Subjects with clinically symptomatic respiratory illness are defined as 
subjects with symptoms consistent with a RTI based on prespecified 
diagnostic criteria. 
Primary 
Objective(s)  
• To determine if RTB101 as compared to placebo decreases the 
percentage of subjects with clinically symptomatic respiratory 
illness (with or without an associated laboratory-confirmed 
pathogen) through Week 16 
Secondary 
Objectives 
• To determine if RTB101 as compared to placebo decreases the 
percentage of subjects with clinically symptomatic respiratory 
illness associated with ≥1 laboratory-confirmed pathogen(s) 
through Week 16 
• To determine the effect of RTB101 as compared to placebo on the 
rate of clinically symptomatic respiratory illnesses associated with 
specific laboratory-confirmed viruses (coronaviruses, human 
metapneumovirus [hMPV], human rhinovirus [HRV]/enterovirus, 
adenovirus, influenza A and B virus, parainfluenza viruses, and 
respiratory syncytial virus [RSV]) through Week 16 
• To determine if RTB101 as compared to placebo decreases the rate 
of clinically symptomatic respiratory illness (with or without an 
associated laboratory-confirmed pathogen) through Week 16 
• To determine if RTB101 as compared to placebo decreases the rate 
of clinically symptomatic respiratory illnesses associated with ≥1 
laboratory-confirmed pathogen(s) through Week 16 


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• To determine if RTB101 as compared to placebo decreases time to 
alleviation of moderate and severe respiratory illness symptoms 
due to clinically symptomatic respiratory illness through Week 16 
• To determine if RTB101 as compared to placebo decreases the 
percentage of subjects with severe symptoms due to clinically 
symptomatic respiratory illnesses through Week 16 
• To assess the safety and tolerability of RTB101 through Week 20 
Exploratory 
Objectives  
• To explore the effect of RTB101 as compared to placebo on the 
rate of all laboratory-confirmed viral respiratory infections with or 
without symptoms through Week 16 
• To explore the effect of RTB101 as compared to placebo on the 
rate of all-cause hospitalizations through Week 16 
• To explore the effect of RTB101 as compared to placebo on the 
rate of hospitalizations associated with RTIs through Week 16  
• To explore the effect of RTB101 as compared to placebo on the 
rate of all-cause Emergency Room (ER) visits through Week 16 
• To explore the effect of RTB101 as compared to placebo on the rate 
of ER visits associated with RTIs through Week 16  
• To explore the effect of RTB101 as compared to placebo on the 
rate of all-cause urgent care clinic visits through Week 16 
• To explore the effect of RTB101 as compared to placebo on the 
rate of urgent care visits for clinically symptomatic respiratory 
illness through Week 16 
• To explore the effect of RTB101 as compared to placebo on the 
rate of all-cause admissions to skilled nursing facilities through 
Week 16 
• To explore the effect of RTB101 as compared to placebo on 
hospital length of stay associated with RTIs through Week 16 
• To explore the effect of RTB101 as compared to placebo on all-
cause hospital length of stay through Week 16   
• To explore the effect of RTB101 as compared to placebo on the 
percentage of subjects with clinically symptomatic respiratory 
illness and the percentage of subjects with clinically symptomatic 
respiratory illness associated with ≥1 laboratory-confirmed 
pathogen(s) through Week 20 
• To explore the effect of RTB101 as compared to placebo on 
change from Baseline in health-related quality of life (HRQoL) as 
assessed by EQ-5D-5L scores during all clinically symptomatic 
respiratory illness episodes and at Week 16 
• To explore the effect of RTB101 as compared to placebo on the 
percentage of subjects with clinically symptomatic respiratory 
illnesses and on the percentage of subjects with clinically 


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symptomatic respiratory illnesses associated with 1 laboratory-
confirmed pathogen(s) through Week 16 who are ≥85 years of age 
or subjects with a medical history of asthma  
• To explore the effect of RTB101 as compared to placebo on the 
rate of clinically symptomatic respiratory illnesses and on the rate 
of clinically symptomatic respiratory illnesses associated with 1 
laboratory-confirmed pathogen(s) through Week 16 in subjects 
who are ≥85 years of age or subjects with a medical history of 
asthma 
• To explore the effect of RTB101 as compared to placebo on the 
incidence of asthma exacerbations through Week 16 in subjects 
with a medical history of asthma 
• To explore the effect of RTB101 as compared to placebo on the 
incidence of urinary tract infections (UTIs) through Week 16 
• To explore the effect of RTB101 on immunologic biomarkers and 
to explore biomarkers that may predict response (e.g. RNA 
expression in whole blood, serum biomarkers, genetic variation) 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, 
parallel-group, Phase 3 study to determine if RTB101 prevents 
clinically symptomatic respiratory illness in elderly subjects. Subjects 
will be enrolled during cold and flu season. The study will be 
comprised of up to a 4-week Screening Period; a 16-week Primary 
Analysis Period (for evaluating efficacy) during which time subjects 
meeting study eligibility criteria will be randomized 1:1 to receive 
RTB101 10 mg or matching placebo once daily through the Week 16 
Visit; a 4-week Short-term Follow-up Period (for evaluating safety and 
efficacy through the Week 20 Visit); and a 28-week Long-term 
Follow-up Period (for evaluating safety through Week 48 by follow-up 
questionnaire). 
Population 
The study population will be comprised of subjects ≥65 years of age 
without  unstable underlying medical conditions including subjects in 
assisted-living or long-term care residential facilities that provide 
minimal assistance, such that the subject is primarily responsible for 
self-care and activities of daily living. 
Number of Subjects Approximately 1066 subjects are planned to be randomized in the 
study. Subjects will be randomized 1:1 to RTB101 10 mg or placebo 
taken orally once daily (approximately 533 subjects will be 
randomized to each arm). 
Inclusion Criteria 
 
Subjects eligible for inclusion in this study must fulfill all of the 
following criteria: 
1. Written informed consent must be obtained before any assessment 
is performed. 


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2. Male and female subjects who, in the clinical judgement of the 
Investigator, are without unstable medical conditions defined as 
conditions that require acute medical intervention or ongoing 
adjustments of concomitant medications (as determined by medical 
history, current concomitant medications and laboratory test results 
at Screening, and physical examination, electrocardiogram (ECG) 
and vital signs at Screening and Baseline). 
3. Subjects must be ≥65 years of age.  
4. Subjects should require no or minimal assistance with self-care and 
activities of daily living. Subjects in assisted-living or long-term 
care residential facilities that provide minimal assistance are 
eligible.  
5. Females must be post-menopausal. Women are considered post-
menopausal and not of child bearing potential if they have had: 
• 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g., age appropriate, history of 
vasomotor symptoms) OR 
• surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least 
six weeks prior to Screening. In the case of oophorectomy 
alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
will she be considered not of child bearing potential. 
6. Sexually active male subjects with a partner of child-bearing 
potential must be willing to wear a condom while on study drug 
and for 1 week after stopping study drug and should not father a 
child in this period. A condom is required to be used also by 
vasectomized men with a partner of child-bearing potential to 
prevent delivery of the drug via seminal fluid. 
7. Subject must weigh at least 40 kg. 
8. Subject must be able to communicate well with the Investigator, 
and to understand and comply with the requirements of the study 
including completing a daily eDiary at home. 
Exclusion Criteria 
 
Subjects will not be eligible if they meet any of the following criteria: 
1. Any subject who: 
 Is a current smoker as assessed by medical history or a 
positive serum cotinine test (or positive urine cotinine test if 
serum cotinine testing is unavailable) at Screening. 
 Stopped smoking ≤1 year prior to Screening. 
 Is a previous smoker with a ≥10 pack year smoking history. 
 Has a household member who currently smokes in the 
house. 
2. Subjects with a medical history of clinically significant lung 
diseases other than asthma (e.g., chronic obstructive pulmonary 


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disease (COPD), emphysema, interstitial pulmonary fibrosis (IPF), 
bronchiectasis, etc.). 
3. Subjects with a Mini Mental Status Examination (MMSE) score 
<24 at Screening. 
4. Subjects with current evidence of a serious and/or unstable medical 
disorder including cardiovascular, respiratory, gastrointestinal, 
renal (including subjects with an estimated glomerular filtration 
rate (eGFR) as estimated by the modified diet in renal disease 
(MDRD) GFR equation that is  ≤30 mL/min/1.73m2), or 
hematologic disorders. 
5. The following cardiac conditions: 
 Unstable angina pectoris or acute ischemic changes on 
ECG at Screening or Baseline 
 History of myocardial infarction (MI), coronary bypass 
surgery, or any percutaneous coronary intervention (PCI) 
within 6 months prior to Screening 
 New York Heart Association functional classification III-
IV congestive heart failure 
 Unstable or life-threatening cardiac arrhythmia 
i. Chronic stable atrial fibrillation is allowed. 
 QTcF>480 msec at Screening or Baseline 
6. Subjects with history of malignancy in any organ system within the 
past 5 years, EXCEPT for the following:  
 Localized basal cell or squamous cell carcinoma of the 
skin. 
 Prostate cancer confined to the gland (AJCC stage 
T2N0M0 or better). 
 Cervical carcinoma in situ. 
 Breast cancer localized to the breast. 
7. Any RTI or acute significant illness (based on the subject’s 
medical history and the clinical judgement of the Investigator) 
which has not resolved at least two (2) weeks prior to Baseline. 
8. Subjects with a history of systemic autoimmune diseases (e.g., 
lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), 
or receiving immunosuppressive therapy (such as mycophenolate, 
tacrolimus, cyclosporine, azathioprine, infliximab) including 
chronic use of prednisone >10 mg daily (however, inhaled 
corticosteroids and the acute use of higher doses of prednisone to 
treat conditions such as exacerbation of asthma or other acute 
conditions are allowed). 
9. Subjects with Type I diabetes mellitus. 
10. Clinically relevant abnormal laboratory values suggesting an 
unknown disease and requiring further evaluation.  
11. Subjects with any one of the following during Screening:  
 white blood cell (WBC) count <2.0 x103/microL. 
 neutrophil count <1.0 x 103/microL. 


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 platelet count <75 x 103/microL.. 
12. Subjects with a history of alcohol or drug abuse within 2 years of 
the Screening visit.  
13. Subjects with any conditions affecting absorption, distribution, or 
metabolism of the study drug (e.g., inflammatory bowel disease, 
gastric or duodenal ulcers, or hepatic disease). For subjects with 
biochemical evidence of liver injury as indicated by abnormal liver 
function tests: 
• Any single parameter of alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase or 
serum bilirubin must not exceed 1.5 x upper limit of normal 
(ULN) in subjects who do not have Gilbert's syndrome. If the 
subject has a history of Gilbert’s syndrome, direct and indirect 
reacting bilirubin should be differentiated, and the direct 
bilirubin must be less than 1.5 x ULN. 
• Any elevation above ULN of more than one parameter of 
ALT, AST, alkaline phosphatase or serum bilirubin will 
exclude a subject from participation in the study. 
14. Subjects with a history of immunodeficiency diseases, including a 
positive human immunodeficiency virus (HIV) test result. 
15. Infection with Hepatitis B virus (HBV) or Hepatitis C virus (HCV). 
16. Subjects who require treatment with strong CYP3A4 or CYP1A2 
inhibitors or inducers, or subjects who require treatment with 
digoxin. 
17. Use of any other investigational medication or participation in any 
other investigational study within 5 half-lives of the investigational 
medication, or within 30 days, whichever is longer; or longer if 
required by local regulations.  
18. Subjects who have received an organ transplant. 
19. Subjects who previously received treatment with RTB101 in 
another clinical study (e.g., CBEZ235Y2201, RTB-BEZ235-202, 
or RTB-101-203). 
Drug Treatment 
RTB101 (dactolisib, previously designated as BEZ235) 
Subjects will receive oral RTB101 10 mg or matched placebo capsule 
once daily for up to 16 weeks.  
Efficacy 
Assessments 
Primary Endpoint:  
• The percentage of subjects with clinically symptomatic respiratory 
illness (with or without an associated laboratory-confirmed 
pathogen) beginning at least 3 days after the start of study drug 
treatment through Week 16 as assessed by pre-specified clinical 
diagnostic criteria 
 
 


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Secondary Endpoints:  
• The percentage of subjects with 1 or more clinically symptomatic 
respiratory illnesses associated with ≥1 laboratory-confirmed 
pathogen(s) beginning at least 3 days after the start of study drug 
treatment through Week 16 as assessed by pre-specified clinical 
diagnostic criteria and respiratory pathogen PCR of 
nasopharyngeal swabs, sputum gram stain and culture, and/or rapid 
influenza diagnostic tests (RIDTs) 
• The rate of clinically symptomatic respiratory illnesses associated 
with specific laboratory-confirmed viruses (coronaviruses, hMPV, 
HRV/enterovirus, adenovirus, influenza A and B virus, 
parainfluenza viruses, and RSV) beginning at least 3 days after the 
start of study drug treatment through Week 16 as assessed by 
respiratory pathogen PCR of nasopharyngeal swabs and/or RIDTs. 
• The rate of clinically symptomatic respiratory illness (with or 
without an associated laboratory-confirmed pathogen) beginning at 
least 3 days after the start of study drug treatment through Week 16 
as assessed by pre-specified clinical diagnostic criteria 
• The rate of clinically symptomatic respiratory illnesses associated 
with ≥ 1 laboratory-confirmed pathogen(s) beginning at least 3 
days after the start of study drug treatment through Week 16 as 
assessed by pre-specified clinical diagnostic criteria and respiratory 
pathogen PCR of nasopharyngeal swabs, sputum gram stain and 
culture, and/or RIDTs 
• The time to alleviation of moderate and severe clinically 
symptomatic respiratory illness symptoms due to clinically 
symptomatic respiratory illness beginning at least 3 days after the 
start of study drug treatment through Week 16 
• The percentage of subjects with severe symptoms due to clinically 
symptomatic respiratory illnesses beginning at least 3 days after the 
start of study drug treatment through Week 16  
• Safety and tolerability will be assessed by report of adverse events 
(AE)/serious adverse events (SAEs), physical exam and ECG 
findings, and safety laboratory values 
 
Exploratory Endpoints: 
• The rate of all laboratory-confirmed viral infections with or 
without symptoms beginning at least 3 days after the start of study 
drug treatment through Week 16 as assessed by respiratory 
pathogen PCR of nasopharyngeal swabs and/or RIDTs (obtained 
during episodes of symptomatic respiratory illnesses) and/or 
respiratory pathogen PCR of mid-turbinate swabs (obtained at 
scheduled study visits, even in the absence of symptoms)  
• The rate of all-cause hospitalizations through Week 16 


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• The rate of hospitalizations associated with RTIs beginning at least 
3 days after the start of study drug treatment through Week 16 
• The rate of all-cause ER visits through Week 16 
• The rate of ER visits associated with RTIs beginning at least 3 days 
after the start of study drug treatment through Week 16 
• The rate of all-cause urgent care clinic visits through Week 16 
• The rate of urgent care clinic visits for clinically symptomatic 
respiratory illness beginning at least 3 days after the start of study 
drug treatment through Week 16 
• The rate of all-cause admissions to skilled nursing facilities 
through Week 16 
• Hospitalization length of stay associated with  RTIs beginning at 
least 3 days after the start of study drug treatment through Week 16   
• All-cause hospitalization length of stay through Week 16  
• The percentage of subjects with 1 or more clinically symptomatic 
respiratory illnesses and the percentage of subjects with 1 or more 
clinically symptomatic respiratory illnesses associated with ≥1 
laboratory-confirmed pathogen(s) beginning at least 3 days after 
the start of study drug treatment through Week 20 as assessed by 
pre-specified clinical diagnostic criteria and respiratory pathogen 
PCR of nasopharyngeal swabs, sputum gram stain and culture, 
and/or RIDTs 
• The change from Baseline in HRQoL as assessed by EQ-5D-5L 
scores during all clinically symptomatic respiratory illness episodes 
beginning at least 3 days after the start of study drug treatment and 
at Week 16 
• The percentage of subjects with one or more clinically 
symptomatic respiratory illnesses and the percentage of subjects 
with one or more clinically symptomatic respiratory illnesses 
associated with 1 laboratory-confirmed pathogen(s) beginning at 
least 3 days after the start of study drug treatment through Week 16 
who are ≥85 years of age or subjects with a medical history of 
asthma   
• The rate of clinically symptomatic respiratory illnesses and the rate 
of clinically symptomatic respiratory illnesses associated with 1 
laboratory-confirmed pathogen(s) beginning at least 3 days after the 
start of study drug treatment through Week 16 in subjects who are 
≥85 years of age or subjects with a medical history of asthma 
• The rate of asthma exacerbations and the percentage of subjects 
with 1 or more asthma exacerbations defined as deterioration of 
asthma symptoms that requires treatment with systemic steroids  
beginning at least 3 days after the start of study drug treatment 
through Week 16 in subjects with a medical history of asthma 
• The rate of UTIs and the percentage of subjects with one or more 
UTIs reported as adverse events. 


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• Change from Baseline to Weeks 4 and 16 in biomarkers in whole 
blood and serum and potentially future pharmacogenomic analysis  
Safety Assessments 
• Physical examination 
• Body temperature 
• Blood pressure, heart rate 
• Respiratory rate 
• ECG 
• Hematology, blood chemistry, urinalysis 
• Adverse events (including SAEs) from time of start of study drug 
treatment until Week 20 
Data Analysis 
The percentage of subjects with clinically symptomatic respiratory 
illness (with or without an associated laboratory-confirmed pathogen) 
beginning at least 3 days after the start of study drug treatment through 
Week 16 is the primary efficacy endpoint for this study. The primary 
analysis of the primary efficacy endpoint will be based on the 
intention-to-treat principle, comprising all subjects who are 
randomized and have received at least one dose of assigned study drug 
during the trial. The primary efficacy endpoint will be analyzed 
through a logistic regression model to obtain an estimate of the 
population odds ratio and associated confidence intervals between 
RTB101 and placebo. This primary efficacy model will be adjusted for 
factors that may influence response to treatment for clinically 
symptomatic respiratory illness, such as age, frailty score, receipt of 
current season influenza vaccination and medical history of asthma, 
CHF or Type 2 diabetes mellitus. 
 
Sample size was determined based on a two-sided comparison between 
RTB101 and placebo. In parts 1 and 2 of the Phase 2b trial, 28.2% of 
subjects had a clinically symptomatic respiratory illness on placebo 
(excluding subjects with COPD and current smokers). With an 
assumed Week 16 clinically symptomatic respiratory illness incidence 
of 28.2% on placebo, and of 19.7% in the RTB101 arm, a total sample 
size of 1066 subjects (equally randomized) will provide 90% power to 
detect a 30% reduction in the percentage of subjects with clinically 
symptomatic respiratory illness between RTB101 and placebo using a 
two-sided test of 0.05 significance. Power analysis was conducted 
using Likelihood Ratio Chi-square Test.    
 
A fixed sequence gate-keeping strategy will be used to control the 
study-wise error rate at a 2-sided α-level of 0.05.  The following 
primary, secondary and exploratory efficacy endpoints will be tested in 
the sequence specified below:  


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Order 
H1 
The percentage of subjects with 1 or more CSRIs 
(with or without an associated laboratory-confirmed 
pathogen) beginning at least 3 days after the start of 
study drug treatment through Week 16. 
H2 
The percentage of subjects with 1 or more CSRIs 
associated with ≥1 laboratory-confirmed pathogen(s) 
beginning at least 3 days after the start of study drug 
treatment through Week 16 as assessed by pre-
specified clinical diagnostic criteria, and respiratory 
pathogen PCR of nasopharyngeal swabs, sputum 
gram stain and culture, and/or RIDTs. 
H3 
The rate of CSRI (with or without an associated 
laboratory-confirmed pathogen) beginning at least 3 
days after the start of study drug treatment through 
Week 16 as assessed by pre-specified clinical 
diagnostic criteria.  
H4 
The rate of CSRIs associated with ≥ 1 laboratory-
confirmed pathogen(s) beginning at least 3 days after 
the start of study drug treatment through Week 16 as 
assessed by pre-specified clinical diagnostic criteria 
and respiratory pathogen PCR of nasopharyngeal 
swabs, sputum gram stain and culture, and/or RIDTs. 
H5 
The time to alleviation of moderate and severe 
respiratory illness symptoms due to CSRI beginning 
at least 3 days after the start of study drug treatment 
through Week 16. 
H6 
The percentage of subjects with severe symptoms 
due to CSRIs beginning at least 3 days after the start 
of study drug treatment through Week 16. 
H7 
The rate of all-cause hospitalizations beginning at 
least 3 days after the start of study drug treatment 
through Week 16.  
H8 
The rate of UTIs beginning at least 3 days after the 
start of study drug treatment through Week 16 
reported as adverse events 
H9 
The percentage of subjects with 1 or more CSRIs 
(with or without an associated laboratory-confirmed 
pathogen) beginning at least 3 days after the start of 
study drug treatment through Week 20. 
 
The primary endpoint, H1, will be tested first at a 2-sided alpha level of 
0.05.  The subsequent endpoints will be tested in the order specified 
above also at a 2-sided alpha-level of 0.05, if and only if the preceding 


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endpoint was found to be statistically significant.  If the preceding 
endpoint in the sequence fails to meet statistical significance, then 
testing of subsequent endpoints will be stopped and no further 
statistical conclusions will be made. 
 
To investigate the impact of missing data assumptions on the primary 
efficacy results, a number of sensitivity analyses, including a tipping 
point analysis will be conducted. Details of the sensitivity analyses, 
will be provided in the statistical analysis plan (SAP).  
 
Safety and Tolerability: 
Safety evaluations will be based on actual treatment received. 
Continuous safety data will be summarized with descriptive statistics 
(arithmetic mean, standard deviation [SD], median, minimum, and 
maximum) by treatment. Categorical safety data will be summarized 
with frequency counts and percentages by dose level. Adverse events 
will be coded using the most current Medical Dictionary for 
Regulatory Activities (MedDRA®) available. A by-subject AE data 
listing, including verbatim term, preferred term, system organ class, 
treatment, severity, and relationship to study drug will be provided. 
The number of subjects experiencing AEs and number of individual 
AEs will be summarized by treatment group, system organ class, and 
preferred term. AEs will also be summarized by severity and by 
relationship to study drug. 
 
Laboratory evaluations, vital signs and ECG assessments will be 
summarized by treatment group and protocol specified collection time 
point. A summary of change-from-baseline at each protocol specified 
time-point by treatment group will also be presented. 
 
Changes from baseline in continuous endpoints may be analyzed using 
repeated measures mixed analysis of covariance model adjusted for 
treatment, time point, treatment-by-time point interaction, and baseline 
values. Binomial endpoints may be summarized and compared 
between RTB101 and placebo via logistic regression. Rates per person 
will be summarized and compared between RTB101 and placebo via 
the Negative Binomial regression.  
 
Further details regarding presentation and analysis of safety data, 
including the approach for stratified data, will be detailed in the 
statistical analysis plan (SAP). 


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Table of Contents 
Sponsor Protocol Signature Page ................................................................................................. 2 
Investigator Agreement................................................................................................................ 3 
Protocol Synopsis ........................................................................................................................ 4 
Table of Contents ....................................................................................................................... 15 
List of Tables ............................................................................................................................. 19 
List of Figures ............................................................................................................................ 19 
List of Abbreviations ................................................................................................................. 20 
 
Introduction ...................................................................................................... 23 
1.1. 
Background ....................................................................................................... 23 
1.2. 
Previous Human Safety and Efficacy Data ....................................................... 26 
1.2.1. Clinical Study CBEZ235Y2201 ....................................................................... 27 
1.2.2. Clinical Study RTB-BEZ235-202..................................................................... 30 
1.2.3. Human Pharmacokinetic Data .......................................................................... 35 
1.3. 
Purpose .............................................................................................................. 36 
 
Study Objectives and Endpoints....................................................................... 36 
 
Investigational Plan .......................................................................................... 39 
3.1. 
Study Design ..................................................................................................... 39 
3.2. 
Study Design Rationale..................................................................................... 45 
3.2.1. Rationale for Choice of Comparator ................................................................. 48 
3.3. 
Risks and Benefits............................................................................................. 48 
 
Population ......................................................................................................... 53 
4.1. 
Inclusion Criteria .............................................................................................. 53 
4.2. 
Exclusion Criteria ............................................................................................. 54 
 
Treatment .......................................................................................................... 56 
5.1. 
Study Treatment ................................................................................................ 56 
5.2. 
Treatment Arms ................................................................................................ 56 
5.3. 
Treatment Assignment and Randomization ...................................................... 56 
5.3.1. Subject Numbering ........................................................................................... 56 
5.3.2. Treatment Assignment and Randomization ...................................................... 57 


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5.3.3. Treatment Blinding and Study Site Staff .......................................................... 57 
5.4. 
Treating the Subject .......................................................................................... 58 
5.4.1. Emergency Breaking of Assigned Treatment Code .......................................... 58 
5.4.2. Permitted Dose Adjustments to Study Treatment ............................................. 59 
5.4.3. Vaccinations ...................................................................................................... 59 
5.4.4. Concomitant Medications ................................................................................. 59 
5.4.5. Prohibited Medications ..................................................................................... 59 
5.5. 
Study Completion and Discontinuation ............................................................ 61 
5.5.1. Completion and Post-Study Treatment ............................................................. 61 
5.5.2. Discontinuation of Study Treatment ................................................................. 61 
5.5.3. Withdrawal of Consent ..................................................................................... 63 
5.5.4. Lost to Follow-up .............................................................................................. 63 
5.5.5. Study Enrollment Stopping Criteria.................................................................. 63 
5.5.6. Early Study Termination by the Sponsor .......................................................... 64 
 
Visit Schedule and Assessments ...................................................................... 64 
6.1. 
Informed Consent Procedures ........................................................................... 77 
6.2. 
Subject Screening.............................................................................................. 77 
6.2.1. Information to be Collected on Screen Failures ............................................... 77 
6.3. 
Dietary, Fluid and Other Restrictions ............................................................... 77 
6.4. 
Subject Demographics/Other Baseline Characteristics .................................... 78 
6.4.1. Hepatitis and HIV Screening ............................................................................ 78 
6.5. 
Treatment Exposure and Compliance ............................................................... 78 
6.6. 
Concurrent Medication ..................................................................................... 78 
6.7. 
Efficacy ............................................................................................................. 78 
6.7.1. Clinically Symptomatic Respiratory Illnesses .................................................. 79 
6.7.2. Laboratory-Confirmed Clinically Symptomatic Respiratory Illness ................ 79 
6.7.3. Assessment of Severity and Duration of Clinically Symptomatic Respiratory    
Illness Symptoms ............................................................................................. 80 
6.7.4. Appropriateness of Efficacy Assessments ........................................................ 80 
6.8. 
Safety ................................................................................................................ 81 
6.8.1. Medical History and Physical Examination ...................................................... 81 
6.8.2. Vital Signs ......................................................................................................... 81 
6.8.3. Height and Weight ............................................................................................ 81 


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6.8.4. Electrocardiogram (ECG) ................................................................................. 81 
6.8.5. Laboratory Evaluations ..................................................................................... 82 
 Hematology ....................................................................................................... 83 
 Clinical Chemistry ............................................................................................ 83 
6.8.6. Appropriateness of Safety Measurements ........................................................ 83 
6.9. 
Pharmacokinetic (PK) Assessments (only for those subjects identified per 
IXRS randomization) ....................................................................................... 83 
6.9.1. PK Analytical Methods ..................................................................................... 84 
6.10. 
Other Assessments ............................................................................................ 85 
6.10.1. Subject-Reported Outcomes Assessments ........................................................ 85 
6.10.2. Health-Care Resource Utilization ..................................................................... 85 
6.10.3. Exploratory Biomarkers .................................................................................... 86 
6.11. 
Use of Residual Biological Samples ................................................................. 86 
 
Safety Monitoring ............................................................................................. 87 
7.1. 
Adverse Events (AEs) ....................................................................................... 87 
7.2. 
Serious Adverse Event (SAE) Reporting .......................................................... 89 
7.2.1. Definition of SAE ............................................................................................. 89 
7.2.2. SAE Reporting .................................................................................................. 90 
7.3. 
Pregnancy Reporting ......................................................................................... 91 
 
Data Review and Database Management ......................................................... 93 
8.1. 
Study Site Monitoring ....................................................................................... 93 
8.2. 
Data Collection ................................................................................................. 94 
8.3. 
Database Management and Quality Control ..................................................... 94 
8.4. 
Data Monitoring Committee ............................................................................. 95 
 
Data Analysis ................................................................................................... 96 
9.1. 
Analysis sets...................................................................................................... 96 
9.2. 
Subject Demographics and Other Baseline Characteristics .............................. 96 
9.3. 
Treatments......................................................................................................... 96 
9.4. 
Analysis of the Primary Variable ...................................................................... 97 
9.4.1. Statistical Model, Hypothesis, and Method Analysis ....................................... 97 
9.4.2. Handling of Missing Value/Censoring/Discontinuations ................................. 99 
9.4.3. Summary Statistics of Safety ............................................................................ 99 
 Vital Signs ......................................................................................................... 99 


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 Electrocardiograms (ECGs) .............................................................................. 99 
 Clinical Laboratory Evaluations ....................................................................... 99 
 Adverse Events ............................................................................................... 100 
9.4.4. Sensitivity Analyses ........................................................................................ 100 
 Primary endpoint ............................................................................................. 100 
 Subpopulations ................................................................................................ 101 
9.5. 
Analyses of Secondary Efficacy Variables ..................................................... 101 
9.6. 
Sample Size Calculation ................................................................................. 103 
9.7. 
Interim Analyses ............................................................................................. 103 
 
Ethical Considerations .................................................................................... 104 
10.1. 
Regulatory and Ethical Compliance ............................................................... 104 
10.2. 
Responsibilities of the Investigator and IRB/IEC ........................................... 104 
10.3. 
Publication of Study Protocol and Results...................................................... 104 
10.4. 
Quality Control and Quality Assurance .......................................................... 104 
 
Protocol Adherence ........................................................................................ 105 
11.1. 
Protocol Amendments ..................................................................................... 105 
11.2. 
Financial Disclosure Reporting Obligations ................................................... 105 
 
References ...................................................................................................... 107 
 
Appendices ..................................................................................................... 111 
13.1. 
Appendix 1: List of Drugs that are CYP450 Inhibitors or Inducers to be used 
with Care or Prohibited with RTB101 Treatment and Narrow Therapeutic 
Index P-gp Substrate that is Prohibited with RTB101 ................................... 111 
13.2. 
Appendix 2: Algorithm for Management of Pneumonitis .............................. 112 
13.3. 
Appendix 3:  EQ-5D-L ................................................................................... 113 
13.4. 
Appendix 4: Clinical Frailty Scale .................................................................. 115 
 


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List of Tables 
Table 2-1  
 Summary of Study Objectives and Endpoints ................................................. 36 
Table 5-1 
 Investigational and Control Drugs .................................................................. 56 
Table 5-2  
 Prohibited Concomitant Medications .............................................................. 60 
Table 6-1 
 Assessment Schedule ...................................................................................... 73 
Table 13-1  
Strong CYP4503A4 Inhibitors (prohibited) ................................................... 111 
Table 13-2  
Strong CYP4503A4 Inducers (prohibited) ..................................................... 111 
Table 13-3  
Strong CYP4501A2 Inhibitors (prohibited) ................................................... 111 
Table 13-4  
Strong CYP4501A2 Inducers (prohibited) ..................................................... 111 
Table 13-5  
Narrow Therapeutic Index P-gp Substrates (prohibited, example below) ..... 111 
 
List of Figures 
Figure 1-1  
Incidence of Specific Pathogens Detected in Subjects ≥ 80 Years of Age 
Hospitalized with Community-acquired Pneumonia (Jain et al., 2015) ....................................... 24 
Figure 1-2  
Inhibition of TORC1 but not TORC2 may be Optimal for Treating Aging 
Related Conditions in Humans ..................................................................................................... 25 
Figure 1-3  
Spectrum of TORC1 Inhibition with Everolimus and RTB101 ....................... 26 
Figure 1-4  
TORC1 Inhibition Decreases Infection Rates in the Elderly ........................... 28 
Figure 1-5  
TORC1 Inhibition Decreases RTI Rates in the Elderly ................................... 29 
Figure 1-6  
Treatment with RTB101 Alone and in Combination with Everolimus but not 
Placebo Treatment Leads to Upregulation of Interferon Pathway Gene Expression ................... 30 
Figure 1-7  
Phase 2b Study Design ..................................................................................... 31 
Figure 1-8  
RTB101 10 mg QD Showed Consistent Benefit as Compared to Placebo in 
Multiple Pre-Specified Analyses of Laboratory (lab)-Confirmed RTIs ....................................... 33 
Figure 1-9  
A Reduction in the Incidence of Laboratory-Confirmed RTIs was Observed in 
Subjects 65 Years of Age and Older (excluding current smokers and COPD subjects) .............. 34 
Figure 3-1  
RTB-101-204 Study Design ............................................................................. 40 
 


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List of Abbreviations 
Abbreviation 
Definition of Term 
ADL 
activities of daily living 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
aspartate aminotransferase 
AUC 
area under the drug concentration versus time curve 
AUC0-24 
area under the drug concentration versus time curve from 0 to 24 hours 
b.i.d./BID 
twice a day 
BAL 
bronchoalveolar lavage 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CHF 
congestive heart failure 
CFR 
code of federal regulations 
CI(s) 
confidence interval(s) 
Cmax 
maximum plasma concentration 
COPD 
chronic obstructive pulmonary disease 
CRO 
contract research organization 
CT 
Computerized tomography 
CTC 
Common terminology criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
CXR 
chest x-ray 
DMC 
data monitoring committee 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eDiary 
electronic diary 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ER 
emergency room 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GI 
gastrointestinal 


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Abbreviation 
Definition of Term 
HBV 
hepatitis virus B 
HCV 
Hepatitis virus C 
HIV 
human immunodeficiency virus 
hMPV 
human metapneumovirus  
HRV 
human rhinovirus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IND 
Investigational New Drug Application  
IEC 
independent ethics committee 
IPF 
interstitial pulmonary fibrosis 
IRB 
independent review board 
i.v. 
intravenous 
IXRS 
interactive voice/web response system 
LFT 
liver function test 
MDRO 
multidrug-resistant organisms 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures model 
MMSE 
Mini Mental Status Examination 
mRNA 
Messenger ribonucleic acid 
MI 
myocardial infarction 
MNAR 
missing not at random 
mTOR 
mechanistic target of rapamycin 
mTORC 
mTOR-raptor signal transduction complex  
OR 
odds ratio 
PCI 
percutaneous coronary intervention 
PCR 
polymerase chain reaction 
PFT 
pulmonary function test 
P-gp 
P-glycoprotein 
PI3K 
phosphatidylinositol 3’kinase 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PSD 
premature subject discontinuation 
q.d/QD 
once a day 
RIDT 
rapid influenza diagnostic test 


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Abbreviation 
Definition of Term 
RNA 
ribonucleic acid 
RS 
randomized set 
RSV 
respiratory syncytial virus 
RTI(s) 
respiratory tract infection(s) 
S6K 
S6 kinase 
SAE(s) 
serious adverse event(s) 
SAF 
safety 
SAP 
statistical analysis plan 
SCR 
screening 
SD 
standard deviation 
SOM 
study operations manual 
T2DM 
type 2 diabetes mellitus 
TORC1 
target of rapamycin complex 1 
TORC2 
target of rapamycin complex 2  
ULN 
upper limit of normal 
U.S. 
United States 
WBC 
white blood cell 
 
 


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 Introduction 
 
Aging is regulated in part by a discrete set of cellular signaling pathways including the 
mechanistic target of rapamycin (mTOR) pathway (Lopez-Otin et al., 2013). Inhibition of the 
mTOR pathway has extended lifespan in every species studied to date and improved the function 
of multiple aging organ systems in old mice including the immune, neurologic and 
cardiovascular systems (Johnson et al., 2013). These data raise the possibility that drugs that 
target the mTOR pathway will have therapeutic benefit in aging-related conditions in humans. 
One of the aging-related conditions that improves in old mice treated with mTOR inhibitors is 
immunosenescence which is the decline in both innate and adaptive immune function that occurs 
during aging. Immunosenescence leads to decreased response to vaccinations and increased rates 
of infections including respiratory tract infections (RTIs) in the elderly. In preclinical studies in 
aged mice, short-term (6-week) treatment with the mTOR inhibitor rapamycin rejuvenated 
hematopoietic stem cell function, increased naïve lymphocyte production, enhanced the immune 
response to influenza vaccination, and increased lifespan (Chen et al., 2009). In addition, the 
mTOR inhibitor RTB101 has been shown to protect mice from a lethal influenza virus challenge 
(Smallwood et al., 2017). These findings raise the possibility that mTOR inhibitors may enhance 
immune function and protect elderly subjects from infections, and in particular RTIs.  
Unmet Medical Need 
Decreasing the incidence of RTIs is a large unmet medical need in people age 65 and above who 
are also the fastest growing population globally (United Nations, 2005).  RTIs are the fourth 
leading cause of hospitalization in people age 65 and over, and the second leading cause of 
hospitalization in people age 85 and over (Pfunter et al., 2013). Even upper RTIs, which are 
usually mild in younger adults, can cause significant morbidity in the elderly. A study of 
community dwelling subjects age 60-90 years of age found that 65% of subjects who developed 
upper respiratory tract infections also developed lower respiratory tract symptoms, 58% had 
systemic symptoms (headache, feverishness, chills, sweating, myalgias and rigors), 28% were 
confined to bed, and 35% were unable to cope with washing, shopping or cooking (Nicholson et 
al., 1997). The risk of cardiovascular events triples during episodes of RTIs, including upper 
RTIs, and the increased cardiovascular risk persists for weeks to months after a RTI episode 
(Musher et al., 2019). Finally, respiratory viruses cause the majority of RTIs, including 
community-acquired pneumonias requiring hospitalization in elderly subjects (Figure 1-1) (Jain 
et al., 2015). Unfortunately, there are currently no effective treatments for most respiratory 
viruses. RTB101 may offer an opportunity to enhance immune function in the elderly and 


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thereby decrease the incidence of RTIs, regardless of the specific pathogen, without inducing 
viral resistance.  
Figure 1-1  
Incidence of Specific Pathogens Detected in Subjects ≥ 80 Years of Age 
Hospitalized with Community-acquired Pneumonia (Jain et al., 2015) 
 
Shown are the annual number of pathogen-specific pneumonia hospitalizations per 10,000 adults 
≥80 years of age with 95% confidence intervals (CIs) (Jain et al., 2015). 
Since most respiratory infections in the elderly are caused by viruses for which there are 
currently no effective treatments, physicians are left with few therapeutic options for RTIs except 
antibiotics. This unnecessary use of antibiotics to treat RTIs contributes to the development of 
multidrug-resistant organisms (MDROs) that have become a major medical concern associated 
with high health care costs and patient morbidity and mortality. Therefore treatment with 
RTB101 may not only decrease RTI-associated morbidity and mortality in the elderly, but also 
limit the emergence of MDROs.  
To address this significant unmet medical need, resTORbio is developing RTB101 to improve 
immune function and reduce the incidence of clinically symptomatic respiratory illness in elderly 
patients. 


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Scientific Background 
mTOR signals via two complexes: target of rapamycin complex (TORC)1 and TORC2 (Figure 
1-2). Many of the beneficial effects of mTOR inhibition on aging in preclinical models are 
mediated by inhibition of TORC1 (Laplante et al., 2012; Lamming et al., 2012). In contrast, 
TORC2 inhibition has been associated with adverse events (AEs) including hyperglycemia and 
hyperlipidemia, and with decreased lifespan in male mice (Lamming et al., 2012; Lamming et 
al., 2014). Therefore, optimal mTOR inhibition for the treatment of aging-related conditions such 
as immunosenescence may be a regimen that inhibits the activity of TORC1 and phosphorylation 
of its downstream targets without inhibiting the activity of TORC2.  
Figure 1-2  
Inhibition of TORC1 but not TORC2 may be Optimal for Treating Aging 
Related Conditions in Humans 
 
Rapalogs such as everolimus are a class of allosteric mTOR inhibitors that are derivatives of 
rapamycin and are partial TORC1 inhibitors. Rapalogs consistently inhibit only the 
phosphorylation of S6 kinase (S6K) downstream of TORC1 (Feldman et al., 2009). RTB101 is a 
dual-kinase inhibitor that inhibits both phosphatidylinositol 3’-kinase (PI3K) and mTOR. 
RTB101 is a more potent inhibitor of mTOR (IC50 <100 nM) than PI3K (IC50  500 nM), and a 
more potent inhibitor of TORC1 (IC50  12 nM) than TORC2 (IC50  77 nM) (Serra et al., 2008). 
Therefore, at low concentrations, RTB101 is a TORC1-specific inhibitor and inhibits 
phosphorylation of S6K and eukaryotic translation initiation factor 4E binding protein 1 (4EPB1) 


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downstream of TORC1 (Serra et al., 2008; Maira et al., 2008; Baumann et al., 2008; Mannick et 
al., 2018). Moreover, low doses of RTB101 (and other catalytic mTOR inhibitors) in 
combination with low doses of everolimus synergistically inhibit all targets tested downstream of 
TORC1 without inhibiting TORC2 activity (Nyfeler et al., 2011; Nyfeler et al., 2012). Thus the 
least broad TORC1 inhibition is expected to be achieved with everolimus monotherapy, more 
broad inhibition is achieved with RTB101 monotherapy, and the most broad inhibition is 
achieved with a combination of low-dose RTB101 + everolimus therapy (Figure 1-3).    
Figure 1-3  
Spectrum of TORC1 Inhibition with Everolimus and RTB101 
 
Two Phase 2 clinical studies in elderly subjects were conducted to determine if RTB101 or 
everolimus alone and in combination improved immune function and thereby decreased infection 
rates in the elderly. The two Phase 2 trials in over 900 elderly subjects demonstrated that 
treatment with 10 mg RTB101 once daily was safe and was associated with clinically meaningful 
reductions in the incidence of RTIs. Analysis of gene expression in whole blood suggested that 
upregulation of innate anti-viral immunity was one of the mechanisms underlying the decreased 
incidence of RTIs observed in elderly subjects treated with RTB101 (Mannick et al., 2018). 
Based on the results of the two Phase 2 clinical trials, resTORbio is proposing to develop 
RTB101 10 mg once daily to prevent clinically symptomatic respiratory illness in elderly 
subjects who are defined as ≥65 years of age. 
 
Exposure data 
As of November 26, 2018, approximately 1088 subjects have been exposed to RTB101, alone or 
in combination with other compounds. RTB101 has been administered to more than 68 healthy 
S6K
Ulk1
TORC1
everolimus
4EBP1
S6K
Ulk1
4EBP1
TORC1
RTB101.  + everolimus
4EBP1
S6K
Ulk1
TORC1
4EBP1
RTB101
Inhibits the phosphorylation of
1 target of TORC1
Inhibits the phosphorylation of 
2 targets of TORC1
Inhibits the phosphorylation of 3 
targets of TORC1
= indicates phosphorylation is inhibited


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subjects in PK studies at doses up to 1000 mg/day. Four hundred and forty-two (442) oncology 
subjects have been exposed to RTB101 either as single agent once daily (q.d.) and twice daily 
(b.i.d.) in doses up to 1600 mg/day (160 times higher than the dose planned for Phase 3 trials to 
reduce the incidence of clinically symptomatic respiratory illness in elderly subjects), or in 
combination with everolimus, trastuzumab, paclitaxel, abiraterone, and MEK162. Development 
in oncology indications is no longer being pursued and there are no subjects enrolled in oncology 
studies.  In trials in elderly subjects, 410 elderly subjects have been exposed to RTB101 alone at 
doses ranging from 5-20 mg/day for up to 6-16 consecutive weeks, and 168 elderly subjects have 
been exposed to 10 mg RTB101 in combination with 0.1 mg everolimus for 6-16 consecutive 
weeks. Of the 410 elderly subjects exposed to RTB101 alone, 176 of those subjects were 
exposed to 10 mg RTB101 daily for 16 consecutive weeks, the intended commercial dose. The 
most relevant data from the two Phase 2 studies in elderly subjects are summarized in sections 
below. For more detailed information, please refer to the RTB101 Investigator’s Brochure (IB). 
 
Study CBEZ235Y2201: Phase 2a clinical study in 264 elderly subjects demonstrating that 
TORC1 inhibition with RTB101 alone or in combination with everolimus enhanced immune 
function in the elderly 
A total of 264 elderly subjects ≥65 years of age, without unstable medical conditions, were 
enrolled in the study and were randomly assigned to receive everolimus 0.1 mg, everolimus 0.5 
mg, RTB101 10 mg, RTB101 10 mg + everolimus 0.1 mg, or placebo once daily. These doses 
were chosen based on results of a previous Phase 2a study that suggested that partial inhibition of 
S6K phosphorylation with everolimus 0.5 mg once daily was better than more complete 
inhibition of S6K phosphorylation with everolimus 20 mg once weekly for improving influenza 
vaccination responses in the elderly (Mannick et al., 2014). Therefore, study CBEZ235Y2201 
included doses of RTB101 and everolimus predicted by modeling and simulation to partially 
inhibit the phosphorylation of S6K. Subjects were treated for 6 weeks with study drug and, after 
a 2-week drug-free interval, were given a seasonal influenza vaccine. Antibody titers to the three 
strains of influenza in the influenza vaccine were measured in serum collected at baseline and 
4 weeks after influenza vaccination. The subjects were then followed for another 9 months off 
study drug. The type, onset, duration, and treatment of any infection experienced during the 
study was collected in patient diaries and in questionnaires administered by the study sites during 
phone calls with subjects that occurred once weekly during the 6 weeks subjects were on study 
drug, and then once monthly for the remainder of the study.  


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Overall, all treatment regimens were well tolerated. There were no significant differences in the 
percentage of subjects experiencing serious adverse events (SAEs) between treatment groups and 
placebo. Only one SAE (syncope in a subject in the placebo cohort) was assessed by an 
Investigator to be related to study drug. Diarrhea was the most frequently reported AE that 
occurred more often in the TORC1 inhibitor than placebo treatment groups and in the majority of 
cases was mild or moderate in severity and self-limited.   
The combination of low-dose everolimus (0.1 mg once daily) and RTB101 (10 mg once daily) 
significantly increased antibody titers to the 3 strains of influenza in the influenza vaccine. In 
addition, RTB101 10 mg once daily alone or in combination with everolimus (0.1 mg once daily) 
was associated with a statistically significant reduction in the annualized rate of all infections 
reported by subjects (Figure 1-4). There was a trend toward a reduction in infection rates in the 
everolimus monotherapy treatment groups, but the reductions were not statistically significant.  The 
findings suggested that broader TORC1 inhibition with either RTB101 alone or in combination with 
everolimus was better than less broad TORC1 inhibition with everolimus monotherapy for reducing 
infection rates in elderly subjects.  
Figure 1-4  
TORC1 Inhibition Decreases Infection Rates in the Elderly 
 
 
Fitted annual rates of infections reported per person per year in each treatment group are shown. Error bars indicate 
95% confidence intervals. 
Most of the infections reported during the trial were RTIs. Both RTB101 monotherapy and 
RTB101 + everolimus combination therapy were associated with a significant reduction as 
compared to placebo in the annualized rate of RTIs reported by subjects (Figure 1-5). 


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Figure 1-5  
TORC1 Inhibition Decreases RTI Rates in the Elderly 
 
                 
Fitted annual rates of respiratory tract infections (RTIs) reported per person per year in the placebo, RTB101 
monotherapy and RTB101+everolimus combination treatment groups are shown. Error bars indicate 95% 
confidence intervals.  
To assess possible molecular mechanisms underlying the reduction in infection rates, messenger 
ribonucleic acid (mRNA) sequencing analysis was performed on whole blood obtained from 
subjects at baseline and after 6 weeks of either placebo or RTB101 alone or in combination with 
everolimus treatment. Whole-blood gene expression data revealed a highly statistically 
significant, low level up-regulation of pathways related to interferon signaling in the TORC1 
inhibitor but not the placebo treatment group (Figure 1-6). The most highly upregulated genes 
were a subset of Type 1 interferon-induced genes that play a critical role in the innate immune 
response to viruses (Mannick et al., 2018). These findings raise the possibility that upregulation 
of antiviral genes may contribute to enhanced immune function and reduced infection rates in the 
elderly treated with TORC1 inhibitors. In particular, the upregulation of antiviral gene 
expression may be one of the mechanisms underlying the reduction in RTIs seen in elderly 
subjects treated with TORC1 inhibitors since most RTIs are viral in origin.  
 


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Figure 1-6  
Treatment with RTB101 Alone and in Combination with Everolimus but not 
Placebo Treatment Leads to Upregulation of Interferon Pathway Gene 
Expression 
 
Pathway enrichment analysis of gene expression changes in whole blood as measured 6 weeks after study drug 
treatment vs. baseline.  This analysis revealed a highly significant enrichment of pathways related to interferon 
signaling after mTOR inhibitor but not placebo treatment.  The x-axis indicates the mean log2-fold change in 
expression of genes in each pathway.  The y-axis indicates the –log10 of the p value of pathway upregulation.  Each 
circle represents a specific biological pathway.  The most significantly upregulated pathways are those skewed 
toward the upper right in each figure.  
 
Study RTB-BEZ235-202: Phase 2b clinical study in 652 elderly subjects demonstrating that 
TORC1 inhibition with RTB101 reduced the incidence of RTIs in elderly at increased risk of RTI-
related morbidity and mortality. 
 
Based on the results of the previous Phase 2a clinical trial, a Phase 2b dose-ranging trial was 
conducted to determine if RTB101 alone or in combination with everolimus decreased the 
incidence of RTIs in elderly subjects at increased risk of RTI-related morbidity and mortality. 
 
This was a 24-week multicenter, randomized, double-blinded, placebo-controlled, parallel group, 
dose-finding adaptive design study to assess the safety, tolerability, and efficacy of RTB101 
alone or in combination with everolimus as compared to placebo in elderly subjects who were at 
increased risk of RTI-related morbidity and/or mortality. Subjects at increased risk for RTI-
related morbidity and/or mortality included subjects who were: 


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• 85 years of age 
• 65 years of age with one or more of the following co-morbidities: 
o Asthma 
o Chronic obstructive pulmonary disease (COPD) 
o Type 2 diabetes mellitus (T2DM) 
o Current smoker 
The primary objective of the study was to determine if RTB101 alone or in combination with 
everolimus decreased the percentage of subjects who develop one or more laboratory-confirmed 
RTIs relative to placebo during the 16 weeks subjects were taking study drug. RTIs were defined 
as upper RTIs, influenza-like illness, lower RTIs (tracheobronchitis) and pneumonia. 
Prespecified clinical criteria were used to diagnose each type of RTI, and laboratory 
confirmation was obtained by respiratory pathogen polymerase chain reaction (PCR) of 
nasopharyngeal swabs, sputum gram stain and culture, and/or influenza rapid antigen tests. 
Subjects were treated with study drug for 16 weeks during the winter cold and flu season and 
then followed for an additional 8 weeks off study drug. In Part 1 of the study conducted during 
winter cold and flu season in New Zealand, 179 subjects were randomized to RTB101 5 mg or 
10 mg once daily or matching placebo. Following the 16-week treatment period in Part 1, an 
interim analysis was performed by an unblinded Data Monitoring Committee (DMC) who 
recommended RTB101 10 mg once daily as the best dose to move forward to Part 2 of the trial. 
The doses used in Part 2 were prespecified based on the RTB101 once daily dose chosen by the 
DMC from Part 1. In Part 2 conducted during winter cold and flu season in the United States 
(U.S.), 473 subjects were randomized to RTB101 10 mg once daily (QD), RTB101 10 mg twice 
daily (BID), RTB101 10 mg in combination with everolimus 0.1 mg once daily, or matching 
placebo.  
Figure 1-7  
Phase 2b Study Design 
 


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RTB-BEZ235-202 Efficacy: 
• The greatest reduction in laboratory-confirmed RTI incidence was observed in the 
RTB101 10 mg once daily treatment group. A 30.6% reduction in the percentage of 
subjects experiencing one or more laboratory-confirmed RTIs was seen in the pooled 
(Parts 1 and 2) RTB101 10 mg once daily treatment group compared with the pooled 
placebo group during 16 weeks of study drug treatment (odds ratio (OR) 0.600 [90% CI 
0.391, 0.921]; nominal p-value=0.025) (Figure 1-8). 
Results of other prespecified exploratory endpoints supported the superiority of RTB101 10 mg 
once daily administration over placebo including: 
• 52.1% reduction in the percentage of subjects with severe laboratory-confirmed RTI 
symptoms compared to placebo (OR=0.437, CI=(0.207, 0.923), nominal p-value=0.034) 
(Figure 1-8).  
• 27.5% reduction in the percentage of subjects with laboratory-confirmed RTIs compared 
to placebo during 24 weeks (16 weeks of study drug treatment and 8 weeks of follow-up 
(OR=0.623, CI=(0.412, 0.942), nominal p-value=0.030). The persistent benefit observed 
at 24 weeks may have been driven by the benefit observed during the 16 weeks of study 
drug treatment because few laboratory-confirmed RTIs occurred in each treatment group 
between weeks 16 to 24 (Figure 1-8).  


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Figure 1-8  
RTB101 10 mg QD Showed Consistent Benefit as Compared to Placebo in 
Multiple Pre-Specified Analyses of Laboratory (lab)-Confirmed RTIs 
 
Odds ratios and 90% confidence intervals (CIs) for each study drug comparison versus 
placebo are shown. Odds ratio illustrate the odds of experiencing one or more laboratory-
confirmed RTIs in the active dose(s) versus placebo. This was calculated by employing a 
logistic regression including a term for treatment, along with a term for each disease 
factor and age as separate covariates, where a nominal p-value for each dose versus 
placebo was computed based on the estimate of the treatment effect. 
Pre-specified analyses evaluating the percentage of subjects with laboratory-confirmed RTIs in 
each of the 5 subgroups of subjects enrolled in the trial (subjects ≥85 years of age, or subjects 
≥65 years of age with asthma, COPD, T2DM or current smoker) identified consistently higher 
responding subgroup populations receiving RTB101 10 mg once daily, including: 


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− Subjects ≥85 years of age  
▪ A 66.7% decrease relative to placebo, OR=0.184 (90% CI=[0.060, 0.568]), in 
the percentage of subjects experiencing one or more laboratory-confirmed 
RTIs during 16 weeks of study drug treatment, (nominal p-value=0.007). 
− Subjects ≥65 years of age with asthma 
▪ A 68.9% decrease relative to placebo, OR=0.105 (90% CI=[0.038, 0.290]), in 
the percentage of subjects experiencing one or more laboratory-confirmed 
RTIs during 16 weeks of study drug treatment (nominal p-value= 0.0001). 
A reduction in the percentage of subjects with laboratory-confirmed RTIs was also seen in 
subjects 65 years of age with T2DM who were treated with RTB101 10 mg once daily as 
compared to placebo (25.3% reduction, OR=0.362 (90% CI=[0.151, 0.867] nominal p-
value=0.028). No reduction in the incidence of RTIs was seen in subjects who were 65 years of 
age with COPD, and a nominal increase in RTIs was observed in current smokers. The efficacy 
seen in asthmatics and lack of efficacy observed in current smokers and subjects with COPD is 
consistent with nonclinical data suggesting that mTOR inhibition alleviates lung allergen-
induced inflammation in asthma models but exacerbates cigarette smoke-induced lung 
inflammation in COPD models (Mushaben et al., 2011; Wang et al., 2018). 
When the non-responding subject populations (current smokers and subjects with COPD) were 
excluded from the analysis, RTB101 10 mg once daily was associated with a 56.9% reduction in 
the percentage of subjects with one or more laboratory-confirmed RTIs.  
Figure 1-9  
A Reduction in the Incidence of Laboratory-Confirmed RTIs was Observed 
in Subjects 65 Years of Age and Older (excluding current smokers and 
COPD subjects) 
 


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RTB-BEZ235-202 Safety: 
Overall, all dosing regimens were well-tolerated in the elderly subjects evaluated in the Phase 2b 
study. There were no appreciable differences in AE profiles among treatment groups. For 
subjects in both active and placebo treatment groups, the majority of AEs were assessed as non-
serious, mild or moderate in severity, and unrelated to study drug treatment. Subjects 
experiencing SAEs were also generally well-balanced between active and placebo treatment 
groups, with the exception of a slightly higher proportion of subjects experiencing SAEs in the 
placebo group relative to the RTB101 5 mg once daily treatment group in Part 1 of the study. 
Overall, the types of SAEs that occurred were consistent with the elderly population under 
evaluation in the study and none was assessed as related to study drug treatment. 
Three of the 652 elderly subject enrolled in the study died (all in Part 2 of the study); one subject 
randomized to receive RTB101 10 mg once daily died from traumatic injuries sustained from 
being hit by a car while riding a bicycle during the 16-week treatment period of the study. Two 
subjects (one randomized to receive RTB101 10 mg twice daily and one randomized to receive 
placebo) died from unknown cause(s) after Week 24 of the study. None of the deaths that 
occurred was attributed to study drug treatment. 
See the RTB101 IB for further details. 
RTB-BEZ235-202 Overall Conclusion: 
In summary, the results of the Phase 2a and 2b trials in over 900 elderly subjects identified a safe 
and efficacious dose (RTB101 10 mg once daily) and patient population (subjects ≥65 years of 
age who are non-smokers and do not have COPD) to study in Phase 3 trials. 
 
The majority of pharmacokinetic data for low dose RTB101 was obtained in high risk elderly 
subjects in clinical study RTB-BEZ235-202. Values for area under the drug concentration versus 
time curve (AUC) and maximum plasma concentration (Cmax) at the 10 mg daily oral dose of 
RTB101 revealed a mean area under the drug concentration versus time curve from 0 to 24 hours 
(AUC0-24) (standard deviation [SD]) of 28.6 (35.9) ng.hr/mL and a Cmax (SD) of 8.373 
(7.853853) ng/mL, but there was substantial variability in PK as reflected by the magnitude of 
the SDs. Additional information about RTB101 pharmacokinetics is contained in the RTB101 
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The purpose of this study is to determine if RTB101 prevents clinically symptomatic respiratory 
illness in elderly subjects ≥65 years of age. Subjects with clinically symptomatic respiratory 
illness are defined as subjects with symptoms consistent with a RTI based on prespecified 
diagnostic criteria. 
 Study Objectives and Endpoints 
The primary, secondary and exploratory objectives and associated endpoints are summarized in 
Table 2-1 below. 
Table 2-1   
Summary of Study Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary Objective 
Endpoint for Primary Objective 
• 
To determine if RTB101 as compared to 
placebo decreases the percentage of 
subjects with clinically symptomatic 
respiratory illness (with or without an 
associated laboratory-confirmed 
pathogen) through Week 16 
• 
The percentage of subjects with clinically 
symptomatic respiratory illness beginning 
at least 3 days after the start of study drug 
treatment through Week 16 as assessed by 
pre-specified clinical diagnostic criteria 
Secondary Objectives 
Endpoints for Secondary Objectives 
• 
To determine if RTB101 as compared to 
placebo decreases the percentage of 
subjects with clinically symptomatic 
respiratory illness associated with ≥1 
laboratory-confirmed pathogen(s) 
through Week 16 
 
• 
The percentage of subjects with 1 or more 
clinically symptomatic respiratory 
illnesses associated with ≥1 laboratory-
confirmed pathogen(s) beginning at least 3 
days after the start of study drug treatment 
through Week 16 as assessed by pre-
specified clinical diagnostic criteria and 
respiratory pathogen PCR of 
nasopharyngeal swabs, sputum gram stain 
and culture, and/or RIDTs 
• 
To determine the effect of RTB101 as 
compared to placebo on the rate of 
clinically symptomatic respiratory 
illnesses associated with specific 
laboratory-confirmed viruses 
(coronaviruses, human metapneumovirus 
[hMPV], human rhinovirus 
[HRV]/enterovirus, adenovirus, influenza 
A and B virus, parainfluenza viruses, and 
respiratory syncytial virus [RSV]) 
through Week 16 
• 
The rate of clinically symptomatic 
respiratory illnesses associated with 
specific laboratory-confirmed viruses 
(coronaviruses, hMPV, HRV/enterovirus, 
adenovirus, influenza A and B virus, 
parainfluenza viruses, and RSV) 
beginning at least 3 days after the start of 
study drug treatment through Week 16 as 
assessed by respiratory pathogen PCR of 
nasopharyngeal swabs and/or RIDTs 
• 
To determine if RTB101 as compared to 
placebo decreases the rate of clinically 
symptomatic respiratory illness (with or 
• 
The rate of clinically symptomatic 
respiratory illness (with or without an 
associated laboratory-confirmed pathogen) 


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Objectives 
Endpoints 
without an associated laboratory-
confirmed pathogen) through Week 16 
beginning at least 3 days after the start of 
study drug treatment through Week 16 as 
assessed by pre-specified clinical 
diagnostic criteria 
• 
To determine if RTB101 as compared to 
placebo decreases the rate of clinically 
symptomatic respiratory illnesses 
associated with ≥1 laboratory-confirmed 
pathogen(s) through Week 16 
• 
The rate of clinically symptomatic 
respiratory illnesses associated with ≥ 1 
laboratory-confirmed pathogen(s) 
beginning at least 3 days after the start of 
study drug treatment through Week 16 as 
assessed by pre-specified clinical 
diagnostic criteria and respiratory 
pathogen PCR of nasopharyngeal swabs, 
sputum gram stain and culture, and/or 
RIDTs 
• 
To determine if RTB101 as compared to 
placebo decreases time to alleviation of 
moderate and severe respiratory illness 
symptoms due to clinically symptomatic 
respiratory illness through Week 16 
• 
The time to alleviation of moderate and 
severe respiratory illness symptoms due 
to clinically symptomatic respiratory 
illness beginning at least 3 days after the 
start of study drug treatment through 
Week 16 
• 
To determine if RTB101 as compared to 
placebo decreases the percentage of 
subjects with severe symptoms due to 
clinically symptomatic respiratory 
illnesses through Week 16 
• 
The percentage of subjects with severe 
symptoms due to clinically symptomatic 
respiratory illnesses beginning at least 3 
days after the start of study drug 
treatment through Week 16 
• 
To assess the safety and tolerability of 
RTB101 through Week 20 
• 
Safety and tolerability will be assessed 
by report of AE/SAEs, physical exam 
and ECG findings, and safety laboratory 
values 
Exploratory Objectives 
Endpoints for Exploratory Objectives 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of all 
laboratory-confirmed viral respiratory 
infections with or without symptoms 
through Week 16 
• 
The rate of all laboratory-confirmed viral 
infections with or without symptoms 
beginning at least 3 days after the start of 
study drug treatment through Week 16 as 
assessed by respiratory pathogen PCR of 
nasopharyngeal swabs and/or RIDTs 
(obtained during episodes of 
symptomatic respiratory illnesses) and/or 
respiratory pathogen PCR of mid-
turbinate swabs (obtained at scheduled 
study visits, even in the absence of 
symptoms) 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of all-
cause hospitalizations through Week 16 
• 
The rate of all-cause hospitalizations 
through Week 16 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of 
hospitalizations associated with 
• 
Rate of hospitalizations associated with 
RTIs beginning at least 3 days after the 


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Objectives 
Endpoints 
respiratory tract infections (RTIs) 
through Week 16  
start of study drug treatment through 
Week 16 
 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of all-
cause Emergency Room (ER) visits 
through Week 16 
• 
The rate of all-cause ER visits through 
Week 16 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of ER 
visits associated with RTIs through Week 
16  
• 
Rate of ER visits associated with RTIs 
beginning at least 3 days after the start of 
study drug treatment through Week 16 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of all-
cause urgent care clinic visits through 
Week 16 
• 
The rate of all-cause urgent care clinic 
visits through Week 16 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of urgent 
care visits for clinically symptomatic 
respiratory illness through Week 16 
• 
The rate of urgent care clinic visits for 
clinically symptomatic respiratory illness 
beginning at least 3 days after the start of 
study drug treatment through Week 16 
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of all-
cause admissions to skilled nursing 
facilities through Week 16 
• 
The rate of all-cause admissions to 
skilled nursing facilities through Week 
16 
• 
To explore the effect of RTB101 as 
compared to placebo on hospital length 
of stay associated with RTIs through 
Week 16 
• 
Hospitalization length of stay associated 
with RTIs beginning at least 3 days after 
the start of study drug treatment through 
Week 16   
• 
To explore the effect of RTB101 as 
compared to placebo on all-cause 
hospital length of stay through Week 16   
• 
All-cause hospitalization length of stay 
through Week 16 
• 
To explore the effect of RTB101 as 
compared to placebo on the percentage of 
subjects with clinically symptomatic 
respiratory illness and the percentage of 
subjects with clinically symptomatic 
respiratory illness associated with ≥1 
laboratory-confirmed pathogen(s) 
through Week 20 
• 
The percentage of subjects with 1 or 
more clinically symptomatic respiratory 
illnesses and the percentage of subjects 
with 1 or more clinically symptomatic 
respiratory illnesses associated with ≥1 
laboratory-confirmed pathogen(s) 
beginning at least 3 days after the start of 
study drug treatment through Week 20 as 
assessed by pre-specified clinical 
diagnostic criteria and respiratory 
pathogen PCR of nasopharyngeal swabs, 
sputum gram stain and culture, and/or 
RIDTs 
• 
To explore the effect of RTB101 as 
compared to placebo on change from 
Baseline in health-related quality of life 
(HRQoL) as assessed by EQ-5D-5L 
scores during all clinically symptomatic 
• 
The change from Baseline in HRQoL as 
assessed by EQ-5D-5L scores during all 
clinically symptomatic respiratory illness 
episodes beginning at least 3 days after 


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Objectives 
Endpoints 
respiratory illness episodes and at Week 
16 
the start of study drug treatment and at 
Week 16 
• 
To explore the effect of RTB101 as 
compared to placebo on the percentage of 
subjects with clinically symptomatic 
respiratory illnesses and on the 
percentage of subjects with clinically 
symptomatic respiratory illnesses 
associated with ≥1 laboratory-confirmed 
pathogen(s) through Week 16 who are 
≥85 years of age or subjects with a 
medical history of asthma  
• 
The percentage of subjects with one or 
more clinically symptomatic respiratory 
illnesses and the percentage of subjects 
with one or more clinically symptomatic 
respiratory illnesses associated with ≥1 
laboratory-confirmed pathogen(s) 
beginning at least 3 days after the start of 
study drug treatment through Week 16 
who are ≥85 years of age or subjects with 
a medical history of asthma   
• 
To explore the effect of RTB101 as 
compared to placebo on the rate of 
clinically symptomatic respiratory 
illnesses and on the rate of clinically 
symptomatic respiratory illnesses 
associated with ≥1 laboratory-confirmed 
pathogen(s) through Week 16 in subjects 
who are ≥85 years of age or subjects with 
a medical history of asthma 
• 
The rate of clinically symptomatic 
respiratory illnesses and the rate of 
clinically symptomatic respiratory 
illnesses associated with ≥1 laboratory-
confirmed pathogen(s) beginning at least 
3 days after the start of study drug 
treatment through Week 16 in subjects 
who are ≥85 years or subjects with a 
medical history of asthma 
• 
To explore the effect of RTB101 as 
compared to placebo on the incidence of 
asthma exacerbations through Week 16 
in subjects with a medical history of 
asthma 
• 
The rate of asthma exacerbations and the 
percentage of subjects with 1 or more 
asthma exacerbation defined as 
deterioration of asthma symptoms that 
requires treatment with systemic steroids  
beginning at least 3 days after the start of 
study drug treatment through Week 16 in 
subjects with a medical history of asthma 
• 
To explore the effect of RTB101 as 
compared to placebo on the incidence of 
UTIs 
• 
The rate of UTIs and the percentage of 
subjects with one or more UTIs reported 
as adverse events 
• 
To explore the effect of RTB101 on 
immunologic biomarkers and to explore 
biomarkers that may predict response 
(e.g., RNA expression in whole blood, 
serum biomarkers, genetic variation) 
• 
Change from Baseline to Weeks 4 and 16 
in biomarkers in whole blood and serum 
and potentially future pharmacogenomic 
analysis 
 Investigational Plan 
 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to assess the 
efficacy and safety of RTB101 for the prevention of clinically symptomatic respiratory illness in 
elderly (defined as ≥ 65 years of age) subjects. Subjects will be enrolled during winter cold and 
flu season. The study will be comprised of up to a 4-week Screening Period; a 16-week Primary 
Analysis Period (for evaluating efficacy and safety) during which time subjects meeting study 


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eligibility criteria will be randomized 1:1 to receive RTB101 10 mg or matching placebo once 
daily through the Week 16 Visit; a 4-week Short-term Follow-up Period (for evaluating safety 
and efficacy through the Week 20 Visit); and a 28-week Long-term Follow-up Period (for 
evaluating safety through Week 48 by follow-up questionnaire).  
Figure 3-1  
RTB-101-204 Study Design 
 
 
Study Periods 
Screening Period: 
Screening Visit  
Screening may occur prior to investigational product being available at the study site. During the 
Screening visit  (maximum 4 weeks prior to Baseline/randomization), the study will be explained 
in detail to subjects and they will be asked to provide informed consent for participation. 
Subjects will be then assessed for eligibility to participate in the trial based on 
inclusion/exclusion criteria. The following assessments will be performed at this visit: Mini 
Mental Status Exam (MMSE); a review of subject demography and medical history (including 
current medical [including cardiac] conditions, prior and current medications); a complete 
physical exam (including height, weight, and vital signs [temperature, respiratory rate, heart rate 
and blood pressure]); and an electrocardiogram (ECG). In addition, a chest X-ray will be 
performed unless the subject has had a chest X-ray within the past 3 months and the film (or 
digital copy) and results of that CXR are available. Blood and urine will be collected for the 
following tests: hematology, chemistry, urinalysis, serum cotinine (or urine cotinine if serum 


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cotinine testing is unavailable), and HIV and hepatitis virus (B and C) screening. Details will be 
provided in the Study Operations Manual (SOM). In exceptional circumstances, when central 
laboratory testing is unavailable, local laboratory testing may occur with the Sponsors prior 
approval. 
Blinded Treatment Phase: 
Treatment Phase (16 weeks) 
Subjects will be treated for 16 weeks with study drug. Approximately 533 subjects will be 
enrolled in each treatment group for a total enrollment of approximately 1066 subjects.  
Baseline Visit 
At the Baseline visit, a review of any changes to the subject’s medical (including cardiac) 
condition or current medications/other therapies will be performed. Subjects will then undergo 
clinical evaluation, including a targeted physical exam. This should include measurements of 
weight and vital signs, including orthostatic blood pressure, and an exam of the lungs, heart, oral 
cavity, and skin. The Clinical Frailty Scale (see Section 13.4 [Appendix 4]) score of each subject 
will also be determined. An ECG will be performed for Baseline safety assessment. Subjects will 
also have blood and urine samples obtained for Baseline safety assessments. In addition, blood 
samples will be obtained for biomarker analyses, including RNA expression and soluble 
biomarkers. Consent for  Optional Blood Storage for Future Use and Consent for Optional 
Pharmacogenetic Analysis will be obtained at the Baseline Visit.  A single blood sample will 
also be obtained at the Baseline Visit in those subjects who sign the option Pharmacogenetic 
Analysis consent form for the purposes of possible future Pharmacogenomic analysis.  A mid-
turbinate nasal swab specimen will be collected.  
Prior to randomization, the inclusion and exclusion criteria will be reviewed again, and eligible 
subjects will be randomized via the IXRS system to 1 of 2 treatment groups in a ratio of 1:1. 
• RTB101 10 mg once daily (QD) 
• Matching placebo QD 
Randomization will be stratified based on the following factors that may influence the incidence 
or severity of clinically symptomatic respiratory illness and/or the response to RTB101 
treatment: 
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2. Age ≥65 and <85 years with a medical history of asthma 
3. Clinical Frailty Scale score 4 
Subjects will be given their first dose of study drug (and time of dosing recorded in the eDiary) 
at the study site and trained on use of the eDiary containing study assessments to be completed at 
home including: 
• Study drug dosing information, to be completed daily through the Week 16 study 
visit 
• Respiratory Illness Symptom Questionnaire, to be completed daily in the evening 
through the Week 20 study visit 
• EQ-5D-5L, to be completed each day subjects report experiencing one or more 
respiratory illness symptoms through the Week 16 study visit 
After randomization, all subjects will complete the Health-Related Quality of Life Questionnaire 
(EQ-5D-5L) and Respiratory Illness Symptom Questionnaire on their eDiary at the Baseline 
visit.  
Subjects will then be sent home with study drug and the eDiary. Subjects will be instructed to 
take their study drug each day with breakfast and to complete the dosing diary in the eDiary at 
the time of study drug administration. Subjects will also be instructed to complete the 
Respiratory Illness Symptom Questionnaire in their eDiary each evening, and to complete the 
EQ-5D-5L in their eDiary each evening, if applicable (i.e., when the EQ-5D-5L appears in their 
eDiary on days they report experiencing one or more respiratory illness symptoms). Adverse 
events will be monitored and reported from the time of study drug administration at the Baseline 
Visit through Week 20. 
Subject Contact/Follow up  
The eDiary responses will be monitored by the Study Investigator or Study Coordinator. The 
Study Investigator or Study Coordinator at the site will contact subjects who miss completion of 
the daily eDiary questionnaires for >1 day and re-train the subject and explain the importance of 
completing the daily eDiary questionnaires. The Study Investigator and Study Coordinator will 
also contact subjects who report at least one respiratory symptom (runny nose, sneezing, stuffy 
nose, sore throat, hoarseness, or cough) reported in 2 consecutive entries in their eDiary and 
instruct the subjects to come to the study site if they are able to within 48 hours for evaluation 
and for collection of a nasopharyngeal swab during the Clinically Symptomatic Respiratory 
Illness (Unscheduled) Visit (see below). Subjects who are unable to come to the study site may 


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also have the nasopharyngeal swab (and, if indicated, a sputum specimen and RIDT) obtained 
during a home visit by trained personnel.  
To determine which subjects may need treatment for influenza, sites will contact subjects who 
record at least 1 respiratory and at least 1 general symptom, both of which are moderate or severe 
on 2 consecutive days in their eDiary. The sites will instruct the subjects to come to the study site 
if they are able to within 24 hours of the second day of eDiary symptom entry to have a 
nasopharyngeal swab and determine whether they require treatment for influenza per standard of 
care. 
Clinically Symptomatic Respiratory Illness Visits (Unscheduled) 
At the Clinically Symptomatic Respiratory Illness Unscheduled Visit, Study Investigators will 
evaluate the subject and perform a targeted physical exam based on the symptoms reported by 
the subject and including vital signs and temperature. Any medications used to treat the clinically 
symptomatic respiratory illness, including antibiotics and any change to current medications, will 
be recorded. In addition, a nasopharyngeal swab will be obtained. Subjects who have a 
productive cough that is changed from baseline should have a sputum specimen obtained for 
gram stain and culture. If clinically indicated, blood and urine samples needed to clinically 
evaluate the subject may be obtained at this visit. Subjects who have influenza-like illness signs 
and symptoms (such as 1 or more respiratory symptom (cough, sore throat or nasal symptoms) 
and 1 or more constitutional symptom (such as body aches or feverishness/chills) should have a 
rapid influenza diagnostic test (RIDT) done. Subjects with influenza-like illness who have 
influenza detected by RIDT or nasopharyngeal swab PCR should receive anti-influenza 
treatment per local standard of care, unless contraindicated, and/or other appropriate medical 
care. If subjects are unable or unwilling to return to the study site for the Clinically Symptomatic 
Respiratory Illness Unscheduled Visit, the nasopharyngeal swab and, if indicated, a sputum 
specimen and RIDT should be obtained at a home visit by trained personnel. Appropriate 
medical care (including referral to their healthcare provider or to a hospital, if indicated) should 
be provided for all clinically symptomatic respiratory illness episodes (including anti-influenza 
treatment, if indicated, in subjects diagnosed with influenza) per local standard of care. Study 
drug treatment can be continued in subjects who require antibiotics or anti-influenza medication 
for treatment of an RTI.  
Weeks 2-12 Visits 
Provided the study drug continues to be well tolerated, subjects will be treated with study drug 
for 16 weeks, during which time they will return to the clinic every 2 weeks (visits Week 2, 4, 6, 


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and 8) for the first 8 weeks, and then every 4 weeks (visit Week 12 and 16) for the final 8 weeks. 
At visit Weeks 2-12 of the study, the subject will have clinical evaluations, including a targeted 
physical exam, which will include measurements of weight, blood pressure, heart rate, 
respiratory rate, and temperature, and an exam of the lungs, heart, oral cavity, and skin. A review 
of any changes to medical (including cardiac) conditions and medications/other therapies will 
also be performed. At all follow up visits, subjects will be queried by site staff regarding any 
visits to the ER, urgent care clinics, and any admission to a skilled nursing facility or hospital 
that may have occurred since their last study visit. Subjects will also have a mid-turbinate swab 
taken at each visit regardless of whether the subject reports respiratory illness symptoms. If 
subject presents with respiratory illness symptoms at this visit they may also have a 
nasopharyngeal swab, RIDT and sputum sample (if applicable) obtained as part of an 
unscheduled visit assessment. Blood and urine specimens will be collected at each visit for safety 
monitoring. An ECG will be performed at Week 4, 8 and 12 visits for safety monitoring. Only 
subjects participating in the PK assessments (per the Interactive Web or Telephone-based 
Response System (IXRS) randomization) will also have blood samples obtained for PK 
assessments at the Week 4 (or 6 if applicable), 8, and 12 visits, and have blood samples obtained 
for RNA expression and soluble biomarker assessments at the Week 4 visit. If PK sampling 
cannot be performed at the Week 4 visit for logistical reasons, it should be collected at the Week 
6 visit instead, but according to the schedule described below for Week 4.  This applies to the 
timing of the biomarker specimens originally scheduled for Week 4 as well.  
Study drug will be dispensed at Day 0, Week 4, Week 8 and Week 12 visits (however, in the 
case of lost or damaged study drug, study drug can be dispensed at any study site visit). The 
subjects should bring their remaining study drug to each study visit. At Study Visits Week 4 (or 
Week 6 if applicable) and Week 12, subjects participating in the PK assessments should be 
instructed to not take their study drug dose at home (it will be administered at the site). At Weeks 
4, 8, and 12, subjects will return study drug and will be dispensed new bottles. At Week 2 and 6, 
subjects will bring their drug supply to the study site to allow site personnel to perform a pill 
count; however, no new study drug will be dispensed at these visits. 
Week 16 Visit 
Subjects will take their last dose of study drug at home and come to the study site to undergo a 
clinical evaluation, including a review of any changes to medical (including cardiac) conditions 
and medications/other therapies, and a complete physical exam, which will include 
measurements of weight and vital signs. An ECG will also be performed for safety monitoring. 
In addition, subjects will have blood and urine samples obtained for safety labs. Blood samples 
will also be obtained for RNA expression and soluble serum biomarker assessments. In addition, 


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a mid-turbinate nasal swab will be obtained. Subjects will be queried by site staff regarding any 
visits to ER, urgent care clinics, any admission to a skilled nursing facility or hospital that may 
have occurred since their last study visit. All subjects will complete the EQ-5D-5L questionnaire 
at the Week 16 visit. All study drugs (RTB101 and placebo) should be returned to the study site. 
Short-term Follow-up Period (Week 20) 
All subjects will return to the study site 4 weeks after their last dose of study drug for a Week 20 
(Short-term Follow-up Period) visit. At the Week 20 visit, subjects will undergo a complete 
physical exam, which will include measurements of weight and vital signs. A review of any 
changes to medical (including cardiac) conditions and medications or other therapies will also be 
performed. Blood and urine will be collected for safety lab evaluation. The eDiary should also be 
returned to site personnel at this visit. 
Subjects who develop medically important laboratory abnormalities or medically important AEs 
should be referred for appropriate medical care, as per the local standard of medical care. If at 
the time of the completion of the Week 20 visit, all adverse events that are unresolved should be 
captured as “ongoing” in the database; however, they should continue to be followed until 
resolution or judged to be permanent by the Investigator (see Section 7.1). 
Long-term Follow-up Period (Week 48) 
After completion of the Short-term Follow-up Period (i.e., the Week 20 Visit), subjects will have 
long term follow-up by telephone questionnaire at Week 48 to collect information regarding any 
hospitalizations, skilled nursing facility admissions and death of subjects since the Week 20 
Visit. 
 
The study is designed as a standard randomized, double-blinded, placebo-controlled study to 
obtain efficacy and safety data for RTB101 in an unbiased fashion. Subjects will be prompted to 
fill out a Respiratory Illness Symptoms questionnaire in the eDiary daily in order to rapidly and 
accurately capture the occurrence of symptoms consistent with an RTI and to enable collection 
of nasopharyngeal swabs if they are able to within 48 hours of symptom confirmation when viral 
detection rates are highest (Ginocchio et al., 2011). Sixteen weeks of treatment is considered a 
sufficient duration to achieve a clinically meaningful reduction in clinically symptomatic 
respiratory illness during winter cold and flu season when there is a peak in the circulation of 
multiple respiratory viruses. PK samples will be obtained in approximately 400 subjects (200 in 


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each treatment group) at weeks 4 (or 6), 8, and 12 to enable characterization of PK after the 
study drug has reached steady state levels. 
Study Population 
Prevention of clinically symptomatic respiratory illness is particularly important in people age 65 
and older in whom RTIs are a leading cause of hospitalization. Data from the Phase 2b trial 
RTB-BEZ235-202 suggests that RTB101 10 mg given once daily for 16 weeks during winter 
cold and flu season was safe and reduced the incidence of laboratory-confirmed RTIs in people 
age > 65. In addition, data from the RTB-BEZ235-202 study suggests that RTB101 had no 
benefit in elderly subjects who were current smokers or had a medical history of COPD. 
Therefore, the Phase 3 study will enroll subjects who are age > 65 and who are not current 
smokers and do not have COPD. A Mini Mental Status Exam will be done at screening to ensure 
that subjects enrolled in the trial have the cognitive ability to understand the informed consent.  
An effort will be made by monitoring screening to have  at least 35% of the total subjects 
enrolled in the trial be from subgroups at increased risk of RTI-related morbidity and mortality 
(defined as age ≥ 85 or age ≥65 and <85 years with a medical history of asthma or congestive 
heart failure). Enhancing immune function and reducing the incidence of clinically symptomatic 
respiratory illness is of particular clinical relevance in these subgroups. RTIs are the second 
leading cause of hospitalization in people age ≥ 85 (Pfunter et al., 2013), the most common cause 
of asthma exacerbations (Nicholson et al., 1993), and the underlying cause of 16% of hospital 
admissions in patients with congestive heart failure (Chin and Goldman, 1997). Enrolling 35% of 
subjects from these subgroups is representative of the target ≥ 65 year old population since ~10% 
of those ≥65 have asthma (Gillman et al., 2012), 12% are ≥85 (U.S. Census 2010) and ~10% of 
individuals > 60 have congestive heart failure (Komanduri S et al., 2017).  
Primary Endpoint 
The primary endpoint of the study is the percentage of subjects who experience at least one 
clinically symptomatic respiratory illness beginning at least 3 days after the start of study drug 
treatment through Week 16. Clinically symptomatic respiratory illness is defined as respiratory 
illness symptoms that are consistent with a RTI based on prespecified diagnostic criteria and 
includes multiple types of RTIs (such as common cold, bronchitis, influenza-like illness, and 
pneumonia) caused by multiple different pathogens. Decreasing the incidence of clinically 
symptomatic respiratory illnesses is medically important in the elderly. Even respiratory illnesses 
such as upper RTIs that are normally mild in younger adults cause significant morbidity in the 
elderly (Nicholson et al., 1997) and significantly increase the risk of cardiovascular events 
(Musher et. al., 2019). The incidence of all clinically symptomatic respiratory illness (with or 
without an associated laboratory-confirmed pathogen) was chosen as the primary endpoint 


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because some infectious pathogens may not be detected with the proposed laboratory detection 
methods. Data from Phase 2 studies suggest that RTB101 upregulates antiviral defenses and 
decreases the incidence of respiratory illness associated with multiple different viruses. 
Clinically symptomatic respiratory illnesses beginning at least 3 days after the start of study drug 
treatment will be analyzed because RTIs may have a 3-day incubation period. Therefore, RTIs 
occurring during the first 3 days of the study may have been acquired prior to initiation of study 
drug treatment. The clinical criteria that will be used in the Phase 3 trial to diagnose clinically 
symptomatic respiratory illnesses (see Section 6.7.1) capture RTI events that were also captured 
in the Phase 2b (RTB-BEZ235-202) trial. Prespecified clinical criteria will be used to diagnose 
clinically symptomatic respiratory illnesses to make sure that diagnosis is consistent across sites.   
Secondary Endpoints 
Secondary endpoints will include the incidence of clinically symptomatic respiratory illnesses 
associated with laboratory-confirmed pathogen(s). Assessment of clinically symptomatic 
respiratory illness that is associated with an infectious pathogen will allow assessment of the 
treatment effect of RTB101 on respiratory illness that is confirmed to be infectious in etiology. 
The incidence of clinically symptomatic respiratory illnesses associated with specific viruses 
(e.g., coronaviruses, hMPV, HRV/enterovirus, adenovirus, influenza A and B virus, 
parainfluenza viruses, and RSV) will also be assessed as a secondary endpoint to determine if 
RTB101 has consistent benefit across different viral infections, and to demonstrate no 
enhancement of any viral infection. Another secondary endpoint will be rate of clinically 
symptomatic respiratory illness because subjects may experience more than one respiratory 
illness during the 16-week treatment period, and RTB101 may decrease not just the percentage 
of subjects with clinically symptomatic respiratory illness but also the rate of clinically 
symptomatic respiratory illnesses. Additional secondary endpoints will determine if RTB101 
decreases not only the incidence but also the severity and duration of respiratory illness 
symptoms. Decreasing the severity and duration of respiratory illness symptoms is a clinically 
important endpoint and will provide further evidence of the clinical benefit of RTB101.  
Exploratory Endpoints 
An exploratory endpoint will be the rate of viral respiratory infection, irrespective of whether the 
infection is symptomatic, to better assess the antiviral effects of RTB101. As an additional 
exploratory endpoint, healthcare resource utilization will be assessed because an important 
benefit of decreasing the incidence of clinically symptomatic respiratory illness may be a 
decrease in healthcare resource utilization by elderly subjects.  Since decreasing the incidence of 
clinically symptomatic respiratory illness may improve the quality of life of elderly subjects, an 


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additional exploratory endpoint will be health related quality of life in all subjects assessed with 
the EQ-5D-5L questionnaire. The incidence of clinically symptomatic respiratory illness in 
subjects with a medical history of asthma or who are 85 years of age will be assessed as 
exploratory endpoints because these subpopulations had the greatest reduction on the incidence 
of laboratory confirmed RTIs after treatment with 10 mg RTB101 once daily as compared with 
placebo in the previous Phase 2b (RTB-BEZ235-202) trial. The incidence of asthma 
exacerbations in subjects with a medical history of asthma will also be assessed since RTIs are 
common causes of asthma exacerbations. Another exploratory endpoint will be the incidence of 
clinically symptomatic respiratory illness and the incidence of symptomatic respiratory illness 
associated with laboratory-confirmed pathogen(s) through Week 20 to assess if the efficacy of 
RTB101 persists for 4 weeks after subjects discontinue study drug. To better understand if the 
incidence of other types of infections may be reduced, the incidence of UTIs will be assessed.  
Finally, RNA expression and soluble serum biomarkers and pharmacogenomics (also known as 
pharmacogenetics)  (Note: pharmacogenomics will only be assessed in those subjects who sign a 
separate consent form to allow collection of a pharmacogenomic (also known as 
pharmacogenetic) sample) will be assessed as exploratory endpoints to assess the effects of 
RTB101 on relevant immunologic markers and to potentially assess the impact of mTOR 
pathway polymorphisms in a pharmacogenomic analysis.  
 
A placebo will be used as a comparator since there is no available drug known to reduce the 
incidence of clinically symptomatic respiratory illness in the elderly. The placebo arm will 
provide data about baseline AE and clinically symptomatic respiratory illness incidence in the 
elderly to which responses in subjects receiving RTB101 can be compared. 
 
The potential benefit to subjects receiving RTB101 of reducing the incidence of clinically 
symptomatic respiratory illness is noted above. The potential risk to subjects in this study will be 
minimized by adherence to the inclusion/exclusion criteria, close clinical monitoring, short study 
duration, and oversight by a DMC. The potential risks of RTB101 treatment are based on 
preclinical toxicology studies, and the observed safety of RTB101 in clinical trials to date. As 
noted above, the risk of AEs should also be minimized in this study by using very low doses of 
RTB101. The dose of RTB101 to be used in the proposed Phase 3 trial (10 mg once daily) is 
120-fold lower than the maximum tolerated dose (1200 mg once daily) established in humans. 
The RTB101 10 mg once daily dose was also demonstrated to be safe and well tolerated in 
elderly subjects in 2 studies: 1) a previous Phase 2a study in which 53 elderly subjects were 


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treated with 10 mg once daily for up to 6 weeks, and 2) a previous Phase 2b study in which 176 
elderly subjects were exposed to 10 mg once daily for up to 16 weeks. Thus, the nonclinical and 
clinical safety data supports the safety of the proposed Phase 3 clinical trial dose of RTB101 (10 
mg once daily) in elderly subjects. However, RTB101-associated AEs seen when RTB101 has 
been used at significantly higher doses in oncology studies  still represent potential risks as 
described below. 
Stomatitis/Mucositis 
Mouth ulcers/stomatitis similar to canker sores are common AEs following treatment with high 
doses of RTB101 in oncology studies.  No increase in the incidence of mouth ulcers/stomatitis 
was observed in elderly subjects treated with RTB101 10 mg once daily as compared to placebo 
in the Phase 2a clinical trial CBEZ235Y2201 and the Phase 2b clinical trial RTB-BEZ235-202. 
However, in CBEZ235Y2201, one subject in the 10 mg RTB101 once daily dosing group 
discontinued study drug treatment due to mouth ulcers of moderate severity.  
If needed, topical treatments are recommended, but alcohol- or peroxide-containing 
mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should 
not be used unless fungal infection has been diagnosed. 
Gastrointestinal Symptoms 
Gastrointestinal symptoms including nausea, vomiting, and diarrhea are common AEs following 
treatment with high doses of RTB101 in oncology studies.  
During the one year of study follow-up of elderly subjects in the Phase 2a clinical trial 
CBEZ235Y2201, diarrhea occurred in: 
• 8% of subjects in the placebo treatment group 
• 19% of subjects in the RTB101 10 mg once daily treatment group 
During the 24 weeks of study follow-up of elderly subjects in the Phase 2b clinical trial RTB-
BEZ235-202, diarrhea occurred in: 
• 4.4% of subjects in the placebo treatment group 
• 4.5% of subjects in the RTB101 10 mg once daily treatment group 
No increase in the incidence of nausea or vomiting was observed in elderly subjects treated with 
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BEZ235-202, however in CBEZ235Y2201, one subject in the RTB101 10 mg treatment group 
discontinued study drug due to nausea.  
In Study RTB-101-204, subjects must be monitored for signs of gastrointestinal irritation.  
Subjects experiencing nausea, vomiting, or diarrhea should receive appropriate medical 
treatment. Study drug should be permanently discontinued if a subject develops a gastrointestinal 
SAE, such as gastrointestinal bleeding or perforation. Study drug should also be permanently 
discontinued if a subject develops oral ulcers, stomatitis, or diarrhea that limits oral intake or is 
associated with dehydration or weight loss (>2% Baseline weight) over 2 or more consecutive 
study visits (see Section 5.5.2). 
Fatigue 
Fatigue/asthenia has been commonly reported following treatment with high doses of RTB101 in 
oncology studies. The incidence of fatigue was similar in the RTB101 10 mg once daily and 
placebo arms in elderly subjects in clinical trials CBEZ235Y2201 and RTB-BEZ235-202.  
Rash 
Rash has been frequently reported following treatment with high doses of RTB101 in oncology 
studies.   
During the one year of study follow-up of elderly subjects in the Phase 2a clinical trial 
CBEZ25Y2201, rash occurred in: 
• 3.8% of subjects in the placebo treatment group  
• 3.8% of subjects in the RTB101 10 mg once daily treatment group 
During the 24 weeks of study follow-up of elderly subjects in clinical trial RTB-BEZ235-202, 
rash occurred in: 
• 2.2% of subjects in the placebo treatment group  
• 0.6% of subjects in the RTB101 10 mg once daily treatment group 
Subjects that experience rash while receiving RTB101 should receive appropriate symptomatic 
treatment. 
Hyperglycemia 


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Hyperglycemia has commonly been seen following treatment with high dose RTB101 in 
oncology clinical trials. The incidence of hyperglycemia was similar in the RTB101 10 mg once 
daily and placebo arms in clinical trials CBEZ235Y2201 and RTB-BEZ235-202. Blood glucose 
levels will be closely monitored throughout the current trial. 
Hematopoietic and Lymphopoietic Systems 
Anemia, leukopenia and thrombocytopenia are common AEs following treatment with high 
doses of RTB101 in oncology studies. No increase in the incidence of anemia, leukopenia or 
thrombocytopenia was observed in elderly subjects treated with RTB101 10 mg once daily as 
compared to placebo in clinical trials CBEZ235Y2201 and RTB-BEZ235-202. Complete blood 
counts will be followed at each visit while subjects are on study drug. 
Lipid Abnormalities 
Lipid disturbances are common in clinical trials of the rapalog class of mTOR inhibitors but are 
uncommon in clinical trials of RTB101.  The incidence of hyperlipidemia was similar in the 
RTB101 10 mg once daily and placebo arms in elderly subjects in clinical trials CBEZ235Y2201 
and RTB-BEZ235-202. Cholesterol and triglyceride levels will be followed at each visit. 
Cardiovascular Events 
Preclinical findings did not indicate prominent cardiac risks of RTB101. In clinical studies with 
high doses of RTB101 in oncology subjects, only few cases of cardiac AEs were reported, and it 
is not clear if RTB101 increases the risk of cardiac events. A suspected case of myocardial 
infarction (MI) was reported in an oncology subject treated with high dose RTB101 (200 mg bid) 
in combination with everolimus, and a suspected case of acute coronary syndrome was reported 
in an oncology subject receiving high dose RTB101 in combination with paclitaxel. No increase 
in the incidence of cardiac events was observed in elderly subjects treated with RTB101 10 mg 
once daily as compared to placebo in clinical trial CBEZ235Y2201. In RTB-BEZ235-202, 3 
elderly subjects with multiple cardiac risk factors had a MI in the RTB101 5 mg once daily 
treatment arm. No MIs occurred in the RTB101 10 mg once daily, RTB101 10 mg twice daily, 
RTB101 10 mg + everolimus or placebo treatment arms. Nevertheless, subjects with active 
severe, uncontrolled and/or unstable cardiac conditions (including subjects with unstable angina 
pectoris or acute ischemic changes on ECG at Screening or Baseline [see Section 4.2]) will be 
excluded from Study RTB-101-204. Central analysis of ECG data in oncology study 
CBEZ235A2101 did not show any evidence for QT prolongation. A preliminary exposure-QT 
analysis showed no significant impact of RTB101 plasma concentration on QT interval. Despite 


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these findings, as a conservative measure, subjects with a QTcF >480 msec at Screening or 
Baseline will also be excluded from study participation (see Section 4.2). 
From the Baseline through the Week 20 Visit (i.e., completion of the Short-term Follow-up 
Period) in Study RTB-101-204, subjects will be queried with regard to any new cardiac 
symptoms (see SOM for details); a cardiac exam will be performed as part of required complete 
and targeted physical examinations (see Table 6-1 [Assessment Schedule]), and ECGs will be 
obtained at the Week 4, Week 8, Week 12, and Week 16 visits post-Baseline. Any QTcF >500 
msec or >60 msec QTcF change from a subject’s Baseline ECG, or any other clinically 
significant abnormal ECG change should be reported as an AE. As a safety precaution, subjects 
experiencing any cardiac-related SAEs (including, but not limited to, MI and unstable angina) 
must permanently discontinue study drug treatment (see Section 5.5.2). 
Liver Toxicity 
Elevated liver function tests (LFTs) have been reported in oncology subjects treated with high 
dose RTB101.  No increase in the incidence of elevated LFTs was observed in elderly subjects 
treated with RTB101 10 mg once daily as compared to placebo in clinical trials CBEZ235Y2201 
and RTB-BEZ235-202.  However, subjects with active hepatitis or with significant LFT 
elevations should be excluded from this RTB101 trial. An elevation of alanine aminotransferase 
(ALT), aspartate aminotransferase (AST) or total bilirubin >3 x ULN should be reported as a 
severe (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3) AE. 
Pneumonitis 
Non-infectious pneumonitis is a class effect of mTOR inhibitors that are rapamycin-derivatives. 
However, it is unclear if RTB101 is associated with an increased risk of interstitial pneumonitis 
even when administered at high doses. In clinical trials of high dose RTB101 in 442 advanced 
cancer subjects, 5 cases of interstitial pneumonitis potentially related to RTB101 have been 
reported. However, 2 of these subjects were also receiving rapamycin-derivatives, and two had 
underlying pneumonia. No elderly subjects developed pneumonitis while receiving low dose 
RTB101 in clinical studies CBEZ235Y2201 or RTB-BEZ235-202.   
Consider a diagnosis of non-infectious pneumonitis in subjects presenting with non-specific 
respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in 
whom infectious, neoplastic, and other causes have been excluded by means of appropriate 
investigations. The lung toxicity has been reported to be completely reversible in most of the 
cases upon drug interruption or discontinuation. The use of corticosteroids may be indicated. See 
Section 13.2 (Appendix 2) for an algorithm for treating interstitial pneumonitis.  


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 Population 
The study population will be comprised of elderly individuals  65 years of age without  unstable 
underlying medical conditions defined as conditions that require acute medical intervention or 
ongoing adjustments of concomitant medications (as determined by medical history, ECG and 
laboratory tests at Screening, and physical examination, ECG and vital signs at Screening and 
Baseline). The goal is to randomize approximately 1066 subjects during winter cold and flu 
season.  
The Investigator must ensure that all patients being considered for the study meet the following 
eligibility criteria. No additional criteria should be applied by the Investigator so that the study 
population will be representative of all eligible subjects. Subject selection is to be established by 
checking through inclusion/exclusion criteria at Screening and Baseline. A relevant record (e.g., 
checklist) of the eligibility criteria must be stored with the source documentation at the study 
site. Deviation from any entry criterion excludes a subject from enrollment into the study. 
 
Subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Male and female subjects who, in the clinical judgement of the Investigator, are without 
unstable medical conditions defined as conditions that require acute medical intervention or 
ongoing adjustments of concomitant medications (as determined by medical history, 
concurrent concomitant medications and laboratory test results at Screening, and physical 
examination, ECG and vital signs at Screening and Baseline). 
3. Subjects must be ≥65 years of age. 
4. Subjects should require no or minimal assistance with self-care and activities of daily living. 
Subjects in assisted-living or long-term care residential facilities that provide minimal 
assistance are eligible.  
5. Females must be post-menopausal. Women are considered post-menopausal and not of child 
bearing potential if they have had: 
• 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) OR 
• surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy 
or tubal ligation at least six weeks prior to Screening. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow 
up hormone level assessment will she be considered not of child bearing potential. 
6. Sexually active male subjects with a partner of child-bearing potential must be willing to 
wear a condom while on study drug and for 1 week after stopping study drug and should not 


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father a child in this period. A condom is required to be used also by vasectomized men with 
a partner of child-bearing potential to prevent delivery of the drug via seminal fluid. 
7. Subjects must weigh at least 40 kg. 
8. Subject must be able to communicate well with the Investigator, and to understand and comply 
with the requirements of the study including completing an eDiary daily at home.  
 
Subjects will not be eligible if they meet any of the following criteria: 
1. Any of the following smoking criteria: 
a. Is a current smoker as assessed by medical history or a positive serum cotinine 
test (or positive urine cotinine test if serum cotinine testing is unavailable) at 
Screening. 
b. Stopped smoking ≤1 year prior to Screening. 
c. Is a previous smoker with a ≥10 pack year smoking history. 
d. Has a household member who currently smokes in the house. 
2. Subjects with a medical history of clinically significant lung diseases other than asthma 
(e.g., chronic obstructive pulmonary disease (COPD), emphysema, interstitial pulmonary 
fibrosis (IPF), bronchiectasis, etc.). 
3. Subjects with a Mini Mental Status Examination (MMSE) score <24 at Screening. 
4. Subjects with current evidence of a serious and/or unstable medical disorder including 
cardiovascular, respiratory, gastrointestinal, renal (including subjects with an estimated 
glomerular filtration rate (eGFR) as estimated by the modified diet in renal disease 
(MDRD) GFR equation 30 mL/min/1.73m2), or hematologic disorders. 
5. The following cardiac conditions: 
a. Unstable angina pectoris or acute ischemic changes on ECG at Screening or 
Baseline 
b. History of MI, coronary bypass surgery, or any percutaneous coronary 
intervention (PCI) within 6 months prior to Screening 
c. New York Heart Association functional classification III-IV congestive heart 
failure 
d. Unstable or life-threatening cardiac arrhythmia 
(Chronic stable atrial fibrillation is allowed)  
e. QTcF >480 msec at Screening or Baseline 
6. Subjects with history of malignancy in any organ system within the past 5 years EXCEPT 
for the following:  
a. Localized basal cell or squamous cell carcinoma of the skin. 


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b. Prostate cancer confined to the gland (AJCC stage T2N0M0 or better). 
c. Cervical carcinoma in situ. 
d. Breast cancer localized to the breast 
7. Any RTI or acute significant illness (based on the subject’s medical history and the 
clinical judgement of the Investigator) which has not resolved at least two (2) weeks prior 
to Baseline. 
8. Subjects with a history of systemic autoimmune diseases (e.g., lupus, inflammatory 
bowel disease, rheumatoid arthritis, etc.), or receiving immunosuppressive therapy (such 
as mycophenolate, tacrolimus, cyclosporine, azathioprine, infliximab) including chronic 
use of prednisone >10 mg daily (however, inhaled corticosteroids and the acute use of 
higher doses of prednisone to treat conditions such as exacerbation of asthma or other 
acute conditions are allowed). 
9. Subjects with Type I diabetes mellitus. 
10. Clinically relevant abnormal laboratory values suggesting an unknown disease and 
requiring further evaluation.  
11. Subjects with any one of the following during Screening:  
a. white blood cell (WBC) count <2.0 x103/microL. 
b. neutrophil count <1.0 x 103/microL. 
c. platelet count <75 x 103/microL.. 
12. Subjects with a history of alcohol or drug abuse within 2 years of the Screening visit. 
13. Subjects with any conditions affecting absorption, distribution, or metabolism of the 
study drug (e.g., inflammatory bowel disease, gastric or duodenal ulcers, hepatic disease). 
For subjects with biochemical evidence of liver injury as indicated by abnormal liver 
function tests: 
• Any single parameter of ALT, AST, alkaline phosphatase or serum bilirubin 
must not exceed 1.5 x upper limit of normal (ULN) in subjects who do not have a 
history of Gilbert's syndrome. If the subject has a history of Gilbert’s syndrome, 
direct and indirect reacting bilirubin should be differentiated, and the direct 
bilirubin must be less than 1.5 x ULN. 
• Any elevation above ULN of more than one parameter of ALT, AST, alkaline 
phosphatase or serum bilirubin will exclude a subject from participation in the 
study. 
14. Subjects with a history of immunodeficiency diseases, including a positive human 
immunodeficiency virus (HIV) test result. 
15. Infection with Hepatitis B (HBV) or Hepatitis C (HCV). 
16. Subjects who require treatment with strong CYP3A4 or CYP1A2 inhibitors or inducers, 
or subjects who require treatment with digoxin. 


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17. Use of any other investigational medication or participation in any other investigational 
study within 5 half-lives of the investigational medication, or within 30 days, whichever 
is longer; or longer if required by local regulations. 
18. Subjects who have received an organ transplant. 
19. Subjects who previously received treatment with RTB101 in another clinical study (e.g., 
CBEZ235Y2201, RTB-BEZ235-202, or RTB-101-203). 
 Treatment 
 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM. 
Table 5-1  
Investigational and Control Drugs 
Study Drug Name 
Formulation 
 
Color 
Unit Dose 
Packaging 
RTB101 
 Capsules 
Pink 
10 mg 
Bulk supply 
bottles 
Matching Placebo 
 Capsules 
Pink 
--- 
Bulk supply 
bottles 
 
Subjects who meet study eligibility criteria will be randomized in a 1:1 ratio to one of the 
following 2 treatment arms. 
• RTB101 10 mg (1 capsule of 10 mg) daily 
• Matching Placebo (1 capsule of RTB101 matching placebo) daily 
 
 
Each subject will be uniquely identified in the study by a combination of his/her study site 
number and a subject number. The study site number will be assigned by the Sponsor. Upon 
signing the informed consent form, the subject will be assigned a subject number by the IXRS 
system.  


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Details regarding the process and timing of treatment assignment and randomization of subjects 
are outlined in the IXRS System User Guide. 
 
At the Baseline visit, all eligible subjects will be randomized via the IXRS to one of the 
treatment arms. The Investigator or his/her delegate will contact the IXRS after confirming that 
the subject fulfills all the inclusion/exclusion criteria (see Section 4 above). The IXRS will 
prompt the user to randomize the subject. The subject identifier number will be used to link the 
subject to a treatment arm and a unique medication number for the bottles of study drug to be 
dispensed to the subject.  
Please reference the IXRS System User Guide for more information on treatment assignment and 
randomization instructions. Randomization will be stratified based on the following factors that 
may influence the incidence and severity of RTIs and the response to treatment: 
1. Age ≥85 
2. Age ≥65 and <85 years with a medical history of asthma 
3. Clinical Frailty Scale score 4 
Randomization will be stratified to ensure that subjects in each of these subgroups are 
randomized equally between the treatment arms to minimize the risk of imbalance between the 
treatment arms. 
The randomization scheme for subjects will be reviewed and approved by a member of the team 
responsible for Randomization schema. Follow the details outlined in the SOM regarding the 
process and timing of treatment assignment and randomization of subjects. 
Details regarding the process and timing of treatment assignment and randomization of subjects 
are outlined in the IXRS System User Guide. 
 
This is a subject, Investigator and Sponsor-blinded study. Subjects, all study site staff, including 
Investigators and study nurses, will remain blinded until all subjects complete the Long-term 
follow up Period (Study Week 48).   
The Sponsor will remain blinded to study treatment until all subjects complete the Short-term 
Follow-up Period (Study Week 20). The identity of the treatments will be concealed by the use 
of active study drug that is identical to matched placebo in packaging, labeling, schedule of 


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administration, appearance, and odor. Unblinding a single subject at the study site for safety 
reasons (necessary for subject medical management) will occur via an emergency process in 
place at the study site (see Section 5.4.1 below). After all subjects complete the Short-term 
Follow-up Period (Study Week 20), the Sponsor and designee may be unblinded. 
 
Study drug will be administered orally by the subject at home with breakfast. Exceptions will be 
at the Baseline Visit, when the study drug will be administered to all subjects at the study site, 
and at the Week 4 (or Week 6 if applicable) and 12 visits, when the study drug will be 
administered (with a light meal) at the site to those subjects identified per the IXRS 
randomization for PK assessments. See the Assessment Schedule of this protocol (Section 6) for 
further details, including dosing windows. 
Treatment compliance will be assessed using 2 methods. First subjects will be instructed to enter 
the time they take their study drug daily in their eDiary. Second, subjects will be instructed to 
bring their remaining study drug to each study visit, and a pill count (study drug accountability) 
will be done at the site.   
 
In order to meet International Conference on Harmonization (ICH) GCP requirements and ensure 
the integrity of the blind, and also to allow for those rare instances when the blind may need to 
be broken in emergency situations, emergency code breaks must only be undertaken when the 
information is essential to treat the subject safely and efficaciously. The Investigator should 
contact (in case of emergency the Investigator can unblind treatment and then contact the 
Sponsor) the Sponsor Medical Monitor prior to breaking the blind to promptly discuss and 
explain the planned or actual unblinding event. Most often, study treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study subject who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IXRS System. When the Investigator contacts the system to break a treatment code for a 
subject, he/she must provide the requested subject identifying information and confirm the 
necessity to break the treatment code. The Investigator will then receive details of the 
investigational drug treatment for the specified subject and a communication confirming this 
information. 
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IXRS System at any time in case of emergency. The Investigator will provide 
the protocol number, the study drug name and the subject identifier number. 


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In addition, the Investigator must provide oral and written information to the subject on how to 
contact the Investigator (or the Investigator’s backup when the Investigator is unavailable) in 
case of emergency, to ensure that un-blinding can be performed at any time. Subjects whose 
treatment has been unblinded must be discontinued from the study treatment (see Section 5.5.2 
below). 
 
For subjects who are unable to tolerate the protocol-specified dosing scheme, the study drug 
treatment should be temporarily interrupted. If the subject is unable to tolerate restarting 
treatment, study drug should be permanently discontinued but the subject should continue to 
complete study assessments (as applicable) including completion of the daily eDiary. The AEs 
leading to study drug dose interruption or discontinuation must be recorded in the electronic case 
report form (eCRF).   
 
The date of the most recent pneumococcal and current seasonal influenza vaccinations of each 
subject should be captured at the Baseline Visit and entered into the Prior Vaccination eCRF 
page.  For subjects who have not received their seasonal influenza or pneumococcal vaccination 
at the time of study entry, influenza and pneumococcal vaccinations per standard of care are 
recommended. It is recommended that other vaccinations such as herpes zoster (shingles), 
measles, mumps, or rubella virus vaccine, or yellow fever vaccine be administered at least 2 
weeks before randomization  or after the Week 20 Visit to avoid having vaccination-associated 
symptoms confound assessments of symptomatic respiratory illness.  
 
 
The site must instruct the subject to report any dosing changes of their concomitant medications, 
or any new medications that they start taking after being enrolled into the study. All medications 
(including vaccinations), procedures and significant nondrug therapies (including physical 
therapy, supplemental oxygen, and blood transfusions) administered after the subject is enrolled 
into the study must be recorded in the eCRF. Each prior and/or concomitant medication must be 
individually assessed against all exclusion criteria and prohibited medications. If in doubt, the 
Investigator should contact the Sponsor Medical Monitor or designee before randomizing a 
subject or any time a new medication needs to be started. 
 


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Use of the treatments displayed in Table 5-2 is NOT allowed while subjects are taking study 
drug. Strong inhibitors and inducers of CYP3A4 and CYP1A2 are prohibited because they may 
substantially alter RTB101 blood levels. Immunosuppressive agents are prohibited because they 
may inhibit the immune response to infections and confound efficacy evaluations. Digoxin is 
prohibited because it is a narrow therapeutic index substrate of P-gp, and RTB101 may inhibit P-
gp in the gut.  Use of any prohibited concomitant medications including St. John’s wort while on 
study drug should be documented as a protocol deviation.  
Table 5-2   
Prohibited Concomitant Medications 
Medication 
Prohibition Period 
Action to be taken 
Strong inhibitors of CYP3A4 (e.g., 
ketoconazole, itraconazole, clarithromycin, 
telithromycin, voriconazole, ritonavir). 
While on study drug  
Discontinue study treatment 
while taking prohibited 
medication and for 5 half-
lives after discontinuation of 
the prohibited medication 
and document as a protocol 
deviation 
Strong inducers of CYP3A4 (e.g., 
carbamazepine, phenytoin, rifampicin, 
rifabutin, St. John’s wort). 
While on study drug 
Discontinue study treatment 
while taking prohibited 
medication and for 5 half-
lives after discontinuation of 
the prohibited medication 
and document as a protocol 
deviation 
Strong inhibitors of CYP1A2 (e.g., 
ciprofloxacin, enoxacin, fluvoxamine(a), 
zafirlukast). 
While on study drug 
Discontinue study treatment 
while taking prohibited 
medication and for 5 half-
lives after discontinuation of 
the prohibited medication 
and document as a protocol 
deviation 
Strong inducers of CYP1A2 (e.g., rifampicin). 
While on study drug 
Discontinue study treatment 
while taking prohibited 
medication and for 5 half-
lives after discontinuation of 
the prohibited medication 
and document as a protocol 
deviation 
Immunosuppressive therapy including 
prednisone > 10 mg daily except for acute 
treatment of conditions such as exacerbation 
of asthma  
While on study drug 
Discontinue study treatment 
while taking prohibited 
medication and for 5 half-
lives after discontinuation of 
the prohibited medication 
and document as a protocol 
deviation 
Digoxin  
While on study drug 
Discontinue study treatment 
while taking prohibited 


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medication and for 5 half-
lives after discontinuation of 
the prohibited medication 
and document as a protocol 
deviation 
 
Subjects who require moderate CYP3A4 inhibitors such as (erythromycin, fluconazole, calcium 
channel blockers) should be followed closely for AEs known to be associated with RTB101 as 
outlined in Section 3.3. 
A list of moderate and strong CYP3A4 and strong CYP1A2 inhibitors and inducers is included 
in Section 13.1 (Appendix 1).  
 
 
A subject will be considered to have completed the Primary Analysis Period of the study for 
efficacy and safety when the subject has completed the Week 16 Visit. The Short-term Follow-
up Period of the study for efficacy and safety will be considered completed when a subject has 
completed the Week 20 visit or has withdrawn consent or discontinued the study prematurely. 
 After completion of the Short-term Follow-up Period of the study, subjects will enter the Long-
term Follow-up Period of the study where a Long Term Follow-Up via questionnaire will be 
administered by telephone at Week 48. Information from this follow-up call on interim 
hospitalization(s), admission(s) to a skilled nursing facility, and/or death occurring since 
completion of the Short-term Follow-up Period of the study (i.e., Week 20) will be captured in 
the study database.  
After completion of the Long-term Follow-up Period of the study, subject participation in the 
study will be considered concluded. 
The Investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study for medical reasons or must refer them for appropriate ongoing care. 
 
Premature discontinuation of study treatment for a subject occurs when study drug is 
permanently stopped earlier than the protocol planned duration, and can be initiated by either the 
subject, the Investigator, or the Sponsor. 


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Study treatment must be permanently discontinued under the following circumstances:  
• Subject decision-subjects may choose to discontinue study drug treatment for any reason at 
any time. 
• The Investigator believes that continuation of study treatment would negatively impact the 
safety of the subject or the risk/benefit ratio of trial participation. This includes any 
laboratory abnormalities that in the judgment of the Investigator, taking into consideration 
the subject’s overall status, prevents the subjects from continuing participation in the study. 
• Any protocol deviation that results in a significant risk to the subject’s safety. 
• Emergence of the following AEs:  
o Hypersensitivity reaction to study drug 
o Gastrointestinal SAE 
o Oral ulcers, stomatitis, or diarrhea that limits oral intake or is associated with 
dehydration or weight loss (>2% from Baseline weight) over two or more 
consecutive study visits 
o Cardiac SAE (including, but not limited to, MI and unstable angina) 
o Study drug-related non-infectious pneumonitis (see Section 13.2 [Appendix 2]) 
• Subject whose treatment has been unblinded. 
If premature discontinuation of study treatment occurs, Investigator must determine the primary 
reason for the subject’s premature discontinuation of study treatment and record this information 
on the CRF. Subjects who permanently discontinue study drug due to an AE should return to the 
study site as soon as possible for an unscheduled visit to return all study drug for reconciliation 
and accountability and to have the following assessments: vital signs, complete physical exam, 
and blood and urine collection for safety labs. Subjects who discontinue treatment for reasons 
other than an AE should return all study drug for reconciliation and accountability at the next 
study visit. UNLESS subjects withdraw their consent (see Section 5.5.3), they should return for 
all remaining study visits (including completing the daily eDiary). If they fail to return for these 
assessments for unknown reasons, every effort (e.g., telephone, e-mail, certified letter) should be 
made to contact the subject as specified in Section 5.5.4 (Lost to follow-up).  
If subjects permanently discontinue study treatment early and DO NOT withdraw consent, study 
participation is expected to continue. At a minimum, attempts should be made to collect the 
following data via the eDiary, at abbreviated study site visits, and/or via telephone contact: 
• Respiratory Illness Symptom Questionnaire completed daily in the eDiary  


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• AEs/SAEs 
• New and/or concomitant treatments 
 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent from the study is defined as when all of the following apply: 
• A subject does not want to participate in the study anymore, and 
• Does not want any further visits or assessments, and 
• Does not want any further study related contacts, and 
• Does not allow analysis of already obtained biologic material. 
In this situation, the Investigator must make every effort (e.g., telephone, e-mail, certified letter) 
to determine the primary reason for the subject’s decision to withdraw their consent and record 
this information in the eCRF. Study treatment must be discontinued (see Section 5.5.2) and no 
further assessments conducted, and the data that would have been collected at subsequent visits 
will be considered missing. Further attempts to contact the subject in the context of the study are 
not allowed unless safety findings require communicating or follow-up. 
 
For subjects whose status is unclear because they fail to appear for study visits without stating an 
intention to discontinue or withdraw, the Investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of telephone 
calls, certified letters, etc. Three (3) attempts to contact the subject should be performed by the 
study site staff and documented in the subject’s source documentation. 
Additionally, a registered/certified letter to the subject (with documentation of the registered letter 
in the subject’s source documentation) should be sent to the subject (or caregiver). 
A subject cannot be considered as lost to follow-up until the time point of their scheduled end of 
Short-term Follow-up Period (i.e., Week 20 Visit) has passed. 
 
If the following criteria are met, an unblinded safety review will be completed by the DMC 
within 48 hours to determine if enrollment needs to be halted: 


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• Three or more subjects develop the same or a clinically similar SAE 
• Three or more subjects experience a Grade 3 or higher AE or laboratory abnormality of 
the same type considered at least possibly related to study drug 
• QTcF >500 msec or >60 msec change from pre-dose Baseline ECG, or any other 
clinically significant abnormal ECG change in any 3 or more subjects 
• Two or more subjects develop ALT, AST or total bilirubin > 3x ULN 
 
The study can be terminated by resTORbio at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory, medical or operational reasons (including slow enrollment). Should this be necessary, 
any remaining subjects enrolled in the study must be seen as soon as possible, treated as a 
prematurely withdrawn subject and an End of Study Visit must be completed. The Investigator 
will be responsible for informing the institutional review board (IRB)/independent ethics 
committee (IEC) of the early termination of the study. 
 Visit Schedule and Assessments  
Screening Visit:  
Screening may occur prior to investigational product being available at the study site. During the 
Screening Visit  (maximum 4 weeks prior to Baseline/randomization), subjects will be assessed 
for eligibility to participate in the trial based on inclusion/exclusion criteria. Subjects will have 
the following assessments/evaluations: 
• Informed Consent (Main Study) 
• Review of medical history and current medical (including cardiac) conditions. 
• Review of prior and concomitant medications. 
• Clinical evaluation, including a complete physical exam to include measurements of 
weight, height, blood pressure, heart rate, respiratory rate, and temperature. 
• Electrocardiogram (ECG) 
• Blood and urine drawn for safety assessments and testing for HIV, Hepatitis B and C 
virus. 
• Serum cotinine test (or urine cotinine test if serum cotinine testing is unavailable) to 
exclude current smokers. 


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• Chest X-ray, unless one was completed in the last three months. 
• Mini Mental Status Examination (MMSE) 
If necessary to address an abnormal laboratory value during the screening period, laboratory 
testing may be repeated on one occasion (as soon as possible) prior to randomization, to rule out 
any laboratory error. 
Baseline (Day 0) Visit: 
At the Baseline visit, subjects will undergo the following evaluations: 
• Complete informed consent for Optional Blood Storage for Future use and Consent for 
Optional Pharmacogenetic Analysis of Pharmacogenomic Blood Specimens (if 
applicable). 
• Review of inclusion/exclusion criteria.  
• Review of medical history and current medical (including cardiac) conditions. 
• Review of prior and concomitant medications including dates of the most recent 
administration (if applicable) of the pneumococcal and the current seasonal influenza 
vaccinations. 
• Clinical evaluation, including a targeted physical exam to include measurements of 
weight, orthostatic blood pressure, heart rate, respiratory rate, and temperature, and an 
exam of the lungs, heart, oral cavity, and skin. 
• Clinical frailty index score assessment (see Section 13.4 [Appendix 4]). 
• ECG for Baseline safety assessment. 
• A mid-turbinate swab will be obtained. 
• Blood and urine samples obtained for Baseline safety assessments. 
• Blood samples will be obtained for biomarker (including RNA expression and soluble 
serum biomarker) analysis. 
• Blood samples will be obtained for potential future pharmacogenomic assessments (for 
consenting subjects only). 
• Once randomized via IXRS, subjects will be administered their first dose of study drug at 
the study site. Subjects will be instructed on how to complete the dosing and the 
Respiratory Illness Symptom Questionnaire in the eDiary daily at home. Subjects will 
then  complete the Health Related Quality of Life (EQ-5D-5L; see Section 13.3 


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[Appendix 3]) and Respiratory Illness Symptom Questionnaire on their eDiary at the 
Baseline visit.  
After assessment for adverse events, subjects will then be sent home with study drug and the 
eDiary. Subjects will be instructed to take study drug at home daily with breakfast and to bring 
remaining study drug to all study visits.  
Provided the study drug continues to be well tolerated, subjects will be treated with study drug 
through the Week 16 Visit, during which time they will return to the clinic every 2 weeks (Visits 
Week 2, 4, 6, and 8) for the first 8 weeks, and then every 4 weeks (Visits Week 12 and 16). 
Week 2 Visit: 
Subjects will return to the study site 2 weeks after starting study drug. The following evaluations 
will be performed: 
• Review of interim and current medical (including cardiac) conditions (see SOM for 
details). 
• Clinical evaluation, including a targeted physical exam to include measurements of 
weight, blood pressure, heart rate, respiratory rate, and temperature, and an exam of the 
lungs, heart, oral cavity, and skin. 
• Assessments for safety including any adverse/serious adverse events and any concomitant 
medications taken since the last study visit.  
• Obtain information about whether subjects have been evaluated in an ER or urgent care 
facility or been admitted to a hospital or skilled nursing facility since their last visit. 
• Blood and urine samples will be obtained for safety assessments. 
• A mid-turbinate swab will be obtained. If a subject presents with respiratory illness 
symptoms at this visit they may also have a nasopharyngeal swab, RIDT and sputum 
sample (if applicable) obtained as outlined in the unscheduled visit assessments. 
• Remaining study drug brought back by the subject to the study visit will be counted to 
ensure compliance and subject will be retrained if compliance is not 100%. Subject will 
be re-dispensed the same study drug that they brought to the visit. 
• Those subjects participating in the PK assessments (per the IXRS randomization) will be 
asked to not take study drug on the morning of their next scheduled study visit (Week 4 
[or Week 6 if applicable]) as the subject will be administered study drug together with a 
light meal at the study site. 


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Week 4 Visit: 
The following evaluations will be performed: 
• Review of interim and current medical (including cardiac) conditions (see SOM for 
details). 
• Clinical evaluation, including a targeted physical exam to include measurements of 
weight, blood pressure, heart rate, respiratory rate, and temperature, and an exam of the 
lungs, heart, oral cavity, and skin. 
• ECG for safety monitoring. 
• Assessments for safety including any adverse/serious adverse events and any concomitant 
medications taken since the last study visit. 
• Obtain information about whether subjects have been evaluated in an ER or urgent care 
facility or been admitted to a hospital or skilled nursing facility since their last visit. 
• Blood and urine will be obtained for safety assessments. 
• A mid-turbinate swab will be obtained. If a subject presents with respiratory illness 
symptoms at this visit they may also have a nasopharyngeal swab, RIDT and sputum 
sample (if applicable) obtained as outlined in the unscheduled visit assessments. 
• PK and biomarker assessments (only for those subjects identified per the IXRS 
randomization for PK assessments):  
o A pre-dose PK sample will be taken after which study drug will be administered 
at the study site together with a light meal. 
o The remaining PK samples will be drawn at the following timepoints post study 
drug administration: 
▪ 30 minutes (±10 minutes) 
▪ 1 hour (±15 minutes) 
▪ 2 hour (±30 minutes) 
▪ 4 hour (±30 minutes) – After obtaining a PK blood sample, blood samples 
for biomarker assessments will also be obtained at the 4 hour time point 
(see SOM and Lab Manual for instructions). 
▪ If PK sampling cannot be performed at the Week 4 visit for logistical 
reasons, it should be collected at the Week 6 visit instead, but according to 
the schedule described above  for Week 4. This applies to timing of 
biomarker samples originally scheduled for Week 4 as well. 


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• Remaining study drug brought back by the subject to the study visit will be counted to 
ensure compliance and subject will be retrained if compliance is not 100%. Subject will 
be dispensed new study drug at this visit. 
Week 6 Visit: 
The following evaluations will be performed: 
• Review of interim and current medical (including cardiac) conditions (see SOM for 
details). 
• Clinical evaluation, including a targeted physical exam to include measurements of 
weight, blood pressure, heart rate, respiratory rate, and temperature, and an exam of the 
lungs, heart, oral cavity, and skin. 
• Assessments for safety including any adverse/serious adverse events and any concomitant 
medications taken since the last study visit. 
• Obtain information about whether subjects have been evaluated in an ER or urgent care 
facility or been admitted to a hospital or skilled nursing facility since their last visit.  
• Blood and urine samples will be obtained for safety assessments. 
• If PK sampling could not be performed at the Week 4 visit for logistical reasons, it 
should be collected at the Week 6 visit instead, but according to the schedule described  
above for Week 4. This applies to timing of biomarker samples originally scheduled for 
Week 4 as well. 
• A mid-turbinate swab will be obtained. If a subject presents with respiratory illness 
symptoms at this visit they may also have a nasopharyngeal swab, RIDT and sputum 
sample (if applicable) obtained as outlined in the unscheduled visit assessments. 
• Remaining study drug brought back by the subject to the study visit will be counted to 
ensure compliance and subject will be retrained if compliance is not 100%. Subject will 
be re-dispensed the study drug that the subject brought to the visit. 
Preparation for Week 8 Visit (PK subjects only): Those subjects participating in the PK 
assessments (per the IXRS randomization) will be instructed to take their study drug at 
home with breakfast and to record the time of dosing in the eDiary on the morning of 
their next scheduled visit (Week 8 Visit). The Week 8 visit should be scheduled 
approximately 7 hours after the subject plans to take their morning dose of medication to 
enable an 8 hour post-dose PK blood draw. 
Week 8 Visit: 


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The following evaluations will be performed: 
• Review of interim and current medical (including cardiac) conditions (see SOM for 
details). 
• Clinical evaluation, including a targeted physical exam to include measurements of 
weight, blood pressure, heart rate, respiratory rate, and temperature, and an exam of the 
lungs, heart, oral cavity, and skin. 
• ECG for safety monitoring 
• Assessments for safety including any adverse/serious adverse events and any concomitant 
medications taken since the last study visit. 
• Obtain information about whether subjects have been evaluated in an ER or urgent care 
facility or been admitted to a hospital or skilled nursing facility since their last visit.   
• Blood and urine will be obtained for safety assessments.  
• A mid-turbinate swab will be obtained. If a subject presents with respiratory illness 
symptoms at this visit they may also have a nasopharyngeal swab, RIDT and sputum 
sample (if applicable) obtained as outlined in the unscheduled visit assessments. 
• For those subjects participating in the PK assessments (identified per the IXRS 
randomization), a post-dose 8 hour (±1 hour) PK sample will be taken.  
Remaining study drug brought back by the subject to the study visit will be counted to ensure 
compliance and subject will be retrained if compliance is not 100%. Subject will be dispensed 
new study drug at this visit.  
• Preparation for Week 12 Visit (PK subjects only): Those subjects participating in the 
PK assessments (per the IXRS randomization) will be asked to not take study drug on the 
morning of their next scheduled study visit (Week 12) as the subject will be administered 
study drug together with a light meal at the study site. 
Week 12 Visit: 
The following evaluations will be performed: 
• Review of interim and current medical (including cardiac) conditions (see SOM for 
details). 
• Clinical evaluation, including a targeted physical exam to include measurements of 
weight, blood pressure, heart rate, respiratory rate, and temperature, and an exam of the 
lungs, heart, oral cavity, and skin. 
• ECG for safety monitoring 


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• Assessments for safety including any adverse/serious adverse events and any concomitant 
medications taken since the last study visit 
• Obtain information about whether subjects have been evaluated in an ER or urgent care 
facility, or been admitted to a hospital or skilled nursing facility since their last visit 
• Blood and urine samples will be obtained for safety assessments. 
• A mid-turbinate swab will be obtained. If a subject presents with respiratory illness 
symptoms at this visit they may also have a nasopharyngeal swab, RIDT and sputum 
sample (if applicable) obtained as outlined in the unscheduled visit assessments. 
• PK assessments (only for those subjects identified per the IXRS randomization):  
o A pre-dose PK sample will be taken after which study drug will be administered 
at the study site together with a light meal. 
o The remaining PK samples will be drawn at the following timepoints post study 
drug administration: 
▪ 30 minutes (±10 minutes) 
▪ 1 hour (±15 minutes) 
▪ 2 hour (±30 minutes) 
• Remaining study drug brought back by the subject to the study visit will be counted to 
ensure compliance and subject will be retrained if compliance is not 100%. Subject will 
be dispensed new study drug at this visit.  
Week 16 Visit: 
The following evaluations will be performed: 
• Review of interim and current medical (including cardiac) conditions (see SOM for 
details). 
• Clinical evaluation, including a complete physical exam to include measurements of 
weight, blood pressure, heart rate, respiratory rate, and temperature. 
• ECG for safety monitoring. 
• Assessments for safety including any adverse/serious adverse events and any concomitant 
medications taken since the last study visit. 
• Obtain information about whether subjects have been evaluated in an ER or urgent care 
facility or been admitted to a hospital or skilled nursing facility since their last visit. 
• Blood and urine will be obtained for safety assessments. 


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• Blood will be obtained for biomarker analysis. 
• Subjects will have a mid-turbinate swab taken. If a subject presents with respiratory 
illness symptoms at this visit they may also have a nasopharyngeal swab, RIDT and 
sputum sample (if applicable) as outlined in the unscheduled visit assessments. 
• Subjects will complete the Health Related Quality of Life (EQ-5D-5L). 
• Remaining study drug will be returned. No study drug will be dispensed as this will be 
end of treatment. 
Week 20 Visit: End of the Short-term Follow-up Period of the Study 
All subjects will be followed up for 4 weeks after their last dose of study drug. The following 
evaluations will be performed: 
• Review of interim and current medical (including cardiac) conditions (see SOM for 
details). 
• Clinical evaluation, including a complete physical exam to include measurements of 
weight, blood pressure, heart rate, respiratory rate, and temperature. 
• If a subject presents with respiratory illness symptoms at this visit they may also have a 
nasopharyngeal swab, RIDT and sputum sample (if applicable) obtained as outlined in 
the unscheduled visit assessments (section 3.1). 
• Assessments for safety including any adverse/serious adverse events and any concomitant 
medications taken since the last study visit. 
• Obtain information about whether subjects have been evaluated in an ER or urgent care 
facility or been admitted to a hospital or skilled nursing facility since their last visit. 
• Blood and urine samples will be obtained for safety assessments. 
• eDiaries will be returned. 
Subject who have AEs that are continuing at the end of the Short-term Follow-up Period (i.e., 
Week 20 Visit) will be captured as “ongoing” in the database; however, the AEs should continue 
to be followed until resolution or judged to be permanent by the Investigator (see Section 7.1). 
Clinically Symptomatic Respiratory Illness Unscheduled Visits 
Refer to Section 3.1. 
Week 48: End of the Long-term Follow-up Period of the Study 


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As part of extended long-term safety follow-up post-treatment, sites will contact subjects by 
telephone at Week 48 to capture information on a questionnaire concerning hospitalization(s), 
skilled nursing facility admission(s) and deaths that have occurred since the Week 20 visit.   
Table 6-1 lists all of the visits and assessments and indicates with an “X” when the assessments 
are performed. Visit windows are provided to ease scheduling of subject visits. Visits that occur 
outside these visit windows will be considered a protocol deviation. Below are some highlights 
of specific activities by visit. More details regarding specific tests and procedures can be found 
below in this section and in the SOM. Adverse events should be monitored throughout the study 
and recorded as described in Section 7, Safety Monitoring.


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Table 6-1  
Assessment Schedule 
Screening 
Baseline 
Primary Analysis (and Study Drug Administration) Period 
Clinically 
Symptomatic 
Respiratory 
Illness Visit 
(Unscheduled
) 
Short-
term 
Follow-
up 
Period 
Long 
Term 
Follow-
Up 
Period 
Day/Week 
Day -28 to 
-1 
Day 0 
Week 
2 
Week 4 
Week 6 
Week 8 
Week 12 
Week 16 
 --- 
Week 20 
Week 48 
Visit Window 
 --- 
---  
±5 
days 
±5 days 
±5 days 
±5 days 
±5 days 
±5 days 
--- 
±5 days 
±4 weeks 
Main Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
Mini Mental Status Exam (MMSE) 
X 
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
X 
X1 
  
  
  
  
  
  
  
  
  
Influenza and pneumococcal 
vaccination history 
 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
Medical History/Interim/Current 
Medical (including cardiac) 
Conditions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Prior & Concomitant 
Medications/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs: Temperature; 
Respiratory Rate; Heart Rate & 
Blood Pressure2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Orthostatic Blood Pressure 
  
X 
  
  
  
  
  
  
  
  
  
Complete Physical Exam 
X 
  
  
  
  
  
  
X 
  
X 
  
Targeted Physical Exam 
(including: oral, lungs, heart, skin) 
  
X 
X 
X 
X 
X 
X 
  
X3 
 
  
ECG Evaluation 
X4 
X4 
  
X 
  
X 
X 
X 
  
  
  
Chest X-Ray5 
X 
  
  
  
  
  
  
  
  
  
  
Hematology, Blood Chemistry, 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
  
Serum Cotinine Test21 
X 
  
  
  
  
  
  
  
  
  
  
HIV/Hepatitis Screen6 
X 
  
  
  
  
  
  
  
  
  
  
Clinical Frailty Scale Scoring7 
  
X 
  
  
  
  
  
  
  
  
  


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Screening 
Baseline 
Primary Analysis (and Study Drug Administration) Period 
Clinically 
Symptomatic 
Respiratory 
Illness Visit 
(Unscheduled
) 
Short-
term 
Follow-
up 
Period 
Long 
Term 
Follow-
Up 
Period 
Day/Week 
Day -28 to 
-1 
Day 0 
Week 
2 
Week 4 
Week 6 
Week 8 
Week 12 
Week 16 
 --- 
Week 20 
Week 48 
Visit Window 
 --- 
---  
±5 
days 
±5 days 
±5 days 
±5 days 
±5 days 
±5 days 
--- 
±5 days 
±4 weeks 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
Study Drug Administration/ 
Dispensation/Return8,9 
  
X9,11 
X10a 
X9,11 
X10a 
X9 
X9,11 
X10b 
  
  
  
Dispensation/Return of eDiary 
  
X12a 
  
  
  
  
  
  
  
X12b 
  
Record Time of Study Drug 
Administration in eDiary 
  
Daily 
  
  
  
Respiratory Symptom 
Questionnaire 
  
Daily through Week 20 
X 
 
  
Health-related Quality of Life 
(HRQoL) EQ-5D-5L13 
  
X 
X13 
X 
X13 
 
  
Any visits to ER/urgent care or 
admission to hospital or skilled 
nursing facility since last study 
visit? 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse Events8 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Mid-Turbinate Nasal Swab 
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
Nasopharyngeal Swab for 
Respiratory Pathogen PCR 
  
  
  
  
  
  
  
  
X14 
  
  
Rapid Influenza Diagnostic Test 
(RIDT) (if clinically indicated) 
  
  
  
  
  
  
  
  
X15 
  
  
Sputum Gram Stain and Culture (if 
clinically indicated) 
  
  
  
  
  
  
  
  
X16 
  
  
Consent for  Optional Blood 
Storage for Future Use and Consent 
for Optional Pharmacogenetic 
Analysis of Pharmacogenomics 
Blood Specimen (for consenting 
subjects only) 
  
X 
  
  
  
  
  
  
  
  
  


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Screening 
Baseline 
Primary Analysis (and Study Drug Administration) Period 
Clinically 
Symptomatic 
Respiratory 
Illness Visit 
(Unscheduled
) 
Short-
term 
Follow-
up 
Period 
Long 
Term 
Follow-
Up 
Period 
Day/Week 
Day -28 to 
-1 
Day 0 
Week 
2 
Week 4 
Week 6 
Week 8 
Week 12 
Week 16 
 --- 
Week 20 
Week 48 
Visit Window 
 --- 
---  
±5 
days 
±5 days 
±5 days 
±5 days 
±5 days 
±5 days 
--- 
±5 days 
±4 weeks 
Blood Collection for RNA 
Expression in Whole Blood and 
Soluble Biomarkers 
  
X 
  
X17 
  
  
  
X 
  
  
  
PK Blood (Plasma) Collection 
  
  
  
X18a 
  
X18b 
X18a 
  
  
  
  
Long Term Follow-Up Questions 
by Telephone20 
  
  
  
  
  
  
  
  
  
  
X 
HIV = human immunodeficiency virus; MMSE = mini mental state examination; PCR = polymerase chain reaction; PK = pharmacokinetics; PSD= Premature subject 
discontinuation from study; RNA = ribonucleic acid; ER = emergency room. 
1 Review of inclusion / exclusion criteria is required at the Baseline evaluation. 
2 Seated blood pressure and heart rate measurements are required for all visits.  
3 The physical exam at the Clinically Symptomatic Respiratory Illness Visit (Unscheduled) for respiratory illness symptoms will be targeted to what is clinically indicated based on the 
subject‘s symptoms. 
4  The ECG for study eligibility determination at Screening and Baseline should be done prior to collection of blood samples for other required study assessments. 
5 Chest x-ray (CXR) does not need to be obtained at Screening if the subject had a CXR performed within the 3 months prior to Screening and the results and the x-ray film or digital copy 
are available. 
6 All subjects will be screened for Hepatitis B surface antigen (HBsAg), Hepatitis C and HIV. Screening for Hepatitis C will be based on HCV antibodies and if positive, HCV RNA levels 
should be determined. Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second technique available at the laboratory study site (e.g., Western blot) 
should be performed. 
7 Clinical Frailty Scale score should be entered into IXRS prior to assignment of randomization code. 
8 Subjects who prematurely discontinue study treatment due to an AE should return to the study site as soon as possible for an unscheduled visit to return all study drug for reconciliation and 
accountability, and to perform the following assessments: Vital signs, Complete Physical Exam, Hematology, Chemistry and Urinalysis. Subjects who discontinue due to a clinically 
symptomatic respiratory illness AE should also undergo respiratory illness assessments such as nasopharyngeal swab collection if not already done. Subjects who discontinue treatment for 
reasons other than an AE should return at the next scheduled visit at which time they will return all study drug for reconciliation and accountability at the next scheduled study visit. 
9 Study drug is dispensed at Day 0, Week 4, Week 8, and Week 12 (however, in the case of lost or damaged study drug, study drug can be dispensed at any study site visit). At Weeks 4, 8 
and 12, subjects will return study drug and will be dispensed new bottles. 


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10a Subjects will not return or be dispensed new study drug at these visits. Subjects will just bring their supply of study drug to the study site for pill count for compliance and then will return 
home with the same supply of study drug. 
10b At visit Week 16 or premature study discontinuation (PSD), all study drug will be returned, and the final study drug accountability will be performed. All subjects will self-administer 
study drug at home on the morning of their Week 16 visit. 
11 All subjects will be administered their first dose of study drug at the site at the Baseline Visit. Approximately 400 subjects (per IXRS randomization) will be required to undergo PK 
assessment in the study (~ 200 from each treatment arm). For subjects participating in the PK analysis for the study, at the Week 4 (or Week 6 if applicable) and Week 12 study visits, study 
drug should not be taken at home and instead study drug will be administered together with a light meal at the study site following the pre-dose PK draw. If PK sampling cannot be 
performed at the Week 4 visit for logistical reasons, it should be collected at the Week 6 visit instead, but according to the schedule described above  for Week 4. This applies to timing of 
biomarker samples originally scheduled for Week 4 as well. 
12a Subject will be given a personal tablet device containing the eDiary and instructions on use at this visit. 
12b The personal tablet device containing the eDiary will be collected from the subject at this visit. 
13 Health Related Quality of Life (EQ-5D-5L) to be completed by all subjects at Baseline and Week 16, and each day that they report experiencing one or more respiratory illness symptoms 
through Week 20. 
14 Nasopharyngeal swabs for respiratory pathogen PCR is to be done during a scheduled or an unscheduled visit for all subjects who report at least one unique respiratory symptom (runny 
nose, sneezing, stuffy nose, sore throat, hoarseness, or cough) on 2 consecutive entries in their eDiary. The swabs should be obtained if they are able to within 48 hours of 2 consecutive 
eDiary entries of one or more unique respiratory symptoms. Subjects who record at least 1 respiratory symptom and at least 1 general (headache, feverishness/chills or loss of appetite) 
symptom , both of which are moderate or severe on two consecutive days in their eDiary, should be brought in within 24 hours of the second day of eDiary symptom entry. Subjects who are 
unable to come to the study site may also have the nasopharyngeal swab (and, if indicated, a sputum specimen and RIDT) obtained during a home visit by trained personnel. Only one 
nasopharyngeal swab should be obtained during each episode of respiratory illness. Nasopharyngeal swabs will be collected through Week 20, see the SOM for more details.  
15 Subjects who develop influenza-like illness symptoms should have a rapid influenza diagnostic test (RIDT) done. Subjects with a positive RIDT should receive anti-influenza treatment 
per local standard of care, unless contraindicated, and/or other appropriate medical care. 
16 Subjects who develop a productive cough that is new or a change from their normal baseline should have a sputum gram stain and culture sent for analysis. 
 
17At the Week 4 (or Week 6 if applicable) visit, only subjects participating in the PK analysis will get blood samples drawn for biomarkers. In these subjects, biomarker samples should be 
obtained 4 hours post-dose (see SOM and Lab Manual for instructions). If PK sampling cannot be performed at the Week 4 visit for logistical reasons, it should be collected at the Week 6 
visit instead, but according to the schedule described above  for Week 4, and this applies to timing of biomarker samples originally scheduled for Week 4 as well. 
18a At Weeks 4 (or Week  6 if applicable) and 12, subjects participating in the PK analysis will not take their study drug at home and instead will take their study drug at the study site. 
18b Subjects participating in the PK analysis should have their Week 8 visit scheduled approximately 7 hours after they take their study medication at home. 
19 If clinically indicated, samples for Hematology, Chemistry and/or Urinalysis may be obtained at the Clinically Symptomatic Respiratory Illness Visit (Unscheduled). 
20 At Week 48, a long-term follow-up questionnaire will be administered by telephone to collect information regarding any hospitalizations, skilled nursing facility admissions and/or death 
since the Week 20 Visit. 
21 If serum cotinine testing is unavailable, urine cotinine may be assessed in lieu of serum cotinine.


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Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation) IRB/IEC-approved informed consent. 
resTORbio or designee will provide to Investigators a proposed informed consent form (ICF) 
that complies with the ICHE6 (R2) GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to this consent form suggested by the Investigator must 
be agreed to by resTORbio before submission to the IRB/IEC.  
 
Information about known side effects can be found in the RTB101 IB. This information will be 
included in the informed consent and should be discussed with the subject during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated to Investigators as appropriate, for example, 
via an Investigator Notification or an Aggregate Safety Finding. New information might require 
an update to the informed consent from and approval from an IRB/EC before being discussed 
with the subject and having the subject consent to the revised informed consent form. 
Consent for  Optional Blood Storage for Future use and Consent for Optional Pharmacogenetic 
Analysis will also be obtained at the Baseline Visit.  
 
 
It is permissible to re-screen a subject once if s/he fails the initial screening assessment(s).  
Please reference IXRS guide for more information on screening and re-screening instructions. 
 
All subjects who have signed the ICF but who have screen failed must have the reason for the 
screen failure (notated by inclusion or exclusion criteria number(s) documented in the IXRS 
system). 
 
During Screening/informed consent review, Baseline visit and subsequent study visits, the 
subjects will be informed and reminded of the following restrictions: 


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• No grapefruit or Seville oranges or their juices, should be consumed for 14 days prior to 
dosing until 7 days following the last dose.  Any consumption of grapefruit or Seville orange 
or their juices during this period should be documented as a protocol deviation.  
• Subjects must be instructed to take the daily dose of study drug with breakfast and should try 
to eat similar types of food at breakfast while taking study drug. Subjects who are 
participating in the PK assessments will be given their study drug together with a light meal 
provided at the site at the Week 4 Visit and at the Week 12 Visit. If PK sampling cannot be 
performed at the Week 4 visit for logistical reasons, it should be collected at the Week 6 visit 
instead, with the same timing of dose relative to a light meal provided at site. 
 
Demographic and Baseline characteristics data to be collected on all subjects include: date of 
birth, age, sex, race, ethnicity, and relevant medical (including smoking) history/current medical 
(including cardiac) conditions present. Where possible, diagnoses and not symptoms must be 
recorded. 
It is at the discretion of the Investigator if clinically significant test findings that occurred prior to 
subject randomization are recorded in the medical history CRF. 
 
All subjects will be screened for HIV, Hepatitis B and C. See the SOM for details. 
 
Compliance will be assessed by a dosing eDiary completed by the subjects daily at home (with 
the exception of the Baseline visit, when it will be completed at the site). In addition, compliance 
will be assessed at each visit by study personnel doing a pill count of remaining study drug 
brought by subjects to the site. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. 
 
For all medications (other than the study drug) initiated after the start of study, the reason for 
prescribing the medication, the start and, where applicable, end dates and change in medication 
dose should be recorded in the eCRF. 
 


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Respiratory illness symptoms will be captured in an eDiary that subjects will complete daily (in 
the evening) at home after the Baseline visit. The eDiary will ask the subject to record whether a 
predefined set of respiratory illness symptoms have occurred during the past 24 hours that are 
new or reflect a change from normal baseline symptoms. The predefined symptoms include both 
respiratory symptoms (runny nose, sneezing, stuffy nose, sore throat, hoarseness, or cough) and 
general symptoms (headache, feverishness/chills, loss of appetite, body aches, or lack of energy). 
A clinically symptomatic respiratory illness will be defined programmatically as the occurrence 
of 2 respiratory symptoms (runny nose/sneezing (programmatically considered one symptom), 
stuffy nose, sore throat, hoarseness, or cough) or 1 respiratory and 1 of the following general 
symptoms (headache, feverishness/chills or loss of appetite), with at least 1 unique respiratory 
symptom (runny nose, sneezing, stuffy nose, sore throat, hoarseness or cough) being reported on 
2 or more consecutive entries in an eDiary, and at least 2 symptoms being at least moderate in 
severity. Subjects who have clinically symptomatic respiratory illness may include subjects with 
a common cold, bronchitis,  influenza-like illness, or pneumonia.    
Further details will be provided in the Statistical Analysis Plan (SAP). 
 
When a subject reports symptoms of a respiratory illness in which at least one unique respiratory 
symptom (runny nose, sneezing, stuffy nose, sore throat, hoarseness, or cough) is reported on 2 
consecutive entries in their eDiary, the sites will contact the subject and instruct the subject to 
come to the study site if they are able to within 48 hours for evaluation and to obtain a 
nasopharyngeal swab. Subjects should only have one nasopharyngeal swab obtained during each 
episode of a respiratory illness. Please refer to the SOM for more details. Laboratory 
confirmation of clinically symptomatic respiratory illness will be obtained using three methods: 
• The FILMARRAY Respiratory panel polymerase chain reaction (PCR) Assay of 
nasopharyngeal swabs in all subjects  
• Sputum gram stain and culture obtained in subjects with a productive cough that is new 
or a change from their normal baseline 
• RIDT obtained in subjects with influenza-like illness symptoms (such as 1 or more 
respiratory symptom (cough, sore throat or nasal symptoms) and 1 or more 
constitutional symptom (such as body aches or feverishness/chills)).  


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Subjects who are unwilling or unable to come to the study site for an unscheduled visit should 
have the nasopharyngeal swab (and sputum specimen or RIDT , if indicated) obtained at a home 
visit by trained personnel. All subjects with influenza-like illness who have influenza detected by 
RIDT or nasopharyngeal swab PCR should receive anti-influenza treatment per local standard of 
care, unless contraindicated, and/or other appropriate medical care.  
Study drug treatment can be continued in subjects who require antibiotics or anti-influenza 
treatment for treatment of an RTI.  
Laboratory-confirmed clinically symptomatic respiratory illness will be defined 
programmatically as a symptomatic respiratory illness that meets the prespecified clinical 
diagnostic criteria outlined in Section 6.7.1 and is associated with a laboratory-confirmed 
pathogen detected by one or more of the 3 methods described above. Further details will be 
provided in the SAP. 
 
Subject will self-assess and report daily in their eDiary the occurrence and severity (absent, mild, 
moderate or severe) of the respiratory illness symptoms. 
These data will be used to determine the time to alleviation of moderate and/or severe clinically 
symptomatic respiratory illness symptoms, and the percentage of subjects who experience severe 
symptoms due to clinically symptomatic respiratory illness. Further details are provided in the 
SAP.  
 
The primary and secondary efficacy assessments selected for this protocol are appropriate to 
measure the incidence, severity and duration of clinically symptomatic respiratory illness. Daily 
reporting of respiratory illness symptoms via an eDiary will help assure that clinically 
symptomatic respiratory illness events are rapidly captured during the trial. Obtaining laboratory 
confirmation if you are able to within 48 hours of symptom confirmation when viral detection is 
likely to be highest using a Food and Drug Administration (FDA)-approved PCR panel assay 
(FilmArray Respiratory Panel, 510(k) NO: K152579 [Dual track]) that detects 17 viral and 3 
bacterial respiratory pathogens will also help increase rates of laboratory-confirmation of 
clinically symptomatic respiratory illness. 
 


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Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Table of Assessments (Table 6-1) detailing when each assessment is to be 
performed. 
 
A complete physical examination will be done at Screening and at Week 16 and Week 20. A 
targeted physical exam of at least lungs, heart, oral cavity, and skin will be done at all other 
scheduled visits. Subjects who come in to the study site for an unscheduled visit due to clinically 
symptomatic respiratory illness will also receive a targeted physical exam based on their 
presenting symptoms.  
A complete medical history should be performed at the Screening visit. The medical history at  
the Baseline visit should include dates of the most recent administration of the pneumococcal 
and current seasonal influenza vaccinations. At all subsequent visits, a review of any new 
interval medical history (including, but not limited to review of any new cardiac symptoms) 
should be performed. See the SOM for details. 
 
The following vital signs will be collected with the subject in a seated position and recorded in 
the source notes and eCRF: 
• Body temperature (oral or tympanic) 
• Blood pressure (BP) 
▪ Orthostatic BP will be measured at the Baseline visit.  
• Heart Rate 
• Respiratory Rate 
 
• Height (cm) 
• Body weight (kg) 
• Body mass index (BMI) will be calculated by the electronic data capture (EDC) 
system as (Body weight (kg) / [Height (m)]2). 
 


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ECGs will be collected in accordance with the schedule outlined in the Table of Assessments 
(Table 6-1). ECGs may be obtained at additional times when deemed clinically necessary. 
ECGs must be reviewed by a qualified physician (the Investigator or qualified designee) at the 
study site. Subjects with acute ischemic changes and/or with a QTcF >480 msec on ECG at 
Screening or Baseline are excluded from study participation (see Section 4.2). In all cases, the 
Investigator must document in the source documents the clinical considerations (i.e., result 
was/was not clinically significant and/or medically relevant) in allowing or disallowing the 
subject to be enrolled in the study. 
Clinically significant ECG changes from Baseline occurring during the study must be evaluated 
for criteria defining an AE and reported as such if the criteria are met. Any QTcF >500 msec or 
>60 msec QTcF change from a subject’s Baseline ECG, or any other clinically significant 
abnormal ECG change from Baseline should be reported as an AE. Appropriate follow-up 
medical care should be provided to all subjects who develop clinically significant ECG changes 
during the study.  
 
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at Screening, the assessment may be repeated once prior 
to randomization for the purpose of inclusion and to rule out laboratory error. If the repeat value 
remains outside of protocol-specified ranges at the Baseline visit, the subject is excluded from 
the study. 
In the case where a laboratory range is not specified by the protocol but is outside the reference 
range for the laboratory at Screening, a decision regarding whether the result is of clinical 
significance or not shall be made by the Investigator and shall be based, in part, upon the nature 
and degree of the observed abnormality. The assessment may be repeated once prior to 
randomization for the purpose of inclusion and to rule out laboratory error. 
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the subject to be enrolled in the study. 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study should be evaluated for criteria defining an AE and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is no 


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longer clinically relevant. In case of doubt, the Sponsor Medical Monitor or designee should be 
contacted. 
 
Hematology  
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (e.g., 
neutrophils, basophils, eosinophils, monocytes, lymphocytes) and platelet count will be 
measured. 
 
Clinical Chemistry 
Alkaline phosphatase, total bilirubin, bicarbonate/CO2, cholesterol, chloride, glucose, potassium, 
AST, ALT, sodium, triglycerides, urea/blood urea nitrogen (BUN) and creatinine will be 
measured. 
At Screening, any single parameter of ALT, AST, alkaline phosphatase, or serum bilirubin must 
not exceed 1.5 x ULN in subjects who do not have Gilbert's syndrome. If the subject has a 
history of Gilbert’s syndrome, direct and indirect reacting bilirubin should be differentiated, and 
the direct bilirubin must be less than 1.5 x ULN. 
At Screening, any elevation above ULN of more than one parameter of ALT, AST, alkaline 
phosphatase, or serum bilirubin will exclude a subject from participation in the study. 
Any elevation of ALT, AST or total bilirubin >3 x ULN from the time of first dose of study drug 
should be reported as a severe (CTCAE Grade 3) AE. 
 
The safety assessments are appropriate for the subject population as well as for monitoring the 
known safety profile of mTOR inhibitors.  
 
PK samples will be collected at the time-points defined in the Table of Assessments (Table 6-1). 
Follow instructions outlined in the SOM regarding sample collection, numbering, processing, 
and shipment. 
Approximately 400 (as identified by the IXRS) subjects (200 in each treatment group) will 
undergo PK sampling at the timepoints described below: 


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Week 4 Visit or Week 6 (if applicable) (Subjects will be instructed not to take their morning 
dose at home that day.) 
1. Pre-dose  
Study drug will be administered at the study site together with a light meal after 
the pre-dose blood sample is obtained. 
2. 30 minutes post-dose (window: ± 10minutes)  
3. 1.0 hours post-dose (window: ± 15 minutes) 
4. 2.0 hours post-dose (window: ± 30 minutes) 
5. 4.0 hours post-dose (window: ± 30 minutes) 
If PK sampling cannot be performed at the Week 4 visit for logistical reasons, it 
should be collected at the Week 6 visit instead, with the same timing of dose 
relative to a light meal provided at site. 
Week 8 Visit (Subjects will be instructed to take their morning dose at home with breakfast, 
approximately 7 hours prior to their scheduled visit.) 
1. 8.0 hours post-dose (window: ± 1 hour) 
Week 12 Visit (Subjects will be instructed not to take their morning dose at home that day.) 
1. Pre-dose  
Study drug will be administered at the study site together with a light meal after 
the pre-dose blood sample is obtained 
2. 30 minutes post-dose (window: ± 10minutes)  
3. 1.0 hours post-dose (window: ± 15 minutes) 
4. 2.0 hours post-dose (window: ± 30 minutes) 
 
RTB101 plasma concentrations will be determined by a LC-MS/MS method following protein 
precipitation. Plasma concentrations of RTB101 metabolites such as M29 and M41 may also be 
measured.  
The analysis may be conducted with mixed-effects (population) methods. A dataset suitable for 
the analysis may be constructed using R (r-project.org, version 3.3.2 or later). The analysis may 
be conducted using the NONMEM system (Icon Development Solutions, Hanover, MD, version 
7.3 or later) and PLT Tools (pltsoft.com; version 5.3.0 or later). One- and two-compartment 


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linear models with first-order absorption and first-order elimination may be evaluated initially. If 
diagnostic graphics suggest that these models are not appropriate, other models will be 
considered. A systemic search will then be applied to determine the impact of covariates such as 
age, body size, gender, race, organ function, clinical frailty score, diarrhea, and drug-drug 
interactions (including concomitant treatment with drugs that alter gastric pH such as proton 
pump inhibitors or gastroprokinetics such as domperidone) on the pharmacokinetic parameters, 
focusing on apparent clearance and absorption rate. Once a final model is determined, model 
validation will include some combination of visual predictive check (with and without 
prediction-correct), likelihood profiles, and bootstrap analyses.  
 
 
Subject-Reported Study Drug Administration 
Subjects will report the time of their daily study drug administration each day in an eDiary. This 
information will be used to assess treatment compliance together with pill count (per section 
5.4). Further details are provided in the SAP.  
Subject-Reported Health Outcomes/Quality of Life 
The EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) will be administered at the Baseline Visit and 
the Week 16 Visit. In addition, subjects will be prompted in their eDiary to complete the EQ-5D-
5L each day that they report experiencing one or more respiratory illness symptoms in their eDiary 
through Week 16. 
EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal (see Section 
13.3 [Appendix 3]). The EQ-5D-5L questionnaire consists of 2 pages: the EQ-5D-5L descriptive 
system and the EQ visual analogue scale (VAS). The descriptive system comprises 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of which is 
divided into 5 levels. The EQ VAS records the patient’s self-rated health on a 20-cm vertical 
visual analogue with “the best health you can imagine” as 100 and “the worst health you can 
imagine” as 0. 
Further information is provided in the SOM and the SAP.  
 


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Information about healthcare resource utilization will be obtained from subjects and from SAE 
reports. The following events occurring between the Baseline and Week 20 visits will be 
recorded in the eCRF:  
• Hospitalizations  
• ER visits 
• Urgent care clinic visits 
• Admissions to a skilled nursing facility 
The following events occurring between the Week 20 and Week 48 visits will be recorded in the 
eCRF at the Long Term Follow Up visit:  
• Hospitalizations  
• Admissions to a skilled nursing facility 
• Death 
 
Blood samples will be obtained for exploratory biomarker analyses, including RNA expression 
in whole blood and soluble biomarkers in serum, in all subjects at the Baseline and Week 16 
visits, and at the Week 4 (or Week 6 if applicable) visit (4 hours after study drug administration) 
only for subjects participating in the PK analysis (as identified by the IXRS). If biomarker and 
PK sampling cannot be performed at the Week 4 visit for logistical reasons, it should be 
performed at the Week 6 visit instead. Biomarkers studied may include, but are not limited to, 
ribonucleic acid (RNA) expression analysis in whole blood samples using RNA analytical 
technologies, such as expression microarrays, immunoassays or others, and serum protein 
expression analysis. The list may be changed or expanded further, as it is recognized that more 
relevant or novel biomarkers may be discovered during the conduct of the study. 
A single blood sample will also be obtained from all subjects who provide consent at the 
Baseline Visit for the purposes of future pharmacogenomic analysis. 
Follow instructions for sample collection, numbering, processing, and shipment provided in the 
SOM. 
 


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Any samples remaining after protocol-defined analyses have been performed may be used for 
additional exploratory analyses, to be defined, if a subject signs the Consent for Optional Blood 
Storage for Future Use. This may include, but is not limited to, using samples for exploratory 
biomarker analyses or other bioanalytical purposes that have yet to be defined (e.g. cross check 
between different study sites and/or stability assessment). Given the exploratory nature of the 
work, the analytical method used for those assessments will not be validated. As such, the results 
from this exploratory analysis will not be included in the clinical study report. 
 Safety Monitoring 
 
An AE is defined as any untoward medical occurrence (i.e., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a study subject from the 
Baseline Visit until the end of study visit (Week 20 Visit). Therefore, an AE may or may not be 
temporally or causally associated with the use of a medicinal (investigational) product. Pre-
existing medical conditions/diseases are considered AEs if they worsen after the Baseline Visit.  
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an AE irrespective if a clinical event has occurred.  
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs also may be detected when they are volunteered by the subject during or 
between visits or through physical examination finding, laboratory test finding, or other 
assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy.  
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values which are non-typical in subjects with underlying 
disease. Investigators, along with other study staff, have the responsibility for managing the 
safety of individual subjects and identifying AEs.  


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All AEs (except RTI AEs) must be recorded on the AE eCRF accompanied by the following 
information: 
• The severity grade using the U.S. Department of Health and Human Services, National 
Institutes of Health, National Cancer Institute’s CTCAE v5.0, available at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. For terms not included, the severity of 
the AE should be based on the following general guidelines: 
o Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) (e.g., 
preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.). 
o Grade 3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL (i.e., bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden). 
o 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
o 
Grade 5 
Death related to AE. 
NOTE:   
▪ Any elevation of ALT, AST or total bilirubin > 3x ULN from the time of first 
dose of study drug should be reported as a Grade 3 (severe) AE.  
• Its relationship to the study treatment: 
o Related 
o Not related  
• Its duration (start and end dates) 
o If the event is ongoing, an outcome of either not recovered/ not resolved or 
recovering/ resolving must be reported. 
• Whether it constitutes an SAE (see Section 7.2 for definition of SAE) and which 
seriousness criteria have been met to define it as an SAE.  
• Action taken regarding investigational treatment.  


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• Outcome (recovered/resolved, recovered/resolved with sequelae, not recovered/resolved, 
recovering/resolving, unknown, fatal). 
Any beneficial therapeutic effects reported by subjects should also be recorded in the adverse events 
CRF. 
 
All AEs (including diagnosed influenza) must be treated per local standard of care. 
Treatment/action taken may include one or more of the following:  
• No action taken (e.g. further observation only)  
• Investigational treatment interrupted/withdrawn 
• Concomitant medication or non-drug therapy given 
• Hospitalization/prolonged hospitalization (see Section 7.2 for definition of SAE) 
• Study participation withdrawn 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the investigational drug, the interventions 
required to treat it, and the outcome.  
Any RTI that meets the definition of an SAE should be reported to resTORbio or designee as per 
Section 7.2.2 and documented on the AE eCRF. 
Any deterioration of asthma symptoms that requires treatment with systemic steroids should be 
recorded as an asthma exacerbation on the AE eCRF. 
 
 
An SAE is defined as any AE (appearance of [or worsening of any pre-existing] undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria: 
• Is fatal or life-threatening  
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
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o Elective or pre-planned treatment for a pre-existing condition that has not 
worsened since the start of study drug treatment.  
o Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission. 
o Social reasons and respite care in the absence of any deterioration in the 
subject’s general condition. 
• Is medically significant, e.g. defined as an event that jeopardizes the subject or 
may require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an ER or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization or development of dependency or abuse (Annex 
IV, ICH-E2D Guideline). 
Any suspected transmission of an infectious agent via a medicinal product is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF. 
SAEs also require individual reporting to resTORbio or designee as per Section 7.2.2. 
 
To ensure subject safety, every SAE, regardless of causality, occurring from the Baseline Visit to 
the Week 20 Visit (i.e., completion of the Short-term Follow-up Period) must be reported to 
resTORbio or designee within 24 hours of learning of its occurrence as described below. Any 
SAEs experienced after completion of the Short-term Follow-up Period of the study should only 
be reported to resTORbio or designee if the Investigator suspects a causal relationship to study 
treatment. 


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Information about all SAEs is collected and recorded on the SAE report form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report. The 
Investigator must assess the relationship of each SAE to each specific component of study 
treatment, complete the SAE report form in English, and submit the completed form within 24-
hours to resTORbio or designee. Detailed instructions regarding the submission process and 
requirements for signature are to be found in the SOM. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the Investigator receiving the follow-up information.  
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of when 
it occurs. 
An SAE considered completely unrelated to a previously reported SAE must be reported 
separately as a new event. 
SAEs experienced by subjects must be followed until resolution or until judged to be permanent 
by the Investigator. 
Follow the detailed instructions outlined in the SOM regarding the submission process for 
reporting SAEs to resTORbio or designee. 
 
Should a female partner of a male subject become pregnant while the male subject is receiving 
study drug or within 7 days after the last dose of study drug, the pregnancy must be reported  
(see the SOM for further information). 
If the female partner of the male subject consents, the Pregnancy Reporting Form/Exposure in 
Utero Form must be completed with all known information regarding the pregnancy at the time 
of reporting. Investigative site personnel will update the form with additional information 
regarding the pregnancy and the outcome of the pregnancy as it becomes available until the 
outcome of the pregnancy is reported. If the outcome of the pregnancy meets the criteria for 
immediate classification as a SAE (i.e., spontaneous abortion, stillbirth, neonatal death within 1 
month of birth, or congenital anomaly [including that in an aborted fetus]), the Investigator will 


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follow the procedures for reporting a SAE within 24 hours of awareness, as described in Section 
7.2.2 of the protocol. A pregnancy in and of itself is not considered an AE; however, unexpected 
complications are considered AEs. After delivery of the child, follow-up information on the 
health of the child will be collected for one year if an additional informed consent form is signed 
by a parent or legal guardian of the child. 


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 Data Review and Database Management 
 
During the study resTORbio or their representatives employ several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the study sites’ data. The study 
monitor will periodically visit the study site to check the completeness of subject records, the 
accuracy of entries on the CRFs (for, at minimum, critical variables related to primary and 
secondary endpoints and safety), the adherence to the protocol and to ICH GCP E6 (R2), the 
progress of enrollment, and ensure that study drug is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the monitor during 
these visits. Continuous remote monitoring of each study site’s data may be performed by the 
Sponsor and/or representative to ensure that data in entered in a timely manner, prior to all on-
study site visits and to address discrepancies that can be identified through remote monitoring.  
The Investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or study site medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the subject's file unless the 
CRF is considered source. The Investigator must also keep the original informed consent form 
signed by the subject, document the process for obtaining informed consent and provide a signed 
copy to the subject. 
The Investigator must give the study monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Additional checks of the consistency of the source data 
with the CRFs are performed according to the study-specific monitoring plan. No information in 
source documents about the identity of the subjects will be disclosed. 
Study Record Retention 
Essential documents should be retained for the period of time required by applicable local law. 
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated Curriculum Vitae (CVs) of the Investigators, 
copies of the completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, 
financial agreements, regulatory approval, drug accountability, study correspondence, and 
subject identification codes. Records will not be destroyed without informing resTORbio in 
writing and giving resTORbio the opportunity to store the records for a longer period of time at 
resTORbio’s expense. 


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Documents not for submission to resTORbio (e.g. signed ICFs) should be maintained by the 
Investigator in strict confidence. 
ICH GCP requires that study records be retained for at least 15 years after the completion or 
discontinuation of the study. 
 
Designated Investigator staff will enter the data required by the protocol (as documented on the 
Delegation of Authority Log) into the CRFs using fully validated software that conforms to 21 
CFR Part 11 requirements. 
• Designated Investigator study site staff will not be given access to the EDC 
system until they have been trained.  
• Automatic validation programs will check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected 
before transfer of the data to the contract research organization (CRO) working on 
behalf of resTORbio.  
• The Investigator must certify that the data entered into the CRFs are complete and 
accurate. 
The subjects will also be recording data directly into an eDiary and these data will serve as the 
source data. Data from the eDiary will be transferred electronically to the clinical database. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification and respects the confidentiality of study participants. 
 
A CRO working on behalf of resTORbio will review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the study site personnel to make 
any required corrections or additions. Queries are sent to the investigational study site using an 
electronic data query. Designated Investigator study site staff are required to respond to the 
query and confirm or correct the data.  
• Coding of medications, medical history and AEs: 
o Prior and/or concomitant medications entered into the database will be coded 
using the WHO Drug Reference List, which employs the Anatomical 
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o Medical history/current medical conditions and AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
Laboratory samples will be processed by a central certified laboratory, and the results will be 
sent to the Investigator, study site staff, and Sponsor or a designated CRO. In exceptional 
circumstances, when central laboratory testing is unavailable, testing of safety labs for 
hematology, chemistry and urinalysis may occur at a local laboratory with the Sponsors prior 
approval. 
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an IXRS. 
• The system will be supplied by a vendor, who will also manage the database.  
• The database will be sent electronically to a designated CRO. 
• Each occurrence of a code break via IXRS will be reported to the clinical team, study 
monitor and Sponsor Medical Monitor. The code break functionality will remain 
available until unblinding or upon request of the Sponsor. 
The occurrence of any protocol deviations will be determined. Protocol deviations will be 
captured via observations by the CRO study monitor or site. 
After these actions have been completed and the database has been declared to be complete and 
accurate, the database will be locked and final study data made available for analysis. 
 
A DMC has been established for the study with the primary goal to perform an ongoing review 
of safety data. The DMC is an external board comprised of physicians with specific knowledge 
of infectious diseases, geriatrics and issues related to conducting clinical studies.  
The DMC will be responsible for the following: 
• Providing ongoing assessments of safety data and the overall risk of the study conduct. 
This will include an ongoing unblinded analysis of GI SAEs and related SAEs, and a 
monthly unblinded analysis of all other SAEs. 
• Advising the Sponsor of the need for study stopping or protocol 
modification/amendments in order to minimize potential risk for subjects.  
• Advising the Sponsor if study enrollment needs to be halted based on review within 48 
hours of safety data outlined in Section 5.5.5. 


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Further details are provided in the DMC charter. 
 Data Analysis 
 
The analysis populations are specified in the table below. The final decision to exclude subjects 
from any analysis population will be made during a blinded data review meeting prior to database 
unblinding. 
Analysis Set 
Description 
Screening (SCR)  
All subjects, who provided informed consent, regardless of the 
subject’s randomization and study treatment status in the study. 
Randomized set (RS) 
All randomised subjects treated or not. 
Full Analysis Set (FAS) 
All subjects in RS who received at least 1 dose of trial medication.  
Per-Protocol (PP) 
All FAS subjects who complete the 16-week treatment period, missed 
< 20% of doses, and had no major protocol deviations impacting 
efficacy data. Clinically important protocol deviations that would lead 
to a subject being excluded from the PP Analysis Set will be defined 
in the SAP. Subjects will be analyzed per the treatment group to 
which they were randomized. 
Safety (SAF) 
All subjects who were administered any dose of any study drug. 
Subjects will be analyzed per the actual study treatment they received. 
The follow-up period will include the Week 20 visit 4 weeks after the 
end of the treatment period.  
 
 
Demographic and background information will be listed by treatment group and subject. Summary 
statistics will be provided by treatment group. Relevant medical history, current medical conditions, 
results of laboratory tests, and any other relevant information will be listed by treatment group and 
subject. 
 
There are two treatments arms: Arm 1: RTB101 10mg, Arm 2: Placebo. 


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The primary efficacy endpoint is the percentage of subjects with clinically symptomatic 
respiratory illness (CSRI), with or without an associated laboratory-confirmed 
pathogen,beginning at least 3 days after the start of study drug treatment through Week 16. 
Analysis of the primary efficacy endpoint will be based on the intention-to-treat principle, 
comprising all subjects who are randomized and have received at least one dose of assigned 
treatment during the trial. Subjects who discontinue study prematurely due to a respiratory tract 
infection (RTI) adverse event (AE) or an RTI serious adverse event (SAE) and did not meet the 
definition of a CSRI will be imputed as having experienced a CSRI; subjects who discontinue 
study prematurely for any reason other than an RTI AE or RTI SAE and did not meet the 
definition of a CSRI will be imputed as not having a CSRI; subjects who completed the study 
and did not meet the definition of a CSRI, but have intermittent missing eDiary data will be 
imputed as not having a CSRI. Details of handling missing data will be further discussed in the 
SAP.  For efficacy, subjects will be analyzed in the treatment group for which they were 
randomized, whereas for safety, subjects will be analyzed based on the treatment they received. 
 
This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of RTB101 10 mg to prevent clinically symptomatic 
respiratory illness in the elderly. All eligible subjects will be randomized in a 1:1 ratio at 
Baseline to receive either RTB101 10 mg or placebo. 
The statistical model for the binary endpoint is logistic regression model.  
Null hypothesis: The true underlying percentage of subjects with at least 1 clinically 
symptomatic respiratory illness (with or without an associated laboratory-confirmed pathogen) 
by Week 16 is equal between RTB101 10 mg and placebo. 
Alternate hypothesis: The true underlying percentage of subjects with at least 1 clinically 
symptomatic respiratory illness (with or without an associated laboratory-confirmed pathogen) is 
not equal between RTB101 10 mg and placebo. 
The primary efficacy endpoint will be analyzed through a logistic regression model to obtain an 
estimate of the population odds ratio and associated CIs between RTB101 and placebo. This 
primary efficacy model will be adjusted for factors that may influence response to treatment for 


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clinically symptomatic respiratory illness, such as age, frailty score, receipt of current season 
influenza vaccination and medical history of asthma, CHF, or Type 2 diabetes mellitus. 
In testing multiple hypotheses, control of the study-wise error rate will be implemented. As the 
number of statistical tests within a trial increases (multiplicity), the chance of making a false 
conclusion (false positive) about a drug’s effect with respect to at least one of the endpoints 
increases, if multiplicity is not addressed. In this study, a fixed sequence gate-keeping strategy 
will be used to control the study-wise error rate at a 2-sided α-level of 0.05.  The following 
primary, secondary and exploratory efficacy endpoints will be tested in the sequence specified 
below:  
 
Order 
H1 The percentage of subjects with 1 or more CSRIs (with or without an associated 
laboratory-confirmed pathogen) beginning at least 3 days after the start of study drug 
treatment through Week 16. 
H2 The percentage of subjects with 1 or more CSRIs associated with ≥1 laboratory-
confirmed pathogen(s) beginning at least 3 days after the start of study drug treatment 
through Week 16 as assessed by pre-specified clinical diagnostic criteria, and 
respiratory pathogen PCR of nasopharyngeal swabs, sputum gram stain and culture, 
and/or RIDTs. 
H3 The rate of CSRI (with or without an associated laboratory-confirmed pathogen) 
beginning at least 3 days after the start of study drug treatment through Week 16 as 
assessed by pre-specified clinical diagnostic criteria.  
H4 The rate of CSRIs associated with ≥ 1 laboratory-confirmed pathogen(s) beginning at 
least 3 days after the start of study drug treatment through Week 16 as assessed by pre-
specified clinical diagnostic criteria and respiratory pathogen PCR of nasopharyngeal 
swabs, sputum gram stain and culture, and/or RIDTs. 
H5 The time to alleviation of moderate and severe respiratory illness symptoms due to 
CSRI beginning at least 3 days after the start of study drug treatment through Week 16. 
H6 The percentage of subjects with severe symptoms due to CSRIs beginning at least 3 
days after the start of study drug treatment through Week 16. 
H7 The rate of all-cause hospitalizations beginning at least 3 days after the start of study 
drug treatment through Week 16.  
H8 The rate of UTIs beginning at least 3 days after the start of study drug treatment through 
Week 16 reported as adverse events 
H9 The percentage of subjects with 1 or more CSRIs (with or without an associated 
laboratory-confirmed pathogen) beginning at least 3 days after the start of study drug 
treatment through Week 20. 
  


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The primary endpoint, H1, will be tested first at a 2-sided alpha level of 0.05.  The subsequent 
endpoints will be tested in the order specified above also at a 2-sided alpha-level of 0.05, if and 
only if the preceding endpoint was found to be statistically significant.  If the preceding endpoint 
in the sequence fails to meet statistical significance, then testing of subsequent endpoints will be 
stopped and no further statistical conclusions will be made.  
 
All efforts will be made to obtain the reason for missing data or discontinuation.  
Of all randomized and treated subjects in the Phase 2b trial, the missing data rate in the 
assessment of the primary endpoint was 0.56% (1/179) and 6.8% (32/473) in the Southern and 
Northern Hemispheres, respectively. The combined missing data rate was 5.1%. It is expected 
that only a minimal amount of missing data will be present in the Phase 3 trial.  
Further steps to reduce and address the occurrence and impact of missing data are planned. 
Subjects who discontinue treatment will be followed and assessed for the evaluation of the 
primary endpoint. To further explore the potential effect of missing data on the reliability of the 
primary efficacy results, and to investigate the response profile of dropout patterns, several 
sensitivity analyses including a tipping point analysis will be conducted (see Section 9.4.4). 
Further details to address missing data are described in Section 9.4.4 and will be provided in the 
SAP. 
 
 
Vital Signs 
Observed values at each visit and changes from Baseline to each post-baseline visit in vital signs 
(BP, heart rate, respiratory rate and temperature) will be summarized by time point and treatment 
group using descriptive statistics. Out-of-range values of vital signs will be tabulated as 
appropriate. All vital signs will be provided in subject data listings.  
 
Electrocardiograms (ECGs) 
Observed values at each visit and changes from Baseline to each post-baseline visit in ECG 
parameters will be summarized by time point and treatment group using descriptive statistics. All 
ECG parameters will also be provided in subject data listings, with values defined as clinically 
relevant highlighted. 
 
Clinical Laboratory Evaluations 


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Laboratory data will be analyzed quantitatively and qualitatively. The latter will be done via 
comparison of laboratory data to their reference ranges. Values outside the reference range as 
well as values defined as clinically relevant will be highlighted in the listings. Treatment groups 
will be compared descriptively with regard to distribution parameters as well as with regard to 
frequency and percentage of subjects with abnormal values or clinically relevant abnormal 
values. Furthermore, laboratory data will be evaluated longitudinally; changes from baseline in 
laboratory parameters will be compared between RTB101 10 mg and placebo. 
 
Adverse Events 
All safety data will be displayed and analyzed using descriptive statistical methods. No formal 
inferential analysis is planned for safety comparison.  
Frequency, intensity and causal relationship of AEs will be tabulated by system organ class after 
coding according to MedDRA. All AEs will be summarized by treatment group. The number and 
percentage of subjects who experienced at least 1 AE will be summarized by SOC and preferred 
term. The percentage will be based on the number of subjects in each treatment group. AEs will 
also be summarized by relationship to intervention and by severity within each treatment group. 
Deaths, SAEs, AEs leading to study drug discontinuation and AEs leading to study 
discontinuation will be tabulated and presented in data listings. Subject level data listings of all 
AEs will be presented. A subject with multiple AEs within a body system is only counted once 
towards the total of this body system.  
 
 
Primary endpoint 
To provide evidence in support of the strength of treatment effect, several sensitivity analyses 
will be conducted.  
 
A tipping point analysis for the primary efficacy endpoint will be conducted to investigate the 
impact of the missing data assumptions on the primary endpoint results, . Missing data from the 
placebo arm due to early treatment discontinuation for any reason other than an RTI AE or RTI 
SAE and/or had ≥7 consecutive days of missing eDiary entries, and did not meet the definition of 
a CSRI, will be imputed with CSRI odds from the placebo group, adjusted for the duration of 
missing eDiary entries through Week 16 in the placebo arm.  For RTB101 subjects who 
discontinue study prematurely for any reason other than an RTI AE or RTI SAE and/or had ≥7 
consecutive days of missing eDiary entries, and did not meet the definition of a CSRI, will be 


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imputed with CSRI odds that vary between that of the RTB101 odds adjusted for the duration of 
missing eDiary entries in the RTB101 arm, and the placebo odds. Subjects who discontinued 
study prematurely due to an RTI AE or RTI SAE will continue  to be imputed as having a CSRI.. 
The objective is to determine the maximum odds in the RTB101 arm that continue to yield 
statistically significant results compared to placebo. Further details on the above tipping point 
analysis and other sensitivity analyses are included in the SAP. 
Supplemental analyses will also be conducted to further understand the impact of missing data 
on the primary efficacy endpoint results, specifically, the primary efficacy analysis will be 
conducted in 1) the Per Protocol analysis set, 2) the subset of subjects who did not discontinue 
from the study prematurely and/or did not have ≥7 consecutive days of missing eDiary entries 
(Completers Analysis 1) and 3) the subset of subjects who did not discontinue from the study 
prematurely (Completers Analysis 2). 
Summary statistics by treatment group will be provided for the number of subjects with any 
missing data due to intermittent missed eDiary entries and premature discontinuation from the 
study. The number of subjects with ≥7, ≥14, ≥21, ≥28, ≥35, ≥42, ≥49, … ≥ 105 consecutive days 
of missing eDiary entries missing data will also be summarized in a similar manner. 
  
Further details on handling missing data will be provided in the SAP. 
 
Subpopulations 
An evaluation of the primary and certain secondary endpoints may be conducted in some 
subpopulations. The following subpopulations may be explored, subjects who are at least 85 
years old, subjects with asthma, the frail elderly, female subjects, subjects with CHF, and also 
subjects who have or have not received a pneumococcal or current season influenza vaccination.   
Details will be provided in the SAP as appropriate. 
 
The key secondary endpoint of “The rate of symptomatic respiratory illnesses associated with 
specific laboratory-confirmed viruses (coronaviruses, hMPV, HRV/enterovirus, adenovirus, 
influenza A and B virus, parainfluenza viruses, and RSV) beginning at least 3 days after the start 
of study drug treatment through Week 16 as assessed by respiratory pathogen PCR of 


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nasopharyngeal swabs and/or RIDTs will be evaluated from an estimation framework where the 
treatment effect and associated CIs are estimated, rather than a framework of multiplicity 
adjustments and statistical significance. This endpoint is not powered to demonstrate a pre-
specified treatment effect. There will be no formal statistical tests of hypotheses and no p-values. 
To demonstrate trends consistent with the primary endpoint for the pre-specified laboratory-
confirmed viruses, the estimated rate of the laboratory-confirmed viruses and associated CIs will 
be compared descriptively between RTB101 versus placebo. 
For secondary endpoints (other than the key secondary endpoint) of a rate outcome (e.g., the rate 
of clinically symptomatic respiratory illnesses (with or without an associated laboratory-
confirmed pathogen) by Week 16 and the rate of clinically symptomatic respiratory illness 
associated with 1 laboratory-confirmed pathogen(s) by Week 16), a negative binomial 
regression model will be used to obtain an estimate of the population rate ratio and associated 
CIs between RTB101 and placebo. The negative binomial model will be adjusted for 
factors/covariates consistent with the primary endpoint.  
The secondary endpoints of (1) percentage of subjects with one or more clinically symptomatic 
respiratory illnesses associated with 1 laboratory-confirmed pathogen(s) by Week 16, and (2) 
percentage of subjects with severe symptoms due to clinically symptomatic respiratory illnesses 
through Week 16, will be analyzed using the same method as the primary efficacy endpoint. 
Next, we demonstrate the evaluation of the secondary endpoint of time to alleviation of moderate 
and/or severe clinically symptomatic respiratory illness symptoms through Week 16. The point 
estimate of the hazard ratios and the associated 95% CIs for RTB101 versus placebo will be 
obtained using the Cox proportional hazards regression model with fixed effects for treatment 
group and covariates consistent with the primary endpoint. An approximate Chi-square test 
based on Wald statistic will be used to compare treatment groups. Survival curves (Kaplan-Meier 
estimates) for the “time to alleviation” (i.e., proportion with no alleviation) may be presented by 
treatment group. 
Exploratory efficacy endpoints will be evaluated in a similar fashion as the primary or secondary 
endpoints, the same set of covariates as for the primary analysis model will be included in each 
model. Specifically, exploratory endpoints with a binary outcome will be analyzed using the 
same methods as the primary endpoint. Time-to-event exploratory endpoints will be evaluated 
using the Cox proportional hazard model, continuous exploratory endpoints may be analyzed 
using an Analysis of Covariance (ANCOVA) model, or by a mixed model repeated measures 
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Exploratory endpoints will be summarized descriptively, as appropriate, continuous endpoints 
will be summarized with the use of box plots, while proportions will be displayed by histograms. 
In addition, changes in biomarker levels over time will be described by treatment group. The 
details of these analyses will be included in the SAP. 
 
Sample size was determined based on a two-sided comparison between RTB101 and placebo. In 
parts 1 and 2 of the Phase 2b trial, 28.2% of subjects had a clinically symptomatic respiratory 
illness on placebo (excluding subjects with COPD and current smokers). With an assumed Week 
16 clinically symptomatic respiratory illness incidence of 28.2% on placebo, and of 19.7% in the 
RTB101 arm, a total sample size of 1066 subjects (equally randomized) will provide 90% power 
to detect a 30% reduction in the percentage of subjects with clinically symptomatic respiratory 
illness between RTB101 and placebo using a two-sided test of 0.05 significance. Approximately 
1066 subjects will be enrolled. Power analysis was conducted using Likelihood Ratio Chi-square 
Test.     
 
There is no planned interim analysis.  


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 Ethical Considerations 
 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guidelines for Good Clinical 
Practice, with applicable local regulations (including European Directive 2001/20/EC, U.S. CFR 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
 
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment materials (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study start, 
the Investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to resTORbio or 
designee monitors, auditors, Quality Assurance representatives, designated agents of resTORbio, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical study site is 
requested by a regulatory authority, the Investigator must inform resTORbio or designee 
immediately that this request has been made. 
 
The key design elements of this protocol will be posted in a publicly accessible database such as 
clinicaltrials.gov or wherever applicable. In addition, upon study completion and finalization of 
the study report the results of this study will be either submitted for publication and/or posted in 
a publicly accessible database of clinical study results. Upon study completion and finalization of 
the study report the results of this trial may be submitted for publication (e.g., peer-reviewed 
journal). 
 
resTORbio maintains a Quality Management system that includes all activities involved in 
quality assurance and quality control, including the assignment of roles and responsibilities, the 
reporting of results, and the documentation of actions and escalation of issues identified during 


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the review of incidents, audits and inspections. Audits of Investigator study sites, vendors, and 
resTORbio systems may be performed independently from those involved in conducting, 
monitoring or performing quality control of the clinical study. Audits are conducted to assess 
GCP compliance with global and local regulatory requirements, protocols and internal standard 
operation procedures. 
 Protocol Adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study subjects. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
Investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.  
Investigators certify that they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by resTORbio 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by resTORbio, health authorities where required, and the IRB/IEC prior to 
implementation.  
Only amendments that are intended to eliminate an apparent immediate hazard to subjects may 
be implemented immediately provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.  
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 must be followed. 
 
Each Investigator (including principal and any sub-Investigators and any other study personnel) 
directly involved in the treatment or evaluation of study subjects is required to provide financial 
disclosure information according to all applicable legal requirements. In addition, Investigators 


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must commit to promptly updating this information if any relevant changes occur during the 
study and for a period of one year after the completion of the study. 
 
 


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Baumann, P., Mandl-Weber, S., Oduncu, F. & Schmidmaier, R. (2008) The novel orally 
bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-
BEZ235, inhibits growth and proliferation in multiple myeloma. Exp Cell Res 315, 485-497, 
doi:10.1016/j.yexcr.2008.11.007. 
Chen C, Liu Y, Liu Y et al (2009). mTOR regulation and therapeutic rejuvenation of aging 
hematopoietic stem cells. Sci. Signal. 2 (98): ra75. 
Feldman ME, Apsel B, Uotila A, et al (2009).  Active-site inhibitors of mTOR target rapamycin-
resistant outputs of mTORC1 and mTORC2 PLoS Biol; 7:e38. 
Gillman A, Douglass JA. Asthma in the elderly. Asia Pac Allergy. 2012 Apr;2(2):101-8.  
Ginocchio, C.C., and McAdam, A.J. (2011). Current Best Practices for Respiratory Virus 
Testing. Journal of Clinical Microbiology 49, S44, doi: 10.1128/JCM.00698-11. 
Goto T, Yoshida K, Tsugawa Y, et al (2016). Infectious Disease-Related Emergency Department 
Visits of Elderly Adults in the United States, 2011-2012. J Am Geriatr Soc;64:31-36. 
Jackson, D. J., Sykes, A., Mallia, P. & Johnston, S. L. (2011) Asthma exacerbations: origin, 
effect, and prevention. J Allergy Clin Immunol 128, 1165-1174, doi:10.1016/j.jaci.2011.10.024. 
Johnson, S. C., Rabinovitch, P. S. & Kaeberlein M. (2013). mTOR is a key modulator of ageing 
and age-related disease. Nature 493, 338-345, doi:10.1038/nature11861. 
Jain S, Self WH, Wunderink RG, et al (2015). Community-Acquired Pneumonia Requiring 
Hospitalization among U.S. Adults. N Engl J Med.; 373:415-427. 
Komanduri S, Jadhao Y, Guduru SS, Cheriyath P, Wert Y. Prevalence and risk factors of heart 
failure in the USA: NHANES 2013 - 2014 epidemiological follow-up study. J Community Hosp 
Intern Med Perspect. 2017 Mar 31;7(1):15-20.  
Lamming, DW, Ye L, Katajisto P, et al (2012). Rapamycin-induced insulin resistance is 
mediated by mTORC2 loss and uncoupled from longevity. Science; 335: 1638-1643.  
Lamming, DW, Mihaylova MM, Katajisto P, et al (2014). Depletion of Rictor, an essential 
protein component of mTORC2, decreases male lifespan. Aging Cell; 13:  911-917.  
Laplante, M & Sabatini DM (2012). mTOR signaling in growth control and disease. Cell; 149: 
274-293.  


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Levant, S., Chari, K. & DeFrances, C. J. (2015) Hospitalizations for patients aged 85 and over in 
the United States, 2000-2010. NCHS Data Brief, 1-8. 
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. (2013). The hallmarks 
of aging. Cell 153, 1194-1217, doi:10.1016/j.cell.2013.05.039. 
Maira, S. M. et al. (2008) Identification and characterization of NVP-BEZ235, a new orally 
available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with 
potent in vivo antitumor activity. Mol Cancer Ther 7, 1851-1863, doi:10.1158/1535-7163.MCT-
08-0017. 
Mannick, J.B., Del Giudice, G., Lattanzi, M., Valiante, N.M., Praestgaard, J., Huang, B., et al. 
(2014). mTOR inhibition improves immune function in the elderly. Sci Transl Med. 6(268), 
268ra179. 
Mannick, J. B. et al. (2018) TORC1 inhibition enhances immune function and reduces infections 
in the elderly. Sci Transl Med 10, doi:10.1126/scitranslmed.aaq1564. 
McNab, F., Mayer-Barber, K., Sher, A., Wack, A. & O'Garra, A. (2015) Type I interferons in 
infectious disease. Nat Rev Immunol 15:87-103. 
Mushaben, E.M., Kramer, E.L., Brandt, E.B., Khurana Hershey, G.K., and Le Cras, T.D. (2011). 
Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic 
asthma. J Immunol 187:5756-5763. 
Musher D.M., Abers, M.S., Coorales-Medina, V. F. (2019). Acute infection and Myocardial 
Infarction. N Engl J Med, 380:171-6. 
Murphy, S.L., Jiaquan, X., Kochnanek, K.D. (2013). Deaths: Final Data for 2010. National Vital 
Statistics Report. 
Nicholson, KG, Kent, J, Ireland DC (1993). Respiratory viruses and exacerbations of asthma in 
adults. BMJ; 307:982-6.  
Nicholson KG, Kent J, Hammersley V, Cancio E (1997). Acute viral infections of upper 
respiratory tract in elderly people living in the community: comparative, prospective, population 
based study of disease burden. BMJ. 315(7115):1060-4. 
Nyfeler B, Bergman P, Triantafellow E, et al (2011). Relieving autophagy and 4EBP1 from 
rapamycin resistance. Mol Cell Biol; 31:2867-76.  


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Nyfeler B, Chen Y, Li X, et al (2012). RAD001 enhances the potency of BEZ235 to inhibit 
mTOR signaling and tumor growth. PLoS One; 7:e48548.  
Pfuntner, A., L.M. Wier, and C. Stocks. (2013). Agency for Healthcare Research and Quality, 
Rockville, MD. 
Ratitch B, O’Kelly M, Tosiello R. (2013). Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models Pharmaceut. Statist; 12:337–347. 
Rockwood K, Sonet al. A global clinical measure of fitness and frailty in elderly people. CMAJ 
2005;173(5):489-95  
Serra V, Markman B, Scaltriti M, et al (2008). NVP-BEZ235, a dual PI3K/mTOR inhibitor, 
prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. 
Cancer Res; 68:8022-30.  
Stone ND, Ashraf MS, Calder J, et al (2012). Surveillance definitions of infections in long-term 
care facilities: revisiting the McGeer criteria. Infect Control Hosp Epidemiol; 33:965-77. 
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Population Prospects.  The 2004 Revision.  New York: United Nations, 2005 in Why Population 
Aging Matters:  A Global Perspective 
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Population Prospects: The 2012 Revision, Highlights and Advance Tables. Working Paper No. 
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Population Prospects: The 2015 Revision, Key Findings and Advance Tables. Working Paper 
No. ESA/WP.241. 
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Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) v5.0, published 
November 27, 2017. Available from: https://evs.nci.nih.gov/ftp1/CTCAE/About.html (accessed 
March 11, 2019). 


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Wang, Y. et al. (2018) MTOR Suppresses Cigarette Smoke-Induced Epithelial Cell Death and 
Airway Inflammation in Chronic Obstructive Pulmonary Disease. J Immunol 200, 2571-2580, 
doi:10.4049/jimmunol.1701681. 
 


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 Appendices 
 
Table 13-1  
Strong CYP4503A4 Inhibitors (prohibited) 
Boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, troleandomycin, voriconazole 
 
Moderate inhibitors (use with caution)  
Amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, crizotinib, darunavir, diltiazem, 
elvitegravir, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, Schisandra 
sphenanthera, tipranavir, tofisopam, verapamil 
Table 13-2  
Strong CYP4503A4 Inducers (prohibited)  
Avasimibe, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, 
troglitazone 
Moderate Inducers (use with caution)  
Bosentan, efavirenz, etravirine, modafinil, nafcillin, ritonavir, talviraline, tipranavir, 
pioglitazone 
Table 13-3  
Strong CYP4501A2 Inhibitors (prohibited) 
Ciprofloxacin, enoxacin, fluvoxamine(a), zafirlukast 
Table 13-4  
Strong CYP4501A2 Inducers (prohibited) 
Rifampin 
Table 13-5  
Narrow Therapeutic Index P-gp Substrates (prohibited, example below) 
Digoxin 
 


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To be applied only if: 
 
 radiological findings of newly-occurring/worsening lung infiltration 
 absence of infectious or malignant etiology (based on diagnostic procedure such as 
bronchoscopy &/or trial of anti-infectious treatment, as appropriate) 
 
CTC 
Grade 
Investigations 
Additional Measures 
1 
CT scan w/ lung windows 
PFTs  
Discontinue study drug 
2 and 3 
Lung monitoring 
CT scan (if only chest X-ray 
carried out) 
Involve pulmonologist (consider 
bronchoscopy) 
PFTs 
Discontinue study drug 
bronchoscopy if indicated (to exclude infection or 
malignancy) 
short course of steroids to be considered if symptoms 
important or persisting beyond I month 
lung monitoring for 2 months then return to initial 
monitoring frequency if no recurrence. 
 
 
continue monthly lung monitoring until return to grade ≤1 
or stabilization 
4 
Lung monitoring 
CT scan (if only chest X-ray 
carried out) 
Involve pulmonologist (consider 
bronchoscopy) 
Repeat PFTs, if possible 
Discontinue study drug 
bronchoscopy with BAL, if possible  
steroids and other support as necessary 
continue monthly lung monitoring until return to grade ≤1 
or stabilization 
Notes: 
PFT (Pulmonary function tests) to include: diffusing capacity corrected for hemoglobin (DLCO); 
spirometry; resting oxygen saturation. 
Guideline for significant deterioration in lung function from baseline: Decrease in Spirometry and/or DLCO 
of 30% and/or O2 saturation 88% at rest on room air. 
Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited 
as possible. Consider tapering dosage at end. 
If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible. 
 
 


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Rockwood K, Sonet et al. (2005). A global clinical measure of fitness and frailty in elderly 
people. CMAJ; 173(5):489-95.  
 

SAP_001.pdf: 
Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 1 of 64 
  
Statistical Analysis Plan for Interventional Studies 
 
Sponsor Name: resTORbio, Inc. 
 
Protocol Number: RTB-101-204 
Protocol Title: A Multicenter, Randomized, Double Blind, Placebo-Controlled, Phase 3 Study to 
Determine if RTB101 Prevents Clinically Symptomatic Respiratory Illness in the Elderly 
 
Protocol Version and Date: Version 05 (Amendment 02) 07-Jun- 2019 
 
Syneos Health Project Code: 7001371 
 
Authors: Wayne Schuck, Principal Biostatistician 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to resTORbio, Inc.  Acceptance of 
this document constitutes agreement by the recipient that no information contained herein will be 
published or disclosed without prior written authorization from an official of resTORbio, Inc.  However, this 
document may be disclosed to appropriate Institutional Review Board and Ethics Committees or duly 
authorized representatives of a national regulatory authority under the condition that they are requested 
to keep it confidential. In the event of an actual or suspected breach of this obligation, Syneos Health 
should be notified promptly. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 2 of 64 
  
I confirm that I have reviewed this document and agree with the content. 
 
Approvals 
Syneos Health Approval 
 
 
 
 
 
Dean Margeson, Principal Biostatitician 
Lead  Biostatistician  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
resTORbio, Inc. Approval 
 
 
 
 
 
William Marshall, MD 
Vice President, Medical Sciences 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
 
M. V. Patricia Bernardo, ScD 
Vice President, Biostatistics 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 3 of 64 
  
Table of Contents 
Revision History ........................................................................... Error! Bookmark not defined. 
Approvals .................................................................................................................................. 2 
 
Glossary of Abbreviations ................................................................................................... 8 
 
Purpose ............................................................................................................................ 10 
 
Study Objectives .............................................................................................................. 11 
 
Endpoints ......................................................................................................................... 16 
 
Analysis Sets .................................................................................................................... 19 
 
Protocol Deviations .......................................................................................................... 20 
 
General Aspects for Statistical Analysis ........................................................................... 21 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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Demographic, Other Baseline Characteristics and Medication ......................................... 25 
 
Efficacy ............................................................................................................................ 27 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 6 of 64 
  
 
Safety ............................................................................................................................... 44 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
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Interim Analyses ............................................................................................................... 47 
 
Changes from Analysis Planned in Protocol ..................................................................... 48 
 
Programming Considerations ........................................................................................... 49 
 
Quality Control ................................................................................................................. 54 
 
Index of Tables ................................................................................................................. 55 
 
Index of Figures................................................................................................................ 63 
 
Index of Listings ............................................................................................................... 64 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 8 of 64 
  
 
Glossary of Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Alanine Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass index 
BDRM 
Blind Data Review Meeting 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
 
Case Report Form 
DMC 
Data Monitoring Committee  
ECG 
Electrocardiogram 
ER 
Emergency Room 
FAS 
Full Analysis Set 
GLM 
Generalized Linear Model 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus  
hMPV 
Human Metapneumovirus 
HRQoL 
Health-Related Quality of Life 
HRV 
 
Human Rhinovirus 
ICH 
 
International Conference on Harmonization 
IPF 
Interstitial Pulmonary Fibrosis 
IXRS 
Interactive Voice/Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MMSE 
Mini Mental Status Examination 
N/A 
 
Not Applicable 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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Abbreviation 
Description 
PCI 
Percutaneous Coronary Intervention 
PCR 
Polymerase Chain Reaction 
PKS 
Pharmacokinetic Set 
PPS 
Per Protocol Set 
PT 
Preferred Term 
RIDT 
Rapid Influenza Diagnostic Test 
RR 
Rate Ratio 
RSV 
Respiratory Syncytial Virus 
RTI 
Respiratory Tract infections 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCR 
Screening Set 
SD 
Standard Deviation 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Table, Figure and Listing 
ULN 
Upper Limit of Normal 
UTI 
Urinary Tract Infection 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
This document is confidential. 
SAP Version: Version 1.0                                                                                                                                                     04 Sep 2019 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 10 of 64 
  
 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables, and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.  
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality control 
of all tables, figures, and listings.   
 
Timings of Analyses 
The study will be unblinded after all subjects complete the final clinic visit (Week 20 visit) or terminate early 
from the study and the database is locked. 
Analysis of the primary efficacy endpoint, including 2 subgroup analyses (specifically, for subjects who are 
≥85 years old and subjects who have a medical history of asthma) are planned after all subjects have 
completed their Week 16 visit to confirm efficacy of RTB101 prior to enrolling subjects in the second Phase 
3 trial (Protector 2) during the northern hemisphere winter cold and flu season. The analysis will be done 
when all datasets required for determination of the primary endpoint have been cleaned, frozen and 
changes to the required data can no longer be made. The Syneos unblinded statistical team will prepare 
the analysis tables and will provide them only to the resTORbio Chief Executive Officer (CEO) and Chief 
Medical Officer (CMO), who are not involved in the RTB-101-204 study conduct.   All resTORbio personnel 
will remain blinded on a subject-level, and only the resTORbio CEO and CMO will be unblinded at a 
treatment-group level at this time. 
A final analysis of other safety and efficacy and/or pharmacokinetics endpoints is planned after all subjects 
complete the final clinic visit (Week 20 visit) or terminate early from the study.  
An independent Data Monitoring Committee (DMC) will be established. The DMC will be responsible for 
the following: 
• 
Providing ongoing assessments of safety data and the overall risk of the study conduct. This will 
include an ongoing unblinded analysis of GI SAEs and unexpected related SAE narratives, and a 
monthly analysis of unblinded listings of all other SAEs.  
• 
Advising the Sponsor of the need for study stopping or protocol modification/amendments in 
order to minimize potential risk for subjects.  
• 
Advising the Sponsor if study enrollment needs to be halted based on review within 48 hours of 
safety data outlined in Section 5.5.5 of the protocol. 
Further details are provided in the DMC charter. 


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Study Objectives 
 
Primary Objective 
The primary objective is to determine if RTB101 as compared to placebo decreases the percentage of 
subjects with clinically symptomatic respiratory illness (with or without an associated laboratory-confirmed 
pathogen) through Week 16. 
 
Secondary Objectives 
The secondary objectives are: 
• 
To determine if RTB101 as compared to placebo decreases the percentage of subjects with 
clinically symptomatic respiratory illness associated with ≥1 laboratory-confirmed pathogen(s) 
through Week 16 
• 
To determine the effect of  RTB101 as compared to placebo on the rate of clinically symptomatic 
respiratory illnesses associated with specific laboratory confirmed viruses (coronaviruses, human 
metapneumovirus [hMPV], human rhinovirus [HRV]/enterovirus, adenovirus, influenza A and B 
virus, parainfluenza viruses, and respiratory syncytial virus [RSV]) through Week 16 
• 
To determine if RTB101 as compared to placebo decreases the rate of clinically symptomatic 
respiratory illness (with or without an associated laboratory-confirmed pathogen) through Week 
16 
• 
To determine if RTB101 as compared to placebo decreases the rate of clinically symptomatic 
respiratory illnesses associated with ≥1 laboratory-confirmed pathogen(s) through Week 16 
• 
To determine if RTB101 as compared to placebo decreases time to alleviation of moderate and 
severe respiratory illness symptoms due to clinically symptomatic respiratory illness through 
Week 16 
• 
To determine if RTB101 as compared to placebo decreases the percentage of subjects with 
severe symptoms due to clinically symptomatic respiratory illnesses through Week 16 
• 
To assess the safety and tolerability of RTB101 through Week 20 
 
Exploratory Objectives 
The exploratory objectives are: 
• 
To explore the effect of RTB101 as compared to placebo on the rate of all laboratory-confirmed 
viral respiratory infections with or without symptoms through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on the rate of all-cause hospitalizations 
through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on the rate of hospitalizations associated 
with RTIs through Week 16  
• 
To explore the effect of RTB101 as compared to placebo on the rate of all-cause Emergency Room 
(ER) visits through Week 16 


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• 
To explore the effect of RTB101 as compared to placebo on the rate of ER visits associated with 
RTIs through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on the rate of all-cause urgent care clinic 
visits through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on the rate of all urgent care clinic visits 
for clinically symptomatic respiratory illness through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on the rate of all-cause admissions to 
skilled nursing facilities through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on hospital length of stay associated with 
RTIs through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on all-cause hospital length of stay 
through Week 16 
• 
To explore the effect of RTB101 as compared to placebo on the percentage of subjects with 
clinically symptomatic respiratory illness and the percentage of subjects with clinically 
symptomatic respiratory illness associated with ≥1 laboratory-confirmed pathogen(s) through 
Week 20 
• 
To explore the effect of RTB101 as compared to placebo on change from Baseline in health-related 
quality of life (HRQoL) as assessed by EQ-5D-5L scores during all clinically symptomatic 
respiratory illness episodes and at Week 16 
• 
To explore the effect of RTB101 as compared to placebo on the percentage of subjects with 
clinically symptomatic respiratory illnesses and on the percentage of subjects with clinically 
symptomatic respiratory illnesses associated with ≥1 laboratory-confirmed pathogen(s) through 
Week 16 who are ≥85 years of age or subjects with a medical history of asthma 
• 
To explore the effect of RTB101 as compared to placebo on the rate of clinically symptomatic 
respiratory illnesses and on the rate of clinically symptomatic respiratory illnesses associated with 
≥1 laboratory-confirmed pathogen(s) through Week 16 in subjects who are ≥85 years of age or 
subjects with a medical history of asthma 
• 
To explore the effect of RTB101 as compared to placebo on the incidence of asthma exacerbations 
through Week 16 in subjects with a medical history of asthma 
• 
To explore the effect of RTB101 as compared to placebo on the incidence of urinary tract infections 
(UTIs) through Week 16 
• 
To explore the effect of RTB101 on immunologic biomarkers and to explore biomarkers that may 
predict response (e.g. RNA expression in whole blood, serum biomarkers, genetic variation) 
 
Brief Description 
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, Phase 3 study to 
determine if RTB101 prevents clinically symptomatic respiratory illnesses (CSRI) in elderly subjects. 
Approximately 1066 subjects will be enrolled during cold and flu season. Subjects who meet the 
inclusion/exclusion criteria will be randomized 1:1 to receive RTB101 10 mg or matching placebo orally 


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once daily for 16 weeks. The study will be composed of: up to a 4-week screening period, a 16-week 
treatment period, and a 4-week short-term follow-up period off study drug through the Week 20 Visit. There 
will also be a long term follow-up by telephone at Week 48. 
 
Subject Selection 
 
Inclusion Criteria 
Subjects eligible for inclusion in this study must fulfill all of the criteria listed in section 4.1 of the protocol. 
 
Exclusion Criteria 
Subjects will not be eligible if they meet any of the criteria listed in section 4.2 of the protocol. 
 
Determination of Sample Size 
Sample size was determined based on a two-sided comparison between RTB101 and placebo. In parts 1 
and 2 of the Phase 2b trial, 28.2% of subjects had a clinically symptomatic respiratory illness on placebo 
(excluding subjects with COPD and current smokers). With an assumed Week 16 clinically symptomatic 
respiratory illness incidence of 28.2% on placebo and 19.7% in the RTB101 arm, a total sample size of 
approximately 1066 subjects (equally randomized) will provide 90% power to detect a 30% reduction in 
the percentage of subjects with clinically symptomatic respiratory illness between RTB101 and placebo 
using a two-sided test of 0.05 significance. Power analysis was conducted using Likelihood Ratio Chi-
square Test. 
 
Treatment Assignment & Blinding 
At the Baseline visit, all eligible subjects will be randomized via the IXRS to one of the treatment arms. 
The Investigator or his/her delegate will contact the IXRS after confirming that the subject fulfills all the 
inclusion/exclusion criteria. The IXRS will prompt the user to randomize the subject. The subject identifier 
number will be used to link the subject to a treatment arm and a unique medication number for the bottles 
of study drug to be dispensed to the subject. 
Randomization will be stratified based on the following factors that may influence the incidence and 
severity of RTIs and the response to treatment: 
1. Age ≥ 85 
2. Age ≥ 65 and <85 years with a medical history of asthma 
3. Clinical Frailty Scale score ≥ 4 
Therefore, the 6 randomization strata are as follows: 
• 
Age ≥  85 and Clinical Frailty Scale score ≥ 4 
• 
Age ≥  85 and Clinical Frailty Scale score < 4 
• 
Age ≥ 65 and <85 years with a medical history of asthma and Clinical Frailty Scale score 
≥ 4 
• 
Age ≥ 65 and <85 years with a medical history of asthma and Clinical Frailty Scale score 
< 4 


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• 
Age ≥ 65 and <85 years with no medical history of asthma and Clinical Frailty Scale 
score ≥ 4 
• 
Age ≥ 65 and <85 years with no medical history of asthma and Clinical Frailty Scale 
score < 4 
The randomization scheme for subjects will be reviewed and approved by a member of the team 
responsible for Randomization schema.  
This is a subject, Investigator and Sponsor-blinded study. Subjects, all study site staff, 
includingInvestigators and study nurses, will remain blinded until all subjects complete the Long-
termFollow up Period (Study Week 48). The Sponsor will remain blinded to study treatment until 
allsubjects complete the Short-term Follow-up Period (Study Week 20). The only exception will be in the 
DMC.  The DMC manager, coordinator, and statistician will have access to unblinded data and perform all 
work in a restricted and secured project folder. The unblinded files will be transferred to the unblinded 
DMC members by the unblinded DMC coordinator.  
 
Administration of Study Medication 
RTB101 10 mg or matching placebo will be dispensed at the Baseline visit, Week 4, Week 8, and Week 
12. Subjects will be instructed to take one dose daily in the morning. Subjects participating in the PK 
assessments (per the IXRS randomization) will be asked not to take study drug on the morning of 
scheduled clinical visits of Week 4 (or alternatively Week 6 in case of logistical need) and Week 12 as the 
subject will be administered study drug with a light meal at the study site. 
 
Study Procedures and Flowchart 
The study will be comprised of up to a 4-week Screening Period; a 16-week Primary Analysis Period (for 
evaluating efficacy and safety) during which time subjects meeting study eligibility criteria will be 
randomized 1:1 to receive RTB101 10 mg or matching placebo once daily through the Week 16 Visit; a 4-
week Short-term Follow-up Period (for evaluating safety and efficacy through the Week 20 Visit); and a 
28-week Long-term Follow-up Period (for evaluating safety through Week 48 by follow-up questionnaire). 
The Blinded Treatment Period has clinical visits every 2 weeks for the first 8 weeks, and every 4 weeks 
thereafter (for a total of 7 visits including the Baseline visit).  
Respiratory illness symptoms will be captured in an eDiary that subjects will complete daily (in the 
evening) at home after the Baseline visit. The eDiary will ask the subject to record their experience with a 
set of predefined respiratory illness symptoms at their worst during the past 24 hours. The subjects record 
whether each symptom was absent, mild, moderate or severe. If the subject experiences any symptom on 
a typical day even though they are not sick, they are instructed to record the symptom as “Absent”. The 
predefined symptoms include both respiratory symptoms (runny nose, sneezing, stuffy nose, sore throat, 
hoarseness, or cough) and general symptoms (headache, feverishness/chills, loss of appetite, body 
aches, or lack of energy). 
The eDiary responses will be monitored by the Study Investigator or Study Coordinator. The 
Study Investigator or Study Coordinator at the site will contact subjects who miss completion of 
the daily eDiary questionnaires for >1 day and re-train the subject and explain the importance of 
completing the daily eDiary questionnaires.  
Study sites will instruct subjects who report at least one respiratory symptom in 2 consecutive entries in 
their eDiary to come to the study site for evaluation, if possible, and for the collection of a nasopharyngeal 
swab. Subjects who are unable to come to the study site may also have the nasopharyngeal swab (and, if 
indicated, a sputum specimen and rapid influenza diagnostic test [RIDT]) obtained during a home visit by 


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trained personnel. 
Details of assessments at each visit are provided in Table 6-1 of the protocol. 
 


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Endpoints 
 
Primary Efficacy Endpoint 
The primary endpoint is the percentage of subjects with CSRIs (with or without an associated laboratory 
confirmed pathogen) beginning at least 3 days after the start of study drug treatment through Week 16 as 
assessed by pre-specified clinical diagnostic criteria defined in 7.2.1 below. 
 
Secondary Efficacy Endpoints 
The secondary endpoints are:  
• 
The percentage of subjects with 1 or more CSRIs associated with ≥1 laboratory-confirmed 
pathogen(s) beginning at least 3 days after the start of study drug treatment through Week 16 as 
assessed by pre-specified clinical diagnostic criteria, and respiratory pathogen PCR of 
nasopharyngeal swabs, sputum gram stain and culture, and/or Rapid Influenza Diagnostic Tests 
(RIDTs). 
• 
The rate of CSRIs associated with specific laboratory-confirmed viruses (coronaviruses, hMPV, 
HRV/enterovirus, adenovirus, influenza A and B virus, parainfluenza viruses, and RSV)  
beginning at least 3 days after the start of study drug treatment through Week 16 as assessed by 
respiratory pathogen PCR of nasopharyngeal swabs, sputum gram stain and culture, and/or 
RIDTs. 
• 
The rate of CSRI (with or without an associated laboratory-confirmed pathogen) beginning at 
least 3 days after the start of study drug treatment through Week 16 as assessed by pre-specified 
clinical diagnostic criteria.  
• 
The rate of CSRIs associated with ≥ 1 laboratory-confirmed pathogen(s) beginning at least 3 days 
after the start of study drug treatment through Week 16 as assessed by pre-specified clinical 
diagnostic criteria and respiratory pathogen PCR of nasopharyngeal swabs, sputum gram stain 
and culture, and/or RIDTs. 
• 
The time to alleviation of moderate and severe respiratory illness symptoms due to a CSRI 
beginning at least 3 days after the start of study drug treatment through Week 16.  
• 
The percentage of subjects with severe symptoms due to CSRIs beginning at least 3 days after 
the start of study drug treatment through Week 16.  
• 
Safety and tolerability will be assessed by report of AE/SAEs, physical exam and ECG findings, 
and safety laboratory values. 
 
Exploratory Endpoints 
The exploratory endpoints are:  
• 
The rate of all laboratory-confirmed viral infections with or without symptoms beginning at least 3 
days after the start of study drug  treatment through Week 16 as assessed by respiratory 
pathogen PCR of nasopharyngeal swabs and/or RIDTs (obtained during episodes of clinically 


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symptomatic respiratory illnesses) and/or respiratory pathogen PCR of mid-turbinate swabs 
(obtained at scheduled clinical visits even in the absence of symptoms). The rate of all-cause 
hospitalizations through Week 16.  
• 
Rate of hospitalizations associated with RTIs beginning at least 3 days after the start of study 
drug treatment through Week 16.  
• 
The rate of all-cause Emergency Room (ER) visits through Week 16.  
• 
Rate of Emergency Room (ER) visits associated with RTIs beginning at least 3 days after the 
start of study drug treatment through Week 16.  
• 
The rate of all-cause urgent care clinic visits through Week 16. 
• 
The rate of urgent care clinic visits for CSRI beginning at least 3 days after the start of study drug 
treatment through Week 16. 
• 
The rate of all-cause admissions to skilled nursing facilities through Week 16. 
• 
Hospitalization length of stay associated with RTIs beginning at least 3 days after the start of 
study drug treatment through Week 16.  
• 
All-cause hospitalization length of stay through Week 16.  
• 
The percentage of subjects with one or more CSRIs (with or without an associated laboratory 
pathogen)  beginning at least 3 days after the start of study drug treatment through Week 20  
• 
The percentage of subjects with 1 or more CSRIs associated with ≥1 laboratory-confirmed 
pathogen(s) beginning at least 3 days after the start of study drug treatment through Week 20 as 
assessed by pre-specified clinical diagnostic criteria and respiratory pathogen PCR of 
nasopharyngeal swabs, sputum gram stain and culture, and/or RIDTs. 
• 
The change from Baseline in HRQoL as assessed by EQ-5D-5L scores during all clinically 
symptomatic respiratory illness episodes beginning at least 3 days after the start of study drug 
treatment through Week 16 and at Week 16.  
• 
The percentage of subjects who are ≥85 years of age with one or more CSRIs beginning at least 
3 days after the start of study drug treatment through Week 16.  
• 
The percentage of subjects who are ≥85 years of age with one or more CSRIs associated with ≥1 
laboratory-confirmed pathogen(s) beginning at least 3 days after the start of study drug treatment 
through Week 16. 
• 
The percentage of subjects who have a medical history of asthma with one or more CSRIs 
beginning at least 3 days after the start of study drug treatment through Week 16. 
• 
The percentage of subjects who have a medical history of asthma with one or more associated 
with ≥1 laboratory-confirmed pathogen(s) beginning at least 3 days after the start of study drug 
treatment through Week 16. 


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• 
The rate of clinically symptomatic respiratory illnesses beginning at least 3 days after the start of 
study drug treatment through Week 16 in subjects who are ≥85 years of age. 
• 
The rate of clinically symptomatic respiratory illnesses associated with ≥1 laboratory-confirmed 
pathogen(s) beginning at least 3 days after the start of study drug treatment through Week 16 in 
subjects who are ≥85 years of age 
• 
The rate of clinically symptomatic respiratory illnesses beginning at least 3 days after the start of 
study drug treatment through Week 16 in subjects with a medical history of asthma. 
• 
The rate of clinically symptomatic respiratory illnesses associated with ≥1 laboratory-confirmed 
pathogen(s) beginning at least 3 days after the start of study drug treatment through Week 16 in 
subjects with a medical history of asthma.. 
• 
The rate of asthma exacerbations defined as deterioration of asthma symptoms that requires 
treatment with systemic steroids beginning at least 3 days after the start of study drug treatment 
through Week 16 in subjects with a medical history of asthma. 
• 
The percentage of subjects with 1 or more asthma exacerbation defined as deterioration of 
asthma symptoms that requires treatment with systemic steroids beginning at least 3 days after 
the start of study drug treatment through Week 16 in subjects with a medical history of asthma 
• 
The percentage of subjects with one or more UTIs reported as adverse events through Week 16. 
• 
The rate of UTIs  reported as adverse events through Week 16. 
• 
Change from Baseline to Weeks 4 and 16 in biomarkers in whole blood and serum and potentially 
future pharmacogenomic analysis. 
 


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Analysis Sets 
 
Screening / Randomized Sets 
The Screening Set (SCR) will include all subjects, who provided informed consent, regardless of the 
subject’s randomization and study treatment status in the study. Unless specified otherwise, this set will 
be used for summaries of subject disposition.  
The Randomized Set (RS) will include all subjects randomized whether treated or not.  
 
Safety Set  
The Safety Set (SAF) will include all subjects who were administered any dose of any study drug. Subjects 
will be analyzed per the actual study treatment they received. The follow-up period will include the Week 
20 visit which is 4 weeks after the end of the treatment period.  The SAF will be used for all analyses and 
presentation of by-subject listings of all safety endpoints. Subjects will be analyzed according the actual 
treatment they received. 
 
Full Analysis Set  
The Full Analysis Set (FAS) will include all randomized subjects who received at least 1 dose of trial 
medication. Subjects will be analyzed according to randomized treatment. The FAS will be used for all 
analyses and presentation of by-subject listings of all efficacy endpoints. 
 
Per Protocol Set  
The Per Protocol Set (PP) will include all subjects who complete the 16-week treatment period, missed < 
20% of doses, and had no major protocol deviations impacting efficacy data. Subjects will be analyzed 
per the treatment group to which they were randomized.  
Protocol deviations will be classified and reviewed for subject inclusion in the PP during a Blind Data 
Review Meeting (BDRM) as described in Syneos SOP 3911.00 (Blind) Data Review and Definition of 
Analysis Sets, prior to unblinding. Criteria for exclusion from the PP will be included in  BDRM Preparation 
Plan. 


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Protocol Deviations 
Protocol deviations will be collected throughout the study in the Medidata Clinical Trial Management 
System (CTMS). Protocol deviations will be reviewed during a BDRM. Details of selection criteria and 
documentation to be provided for review will be described in the BDRM Preparation Plan. 
 


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General Aspects for Statistical Analysis 
 
General Methods 
All analyses and outputs will be produced using SAS® version 9.4 or later. Unless otherwise specified, 
efficacy and safety summaries will be presented for each treatment. All other summaries will be presented 
for each treatment and overall. Continuous variables will be summarized using the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. Categorical variables 
will be summarized using number of observations (n), frequency, and percentages of subjects. 
All relevant subject data will be included in listings. All randomized subjects entered into the database will 
be included in subject data listings. All by visit summaries will use the nominal visit. Unscheduled visits 
will not be summarized but will be included in the listings.  
 
Key Definitions 
 
Clinically Symptomatic Respiratory Illness (CSRI) 
A CSRI is defined as the occurrence of:  
 
a. At least 2 respiratory symptoms (runny nose/sneezing [considered one symptom], stuffy nose, sore 
throat, hoarseness, or cough) OR 1 respiratory symptom and 1 of the following general symptoms 
(headache, feverishness/chills or loss of appetite),  
 
AND 
b. at least 1 of these respiratory symptoms (runny nose, sneezing, stuffy nose, sore throat, hoarseness 
or cough) in (a) above being reported on 2 or more “consecutive entries” in the eDiary, and must  
i. 
overlap with another respiratory or general symptom for at least 1 day, or  
ii. 
be reported on a consecutive day to another respiratory or general symptom in the eDiary 
      AND 
c. any 2 or more symptoms (respiratory and/or general) reported during the CSRI event that are at least 
moderate in severity.  
 
All CSRI-defining symptoms (i.e., runny nose, sneezing , stuffy nose, sore throat, hoarseness, cough, 
headache, feverishness/chills or loss of appetite)  that occur after the start of a CSRI event will be 
included as part of a single CSRI event unless there is a  period of ≥ 7 consecutive entries during which 
all CSRI-defining symptoms are reported as “Absent”  in the eDiary. 
“consecutive entries” include situations in which eDiary entries were missing for 1-6 days in between 2 
days in which the symptom was reported. For example, if on Day 3 and Day 9  runny nose was reported 
but eDiary entries were missing from Days 4-8, then runny nose will be considered as reported for 2 
consecutive entries.  This definition of “consecutive entries” does not include situations in which subjects 
report all symptoms as “Absent”.  If ≥ 7 days of eDiary entries are missing, then symptoms reported 
before and after the ≥7 days of missing entries will not be considered consecutive eDiary entries.   
The start date of the CSRI will be the start date of the first respiratory symptom reported as part of the 
CSRI.  Note that the start date of a CSRI will always be based on the start date of the respiratory 
symptom and not a general symptom. 


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The end date of the CSRI will be defined as the latest date that any of the CSRI-defining symptoms for 
the same CSRI event were reported. 
A separate CSRI event will not be diagnosed until a subject has ≥ 7 consecutive  days during which all 
CSRI-defining symptoms are reported as “Absent”  after the end date of the prior CSRI episode.   If 
missing days of eDiary entries are sandwiched between 2 days of eDiary entries during which all CSRI-
defining symptoms are reported as “Absent”, then all symptoms will also be considered as “Absent” for 
the missing eDiary entries, and a separate CSRI event can be diagnosed if the ≥ 7 consecutive  days 
criterion is met. For example, if on Day 4 and Day 10 all symptoms were reported as “Absent” in the 
eDiary, and on Days 5-9 the eDiary entries were missing, then all  symptoms will be considered as 
“Absent” on Days 5-9. Therefore all symptoms will be considered as “Absent” for 7 consecutive days 
(Days 4-10), and a separate CSRI can be diagnosed. 
Only CSRIs having a start date at least 3 days after the start of study drug and meet the definition of a 
CSRI by the specified time point (Week 16 or Week 20) will be included in the analysis.  Only data 
recorded in the eDiary through the evening before the Week 16 visit will be included in all analyses of 
CSRIs for the Week 16 endpoint. Similarly, only data recorded in the eDiary through the evening before 
the Week 20 visit will be included in all analyses of CSRIs for the Week 20 endpoint. 
 
First Dose Date 
For any randomized subject, if there are any entries in the eDiary indicating the subject took study drug at 
any time during the study, then the first dose date will equal the randomization date because all subjects 
receive their first dose of study drug at the site during the Baseline (randomization) visit.  However, if 
there are no entries in the eDiary indicating the subject took study drug at any time during the study 
(including at the Baseline visit), then the first dose date will be missing and the subject will be considered 
randomized but not treated. 
 
Study Day 
Study day 1 is defined as as the first dosing day of study drug. Subsequent days are numbered 
consecutively (Day 2, Day 3, etc.). Before the day of study drug administration, study days are numbered 
sequentially with negative values (i.e., Day -1, Day -2, etc.). There is no Day 0.  
 
Baseline 
Baseline is defined as the last measurement taken before the first dose of double-blind treatment on Day 
1, unless otherwise specified. 
 
Missing Data 
Every effort will be made to collect all data at specified timepoints, according to the schedule of study 
events. 
For the primary efficacy endpoint of occurrence of CSRI, subjects who did not meet the study definition 
for CSRI and discontinue the study prematurely due to a respiratory tract infection (RTI) adverse event 
(AE) or RTI serious adverse event (SAE) will be imputed to have experienced a CSRI; subjects who 
discontinue the study prematurely due to any reason aside from an RTI AE or RTI SAE and did not meet 
the CSRI definition will be imputed as having no CSRI; subjects who completed the study who did not 
meet the CSRI definition and have intermittent missing eDiary data will be imputed  as having no CSRI. 


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Partial dates of medications will be imputed solely for the purpose of defining prior/concomitant status for 
medications.  Dates will be defined using the hierarchy of derivations below. 
• 
For missing start day where month and year are present, the start day will be set to the 1st of the 
month, unless the month and year are the same as the first dose month and year and the 1st of 
the month is before the first dose date, in which case, the start date will be set to the first dose date.  
• 
For missing start day and month where year is present, the start day and month will be set to 
January 1st, unless the year is the same as the first dose year and January 1st is before the first 
dose date, in which case, the start date will be set to the first dose date.  
• 
For missing end day where month and year are present, the end day will be set to the last day of 
the month, unless the month and year are the same as the trial termination month and year, in 
which case, the end date will be set to the trial termination date.  
• 
For missing end day and month, where year is present, the end date will be set to the trial 
termination date if the years are the same.  If the trial termination year is greater than the end year, 
the end day and month will be set to December 31st. 
 
Visit Windows 
Visit window will not be used in the summarization or analysis of data. 
 
Pooling of Centres 
Pooling of centers or countries will not be done. Center and country will not be included in the statistical 
model. 
 
Subgroups 
The analyses of the primary endpoint and selected secondary endpoints (listed below) will be repeated 
for the following subpopulations of the FAS: 
• 
Age Group (≥85 years old vs. <85 years old) 
• 
Clinical Frailty Scale score (≥4 vs. <4) 
• 
History of asthma (Y/N) 
• 
Congestive heart failure (CHF) (Y/N) 
• 
Received a pneumococcal vaccination (Y/N) 
• 
Received current season influenza vaccination (Y/N)) 
• 
Gender (Male vs. Female) 
In each of the subgroup analyses, the independent variable relating to the subgroup will be dropped from 
the model, if applicable. 
The selected secondary endpoints include  
(1) The percentage of subjects with CSRIs associated with ≥1 laboratory-confirmed pathogen(s) 
beginning at least 3 days after the start of study drug treatment through Week 16  


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(2) The rate of CSRIs (with or without an associated laboratory-confirmed pathogen) beginning at 
least 3 days after the start of study drug treatment through Week 16 
(3) The rate of CSRIs associated with ≥1 laboratory-confirmed pathogen(s) beginning at least 3 days 
after the start of study drug treatment through Week 16 
 


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
Subject disposition will be presented for all subjects in the Screening Set, which include the following: 
• 
Number of subjects enrolled (i.e. signed Informed Consent) 
• 
Number of screened, screen failures and reason for screen failure 
• 
Number (%) of subjects randomized  
Among the randomized subjects, the following will be summarized  
• 
Number (%) of subjects in the Safety Set 
 
• 
Number (%) of subjects in the Full Analysis Set 
• 
Number (%) of subjects in the Per-Protocol Set 
• 
Number (%) of subjects who completed the study through Week 16 
• 
Number (%) of subjects who completed the study through Week 20 
• 
Number (%) of subjects who discontinued treatment and their reason 
• 
Number (%) of subjects who discontinued study prematurely and their reason 
A separate by-subject listing of subject disposition and withdrawal will also be provided for the Screening 
Set. Subjects who screen failed will be included in this listing along with the reason for the screen failure. 
Reasons for exclusion from analysis sets will be summarized in the Randomized Set and listed. 
 
Protocol Deviations 
All protocol deviations will be listed in the Randomized Set.  Major protocol deviations will be summarized 
in the Randomized Set. 
 
Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized for the Safety Set by actual 
treatment, for  Randomized,  Full Analysis, and Per Protocol Sets by randomized treatment and overall. 
Summary statistics and by-subject listings will be provided. 
Demographics and baseline characteristics will include age, sex, ethnicity, race, weight, height, body 
mass index (BMI), age ≥ 85 (Y/N), age ≥ 65 and <85 years, with a medical history of asthma (Y/N), 
medical history of congestive heart failure (Y/N), medical history of Type 2 Diabetes Mellitus (Y/N), 
Clinical Frailty Scale score ≥ 4 (Y/N), Clinical Frailty Score (ordinal), receipt of current season influenza 
vaccine (Y/N) and each of the stratification levels (age ≥ 85 and clinical frailty score ≥ 4;  age ≥ 85 and 
clinical frailty score < 4;  65 ≤ age < 84, clinical frailty score ≥ 4 and medical history of asthma;  65 ≤ age 


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< 84, clinical frailty score ≥ 4 and no medical history of asthma; 65 ≤ age < 84, clinical frailty score < 4 
and medical history of asthma; and 65 ≤ age < 84, clinical frailty score < 4 and no medical history of 
asthma).       
Age at Screening = (Screening visit date - date of birth + 1) / 365.25 and truncated to complete years. 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
Similarly, baseline disease characteristics will be summarized for the Safety Set, Randomized,  Full 
Analysis, and Per Protocol Sets. 
By-subject listing of all demographic and baseline disease characteristic data will be provided for the Full 
Analysis Set. 
 
Medical History and Concomitant Diseases 
A summary table of the number and percentage of subjects by medical history, system organ class (SOC) 
and preferred term will be produced from the Safety Set. Medical history will be sorted alphabetically by 
SOC and in descending order of subjects per preferred term within each SOC.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
22.0 or higher.  
A separate by-subject listing of medical history will also be provided. 
 
Medication 
All prior and concomitant medications will be summarized based on classification using the Anatomical 
Therapeutic Chemical (ATC) classification and preferred drug name from the World Health Organization 
Drug Dictionary, version Mar 2019, or later.  
A separate by-subject listing of medications will also be provided for the Safey Set. 
 
Prior Medication 
Prior medications are defined as medications entered in the eCRF that either start, or end before the first 
dose of study medication. Prior medications will be summarized by ATC level 2 and preferred drug name 
for the Safety Population. 
Prior medications which continue after first dose of study medication will also be classified as a 
concomitant medication. 
 
Concomitant Medication 
Concomitant medications are defined as medication on the eCRF that are taken on, after, or are ongoing 
at the start date of dosing. Concomitant medications will be summarized by ATC level 2 and preferred 
drug name for the Safety Population. 


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Efficacy 
 
Multiple Testing Strategy 
A fixed sequence gate-keeping strategy will be used to control the study-wise error rate at a 2-sided α-
level of 0.05.  The following primary, secondary and exploratory efficacy endpoints will be tested in the 
sequence specified below:  
Order 
H1 
The percentage of subjects with 1 or more CSRIs (with or without an associated laboratory-
confirmed pathogen) beginning at least 3 days after the start of study drug treatment through 
Week 16. 
H2 
The percentage of subjects with 1 or more CSRIs associated with ≥1 laboratory-confirmed 
pathogen(s) beginning at least 3 days after the start of study drug treatment through Week 16 
as assessed by pre-specified clinical diagnostic criteria, and respiratory pathogen PCR of 
nasopharyngeal swabs, sputum gram stain and culture, and/or RIDTs. 
H3 
The rate of CSRI (with or without an associated laboratory-confirmed pathogen) beginning at 
least 3 days after the start of study drug treatment through Week 16 as assessed by pre-
specified clinical diagnostic criteria.  
H4 
The rate of CSRIs associated with ≥ 1 laboratory-confirmed pathogen(s) beginning at least 3 
days after the start of study drug treatment through Week 16 as assessed by pre-specified 
clinical diagnostic criteria and respiratory pathogen PCR of nasopharyngeal swabs, sputum 
gram stain and culture, and/or RIDTs. 
H5 
The time to alleviation of moderate and severe respiratory illness symptoms due to CSRI 
beginning at least 3 days after the start of study drug treatment through Week 16. 
H6 
The percentage of subjects with severe symptoms due to CSRIs beginning at least 3 days after 
the start of study drug treatment through Week 16. 
H7 
The rate of all-cause hospitalizations beginning at least 3 days after the start of study drug 
treatment through Week 16.  
H8 
The rate of UTIs beginning at least 3 days after the start of study drug treatment through Week 
16 reported as adverse events 
H9 
The percentage of subjects with 1 or more CSRIs (with or without an associated laboratory-
confirmed pathogen) beginning at least 3 days after the start of study drug treatment through 
Week 20. 
  
The primary endpoint, H1, will be tested first at a 2-sided alpha level of 0.05.  The subsequent endpoints 
will be tested in the order specified above also at a 2-sided 0.05 alpha-level of 0.05, if and only if the 
preceding endpoint was found to be statistically significant.  If the preceding endpoint in the sequence 
fails to meet statistical significance, then testing of subsequent endpoints will be stopped and no further 
statistical conclusions will be made. 
 
 
 
Estimands 
This section presents a structured framework that link trial objectives with suitable and precise definition 
of how treatment effects are to be estimated. The estimand, which is the target of estimation to address 


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the scientific question of interest posed by the trial objective, with its 4 attributes as specified in the ICH 
E9(R1) Draft Addendum on Estimands and Sensitivity Analysis in Clinical Trials 2017, are provided below 
for the primary objective and key secondary objectives. 
 
Primary Objective Estimand 
The estimand used to address the primary objective “To determine if RTB101 as compared to placebo 
decreases the percentage of subjects with a CSRI (with or without an associated laboratory-confirmed 
pathogen) through Week 16”  is defined by the following: 
• 
Population:  
• 
Subjects in the FAS population 
• 
Variable:  
• 
Occurrence of a CSRI, with or without an associated laboratory-confirmed pathogen, by 
the Week 16 visit  
• 
Intercurrent events:  
• 
If a subject discontinues study prematurely due to an RTI AE or RTI SAE and the subject 
did not meet the definition of a CSRI, impute the subject experienced a CSRI 
• 
If a subject discontinues study prematurely for any reason other than an RTI AE or RTI 
SAE  and the subject did not meet the definition of a CSRI, impute the subject did not 
have a CSRI 
• 
If a subject completed the study and has intermittent missing eDiary data and the subject 
did not meet the definition of a CSRI, impute the subject did not have a CSRI 
• 
Population-level summary:   
• 
odds ratio, i.e. the ratio of  the odds of having a CSRI in subjects treated with RTB101 
compared to the odds of having a CSRI in subjects treated with placebo by the Week 16  
visit 
 
Secondary Objective Estimands 
 
1. The estimand for the secondary objective “To determine if RTB101 as compared to placebo 
decreases the percentage of subjects with a CSRI associated with ≥1 laboratory-confirmed 
pathogen(s) through Week 16” is defined by the following: 
 
• 
Population:  
• 
Subjects in FAS population 
• 
Variable:  
• 
Occurrence of a CSRI with ≥1 laboratory-confirmed pathogen(s) by the Week 16 visit  


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• 
Intercurrent events:  
• 
If a subject discontinues study prematurely due to an RTI AE or RTI SAE and the subject 
did not meet the definition of  a CSRI associated with ≥1 laboratory-confirmed 
pathogen(s), assume the subject experienced a CSRI with ≥1 laboratory-confirmed 
pathogen(s) 
• 
If a subject discontinues study prematurely for any reason other than an RTI AE or RTI 
SAE , and the subject did not meet the definition of a CSRI associated with ≥1 laboratory-
confirmed pathogen(s), impute the subject did not have a CSRI with ≥1 laboratory-
confirmed pathogen(s) 
• 
If a subject completed the study and has intermittent missing eDiary data and the subject 
did not meet the definition of a CSRI associated with ≥1 laboratory-confirmed 
pathogen(s), impute the subject did not have a CSRI with ≥1 laboratory-confirmed 
pathogen(s) 
 
• 
Population-level summary:   
• 
odds ratio, i.e. the  ratio of the odds of having a CSRI with ≥1 laboratory-confirmed 
pathogen(s)  in subjects treated with RTB101 compared to the odds of having a CSRI 
with ≥1 laboratory-confirmed pathogen(s) in subjects treated with placebo by the Week 
16  visit 
2. The estimand for the secondary objective “To determine if RTB101 as compared to placebo 
decreases the rate of CSRIs, with or without an associated laboratory-confirmed pathogen, 
through Week 16” is defined by the following: 
 
• 
Population:  
• 
Subjects in FAS population 
• 
Variable:  
• 
Number of CSRIs with or without an associated laboratory-confirmed pathogen through 
the Week 16 visit 
• 
Intercurrent events:  
• 
If a subject discontinues study prematurely due to an RTI AE or RTI SAE and the subject 
did not meet the definition of a CSRI, assume the subject experienced one CSRI  
• 
If a subject discontinues study prematurely for any  reason other than an RTI AE or RTI 
SAE and the subject did not meet the definition of a CSRI, impute the subject did not 
have a CSRI 
• 
If a subject completed the study and has intermittent missing eDiary data and the subject 
did not meet the definition of a CSRI, impute the subject did not have a CSRI 
• 
Population-level summary:   


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• 
rate ratio, i.e. the ratio of the rate of having a CSRI (with or without an associated 
laboratory-confirmed pathogen) in subjects treated with RTB101 compared to the rate of 
having a CSRI (with or without an associated laboratory-confirmed pathogen) in subjects 
treated with placebo by the Week 16  visit 
3. The estimand for the secondary objective “To determine if RTB101 as compared to placebo 
decreases the rate of CSRIs associated with ≥1 laboratory-confirmed pathogen(s) through Week 
16” is defined by the following: 
 
• 
Population:  
• 
Subjects in FAS population 
• 
Variable:  
• 
Number of CSRIs with ≥1 laboratory-confirmed pathogen(s) through Week 16 
• 
Intercurrent events:  
• 
If a subject discontinues study prematurely due to an RTI AE or RTI SAE and the subject 
did not meet the definition of a CSRI associated with ≥1 laboratory-confirmed 
pathogen(s) , assume the subject experienced one CSRI associated with ≥1 laboratory-
confirmed pathogen(s) 
• 
If a subject discontinues study prematurely for any reason other than an RTI AE or RTI 
SAE, and the subject did not meet the definition of a CSRI associated with ≥1 laboratory-
confirmed pathogen(s), impute the subject did not have a CSRI associated with ≥1 
laboratory-confirmed pathogen(s) 
• 
If a subject completed the study and has intermittent missing eDiary data and the subject 
did not meet the definition of a CSRI associated with ≥1 laboratory-confirmed 
pathogen(s), impute the subject did not have a CSRI associated with ≥1 laboratory-
confirmed pathogen(s) 
• 
Population-level summary:  
• 
rate ratio, i.e. the ratio of the rate of having a CSRI with ≥1 laboratory-confirmed 
pathogen(s)  in subjects treated with RTB101 compared to the rate of having a CSRI with 
≥1 laboratory-confirmed pathogen(s) in subjects treated with placebo by the Week 16  
visit 
4. The estimand for the secondary objective “To determine if RTB101 as compared to placebo 
decreases the percentage of subjects with severe symptoms due to clinically symptomatic 
respiratory illnesses through Week 16” is defined by the following: 
 
• 
Population:  
• 
Subjects in FAS population 
• 
Variable:  


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• 
Occurrence a CSRI with severe symptoms by the Week 16 visit 
• 
Intercurrent events:  
• 
If a subject discontinues study prematurely due to an RTI AE or RTI SAE and the subject 
did not meet the definition of a CSRI with severe symptoms, assume the subject 
experienced a CSRI with severe symptoms 
• 
If a subject discontinues study prematurely for any reason other than an RTI AE or RTI 
SAE and the subject did not meet the definition of a CSRI with severe symptoms, impute 
the subject did not have a CSRI with severe symptoms 
• 
If a subject completed the study, has intermittent missing eDIary data and the subject did 
not meet the definition of a CSRI with severe symptoms, impute the subject did not have 
a CSRI with severe symptoms 
• 
Population-level summary:   
• 
odds ratio, i.e. the ratio of the odds of having a CSRI with severe symptoms in subjects 
treated with RTB101 compared to the odds of having a CSRI with severe symptoms in 
subjects treated with placebo by the Week 16  visit 
5. The estimand for the secondary objective “To determine if RTB101 as compared to placebo 
decreases time to alleviation of moderate and severe respiratory illness symptoms through Week 
16” is defined by the following: 
 
• 
Population:  
• 
Subjects in FAS population 
• 
Variable:  
• 
Time to alleviation of moderate and severe CSRI symptoms 
• 
Intercurrent events:  
• 
If a subject discontinues study prematurely due to an RTI AE or RTI SAE and time to 
alleviation of moderate and severe respiratory illness symptoms has not been reached, 
subject is censored on the date of last eDiary entry  
• 
If a subject discontinues study prematurely for any other reason than an RTI AE or RTI 
SAE and time to alleviation of moderate and severe respiratory illness symptoms has not 
been reached, subject is censored on the date of last eDiary entry 
• 
If a subject completed the study and has intermittent missing eDiary data and time to 
alleviation of moderate and severe respiratory illness symptoms has not been reached, 
subject is censored on the date of last eDiary entry 
• 
Population-level summary:   


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• 
hazard ratio, i.e. the hazard rate of alleviation of moderate and severe respiratory illness 
symptoms in subjects treated with RTB101 divided by the hazard rate of alleviation of 
moderate and severe respiratory illness symptoms in subjects treated with placebo by the 
Week 16  visit 
 
Primary Efficacy Endpoint Analysis 
 
Primary Analysis of the Primary Endpoint  
The primary efficacy endpoint is the percentage of subjects with at least one CSRI, with or without an 
associated laboratory-confirmed pathogen, beginning at least 3 days after the start of study drug 
treatment through Week 16 (H1).  
The primary efficacy endpoint will be analyzed through a logistic regression model to obtain an estimate 
of the population odds ratio, i.e. the odds of having a CSRI in subjects treated with RTB101 compared to 
the odds of having a CSRI in subjects treated with placebo and its associated confidence interval. The 
logistic regression model will be adjusted for factors that are known to be prognostic of outcome, 
specifically age (continuous covariate), clinical frailty score (ordinal covariate), medical history of diabetes 
mellitus type 2 (T2DM, Y/N), congestive heart failure (CHF, Y/N) asthma (Y/N), and receipt of current 
season influenza vaccination (Y/N).  Presence or absence of asthma will be obtained from medical history 
records and not the stratification level entered at baseline.   
Analysis of the primary efficacy endpoint will be based on the estimand for the primary objective 
described above. 
Summary statistics will be presented along with a full data listing 
 
Sensitivity and Supplemental Analyses of the Primary Endpoint  
The following sensitivity analyses are planned to provide evidence in support of the strength of treatment 
of RTB 101 10 mg as compared to placebo.   
9.3.2.1. 
Sensitivity Analyses  
For placebo subjects who discontinue study prematurely for any reason other than an RTI AE or RTI SAE  
and/or had ≥7 consecutive days of missing eDiary entries, and did not meet the definition of a CSRI, 
impute with CSRI odds from the placebo group, adjusted for the duration of missing eDiary entries 
through Week 16 in the placebo arm (as described in (1) below).  For RTB101 subjects who discontinue 
study prematurely for any reason other than an RTI AE or RTI SAE and/or had ≥7 consecutive days of 
missing eDiary entries, and did not meet the definition of a CSRI, impute with CSRI odds that vary 
between that of the RTB101 odds adjusted for the duration of missing eDiary entries in the RTB101 arm, 
and the placebo odds. Subjects who discontinued study prematurely due to an RTI AE or RTI SAE will 
continue  to be imputed as having a CSRI.The maximum odds that yields statistically significant results 
will be computed and reported as the “tipping point”.   
Adjustment for the duration of missing eDiary entries in each arm will be calculated as follows: 
For each arm, 
(1) Among subjects who have missing eDiary data through the Week 16 Visit, add the number of 
days in which subjects did not enter data in their eDiary, including only the periods that have ≥7 


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consecutive days of missing eDiary entries i.e. exclude days in which eDiary data was not 
entered between 1-6 days only.   For subjects who discontinue study prematurely, the duration of 
missing eDiary entries will be calculated as the number of days from the last eDiary entry until 16 
weeks after the start of study drug treatment. 
(2) Add the number of days missed  in (1) for all subjects.  
(3) Calculate the total number of expected eDiary entry days for subjects with missing data, i.e. 
number of subjects with missing data multiplied by 111 days (16 weeks).    
(4) Divide (2) by (3).   
The result obtained in (4) provides the  adjustment factor used to adjust for the duration of 
missing eDiary entries in each arm. 
1. For placebo subjects who discontinue study prematurely for any reason other than an RTI AE or 
RTI SAE, and did not meet the definition of  a CSRI, impute with CSRI odds from the placebo 
group, adjusted for the duration of missing eDiary entries in the placebo arm.   For RTB101 
subjects who discontinue study prematurely for any reason other than an RTI AE or RTI SAE, 
and did not meet the definition of a CSRI, impute with CSRI odds that vary between that of the 
RTB101 odds, adjusted for the duration of missing eDiary entries in the RTB101 arm,  and the 
placebo odds . Subjects who discontinued study prematurely due to an RTI AE or  RTI SAE will 
continue  to be imputed as having a CSRI. The maximum odds that yields statistically significant 
results will be computed and reported as the “tipping point”.  Adjustment for the duration of 
missing eDiary entries for each arm will be calculated in the same manner as described under 
Sensitivity Analysis 1 above. 
 
2. Conduct the same sensitivity analysis described in 1 above, for subjects with the following 
number of days with consecutive days of missing eDiary entries through the Week 16 visit: 
a. ≥14 consecutive days of missing eDiary 
b. ≥21 consecutive days of missing eDiary 
c. ≥28 consecutive days of missing eDiary 
d. ≥56 consecutive days of missing eDiary 
e. ≥84 consecutive days of missing eDiary 
Adjustment for the duration of missing eDiary entries for each arm will be calculated in the same 
manner as described under Sensitivity Analysis 1 above, with the following modifications:   
• 
for 3a, only count subjects that  have ≥14 consecutive days of missing eDiary entries 
i.e. exclude days in which eDiary data was not entered for 1-13 days when 
calculating the number of missed days 
• 
for 3b, only count subjects that ≥21 consecutive days of missing eDiary entries 
i.e. exclude days in which eDiary data was not entered for 1-20 days when 
calculating the number of missed days.      
Modify criteria for 3c-3e in a similar fashion. 
9.3.2.2. 
Supplemental Analyses and Summaries 
1. The primary analysis described in 9.3.1 above will be conducted in the Per Protocol (PP) population. 
2. The primary analysis described in 9.3.1 above9.3.1 above will be conducted in the subset of subjects 
who did not discontinue from the study prematurely and/or did not have ≥7 consecutive days of missing 
eDiary entries. (Completers Analysis 1) 


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3.. The primary analysis described in 9.3.1 above will be conducted in the subset of subjects who did not 
discontinue from the study prematurely. (Completers Analysis 2) 
4.. Summary statistics (n, mean, SD, median, quartiles, minimum, maximum) and corresponding box plots 
by treatment group will be provided for the number of subjects with any missing data due to intermittent 
missed eDiary entries and premature discontinuation from the study. The number of subjects with ≥7, 
≥14, ≥21, ≥28, ≥35, ≥42, ≥49, … ≥ 105 consecutive days of missing eDiary entries missing data will also 
be summarized in a similar manner.   
 
Analyses of Secondary Efficacy Endpoints  
 
Percentage of Subjects with One or More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
The percentage of subjects with CSRIs associated with ≥1 laboratory-confirmed pathogen(s) beginning at 
least 3 days after the start of study drug treatment through Week 16 (H2) as assessed by pre-specified 
clinical diagnostic criteria and respiratory pathogen PCR of nasopharyngeal swabs, sputum gram stain 
and culture, and/or RIDTs will be analyzed in the same manner as the primary efficacy analysis as 
described in 9.3.1  based on the estimand for the secondary objective corresponding to this endpoint 
described in 9.2.2 above. 
Laboratory results from a specimen obtained within 3 days before the CSRI start date through the CSRI 
end date will be used to determine if the CSRI is associated with ≥1 laboratory-confirmed pathogen. 
Laboratory confirmation includes a positive respiratory pathogen PCR of nasopharyngeal swabs, sputum 
gram stain and culture, and/or RIDT.  If multiple specimens are obtained for a particular CSRI, then any 
positive result will be counted as laboratory confirmation if it occurs within 3 days before the CSRI start 
date through the CSRI end date. A laboratory-confirmed CSRI may be associated with multiple 
pathogens. Note that organisms considered to identify a positive sputum specimen should meet standard 
microbiological laboratory criteria of  growing from a sputum specimen with > 25 WBC/hpf and < 10 
Squamous cells/ hpf, and they have matching morphology on gram stain and culture. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Clinically Symptomatic Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) 
The rate of CSRIs (with or without an associated laboratory-confirmed pathogen) beginning at least 3 
days after the start of study drug treatment through Week 16 (H3) will be analyzed based on the negative 
binomial distribution. The first 3 days of study drug treatment will not be included in determining the 
denominator of rate. 
A generalized linear model analysis will be conducted using the number of CSRIs per 16-week period 
(illnesses/16 weeks) as the dependent variable and will include treatment group, age (continuous 
covariate), Clinical Frailty Scale score (ordinal covariate), medical history of diabetes mellitus type 2  
(Y/N), medical history of asthma (Y/N) medical history of CHF (Y/N), and receipt of current season 
influenza vaccination (Y/N) as fixed effects.  


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The rate ratio (RR) (RTB101 dose group to placebo) of the treatment effect will be derived from the model 
along with the 95% 2-sided confidence interval (CI). Model-adjusted mean rates for each treatment group 
and their corresponding 95% 2-sided CI will also be calculated.  
The “log” link function will be used in the model and an offset term will be included to account for variable 
lengths of treatment exposure across the subjects.  The unadjusted rate of CSRI per subject through 
Week 16 will be calculated by summing the number of total CSRIs per subject through Week 16 within 
each treatment group. 
Analysis of  this endpoint will be based on the estimand for the secondary objective corresponding to this 
endpoint described in 9.2.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Clinically Symptomatic Respiratory Illness Associated with ≥1 Laboratory-
confirmed Pathogen(s) 
The rate of CSRIs associated with ≥1 laboratory-confirmed pathogen(s) beginning at least 3 days after 
the start of study drug treatment through Week 16 (H4) as assessed by pre-specified clinical diagnostic 
criteria and respiratory pathogen PCR of nasopharyngeal swabs, sputum gram stain and culture, and/or 
RIDTs  will be analyzed in the same manner as described in 9.4.2 above, based on the estimand for the 
secondary objective corresponding to this endpoint described in 9.2.2 above. Section 9.4.1 describes 
which laboratory result will be used to determine if the CSRI is associated with ≥1 laboratory-confirmed 
pathogen. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Time to Alleviation of Moderate and Severe Respiratory Illness Symptoms  
The time to alleviation of moderate and severe symptoms due to a CSRIs beginning at least 3 days after 
the start of study drug treatment through Week 16 (H5) will be analyzed as a secondary endpoint. 
The time to alleviation of moderate or severe symptoms is defined as the time when all of 6 respiratory 
symptoms (runny nose, sneezing, stuffy nose, sore throat, hoarseness, or cough) and 3 general 
symptoms (headache, feverishness/chills or loss of appetite) have been assessed by the patient as 
Absent or Mild in the patient eDiary from the earliest start date of any moderate or severe symptoms 
associated with the CSRI among all subjects with ≥1 CSRI through the Week 16 visit. For subjects with 
>1 CSRI, the longest time to alleviation of moderate or severe symptoms among the CSRIs will be used 
for the analysis. 
The time to alleviation of moderate and severe symptoms (days) = (earliest date all symptoms due to a 
CSRI are Absent or Mild – earliest start date among all moderate or severe symptoms) +1 
Risk set: Subjects who have a ≥1 CSRI. 
Time origin: Earliest start date of moderate or severe symptom associated with a CSRI. 
For subjects who were not observed to have an alleviation of their moderate or severe symptoms, time to 
alleviation of moderate or severe symptoms will be censored on the date of last eDiary entry.  


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The point estimate of the hazard ratios and the associated 95% confidence intervals for RTB101 versus 
placebo will be obtained using the Cox proportional hazards regression model with fixed effects for 
treatment group, age (continuous covariate), Clinical Frailty Scale score (ordinal covariate), medical 
history of diabetes mellitus type 2  (Y/N), medical history of asthma (Y/N) and medical history of CHF 
(Y/N) as covariates. An approximate Chi-square test based on Wald statistic will be used to compare 
treatment groups.  
Summary statistics and associated survival curves (Kaplan-Meier estimates) will be presented along with 
a full data listing by treatment group. 
 
Percentage of Subjects with Severe Symptoms due to Clinically Symptomatic 
Respiratory Illnesses  
The percentage of subjects with severe symptoms due to CSRIs beginning at least 3 days after the start 
of study drug treatment through Week 16 (H6) will be analyzed in the same manner as the primary 
efficacy endpoint, as described in 9.3.1 above based on the estimand for the secondary objective 
corresponding to this secondary endpoint as described in 9.2.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Clinically Symptomatic Respiratory Illnesses Associated with Specific 
Laboratory-confirmed Viruses 
A comparison of the rate of clinically symptomatic respiratory illnesses associated with specific laboratory-
confirmed viruses (coronaviruses, hMPV, HRV/enterovirus, adenovirus, influenza A and B virus, 
parainfluenza viruses, and RSV) beginning at least 3 days after the start of study drug treatment through 
Week 16 as assessed by respiratory pathogen PCR of nasopharyngeal swabs and/or RIDTs is not 
powered to demonstrate a pre-specified treatment effect. This endpoint will be analyzed in the same 
manner as described in  9.4.2 above. However, there will be no formal statistical tests conducted and no 
p-values will be presented. To demonstrate trends consistent with the primary endpoint for the pre-
specified laboratory-confirmed viruses, the estimated rate of the laboratory-confirmed viruses and 
associated CIs will be presented by treatment arm.  
 
 
Analyses of Exploratory Efficacy Endpoints 
 
Rate of All Laboratory-confirmed Viral Infections with or without Symptoms 
The rate of all laboratory-confirmed viral infections with or without symptoms beginning at least 3 days 
after the start of study drug treatment through Week 16 as assessed by respiratory pathogen PCR of 
nasopharyngeal swabs and/or RIDTs (obtained during episodes of clinically symptomatic respiratory 
illnesses) and/or respiratory pathogen PCR of mid-turbinate swabs (obtained at required clinical visits 
even in the absence of symptoms) will be analyzed in the same manner as described in  9.4.2 above. 
All positive results from specimens (respiratory pathogen PCR of nasopharyngeal swabs or midturbinate 
swabs and/or RIDT)  collected at least 3 days after the start of study drug treatment through Week 16, 
which may or may not be associated with a CSRI, will count as laboratory-confirmed viral infections (both 
symptomatic and asymptomatic).  


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Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of All-cause Hospitalizations 
The rate of all-cause hospitalizations beginning at least 3 days after the start of study drug through Week 
16 (H7) will be analyzed in the same manner as described in  9.4.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Hospitalizations Associated with RTIs 
The rate of hospitalizations associated with RTIs beginning at least 3 days after the start of study drug 
through Week 16 will be analyzed in the same manner as described in  9.4.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of All-cause Emergency Room Visits 
The rate of all-cause Emergency Room (ER) visits beginning at least 3 days after the start of study drug 
through Week 16 will be analyzed in the same manner as described in  9.4.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Emergency Room Visits with RTIs 
The rate of ER visits associated with RTIs beginning at least 3 days after the start of study drug treatment 
through Week 16 will be analyzed in the same manner as described in  9.4.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of All-cause Urgent Care Clinic Visits for Clinically Symptomatic Respiratory 
Illness 
The rate of all-cause urgent care clinic for clinically symptomatic respiratory illness visits beginning at 
least 3 days after the start of study drug treatment through Week 16  will be analyzed in the same manner 
as described in  9.4.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of All-cause Urgent Care Clinic Visits 
The rate of all-cause urgent care clinic visits beginning at least 3 days after the start of study drug through 
Week 16 will be analyzed in the same manner as described in  9.4.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of All-cause Admissions to Skilled Nursing Facilities 
The rate of all-cause admissions to skilled nursing facilities beginning at least 3 days after the start of 
study drug through Week 16 will be analyzed in the same manner as described in 9.4.2 above  
Summary statistics will be presented along with a full data listing by treatment group. 


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Hospitalization Length of Stay Associated with RTIs 
Total hospitalization length of stay associated with RTIs beginning at least 3 days after the start of study 
drug treatment through Week 16 will be analyzed as an exploratory endpoint.  
Total hospitalization length of stay associated with RTIs will consist of the total duration of hospitalizations 
associated with RTIs for each subject starting between 3 days after the start of study drug and prior to 
Week 16. Duration of a hospital stay is defined as (hospital discharge date –hospital admission date) +1. 
The analysis will be performed using the Analysis of Covariance model (PROC MIXED) with fixed effects 
for treatment group, age (continuous covariate), Clinical Frailty Scale score (ordinal covariate), medical 
history of diabetes mellitus type 2 (Y/N), medical history of asthma (Y/N), medical history of CHF (Y/N), 
and receipt of current season influenza vaccination (Y/N) as covariates. The least squares (LS) means, 
differences between LS means, a 95% 2-sided CLs for the difference and the p-values from model effects 
will be reported for overall treatment to evaluate the treatment effect. 
Summary statistics, including Least Squares Mean and standard error for each treatment and the 
treatment difference  will be presented along with a full data listing by treatment group. 
 
Percentage of Subjects with 1 or more Clinically Symptomatic Respiratory Illnesses 
(with or without an Associated Laboratory-confirmed Pathogen) through Week 20 
The percentage of subjects with 1 or more CSRIs (with or without an associated laboratory-confirmed 
pathogen) beginning at least 3 days after the start of study drug treatment through Week 20 (H9) will be 
analyzed in the same manner as the primary efficacy analysis as described in 9.3.1 above. 
Summary statistics will be presented along with a full data listing by treatment group.  
 
Percentage of Subjects with 1 or more Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) through Week 20 
The percentage of subjects with 1 or more CSRIs associated with ≥1 laboratory-confirmed pathogen(s) 
beginning at least 3 days after the start of study drug treatment through Week 20 as assessed by pre-
specified clinical diagnostic criteria and respiratory pathogen PCR of nasopharyngeal swabs, sputum 
gram stain and culture, and/or RIDTs will be analyzed in the same manner as the primary efficacy 
analysis as described in 9.3.1 above. Section 9.4.1 describes which laboratory result will be used to 
determine if the CSRI is associated with ≥1 laboratory-confirmed pathogen. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
All-cause Hospitalization Length of Stay 
 All-cause hospitalization total length of stay beginning at least 3 days after the start of study drug through 
Week 16 will be analyzed in the same manner described in 9.5.9 above.   
Summary statistics will be presented along with a full data listing by treatment group. 


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Change from Baseline in EQ-5D-5L Scores during All Clinically Symptomatic 
Respiratory Illness Episodes and at Week 16   
The change from Baseline in HRQoL as assessed by EQ-5D-5L Visual Analog Scale (VAS) scores during 
all CSRI episodes beginning at least 3 days after the start of study drug treatment through Week 16 and 
at Week 16 will be analyzed using a Mixed Model Repeated Measure model (PROC MIXED). The model 
will include the change from Baseline in EQ-5D-5L (measured each day during a CSRI event and at the 
Week 16 visit) as the dependent variable and will include patient as a random effect, and fixed effects of 
treatment group, Baseline EQ-5D-5L, time (study day the measure was taken), and a treatment-by-time 
interaction.  
The Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. An 
unstructured (general) covariance structure will be assumed initially to model the within-subject errors; 
however, other covariance structures will be tested and may be used in the final model if a better fit is 
evident. The least squares (LS) means, differences between LS means, a 95% 2-sided CLs for the 
difference and the p-values from model effects will be reported for overall treatment to evaluate the 
treatment effect. 
Summary statistics for the VAS and individual items and associated boxplot for VAS  will be presented 
along with a full data listing of EQ-5D-5L data by treatment group. 
 
Percentage of Subjects with One or More Clinically Symptomatic Respiratory Illnesses 
(with or without an Associated Laboratory-confirmed Pathogen) through Week 16 who 
are ≥85 years of age 
The percentage of subjects with one or more CSRIs beginning at least 3 days after the start of study drug 
treatment through Week 16 who are ≥85 years of age will be analyzed in the same manner as the primary 
efficacy analysis as described in 9.3.1 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Clinically Symptomatic Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) through Week 16 in Subjects who are ≥85 years of 
age 
The rate of CSRIs (with or without an associated laboratory-confirmed pathogen) beginning at least 3 
days after the start of study drug treatment through Week 16 in subjects who are ≥85 years of age will be 
analyzed in the same manner as described in  9.4.2 above. Summary statistics will be presented along 
with a full data listing by treatment group. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Percentage of Subjects with One or More Clinically Symptomatic Respiratory Illnesses 
(with or without an Associated Laboratory-confirmed Pathogen) through Week 16 who 
have a Medical History of Asthma   
The percentage of subjects with one or more CSRIs at least 3 days after the start of study drug treatment 
through Week 16 who have a medical history of asthma  will be analyzed in the same manner as the 
primary efficacy analysis as described in 9.3.1 above. 


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Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Clinically Symptomatic Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) through Week 16 in Subjects who have a Medical 
Hstory of Asthma 
The rate of CSRIs (with or without an associated laboratory-confirmed pathogen) beginning at least 3 
days after the start of study drug treatment through Week 16 in subjects who have a medical history of 
asthma will be analyzed in the same manner as described in 9.4.2 above. Summary statistics will be 
presented along with a full data listing by treatment group. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Percentage of Subjects with One or More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) through Week 16 who are ≥85 
years of age 
The percentage of subjects with one or more CSRIs associated with ≥1 laboratory-confirmed pathogen(s) 
at least 3 days after the start of study drug treatment through Week 16 who are ≥85 years of age will be 
analyzed in the same manner as the primary efficacy analysis as described in 9.3.1 above. Section 9.4.1 
describes which laboratory result will be used to determine if the CSRI is associated with ≥1 laboratory-
confirmed pathogen. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Percentage of Subjects with One or More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) through Week 16 who have a 
Medical History of Asthma   
The percentage of subjects with one or more CSRIs associated with ≥1 laboratory-confirmed pathogen(s) 
at least 3 days after the start of study drug treatment through Week 16 who have a medical history of 
asthma will be analyzed in the same manner as the primary efficacy analysis as described in 9.3.1 above. 
Summary statistics will be presented along with a full data listing by treatment group. Section 9.4.1 
describes which laboratory result will be used to determine if the CSRI is associated with ≥1 laboratory-
confirmed pathogen. 
 
Rate of Clinically Symptomatic Respiratory Illnesses Associated with ≥1 Laboratory-
confirmed Pathogen(s) through Week 16 in Subjects who are ≥85 years of age 
The rate of CSRIs associated with ≥1 laboratory-confirmed pathogen(s) in subjects who are ≥85 years of 
age beginning at least 3 days after the start of study drug treatment through Week 16 will be analyzed in 
the same manner as described in  9.4.2 above.  Section 9.4.1 describes which laboratory result will be 
used to determine if the CSRI is associated with ≥1 laboratory-confirmed pathogen. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Clinically Symptomatic Respiratory Illnesses Associated with ≥1 Laboratory-
confirmed Pathogen(s) through Week 16 in Subjects with a Medical History of Asthma 
The rate of CSRIs associated with ≥1 laboratory-confirmed pathogen(s) in subjects with a medical history 
of asthma beginning at least 3 days after the start of study drug treatment through Week 16 will be 


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analyzed in the same manner as described in  9.4.2 above. Section 9.4.1 describes which laboratory 
result will be used to determine if the CSRI is associated with ≥1 laboratory-confirmed pathogen. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Rate of Asthma Exacerbations through Week 16 in Subjects with a Medical History of 
Asthma 
The rate of asthma exacerbations, defined as deterioration of asthma symptoms that requires treatment 
with systemic steroids, beginning at least 3 days after the start of study drug treatment through Week 16 
in subjects with a medical history of asthma will be analyzed in the same manner as described in 9.4.2 
above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Percentage of Subjects with 1 or more Asthma Exacerbation through Week 16 in 
Subjects with a Medical History of Asthma 
The percentage of subjects with 1 or more asthma exacerbation defined as deterioration of asthma 
symptoms that requires treatment with systemic steroids beginning at least 3 days after the start of study 
drug treatment through Week 16 in subjects with a medical history of asthma will be analyzed in the same 
manner as the primary efficacy analysis as described in 9.3.1 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Change from Baseline to Weeks 4 and 16 in Biomarkers in Whole Blood 
Blood samples will be obtained for exploratory biomarker analyses, including RNA expression in whole 
blood and soluble biomarkers in serum, in all subjects at the Baseline and Week 16 visit, and for subjects 
in the pharmacokinetic analysis subset (approximately 400 subjects) at the Week 4 or Week 6 visit (4 
hours after study drug administration). The RNA expression to be measured may include:  
• 
IFNG  
• 
IFI44L 
• 
IFIT5 
• 
IFIH1 
• 
MSR1 
• 
IFIT1 
• 
IFIT2 
• 
HERC5 
• 
MX1 
• 
IFITM3 
• 
OAS2 
• 
IFIT3 
• 
RSAD2 
• 
ISG15 
• 
IFI27 
• 
IFI6 
• 
STAT2 


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• 
STAT1 
• 
SOCS3 
• 
IRF7 
• 
OASL 
• 
OAS3 
The list may be changed or expanded further, as it is recognized that more relevant or novel biomarkers 
may be discovered during the conduct of the study. 
Summary statistics of the biomarkers by clinical visit and their associated change from baseline values 
will be presented along with a full data listing by treatment group. 
 
Rate of Urinary Tract Infections (UTIs) Reported as Adverse Events 
The rate of UTIs beginning at least 3 days after the start of study drug treatment through Week 16 (H8)  
reported as adverse events will be analyzed in the same manner as described in  9.4.2 above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Percentage of Subjects with One or more UTIs Reported as Adverse Events. 
The percentage of subjects with 1 or more UTIs reported as adverse events beginning at least 3 days 
after the start of study drug treatmentthrough Week 16 will be analyzed in the same manner as the 
primary efficacy endpoint analysis described in 9.3.1 above.  
Summary statistics will be presented along with a full data listing by treatment group. 
 
Percentage of Subjects with Expanded-Definition Clinically Symptomatic Respiratory 
Illness (with or without an associated laboratory-confirmed pathogen) by Week 16 
Percentage of subjects with expanded-definition clinically symptomatic respiratory illness (with or without 
an associated laboratory-confirmed pathogen) beginning at least 3 days after the start of study drug 
treatment by Week 16 will be analyzed as an exploratory analysis. Expanded-definition clinically 
symptomatic respiratory illness is defined similarly to the primary endpoint except the general symptoms 
of body aches and lack of energy will be included in the list of general symptoms for the purpose of 
identifying a case of an expanded CSRI. 
The analysis method will be the same as the primary endpoint efficacy analysis as described in 9.3.1 
above. 
Summary statistics will be presented along with a full data listing by treatment group. 
 
Additional Sensitivity/Exploratory Analyses 
 
Percentage of Subjects with One or More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) Including Assessment using 
Midturbinate Swabs 
The percentage of subjects with CSRIs associated with ≥1 laboratory-confirmed pathogen(s) beginning at 
least 3 days after the start of study drug treatment through Week 16 as assessed by pre-specified clinical 
diagnostic criteria and respiratory pathogen PCR of nasopharyngeal swabs or midturbinate swabs, 


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sputum gram stain and culture and/or RIDTs will be analyzed in the same manner as the primary efficacy 
analysis as described in 9.3.1 above.  
Laboratory results from a specimen obtained within 3 days before the CSRI start date through the CSRI 
end date will be used to determine if the CSRI is associated with ≥1 laboratory-confirmed pathogen. 
Laboratory confirmation includes a positive respiratory pathogen PCR of nasopharyngeal swabs, sputum 
gram stain and culture, RIDT, and/or respiratory pathogen PCR of midturbinate swabs.  If multiple 
specimens are obtained for a particular CSRI, then any positive result will be counted as laboratory 
confirmation if it occurs within 3 days before the CSRI start date through the CSRI end date. A laboratory-
confirmed CSRI may be associated with multiple pathogens. 
 
Rate of Clinically Symptomatic Respiratory Illness Associated with ≥1 Laboratory-
confirmed Pathogen(s) Including Assessment using Midturbinate Swabs 
The rate of CSRIs associated with ≥1 laboratory-confirmed pathogen(s) beginning at least 3 days after 
the start of study drug treatment through Week 16 as assessed by pre-specified clinical diagnostic criteria 
and respiratory pathogen PCR of nasopharyngeal swabs or midturbinate swabs, sputum gram stain and 
culture and/or RIDTs will be analyzed in the same manner as described in 9.4.2 above. 9.6.1 describes 
which laboratory result will be used to determine if the CSRI is associated with ≥1 laboratory-confirmed 
pathogen. 
Summary statistics will be presented along with a full data listing by treatment group. 


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Safety 
Safety analyses will be conducted on the Safety Set (SAF) and will be assessed on the basis of adverse 
event (AE), clinical laboratory data, ECG parameters, physical examinations, and vital signs.  
 
Extent of Exposure 
Duration of exposure is defined as (Date of Last Dose – Date of First Dose) +1. If date of last dose is 
unknown then the date of last clinical visit no later than the Week 16 Visit will be used to impute the date 
of last dose. If there are temporary dose interruptions based on the data from the eCRF, then only the 
periods of time when study drug interruption did not occur will be used to calculate the duration of 
exposure. Duration of exposure will be summarized using descriptive statistics by treatment group. The 
duration of exposure (in days) will also be categorized as follows: <7, 7-<14, 14-<28, 28-<42, 42-<46, 56-
<70, 70-<84, 84-<98, 98-<112, ≥112, and tabulated by treatment group.. 
A listing including study drug administration information from the eDiary will be presented. 
 
Treatment Compliance  
Treatment compliance will be summarized as the number (%) of subjects indicated as compliant (>=80%) 
on the eCRF by treatment group. 
Subjects are expected to take 1 tablet of study medication once per day through the Week 16 visit.   
 
Adverse Events  
An adverse event is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. All adverse events (AEs) will be coded using the MedDRA 
version 22.0 or higher. Only treatment-emergent adverse events, defined as any adverse events that start 
or increase in intensity on or after the first dose of double-blind treatment (Study Day 1), were collected in 
this study. The following listings of AEs will be provided by subjects:  
• 
All AEs, 
• 
Serious adverse events (SAEs) 
• 
AEs leading to death 
• 
AEs leading to study withdrawal 
• 
AEs leading to study drug discontinuation 
• 
Severe AEs 
• 
Study drug related AEs 
• 
Study drug related SAEs  
Adverse Events will be included in summary tables by treatment received. An overall summary table of 
AEs through Week 20 will be produced for the following categories:  


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• 
Any AE 
• 
Grade 1 (Mild) AEs, Grade 2 (Moderate) AEs,  Grade 3 (Severe) AEs, Grade 4 (Severe and Life 
Threatening), and Grade 5 (Fatal) AEs 
• 
Study drug-related AEs 
• 
Serious AEs  
• 
Study drug-related Serious AEs 
• 
AEs leading to permanent study drug discontinuation 
• 
AEs leading to study discontinuation  
• 
AEs leading to death  
All AEs will be classified by SOC and PT. Frequency count of AEs, the number of unique subjects 
experiencing an AE, percentage of unique subjects experiencing an AE and total number of events will be 
tabulated by treatment. For the number of unique subjects reporting, if a subject reported more than one 
AE that was coded to the same SOC or PT, the subject will be counted only once for that specific SOC or 
PT.  
The following summaries of AEs will also be provided: 
• 
AEs by SOC and PT  
• 
Treatment-related AEs by SOC and PT 
• 
AEs by SOC, PT and maximum severity 
• 
AEs by SOC, PT and causality relationship 
• 
Serious AEs by SOC and PT 
• 
Serious treatment-related AEs by SOC and PT 
• 
AEs leading to study withdrawal by SOC and PT 
• 
TEAEs leading to study drug discontimuation by SOC and PT 
• 
AEs leading to death by SOC and PT 
For AEs presented by relationship to study treatment, the strongest relationship to study treatment(s) 
during the clinical trial will be presented for each subject if coded to the same SOC or PT. For AEs 
presented by severity, the worst severity during the clinical trial will be presented for each subject if coded 
to the same SOC or PT. If either relationship or severity is missing, then the strongest relationship 
(related) or worst severity (severe) will be assigned. 


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Laboratory Evaluations 
Blood samples for hematology, chemistry, and urine samples for urinalysis are to be collected at 
screening, Baseline,  Weeks 2, 4, 6, 8,  12, 16, and 20 visits. All results will be provided using 
International System of Units (SI). 
Descriptive statistics for hematology, chemistry, and urine will be provided for each test parameter and for 
change from baseline summarized by visit and treatment grou. Shift tables (i.e., low-normal-high at 
Baseline versus low-normal-high at each post-baseline visit in a 3-by-3 contingency table) will be 
provided for hematology, biochemistry, and urine to assess changes from Baseline in laboratory values 
by visit and by treatment group. Listings of abnormal laboratory values, defined as values that are either 
<0.5x lower limit of normal (LLN) or >2x upper limit of normal (ULN) for each hematology and chemistry 
test parameter will be provided. 
Boxplots for the change from baseline values for each post-baseline visit for hematology, chemistry and 
urinalysis (numerical results only) test parameters will be generated by treatment group, with LLN, ULN, 
0.5x LLN and 2x ULN values plotted for each test parameter. 
Separate listings of all laboratory data will be provided for all laboratory evaluations (hematology, 
biochemistry, and urinalysis). 
 
Vital Signs  
Vital signs consist of temperature; respiratory rate; heart rate, and seated Blood Pressure. Vital signs are 
collected at Screening, Baseline, Weeks 2, 4, 6, 8, 12, 16, and 20 visits. 
Observed values at each visit and changes from Baseline to each post-baseline visit in vital signs will be 
summarized by visit and treatment group using descriptive statistics. Shift tables (i.e., low-normal-high at 
Baseline versus low-normal-high at each post-baseline visit in a 3-by-3 contingency table) will be 
provided to assess changes from Baseline in each vital sign value by visit and treatment group.  
All vital signs will be provided in subject data listings. 
 
ECG 
A 12-lead ECG will be performed during the study at Screening, Baseline, Week 4, Week 8, Week 12, 
and Week 16.  
Observed values at each visit and changes from Baseline to each post-baseline visit in ECG parameter 
will be summarized by visit and treatment group using descriptive statistics. A summary of abnormal 
results for QTc, QTcB, and QTcF. Abnormal values will be categorized as >450 msec, >480 msec, >500 
msec, change from baseline >30 msec, and/or change from baseline >60 msec. 
Listings will be provided for all ECG parameters and interpretive results. 
 
Physical Examination 
A complete physical examination will be done at Screening, Week 16, and Week 20. A targeted physical 
exam of at least oral cavity, skin, heart and lungs will be done at all other visits. Listings will be provided 
for all physical exams. 


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Interim Analyses 
There is no planned interim analysis. 


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Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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Changes from Analysis Planned in Protocol 
The following changes from the analyses planned in the protocol were included in this SAP: 
(1) The subgroup analysis by gender was added (see Section 7.6 above)  to the list of 
subpopulations specified in Section 9.4.4.2 of the protocol. 
(2) In Section 9.4 of the protocol, it was stated that no imputation for missing data will be done for the 
primary analysis of the primary efficacy endpoint.  This was modified such that subjects who 
discontinued study prematurely due to an RTI AE or RTI SAE will be imputed to have 
experienced a CSRI (see Section 7.3 above), 
(3) An additional factor, i.e. receipt of current season influenza vaccination (Y/N), was added (see 
Section 9.3.1 above) to the logistic regression model specified for the primary analysis of the 
primary efficacy endpoint specified in Section 9.4.1 the protocol. 
(4) In Section 9.4.1 of the protocol, a gate-keeping strategy for testing multiple endpoints for a 
primary family (F1), secondary family (F2) and exploratory family (F3) of endpoints was specified.   
The testing strategy was modified such that families of endpoints will no longer be defined; 
instead a set of 9 endpoints will be tested using a fixed sequence gate-keeping strategy, as 
specified in Section 9.1 above. 
(5) Supplemental analyses for the Completers 1 and Completers 2 populations described in Section 
9.3.2.2 above were added. 
(6) Analyses of 4 endpoints not specified in the protocol were included here (see Sections 9.5.26, 
9.5.27, 9.6.1 and 9.6.2 above)  as exploratory and/or sensitivity analyses, specifically the 
analyses of 
a. the percentage of subjects with expanded-definition CSRIs (with or without an associated 
laboratory-confirmed pathogen) beginning at least 3 days after the start of study drug 
treatment by Week 16,  
b. the rate of expanded-definition CSRIs (with or without an associated laboratory-confirmed 
pathogen) beginning at least 3 days after the start of study drug treatment by Week 16,   
c. the percentage of subjects with CSRIs associated with ≥1 laboratory-confirmed pathogen(s) 
beginning at least 3 days after the start of study drug treatment through Week 16 which 
includes assessment by respiratory pathogen PCR of midturbniate swabs, aside from the 
assessments based on  the respiratory pathogen PCR of nasopharyngeal swabs, sputum 
gram stain and culture and/or RIDTs, to determine laboratory confirmation of pathogens, and   
d. the rate of CSRIs associated with ≥1 laboratory-confirmed pathogen(s) beginning at least 3 
days after the start of study drug treatment through Week 16 which includes assessment by 
respiratory pathogen PCR of midturbniate swabs, aside from the assessments based on  the 
respiratory pathogen PCR of nasopharyngeal swabs, sputum gram stain and culture and/or 
RIDTs, to determine laboratory confirmation of pathogens. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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Programming Considerations 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 (SAS Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure output will 
adhere to the following specifications.   
 
General Considerations 
• 
One SAS program can create several outputs, or a separate SAS program will be created for each 
output. 
• 
One output file can contain several outputs or each output will be stored in a separate file. 
• 
Output files will be delivered in Word format or portable document format pdf. 
• 
Numbering of TFLs will follow ICH E3 guidance  
 
Table, Listing, and Figure Format 
 
General 
• All TFLs will be produced in landscape format on American letter size, unless otherwise specified.  
• All TFLs will be produced using the Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities. 
• The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
• Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• TFLs will be in black and white (no color), unless otherwise specified 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
• Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
• 
All output should have the following header at the top left of each page: 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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• 
resTORbio, Inc. Protocol RTB-101-204 (Syneos Health study number 7001371) 
• Draft/Final Run <date> 
• All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. 
 
Display Titles 
• Each TFL are identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination. A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the 
•  Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial upper-
case characters.  
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column (if applicable). P-values may be presented under 
the total column or in separate p-value column (if applicable). Within-treatment comparisons may 
have p-values presented in a row beneath the summary statistics for that treatment. 
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
• The order of treatments in the tables and listings will be Placebo first in the case of placebo 
controlled studies and Active comparators first in the case of active comparator trials, followed by a 
total column (if applicable). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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Body of the Data Display 
13.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
13.2.5.2. 
Table Conventions 
• Units will be included where available 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
• An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more subjects.  
• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0.  A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
the treatment group who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places.  
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment group in decreasing order, assuming all terms are coded. Within 
the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), 
and adverse events (by preferred term) are displayed in decreasing order. If incidence for more 
than 1 term is identical, they should then be sorted alphabetically. Missing descriptive statistics or 
p-values which cannot be estimated are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
• For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont.)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
13.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• Units will be included where available 
13.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, clinical visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page.  
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures, or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and  Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output.”   


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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Index of Tables 
Table Number 
Name 
Analysis Set 
14.1.1 
Subject Disposition 
Screening Set 
 
 
 
14.1.2.1 
Major Protocol Deviations 
Randomized Set 
14.1.2.2 
Reasons for Exclusion from Analysis Sets 
Randomized Set 
 
 
 
14.1.3.1.1 
Subject Demographic and Baseline Characteristics 
Randomized Set 
14.1.3.1.2 
Subject Demographic and Baseline Characteristics 
Safety Set 
14.1.3.1.3 
Subject Demographic and Baseline Characteristics 
Full Analysis Set 
14.1.3.1.4 
Subject Demographic and Baseline Characteristics 
Per Protocol Set 
 
 
 
14.1.3.2.1 
Baseline Disease Characteristics 
Randomized Set 
14.1.3.2.2 
Baseline Disease Characteristics 
Safety Set 
14.1.3.2.3 
Baseline Disease Characteristics 
Full Analysis Set 
14.1.3.2.4 
Baseline Disease Characteristics 
Per Protocol Set 
 
 
 
14.1.3.3 
Medical History 
Safety Set 
 
 
 
14.1.4.1 
Prior Medications 
Safety Set 
14.1.4.2 
Concomitant Medications 
Safety Set 
 
 
 
14.1.5 
Treatment Compliance 
Safety Set 
 
 
 
14.2.1.1.1 
Primary Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Logistic Regression 
Analysis 
Full Analysis Set 
14.2.1.1.2 
Sensitivity Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Tipping Point Analyses 
Full Analysis Set 
 
14.2.1.1.3 
Supplemental Analysis: Percentage of Subjects with One 
or More Clinically Symptomatic Respiratory Illnesses (with 
or without an  Associated Laboratory-confirmed 
Pathogen) Beginning at Least 3 Days After the Start of 
Study Drug Treatment through Week 16: Logistic 
Regression Analysis 
Per Protocol Set 
14.2.1.1.4 
Supplemental Analysis: Percentage of Subjects with One 
or More Clinically Symptomatic Respiratory Illnesses (with 
or without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Completers Analysis 1 
Full Analysis Set 
 
14.2.1.1.5 
Supplemental Analysis: Percentage of Subjects with One 
or More Clinically Symptomatic Respiratory Illnesses (with 
or without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Completers Analysis 2  
Full Analysis Set 
 


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Table Number 
Name 
Analysis Set 
14.2.1.1.6 
Summary of Subjects with Missing eDiary Data 
Full Analysis Set 
14.2.1.1.7 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 By Subject Age: Logistic 
Regression Analysis 
Full Analysis Set 
 
 
14.2.1.1.8 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Clinical Frailty Scale 
Score: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.1.1.9 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Medical History of 
Asthma: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.1.1.10 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Medical History of 
Congestive Heart Failure: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.1.1.11 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Pneumococcal 
Vaccination: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.1.1.12 
Subpopulation Analysis of the Percentage of Subjects 
with One or More Clinically Symptomatic Respiratory 
Illnesses (with or without an Associated Laboratory-
confirmed Pathogen) Beginning at Least 3 Days After the 
Start of Study Drug Treatment through Week 16 by 
Current Season Influenza Vaccination: Logistic 
Regression Analysis 
Full Analysis Set 
 
14.2.1.1.13 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses (with or 
without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Gender: Logistic 
Regression Analysis 
Full Analysis Set 
 
 
 
14.2.2.1.1 
Percentage of Subjects with One or More Clinically 
Symptomatic Respiratory Illnesses Associated with ≥1 
Laboratory-confirmed Pathogen(s) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16: Logistic Regression Analysis 
Full Analysis Set 


Statistical Analysis Plan for Interventional Studies 
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Table Number 
Name 
Analysis Set 
14.2.2.1.2 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Subject Age: Logistic 
Regression Analysis 
Full Analysis Set 
 
14.2.2.1.3 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Clinical Frailty Scale 
Score: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.2.1.4 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Medical History of 
Asthma: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.2.1.5 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Medical History of 
Congestive Heart Failure: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.2.1.6 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Pneumococcal 
Vaccination: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.2.1.7 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Current Season Influenza 
Vaccination: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.2.1.8 
Subgroup Analysis: Percentage of Subjects with One or 
More Clinically Symptomatic Respiratory Illnesses 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 by Gender: Logistic 
Regression Analysis 
Full Analysis Set 
14.2.2.2.1 
Rate of Clinically Symptomatic Respiratory Illnesses (with 
or without an Associated Laboratory-confirmed Pathogen) 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Generalized Linear Model 
Analysis 
Full Analysis Set 


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Table Number 
Name 
Analysis Set 
14.2.2.2.2 
Subgroup Analysis: Rate of Clinically Symptomatic 
Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16 by Subject Age: Generalized Linear Model 
Analysis 
Full Analysis Set 
 
14.2.2.2.3 
Subgroup Analysis: Rate of Clinically Symptomatic 
Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16 by Clinical Frailty Scale Score: Generalized 
Linear Model Analysis 
Full Analysis Set 
 
14.2.2.2.4 
Subgroup Analysis: Rate of Clinically Symptomatic 
Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16 by Medical History of Asthma: General Linear 
Model Analysis 
Full Analysis Set 
 
14.2.2.2.5 
Subgroup Analysis: Rate of Clinically Symptomatic 
Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16 by Medical History of Congestive Heart Failure: 
General Linear Model Analysis 
Full Analysis Set 
 
14.2.2.2.6 
Subgroup Analysis: Rate of Clinically Symptomatic 
Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16 by Pneumococcal Vaccination: General Linear 
Model Analysis 
Full Analysis Set 
 
14.2.2.2.7 
Subgroup Analysis: Rate of Clinically Symptomatic 
Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16 by Current Season Influenza Vaccination: 
General Linear Model Analysis 
Full Analysis Set 
 
14.2.2.2.8 
Subgroup Analysis: Rate of Clinically Symptomatic 
Respiratory Illnesses (with or without an Associated 
Laboratory-confirmed Pathogen) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16 by Gender: General Linear Model Analysis 
Full Analysis Set 
14.2.2.3.1 
Rate of Subjects with One or More Clinically Symptomatic 
Respiratory Illnesses Associated with ≥1 Laboratory-
confirmed Pathogen(s) Beginning at Least 3 Days After 
the Start of Study Drug Treatment through Week 16: 
Generalized Linear Model Analysis 
Full Analysis Set 
14.2.2.3.2 
Subgroup Analysis: Rate of Subjects with One or More 
Clinically Symptomatic Respiratory Illnesses Associated 
with ≥1 Laboratory-confirmed Pathogen(s) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16 by Subject Age: Generalized Linear 
Model Analysis 
Full Analysis Set 
 


Statistical Analysis Plan for Interventional Studies 
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Table Number 
Name 
Analysis Set 
14.2.2.3.3 
Subgroup Analysis: Rate of Subjects with One or More 
Clinically Symptomatic Respiratory Illnesses Associated 
with ≥1 Laboratory-confirmed Pathogen(s) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16 by Clinical Frailty Scale Score: 
Generalized Linear Model Analysis 
Full Analysis Set 
 
14.2.2.3.4 
Subgroup Analysis: Rate of Subjects with One or More 
Clinically Symptomatic Respiratory Illnesses Associated 
with ≥1 Laboratory-confirmed Pathogen(s) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16 by Medical History of Asthma: 
Generalized Linear Model Analysis 
Full Analysis Set 
 
14.2.2.3.5 
Subgroup Analysis: Rate of Subjects with One or More 
Clinically Symptomatic Respiratory Illnesses Associated 
with ≥1 Laboratory-confirmed Pathogen(s) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16 by Medical History of Congestive Heart 
Failure: Generalized Linear Model Analysis 
Full Analysis Set 
 
14.2.2.3.6 
Subgroup Analysis: Rate of Subjects with One or More 
Clinically Symptomatic Respiratory Illnesses Associated 
with ≥1 Laboratory-confirmed Pathogen(s) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16 by Pneumococcal Vaccination: 
Generalized Linear Model Analysis 
Full Analysis Set 
 
14.2.2.3.7 
Subgroup Analysis: Rate of Subjects with One or More 
Clinically Symptomatic Respiratory Illnesses Associated 
with ≥1 Laboratory-confirmed Pathogen(s) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16 by Current Season Influenza 
Vaccination: Generalized Linear Model Analysis 
Full Analysis Set 
 
14.2.2.3.8 
Subgroup Analysis: Rate of Subjects with One or More 
Clinically Symptomatic Respiratory Illnesses Associated 
with ≥1 Laboratory-confirmed Pathogen(s) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16 by Gender: Generalized Linear Model 
Analysis 
Full Analysis Set 
14.2.2.4 
Time to Alleviation of Moderate and Severe Respiratory 
Illness Symptoms Due to Clinically Symptomatic 
Respiratory Illnesses Beginning at Least 3 Days After the 
Start of Study Drug Treatment through Week 16: Cox 
Proportional Hazards Regression Analysis 
Full Analysis Set 
14.2.2.5 
Percentage of Subjects with Severe Respiratory Illness 
Symptoms due to Clinically Symptomatic Respiratory 
Illnesses Beginning at Least 3 Days After the Start of 
Study Drug Treatment through Week 16: Logistic 
Regression Analysis 
Full Analysis Set 
14.2.2.6 
Rate of Clinically Symptomatic Respiratory Illnesses 
Associated with Specific Laboratory-confirmed Viruses 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16 
Full Analysis Set 
 
 
 


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Table Number 
Name 
Analysis Set 
14.2.3.1 
Rate of All Laboratory-confirmed Viral Infections with or 
without Symptoms Beginning at Least 3 Days After the 
Start of Study Drug Treatment through Week 16: 
Generalized Linear Model Analysis 
Full Analysis Set 
14.2.3.2 
Rate of All-cause Hospitalizations Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16: Generalized Linear Model Analysis 
Full Analysis Set 
14.2.3.3 
Rate of Hospitalizations Associated with RTIs Beginning 
at Least 3 Days After the Start of Study Drug Treatment 
through Week 16: Generalized Linear Model Analysis 
Full Analysis Set 
14.2.3.4 
Rate of All-cause Emergency Room Visits Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16: Generalized Linear Model Analysis 
Full Analysis Set 
14.2.3.5 
Rate of Emergency Room Visits Associated with RTIs 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Generalized Linear Model 
Analysis 
Full Analysis Set 
14.2.3.6 
Rate of All-cause Urgent Care Clinic Visits Beginning at 
Least 3 Days After the Start of the Study Drug Treatment 
through Week 16: Generalized Linear Model Analysis 
Full Analysis Set 
14.2.3.7 
Rate of Urgent Care Clinic Visits for Clinically 
Symptomatic Respiratory Illness Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 16: Generalized Linear Model Analysis 
Full Analysis Set 
14.2.3.8 
Rate of All-cause Admissions to Skilled Nursing Facilities 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Generalized Linear Model 
Analysis 
Full Analysis Set 
14.2.3.9 
Hospitalization Length of Stay Associated with RTIs 
Beginning at Least 3 Days After the Start of Study Drug 
Treatment through Week 16: Analysis of Covariance 
Full Analysis Set 
14.2.3.10  
All-cause Hospitalization Length of Stay Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16: Analysis of Covariance 
Full Analysis Set 
14.2.3.11 
Percentage of Subjects with One or more Clinically 
Symptomatic Respiratory Illnesses (with or without an 
Associated Laboratory-confirmed Pathogen) Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 20: Logistic Regression Analysise 
 
14.2.3.12 
Percentage of Subjects with One or more Clinically 
Symptomatic Respiratory Illnesses Associated with ≥1 
Laboratory-confirmed Pathogen(s) Beginning at Least 3 
Days After the Start of Study Drug Treatment through 
Week 20: Logistic Regression Analysis 
Full Analysis Set 
14.2.3.13 
Change from Baseline in EQ-5D-5L Scores during All 
Symptomatic Respiratory Illness Episodes Beginning at 
Least 3 Days After the Start of Study Drug Treatment 
through Week 16: Mixed Model Repeated Measure 
Analysis 
Full Analysis Set 


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Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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Table Number 
Name 
Analysis Set 
14.2.3.14 
Rate of Asthma Exacerbations Beginning at Least 3 Days 
After the Start of Study Drug Treatment through Week 16 
in Subjects with Medical History of Asthma: Generalized 
Linear Model Analysis 
Full Analysis Set 
 
14.2.3.15 
Percentage of Subjects with One or More Asthma 
Exacerbation Beginning at Least 3 Days After the Start of 
Study Drug Treatment through Week 16 in Subjects with 
Medical History of Asthma: Logistic Regression Analysis 
Full Analysis Set 
 
14.2.3.16 
Change from Baseline to Weeks 4 and 16 in Biomarkers 
in Whole Blood 
Full Analysis Set 
14.2.3.17 
Rate of UTIs Reported as Adverse Events through Week 
16 
Full Analysis Set 
 14.2.3.18 
Percentage of Subjects with One or More UTIs Reported 
as Adverse Events through Week 16 
Full Analysis Set 
14.2.3.19 
Percentage of Subjects with Expanded-Definition 
Clinically Symptomatic Respiratory Illness (with or without 
an associated laboratory-confirmed pathogen) Beginning 
at Least 3 Days after the Start of Study Drug Treatment 
through Week 16 
Logistic Regression Analysis 
Full Analysis Set 
 
 
 
14.2.4.1 
Percentage of Subjects with One or More Clinically 
Symptomatic Respiratory Illnesses Associated with ≥1 
Laboratory-confirmed Pathogen(s) Including Assessment 
using Midturbinate Swabs 
Logistic Regression Analysis 
Full Analysis Set 
14.2.4.2 
Rate of Clinically Symptomatic Respiratory Illness 
Associated with ≥1 Laboratory-confirmed Pathogen(s) 
Including Assessment using Midturbinate Swabs  
Generalized Linear Model Analysis 
Full Analysis Set 
 
 
 
14.3.1.1 
Adverse Events – Overall Summary 
Safety Set 
14.3.1.2 
Adverse Events by System Organ Class and Preferred 
Term 
Safety Set 
14.3.1.3 
Treatment-Related Adverse Events by System Organ 
Class and Preferred Term 
Safety Set 
14.3.1.4 
Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity 
Safety Set 
14.3.1.5 
Adverse Events by System Organ Class, Preferred Term, 
and Causality Relationship 
Safety Set 
14.3.1.6 
Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
14.3.1.7 
Serious Treatment-Related Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
14.3.1.8 
Adverse Events Leading to Withdrawal from Study by 
System Organ Class and Preferred Term 
Safety Set 
14.3.1.9 
Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
Safety Set 
14.3.1.10 
Adverse Events Leading to Death by System Organ Class 
and Preferred Term 
Safety Set 
 
 
 
14.3.2.1 
Deaths, Listing 
Safety Set 


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Table Number 
Name 
Analysis Set 
14.3.2.2 
Serious Adverse Events, Listing 
Safety Set 
14.3.2.3 
Adverse Events Leading to Death, Listing 
Safety Set 
14.3.2.4 
Adverse Events Leading to Withdrawal from Study, 
Listing 
Safety Set 
14.3.2.5 
Adverse Events Leading to Study Drug Discontinuation, 
Listing 
Safety Set 
14.3.2.6 
Severe Adverse Events, Listing 
Safety Set 
14.3.2.7 
Treatment-Related Adverse Events, Listing 
Safety Set 
14.3.2.8 
Serious Treatment-Related Adverse Events, Listing 
Safety Set 
 
 
 
14.3.4.1.1.1 
Hematology: Summary by Visit and Change from 
Baseline 
Safety Set 
14.3.4.1.1.2 
Hematology: Abnormal Results, Listing 
Safety Set 
14.3.4.1.1.3 
Hematology: Shift from Baseline Grade to Each Visit 
Grade 
Safety Set 
14.3.4.1.2.1 
Blood Chemistry: Summary by Visit and Change from 
Baseline 
Safety Set 
14.3.4.1.2.2 
Blood Chemistry: Abnormal Results, Listing 
Safety Set 
14.3.4.1.2.3 
Blood Chemistry: Shift from Baseline Grade to Each Visit 
Grade 
Safety Set 
14.3.4.1.3.1 
Urinalysis: Shift from Baseline Grade to Each Visit Grade 
Safety Set 
14.3.4.2.1 
Summary of 12-lead ECG by Visit and Change from 
Baseline 
Safety Set 
14.3.4.2.2 
Summary of Overall ECG Interpretation by Visit 
Safety Set 
14.3.4.2.3 
Summary of Abnormal Abnormal QTc, QTcB, and QTcF 
Results  by Visit  
Safety Set 
14.3.4.3.1 
Summary of Vital Signs by Visit and Change from 
Baseline 
Safety Set 
14.3.4.3.2 
Vital Signs: Shift from Baseline to Last On-Study Value 
Safety Set 
14.3.4.4 
Extent of Exposure 
Safety Set 


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Index of Figures 
Figure Number 
Name 
Analysis Set 
14.2.1.1 
Boxplots for the Summary of Subjects with Missing Data 
Full Analysis Set 
14.2.1.2 
Kaplan Meier Curves of Time to Alleviation of Moderate and 
Severe Respiratory Illness Symptoms Due to Clinically 
Symptomatic Respiratory Illnesses Beginning at Least 3 
Days after the Start of Study Drug Treatment through Week 
16 
Full Analysis Set 
14.2.1.3 
Boxplots for EQ-5D-5L Visual Analog Scale 
Full Analysis Set 
14.3.1 
Hematology:  Change from Baseline to Post-Baseline Visits  
Safety Set 
14.3.2 
Chemistry:  Change from Baseline to Post-Baseline Visits 
Safety Set 
14.3.3 
Urinalysis (Numerical Results):  Change from Baseline to 
Post-Baseline Visits 
Safety Set 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: resTORbio, Inc.; Protocol No.: RTB-101-204 
 
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Index of Listings 
Listing Number 
Name 
Analysis Set 
 
16.2.1.1 
Subject Disposition 
Screening Set 
 
 
 
16.2.2.1 
Protocol Deviations 
Randomized Set 
 
 
 
16.2.3.1 
Inclusion Criteria Violations 
Screening Set 
16.2.3.2 
Exclusion Criteria Violations 
Screening Set 
16.2.3.3 
Exclusions from Analysis Sets 
Randomized Set 
 
 
 
16.2.4.1 
Demographics  
Full Analysis Set 
16.2.4.2 
Medical History 
Safety Set 
16.2.4.3 
Baseline Characteristics 
Full Analysis Set 
16.2.4.4 
Concomitant Medications 
Safety Set 
16.2.4.5 
Prior Vaccinations 
Safety Set 
 
 
 
16.2.5.1 
Study Drug Administration 
Safety Set 
16.2.5.2 
Study Drug Compliance 
Safety Set 
16.2.5.4 
Pharmacokinetic Sample Collection 
Safety Set 
16.2.5.5 
Pharmacogenomics Sample Collection 
Safety Set 
 
 
 
16.2.6.1.1 
Respiratory Symptom Questionnaire 
Full Analysis Set 
16.2.6.1.2 
Clinically Symptomatic Respiratory Illness 
Full Analysis Set 
16.2.6.2.1 
Nasopharyngeal Swab for Pathogen PCR 
Full Analysis Set 
16.2.6.2.2 
Mid-Turbinate Nasal Swab for Pathogen PCR 
Full Analysis Set 
16.2.6.2.3 
Rapid Influenza Antigen Diagnostic Test (RIDT) 
Full Analysis Set 
16.2.6.2.4 
Sputum Gram Stain and Culture 
Full Analysis Set 
16.2.6.3.1 
Hospitalization 
Full Analysis Set 
16.2.6.3.2 
Emergency Room Visit 
Full Analysis Set 
16.2.6.3.3 
Urgent Care Facility Visit 
Full Analysis Set 
16.2.6.3.4 
Skilled Nursing Facility Admission 
Full Analysis Set 
16.2.6.3.5 
EQ-5D-5L Questionnaire 
Full Analysis Set 
16.2.6.3.6 
Asthma Exacerbation 
Full Analysis Set 
16.2.6.3.7 
Biomarkers 
Full Analysis Set 
 
 
 
16.2.7.1 
Adverse Events 
Safety Set 
 
 
 
16.2.8.1.1 
Hematology 
Safety Set 
16.2.8.1.2 
Blood Chemistry 
Safety Set 
16.2.8.1.3 
Urinalysis 
Safety Set 
 
 
 
16.2.8.2.1 
Vital Signs 
Safety Set 
16.2.8.2.2 
Electrocardiogram (ECG) 
Safety Set 
16.2.8.2.3 
Physical Examination 
Safety Set 
16.2.8.2.4 
Chest X-Ray 
Safety Set 
16.2.8.2.5 
Vital Status 
Safety Set