A Phase 3 Study to Determine if RTB101 Prevents Clinically Symptomatic Respiratory Illness in the Elderly
Phase: PHASE3
Conditions: Respiratory Tract Infections
Sponsor: Restorbio Inc.

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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 
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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 
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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 
IB. 

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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 
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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: 
1. Age ≥85 

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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 
RTB101 10 mg once daily as compared to placebo in clinical trials CBEZ235Y2201 and RTB-

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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 
model (MMRM).  

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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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 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.