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Trial registered on ANZCTR


Registration number
ACTRN12619000628145
Ethics application status
Approved
Date submitted
11/04/2019
Date registered
29/04/2019
Date last updated
13/05/2019
Date data sharing statement initially provided
29/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of RTB101 on Respiratory Illness Associated with Laboratory-Confirmed Pathogens in the Elderly
Scientific title
A Multicenter, Randomized, Double Blind, Placebo-Controlled, Phase 3 Study
to Determine if RTB101 Prevents Clinically Symptomatic Respiratory Illness
in the Elderly
Secondary ID [1] 297805 0
RTB-101-204
Universal Trial Number (UTN)
Trial acronym
PROTECTOR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Respiratory Illness 312178 0
Condition category
Condition code
Infection 310728 310728 0 0
Studies of infection and infectious agents
Respiratory 310965 310965 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 311039 311039 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Subjects meeting study eligibility criteria will be randomized 1:1 to receive RTB101 (dactolisib) 10 mg or matching placebo once daily for 16 weeks. The RTB101 drug product or matching placebo is a capsule for oral intake.
In order to assure subject’s compliance with the interventions drug capsule return is monitored by the site’s study team members at every visit during the treatment phase at visits week 2, week 4, week 6,week 8, week 12 and week 16. Furthermore subjects are required to document study drug administration by recording time and date into the electronic diary provided. A respiratory symptom questionnaire is required to be answered on a daily basis using this eDiary, too.
The sites will have access to the subjects’ adherence to the eDiary completion rate and can remind/re-educate subjects about the need to complete and how to complete the eDiary if they forget or cannot access their eDiary.
The study will be composed of up to a 4-week screening period, a 16-week treatment period and a 1-week follow-up period off study drug. There will also be a long term follow-up by telephone at Week 48.
At the same time points laboratory testings (Hematology, Blood Chemistry, Urinalysis) and measurement of body weight and vital signs are performed. Until the week 12 visit a targeted physical examination is performed by the Principal Investigators at site. A complete physical examination is performed at both the screening visit and at the week 16 visit.
Intervention code [1] 314057 0
Prevention
Intervention code [2] 314210 0
Treatment: Drugs
Comparator / control treatment
Subjects will be randomized to either receive RTB101 or placebo with both a 50% chance each.
Placebo is a microcellulose capsule looking exactly the same way as the capsule containing the study drug under investigation. It contains all the same ingredients except for RTB101 . The main ingredient is Lactose Monohydrate
Control group
Placebo

Outcomes
Primary outcome [1] 319576 0
To determine if RTB101 decreases as compared to placebo the percentage of subjects with one or more symptomatic respiratory illnesses associated with more than one 1 laboratory-confirmed pathogen(s) through Week 16.
A questionnaire was developed for this study and its content validated. Subjects self-report their symptoms in a eDiary. Frequent cold symptom entries will trigger a request to come in for an office visit for a nasal swab to detect pathogens (e.g., cold viruses).
Timepoint [1] 319576 0
Beginning at least 3 days after the start of study drug treatment through Week 16.
Symptoms are collected via the eDiary daily by asking subjects to complete the diary each day in the evening. Subjects will come in for an unscheduled visit and get a nasal swab and other assessments if flu like symptoms are suspected, rapid influenza diagnostic test (RIDT), and Sputum gram stain.
Secondary outcome [1] 369703 0
To determine if RTB101 as compared to placebo decreases the rate of symptomatic respiratory illnesses associated with more than 1 laboratory-confirmed pathogen(s) through Week 16.
For this study a questionnaire was developed and its content validated. This endpoint is assessed by patient self-report of symptoms by a questionnaire administered daily in an eDiary. Two consecutive daily entries of a symptom will trigger a subject being asked to come to the site for a Nasopharyngeal swab to detect pathogens (e.g., cold viruses). A positive test for a pathogen confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days)
Timepoint [1] 369703 0
Beginning at least 3 days after the start of study drug treatment through Week 16.
Subject's daily self-assessment by eDiary and an unscheduled visit only if repeated symptom(s) indicate a possible infection. A positive test for a pathogen at an unscheduled visit triggered by a repeated symptom confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days).
Secondary outcome [2] 369704 0
To determine if RTB101 as compared to placebo decreases the percentage of subjects with symptomatic respiratory illness (with or without an associated laboratory-confirmed pathogen) through Week 16.
A questionnaire was developed for this study and its content validated. Enrolled subjects' daily self-assessment by eDiary confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days).
Lab confirmed pathogen is when a positive test for a pathogen (from a nasal swab or culture) confirms the outcome/endpoint of a symptomatic respiratory illness as defined above.

Timepoint [2] 369704 0
Beginning at least 3 days after the start of study drug treatment through Week 16.
Enrolled subjects' daily self-assessment by eDiary and an unscheduled visit only if repeated symptom(s) indicate a possible infection. A swab and in some cases sputum test for a pathogen at an unscheduled visit triggered by a repeated symptom confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days).
Secondary outcome [3] 369705 0
To determine if RTB101 as compared to placebo decreases the rate of symptomatic respiratory illness (with or without an associated laboratory-confirmed pathogen) through Week 16.
For this study a questionnaire was developed and its content validated.
Enrolled subject's daily self-assessment by eDiary and an unscheduled visit only if repeated symptom(s) indicate a possible infection. A positive test for a pathogen at an unscheduled visit triggered by a repeated symptom confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days).
Timepoint [3] 369705 0
Beginning at least 3 days after the start of study drug treatment through Week 16.
Enrolled subjects' daily self-assessment by eDiary and an unscheduled visit only if repeated symptom(s) indicate a possible infection. A swab and in some cases sputum test for a pathogen at an unscheduled visit triggered by a repeated symptom confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days).
Secondary outcome [4] 369706 0
To determine if RTB101 as compared to placebo decreases time to alleviation of moderate and severe symptoms due to respiratory illnesses associated with more than one laboratory-confirmed pathogen(s) through Week 16.
For this study a questionnaire was developed and its content validated. Enrolled subjects self-report their symptoms in a eDiary and frequent cold symptom entries will triggers a request to come in for an office visit for a nasal swab to detect pathogens (e.g., cold viruses).
Timepoint [4] 369706 0
Beginning at least 3 days after the start of study drug treatment through Week 16.
Enrolled subjects' daily self-assessment by eDiary and an unscheduled visit only if repeated symptom(s) indicate a possible infection. A swab and in some cases sputum test for a pathogen at an unscheduled visit triggered by a repeated symptom confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days).
Secondary outcome [5] 369707 0
To determine if RTB101 as compared to placebo decreases the percentage of subjects with severe symptoms due to respiratory illnesses associated with more than one laboratory-confirmed pathogen(s) through Week 16.
For this study a questionnaire was developed for this study and its content validated. Enrolled subjects self-report their symptoms in a eDiary and frequent cold symptom entries will triggers a request to come in for an office visit for a nasal swab to detect pathogens (e.g., cold viruses).
Timepoint [5] 369707 0
Beginning at least 3 days after the start of study drug treatment through Week 16.
Enrolled subjects' daily self-assessment by eDiary and an unscheduled visit only if repeated symptom(s) indicate a possible infection. A swab and in some cases sputum test for a pathogen at an unscheduled visit triggered by a repeated symptom confirms the outcome/endpoint of a symptomatic respiratory illness defined as 2 or more pre-defined cold symptoms present (one must be present for at least 2 days).
Secondary outcome [6] 369708 0
To assess the safety and tolerability of RTB101 through Week 16.
Physical Examination, Vital Signs, Height and Weight and Laboratory Evaluations will be constantly compared versus subject's baseline values .
Timepoint [6] 369708 0
Complete physical examination will be done at Screening and at Week 16. A targeted physical exam of at least oral cavity, skin, and lungs will be done at all other scheduled visits. Subjects who come in to the study site for an unscheduled visit due to symptomatic respiratory illness will also receive a targeted physical exam based on their presenting symptoms.
At every study visit body temperature, blood pressure, heart rate, respiratory rate, hematology, blood chemistry, urinalysis and adverse events (including SAEs) from time of start of study drug treatment until week 17. are checked. and will be recorded.
Laboratory data will be compared to protocol-specified ranges at Screening. an all susbequent visits.
Clinically relevant deviations of laboratory test results occurring during or at completion of the study should be evaluated for criteria defining an adverse event 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 longer clinically relevant.
Secondary outcome [7] 369709 0
Long-Term Follow Up
Timepoint [7] 369709 0
This phone call will be conducted at week 48 in order to determine mortality, hospitalization and admission to a skilled nursing facility. This is to be seen as a composite outcome measured by multiple factors.

Eligibility
Key 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.
2. Male and female subjects who in the clinical judgement of the Investigator are without unstable medical conditions (as determined by medical history, electrocardiogram (ECG) and laboratory tests at Screening, and physical examination and vital signs at Screening and Baseline).
3. Subjects must be 65 years of age or older
4. Subjects who need 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 ago. 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.
Minimum age
65 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects will not be eligible if they meet any of the following criteria:
1. Any subject who:
a. Is a current smoker as assessed by medical history or a positive cotinine test at Screening.
b. Stopped smoking less than or equal to 1 year prior to screen
c. Is a previous smoker with a more than or equal to 10 pack year smoking history
d. Has any household member who smokes more than or equal to 1 pack per day of cigarettes
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 less than 24 at Screening.
4. Subjects with current evidence of a serious and/or unstable cardiovascular, respiratory, gastrointestinal, renal (including subjects with an eGFR less than or equal to 50 mL/min/1.73m2), hematologic or other medical disorder.
5. The following cardiac conditions:
a. Unstable angina pectoris or acute ischemic changes on ECG during Screening.
b. History of myocardial infarction (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.
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.
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 respiratory tract infection 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 initial dosing.
8. Subjects with a history of a systemic autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), or receiving immunosuppressive therapy including chronic use of prednisone more than 10 mg daily (however, acute use of higher doses of prednisone to treat conditions such as exacerbation of asthma or other acute conditions is 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 less than 2000/mL.
b. neutrophil count less than 1000/mL.
c. platelet count less than 7500/mL..
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 patients 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)
• 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 an investigational medication or participation in an investigational study within 5 half-lives of the investigational medication, or within 30 days, whichever is longer; or longer if required by local regulations. Subjects previously treated with RTB101 and/or everolimus in study CBEZ235Y2201, RTB-BEZ235-202, or RTB-BEZ235-203 will be eligible to participate in this study if they meet all other inclusion and exclusion criteria.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by phone/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using procedures like coin-tossing to determine if patient will receive active substance or placebo.
At the Baseline visit, all eligible subjects will be randomized via the interactive response system study personnel is using at the site ("IXRS") to one of the treatment arms. The Investigator or his/her delegate will contact the IXRS after confirming that the subject fulfills all the inclusion/exclusion criteria. The IXRS will prompt the user to randomize the subject. The subject identifier number will be used to link the subject to a treatment arm and a unique medication number for the bottles of study drug to be dispensed to the subject.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / 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 and medical history of diabetes mellitus type 2 or asthma.
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.
Further tests of hypotheses will occur on some secondary endpoints. The second family of hypotheses will be tested using a sequentially rejective multiple testing procedure at full alpha of 0.05, if and only if the primary endpoint is significant. This procedure will pass alpha from the secondary family to the exploratory family only when all the null hypotheses in the secondary family are rejected. Tests of hypotheses will be illustrated using the graphical approach.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 21373 0
New Zealand
State/province [1] 21373 0
All

Funding & Sponsors
Funding source category [1] 302331 0
Commercial sector/Industry
Name [1] 302331 0
resTORbio Inc.
Address [1] 302331 0
500 Boylston Street
12th Floor
Boston MA 02116 USA
Country [1] 302331 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
INC Research Australia Pty Limited
Address
159 Port Road
Hindmarsh
South Australia 5007
Country
Australia
Secondary sponsor category [1] 302211 0
Commercial sector/Industry
Name [1] 302211 0
resTORbio Inc.
Address [1] 302211 0
500 Boylston Street
12th Floor
Boston MA 02116
Country [1] 302211 0
United States of America
Secondary sponsor category [2] 302219 0
Commercial sector/Industry
Name [2] 302219 0
INC Research New Zealand Limited
Address [2] 302219 0
Unit G1
1422 Triton Drive
Rosedale
Auckland 0632
Country [2] 302219 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303031 0
HDEC
Ethics committee address [1] 303031 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 303031 0
New Zealand
Date submitted for ethics approval [1] 303031 0
07/02/2019
Approval date [1] 303031 0
26/03/2019
Ethics approval number [1] 303031 0
Ethics ref: 19/NTA/23
Ethics committee name [2] 303032 0
Bellberry Human Research Ethics Committee
Ethics committee address [2] 303032 0
Level 39, Rialto South Tower 525 Collins Street
Melbourne Victoria 3000
Postal: GPO Box 375 MELBOURNE VIC 3001
Ethics committee country [2] 303032 0
Australia
Date submitted for ethics approval [2] 303032 0
06/03/2019
Approval date [2] 303032 0
08/04/2019
Ethics approval number [2] 303032 0
Application No: 2019-02-159

Summary
Brief summary
The purpose of this study is to determine if RTB101 helps decrease the percentage and rate of clinically symptomatic respiratory illness that are either confirmed by laboratory test or not. The study will also find out whether it decreases the duration of moderate and severe symptoms due to all clinically symptomatic respiratory illness that are confirmed with a laboratory test.
The study will also see if RTB101 is safe to use.
The study will also look at rate of respiratory illnesses that occur with specific viruses.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92138 0
Dr Dean Quinn
Address 92138 0
P3 Research Ltd, Wellington Clinical Research Unit, 1st Floor, 121 Adelaide Rd, Newton, Wellington 6242
Country 92138 0
New Zealand
Phone 92138 0
+64 4 801 0002 (ext 754)
Fax 92138 0
+64 4 389 7468
Email 92138 0
dean@p3research.co.nz
Contact person for public queries
Name 92139 0
Dr Sarb Shergill PhD
Address 92139 0
resTORbio Inc.
500 Boylston Street
12th Floor
Boston 02116, MA
Country 92139 0
United States of America
Phone 92139 0
+1 857 315 5526
Fax 92139 0
Email 92139 0
SShergill@restorbio.com
Contact person for scientific queries
Name 92140 0
Dr Sarb Shergill PhD
Address 92140 0
resTORbio Inc.
500 Boylston Street
12th Floor
Boston 02116, MA
Country 92140 0
United States of America
Phone 92140 0
+1 857 315 5526
Fax 92140 0
Email 92140 0
SShergill@restorbio.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results