PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study
Phase: PHASE2
Conditions: Asthma
Sponsor: University of North Carolina, Chapel Hill

PrecISE: Precision Interventions for Severe and/or Exacerbation-Prone Asthma Network 
National Clinical Trial (NCT) Identified Number:  NCT04129931 
IND Sponsor: University of North Carolina at Chapel Hill 
Funded by: National Heart, Lung, and Blood Institute 
Version Number:  v 3.3 
27 September 2024 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
9.2 Sample Size 
Determination 
Indicate that 93 participants (2:1 
ratio of biomarker positive to 
negative participants) is needed 
when futility analysis is not 
performed for an intervention. 
 
Clarify the sample size needed when futility analysis is 
not performed. 
1.3 Schedule of 
Activities 
Indicate that some procedures 
and assessments are not 
required at the participant’s last 
Visit X.6 
Since the participant will not be participating in 
another treatment period, some assessments and 
procedures are not necessary. 
9.4 Populations for 
Analyses 
Revise population definitions 
and move details to the  
Statistical Analysis Plan 
Clarification.   
 
 
 
 
 
 

  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................ 1 
1 
PROTOCOL SUMMARY ............................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 5 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 7 
2 
INTRODUCTION .......................................................................................................................... 10 
2.1 
Study Background and Rationale .................................................................................................... 10 
2.2 
Risk/Benefit Assessment .................................................................................................................. 11 
2.2.1 
Known Potential Risks ................................................................................................................. 12 
2.2.2 
Known Potential Benefits ............................................................................................................ 15 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................. 15 
4 
STUDY DESIGN ........................................................................................................................... 16 
4.1 
Overall Design .................................................................................................................................... 16 
4.2 
Scientific Rationale for Study Design.............................................................................................. 17 
4.3 
Justification for Dose ......................................................................................................................... 18 
4.4 
End of Study Definition ..................................................................................................................... 18 
5 
STUDY POPULATION ................................................................................................................. 18 
5.1 
Inclusion Criteria ................................................................................................................................ 18 
5.2 
Exclusion Criteria ............................................................................................................................... 21 
5.3 
Randomization Criteria ..................................................................................................................... 24 
5.4 
Lifestyle Considerations .................................................................................................................... 25 
5.5 
Screen Failures .................................................................................................................................. 25 
5.6 
Strategies for Recruitment and Retention ...................................................................................... 25 
6 
STUDY INTERVENTION ............................................................................................................. 26 
6.1 
Study Intervention(s) Administration ............................................................................................... 26 
6.1.1 
Study Intervention Description ................................................................................................... 26 
6.1.2 
Dosing and Administration .......................................................................................................... 26 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 26 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 27 
6.4 
Study Intervention Compliance ........................................................................................................ 29 
6.5 
Concomitant Therapy ........................................................................................................................ 29 
6.5.1 
Controller Medication ................................................................................................................... 31 
6.5.2 
Rescue Medicine .......................................................................................................................... 31 
6.5.3 
Episodes of Worsening Asthma/Exacerbations ....................................................................... 32 
6.5.4 
Major Changes in Therapy .......................................................................................................... 33 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................... 35 
7.1 
Discontinuation of Study Intervention ............................................................................................. 35 

  
 
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7.1.1 
Discontinuation of a Participant’s Assigned Intervention........................................................ 35 
7.1.2 
Discontinuation of an Intervention from the Master Protocol ................................................. 36 
7.1.3 
Discontinuation of the Study ....................................................................................................... 36 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 36 
7.3 
Lost to Follow-Up ............................................................................................................................... 37 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 38 
8.1 
Efficacy Assessments ....................................................................................................................... 38 
8.2 
Safety and Other Assessments ....................................................................................................... 40 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 44 
8.3.1 
Definition of Adverse Events (AE) ............................................................................................. 44 
8.3.2 
Definition of Suspected Adverse Reaction ............................................................................... 44 
8.3.3 
Definition of Serious Adverse Events (SAE) ............................................................................ 44 
8.3.4 
Responsibilities ............................................................................................................................. 45 
8.3.5 
Classification of an Adverse Event ............................................................................................ 45 
8.3.6 
Serious Adverse Event Reporting .............................................................................................. 47 
8.3.7 
Reporting Events to Participants ................................................................................................ 48 
8.3.8 
Reporting of Pregnancy ............................................................................................................... 48 
8.4 
Unanticipated Problems .................................................................................................................... 48 
8.4.1 
Definition of Unanticipated Problems (UP) ............................................................................... 48 
8.4.2 
Unanticipated Problem Reporting .............................................................................................. 49 
9 
STATISTICAL CONSIDERATIONS ........................................................................................... 49 
9.1 
Statistical Hypotheses ....................................................................................................................... 49 
9.2 
Sample Size Determination .............................................................................................................. 49 
9.3 
Design Adaptations ........................................................................................................................... 50 
9.4 
Populations for Analyses .................................................................................................................. 51 
9.5 
Statistical Analyses............................................................................................................................ 51 
9.5.1 
General Approach ........................................................................................................................ 51 
9.5.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................................... 52 
9.5.3 
Safety Analyses ............................................................................................................................ 52 
9.5.4 
Baseline Descriptive Statistics ................................................................................................... 53 
9.5.5 
Planned Interim Analyses ........................................................................................................... 53 
9.5.6 
Optimization of Target Subgroups ............................................................................................. 53 
9.5.7 
Tabulation of Individual Participant Data .................................................................................. 53 
9.5.8 
ExpLoratory Analysis ................................................................................................................... 53 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 53 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 53 
10.1.1 
Informed Consent Process ......................................................................................................... 53 
10.1.2 
Study Discontinuation and Closure............................................................................................ 56 
10.1.3 
Confidentiality and Privacy .......................................................................................................... 57 
10.1.4 
Future Use of Stored Specimens and Data .............................................................................. 57 
10.1.5 
Key Roles and Study Governance ............................................................................................. 59 
10.1.6 
Safety Oversight ........................................................................................................................... 62 

  
 
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10.1.7 
Clinical Monitoring ........................................................................................................................ 64 
10.1.8 
Quality Assurance and Quality Control ..................................................................................... 65 
10.1.9 
Data Handling and Record Keeping .......................................................................................... 65 
10.1.10 
Protocol Deviations ...................................................................................................................... 66 
10.1.11 
Publication and Data Sharing Policy ......................................................................................... 67 
10.1.12 
Conflict of Interest Policy ............................................................................................................. 67 
10.2 
Additional Considerations ................................................................................................................. 67 
10.3 
Abbreviations ...................................................................................................................................... 68 
10.4 
Protocol Amendment History ........................................................................................................... 71 
11 
REFERENCES .............................................................................................................................. 75 
 

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STATEMENT OF COMPLIANCE 
The PrecISE study will be conducted in accordance with International Council on Harmonization E6 
Guideline for Good Clinical Practice (ICH E6 GCP), applicable United States (US) Code of Federal 
Regulations (CFR), and the NHLBI Terms and Conditions of Award. The study is being conducted under 
an Investigational New Drug application (IND) from the US Food and Drug Administration (FDA), and Dr. 
David B. Peden, MD, MS of the University of North Carolina at Chapel Hill is the IND sponsor. The PrecISE 
Principal Investigators will assure that no deviation from or changes to the protocol will take place 
without prior agreement from Dr. Peden (as IND sponsor) and the NHLBI (as funding agency), FDA 
review, and documented approval from the Institutional Review Board (IRB), except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this 
study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the central IRB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study.  When changes are 
made to the consent form; a determination will be made regarding whether a new consent needs to be 
obtained from participants who had provided consent earlier using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
The PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone 
Asthma Network) Study 
 
Background and 
Rationale 
PrecISE is an NHLBI-sponsored network established to conduct a phase 2 
proof-of-concept study to test interventions in biomarker-defined 
subgroups of patients with severe asthma. Severe asthma affects 5 - 10% 
of all patients with asthma (~2.5 million Americans), and patients with 
severe asthma experience substantial morbidity and require extensive use 
of healthcare resources.1 Despite the use of high dose inhaled 
corticosteroids and a second controller (and/or systemic corticosteroids), 
severe asthma patients continue to have poor control, low lung function 
and/or increased risk of severe exacerbations. Consequently, there is a 
need to investigate novel interventions for utility as targeted therapies in 
this patient population. 
The PrecISE Investigators proposed novel interventions in biomarker-
based subgroups, with the goals of gaining information about the efficacy 
of the interventions in the severe asthma patient population and 
additional information on the utility of the biomarkers in identifying 
patients for treatment. Over 30 interventions were proposed, and six were 
selected by the PrecISE Steering Committee for initial study based on 
feasibility, scientific enthusiasm about preliminary evidence of efficacy, 
safety, and potentially useful biomarkers. Additional interventions were 
identified for consideration as the study progresses, particularly if any of 
the initial interventions are discontinued during the study for low 

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likelihood of success or safety issues. Due to delays incurred by the Covid-
19 pandemic, the number of interventions to be initially investigated was 
reduced to five.  
 
All interventions will be studied under one master protocol using an 
adaptive platform trial design2,3 to assess multiple interventions 
simultaneously, while also obtaining information on biomarker utility in 
predicting responsiveness to each treatment.  Interventions may be 
discontinued and new interventions entered into the study, as data accrue 
on the safety and efficacy of the various interventions. Definitions of 
patient subgroups targeted by each intervention and the biomarkers used 
to define them are adapted prospectively during the study. By 
prospectively enriching patient population we increase the chance of 
demonstrating a treatment effect at the end of the trial, as testing the 
efficacy of an intervention in an unenriched population of all participants 
may results in failure to detect the treatment effect.  
 
The master protocol, described in the following sections (1.2 – 10.4), 
contains all aspects of the study design and all study elements and 
procedures common across the various interventions. Details of each of 
the interventions planned for study, including the rationale for their 
selection into the study and intervention-specific study procedures 
required for each, are provided in Appendices I-V. As additional 
interventions are selected for study, appendices for each will be added to 
the master protocol as protocol amendments and submitted to the DSMB 
and IRB for their approval and to the FDA for its review prior to 
implementation.  
 
Our approach to designing PrecISE provides flexibility in studying multiple 
novel interventions at the same time and adaptability in defining patient 
subgroups targeted for therapy and in stopping some interventions and 
starting others through interim decision-making utilizing accruing data. 
The anticipated result is a wealth of information about the efficacy and 
safety of new treatments for severe asthma and about which patients 
might benefit from those treatments in the future, providing a precision 
medicine solution in an area of significant unmet medical need.   
 
Overall Study 
Description: 
 
The PrecISE Study is an adaptive platform trial conducted under a single 
Master Protocol to identify new therapies for severe asthma that are 
effective in biomarker-defined subgroups of participants. Five novel 
therapies will initially be investigated.  The trial is designed to meet our 
primary objectives, namely, to: (1) identify novel therapies that work in 
biomarker-defined subgroups of participants with severe asthma, and (2) 
optimize the subgroups targeted for treatment by refining the biomarker 
and subgroup definitions.  
 
For each participant, the study consists of three phases: (i) an initial 
screening phase, (ii) a 2-period crossover phase, and (iii) a single-period 

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crossover phase with successive re-randomizations. Common platforms 
for biomarker screening will be used during the initial screening period to 
determine a participant’s biomarker profile. Throughout the study, 
interventions will be randomly assigned based on these biomarker 
profiles. Participants will have a higher likelihood of assignment to an 
intervention that targets their particular profile. Subgroup definitions and 
associated treatment assignment probabilities are adapted as data 
accumulate throughout the study. 
 
Following the initial screening period, participants will be randomly 
assigned to interventions based on their biomarker profile and enter a 2-
period, double-blind crossover phase consisting of two 16-week treatment 
periods separated by an 8-week washout period. Note that longer 
washout periods will be considered for therapies with a half-life longer 
than 11 days. Treatment sequence will be randomly assigned as either test 
treatment followed by matching placebo or vice-versa.  
 
At the conclusion of the 2-period crossover phase and washout period, 
participants enter the single-period crossover phase of the study 
consisting of successive single 16-week treatment periods followed by 8-
week (or longer) washout periods. For each single-period crossover 
treatment, participants are randomly assigned to interventions based on 
their biomarker profiles that were determined during the initial screening 
period. The biomarker-based treatment assignment probabilities will be 
adapted during the study as data on the utility of the biomarkers in 
predicting treatment response accumulate. 
 
A small percentage of participants will receive placebo in this phase 
(periods 3-6) to assess seasonal and sequence effects throughout the 
study (no participant will receive more than three placebos during the 
study). Masking of treatment assignments will be maintained by matching 
a participant’s placebo to one of the available interventions for which the 
participant is eligible and has not yet received.  
   
Periodic reviews of safety data will be performed by the Data and Safety 
Monitoring Board (DSMB) at pre-specified intervals throughout the study, 
and interventions found to pose significant safety risks in the severe 
asthma population will be dropped from the study.  
 
Interventions may enter the study at different times, depending on their 
availability, and may be discontinued, as noted above. Additional 
interventions may be proposed depending on the progress of the study 
and innovations in potential treatments for severe asthma.  
 
Our study timelines and enrollment goals are such that, depending on the 
time of enrollment, each participant will receive up to five test treatments  
 

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Objectives: 
 
Primary Objectives: (1) Identify novel therapies that work in biomarker-
defined subgroups of severe asthmatic participants; (2) Optimize the 
subgroups targeted for treatment by refining the biomarkers and 
subgroup definitions. 
 
Secondary Objectives: (1) Gain information about potential 
response/pharmacodynamic biomarkers for selected therapies; (2) Explore 
the safety and effectiveness of selected therapies in adolescent 
participants with severe asthma. 
 
 
Endpoints: 
There are 2 primary efficacy endpoints: 
 1) FEV1 percent predicted, assessed prior to bronchodilator     
administration 
 2) Asthma symptom control, assessed via the Juniper Asthma Control 
Questionnaire (ACQ-6) 
 
Study Population: 
The sample will include 395 adult and pediatric (12-18 years of age) 
participants who meet modified guideline criteria for severe asthma and 
who are currently uncontrolled or continue to have exacerbations.   
Participants must be at least 12 years of age, on a stable regimen of 
asthma medications prior to enrollment, and satisfy other 
inclusion/exclusion criteria. Not all interventions will be studied in 
adolescents (see Appendices I-V).  We anticipate that at least two of the 
interventions will be studied in both adults and adolescents. 
 
Sample Size: 
 
A sample size of 111 participants is required to achieve 80% power to 
detect a treatment effect with respect to at least one of the two primary 
endpoints (FEV1  or asthma symptom control) equal to 0.3 times the 
standard deviation of that endpoint, taking into account the possibility to 
stop for futility and assuming a treatment period discontinuation rate 
(active or placebo) of 10%.  The Type I error probability will be controlled 
under the global null hypothesis (no effect on either endpoint) at α ≤ 0.10 
(see Section 9.2).  A sample size of 111 participants, at least 74  targeted 
by the intervention, is required to support the final precision medicine 
analysis. Secondary efficacy analyses will be conducted in pediatric 
participants, but power to support hypothesis testing will be limited for 
these analyses. 
 
Interim Analysis: 
 
 
 
 
 
 
 
 
 
 
Interim analyses will be conducted for the following purposes.  (1) A single 
interim analysis for futility may be conducted for each test treatment 
based on data from the a priori best subgroup, biomarker positive, 
patents.  Test treatments demonstrating futility will be dropped from the 
trial.  A futility analysis will be also performed in biomarker negative 
patents. Further enrollment to test treatments demonstrating futility in 
biomarker negative subgroup will be limited to biomarker positive 
participants.  (2) An interim analysis to estimate the within-participant, 
between-period correlation might be conducted pooling data across test 
and placebo treatment periods, maintaining the masking of treatment 
assignments. If the correlation is much higher than we hypothesized, we 

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Final Analysis: 
will reduce the required sample size prior to unmasking of treatment 
assignments and modify the final analysis plan to reflect this change. The 
timing of these interim analyses, will depend on the time the treatment is 
available to enter the Master Protocol, as well as participant accrual. 
 
An intervention will be considered effective if it is effective on at least one 
of the two primary outcomes. The analysis model for the final efficacy 
analysis will take into account the correlations on outcomes assessed for 
the same patient across the different treatment periods. The final analysis 
will include pairs of the treatment and matching placebo from the first two 
periods of the trial, as well as unmatched observations on the same 
patient. Mixed model repeated measures methods will be used for the 
primary analysis (see Section 9.5).  
 
Phase: 
Phase 2 proof-of-concept study 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
Approximately 35 U.S. sites; all sites are clinic settings.   
Description of Study 
Intervention: 
Five novel treatments for severe asthma will be studied, each targeting a 
specific, biomarker-defined subgroup of participants.  Candidates currently 
include novel medications and dietary supplements that target 
mechanisms relevant to asthma pathology.  
 
Study Duration: 
Approximately 62 months from first participant screened until last 
participant follow-up   
 
Participant Duration: 
Treatment Supply: 
 
Participant duration will be variable based on the time they enter the 
study and the number of treatments for which they are eligible (see 
Section 4.4). We anticipate needing approximately 850 months of 
treatment (active or placebo) for each intervention.  
 
1.2 
SCHEMA 
 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
PrecISE Visit Structure 
 
 
Procedures 
Visit SA: Screening 
 
Visit SB: Optional as 
needed to qualify 
Visit SC:  Compliance 
check* 
Visit 0: Run-In Visit, Safety 
Labs & Biomarkers 
Visit X.1: Treatment Visit 1 
Visit X.2: Treatment Visit 2 
 
Visit X.3: Treatment Visit 3 
 
Visit X.4: Treatment Visit 4 
Visit X.5: End of Treatment 
Visit 
Visit X.6: Washout 
 
Consent, Demographics, 
Contact Info, Registry1 
X 
 
 
 
 
 
 
 
 
 
Complete Physical Exam 
X 
X 
 
 
X 
 
 
 
 
 
Brief Physical Exam by 
Coordinator 
 
 
 
X 
 
X4 
X 
X4 
X 
X11 
CompEx Diary Assessment1  
 
 
X 
X 
X 
X 
X 
X 
X 
X11 
Compliance Assessment1 
 
 
X 
X 
X 
X 
X 
X 
X 
X11 
Dispense Controller 
Medication1  
X 
X 
 
X 
X 
X 
X 
X 
X 
X11 
Dispense and train on e-
diary and home 
spirometers1 
X 
X 
 
 X 
 
 
 
 
 
 
Assess that participant 
meets or continues to meet 
inclusion criteria1 
 
 
 
X 
X 
 
 
 
 
X11 
Intervention Assignment 
(occurs between visits 0 and 
1.1 for the first period) 1 
 
 
 
X 
 
 
 
 
 
X11 
Treatment Assignment 
(active or placebo) 1 
 
 
 
 
X 
 
 
 
 
 
Dispense Study Treatment1 
 
 
 
 
X 
X 
X 
X 
 
 
Medical, Asthma and Allergy 
History questionnaires1 
X 
X 
 
 
 
 
 
 
 
X 
Adolescent School 
questionnaire (participants 
in school only) 1 
X 
 
 
 
 
 
 
 
 
 
Validated questionnaires (to 
determine sleep apnea, 
GERD, depression, sinus 
disease, vocal cord 
dysfunction) 1 
X 
X 
 
 
 
 
 
 
 
 

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PrecISE Visit Structure 
 
 
Procedures 
Visit SA: Screening 
 
Visit SB: Optional as 
needed to qualify 
Visit SC:  Compliance 
check* 
Visit 0: Run-In Visit, Safety 
Labs & Biomarkers 
Visit X.1: Treatment Visit 1 
Visit X.2: Treatment Visit 2 
 
Visit X.3: Treatment Visit 3 
 
Visit X.4: Treatment Visit 4 
Visit X.5: End of Treatment 
Visit 
Visit X.6: Washout 
 
Validated questionnaires for 
Quality of Life and Work 
Productivity1 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Socioeconomic 
information/Household1 
X 
 
 
 
 
 
 
 
 
 
Asthma and non-asthma 
medication (concomitant 
medications) status1  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blinding Index questionnaire 
 
 
 
 
 
 
 
 
X 
 
Pulmonary Function, Asthma Control and Exacerbations 
Spiro PRE with specified 
med withholds2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X11 
Spiro POST 4 puffs albuterol2 
 
 
 
X 
X 
 
 
 
X 
 
Maximum Bronchodilator (4 
+ 2 + 2 puffs albuterol) 
X 
 
 
X3 
 
 
 
 
 
 
Methacholine challenge (if 
needed) 
 
X 
 
 
 
 
 
 
 
 
DLCO (if needed bc 
+smoking Hx) 
 
X 
 
 
 
 
 
 
 
 
Cotinine (if needed bc 
+smoking Hx) 
 
X 
 
 
 
 
 
 
 
 
ACQ-61 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Exacerbation History/Health 
care utilization 
questionnaire1 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Urine: Pregnancy test 
(females of childbearing 
potential) 
X 
X 
 
X 
X 
X4 
X 
X4 
X 
X11 
Blood: CBC with Differential 
Count 
 
 
 
X 
X 
X4 
X 
X4 
X 
X11 
Blood: Chemistry Panel 
(including liver function 
tests) 
 
 
 
X 
X 
X4 
X 
X4 
X 
X11 
Blood: Triglycerides (non-
fasting) 
 
 
 
X 
 
 
 
 
 
 

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PrecISE Visit Structure 
 
 
Procedures 
Visit SA: Screening 
 
Visit SB: Optional as 
needed to qualify 
Visit SC:  Compliance 
check* 
Visit 0: Run-In Visit, Safety 
Labs & Biomarkers 
Visit X.1: Treatment Visit 1 
Visit X.2: Treatment Visit 2 
 
Visit X.3: Treatment Visit 3 
 
Visit X.4: Treatment Visit 4 
Visit X.5: End of Treatment 
Visit 
Visit X.6: Washout 
 
Blood: Viral screens – Hep B 
and C, HIV Types 1 and 2 
 
 
 
X 
 
 
 
 
 
 
Blood: TB via QuantiFERON5   
 
 
 
X 
 
 
 
 
 
 
Radiology (CXR), not 
required if the participant 
has a negative 
QuantiFERON5 
 
 
 
X 
 
 
 
 
 
 
Cardiology (EKG) 
 
 
 
X 
 
 
 
 
 
 
Adverse event assessment1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Primary Predictive Biomarkers 
Blood eosinophils (CBC with 
diff) 
 
 
 
X 
X 
 
 
 
 
 
Plasma IL-6 
 
 
 
X 
 
 
 
 
 
 
FeNO 
 
 
 
X 
X 
 
 
 
 
 
Genotyping 
 
 
 
X 
 
 
 
 
 
 
Response/pharmacodynamic biomarkers 
Blood eosinophils (CBC with 
diff) 
 
 
 
 
 
X4 
X 
X4 
X 
X11 
Plasma IL-6 
 
 
 
 
 
 
 
 
 
 
FeNO 
 
 
 
 
 
X4 
X 
 
X 
 
Additional Phenotyping Procedures  
Sputum induction6 
 
 
 
X 
 
 
 
 
 
 
CT scan for lung 
phenotyping6 
 
 
 
X 
 
 
 
 
 
 
Blood: PBMCs7 
 
 
 
 
X8 
 
 
 
X 
 
Urine for biorepository 
 
 
 
 
X 
 
X 
 
X 
 
Blood for RNA9 
 
 
 
X 
 
 
 
 
 
 
Other blood (plasma, serum) 
for biorepository 
 
 
 
 
X 
X4 
X 
X4 
X 
 
Nasal EPX10 
 
 
 
X 
X 
 
X 
 
X 
 
*Visit SC is optional. All other visits are approximately 4 weeks apart. Treatment visits X.1-X.6 are 
repeated each treatment period. 
1 These procedures and assessments may be conducted remotely via phone, videoconference or 
electronic survey methods. 

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2 Spirometry may be conducted in the home and/or in the clinic. 
3 Optional at site discretion to demonstrate reversibility 
4 Not required for adolescents at VX.2 and VX.4. 
5Blood for TB via QuantiFERON is collected on adults only 
6 If not collected before V1.1, the Sputum and CT can be collected before or at V2.1 or before or at V3.1. 
Sputum induction and CT scans may not be conducted at all sites. 
7 PBMCs may not be collected at all sites. 
8 PBMC is only collected at V1.1.   
9 Blood for RNA if not collected before V1.1, should be collected at V2.1, and, again, at V3.1. 
10 Nasal EPX can be skipped if the institution requires a COVID test before the procedure. Nasal EPX 
collection is optional at the site level. 
11 Not required at the final VX.6. 
Note: Due to the COVID-19 pandemic, not all procedures will be conducted at all clinic visits. 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY BACKGROUND AND RATIONALE  
Severe asthma affects 5 - 10% of all patients with asthma (~2.5 million Americans) and patients with 
severe asthma experience substantial morbidity and require extensive use of healthcare resources.1 
Despite the use of high dose inhaled corticosteroids and a second controller (and/or systemic 
corticosteroids), severe asthma patients continue to have poor control, low lung function and/or 
increased risk of severe exacerbations.   
While most asthma is controlled by currently available therapy including beta-agonists and inhaled 
corticosteroids, severe asthma continues to produce symptoms and/or exacerbations despite these 
currently available therapies.1  Persistent symptoms impair quality of life, lead to loss of days from work 
and school and impose a high personal and societal economic burden.  Recurrent exacerbations lead to 
loss of days from school and work and are associated with accelerated loss of lung function.  In addition, 
recurrent exacerbations are treated with oral corticosteroids; 52% of adults enrolled in the NHLBI Severe 
Asthma Research Program 3 (SARP3) had received at least two courses of systemic corticosteroids in the 
prior year.5  Many patients experience substantial side effects from these short courses, including sleep 
problems, mood changes, increases in appetite and weight gain, challenges in maintaining glucose 
control in patients with diabetes, and hypertension.  Furthermore, a recent study of over 1.5 million 
commercially-insured Americans showed that short term use of oral corticosteroids for any condition 
(including asthma) was associated with significantly increased risks of developing sepsis, venous 
thromboembolism, and bone fracture within 30 days of corticosteroid use.6  Thus, identification of 
therapeutic strategies that reduce asthma symptoms or reduce the risk of exacerbations among patients 
with severe asthma is essential.  
Optimal treatment for patients with severe asthma is uncertain, because the pathophysiologic 
underpinnings of severe asthma are heterogeneous.1  For example, in the cluster analyses performed 
using SARP data, five clusters of asthma were identified. Three of them were characterized by early 
onset of disease and aeroallergen sensitivity (cluster 1: mild, 2: moderate and 4: severe).7 Other patients 
with severe asthma may have fixed or progressive reductions in lung function (cluster 5) or a later age of 

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asthma onset (cluster 3). Finally, a subgroup of patients with severe asthma have persistent eosinophilic 
or neutrophilic airway inflammation (clusters 4 and 5).  
Other factors that may influence asthma severity include disease duration, sex, obesity, and respiratory 
infections. A treatment may be effective for only a subset of patients with particular 
phenotypes/endotypes of severe asthma or other factors. The newest therapies for severe asthma, 
those targeting eosinophils, appear to be primarily effective in patients with Type 2 inflammation.  In 
the ACRN TALC study,8 African-Americans were less responsive to each of three add-on therapeutic 
regimens than Caucasians. Traditional biomarker-stratified parallel arm trial designs are inefficient and 
could be considered as a barrier to drug discovery for newly recognized inflammatory pathways and/or 
uncommon patient subsets. Therefore, a need exists to take a personalized medicine approach to severe 
asthma, with treatments that are tailored to an individual participant’s clinical or biomarker profile. 
Precision medicine allows more patients to receive the specific treatment that is likely to be best for 
them. Severe asthma is a disease that stands to benefit from the use of novel trial designs and statistical 
methods to identify effective targeted therapies. The goal of this trial design is to efficiently use 
resources to test treatments in specific subgroups of patients. The adaptive platform design proposed 
here has multiple advantages. It allows rapid evaluation of innovative therapies while holding out the 
potential of providing information on informative phenotypic biomarkers and possibly early-response/ 
pharmacodynamic biomarkers.  It permits patients to receive multiple interventions and will ultimately 
provide information on therapies that might be most suited to them.  Design features that allow for this 
flexibility include shortening the required time to follow up participants, reducing the number of 
participants in different treatments, and initiating novel treatments more quickly.  
The background information for individual test treatments is found in Appendices I–V, Section 2.2. 
2.2 
RISK/BENEFIT ASSESSMENT   
The overall burden of severe asthma is much greater than that associated with mild-to-moderate 
disease.  In addition to the side effects and decreased efficacy of systemic corticosteroids in these 
patients (reviewed in Section 2.1), many patients with severe asthma have daily symptoms, functional 
impairment and frequent health care utilization. These indicators of morbidity persist despite 
introduction of newer therapeutic strategies which are not uniformly effective across the spectrum of 
severe asthma. Discussions with patients and advocacy organizations indicate that patients with severe 
asthma are often also frustrated by their current clinical care, particularly if they do not have access to 
an asthma specialist.  
Participants in these forums have expressed a general interest in learning more about the subsets of 
severe asthma and a willingness to try new medications, even those associated with side effects.  
The PrecISE Network convened three Participant Advisory Councils (PAC, see Section 5.5) in the 
Midwest, Southeast, and Southwest.  These PACs consisted of twenty adults with severe asthma who 
completed a half-day workshop with PrecISE investigators.  Input of the PAC was incorporated into the 
creation of this master protocol and will be briefly summarized.  
The PAC expressed the opinion that they would recommend participating in a PrecISE protocol to others 
with severe asthma, and specifically commented that use of the placebo, multiple treatment periods, 
and a washout period are acceptable features of a clinical trial.  The PAC also expressed a willingness to 
undergo multiple sequential interventions followed by washout periods with the possibility of placebos 
during treatment periods. Finally, most patient advisors felt that the study procedure and visit burden 
was acceptable for the potential benefit of advancing the state of knowledge in the treatment of severe 
asthma. However, there was concern among patients about the length and number of visits and the 

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number of PFTs to be performed.  Therefore, the investigators reduced the number of PFTs and visits in 
consideration of this feedback.  The PrecISE Network also conducted one-on-one interviews with five 
adolescents with severe asthma and their caregivers.  Overall, parents were very protective of their 
children and less enthusiastic about the trial. They were concerned about use of placebos but expressed 
that they would be willing to consider the trial if their physician recommended it.  The pediatric 
committee considered the concerns of the caregivers and understands how important physician 
recommendation for the trial will be in recruitment of these patients. 
The risks of study participation and the specific interventions in PrecISE are reviewed in Appendices I-V, 
Section 2.3, but in general, include risks of worsening asthma control, major infection, diarrhea and 
electrolyte abnormalities. In addition to safety lab monitoring, the overall risk of these side effects is 
mitigated by the short treatment periods (16 weeks) in this protocol, followed by washout periods of 
the study treatments. 
The following sections also discuss the nonpharmacologic risks and benefits of study participation. 
2.2.1 KNOWN POTENTIAL RISKS  
Participating in the research study has the potential for some risks to the research participant. The risks 
of our therapeutic interventions are listed for each intervention under its respective section. In addition, 
we have delineated below the risks of our research procedures, which may include physical, 
psychological, social, or legal risks. 
The risk of disclosure of study participation is a risk to participants in the study.  
Questionnaires pertaining to related allergy, asthma and pulmonary symptoms, medication, and history 
will be conducted as part of the study and may be considered burdensome and repetitive. This may 
occur but is not considered a serious risk to the research participant. 
Venipuncture to collect blood for biomarkers and safety studies is occasionally associated with minor 
bruising, risk of infection, discomfort, feeling light headed, or faint. 
Spirometry measurements are conducted to evaluate a participant’s lung function. Spirometry can 
cause any participant to become light-headed or dizzy. This may make asthmatic participants wheeze or 
experience shortness of breath or chest tightness, or they may worsen these symptoms if they were 
already occurring. The chance of these symptoms occurring is not common but treatment (including 
albuterol) will be available to the participant if any of the symptoms should occur. During the procedure, 
albuterol will also be given to determine reversibility. Common risks associated with albuterol include 
headache, increased pulse rate, and shakiness of hands. Uncommon risks include heart pounding or 
racing, mouth and throat irritation and muscle cramps. Rare side effects include low blood potassium, 
irregular heartbeat or heart rhythm, hyperactivity and an immediate increase in wheeze after dosing. 
The same potential risks associated with spirometry conducted in the clinic exist for spirometry 
conducted in the home. Participants will have treatment (including albuterol) at home to treat any of 
the symptoms listed above, should they occur. Moreover, the study coordinator will be video-
conferencing with the participant during in-home spirometry assessments to monitor the participant’s 
safety. 
As part of the preparation for spirometry testing, a participant may be asked to withhold using certain 
medications prior to certain breathing tests and study visits. An increase in allergy or asthma symptoms 
may occur as a result.  
Methacholine may cause coughing, chest tightness, shortness of breath, and wheezing. On rare 
occasion, severe bronchospasm can occur.  

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Induced sputum can be associated with bronchospasm in participants with asthma.  
Urine will be collected by clean-catch and there are no foreseeable risks to its collection. 
Exhaled nitric oxide is a non-invasive procedure to measure the amount of nitric oxide in exhaled breath 
and there are no clinically significant risks to its measurement. 
Pregnant or nursing women are not permitted to participate in this study. Certain procedures and test 
treatments could cause harm to the fetus including but not limited to radiation from the CT scan, and 
methacholine inhalation. Females of childbearing potential will be required to use acceptable methods 
of birth control and will undergo pregnancy tests regularly throughout the study. 
Low-dose chest CT has been used safely in numerous clinical research studies of COPD and asthma. 
However, x-ray Radiation from CT at clinical exposure levels has been shown to have a nominal cancer 
risk at the population level. To minimize this risk, CT dose levels are kept to a minimum and not all lung 
volumes are scanned for all time points. For the proposed CT protocol, participants receive a total 
effective dose of 3 times the annual background radiation (3.3 mSv) for the total of the 21-month 
treatment period. This is lower overall than the effective dose in comparable studies such as SARP III 
despite more frequent monitoring. Additional time points may be specified using a 50% reduced dose 
protocol developed within QIBA (http://qibawiki.rsna.org/index.php/Lung_Density_Biomarker_Ctte). 
Noise associated with lower dose is mitigated using median filtering or iterative reconstruction (where 
available).  
Protection against risk 
Safety monitoring is multifaceted, including addressing safety of the research participants, processes for 
minimizing research-associated risk, protection of study data and participant identification, and review 
and reporting of adverse and unanticipated events. This information is outlined in the Data and Safety 
Monitoring Plan for the study (see Section 10.1.6). Adverse events will be reviewed by the Data, 
Modeling and Coordinating Center (DMCC), IRB, PrecISE Data and Safety Monitoring Board (DSMB), and 
NIH, as required. Any participant may choose to withdraw from the study at any time, and any 
participant may be electively discontinued from the study by the PI.   
Every precaution is taken to ensure participant safety. The measures taken to minimize risk are 
described in the section below under each specific procedural risk. The staff responsible for this protocol 
are skilled in the management of severe asthma, allergies, and anaphylaxis. All coordinators 
administrating study medications will be certified in preparation and administration. Venipuncture and 
test treatment administration will be performed by trained medical personnel using aseptic technique. 
Having experienced research staff following established guidelines for all study procedures will help 
reduce the risk to participants. All PrecISE clinical centers have extensive experience in the performance 
of these procedures, and safety checks and procedures are in place to minimize risk.   
Central training on study procedures and systems will be held for clinical personnel prior to study start 
and will be recorded for use by new staff members as needed during the study.  If new procedures or 
forms are adopted by the study, additional training will be conducted via webinars.  New clinical center 
staff will be trained by experienced staff at their site in addition to the training modules available via 
webinars.  Each clinical site staff member will be certified on study procedures and systems, and 
certification records will be maintained at the sites for auditing. 
 
 

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Minimization of research-related risk 
The protocol includes information about processes by which procedure related research risk is 
minimized.  
The risks for each of the interventions we propose is described in Appendices I-V, Section 2.3, as are the 
strategies to minimize risk.  For each of the interventions, we will exclude patients at high risk for known 
side effects of the intervention.  Throughout (and after the intervention if appropriate) we will monitor 
for known side effects as well as unknown and unexpected side effects.  Suspension of therapy and 
discontinuation of therapy thresholds have been specified. 
Risk of disclosure will be minimized through the use of several procedures.  The DMCC operates under 
FISMA (Federal Information Security Management Act) guidelines, and the data management system 
used in PrecISE is compliant with FDA 21 CFR Part 11, which establish security policies for the study 
databases, such as requiring use of strong passwords, limiting access to data based on study role, and 
the use of secure sockets layer encryption during data transmission.  Within the data management 
system, data elements are persisted in a format which isolates personal identifying information from 
other data elements.   
During the questionnaires, a participant can refuse to answer any question that makes them feel 
uncomfortable. 
The risk of venipuncture is minimized by allowing the participants to recline during the venipuncture.  
Aseptic technique will be used to prevent infection. 
Risks related to spirometry and reversibility will be minimized by monitoring participants for 
development of asthma symptoms or drop in lung function during the procedure. For in-home 
spirometry, monitoring will be conducted by video-conference. 
The risk of methacholine challenge is minimized by gradually increasing the agonist dose, while 
monitoring pulmonary functions after each dose. Participants with a baseline FEV1 <50% of predicted 
will not undergo bronchoprovocation. Albuterol is readily available to treat any symptoms. Lung 
function is monitored throughout the challenge, and methacholine dosing is stopped once lung function 
declines by 20%. Any acute severe bronchospasm will be treated with an inhaled beta-agonist. Medical 
and nursing personnel, medication, and equipment will be available at the study sites to treat and 
manage any bronchoconstriction episodes.  If symptoms become intolerable at any time during the 
procedure, the procedure will be stopped. 
Withholding asthma medications can cause chest tightness and wheezing. Participants are informed 
that if they cannot hold their medications and feel they need to take them, they should do so and call 
the study coordinator to let them know. 
The risk of sputum induction is minimized by monitoring participants for development of asthma 
symptoms or drop in lung function during the procedure. Pre-medication with albuterol will be provided 
and albuterol treatment will be available for clinically significant symptoms or drop in FEV1 >20% during 
or after the induction. 
To minimize risks during pregnancy, females of childbearing potential must have a negative pregnancy 
test prior to any testing and prior to any test treatment administration. They must agree to use 
acceptable forms of birth control throughout the study. 
Risks related to administration of prednisone to treat significant asthma exacerbations will be 
minimized by prescribing the shortest course of prednisone that is possible and monitoring for adverse 
events.  

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Although there are no proven harmful effects from the doses of radiation received during the CT scans 
proposed in this study, long term effects on the participant’s health cannot be ruled out. Special 
precautions are taken for all of the procedures involving radiation to minimize the amount of radiation.  
This includes the use of low-dose CT scans when possible and the use of breast shields in the CT scans of 
women and adolescents. 
 
2.2.2 KNOWN POTENTIAL BENEFITS  
Although the goal of testing these add-on therapies is to find new therapies that improve lung function, 
asthma symptoms, or the risk of loss of asthma control events, there is no guaranteed benefit from 
participating in the trial. Some participants with asthma may achieve psychological benefit from 
involvement in an important research study and from interaction with the study staff. There is a 
possibility that the information obtained from participation in this study or treatments used will also 
directly benefit the participating participants. All research procedures will be completed free of charge 
to the research participants, including provision of asthma controller medications (if available). 
Participation in these studies may ultimately help in future understanding of the treatment and 
progression of respiratory diseases and learn more about the phenotypes that predict favorable and 
unfavorable responses to medications. Although some of the study procedures contain risks, the 
participants will be well monitored not only by the study personnel but also by the DSMB and the IRB.  
Because the study will be conducted under an IND, the study will provide reports to the FDA as required 
by federal regulations.  Risks will be minimized on site by close monitoring, thorough training prior to 
and during the study, and appropriate written documentation (Manual of Procedures).  
The knowledge to be gained from this study is important.  Asthma is characterized by striking 
heterogeneity that influences its severity and responsiveness to treatment. The Severe Asthma Research 
Program (SARP) has found severe asthma to include multiple phenotypes that contribute to ongoing 
impairment and risks for exacerbations. However, precision in predicting treatment responses in severe 
asthma is limited, and the lack of data to inform treatment guidelines in these high-risk participants 
remains a major unmet need. As a next step to better identify modifiable treatment targets and more 
effective treatments, we have focused on establishing underlying molecular causes (endotypes) that 
drive phenotypic disease expression in severe asthma subpopulations. Although traditional parallel 
group or cross-over designs for randomized, placebo-controlled clinical trials can provide guidance as to 
the efficacy of test treatments, adaptive trial designs offer more flexibility and efficiency in selecting 
personalized treatment options for severe asthma. Our vision is to develop personalized medicine 
approaches for the treatment of severe asthma phenotypes that are directed at disease pathogenesis, 
and will facilitate drug development and ultimately impact clinical practice. 
The risk/benefit assessment information for individual test treatments is found in Appendices I–V, 
Section 2.3. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
The study has two primary objectives: 
1. Identify novel therapies that work in biomarker-defined subgroups of severe asthma patients 
2. Optimize the subgroups targeted for treatment by refining the biomarkers and subgroup 
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To achieve the first objective, we will perform hypothesis tests for comparisons of each intervention to 
placebo, (independently of the other interventions) for each of the two primary endpoints (defined 
below).  An intervention will be considered efficacious if significant benefit is found with respect to 
either of the two primary endpoints.  To achieve the second objective, we will enroll participants outside 
the target subgroups and optimize the target subgroup definitions using precision medicine methods 
performed during the final analysis. 
The study also has two secondary objectives:  
1. Gain information about potential response/pharmacodynamic biomarkers for selected 
therapies 
2. Explore the safety and effectiveness of selected therapies in adolescent patients with severe 
asthma 
For the first secondary objective, we will identify which response/pharmacodynamic biomarkers could 
potentially serve as early or intermediate outcomes for an investigation.  These biomarkers may prove 
useful in predicting whether a treatment will be effective with respect to clinical outcomes, which could 
in turn inform future trials of the treatment.  For the second, we will describe trends with respect to the 
primary efficacy outcomes observed in the adolescent subgroup and determine if the risk profile of an 
intervention appears to differ between adults and adolescents.  We do not expect to have sufficient 
power for formal hypothesis tests of effects in the adolescent subgroup alone or for a test of age by 
treatment interactions. 
We have defined two primary endpoints: 
1)  FEV1 percent predicted, assessed prior to bronchodilator administration 
2) Asthma symptom control, assessed via the Juniper Asthma Control Questionnaire (ACQ-6) 
An intervention will be considered beneficial if it demonstrates improvement with respect to either of 
the two primary endpoints relative to placebo, and optimization of the subgroup to be targeted by each 
intervention will be performed taking both primary endpoints into account.  See Section 8.1 for details 
about assessments for each of these two primary endpoints. 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
The PrecISE Network is undertaking an adaptive platform trial conducted under a single Master Protocol 
to identify new therapies for severe asthma that are effective in biomarker-defined subgroups of 
participants. Five therapies will initially be investigated. The trial is designed to meet our primary 
objectives, namely, to: (1) Identify novel therapies that work in biomarker-defined subgroups of 
participants with severe asthma, and (2) Optimize the subgroups targeted for treatment by refining the 
biomarker and subgroup definitions.  
For each participant, the study consists of three successive phases: (i) an initial screening phase, (ii) a 2-
period crossover phase, and (iii) a single-period crossover phase with successive re-randomizations. 
Common platforms for biomarker screening will be used during the initial screening period to determine 
a participant’s biomarker profile. Throughout the study, interventions will be randomly assigned based 
on these biomarker profiles. Participants will have a higher likelihood of assignment to an intervention 
that targets their particular profile. Subgroup definitions and associated treatment assignment 
probabilities are adapted as data accumulate throughout the study. 

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Following the initial screening period, participants will be randomly assigned to interventions based on 
their biomarker profile and enter a 2-period, double-blind crossover phase consisting of two 16-week 
treatment periods separated by a washout period. Treatment sequence will be randomly assigned as 
either test treatment followed by matching placebo or vice-versa. 
At the conclusion of the 2-period crossover phase and a washout period, participants enter the single-
period crossover phase of the study consisting of successive single 16-week treatment periods followed 
by washout periods.  Participants are randomly assigned to interventions based on their initial 
biomarker profiles as ascertained during the screening period to reduce the likelihood of 
misidentification based on carry over effects from a treatment. The biomarker-based treatment 
assignment probabilities will be adapted during the study as data on the utility of the biomarkers in 
predicting treatment response accumulate.  
The duration of the washout period following interventions with half-lives of 11 days or less is eight 
weeks. If the half-life of an intervention is longer than 11 days, the duration of the washout period will 
be determined such that the time from last administration of the intervention to the time of the start of 
the next treatment is equal to or exceeds five half-lives of the intervention (see Appendices I-V).  
A small percentage of participants will receive placebo again in periods 3-6 to assess seasonal and 
sequence effects throughout the study (no participants will receive more than 3 placebos during the 
study). Masking of treatment assignments will be maintained by matching a participant’s second 
placebo (if assigned) with one of the available interventions for which the participant is eligible but has 
not yet received (see Section 6.3). Placebo data will be shared across interventions for comparative 
analyses of efficacy and safety of each intervention, independently of the others in the study, so that the 
number of placebo periods are minimized (see Section 9.5). 
Two of the interventions will be studied in adolescents. The treatment assignment probabilities at each 
period will be restricted accordingly. 
Based on our power calculations and analysis assumptions, a total of 111 participants both within and 
outside a priori best subgroup are needed for the final efficacy analysis (see Section 9.2) of each 
intervention. 
Reviews of safety data will be performed by the DSMB at periodic intervals throughout the study, and 
interventions found to pose significant safety risks in the severe asthma population will be dropped 
from the study. In addition, we plan to perform a single interim analysis for futility for each intervention 
(independently of the others) to allow for early stopping. Those that have not been eliminated due to 
either futility or safety will continue to accrue patients.  
Interventions may enter the study at different times, depending on their availability, and may be 
discontinued, as noted above.  
Our current study timelines and enrollment goals are designed so that each participant will receive up to 
five test treatments, depending on their time of enrollment. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
As described above, participants with severe asthma who remain poorly controlled despite the 
availability of effective asthma therapies account for a large proportion of the morbidity and mortality 
associated with the disease.  This phase 2 proof-of-concept trial is designed to provide preliminary 
evidence of effectiveness of up to six novel therapies that target specific phenotypes of severe asthma 
participants based on their biomarker profiles.  Additionally, we believe that each therapy investigated 
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platform trial has tremendous advantage over a traditional design in terms of efficiency of participant 
recruitment. The optimal subgroup of participants, defined by biomarker profiles that should be 
targeted by each therapy, will be determined through precision medicine analyses.  
 
4.3 
JUSTIFICATION FOR DOSE 
The justifications for doses for individual test treatments are found in Appendices I-V, Section 4.3. 
 
4.4 
END OF STUDY DEFINITION 
The study will end approximately 62 months after randomization begins. At the end of the study, 
participants will have completed varying numbers of treatment periods (test treatments and placebo) 
through the crossover design, depending on their enrollment dates.  The number of periods will range 
from 2-6, with the majority of participants expected to complete four or fewer periods during the study. 
An intervention may be stopped early for safety or futility. Consideration will not be given to stopping 
treatments based on early evidence of efficacy, to ensure sufficient power is available to support the 
final efficacy analysis and precision medicine analyses. If not stopped early, an intervention will be 
stopped when the total required sample size has been reached.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
To be eligible to enter the screening period, an individual must meet all of the following inclusion 
criteria:  
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
3. Male or female, age ≥ 12 years 
4. Stable asthma medications 
a. No change in asthma medications for the past interval of time based on the participant’s 
circumstances: 
i. 
Participants who have not been on a biologic (Table 1C) in the past 4 months must 
have all asthma medications stable for the last month 
ii. Participants currently on a biologic to be continued during PrecISE must be stable on 
that biologic for 2 months, with all other asthma medications stable for one month 
iii. Participant who stopped a biologic listed in Table 1C prior to screening must be free 
of treatment for 4 months. Other biologics not listed in Table 1C would be evaluated 
separately based on the half-life of the new medications. 
These rules also apply if the biologic (Table 1C) is prescribed for other conditions, such 
as atopic dermatitis etc.  
b. Use of medium or high dose inhaled corticosteroids (ICS) (defined by Table 1A) AND 
c. Use of an additional asthma controller/biologic (defined in Tables 1B and 1C) AND 

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d. For participants who enter into the run-in on medium dose ICS: they will be switched to 
high dose ICS; the participant’s Visit 0 should occur at least 4 weeks after initiation of 
the high dose ICS; to qualify, the participant must meet one of the first two entry criteria 
for uncontrolled asthma (low FEV1 with reversibility or high ACQ-6 score). 
 
5. Verification of the asthma diagnosis at VSA or VSB demonstrated by either bronchodilator 
reversibility or methacholine responsiveness.  This can be verified by direct measurement 
during the run-in or by historical evidence of either criterion.  Historical evidence of testing 
must have been performed under either the 2017 ERS technical standard9 or the 1999 ATS 
Guidelines10, and full sets of flow volume loops require review and approval by the 
Spirometry core.  These criteria are defined as: 
• An increase in FEV1 ≥12% AND 200 ml after up to 8 puffs of albuterol OR 
• Positive methacholine defined as PD20 ≤400 mcg (PC20 ≤ 16 mg/ml for historic data).  
 
6. Baseline poor or uncontrolled asthma at VSA and Visit 0, defined as meeting at least one of 
the following: 
• Poor symptom control – Asthma Control Questionnaire (ACQ-6) Score ≥1.5  
• Frequent exacerbations – Participants on high dose ICS at screening: ≥ 1 exacerbation 
defined as a documented burst of systemic corticosteroids (>3 days for adults and 
adolescents or >1 day for adolescents treated with dexamethasone) in prior year for 
those not receiving chronic OCS or an increase in >50% of baseline corticosteroid dose for 
≥3 days in those receiving chronic OCS.  
 
For patients on a biologic agent who do not meet criteria for low FEV1 or ACQ 
score, at least one asthma exacerbation must have occurred at least 2 months 
after the initiation of the biologic agent.  The definition of acceptable 
documentation for asthma exacerbations can be found in Section 6.5.3. 
• Low lung function with potential for improvement – During the run-in, the FEV1 <80% 
predicted (for adults≥18) or FEV1<90% (pediatric participants <18).  
 
The potential to improve is defined at Visit 0 by an improvement of 12% OR 200 
mL after up to eight puffs of bronchodilator has been administered.    
7. 
Agreement to adhere to Lifestyle Considerations (see Section 5.4) throughout study 
duration 
8. 
Owns or is able to obtain a device compatible with the eDiary system used for CompEx.  As 
of February 2020, the system requirements are an iOS 11+ device such as iPhone, iPad or 
iPod, or a smartphone or tablet running on Android 5.0+. 
  
 
 
 
 
 
 
 
 
 
 
 

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Table 1A: Definitions of lower and high dose ICS daily dosing for protocol qualification 
Inhaled corticosteroid (ICS) 
Lower dose* (mcg) 
High dose (mcg) 
Beclomethasone (Qvar) – HFA (40,80) 
160-320 
>320 
Budesonide (Symbicort) – HFA (80,160)1  
320-639 
≥640 
Budesonide (Pulmicort Flexhaler) – DPI 
(90,180)1 
360-720 
>720 
Budesonide (Pulmicort Respules) – nebulized2 
500-999 
≥1000 
Budesonide (Breztri)  
320 - 639 
≥640 
Ciclesonide (Alvesco) – HFA (80,160) 
160-320 
>320 
Fluticasone furoate (BREO, Arnuity Ellipta, 
Trelegy Ellipta) – DPI  
100-199 
≥200 
Fluticasone propionate (Flovent) – HFA 
(44,110,220)3 
220-440 
>440 
Fluticasone propionate (Diskus, Armonair 
respiclick) – DPI (50,100,250) 
250-500  
>500 
Fluticasone propionate (Advair) – DPI 
(100,250,500) 
250-500 
>500 
Fluticasone propionate (Advair) – HFA 
(45,115,230) 
230-460 
>460 
Fluticasone propionate (AirDuo) – DPI (113) 
226-452 
>452 
Mometasone HFA (Asmanex HFA) (100,200) 
200-400 
>400 
Mometasone (Dulera) – HFA (50,100,200)  
200-400 
>400 
Mometasone (Asmanex Twisthaler) – DPI 
(110,220) 
220-440 
>440 
HFA= Hydrofluoroalkane inhaler 
DPI= Dry Powder Inhaler 
*Doses from which patients can be switched to high dose in the run-in to ascertain whether they 
will meet entry criteria (these doses are also referred to as medium doses) 
1Not included in GINA table 
2Not included in GINA for adult dosing 
3Converted to US product 
 
 

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Table 1B: Medications that qualify as an additional asthma controller 
Long Acting Beta Agonists (LABA) 
Long Acting Muscarinic Antagonist (LAMA) 
Leukotriene Modifiers 
Theophylline 
 
Table 1C: Medications that qualify as biologics 
Anti IgE : Omalizumab  
Anti IL-5: Mepolizumab, Reslizumab, Benralizumab 
Anti IL-4R: Dupilumab 
Anti TSLP: Tezepelumab 
 
 
5.2 
EXCLUSION CRITERIA 
An individual will be excluded from participation in this study if they meet any of the following criteria: 
9.   Current participation in an interventional trial (e.g. drugs, diets, etc.) 
10. Enrollment in a clinical trial where the study medication was administered within the past 
60 days or within 5 half-lives (whichever is greater) 
11. Physician diagnosis of other chronic pulmonary disorders associated with asthma-like 
symptoms, including, but not limited to, cystic fibrosis (CF), chronic obstructive pulmonary 
disease (COPD), chronic bronchitis, emphysema, severe scoliosis or chest wall deformities 
that affect lung function, or congenital disorders of the lungs or airways. 
12. Receiving one or more immune-modulating therapies for diseases other than asthma. This 
does not include biologics that are also approved for asthma.   
13. Receiving methotrexate, mycophenolate (CellCept®), or azathioprine (Imuran®)  
14. Receiving aero allergen immunotherapy and not on at least 3 months of maintenance 
allergen immunotherapy  
15. Underwent a bronchial thermoplasty within the last two years 
16. Premature birth 
– Born before 32 weeks of gestation  
– For those born between 32 and 35 weeks, we will exclude patients who went home 
from hospital on oxygen or have ever had a diagnosis of bronchopulmonary dysplasia 
(BPD) /Chronic lung disease (CLD).  
 
Regarding the diagnosis of BPD and CLD, the investigator will discuss what is 
known about perinatal course, supported by medical record review, if available. 
If the patient received oxygen for 28 or more days or went home from the 
hospital on oxygen, then the patient will be excluded. 
17. Uncontrolled hypertension, defined as systolic blood pressure > 160 mm/Hg or diastolic 
blood pressure > 100 mm/Hg 
18. History of malignancy except non-melanoma skin cancer within the last five years 

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19. History of smoking  
Participants with a history of smoking who meet the following criteria may be included 
in PrecISE: 
- Participant is <30 years old, smoked < 5 years and none in the past year, and 
has a normal urine cotinine 
- Participant is ≥30 years old, smoked < 10 pack years and none in the past year, 
and has a normal urine cotinine 
- Participant is ≥ 40 years old, smoked 10-20 pack years and none in the past 
year, and has a normal urine cotinine and a normal DLCO (>70% predicted) 
If participant meets any of the following criteria, they are excluded: 
- Participant is <30 years old and smoked for ≥5 pack-years 
- Participant is 30-39 years old and smoked for ≥10 pack years 
- Participant is ≥40 years old and smoked ≥ 20 pack years 
 
 
* Smoking equivalent pack years.  One pack of cigarettes a day for 1 year is equivalent 
to: 
o 1 cigar or pipe per day for 1 year 
o Smoked hookah or shisha =1 session per day for 1 year 
o Vaped e-cigarettes =0.5 mLs e-liquid per day for 1 year, or =1 
cartridge/tank/pod per day for 1 year 
o 1 use of marijuana per day for 1 year 
 
20. Active use of any inhalant >1 time weekly in the past year 
- Active smoking of conventional tobacco, inhaling of marijuana or other drugs, or 
vaping of e-cigarettes or vape pods >1 time per week in the past year. 
- Any form of tobacco qualifies, such as: 1 cigarette, 1 hookah or shisha sessions, 1 cigar, 
1 pipe, etc. 
- Any electronic (e)-device included: e-cigarette e-cig, mod, vape pen, JUUL, e-cigar, e-
hookah, e-pipe, vape pods, etc. 
- Any form of inhaled marijuana, including smoking marijuana leaves or inhaling THC via 
e-cigarette or device 
21. Substance abuse within the last year 
22. Unwillingness to practice medically acceptable birth control or complete abstinence during 
the study, current pregnancy, or lactation. Medically acceptable birth control/abstinence is 
defined as: 
- Career, lifestyle, or sexual orientation precludes intercourse with a male partner 
- For those in a monogamous relationship that precludes sexual activity with other 
partners, one of the sexual partners has been sterilized by vasectomy (in males) or 
hysterectomy and/or bilateral salpingo-oophorectomy (in females) 
- Use of highly effective methods of birth control defined as those, alone or in 
combination, that result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly. Contraception should be used for at least 1 month prior to 

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screening, throughout study participation and for an additional 16 weeks after the end of 
the final test treatment.   
For females of child-bearing potential, pregnancy tests will be given prior to study 
enrollment and at each clinic visit. 
Each male participant will agree to inform his sexual partner(s) of the potential for harm 
to an unborn child. If a sexual partner becomes pregnant while he is participating in the 
study, he will notify study staff within 24 hours of receiving medical confirmation.  His 
partner will be advised to promptly notify her doctor.   
Any pregnancy (of a participant or a partner) will be monitored for adverse events with 
respect to pregnancy outcome until one month after birth. 
23. Requirement for daily systemic corticosteroids above 10 mg of prednisone (or equivalent) 
per day for the past 2 months. 
24. Respiratory infection within 1 month of screening 
25. Intubation for asthma in the last 12 months 
26. Use of warfarin, current or last 30 days 
27. Any clinically significant abnormal findings in the history, physical examination, vital signs, 
electrocardiogram, hematology or clinical chemistry during run-in period, which in the 
opinion of the site investigator, may put the participant at risk because of his/her 
participation in the study, or may influence the results of the study, or the participant’s 
ability to complete the entire duration of the study. 
28. Additional exclusions for specific interventions (and not for others) are listed in the 
Appendices I-V, Section 5.2.     
 
Safety Exclusion Criteria 
Participants who meet the following criteria will be excluded from the study:   
• 
Hemoglobin < 10 g/dL 
• 
ANC <1000/µl for black participants, <1500/µl for other participants 
• 
Lymphocytes <500/µl 
• 
Platelet count <100,000/µl 
• 
ALT/AST >2x ULN 
• 
Bilirubin ≥2x ULN 
• 
Estimated glomerular filtration rate (eGFR) <54 ml/min/1.73 sq m on two sequential tests 
performed within 2-4 weeks OR eGFR 54-60 ml/min/1.73 sq m and proteinuria detected on 
urine dipstick 
• 
Positive Human Immunodeficiency Virus, Types 1 & 2 (HIV 1&2) Ab/Ag immunoassay 
followed by a confirmatory positive test (Geenius™ HIV-1/HIV-2 antibody differentiation 
immunoassay) 
• 
Positive Hepatitis B surface Ag (active infection) or Hepatitis B core total antibody (marker of 
past infection that could reactivate) 
• 
Positive Hepatitis C RNA test following positive Hepatitis C Antibody 
• 
EKG with significant clinical findings 
Adult participants (age≥18) will be screened for TB.  A positive QuantiFERON-TB Gold test requires 
further screening.  A participant may be included in PrecISE if at least one of the following criteria are 
met: 
• 
A chest radiograph (CXR) done within the last six months of the test that shows no evidence 
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• 
A chest CT scan done within the last six months of the test showing no evidence of active TB  
• 
Documentation of adequate treatment for latent TB.  
In cases of an indeterminate QuantiFERON-TB test result, a second blood specimen must be drawn. A 
chest x-ray is not required if the participant has a negative QuantiFERON-TB Gold test. 
Adolescent participants (age<18) will not be screened for TB. 
 
Comorbid Conditions 
Comorbidities are commonly present in severe asthma. Specific questionnaires will be used to identify 
common comorbidities as follows: 
•    Sleep apnea: STOP-BANG 
•    GERD (GERD- Questionnaire) 
•    VCD (Pittsburgh vocal cord dysfunction index) 
•    Chronic Rhinitis Sinusitis (Sinonasal questionnaire-SNQ5) 
•    Depression- Anxiety (Hospital anxiety and depression Scale: HADS) 
These questionnaires are best used as screening tools. As such they typically have high sensitivity but 
relatively low specificity. Many of their symptoms overlap with the symptoms reported by participants 
with asthma who do not suffer from these conditions. Therefore, participants who meet the established 
cut offs for these questionnaires will need to be evaluated by the investigator to consider the clinical 
significance of the positive questionnaire based on history and physical and available testing.  The 
investigator will need to judge the presence, severity and control of a specific condition and determine if 
it is sufficiently controlled to keep the participant in the PrecISE protocol. If the comorbid condition(s) 
is/are not adequately controlled, the investigator may refer the participant for further 
evaluation/treatment, prior to enrollment in PrecISE.  Rescreening is permitted (after at least four 
weeks) to determine if the participant is able to move forward in PrecISE once the comorbid condition(s) 
is/are under adequate control. It is expected that some of the participants may also have other 
conditions such as cardiovascular disease, diabetes and obesity. These should be evaluated clinically as 
part of the complete history and physical done at initial evaluation. Their inclusions should be based on 
the investigator clinical judgement in line with good clinical practice principles. 
5.3 
RANDOMIZATION CRITERIA 
In order to be eligible to enter the study following run-in period, an individual must meet all of the 
following additional randomization criteria:  
• 
Must have stable asthma medications in the 4 weeks prior to visit 1.1 and no major change in 
therapy during the run in except for switching from medium to high dose ICS 
• 
Must still meet criteria for poor baseline asthma control as defined above. For asthma 
exacerbation criteria, the exacerbation must have occurred within the past year from the 
start of the run-in period 
• 
To be eligible for randomization, individuals must demonstrate adherence by: 
o taking controller medications ≥70% of scheduled doses and completing e-diaries and 
PEFs ≥70% [20/28 possible entries] during any 14 consecutive days among the 21 
days prior to visit 0. 
o taking controller medications ≥70% of scheduled doses 28 days prior to visit 1.1 
o completing e-diaries and PEFs ≥70% [40/56 possible entries] 28 days prior to visit 1.1 
o completing e-diaries and PEFs ≥70% [20/28 possible entries] 14 days prior to Visit 1.1 
for establishment of the CompEx baseline. 
All criteria assessed 3 days prior to visit 0 or visit 1.1  

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Electronic surveys, and occasionally paper diaries, may be used as a backup data source for 
recording e-diary and peak flow measurements if data are missing due to a technical issue 
with the electronic data system.  
Individuals who do not meet the adherence criteria prior to target dates for visits 0 and 1.1 
will be retrained, either in-person or by telephone.  The scheduled visit will be postponed to 
allow the participant to bring adherence up to the 70% targets.  If the participant has already 
been allowed 4 additional weeks in the screening period and does not meet adherence 
requirements, then he or she will be considered a screen failure.  Depending on the 
circumstances, these individuals may be allowed to re-enroll at a later time. Participants may 
be contacted via phone to ensure safety and to assess any issues that may be ongoing during 
screening. 
 
 
5.4 
LIFESTYLE CONSIDERATIONS 
Throughout the duration of this study, participants are asked to: 
• 
Abstain from use of all tobacco products and nicotine containing products (including e-cigarettes, 
patches) 
• 
Abstain from use of inhaled marijuana 
• 
Abstain from use of any illegal drugs including abuse of prescription drugs 
5.5 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomized to a test treatment. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
Screening visits (see Section 8.2) are designed to ensure that participants meet inclusion criteria for lung 
function and criteria for bronchodilator reversibility or methacholine reactivity.  
Individuals must wait 4 weeks after screen failure to undergo rescreening. Participant’s visit will be 
delayed rather than a rescreen, if he/she fails to meet the criteria for participation or randomization in 
the trial during the initial screening for reasons such as: 
• 
An asthma exacerbation within two months of initiation screening/during run-in 
• 
A respiratory infection within one month of screening 
• 
Inability to demonstrate adherence to daily diaries, and PEFs of at least 70% for the two weeks prior to 
Visit 1.1 
 
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Asthma patients will be recruited largely from a variety of settings, via direct contact in clinical settings, 
advertisement, word of mouth, social media, mass mail and mass email; however, some severe asthma 
patients may come from hospitals and emergency departments, urgent cares and primary care practices 
A conscious effort will be made to have a balanced representation of males and females and various 

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ethnic groups. Participants who have already participated in studies focused on severe asthma, and 
have expressed interest in clinical trials would be an initial target for recruitment. Study goals, risks and 
benefits will be explained as part of the informed consent process. Various approaches will be 
considered to enhance participant retention including: scheduling flexibility, offering time with a 
physician investigator to examine the participant and answer their questions at each visit, thus building 
a connection and trust, regular phone call from the coordinators (or electronic messaging), postcard 
reminders, birthday cards and Thank You notes, updates on study progress (such as regular study 
newsletter targeted at the participants, celebrating milestones), participant support groups and 
invitation to provide input into future studies. 
The PrecISE Network convened a Participant Advisory Council (PAC) which provided patient-level input 
about the potential experience of enrolling and participating in this trial. The insights gained from the 
PAC will be deployed in real-time to assist with recruitment and retention. As part of this effort, the 
network has also incorporated investigators with expertise in leveraging human-centered design 
methods in clinical trials to promote effective recruitment and retention strategies fit-for-purpose. 
Three PAC meetings were convened in Fall of 2018 and Winter of 2019 (also discussed in Section 2.2 
Risk/Benefit Assessment).  These meetings occurred in different regions of the US including the 
Southwest, Southeast, and Midwest and were each four hours long.  A total of twenty adults 
participated and provided in-depth feedback on the length of study, visit schedule, randomizations and 
procedures, study medications, monitoring, compensation, recruitment and retention.  In addition, one-
on-one interviews were conducted with six adolescents and their primary caregiver to understand their 
perspective on these important aspects trial.    
Recruitment and retention throughout the study will be monitored by the Recruitment and Retention 
Committee.  This committee will oversee development of materials to facilitate recruitment and 
retention, monitor progress with respect to both as the study progresses, and develop strategies for 
addressing recruitment and retention issues as they arise.  The DSMB will monitor accrual at each 
clinical center based on periodic summary reports provided by the DMCC for their review (see Section 
10.1.6) and make recommendations on proposals to address recruitment or retention challenges, such 
as adding more clinical centers or extending enrollment, if needed. 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Details about each of the interventions being considered for initial study are provided in Appendices I-V, 
Section 6.1.1.  As new interventions are identified for study under the master protocol, additional 
appendices describing each will be added via protocol amendment. 
6.1.2 DOSING AND ADMINISTRATION 
The dosing and administration information for the initial five individual interventions is found in 
Appendices I-V, Section 6.1.2. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
The preparation/handling/storage/accountability information for the individual interventions is found in 
Appendices I-V, Section 6.2. 

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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Placebo administration and masking 
Each test treatment will have its own placebo that matches the test treatment in mode of 
administration, color, size, and/or taste. Each participant will receive at least one placebo during their 
participation in the network.    
In the first two periods, each participant will receive a test treatment and its matching placebo, with the 
order being randomly determined (a two-period crossover design). After the first two periods, a test 
treatment will be randomly selected for each participant in each period.  Participants may receive a 
second placebo during periods 3-6. The number of participants receiving a second placebo will be 
monitored throughout the study, and the probability of a second placebo assignment adjusted so that 
approximately 25% of participants receive a second placebo.  Masking of treatment assignments will be 
maintained by matching a participant’s additional placebo(s) (if assigned) with one of the available 
interventions for which the participant is eligible but has not yet received. Note that a participant may 
discontinue treatment early in their initial placebo period (period 1 or 2) due to safety or other reasons. 
In this case, the probability of additional placebo assignment(s) may be adjusted such that the 
participant may be assigned to placebo for at most three periods.  Further details about randomization 
are provided in the Statistical Analysis Plan. 
Examples of possible treatment sequences are shown in Figure 1. No participant will receive placebo in 
more than three periods unless the participant experiences a major change in therapy and is re-enrolled 
(Section 6.5.3).  This strategy results in participants enrolled earlier, and therefore eligible for more 
treatment periods, having a higher chance of receiving a second placebo than participants enrolled later 
in the trial, when fewer treatment periods are available before the study ends.  
The initial randomization to a complete two-period crossover design, with all participants receiving 
placebo during one of these two periods, allows for efficient estimation of treatment effects to support 
futility analysis of each test treatment early in the study.  The addition of a randomly assigned additional 
placebo(s) allows for the estimation of time differences in placebo response and the potential to adjust 
the final efficacy analysis for any time trends observed.  Because some participants will receive two 
placebos with different modes of administration (e.g., oral and injection or dietary and oral, etc.), we 
will also be able to estimate differences in placebo response between different modes of placebo 
administration. 
The additional placebo(s) also provides some protection against expectation bias (relative to outcome 
assessments and other reporting behaviors) on the part of both the participants and the 
investigators/clinical staff, because there is a positive probability of placebo assignment in each 
treatment period for periods 3-6. 
In addition to the safety assessments conducted on all participants throughout the trial (see Section 8), 
one or more interventions may require additional safety monitoring specific to that intervention (see 
Appendices I-V for additional safety requirements for each intervention).  Participants randomly 
assigned to an intervention or its matching placebo will receive the treatment specific safety 
assessments required during the assigned periods.  Performing the additional safety assessments on the 
matching placebo participants will help maintain the masking of treatment assignments for the study. 
Note also that to further maintain masking in periods 3-6, a participant can get a placebo matched to 
intervention A only if the participant has not yet received intervention A, and a participant who has 
completed a period with placebo matched to intervention A is not eligible to receive intervention A for 
the remainder of the study. 

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Figure 1: Example Treatment/Placebo Sequences  
 
 
Treatment assignment  
Predictive biomarkers will be used to define an initial subgroup to target for each intervention based on 
a priori information available at the time the intervention enters the trial.  During the screening period, 
biomarkers will be assessed using common screening platforms to determine the biomarker profile for 
each participant.  Based on these biomarker profiles, a determination will be made as to which 
participants should be targeted by which interventions.  The biomarker profile determined at screening 
will be used to inform the randomizations at all treatment periods. 
For the initial two-period crossover phase, participants will first be assigned to an intervention based on 
their biomarker profile using a biased-coin type design that favors treatments targeting the particular 
profile of most participants.  A second randomization then occurs to determine the crossover sequence, 
i.e., whether participant receives test treatment followed by placebo (T:P) or placebo followed by test 
treatment (P:T).  In subsequent treatment periods (periods 3-6), the same biased-coin design will be 
repeated to assign interventions, but restricted to interventions not yet received by a participant in prior 
periods. 
The target subgroups initially defined for each intervention will have some degree of overlap, such that 
some participants will be targeted by more than one intervention.  The randomization probabilities at 
any point in the trial will reflect the priorities in place at that time.  For example, interventions that have 
not yet reached the required sample size to test for futility will be favored over interventions that have 
already enrolled enough participants to conduct the futility analysis. 
Apart from intervention-specific predictive biomarkers, treatment assignment will take into account 
three factors thought to be prognostic for asthma outcomes: past-year exacerbations at the study’s 
baseline (assessed during the initial screening period), blood eosinophils, and plasma IL-6 levels. The 

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goal is to ensure that participants contributing to the efficacy analysis (interim and final) of each test 
treatment resemble the severe asthma subpopulation with respect to these three factors.  Initial targets 
for balancing with respect to these three factors will be based on the factor distributions in the SARP 
database.  Randomization will be implemented in such a way that biomarker positive participants 
assigned to an intervention are likely to include at least 50% of the SARP distribution as far as baseline 
past year exacerbations ≥ 2.  For example, if a random sample from the biomarker positive subgroup for 
a particular intervention would be expected to have 35% of participants with baseline past year 
exacerbations ≥ 2 based on SARP data, where possible, randomization will favor treatments that have 
less than 0.5*35% = 13% of participants with baseline past year exacerbations ≥ 2.  Similarly, we will 
balance assignments with respect to blood eosinophils ≥300 µl and plasma IL-6 level ≥ 3.1. As data 
accumulate in the trial, the initial targets based on SARP distributions will be refined reflecting the 
PrecISE study population.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
The following mechanisms will be employed to determine protocol and medication adherence and 
measure outcomes: 
1. An electronic peak flow meter/e-diary device will be used to measure peak expiratory flows 
(PEF). The device will serve to obtain PEF and will function as a general adherence check (date 
and time are electronically recorded). Electronic measurements will be transmitted to a central 
platform and a compliance report will be reviewed with the participants. PrecISE coordinators 
will provide positive feedback to participants who demonstrate good adherence, and ongoing 
encouragement when warranted. 
2. The PrecISE network will leverage the e-diary platform from Propeller Health (or other 
provider) to administer a daily question for self-report of intervention compliance. Qualtrics e-
diaries have been developed as a backup to the e-diaries provided by Propeller Health.  In 
addition, adherence with the e-diary symptom questions for use in the CompEx serves as a 
proxy for study procedure adherence in general. A financial compensation structure is planned 
to promote e-diary adherence, which will in turn promote intervention compliance. Recognizing 
that self-report may not be fully adequate in assessing intervention adherence, we will use the 
following procedures/measures to assess adherence as appropriate for each intervention (see 
appendices): counts of returned pills or capsules for oral formulations, counts of returned 
packets for powder formulations and counts of in-clinic injections. 
 
3. Participants who take fewer than 60% of doses (active or placebo) required in a 16-week 
treatment period will be considered in violation of the protocol for that treatment period.  The 
treatment period will be excluded from the per protocol analysis population (see Section 9.4).  
 
6.5 
CONCOMITANT THERAPY 
Concomitant medications will be reviewed at each study visit. Participants who are receiving immune-
modulating therapies for diseases other than asthma will not be permitted to enroll.  Participants who 
are taking biological agents for asthma will be permitted to enroll in the study and will be asked to 
continue their current biologic throughout the study. Intervention-specific lists of excluded medications 
are included in Appendices I-V. Table 2 shows the required washout time prior to Screen Visit and visits 
with spirometry, BDR or methacholine. These withholds may also be used for home spirometry. 

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Table 2 
 
 
 
Washout prior to Screen Visit and visits with 
Spirometry, BDR or methacholine 
Inhaled beta-adrenergic agonists (intermediate-acting, e.g., 
albuterol, terbutaline, metaproterenol, pirbuterol, bitolterol)  
≥ 6 hours 
Inhaled long-acting beta-agonists (e.g., Salmeterol/formoterol) 
Taken twice daily 
Taken once daily 
≥ 24 hrs  
≥ 36 hrs 
Inhaled anticholinergics  
Long acting taken twice daily 
Long acting taken once daily 
Short-acting: ≥6 hours 
Long acting BID: ≥24 hours  
Long acting QD: ≥36 hours 
Short-acting theophylline (e.g., Slophyllin tablets) 
≥ 12 hours 
Long-acting theophylline (e.g., Theo-Dur, Slo-bid, Theo24, 
Uniphyl) 
≥ 24 hours 
Leukotriene modifiers (Singulair, Accolate, Zyflo) 
≥ 24 hours 
Methylxanthine-containing foods or beverages (e.g., coffee, 
tea) or medications 
≥ 4 hours 
 
Chronic daily or intermittent use of the following medications is allowed (some exclusions may apply for 
specific interventions – see appendices):  
• oral contraceptives and other hormonal forms of contraceptives (e.g., DepoProvera-7, Norplant-7) 
• estrogen / progesterone replacement therapy for post-menopausal women 
• vitamins and calcium supplements 
• any nasal inhaled corticosteroid used at a stable dose throughout the entire study  
• acetaminophen 
• non-steroidal anti-inflammatory medications (e.g., aspirin, naproxen, ibuprofen, Cox-2 inhibitors) 
• thyroid replacement medications 
• lipid-lowering medication 
• stable dose medical therapy for well-controlled hypertension and well-controlled diabetes, except 
those meds specifically excluded due to specific intervention exclusions 
• medium and low potency topical cutaneous steroids  
• nasal saline spray 
• topical eye preparations for allergic eye symptoms (e.g. antihistamines, NSAIDs, or antiallergic 
compounds) 
• diuretics and specific antihypertensives (e.g. calcium channel blockers, clonidine, etc.) 
• acyclovir 
• oral and topical antihistamines  
• pseudoephedrine and oxymetazoline and other decongestants  
• antibiotics for acne 
• non-macrolide antibiotics 
• macrolide antibiotics (both chronic and acute use)  

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• stool softeners and bulk laxatives 
• H2 blockers and proton pump inhibitors for GERD 
• Imitrex for migraines 
• Propecia (finasteride) 
• SSRI class antidepressants 
• non-SSRI antidepressants 
• migraine analgesics (e.g., butalbital) 
• antianxiety agents 
• ACE inhibitors 
• Librax 
• CNS stimulants/appetite suppressants 
 
Chronic use of the following medications is not allowed: 
• Methotrexate 
• Mycophenolate (CellCept®) 
• Azathioprine (Imuran®) 
• Immune-modulating therapies for diseases other than asthma 
 
6.5.1 CONTROLLER MEDICATION 
 
Participants must be taking an additional asthma controller/biologic (defined in Tables 1B and 1C in 
Section 5.1).  Study sites provide controller medication from our supplier to participants beginning at the 
Screening Visit and at every subsequent visit while the participant is in the study.  If a participant prefers 
to continue the controller medication, they regularly use rather than switch to the controller medication 
provided by the study, they will be allowed to do so. This information will be documented.  
Participants will be encouraged to continue on the provided controller medication for the duration of 
the trial. If a subject decides to switch controller medication during the trial, this may be allowed, but 
the cost will not be covered by the trial. Participants will be encouraged to wait until the end of their 
current 4-month treatment period before changing medications. See Section 6.5.4 for more information 
on allowed changes in controller medication during the trial. 
 
6.5.2 RESCUE MEDICINE  
 
Study sites provide inhaled rescue medication from our supplier to participants beginning at the 
Screening Visit and at every subsequent visit while the participant is in the study.  Participants may use 
their personal rescue medication as needed as prescribed by their treating physician if they prefer it to 
the study supplied rescue medication. 
• 
Rescue medications may include: albuterol, levalbuterol, ipratroprium and 
albuterol/Ipratropium. Participants may not use ICS/LABA combination drugs for rescue – i.e. 
no SMART therapy. 
• 
The use of rescue medications is allowable at any time during the study. 
• 
The study will record the use of rescue medications. 
 

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6.5.3 EPISODES OF WORSENING ASTHMA/EXACERBATIONS 
An asthma exacerbation in PrecISE is defined as a worsening of asthma requiring the use of a systemic 
corticosteroid (at least 3 days of treatment) to prevent a serious outcome. This definition is consistent 
with recommendations from the NIH Outcomes Workshop.11  Events meeting one or more of the 
following criteria will be recorded as asthma exacerbations during the study: 
• 
All worsening asthma events in which systemic corticosteroids were initiated to prevent a 
serious outcome, including use of systemic corticosteroids in association with any form of 
healthcare provider encounter 
• 
All asthma-specific emergency department or urgent care visits that involved treatment with 
systemic corticosteroids (defined as evaluation and treatment for <24 hours in an ED or 
urgent care center) 
• 
All asthma-specific hospitalizations that involved treatment with systemic corticosteroids 
(defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare 
facility for ≥24 hours) (also reported as a serious adverse event) 
• 
All asthma-specific intensive care unit admissions or intubations (also reported as a serious 
adverse event) 
• 
All asthma-related deaths (also reported as a serious adverse event) 
For the purposes of this study, a course of oral systemic corticosteroids (OCS) is defined as any increase 
of at least 20 mg prednisone or double the daily maintenance dose for a minimum of 3 days. Note that a 
single depo-injectable dose of corticosteroids or oral dexamethasone will be considered equivalent to a 
3-day course of OCS.  If the maintenance dose is <5 mg, an increase must be both a doubling of that 
dose and at least a 5 mg increase (e.g., 2.5 mg would need to increase to at least 7.5 mg to count as a 
course).  
The recommended course of OCS for treatment of an asthma exacerbation that occurs during the study 
is prednisone 60 mg x 3 days, then tapering by 10 mg each day (60-60-60-50-40-30-20-10-0). If the 
patient is receiving OCS on a daily basis, the taper ends at that dose.  A patient receiving a course of OCS 
that differs from this recommendation will still be considered as having had an exacerbation, provided 
one of the defining criteria for an asthma exacerbation listed above is met.  
Two courses of systemic corticosteroids must be separated by at least two weeks to count as two 
exacerbations. The two-week clock starts when the corticosteroid course for the first exacerbation ends. 
Exacerbations may result in treatment discontinuation and re-randomization (see Section 7.1) or 
withdrawal from the study (see Section 7.2).  
If no asthma symptoms are present when a course of OCS is started during the study, the OCS use 
should be reported as a concomitant medication, but the event would not qualify as an asthma 
exacerbation.  For example, if an adult participant starts an OCS course because a family member 
developed a viral respiratory infection, this OCS course would not be considered a steroid course for 
asthma, but it would be recorded as a concomitant medication.  
Acceptable documentation to support an exacerbation, in order of preference, is as follows: 
• 
Discharge summaries from a hospital, emergency room, or an urgent care facility indicating that 
a subject was hospitalized/treated with systemic corticosteroids for an asthma exacerbation 

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• 
Signed and dated notes from a referring physician, including information regarding diagnosis 
and treatment of an exacerbation with systemic steroids 
• 
Evidence of prescriptions provided by the participant for systemic corticosteroids used during an 
exacerbation 
• 
A documented conversation that is recorded in a timely manner between the investigator/nurse 
or nurse practitioner and a subject who is already on an OCS action plan, detailing the diagnosis 
and treatment of an asthma exacerbation.   
• 
A documented conversation between the treating/referral physician, health care provider, or 
nurse/nurse practitioner certifying that a participant was treated for an exacerbation with 
corticosteroids at their clinic or under their supervision.  The dates (month/year) of the 
exacerbations and verbal confirmation that appropriate prescriptions were provided is 
necessary.  This option should be used only if reasonable attempts to procure participant 
records have been unsuccessful. 
Participants may receive treatment for asthma exacerbations during the study outside of the PrecISE 
study clinics.  We recognize that participants may live some distance from a study site; may wish to have 
exacerbations managed by their usual provider; may be at work, traveling, or away from home when the 
exacerbation occurs; and/or may have health insurance that precludes treatment at the PrecISE study 
site or affiliated hospital. The ethical management of asthma exacerbations in study participants 
requires that 1) we are prepared to help participants manage these exacerbations, 2) we work to ensure 
the safety of participants when they seek assistance for an exacerbation, and 3) we work collegially with 
other health care providers who may be called upon to treat a PrecISE participant.   
An informational pamphlet will be provided to each study participant that they can give to a provider in 
the event of an asthma exacerbation. This pamphlet will inform the provider of: a) the general nature of 
the PrecISE study, b) the types of interventions in the study, and c) contact information for the study 
sites. 
6.5.4 MAJOR CHANGES IN THERAPY 
The PrecISE study has special challenges, as participants have severe and/or exacerbation prone asthma 
not adequately controlled on high-dose ICS plus additional therapy such as a LABA, LAMA, oral CSs, or all 
three, they may already be on a biologic for their asthma due to disease severity, and they may be in the 
study for as long as 40 months.  As a result, some participants may have their treatment changed while 
in the study.  The number of participants in whom this occurs is difficult to predict, but as more 
treatments, especially biologics, for severe asthma become available, it is likely to increase. 
A major change is:  
• 
the addition, dose adjustment (see below) or discontinuation of an oral corticosteroid for a 
period of time greater than that specified under treatment of exacerbations (Section 6.5.3) with 
the intention of continuing such therapy.  
• 
the addition, dose adjustment, or period adjustment of a parenteral corticosteroid administered 
during the study; 
• 
the addition, dose adjustment, or discontinuation of an additional asthma controller (note that 
changes within a class of therapy that do not change the dose of that type of therapy are not 
major changes) 
• 
 the addition, dose adjustment, or discontinuation of a biologic therapy believed to affect 
asthma, 
• 
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• 
 the addition or discontinuation of azithromycin to a participant’s baseline (chronic) regimen for 
the treatment of asthma.  
A major change in asthma therapy typically occurs due to worsening (or dramatic improvement of) 
asthma, or a perception of worsening asthma by a treating physician, or the availability of a new therapy 
the treating physician wants to prescribe in the absence of a change in the participant’s overall status.  
Such a change generally occurs outside the period of an asthma exacerbation.  
A 5 mg/d change in prednisone (or equivalent) therapy for patients on chronic therapy, outside the strict 
definition of treatment for an asthma exacerbation in Section 6.5.3, is considered a major change in 
therapy. Additionally, since the maximum dose of oral prednisone allowed for entry into the study is 10 
mg, an increase in oral prednisone therapy to greater than 10 mg daily, outside the strict definition of 
treatment for an asthma exacerbation in Section 6.5.3, is considered a major change in therapy.  
The addition, dose modification, or discontinuation of any immune-modulating therapy, thought to 
potentially affect asthma pathobiology, for non-asthmatic disease will also be considered a major 
change in therapy.  These treatment changes make it difficult to assess the specific effect of the asthma 
intervention. 
It is expressly noted that a change within a class of therapy that does not change the total dose of that 
type of therapy is not considered a major change. For example, the patient’s insurer may decide to 
cover one brand of combination ICS/LABA therapy, and the patient may then want or need to switch 
from the brand he/she is currently using. As another example, a patient may change (for insurance 
reasons) from one anti-IL-5 biologic to another. These are not considered major changes, whereas a 
change from one biologic to another for purposes of achieving increased therapeutic efficacy would be 
considered a major change. 
A major change in therapy can occur during a treatment period (test treatment or placebo) or a washout 
period.  In most asthma studies with an intervention lasting up to 12 months, major therapy changes 
(e.g., addition of a biologic) are not permitted. Consistent with this practice, major changes in therapy 
will be discouraged during the 4-month treatment periods in PrecISE. 
If a participant has a major change in therapy during a treatment period, he/she will discontinue their 
current assigned treatment, and then discontinue the study. The following guidelines apply: 
• 
Changes that require removal of a therapy, or a decreased dose of therapy, should include the 
reason for the removal (e.g., adverse event from the medication).  
• 
Likewise, changes that require a new medication for asthma control (e.g., introduction of an 
anti-IL-5 directed biologic) should include the reason for the addition. When feasible, it is 
recommended that such changes be done at the end of, rather than in the middle of, an 
intervention. However, patient safety is paramount in such additions of therapy, and the PrecISE 
study will not override the judgment of the treating physician. 
• 
Following discontinuation from the study due to a major change in therapy, the participant has 
the option of re-entering the study as a new participant. Inclusion criteria will be re-assessed to 
see if the patient still meets the criteria for uncontrolled severe asthma after the change in 
therapy. The patient will undergo the usual screening and run-in process and additional 
specimens will be collected. The participant’s biomarker profiled will be reassessed to 
determine randomization probabilities.  The participant will not receive any interventions 
already received when previously enrolled. 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
7.1.1 DISCONTINUATION OF A PARTICIPANT’S ASSIGNED INTERVENTION 
Participants will be monitored for safety during the trial and the occurrence of certain adverse events or 
laboratory abnormalities will result in discontinuation from the participant’s current treatment; that is, 
participation in the current treatment period will stop, and the participant will enter the washout 
period.  The following adverse events or lab abnormalities will result in discontinuation from the 
participant’s current treatment: 
1. Serious infection (including pneumonia, cellulitis, kidney or neurologic infections, and any 
bacteremia/sepsis). 
2. Any bleeding event thought to be associated with a platelet count reduction per the judgment 
of the center investigator. 
3. Any other adverse event, per judgment of the center investigator, requiring discontinuation 
from treatment. 
4. Laboratory values are monitored per the schedule of activities in Section 1.3. For adults, the 
below lab tests will be assessed at every 4-week visit during the treatment period. Abnormalities 
in the following laboratory values require prompt retesting within 3 to 5 days: 
• 
ANC <1000/µl for black participants, <1500/µl for other participants. 
• 
Lymphocyte count <500/mm3. 
• 
Platelet count <50,000/mm3. 
• 
Hemoglobin <9.0 g/dL. 
• 
AST and/or ALT elevation >3 times the upper limit of normal.  
• 
Bilirubin ≥2 times the upper limit of normal. 
• 
Calculated eGFR < 54 mL/min/1.73 m2 and baseline eGFR was >60 mL/min/1.73 m2 OR 
calculated eGFR < 50 mL/min/1.73 m2 and baseline eGFR was 54-60 mL/min/1.73 m2 
 
If both tests violate the following cut-off values, the participant is removed from treatment: 
a. Two sequential platelet counts <50,000/mm3.  
b. One platelet count <25,000/mm3 unless the confirmatory test demonstrates a count 
>50,000/mm3.  Treatment must be withheld pending the confirmatory retest.  
c. Two sequential neutrophil counts <500/mm3.  
d. Two sequential lymphocyte counts <500/mm3. 
e. Two sequential hemoglobin assessments <8.0 g/dL or >30% below the participant’s 
initial baseline value or the baseline value for the current treatment period. 
f. Two sequential AST or ALT elevations >3 times the upper limit of normal with at least 
one total bilirubin value ≥2 times the upper limit of normal.   
g. Two sequential AST or ALT elevations >3 times the upper limit of normal accompanied 
by symptoms consistent with hepatic injury, per the judgment of the center 
investigator. 

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h. Two sequential AST or ALT elevations >5 times the upper limit of normal, regardless of 
total bilirubin or accompanying symptoms. 
i. 
Two sequential decreases in eGFR  < 54 mL/min/1.73 m2 and baseline eGFR was >60 
mL/min/1.73 m2 OR eGFR < 50 mL/min/1.73 m2 and baseline eGFR was 54-60 
mL/min/1.73 m2 
5. Any safety issue that has required or will require (per the investigator’s judgment) interruption 
to treatment for >28 days. 
6. Any event (i.e. asthma exacerbation, asthma treatment, or any other medical condition) 
requiring 21 or more contiguous days of prednisone above the participant’s usual baseline dose. 
 
Specific interventions may have additional safety criteria for discontinuing treatment (see appendices). 
A participant will be discontinued from treatment if, during an exacerbation, he/she 
• 
Is admitted to an ICU and requires non-invasive positive pressure ventilation or 
• 
Experiences three exacerbations during a treatment period.   
If, following treatment discontinuation for any of the criteria listed above, participants are deemed 
eligible (by safety criteria) to continue in the study, they will enter the 8-week (or longer) washout 
period preceding the next intervention.  Entry into the washout period will begin at least 7 days after 
completing treatment of the exacerbation with oral or parenteral corticosteroids.   
Participants who respond to treatment with systemic corticosteroids or who receive a single IM injection 
of steroid at the beginning of an exacerbation will not be discontinued from treatment, unless this is 
their 3rd exacerbation within the same treatment period, in which case, the above treatment 
discontinuation criteria apply.  
7.1.2 DISCONTINUATION OF AN INTERVENTION FROM THE MASTER PROTOCOL 
The DSMB will review accumulating data throughout the study to determine if an intervention should be 
terminated from the PrecISE study for safety reasons. Interventions may also be discontinued from the 
study based on the interim futility analyses planned for the trial. Rules for termination for specific 
interventions due to safety may be required and, if so, will be specified in the appendix to this protocol 
for the intervention. If an intervention is discontinued from the study for either futility or safety reasons, 
participants who are receiving the intervention or its matching placebo will immediately begin an 8-
week (or longer) washout phase and be re-randomized to another treatment. 
7.1.3 DISCONTINUATION OF THE STUDY 
At this time, we do not anticipate there will be a reason to stop the entire PrecISE study, with the 
exceptions of termination of funding by NHLBI or poor recruitment to the point where the study is 
highly unlikely to meet its goals. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
A participant may be discontinued from the study if he/she is shown to not meet the inclusion criteria 
based on new information that was not available at the time of initial enrollment (e.g. uncovering a 
diagnosis of another lung disease), and continuing in the study poses a safety risk.  Participants should 
not be discontinued for reasons other than new information that constitutes a safety risk.  For example, 
if new information indicates that a participant meets one of the exclusion criteria for a test treatment, 
but the criteria does not pose a safety risk to the participant, then the participant should not be 

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discontinued.  In this case, the participant will be considered in violation of the protocol for that period 
and excluded from the per protocol analysis (see Section 9.4).  In general, participants with poor 
compliance but at no increased risk will continue in the study to complete all study assessments and 
minimize attrition.   
Other criteria for participant discontinuation at any point in the study: 
1. Safety laboratory exclusions as defined in Sections 5.2 and 7.1 that do not resolve in the 
washout phase that in the judgment of the site physician or Safety Committee constitutes 
an on-going safety risk for the participant. 
2. Participant or parent of participant (for children) withdraws consent or child withdraws 
assent. 
3. Participant becomes pregnant. 
4. Study physician determines that continuation in the study is not in the best interest of the 
participant. 
5. Participant suffers life-threatening asthma exacerbation.  A life-threatening asthma 
exacerbation is defined as an ICU admission requiring intubation, hypoxic seizure or loss of 
consciousness.   
6. Frequent asthma exacerbations  
a. For participants with 3 or fewer asthma exacerbations in the prior year at 
screening, the participant has five or more exacerbations in one year of the study. 
b. For participants with 4 or more asthma exacerbations in the prior year at 
screening, the participant has a 50 percent or greater increase in exacerbations in 
one year of the study, compared to the prior year at screening.  
7. Frequent hospitalizations 
a. For participants who have 3 or fewer hospitalizations in the prior year at screening, 
the participant has four or more hospitalizations (greater than 24 hours) in one 
year of the study. 
b. For participants who have 4 or more hospitalizations in the prior year at screening, 
the participant has a 50 percent or greater increase in hospitalizations in one year 
of the study, compared to the prior year at screening. 
8. Participant has a major change in therapy (see Section 6.5.4).  
As always, the participant can withdraw consent from the master protocol at any point, and that will 
lead to discontinuation from the study.  At that point, the investigator will make reasonable effort to 
ensure participant’s well-being and safety and provide a termination visit with appropriate 
documentation. 
The site investigator may decide to stop a participant’s treatment due to side effects or other safety 
concerns.  In that case, the participant would immediately begin the washout phase and then receive 
the treatment assigned according to their initial crossover sequence (period 2), or be re-randomized for 
the next treatment (period 3-6).  If a participant elects to withdraw their consent from a treatment, this 
will result in discontinuation from the entire study. 
 
7.3 
LOST TO FOLLOW-UP 
Participants who do not show up for a scheduled visit will be contacted by available means (calling, 
email, text). If an emergency number is provided, it can be used to contact the participant, at least to 
ensure they are doing well. The study coordinator will also contact the patient’s referring physician.  
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and written requests to contact the clinical site, he or she can be considered to have been lost to follow-
up. A termination form should be completed by the investigator to record the exit of the participant 
from the study. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Primary Efficacy Assessments:  Efficacy of each intervention will be evaluated with respect to lung 
function and asthma symptom control.  Lung function will be measured prior to and post bronchodilator 
administration (pre-BD and post-BD).  The American Thoracic Society (ATS) criteria for assessing lung 
function will be applied for spirometric maneuvers.  A central spirometry reading center will provide 
quality control over-reads of the measurements and identify any issues requiring retraining of clinical 
staff.  The primary efficacy outcome with respect to lung function is FEV1 percent predicted pre-BD.   
Asthma symptom control will be measured using six items from the Juniper Asthma Control 
Questionnaire (ACQ-6) corresponding to five self-reported symptoms and self-reported rescue BD use. 
The primary efficacy outcome with respect to asthma control symptoms is the average score of these six 
items (range 0-6).   
Secondary Efficacy Assessments: The use of CompEx events as a secondary endpoint provides a measure 
of loss of asthma control with statistical properties that approximate exacerbations but with a shorter 
follow-up time.4 CompEx is a composite outcome specific to asthma that combines clinically-relevant 
deteriorations captured by diary events with exacerbations, thereby providing an increase in power 
compared to using exacerbations alone (see Section 9.2). Exacerbations will be analyzed as a secondary 
efficacy endpoint. 
CompEx events include exacerbations and deterioration events defined based on  
1) Daily recordings of peak expiratory flow (PEF) morning/evening (L/min) 
2) Reliever use morning/evening (doses) 
3) Symptoms morning/evening (score 0–3) assessed from twice-daily diary recordings 
Participants will be asked to describe their morning symptoms using the following scale: 0-No symptoms 
to report, 1-I was aware of my symptoms but they were easily tolerated, 2- I had problems sleeping due 
to my asthma, 3-I could not sleep because of my asthma.  Participants will be asked to describe their 
evening symptoms using the following scale: 0-No symptoms to report, 1-I was aware of my symptoms 
but they were easily tolerated, 2- I had problems performing my normal activities due to my symptoms. 
3-I could not perform my normal activities because of my asthma. 
 The diary event can occur as defined by threshold and slope criteria within a moving window of 5-day 
length. Evening and morning recordings are treated as separate variables. The baseline levels of 
deterioration are calculated for each individual as the mean over the 5-10 days ending just before the 
day of randomization for each of the diary variables. No imputation of missing diary data after the 
randomization is performed. Deterioration criteria is assessed for each (single) diary variable for 
thresholds and slopes as follows:  
Thresholds: The change from baseline is calculated. If two consecutive days fulfil the chosen threshold 
limit as defined in Table 3, the deterioration criterion is met.  

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Slopes: A slope is calculated via linear regression over 5 days. If the slope fulfills the chosen cut-point as 
defined in Table 3, the deterioration criterion is met.  
Diary event start definition: A diary event can occur when (i) the threshold deterioration criterion is met 
for at least two diary variables, or when (ii) the threshold deterioration criterion is met for one diary 
variable, and the slope criterion is fulfilled for all included variables. In case of (i), the diary event is 
defined to start on the first day of the two consecutive deterioration days (event days 0–1). Any missing 
data in this two-day window will make the event missing. In case of (ii), the event is defined to start on 
the first of the two days fulfilling the threshold criterion. This means that the slopes are calculated for 
days -4 to 0 of an event. At least two days with data are needed to calculate slopes in order to qualify as 
an event. The end of a diary event is the last day that the criteria for a diary event is fulfilled. In order to 
be counted as a new diary event it must be preceded by at least 7 days in which neither criterion for a 
diary event is fulfilled.  
Table 3 
Diary variable 
PEF (P) 
morning/evening 
Reliever use (R) 
morning/evening 
Symptoms (S) 
morning/evening 
Threshold type 
Decrease from baseline 
(%) 
Increase from baseline 
(doses) 
Increase from baseline 
(scores) or absolute 
maximum score 
Threshold  
15 
1.5 
1 
Slope type 
Decrease rate 
(% per day) 
Increase rate 
(doses per day) 
Increase rate 
(scores per day) 
Slope 
3 
0.3 
0.2 
 
Other secondary efficacy assessments  
1. FEV1, post-BD 
2. FVC, pre-BD 
3. Exacerbations, time to first (as defined in Section 6.5.3) 
4. Symptom Free days (defined using diary/CompEx data)  
5. Healthcare utilization 
a. Asthma-specific ED visits 
b. Asthma-specific hospital admissions 
c. Asthma-specific ICU admissions  
6. Asthma free days using the AsthmaNet definition12,13 
Exploratory efficacy assessments 
1. Rate of recovery from exacerbation, time to improvement 
2. Economic burden of disease assessment (Days missed from work/school, cost of 
hospitalizations) 
3. AQLQ (Asthma Quality of Life Questionnaire)  
4. WPAI (Work Productivity and Activity Impairment Questionnaire)14 
5. Modified ASSESS (Asthma Severity Scoring System)15  
 

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8.2 
SAFETY AND OTHER ASSESSMENTS 
All participants who enter PrecISE will undergo a series of visits, each with different intent and visit-
specific assessments.  Some of these assessments and procedures may be conducted remotely via 
phone, videoconference or electronic survey methods. Please refer to the visit structure (Section 1.3) for 
specific details related to these assessments.   
1. Discussion and signing of informed consent and registration into the study.  Informed consent 
will be obtained from the participant or the legal guardian if the participant is a child less than 
18 years of age.  Assent will also be obtained from adolescent participants.  The informed 
consent will include the core characterization and longitudinal procedures to be conducted at all 
sites, including the sharing of data and the storage and distribution of samples. 
2. Assessments for inclusion/exclusion related to asthma status and overall general health as 
directed by the clinical coordinators and/or attending medical personnel.  These assessments 
will include the following: 
a. Full medical history obtained by the clinical coordinator.  This will include vital signs, 
height, and weight.  Further, the medical history will collect data related to family 
history, recent asthma symptoms and acute episodes of asthma, asthma triggers, 
allergies, and smoking history.  Details will be collected on prior disease, illnesses, and 
surgeries the participant has had.  Mediation history will be collected.  Smoking history 
will be collected, including use of inhaled nicotine products.   
b. Information on the use of asthma treatments at school will be obtained from middle 
and high school participants.  Information will be collected about the location of the 
participant’s rescue medication while at school (self-carry versus nurse’s office), prior 
experience with the most recent asthma attack at school and whether the school allows 
the participant to receive medications during the school day.  
c. Physical examination by qualified medical professional.  This examination will take place 
at the beginning of the study and before each new treatment arm.  Additional, non-
scheduled physical examinations will take place if needed during the study to support 
patient safety and exacerbation management. 
d. Comorbid condition surveys/questionnaires.  These surveys are conducted with the 
purpose of determining the general health of the potential participants and their 
feasibility for inclusion as determined by the attending physicians.  Based upon these 
surveys and questionnaire, the attending physician may decide to treat the comorbidity 
and invite the participant back for reevaluation or the attending physician may decide 
that the comorbidity is too severe for the participant to enter the study. These 
surveys/questionnaires include: 
i. Sleep (STOP-BANG) 
ii. Sinus disease (SNQ5) 
iii. Depression/Anxiety (HADS) 
iv. Vocal cord dysfunction (Pittsburgh vocal dysfunction survey) 
v. Gastroesophageal reflux disease (using the GERDQ to establish uncontrolled 
GERD) 
e. Pulmonary function tests (PFT).  Spirometry before and after bronchodilator (up to 8 
puffs of albuterol during screening for qualification for reversibility and 4 puffs of 
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screening visits and throughout the study to capture key lung function parameters, such 
as pre- and post-BD forced expiratory volume, which is used to monitor both asthma 
control and treatment outcomes. Spirometry is a maneuver whereby a participant will 
inhale as big a breath as possible and then blow it out as fast and as long as possible 
until no more air can leave the lungs.  The volume of air leaving the lungs is recorded 
continuously.  Spirometry will be conducted according to the SOPs defined in the MOPs.  
As a result of the COVID-19 pandemic, spirometry may be conducted at home or in the 
clinic.  For home spirometry assessments, a portable spirometer (see 3.c below) is used 
by participants in conjunction with application software to record the maneuvers. 
f. Methacholine challenge studies will be used to determine asthma status for a subset of 
participants who fail to bronchodilate during standard pulmonary function testing, yet 
who are suspected to have severe asthma based upon medical history.  Positive 
methacholine challenge will be needed for those participants to enter the study.  During 
this maneuver, the participant will be asked to inhale a small dose of methacholine, 
followed by spirometry.  If there is no change in baseline after the challenge, additional 
methacholine is delivered until a significant drop (≥ 20% of baseline) in lung function or 
symptoms occurs.  Bronchodilators are then given to reverse the effects.   
g. DLCO (if needed based on smoking history).  This assessment will be conducted to 
establish that potential participants with a smoking history, who say they no longer 
smoke, do not have evidence of underlying smoking-related disease, such as 
emphysema related to chronic obstructive pulmonary disease.  Evidence of underlying 
lung disease associated with previous smoking history will be an exclusion criterion.   
h. Urine cotinine (if needed based on smoking history). The assessment will be conducted 
to establish that potential participants with a smoking history, who say they no longer 
smoke, are indeed not smoking.  A positive cotinine for smoking will be an exclusion 
criterion. 
i. 
Socioeconomic information for the household.  This information will be collected to 
determine in post hoc analyses if treatment effects are related to important 
socioeconomic factors.   
j. 
Immunoglobulin E.  This test will be used to provide basic, necessary phenotyping of the 
severe asthma population in PrecISE.  This evaluation will occur from a blood sample 
and only once during the recruitment visits.   
3. Additional surveys/questionnaires will be used throughout the study to capture other relevant 
features.  These include: 
a. Asthma Control Questionnaire (ACQ-6) will be used throughout the study to capture 
asthma symptoms. 
b. The Asthma Quality of Life Questionnaire (AQLQ) and the WPAI (work productivity) 
questionnaires will be used throughout the study to capture the quality of life 
endpoints. 
c. Issuing of E-Diary (and E-Diary training) will occur throughout the study in order to 
capture the participants’ day-to-day medication use, asthma symptoms, and home 
spirometry.  Participants will be provided with an e-diary, which they will be asked to 
maintain at home throughout their participation in the study. Electronic surveys, and 
occasionally paper forms, will be available as a back-up.  
i. If adherence < 70% to controller medications and/or E-Diary is determined to be 
occurring throughout the course of the study, in-person visits or telephone calls 
may be scheduled for adherence training. 

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ii. The E-Diary will also capture the questions related to the CompEx events end-
point. 
iii. Participants will also be asked to utilize a home spirometer to capture daily peak 
flow, which is a component of the CompEx events end-point.  
d. A second home spirometer will be issued to collect FEV1 data by the ZEPHYRx system at 
study visits or at home. 
e. Asthma medication and concurrent medication assessment 
f. Exacerbation and adverse event evaluation 
g. Blinding Index questionnaire to capture participant’s perception of whether they 
received an active treatment or a matching placebo in the current period 
4. Safety labs (primarily used to establish the health of the participant and potentially to exclude 
participant from certain treatments).  All safety labs will be conducted in a CLIA certified Core 
Laboratory selected by the PrecISE Network to ensure standardization of test reads across 
clinical sites.  Most safety labs will be performed at a primary laboratory to ensure 
standardization of test reads across clinical sites. In this scenario, biological specimens are 
collected from the participants and the specimens are immediately sent to the Core Laboratory.  
Some safety labs may be performed at patient service centers.  In all cases, results will be 
communicated back to the clinical centers and/or the DMCC where they will be analyzed and 
used for randomization/exclusion decisions.  Further, safety labs will be collected throughout 
treatment periods and before each new treatment arm.   
a. Urine Pregnancy test for all women of childbearing potential will be utilized in order to 
exclude pregnant individuals from the study.  This test will be conducted at the sites 
using a urine dipstick. 
b. Complete blood cell count with differentials 
c. Comprehensive metabolic panel 
d. Additional safety labs will be performed on all participants that are to be randomized 
and these may be further evaluated during the treatment in an intervention-specific 
manner. Based upon the values of these test, some participants may be excluded from 
certain treatments.  Details of these intervention-specific safety laboratory tests are 
outlined in the Appendices.  These include 
i. Triglycerides 
ii. Ketonuria and/or blood glucose 
iii. Serum phosphate  
iv. Hepatitis B and Hepatitis C testing 
v. HIV testing 
vi. QuantiFERON test for tuberculosis 
5. To obtain information needed for randomization, the following biomarkers will be obtained 
(refer to the visit structure for details of timing).   
a. Blood eosinophils (will come from complete blood count; in most cases the blood for 
this is also drawn for safety reasons) will be taken utilizing standard phlebotomy. 
b. Single nucleotide polymorphism (SNP) genotypes.  Limited genotypes (intervention-
specific) will be determined from a blood sample used to isolate DNA.  The SNP 
genotype analysis will be conducted in a CLIA-certified Core Laboratory. 
c. Plasma IL-6 will be obtained from EDTA treated plasma  
d. Exhaled nitric oxide level will be determined using an instrument to measure fractional 
exhaled nitric oxide (FeNO).  This instrument will be used during the visits outlined in 
the visit structure.  The test is easy to conduct and requires that the participant exhale 

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into the mouthpiece of the FeNO measuring instrument for approximately 10 seconds.  
SOPs and MOPs will be developed to ensure standardization of the test.   
6. Specimen collection for biomarker and subsequent exploratory studies.  In general, the samples 
collected for this purpose will be processed after collection at the collection site and aliquoted 
according to standardized MOPs and SOPs, and shipped quarterly to the PrecISE Network 
Biorepository Core.  The Biorepository Core will store de-identified barcoded samples. When 
requested by the PrecISE study investigators according to study needs and priorities, the 
samples will be sent to appointed laboratories for specific-analyses testing.   The following 
provides a general guideline of possible samples collected and procedures performed.  
a. Blood:  At various times throughout the study (refer to visit structure) blood will be 
drawn for processing and subsequent biomarker exploration.  Standardized phlebotomy 
techniques outlined in SOPs and MOPs will be conducted.  At no time will maximal blood 
draw volumes be exceeded.  Blood samples will provide the opportunity to explore a 
variety of blood-specific biomarkers as well as evaluation of white blood cell 
characterization (peripheral blood mononuclear cells via flow cytometry or RNA 
expression studies) and DNA samples for genotyping. 
b. Urine will be collected and processed according to standardized MOPs and SOPs. 
c. Stool will be collected using standardized stool collection kits. Stool will be used for 
microbiome studies. 
d. Induced Sputum.  Sputum induction is a relatively simple, repeatable, and non-invasive 
method to collect airway secretions, thus, they are a highly asthma-relevant biological 
sample type.  Sputum samples will provide an opportunity to establish the inflammatory 
cell differential and counts in the patient’s airways, while providing an opportunity for 
extended studies (e.g., gene expression, microbiome, and sputum biomarkers such as 
tryptase). Sputum cell counts will be determined in a central core laboratory. Other 
sputum biospecimens will be stored in the Biorepository after processing. 
The process of sputum collection involves nebulization of 3% saline to induce cough and 
sputum production.  Hypertonic aerosols such as 3% can induce bronchoconstriction in 
patients with asthma, and pre-treatment with albuterol will be provided to guard 
against such bronchoconstriction.  In addition, participants with low FEV1 will undergo 
sputum induction with an isotonic aerosol (0.9% saline).  Specific and standardized 
procedures for sputum induction are described in SOPs and MOPs.  The procedures for 
sputum induction differ in adults and in adolescents, as follows, with differences 
designed to have a more conservative protocol in the adolescents: 
- Adolescents: For participants with a post bronchodilator FEV1% >70%, sputum will 
be induced using 3% saline; for participants with a post bronchodilator FEV1% < 70%, 
sputum will be induced using 0.9% saline. 
- Adults: For participants with a post bronchodilator FEV1% >50%, sputum will be 
induced using 3% saline; for participants with a post bronchodilator FEV1% < 50%, 
sputum will be induced using 0.9% saline. 
e. Exhaled breath condensate will be collected using RT-tubes, which condense air that is 
breathed out of the participants’ lungs during a short period (~10 minutes).  The 
participant is asked to breathe through a mouthpiece during this time.  They can come 
off of the mouthpiece to cough and/or swallow.  The sample will then be spun from the 
condensation tube and stored for shipment to the Biorepository Core Laboratory.   
f. Nasal swabs will allow for capture of samples from this region for biomarker studies (for 
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7. High Resolution CT scan of the chest will occur at the qualification visit following four puffs of 
albuterol before treatment start during the run-in period on all participants who meet entry 
criteria for severe asthma and compliance.  In addition to providing a method to detect latent 
tuberculosis, noninvasive measures, such as imaging, can measure airway structure and 
remodeling, as well as air trapping, mucus plugs, and other parameters relevant to asthma 
pathophysiology.  The PrecISE Network will work with an established Radiology Reading Center 
to provide standardization and harmonization of all CT imaging protocols.  This Center will also 
provide initial quantitative CT analyses following the protocol outlined in the MOPs.  The basic 
CT scan protocol will consist of obtaining multi-detector CT (MDCT) images of the entire lung at 
full inspiration (Total Lung Capacity = TLC) and at the end of expiration (Residual volume=RV).  
The images from the MDCT chest scans will be stored locally and sent electronically to the 
Radiology Core using software that assures protocol compliance and de-identification.  Scans 
will be read by local radiologists to rule on the presence of clinically actionable conditions, such 
as pneumonia or nodules.   
8. Study treatment administration will occur during the treatment periods as outlined in the visit 
structure.  The study coordinators will provide the participants with the study treatment and 
instructions as to how it should be used.  Both the coordinator and the participant will be 
blinded as to whether or not the participant will be receiving active treatment or placebo.  
a. Visits during the treatment period will be used to evaluate if the participant is compliant 
with the taking of their assigned active treatment/placebo.    
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related (21 CFR 312.32(a)).  Adverse events occurring after the 
participant provides informed consent will be recorded. 
8.3.2 DEFINITION OF SUSPECTED ADVERSE REACTION 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means 
there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
8.3.3 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
● death 
● a life-threatening adverse event 
● inpatient hospitalization ≥ 24 hours or prolongation of existing hospitalization 
● a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
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● Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient and may require intervention to prevent one of 
the other outcomes listed in the definition above.  
This definition permits either the Medical Monitor or the investigator to decide whether an event is 
serious. Serious adverse events are critically important for the identification of significant safety 
problems. Therefore, if either the Medical Monitor or investigator believes that the event is serious, the 
event must be considered serious and evaluated by the sponsor for expedited reporting (21 CFR 
312.32(a) and 312.32(c)(1)). 
8.3.4 RESPONSIBILITIES 
Primary responsibility for AE identification, documentation, and assessment of severity and relationship 
to study agents can be determined by either the investigator or Medical Monitor. The medical personnel 
who perform these assessments must be directly involved in the clinical evaluation of the research 
participants. 
 
8.3.5 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.5.1 SEVERITY OF EVENT 
For adverse events (AEs), the following guidelines will be used to describe severity.  
● Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
● Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
● Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
 
8.3.5.2 RELATIONSHIP TO STUDY INTERVENTION 
The site investigator and/or Medical Monitor is responsible for assessing the relationship between the 
AE and the study agent(s). Site investigators must provide the initial assessment as to whether there is a 
reasonable possibility that the study agent(s) caused or contributed to a SAE. The relationship 
assessment, based on clinical judgment, often relies on the following:  
• 
A temporal relationship between the event and administration of the study agent(s),  
• 
A plausible biological mechanism for the agent to cause the AE,  
• 
Another possible etiology for the AE,  
• 
Previous reports of similar AEs associated with the study agent or other agents in the same 
class, and  
• 
Recurrence of the AE after re-challenge or resolution after de-challenge, if applicable.  
Further assessment of causality is provided by the DSMB based on accumulating safety reports between 
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The terms used to assess the relationship of an event to study agent are:  
• 
Related – There is a reasonable possibility that the AE may be related to the study agent(s).  
• 
Not Related – There is not a reasonable possibility that the AE is related to the study agent(s).  
 
8.3.5.3 EXPECTEDNESS  
Expected AEs are AEs that have been previously observed with use of the study agent(s) and are listed in 
the package insert or Investigator’s Brochure. Expectedness is not based on what might be anticipated 
from the pharmacological properties of the study agent or for the disease or study population under 
study.  
An adverse event or suspected adverse reaction is considered ‘unexpected’ if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed. Further details 
are provided in the MOP Chapter 13, Safety and Adverse Events. 
Blood draw: Participants may experience some lightheadedness or nausea while having blood drawn. 
There is a risk of bruising at the site where the needle enters the skin and a remote risk of infection. 
Spirometry and maximum bronchodilation: Participants may experience shortness of breath while 
doing spirometry, or, very rarely, syncope. Temporary wheezing and chest tightness occur 
infrequently (5% of the time).  Following the bronchodilator, a transient increase in heart rate and 
tremor is likely (>25% chance).  
Methacholine Challenge: Participants may experience shortness of breath, coughing, lightheadedness 
and dizziness. In rare cases, some participants have experienced a severe asthma attack or a reaction 
to the methacholine. Participants with a pre-diluent FEV1 of >50% predicted (>70% in children aged 12 
to 17 years) and at least one liter will undergo the methacholine testing if they do not have a historical 
methacholine from testing performed under either the 2017 ERS technical standard9 or the 1999 ATS 
Guidelines10.  
Sputum Induction: Participants may experience a salty after taste in the mouth, coughing, a feeling of 
needing to swallow, a sore throat, shortness of breath, wheezing, chest tightness, lightheadedness, 
nausea or headache. In rare cases, some participants have had a severe asthma attack or a reaction to 
the salty water that they breathe in. Bronchodilator treatment will be available if this occurs. The 
following safety procedures will be followed for the sputum induction procedure: 
• 
Adolescent participants with a post bronchodilator FEV1% >70%, sputum will be induced using 
3% saline; for adolescent participants with a post bronchodilator FEV1% < 70%, sputum will be 
induced using 0.9% saline. 
• 
Adult participants with a post bronchodilator FEV1% >50%, sputum will be induced using 3% 
saline; for adult participants with a post bronchodilator FEV1% < 50%, sputum will be induced 
using 0.9% saline. 
• 
a physician will be available during the challenge;  
• 
study staff will calculate and record the peak flow and FEV1 value that equals both a 10% and 
20% fall in lung function based upon the recorded post-BD peak flow and FEV1 values; and  
• 
participants will not be discharged until their FEV1 is within 10% of their post bronchodilator 
FEV1. 
  

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Withholding medication: After consenting, participants will be asked to hold certain medications prior 
to each visit for the purpose of lung function testing. Participants may experience an increase in their 
asthma symptoms from holding their daily medications. If participants are unable to hold their 
medications, they are instructed to take the medication as needed and to call the study staff. This will 
also be documented and the participant will proceed with the scheduled procedure.  
Conditions common in adolescents and adults who have severe asthma will be considered expected for 
IND reporting purposes. Examples include sinus infections, pneumonia, and sinus surgery.  
For other events, a site investigator or sub-investigator will be responsible for determining whether an 
adverse event (AE) is expected or unexpected.  An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously described for 
the test treatment.  Test intervention-specific expected adverse events are described in the appendices. 
8.3.5.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study intervention (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
A site physician investigator or sub-investigator will record all reportable events between the time the 
participant provides informed consent through 8 weeks after their last treatment or a period 
corresponding to five half-lives of the treatment last received, whichever is longer (Section 4.1).  At each 
study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will 
be followed for outcome information until resolution or stabilization. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
Study investigators will immediately notify the DMCC of any serious adverse event, whether or not 
considered test treatment-related, including those listed in the protocol or investigator brochure.  The 
report must include an assessment of whether there is a reasonable possibility that the test treatment 
caused the event.  
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the DMCC and should be provided as soon as possible. 

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The DMCC will be responsible for notifying the FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after initial 
receipt of the information.  In addition, the DMCC must notify the FDA and all participating investigators 
in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the DMCC determines that the information 
qualifies for reporting. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
An unexpected finding may occur whenever safety testing or imaging (CT) of the lung are done. These 
unexpected findings can have clear or uncertain clinical significance. For example, clear clinical 
significance means that the testing shows a problem that may be treatable and that we generally know 
what the risks are of not treating the problem. Uncertain clinical significance means that the test result 
is unusual or outside the boundaries of “normal”, but we do not know if it might affect the health of the 
participant, and treatment may not be appropriate or possible. In this study, the participant will be 
informed of any findings of clear clinical significance that may be discovered during the imaging 
procedure or safety laboratory test, but the participant will not be informed if there are findings of 
uncertain clinical significance. There may be benefits to learning such results (such as early detection 
and treatment of a medical condition), but there are risks as well (such as problems with getting 
insurance or employment, or becoming worried about a finding for which no treatment is required or 
appropriate). Participants may choose to have their physician informed of any findings of clear clinical 
significance that are reported. Participants will indicate their decision in the consent form regarding 
informing their physician and having the report placed in their medical record. 
 
8.3.8 REPORTING OF PREGNANCY  
Pregnancy, lactation or plans to get pregnant are exclusion criteria for this study. Females of child-
bearing potential must use a medically accepted method of birth control from the time of enrollment 
until 16 weeks following the last dose of study drug. Urine pregnancy testing will be performed at 
regular intervals during the study on females of childbearing potential. If a participant becomes 
pregnant during the study, study treatment will be discontinued. If permission is granted, pregnant 
study participants or pregnant partners of study participants will be followed through pregnancy and 
delivery. Safety data will be collected during this interval. 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
Unanticipated Problem Involving Risk to Participants or Others (UPIRSO): Any incident, experience, or 
outcome that: 
• 
Is unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Is related or possibly related to a participant’s participation in the research; and 

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• 
Is serious or suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
recognized. 
Unexpected AE: An AE, the nature or severity (intensity) of which is not consistent with the applicable 
agent information (Investigator’s Brochure, package insert, or summary of agent characteristics). 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing IRB and to the DMCC. The UP 
will be entered into the DMS and will include the following information: 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported to the IRB and to the DMCC as 
soon as possible after the investigator becomes aware of the event. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
Two primary endpoints are specified to assess treatment efficacy (study objective #1):  
1)  FEV1 percent predicted, assessed prior to bronchodilator administration 
2)  Asthma symptom control, assessed via the Juniper Asthma Control Questionnaire (ACQ-6) 
FEV1 percent predicted and ACQ-6 score will be measured at the start and the end of each treatment 
period.  Efficacy analyses will compare the end-of-period outcome values between test treatment and 
placebo.   
For the first primary study objective (overall assessment of efficacy), the following hypotheses will be 
tested: 
1. Test treatment T does not improve FEV1 percent predicted compared to placebo (the null hypothesis) 
versus T is different from placebo. 
2. Test treatment T does not improve asthma symptom control assessed via ACQ-6 compared to placebo 
(the null hypothesis) versus T is different from placebo. 
The second primary objective involves estimation of the optimal subgroup for targeting participants for 
each intervention.  No formal statistical hypotheses will be tested for this objective.  
9.2 
SAMPLE SIZE DETERMINATION 
An intervention is considered efficacious if significant benefit is shown for either of the two primary 
endpoints (FEV1% predicted, and ACQ-6).  Because there are multiple chances for a test treatment to 

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demonstrate efficacy, multiplicity adjustments are required.  We will use the Hochberg method to adjust 
for multiplicity. 
A sample size of 111 participants is required to achieve 80% power to detect a treatment effect with 
respect to at least one of the two primary endpoints equal to 0.3 times the standard deviation (SD) of 
that endpoint, taking into account the possibility to stop for futility. The Type I error probability will be 
controlled under the global null hypothesis (no effect on either endpoint) at α ≤ 0.10. Power was 
estimated under the assumption of a within-participant, between-period correlation of responses on 
consecutive placebo and test treatment, τ, of 0.70 and a treatment period discontinuation rate of 0.10. 
The required sample size for interventions with treatment period drop-out rates significantly different 
from 0.10, assessed based on pooled placebo and active treatment data, may be adjusted during the 
trial, prior to any unblinding. If futility analysis is not feasible for an intervention due to difficulty in 
participant accrual, 93 participants (2:1 ratio of biomarker positive to negative participants) are required 
to provide the same power described above.  
Examples of treatment effects yielding a 0.3 standardized effect size include: a difference of 4.3 percent 
predicted FEV1 between intervention and placebo with a SD of 14.5 percent predicted; and a difference 
of 0.18 in average ACQ-6 symptom scores between the intervention and placebo with a SD of 0.6.    
Given the experimental nature of the trial, the Type I error rate will be controlled at the two-sided 0.1 
level. Our analysis method ensures a strong control of the Type I error rate at this level. Taking into 
account our stopping rule for futility, the Type I error rate is equal to about 0.05, two-sided, for τ = 0.70.  
Based on participant accrual to date (at the time of protocol version 3.1) and assuming continued 
accrual of 12 participants per month, the target number of 395 participants and a study duration of at 
least 50 months should result in enough participant-periods to support the evaluation of 5 
interventions. These calculations take into account a study discontinuation rate of 0.02 every 4 weeks 
(or approximately 24% per year). That is, the probability for a participant to permanently drop-out of the 
study in any 4-week time period is 0.02. 
9.3 
DESIGN ADAPTATIONS 
For each intervention, an a priori best subgroup is specified based on the literature and data available at 
the time the intervention enters the trial. Participants belonging to this a priori best  subgroup are 
referred to as biomarker positive for that intervention. Treatment assignment probabilities will be 
initially set to achieve an approximate 2:1 ratio of biomarker positive and negative participants for each 
intervention. This treatment allocation will allow us to gather information on the association of 
biomarkers and interventions early in the study.  A single interim analysis for futility may be performed  
for each intervention (independently of the others) after test treatment and placebo (matched or 
unmatched) data are available for approximately 34 biomarker positive participants. Those 
interventions that have not been eliminated due to either safety concerns or futility will continue to be 
assigned to participants for the remainder of the study until the required number of participants is 
assigned to each intervention. A futility analysis will be also performed in biomarker negative patents. 
Further enrollment to test treatments demonstrating futility in biomarker negative subgroup will be 
limited to biomarker positive participants.   
An interim analysis to estimate the within-participant (between-period) correlation, pooling data across 
test and placebo treatment periods while maintaining masking of treatment assignments, was planned 
and has now been conducted (at the time of protocol version 3.1). The within-participant (between-
period) correlation for FEV1 and ACQ was much higher than 0.38, originally hypothesized; therefore, the 
required sample size for the final analysis has been reduced. 

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The DSMB will review interim analysis data for purposes of stopping an intervention due to futility,  
in addition to performing their other safety oversight responsibilities (see Section 10.1.6).  A 
second independent advisory group, the Protocol and Adaptations Review Committee or PARC, will 
advise on study adaptations and on new interventions that may be considered for entry into the 
study.  The PARC will not review any unblinded data or comparative analyses to avoid the potential 
for bias in making their recommendations. 
 
9.4 
POPULATIONS FOR ANALYSES 
Screening Population 
Participants who are screened but not randomized will be reported, but not included in any efficacy or 
safety analyses of study data.  SAEs occurring during the screening period will also be reported. 
Safety Population 
The Safety Population for each intervention will consist of all participants randomized to that 
intervention who received at least one dose of study medication. This population will form the basis for 
all safety analyses and selected secondary efficacy analyses of the intervention. 
Intention-to-Treat (ITT) Population 
The ITT population for each intervention will consist of all participants randomized to that intervention.  
The primary and secondary analyses will be conducted using the modified intention-to-treat (mITT) 
population, where a participant receives study drug (test treatment or placebo) and contributes at least 
one post-baseline measurement for each of the primary clinical endpoints during the treatment period 
in which the participant receives the intervention.   
 
Per-Protocol Population 
The per protocol population for each intervention consists of all participants in the mITT population who 
complete study treatment and are in reasonable compliance with the protocol during the treatment 
period in which the participant received the intervention and in at least one placebo period. Additional 
details are contained in the Statistical Analysis Plan.   
Membership in the per-protocol population will be determined prior to unmasking of treatment 
assignments to avoid the potential for bias.  The population will form the basis for selected secondary 
efficacy analyses.  
 
9.5 
STATISTICAL ANALYSES 
9.5.1 GENERAL APPROACH 
An intervention will be considered effective if it is effective on at least one of the two primary outcomes. 
The analysis model for the final efficacy analysis will take into account the correlations on outcomes 
assessed for the same patient across the different treatment periods. The final analysis will include pairs 
of the treatment and matching placebo from the first two periods of the trial, as well as unmatched 
observations on the same patient. Mixed model repeated measures methods will be used for the 
primary analysis.  

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A single futility analysis may be conducted for each intervention during the trial. The objective of the 
futility analysis is to stop interventions showing no signal of efficacy on either of the two primary 
endpoints. The final precision medicine analyses will use machine learning methods to optimize the 
target subgroup definition for each intervention. These methods rely on outcomes assessed for patients 
both within and outside the target subgroups and may result in changes to the cut-points for a particular 
biomarker used to delineate the positive and negative patients, or to changes in the biomarker 
themselves.    
9.5.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The final analysis to assess the efficacy of an intervention will be performed when accrual and follow-up 
for that intervention is complete.  Treatment effects with respect to each of the two primary endpoints 
will be estimated using a mixed-model for repeated measures (MMRM) that appropriately takes into 
account the within-participant correlations between periods. A detailed description of the analysis 
model is provided in the Statistical Analysis Plan.  
No adjustment for multiplicity with respect to the multiple interventions in the study is planned.  
Success is defined independently for each intervention, and interventions will not be compared to each 
other in the efficacy analyses.  Adjustment for multiplicity across the two primary outcomes will be 
performed using the Hochberg method within each intervention.  
9.5.2.1 MISSING DATA 
We will use multiple imputation to handle missing data for the primary efficacy outcomes in a treatment 
period. Details of the planned imputation procedures and associated sensitivity analyses are provided in 
the Statistical Analysis Plan. Analysis of the Secondary Endpoint(s) 
Secondary endpoints such as CompEx, FVC pre-BD, FEV1 post-BD, symptom free days (defined using 
diary/CompEx data) and asthma free days will be analyzed similar to the primary analysis model. Details 
of secondary analyses are provided in the Statistical Analysis Plan. 
 
9.5.3 SAFETY ANALYSES 
Safety data will be evaluated on an ongoing basis.  Monthly reports of serious adverse events will be 
provided to the chair of the DSMB. The DSMB will be unblinded to assigned treatment.  More 
comprehensive reports will be provided to all DSMB members on a regular schedule as determined by 
the DSMB.  These reports will include incidence of treatment-emergent adverse events by assigned 
treatment group.  Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse event rates (and severity non-serious adverse events) will be compared between 
active and placebo periods for each intervention.  Note that for a particular intervention, all placebo 
periods for participants receiving the intervention will be included, and not just those where the 
matching placebo was received.   
Based on the results of these reviews, the DSMB will recommend to the NHLBI whether to continue or 
discontinue each test treatment. In addition, the DSMB will be monitoring all of the safety data 
throughout the course of the trial and will be notified as soon as possible of any SAE that is deemed 
both unexpected and related to treatment. All SAEs will be reviewed at each DSMB meeting. 
Final safety analyses will be performed for each intervention, once the intervention completes and all 
follow-up data are obtained.  Descriptive summaries (tables and graphs) of safety endpoints, including 
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treatment versus placebo, and hypothesis tests for differences between groups will be generated for 
selected parameters. 
 
9.5.4 BASELINE DESCRIPTIVE STATISTICS 
The run-in period is considered to be the baseline evaluation period. The initial statistical analysis will 
focus on summarizing the baseline characteristics of the study participants. Details of these analyses are 
provided in the Statistical Analysis Plan. 
 
9.5.5 PLANNED INTERIM ANALYSES  
Details of the planned interim analyses for futility are provided in the Statistical Analysis Plan.  
 
9.5.6 OPTIMIZATION OF TARGET SUBGROUPS 
We designed the precision medicine analysis to highlight the best treatments for key patient subgroups.   
The therapies selected for PrecISE might only work in their predictive biomarker subgroups; their effect 
on participants outside of the best subgroup may be rather small. Primary and secondary predictive 
biomarkers are specified for each intervention. The a priori best subgroup is specified as a function of 
the primary predictive biomarker for each intervention before the study begins (or the intervention 
enters the study) based on the best available information at that time. More details are provided in the 
Statistical Analysis Plan.   
9.5.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Data listings of individual participant data that include treatment assignment will not be shared with 
investigators outside the DMCC until database lock.  Data listings of individual SAEs will be prepared by 
unblinded DMCC statisticians and programmers, and shared with the DSMB in confidential reports.  The 
data will be scrubbed of identifiable information prior to release to a public data repository.  
9.5.8 EXPLORATORY ANALYSIS 
Exploratory analyses will be performed at the end of the study to identify the best target subgroup for 
each intervention using all available data and to explore individualized treatment rules for interventions 
with overlapping target subgroups. Details of the planned exploratory analyses are provided in the 
Statistical Analysis Plan.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
Potential participants will be asked to provide consent to the master protocol at the initial screening 
visit at week 0 through a master consent document.  Our general approach to the consent process is to 
explain the design of the master protocol to each potential participant, why this design is ideal for 
testing novel therapies and determining which therapies work for which patients, how participation in 

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the master protocol will allow participants to “try out” multiple therapies, why their participation is 
important, and how their data will contribute to the research. The goal is to obtain buy-in from potential 
participants on the study design as a whole and explain clearly what they can expect from participation 
in the study (e.g., expected study duration given their enrollment date, opportunity for multiple 
sequential treatments, possibilities of placebo, etc.).  The master consent form will provide details about 
the possible interventions each potential participant may receive. 
Separate master consent forms will be used for adults and adolescents.  The master consent document 
for adults will describe the interventions that are being studied in PrecISE at the time the participant is 
enrolled, and explain that the participant may receive any of these interventions during their 
participation in the study through a series of re-randomizations and treatment assignments (provided 
no safety exclusions specific to any of the interventions apply). Their consent applies to the set of 
available interventions, and if they are not willing to provide consent, they are not eligible for the study.  
Consent will not be obtained for each intervention individually, to avoid the potential for bias.  In a 
similar manner, a parent or guardian will provide consent for each adolescent’s participation in the 
study; adolescent participants will provide assent.   
New participants will be consented to the new set of possible interventions, and active participants will 
be re-consented to the new set of possible interventions.  Again, this consent will be to the master 
protocol (the set of possible interventions) and not to any individual intervention, because at any point 
of re-randomization, a participant may receive any one of the interventions.  If an active participant 
refuses to be re-consented, they may continue their participation in the study, but with a reduced set of 
possible interventions reflecting those remaining after the treatment determined to be futile was 
discontinued from the study and before introducing the new agent. Participants who refused to consent 
to some interventions but then changed their mind and are willing to take any of the five interventions 
will be allowed to do so.  
Parents or guardians of adolescents will receive a different consent form that will specify the set of 
interventions approved for study in that population.  A corresponding assent form will be provided to 
adolescents. Each adolescent recruited to PrecISE will be asked to provide assent to receive either of the 
two interventions or placebo at any of the three treatment periods for which they will remain in the 
study (because no participant will be assigned to the same treatment twice, adolescents would only 
remain in the study for three periods, if two treatments are approved for them).   
Note that participants will also be asked to consent to storage of and future use of their biospecimens 
separately from their consent to study participation.  Participants will be able to consent to the study 
(including use of biospecimens in PrecISE) but opt out of having their biospecimens stored for future 
use. 
This study will be reviewed under a single IRB at Vanderbilt University.  All other US sites will rely on 
Vanderbilt University’s IRB, and an IRB Authorization Agreement (IAA), also known as a reliance 
agreement, will be established for each site institution.  Once fully executed, a copy of the IAA will be 
submitted to the DMCC, with the original agreement filed on site. The DMCC will ensure that every 
consent form meets federal requirements and presents accurate information, as determined by the 
protocol team and NIH regulatory officials, and the current consent form will be kept on file and 
available for review. 
In obtaining and documenting informed consent, PrecISE study investigators and study teams will 
comply with applicable regulatory requirements, namely, ICH, GCP and other regulatory requirements 
including Title 45 Part 46 of the Code of Federal Regulations (45 CFR 46), 21 CFR 11 (Electronic Records), 

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21 CFR 50 (Protection of Human Subjects), 21 CFR 54 (Financial Disclosure of Clinical Investigators), 21 
CFR 56 (Institutional Review Boards), and 21 CFR 312 (Investigational New Drug Application).  
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting administration 
of the study intervention.  The following consent materials are submitted with this protocol: 
• 
Adult Consent Form_English 
• 
Adult Consent Form_Spanish 
• 
Minor Subjects Assent Form_English 
• 
Minor Subjects Assent Form_Spanish 
Basic consent elements and appropriate additional elements as outlined in 45 CFR §46.116 and 21 CFR 
§50.25 include: 
• 
Statement that the study involves research; 
• 
Explanation of the purposes of the research, the expected duration of the subject’s 
participation, and a description of the procedures to be followed; 
• 
A statement of the conditions and period of time under which the participant’s data will be 
stored and will be accessible; 
• 
A description of any foreseeable risks or discomforts to the participant; 
• 
Identification of any procedures which are experimental; 
• 
Reasonably expected benefits to participant or others; 
• 
Disclosure of alternative procedures; 
• 
Confidentiality measures; 
• 
Explanation of compensation and medical treatment, if any, for injury; 
• 
A statement that participation is voluntary, refusal to participate will involve no penalty or loss 
of benefits and that the participant may discontinue participation in any time without penalty or 
loss of benefits; and 
• 
An explanation of whom to contact for answers to pertinent questions about the research and 
research participant’s rights, and whom to contact in the event of a research-related injury to 
the participant, for research questions, or for questions about rights. 
Additional elements include:  
• 
Unforeseeable risks to the participant and/or to the fetus or embryo in case of pregnancy; 
• 
Circumstances under which participation may be terminated without regard to participant’s 
consent; 
• 
Additional costs to participant resulting from study participation; 
• 
Consequences of the decision to withdraw and procedures for orderly termination of 
participation by the participant; 
• 
New study findings which may affect the participant’s decision to continue; and 
• 
Approximate number of study participants. 
Informed consent form requirement for clinical trials: 
• 
The FDA and NIH have mandated that all informed consent documents inform patient 
volunteers that trial data will be added to the national clinical trial registry databank at 
ClinicalTrials.Gov.  The exact wording to be included in the documents reads: “A description of 

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this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.” 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be IRB-approved 
and the participant will be asked to read and review the document. The investigator or study 
coordinator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants, this 
includes explaining the study in Spanish, for Spanish speakers.   In addition, study staff will request 
assent from minors after receiving parental permission. Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants should 
have the opportunity to discuss the study with their family or surrogates or think about it prior to 
agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. Consent may also be obtained 
remotely. In this case, the consent form will be provided to the participant. It will be reviewed with the 
participant over the phone or during a video call. The participant may sign the consent form and return 
it to the site, or the form may be signed electronically, provided a software tool that is compliant with 
the Code of Federal Regulations (CFR) 21 Part 11 concerning electronic signatures is available at the site. 
The rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
The study or any of the interventions included in PrecISE may be temporarily suspended or prematurely 
terminated if there is sufficient reasonable cause (see examples below). Written notification, 
documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to study participants, investigators, the NHLBI, the Food and Drug Administration and 
other relevant regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator at each study site will promptly inform study participants, the IRB, and the sponsor and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule.  Please refer to Section 7, Study 
Intervention Discontinuation and Participant Discontinuation/Withdrawal, for handling of enrolled 
study participants. 
Circumstances that may warrant termination or suspension of the study include, but are not limited to: 
●     Determination of unexpected, significant, or unacceptable risk to participants 
●     Insufficient compliance to protocol requirements 
●     Data that are not sufficiently complete and/or evaluable 

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The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy NHLBI, the IRB and/or other regulatory agencies.  
There are multiple interventions in this study, and it may be that a specific intervention will be 
terminated due to safety or futility, based on recommendations from the DSMB (Section 10.1.6).  In this 
case, the parent study will continue with the other active and planned interventions. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their test treatments. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, or 
regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the DMCC. The study data entry and study management systems used 
by clinical sites and by the DMCC will be secured and password protected (see Section 2.3 for additional 
details). At the end of the study, all study databases will be de-identified and archived at the NHLBI data 
repository. 
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
PrecISE will be collecting specimens on all participants. Strict confidentially standards are in place and 
will be maintained to protect the privacy of PrecISE participants. Biospecimen samples will be labeled 
with a unique identifier that does not contain any protected health information or otherwise identify a 
participant. Biospecimens collected will not be stored long-term at the clinical sites but rather will be 
used immediately for analyses (sent to a Clinical Laboratory Vendor) or deposited in batches at PrecISE 

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study-approved Central Core laboratories.  These specimens will not be individually identifiable by the 
laboratories, clinical centers, or DMCC personnel. The DMCC will develop and maintain a tracking 
system whereby study participants can modify their level of consent for their use of any stored samples 
for future studies. Participants can ask that any specimens still in storage be destroyed and not included 
in future analyses. The request to remove stored specimens will be made at the clinical centers to 
preserve participant confidentiality.  
Genetic studies utilizing the participant’s DNA will be conducted in PrecISE.  The participant will be fully 
informed of the intended extent of these studies, which range from single nucleotide polymorphism 
testing for specific variants to inform randomization to potentially full genome sequencing to inform 
baseline characterization and treatment responses.  In the event a new genetic marker is found during 
the course of PrecISE, participants with this hypothetical marker may be notified if they consent to this 
notification. Some of the analyses conducted as part of PrecISE are not intended to be diagnostic, and 
may not take place in a Clinical Laboratory Improvement Amendments (CLIA) certified lab. Some 
analyses, however, will be conducted in CLIA labs and may potentially include participant notification as 
part of the study protocol. 
Beyond DNA, other “omics” studies will also be conducted in PrecISE.  These may include studies to 
evaluate the RNA transcriptome and the microbiome, and they could potentially include studies 
involving the metabolome, the epigenome, and the proteome.  The participant will be fully informed of 
the intended and/or potential extent of these studies.   
Data collected for this study will be analyzed and stored at the study’s DMCC (Collaborative Studies 
Coordinating Center, Department of Biostatistics, Gillings School of Global Public Health, The University 
of North Carolina at Chapel Hill).   After the study is completed, the de-identified, archived data will be 
transmitted to and stored at NHLBI’s Biologic Specimen and Data Repository Information Coordinating 
Center (BioLINCC) for use by other researchers including those outside of the study. Permission to 
transmit data to BioLINCC will be included in the informed consent.  
With the participant’s approval and as approved by the study’s single IRB, de-identified biological 
samples will also be stored at BioLINCC after the study is completed. These samples could be used for 
future research.  
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed. When the study is completed, 
access to study data and/or samples will be provided through BioLINCC. 
See Section 10.1.3, Confidentiality and Privacy and Section 10.1.9, Data Handling and Record Keeping, 
for further information on future use of study records.  
 
 
 
 
 
 
 

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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Study Leadership include: 
NHLBI 
Tom Croxton, PhD 
National Heart, Lung, and Blood Institute 
67601 Rockledge Drive Suite 10042 
Bethesda, MD  20892 
croxton@nhlbi.nih.gov 
Lisa Viviano 
National Heart, Lung, and Blood Institute 
67601 Rockledge Drive Suite 10042 
Bethesda, MD  20892 
lisa.viviano@nhlbi.nih.gov 
 
Steering Committee Chairs 
Steve Georas, MD 
University of Rochester Medical Center 
601 Elmwood Avenue 
Rochester, NY  14620 
585-472-0362 
Steve_georas@urmc.rochester.edu 
 
Rosalind Wright, MD 
Mount Sinai School of Medicine 
145 Beach Avenue 
Larchmont, NY  10538 
781-771-9034 
Rosalind.wright@mssm.edu 
 
Data, Modeling and Coordinating Center 
Anastasia Ivanova, PhD 
UNC -Chapel Hill 
3101 McGavran-Greenberg Hall 
Chapel Hill, NC  27599-7240 
919-843-8086 
aivanova@bios.unc.edu 
Kevin Anstrom, PhD 
UNC -Chapel Hill 
123 W. Franklin Street, Suite 450 
Chapel Hill, NC  27516 
919-962-2190 
kevin.anstrom@unc.edu 
 
David B Peden, MD, MS 
UNC Chapel Hill School of Medicine 
554 Human Studies Facility, CB#7310 
Chapel Hill, NC  27599-7290 
919-966-0768 
peden@med.unc.edu 
 
 
Boston Partnership 
Elliot Israel, MD 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA  02115 
617-732-8110 
eisrael@partners.org 
 

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Cleveland/UVA 
Serpil Erzurum, MD 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH  44195 
216-444-5849 
erzurus@ccf.org 
Ben Gaston, MD 
Indiana University 
1044 West Walnut Street 
Indianapolis, IN 46202 begaston@iu.edu 
 
William Teague, MD 
University of Virginia 
Lane Road, room 2014 
Charlottesville, VA  22908 
770-595-4600 
Wgt2p@virginia.edu 
 
 
Denver 
Stanley Szefler, MD 
Children’s Hospital Colorado 
13123 E. 16th 
Aurora, CO  80045 
720-777-0985 
Stanley.szefler@childrenscolorado.org 
Michael Wechsler, MD 
National Jewish Health 
1400 Jackson Street, J215 
Denver, CO  80206 
617-285-4987 
wechslerm@njhealth.org 
 
Arizona/Wake Forest 
Eugene Bleecker, MD 
University of Arizona 
1230 N. Cherry, 2nd Floor, Room 2964 
Tucson, AZ  85721 
520-626-8624 
erbleecker@email.arizona.edu 
Monica Kraft, MD 
 
Mount Sinai School of Medicine 
1468 Madison Ave 
New York, NY  10029 
Monica.kraft@mssm.edu 
 
UC San Diego 
Praveen Akuthota, MD 
UC at San Diego  
9500 Gilman Drive, MC 0643 
La Jolla, CA  92093 
858-822-4106 
pakuthota@ucsd.edu 
Sonia Jain, PhD 
UC at San Diego 
9500 Gilman Drive, MC 0725 
La Jolla, CA  92093 
858-822-2388 
sojain@ucsd.edu 
 

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Panduragan Vijayanand, MD, PhD 
La Jolla Institute 
Athena Circle 
La Jolla, CA  92037 
858-752-7467 
vijay@lji.org 
 
 
UC San Francisco 
John Fahy, MD 
UC at San Francisco 
513 Parnassus Avenue, room HSE 1307 
San Francisco, CA  94116 
415-476-9940 
John.fahy@ucsf.edu 
 
 
Chicago 
Sharon Rosenberg, MD 
Northwestern University 
240 E. Huron, Suite 2-410 
Chicago, IL  60611 
312-695-6833 
sharon-rosenberg@northwestern.edu 
Steve White, MD 
University of Chicago 
5841 S. Maryland Avenue, MC 6076 
Chicago, IL  60637 
773-702-1856 
swhite@medicine.bsd.uchicago.edu 
 
Pittsburgh  
Sally Wenzel, MD 
University of Pittsburgh 
3459 Fifth Avenue 
Pittsburgh, PA  15213 
412-802-6859 
swenzel@pitt.edu 
 
 
Wisconsin / Illinois-Chicago 
Loren Denlinger, MD, PhD 
University of Wisconsin 
600 Highland Avenue 
Madison, WI  53792 
608-261-1552 
lcd@medicine.wisc.edu 
Nizar Jarjour, MD 
University of Wisconsin 
600 Highland Avenue 
Madison, WI  53762 
608-263-3035 
njarjour@uwhealth.org 
 

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Jerry Krishnan, MD, PhD 
University of Illinois at Chicago 
1220 S. Wood Street, Room 3002 
Chicago, IL  60638 
312-413-0637 
jakris@uic.edu 
 
 
University of Kansas/Vanderbilt 
Mario Castro, MD 
University of Kansas School of Medicine 
3901 Rainbow Boulevard 
Kansas City, KS  66160 
(913) 588-7529   
mcastro2@kumc.edu 
 
 
 
Study leadership includes an Executive Committee and a Steering Committee.  The Executive Committee 
is composed of members from NHLBI, the DMCC, the chairs of the Steering Committee and two 
representatives from the clinical centers.  The Steering Committee consists of all members of the 
Executive Committee and all PIs from the clinical centers.  
 
10.1.6 SAFETY OVERSIGHT 
An independent data and safety monitoring board (DSMB) will be established and charged with 
oversight of data quality, study integrity, and safety of participants. In addition to monthly reports 
of serious adverse events (SAEs), the DSMB will review unblinded data reports semi-annually and 
make recommendations to the NHLBI to ensure that participants are not exposed to undue risks.  
Summary reports of recommendations will be sent to site investigators and the central IRB. 
For each intervention, the PrecISE DSMB will make recommendations as to whether the 
intervention should be stopped for safety reasons based on periodic monitoring of adverse events 
and other safety parameters.  Regularly scheduled meetings will be held to review safety data 
reports prepared by the DMCC that include summary statistics by treatment group for adverse 
events, laboratory parameters, and other safety outcomes.  Ad hoc meetings to review safety data 
can also occur if triggered by unusually high or unexpected SAE reporting. 
The DSMB will also determine if an intervention should be recommended for discontinuation due 
to futility based on the results of a single interim analysis conducted for this purpose, 
approximately half-way through recruitment for that intervention.  DSMB meetings to discuss 
futility analyses are triggered by enrollment targets and data availability.  The DMCC will prepare a 
report summarizing the futility analysis results and corresponding stopping boundaries for each 
intervention in advance of the meeting (see Section 9.5.6).  If the results of the futility interim 
analysis for an intervention are on or near the stopping boundary, the DSMB will weigh the benefit 
and risks of the intervention based on data accumulated to date, and make their recommendation 
accordingly. 
Once a determination is made to recommend discontinuation of an intervention for either reason 
(futility or safety), the DSMB will summarize their deliberations to arrive at the recommendation, 

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and the DMCC will prepare a report for the NHLBI Project Office and the Steering Committee that 
summarizes the results of analyses supporting the recommendations, the stopping boundaries or 
rules used, and the DSMB’s summary of their deliberations to arrive at the decision.  The DMCC will 
then work with the Steering Committee to develop an appropriate communication plan for the 
various stakeholders.   
A second independent advisory group, the Protocol and Adaptations Review Committee (PARC), 
will be established to advise on study adaptations and other protocol amendments that may be 
needed throughout the study.  The adaptive design of PrecISE allows for adaptation to the 
subgroups targeted for each intervention following pre-specified adaptation rules (see Section 9.3).  
Consistent with good clinical practice and FDA guidance on data monitoring committees, DSMBs 
privy to unblinded comparative results by treatment group should not be involved in other 
decisions about changes to the study design or protocol, to minimize the possibility of bias.3,16-18 
The PARC will be formed to oversee study adaptations and recommend other changes to the study 
protocol, including the addition of new interventions to the study.  This group will not review any 
unblinded data or comparative analyses to avoid the potential for bias in making their 
recommendations. 
 
 
DSMB Members 
Members of the PrecISE DSMB are independent experts chosen on the basis of their expertise and 
scientific rigor. They are not associated with the trial or with the pharmaceutical companies that supply 
the study agents. Committee members’ areas of expertise span the disciplines relevant to the conduct 
of this clinical trial, including clinical trials, pharmacology, biostatistics, and clinical care of participants 
with asthma. 
DSMB Mandates 
The DSMB has the responsibility to review the research protocol and to evaluate the progress of the trial 
overall and at each participating clinical center. This includes accrual, data quality and completeness, 
episodes of exacerbations, hospitalization, mortality, other toxicities, and protocol violations. Serious 
unexpected and related events will be disclosed to the committee between meetings. The DSMB will 
also review interim endpoint data (both primary and secondary endpoints) to assess futility of each 
intervention.  
Concurrently, the DSMB will evaluate the safety of each intervention studied under the Master Protocol 
as the trial progresses, considering evolving scientific discoveries or treatment options that may affect 
the desirability of continued treatment with any one of the interventions. At the conclusion of each 
meeting, the DSMB will recommend whether each intervention be continued. If an intervention proves 
to be more harmful than expected in terms of mortality or severe morbidity, we will stop treatment of 
all participants currently assigned to the intervention, and that intervention will be removed from the 
possible re-randomization assignments for ongoing participants. New enrollees will receive a master 
consent form reflecting the removal of any intervention discontinued for safety or futility reasons. This 
decision will be made by NHLBI on recommendation of our DSMB. 
Frequency of DSMB Meetings 
The DSMB will meet via webinar every 3-6 months to review study progress and safety for each 
intervention.  Additional meetings to review the futility of each intervention will be scheduled based on 

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accrual rates and data availability for the interventions.  These meetings will likely take place via 
webinars, due to the need to schedule them at different times for different interventions.  Ad hoc 
meetings may also be scheduled via webinar, if particular safety issues for any of the interventions arises 
in between the regularly scheduled meetings. 
DSMB Meeting Structure 
The PrecISE principal investigators, the DMCC statisticians (blinded and unblinded), NHLBI 
representatives and on occasion other key personnel, will participate in the meetings’ open sessions.  
Open sessions include consideration of recruitment, retention, and general scientific issues. The DSMB’s 
voting members will discuss the unblinded by-treatment data for each intervention in a closed session.  
These data include adverse events, and material that should be kept confidential from the investigators. 
Frequency and content of reports to the DSMB 
In advance of each meeting, the unblinded statistician at the DMCC will prepare a report for DSMB 
review. The report will contain the following categories of information aggregated by treatment group, 
where applicable: 
• 
Current enrollment status and timeline for completion of follow-up 
• 
Adverse events reported, both serious and non-serious, including hospitalizations and any mortality 
• 
Major and minor protocol violations and deviations 
• 
Numbers of participants whose study medication is discontinued 
In the safety reports, the DMCC will label the treatment groups as “A”, “B”, etc. to lessen the chance of 
accidental unmasking.  The unblinded DMCC statistician will provide the treatment for each code to 
DSMB members as needed, and the same code mapping will be used for all meetings. 
Serious events are reported to the DSMB monthly, and serious adverse events that are unexpected and 
related to treatment are reported within 15 days from the time the DMCC is notified of the event.   
Frequency, content, and distribution of meeting reports 
Following each meeting of the DSMB, its chair will prepare a summary of the questions raised by 
committee members, monitoring recommendations, and recommendations for the continuation of 
treatments. This report will be distributed confidentially to meeting participants. The committee’s 
secretary also prepares a redacted summary of this report, focusing on safety issues, for distribution to 
PrecISE investigators and their IRBs. 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of study participants are 
protected, that the reported study data are accurate, complete, and verifiable, and that the conduct of 
the study is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).   Monitoring for this study will be performed by the DMCC. 
Areas of Focus 
• 
Staff training  
• 
Human subjects protection 
• 
Protocol compliance 
• 
Regulatory compliance 
• 
Laboratory SOPs and compliance. 

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• 
Quality assurance 
• 
Safety 
• 
Adverse event reporting 
• 
Integrity of research data and samples 
Two types of data monitoring will be conducted during the study: on-site monitoring and central 
monitoring.  On-site monitoring refers to a review of the data that takes place at the clinical site 
whereas central monitoring refers to activities that can be conducted at the data coordinating center. 
Monitoring Activities will include: 
• 
Review of credentials, training records, and delegation of duties logs. 
• 
Review of 100% of Consent Forms. 
• 
Review of reports on missed events, missing data, protocol deviations, and unanticipated problems. 
• 
Comparison of CRFs to source documentation to ensure data are accurate and complete.  
• 
Review of documentation for AEs, SAEs, and UPs. 
• 
Review of critical fields such as eligibility, study endpoints, and SAEs. 
• 
Regulatory Files: Limited reviews at interim visits, e.g., IRB annual reviews, safety reporting, IRB 
submissions of protocol deviations, and updated essential documents. 
• 
Laboratory Review: Full laboratory review of processing and storage of specimens at first and close-
out visits and at least biannually.  Assessment of laboratory specimens stored at the clinical site. 
The DMCC will provide copies of on-site monitoring reports within 10 business days of the visit.  
Details of clinical site monitoring are documented in the PrecISE Clinical Monitoring Plan (CMP). The 
CMP describes in detail who will conduct the monitoring, at what frequency monitoring will be done, at 
what level of detail monitoring will be performed, and the distribution of monitoring reports.   
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system. The 
database will include real-time data QC checks.  Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonization Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the DMCC, and inspection by local and regulatory 
authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  

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Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
Data recorded in the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MEDDRA) and 
concomitant medications will be coded using the National Drug Code (NDC) Directory. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into the PrecISE Data Management System, a 21 CFR 
Part 11-compliant data capture system provided by the PrecISE DMCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 3 years after the completion of research in 
accordance with HHS regulations.   These documents will be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of NHLBI. It is 
the responsibility of NHLBI to inform the investigators when these documents no longer need to be 
retained. 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff.  As 
a result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, Section 5.1.1  
• 
5.20 Noncompliance, Sections 5.20.1, and 5.20.2.  
Protocol deviations require reporting to the DMCC, and to the oversight IRB, and additional 
source/supporting documents may be requested and should be kept in the participant’s record.  Sites 
should notify the DMCC in accordance with the Manual of Procedures.   
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 15 working days of identification of the protocol deviation, or within 15 working days 
of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents and reported to the DMCC. Protocol deviations must be sent to the reviewing IRB per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the MOP. 
 
 

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10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this study will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers after the completion 
of the primary endpoint manuscript by contacting NHLBI’s BioLINCC.  Industry partners who are 
providing study agents will be provided with serious adverse events reports that occur when 
participants are receiving their product.  Additional details about the data sharing policy are provided in 
MOP Appendix 9. 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of 
these data for subsequent research. Large-scale data include genome-wide association studies (GWAS), 
SNP arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data. 
The Publications Committee will be responsible for developing publication procedures and resolving 
authorship issues.   
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of the PrecISE study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of investigators who have a 
role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, investigators who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct of 
this trial.  The study leadership in conjunction with the NHLBI has established policies and procedures 
for investigators to disclose all conflicts of interest and has established a mechanism for the 
management of all reported dualities of interest.  These policies are outlined in the PrecISE Manual of 
Procedures. 
 
10.2 ADDITIONAL CONSIDERATIONS 
None  
 
 
 
 
 

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10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
ACE 
Angiotensin-converting enzyme (ACE) inhibitors 
ACQ-6 
Asthma Control Questionnaire 
ACRN 
TALC 
Asthma Clinical Research Network Tiotropium Bromide as an Alternative to Increased 
Inhaled Corticosteroid in Patients Inadequately 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AQLQ 
Asthma Quality of Life Questionnaire 
ATS 
American Thoracic Society 
BD 
Bronchodilator 
BDR 
Bronchodilator Response 
BioLINCC 
Biologic Specimen and Data Repository Information Coordinating Center 
CARE 
Childhood Asthma Research and Education Network Trial 
CC 
Coordinating Center 
CF 
Cystic Fibrosis 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CNS 
Central Nervous System 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DLCO 
Diffusing Capacity for Carbon Monoxide 
DMCC 
Data, Modeling and Coordinating Center 
DMS 
Data Management System 
DPI 
Dry Powder Inhaler 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
ED 
Emergency Department 
FDA 
US Food and Drug Administration 
FDAAA 
US Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
FeNO 
Fractional exhaled Nitric Oxide 
GCP 
Good Clinical Practice 
GERD 
Gastroesophageal Reflux Disease 
GLP 
Good Laboratory Practices 

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GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HADS 
Hospital Anxiety and Depression Scale 
HFA 
Hydrofluoroalkane 
HHS 
Health and Human Services 
HIPAA 
Health Insurance Portability and Accountability Act  
IAA 
IRB Authorization Agreement 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
ICS 
Inhaled Corticosteroids 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LABA 
Long Acting Beta Agonists 
LAMA 
Long Acting Muscarinic 
LSMEANS 
Least-squares Means 
MDCT 
Multi-detector CT 
MDI 
Metered Dose Inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-Model for Repeated Measures 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NDC 
National Drug Code 
NHLBI 
National Heart Lung and Blood Institute 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NSAIDS 
Nonsteroidal Anti-Inflammatory Drugs 
OHRP 
Office for Human Research Protections 
PAC 
Participant Advisory Council 
PEF 
Peak Expiratory Flows 
PFT 
Pulmonary Function Test 
PI 
Principal Investigator 
PrecISE 
Precision Interventions for Severe and/or Exacerbation-Prone Asthma Network 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARP 
Severe Asthma Research Program 
SD 
Standard Deviation 
SFAR 
Score for Allergic Rhinitis 

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sIRB 
Single Institutional Review Board 
SMC 
Safety Monitoring Committee 
SNP 
Single Nucleotide Polymorphism 
SNQ5 
Sinunasal Questionnaire 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UNC 
University of North Carolina 
UNC-CH 
University of North Carolina at Chapel Hill 
UP 
Unanticipated Problem 
UPIRSO 
Unanticipated Problem Involving Risk to Subjects or Other 
US 
United States 
VCD 
Pittsburgh Vocal Cord Dysfunction Index 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2.5 
9/10/2021 
1.3 Schedule of Activities 
A triglycerides measurement was added 
at Visit 0 so that participants with high 
baseline triglyceride levels could be 
excluded from the clazakizumab 
treatment arm.  
Safety  
2.5 
9/10/2021 
5.1 Inclusion Criteria  
The inclusion criteria for stable asthma 
medications was clarified.   
Clarification 
2.5 
9/10/2021 
5.3 Randomization Criteria  
The randomization criteria for stable 
asthma meds in the 4 weeks prior to 
randomization was clarified. 
 
Clarification 
2.5 
9/10/2021 
6.3 Measures to Minimize Bias: 
Randomization and Blinding  
The text was clarified to specify that 
participants will not receive more than 
three placebos during their participation 
in the network.   
 
Clarification 
2.5 
9/10/2021 
8.2 Safety and Other Assessments  
The text was revised to clarify that 
spirometry may be conducted at home 
or in the clinic. 
 
Clarification 
3.0 
11/19/2021 
The sample size has been reduced from 
800 to 600, the number of interventions 
has been reduced from six to five and 
the duration of the study has been 
extended from 42 months to 54 months.  
The text has been revised to clarify that 
participants will receive no more than 
three placebos during the study. 
Clarification 
3.0 
11/19/2021 
A training session was added at V0 to 
accommodate remote spirometry.  
Safety labs (pregnancy test, CBC and 
chemistry panel), FeNO and 
biorepository specimens are no longer 
Clarification 

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required for adolescents at visits X.2 and 
X.4.  PBMCs will not be required at visit 
X.1 except visit 1.1.  Some procedures 
(sputum, CT scans, PBMCs) will not be 
collected at all sites. 
3.0 
11/19/2021 
For participants whose asthma diagnosis 
has been verified at VSA/VSB but whose 
measure of poor asthma control at V0 is 
reliant on low lung function, the 
definition of the potential for 
improvement on study has been 
modified. 
Recruitment 
3.0 
11/19/2021 
The definition of participants at risk for 
bronchopulmonary dysplasia has been 
revised. 
Recruitment 
3.0 
11/19/2021 
The upper limits of tobacco 
consumption and vaping session 
frequency have been modified. 
Recruitment 
3.0 
11/19/2021 
The kidney function exclusion criteria 
(eGFR) have been revised. 
Recruitment 
3.0 
11/19/2021 
The kidney function criteria for 
discontinuing a participant’s 
intervention was revised. 
Retention 
3.0 
11/19/2021 
The criteria for discontinuing a 
participant who meets the study’s safety 
exclusion criteria was revised. 
Retention 
3.0 
11/19/2021 
The study now has a statistical analysis 
plan; much of the text has been moved 
from Section 9 of the protocol to the 
analysis plan. 
Simplification 
3.1 
2/23/2023 
 
1.1 Synopsis 
The sample size has been reduced from 
600 to 395 and the duration of the study 
has been extended from 54 months to 
62 months.  The CompEx events 
endpoint has been moved from a 
primary endpoint to a secondary 
endpoint. 
 
 
Clarification 
3.1 
2/23/2023 
 
1.3 Schedule of Activities 
Physical exams are no longer required 
for adolescents at visits X.2 and X.4.   
 
Clarification 

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3.1 
2/23/2023 
3  Objectives and Endpoints 
The CompEx events endpoint has been 
moved from a primary endpoint to a 
secondary endpoint. 
 
Clarification 
3.1 
2/23/2023 
6.5.4 Major Changes in Therapy 
The addition, dose adjustment or 
discontinuation of a beta blocker during 
the study is now considered a major 
change in therapy.  Participants with a 
major change in therapy will discontinue 
treatment immediately and then 
withdraw the study. 
 
Clarification 
3.1 
2/23/2023 
8.1 Efficacy Assessments 
The CompEx events endpoint has been 
moved from a primary endpoint to a 
secondary endpoint. 
Clarification 
3.1 
2/23/2023. 
9.2 Sample Size Determination 
The sample size has been reduced from 
600 to 395.  The size required to enroll 
to each intervention has been reduced 
from 200 to 111. 
Clarification 
3.1 
2/23/2023 
5.2 Exclusion Criteria 
The smoking history exclusion criteria 
has been revised 
Clarification 
3.1 
2/23/2023 
6.5.4 Major Changes in Therapy 
It was clarified that the addition, dose 
adjustment, or discontinuation of an 
additional asthma controller is a major 
change in therapy 
Clarification 
3.1 
2/23/2023 
9.5.1 Statistical Analysis – General 
Approach 
Clarification 

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The secondary endpoint CompEx was 
removed from the interim futility 
analyses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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